BROJ / NUMBER 1-2 GODINA / VOLUME 9 SIJE»ANJ - VELJA»A JANUARY - FEBRUARY 2014

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1 BROJ / NUMBER 1-2 GODINA / VOLUME 9 SIJE»ANJ - VELJA»A JANUARY - FEBRUARY 2014 ISSN X (Print) ISSN (Online) UDK/UDC (051)=164.42=111

2 »asopis Hrvatskoga kardioloπkog druπtva Journal of the Croatian Cardiac Society Godina Volume 9 Broj Number 1-2 SijeËanj - VeljaËa January - February 2014 Sadræaj / Table of contents Aritmologija i elektrostimulacija pregled stanja u Hrvatskoj Arrhythmology and cardiac pacing an overview of the situation in Croatia stranica / page 3-11 Almanac 2013.: aritmije i elektrostimulacija srca Almanac 2013: cardiac arrhythmias and pacing stranica / page Kardiomiopatija inducirana ventrikulskim ekstrasistolama Ventricular extrasystole induced cardiomyopathy stranica / page Ablacija ventrikularnih aritmija iznad semilunarnih valvula Ablation of ventricular arrhythmias above semilunar valves stranica / page Pristup bolesniku s poremeêajem provoappleenja uzrokovan Lyme boreliozom Approach to a patient with conduction disturbance caused by Lyme borreliosis stranica / page Double fire rijetka, a joπ ËeπÊe neprepoznata aritmija Double fire a rare and commonly unrecognized arrhythmia stranica / page Inhibitori ADP-om ovisne agregacije trombocita Inhibitors of ADP-dependent platelet aggregation stranica / page Almanah 2014.: stabilna koronarna bolest srca Almanac 2014: stable coronary artery disease stranica / page Almanac 2013.: stabilna koronarna bolest srca Almanac 2013: stable coronary artery disease stranica / page Cor triatriatum sinister u trudnice A case of cor triatriatum sinister during pregnancy stranica / page Uputa autorima Guidelines for authors stranica / page 75 Smanjenje tereta koronarne bolesti srca na dokazima utemeljenim principima lijeëenja Evidence-based treatment approaches in reducing the burden of coronary heart disease stranica / page formerly Kardio list Nakladnik i izdavaë / Editing and publishing company: Hrvatsko kardioloπko druπtvo / Croatian Cardiac Society Adresa / Address: KiπpatiÊeva 12, HR Zagreb, Croatia Telefon /Phone: kardio@kardio.hr URL: Za nakladnika / For Publisher: Davor MiliËiÊ (HR) Glavni urednik / Editor-in-Chief: Mario Ivanuπa (HR) UredniËki odbor / Editorial Board: Marko Boban, Sandro Brusich, Mario Ivanuπa, Anita JukiÊ, Sandra MakaroviÊ, Ivica PremuæiÊ MeπtroviÊ, eiti PrvuloviÊ, Alen RuæiÊ, Kristina Selthofer-RelatiÊ i Hrvoje VraæiÊ Savjet / Advisory Board: Mijo Bergovec (HR), Bojan JelakoviÊ (HR), Æarko MavriÊ (HR), Davor MiliËiÊ (HR), Jure Mirat (HR), Vjeran NikoliÊ- Heitzler (HR), Dubravko PetraË (HR), Stojan PoliÊ (HR), Æeljko Reiner (HR) i Luka ZaputoviÊ (HR) TehniËki urednik / Technical Editor: Stjepan Horvat (HR) Priprema / Editing prepared by:»vor d.o.o. Bjelovar Tisak / Printed by: Denona d.o.o. Zagreb Prijevod / Translated by: Studium d.o.o. Zagreb Naklada / Print run: copies Informacije o pretplati / Subscription info: Tiskano izdanje je besplatno za lijeënike, a mreæno izdanje je u cijelosti dostupno svima. / Physicians can receive the print editions of Cardiologia Croatica free of charge. Cardiologia Croatica is open access journal with free and unrestricted access for all online readers.»lanci su kategorizirani prema Uputama za uredniπtva Ëasopisa koji su dostupni na portalu HrËak / The articles are categorized according to Instructions for journal editorial boards available at the HrËak web site: Copyright: Hrvatsko kardioloπko druπtvo / Croatian Cardiac Society. This publication was printed with an unrestricted educational grant from: Krka-Farma d. o. o., Zagreb, Croatia Hrvatsko kardioloπko druπtvo Croatian Cardiac Society Adresa / Address: Hrvatsko kardioloπko druπtvo HR Zagreb, KiπpatiÊeva 12, Croatia kardio@kardio.hr Æiro-raËun: OIB: Predsjednik / President: Dopredsjednik / Vice-President: Tajnik / Secretary: RizniËar / Treasurer: Davor MiliËiÊ Diana DeliÊ-BrkljaËiÊ Darko PoËaniÊ Eduard MargetiÊ Upravni odbor / Management: Robert Bernat, Duπka Glavaπ, Mladen JukiÊ, Viktor PerπiÊ, Pejo SamardæiÊ, Maja Strozzi, Josip Vincelj, Luka ZaputoviÊ i predsjednici podruænica HKD. Cardiologia CROATICA 2014;9(1-2):2.

3 Pregledni Ëlanak / Review article Aritmologija i elektrostimulacija pregled stanja u Hrvatskoj Arrhythmology and cardiac pacing an overview of the situation in Croatia Sandro Brusich 1 *, Hrvoje VraæiÊ 2 1 KliniËki bolniëki centar Rijeka, Rijeka, Hrvatska 1 University Hospital Centre Rijeka, Rijeka, Croatia 2 KliniËka bolnica Dubrava, Zagreb, Hrvatska 2 University Hospital Dubrava, Zagreb, Croatia SAÆETAK: Unazad nekoliko godina prisutan je znaëajan napredak u zbrinjavanju bolesnika s poremeêajima srëanog ritma, kako u svijetu, tako i u Republici Hrvatskoj. Ovaj pregledni Ëlanak prikazuje postojeêe stanje u podruëju aritmologije i elektrostimulacije u Republici Hrvatskoj. NajveÊi napredak vidljiv je u podruëju elektrofiziologije znaëajnim poveêanjem broja uëinjenih kateterskih ablacija aritmija, a osobito ablacije fibrilacije atrija. Prisutni su i znatni pomaci u novim spoznajama u podruëju elektrostimulacije, daljnji porast u brojnu centara gdje se takvi postupci provode, kao i u broju uëinjenih postupaka, pri Ëemu edukacija prati nove spoznaje i trendove, sve s ciljem kako bi naπim bolesnicima omoguêili dulje preæivljenje i bolju kvalitetu æivota. Meappleutim, glavni izazovi koji ostaju pred nama nisu se bitno promijenili u odnosu na prijaπnje godine, a osnovno je pronalazak dodatnih sredstava koji bi osigurali bolju prevenciju nagle srëane smrti neophodnim poveêanjem broja ugradnje implantabilnih kardioverter defibrilatora i ureappleaja za resinkronizacijsku terapiju. Prostor za poboljπanje je znatan, pri Ëemu se ne moæe dovoljno naglasiti vaænost ustrajne aktivnosti struënog druπtva u ovom podruëju. KLJU»NE RIJE»I: aritmologija, elektrofiziologija, elektrostimulacija srca, fibrilacija atrija. SUMMARY: In the past few years there has been a significant progress in the management of patients with heart rhythm disorders both in the world and in Croatia. This review article summarizes the current situation in the area of arrhythmology and cardiac pacing in the Republic of Croatia. The greatest improvement is seen in the field of electrophysiology due to a significant increase in the number of performed electrophysiological procedures, particularly catheter ablation of atrial fibrillation. There are also significant advancements in new insights in the field of electrical stimulation, a further increase in a number of centers where such procedures are performed, as well as in the number of performed procedures where education follows new insights and trends, all with an aim to enable our patients to have prolonged survival and a better quality of life. However, some major challenges we are facing have not significantly changed compared to the previous year, and the basic one is finding additional resources to ensure better prevention of sudden cardiac death by necessary increasing the implantation rate of implantable cardioverter defibrillators and cardiac resynchronization therapy devices. The room for improvement is great, whereas we can not sufficiently emphasize the importance of persistent activities of the professional society in this area. KEYWORDS: arrhythmology, electrophysiology, cardiac pacing, atrial fibrillation. CITATION: Cardiol Croat. 2014;9(1-2):3-11. Uvod Aritmologija se ubraja meappleu najkompleksnije i najzahtjevnije dijelove ne samo kardiologije, nego i cijele kliniëke medicine. Sve boljim razumijevanjem patofizioloπkih mehanizama aritmija i primjenom novih tehnoloπkih dostignuêa zna- Ëajno su se unaprijedile moguênosti lijeëenja bolesnika s poremeêajima srëanog ritma. UnatoË brojnim problemima, a zahvaljujuêi velikom trudu i entuzijazmu lijeënika koji se bave ritmologijom u Republici Hrvatskoj, u zadnjih godina prati se znaëajan napredak u Introduction Arrhythmology is among the most complex and most demanding parts not only of cardiology, but also the entire clinical medicine. All the better understanding of the pathophysiological mechanisms of arrhythmias and the use of new technological advancements have significantly improved the treatment options for patients with heart rhythm disorders. Despite many problems, and owing to great efforts and enthusiasm of physicians who deal with rhythmology in the Republic of Croatia, we have seen a significant advancement 2014;9(1-2):3. Cardiologia CROATICA

4 podruëju srëane elektrofiziologije i elektrostimulacije (u daljnjem tekstu elektrofiziologija i elektrostimulacija). Sukladno Ëlanku koji prati ovaj pregledni rad 1, prikazat Êemo trenutno stanje ritmologije i elektrostimulacije u Republici Hrvatskoj bazirajuêi se prvenstveno na sluæbenim podacima objavljenim u EHRA White Book od do godine (izvjeπêe European Heart Rhythm Association) te na joπ nesluæbenim podacima prikupljenih iz osobne komunikacije za godinu 2,3. Elektrofiziologija Elektrofiziologija je dio ritmoloπkog portfolija u kojemu je doπlo do najveêeg napretka u zadnjih nekoliko godina, a koji se manifestirao znaëajnim porastom broja obavljenih elektrofizioloπkih zahvata u Ëitavoj Republici Hrvatskoj, Ëime se djelomiëno smanjio veliki nesrazmjer u usporedbi s ostalim zemljama u regiji 4. in the field of cardiac electrophysiology (hereinafter electrophysiology) and cardiac pacing in recent years. In accordance with the article that accompanies this review article 1, we shall show the current state of rhythmology and electrostimulation in the Republic of Croatia, primarily based on official data published in the EHRA White Book from 2011 to 2013 (the Report European Heart Rhythm Association) and the still unofficial data collected from personal communications in ,3. Electrophysiology Electrophysiology is a part of rhytmological portfolio which has seen the greatest progress in the last few years, being reflected in a significant increase in the number of performed electrophysiological procedures throughout the Republic of Croatia, resulting in a partial reduction of the huge disproportion in comparison with other countries in the region 4. Table 1. Overview of interventional electrophysiology in Croatia from 2010 to * Number of ablation centers Number of ablations performed NA Mean number of ablations perfrmed NA Number of atrial fibrillation ablations NA *unofficial framework data; NA = not available U Tablici 1 prikazani su relevantni podaci elektrofizioloπkih zahvata u Republici Hrvatskoj od do Trenutno postoje pet elektrofizioloπkih laboratorija od Ëega Ëetiri na zagrebaëkom podruëju i jedan u Zadru. Svake godine vidljiv je znaëajan porast broja obavljenih zahvata te se procjenjuje da je tijekom godine obavljeno oko 700 elektrofizioloπkih zahvata. NajznaËajniji je porast kompleksnijih zahvata uz uporabu trodimenzionalnih (3D) navigacijskih sustava, a osobito broja ablacija fibrilacije atrija (FA), πto je u skladu sa svjetskim trendovima. Osnovni problemi koji sprjeëavaju dodatni razvoj ove grane medicine jesu nedostatak adekvatnih financijskih sredstava za nabavku potroπnog materijala, osobito skupljih katetera za kompleksnije zahvate koji koriste navigacijske sustave te nedostatak adekvatne DijagnostiËko-terapijske skupine (DTS) u hrvatskom bolniëkom sustavu kojima bi se moglo na pravilan naëin obraëunati i vrednovati uëinjeni bolniëki rad. Dodatni problem je joπ uvijek nedovoljno razvijena svijest o ovoj moguênosti lijeëenja meappleu bolesnicima, lijeënicima obiteljske medicine te odreappleenog broja lijeënika specijalista πto dovodi do nedovoljnog upuêivanja bolesnika u specijalizirane ustanove. Na taj naëin, zbog nepridræavanja smjernicama Europskog kardioloπkog druπtva (ESC), uskraêuje se bolesnicima efikasna metoda koja u brojnim sluëajevima moæe dovesti do potpunog izljeëenja, izlaæe ih se dugotrajnom uzimanju antiaritmika sa svojim potencijalnim nuspojavama te nepotrebno optereêuje Ëitavi zdravstveni sustav. Fibrilacija atrija FA je najëeπêa postojana srëana aritmija koja se javlja u oko 1-2% opêe populacije. Sukladno navedenim podacima u Table 1 presents the relevant data of electrophysiological procedures in the Republic of Croatia from 2010 to Currently there are five electrophysiological laboratories, out of which four in the region of Zagreb and one in Zadar. Every year we can see a substantial increase in the number of procedures performed and it is estimated that during the year 2013 some 700 electrophysiological procedures were performed. The increase in complex procedures using three-dimensional (3D) navigation systems, in particular in the number of atrial fibrillation (AF) catheter ablations is significant, which is in line with global trends. The main problems preventing further development of this branch of medicine are the lack of required financial resources for the purchase of supplies, particularly more expensive catheters for more complex procedures using navigation systems and the lack of adequate diagnosis-related group (DRG) in the Croatian hospital system, which would be used for calculation and valuation of the performed clinical work in a proper way. An additional problem is still a lack of awareness about this treatment option among the patients, family physicians and a certain number of medical specialists leading to a lack of sufficient referrals of patients to specialized institutions. In this way, due to non-compliance with the guidelines of the European Society of Cardiology (ESC), the patients are denied an efficient method which in many cases can lead to a complete cure, they are exposed to long-term antiarrhythmic therapy with their potential side-effects and the entire health system is unnecessarily burdened. Atrial fibrillation AF is the most common persistent cardiac arrhythmia, which occurs in about 1-2% of the general population. In accor- Cardiologia CROATICA 2014;9(1-2):4.

5 Hrvatskoj vjerojatno viπe od bolesnika boluje od FA. Prisustvo FA uzrokuje dvostruki porast smrtnosti i peterostruki porast rizika za moædani udar, a jedan od pet svih moædanih udara povezan je s ovom aritmijom. Ishemijski moædani udar povezan s FA je Ëesto fatalan, a u bolesnika koji preæive zaostaje teæi stupanj invalidnosti i imaju veêu sklonost recidiva nego bolesnici s drugom etiologijom moædanog udara. Zbog svega navedenog osnovna i jedina terapija koja dokazano smanjuje mortalitet u bolesnika s FA je prevencija moædanog udara primjenom antikoagulantne terapije 5,6. Drugi veliki napredak uz katetersku ablaciju u lijeëenju bolesnika s FA koji je prisutan u zadnjih nekoliko godina na naπim prostorima je dostupnost novih oralnih antikoagulansa (NOAK) 6,7. U Hrvatskoj su trenutno dostupna dva NOAK-a: dabigatran i rivaroxaban, a ove godine oëekuje se i registracija apixabana. NOAK dijelimo u dvije skupine: direktne inhibitore trombina (dabigatran), koji je od lipnja god na dopunskoj listi Hrvatskog zavoda za zdravstveno osiguranje i na inhibitore aktiviranog faktora X (rivaroxaban i apixaban). Za razliku od antagonista vitamina K koji djeluju na viπe faktora koagulacijske kaskade, NOAK djeluju specifiënije na samo jedan koagulacijski faktor. Velike randomizirane studije i metaanalize pokazale su neinferiornost NOAK u usporedbi s inhibitorima vitamina K u redukciji tromboembolijskih incidenata te bolji profil sigurnosti u vidu smanjenja uëestalosti krvarenja, osobito intrakranijskog krvarenja. Osnovni problemi koji joπ uvijek ograniëavaju veêu penetraciju NOAK meappleu bolesnicima s FA jesu viπa cijena nego antagonista vitamina K, nepokrivanje odnosno djelomiëno pokrivanje troπkova od strane zdravstvenog osiguranja u Republici Hrvatskoj i joπ uvijek nedovoljna edukacija lijeënika i bolesnika o efikasnosti i sigurnosti ove vrste antikoagulantne terapije. S obzirom na spomenute napretke u lijeëenju FA, dostupnosti novih europskih smjernica, pojavila se potreba za sustavno sakupljanje suvremenih podataka o postupanju i lijeëenju bolesnika s FA u zemljama Ëlanicama ESC. Zbog navedenog ESC je pokrenuo program izrade registra bolesnika s FA s ciljem dobivanja suvremenih podataka kako bi se ustanovilo da li su dijagnostiëki i terapijski postupci u bolesnika s FA u skladu sa suvremenim smjernicama, procijenilo upotrebu strategije kontrole ritma kao πto su kateterska ablacija FA, simptome, kvalitetu æivota, morbiditet i mortalitet u bolesnika s FA. U skladu s ESC, Radna skupina za aritmije i elektrostimulaciju Hrvatskoga kardioloπkog druπtva (HKD) pokrenula je takoappleer projekt izrade Hrvatskog registra bolesnika s FA kako bi se dobili adekvatni podaci o incidenciji, prevalenciji, morbiditetu i mortalitetu bolesnika s FA, trendovima lijeëenja, farmakoekonomici, a sve u cilju razvoja bolje strategije lije- Ëenja bolesnika s FA u Republici Hrvatskoj. Elektrostimulacija srca Napredak u podruëju elektrostimulacije oëituje se ne samo u smanjenju cijena ureappleaja za elektroterapiju, veê i dostupnoπêu sve kvalitetnijih podataka iz velikih randomiziranih kliniëkih studija koje sve bolje pokazuju koji bolesnici od navedene terapije mogu imati koristi nasuprot onim skupinama bolesnika kod kojih nije izgledno da Êe od takve terapije imati znatne koristi (dok πtetne posljedice mogu biti znaëajne). Pri tome, nekoë relativno rijetke metode lijeëenja poput ugradnje ureappleaja za srëanu resinkronizaciju (CRT) i ureappleaja za spreëavanje nagle srëane smrti (ICD) postale su sveprisutne u Republici Hrvatskoj, pri Ëemu je najznaëajnija dance with these data, probably more than 60,000 patients suffer from AF in Croatia. AF confers a double increase in mortality and fivefold increase in the risk of stroke, and one in five of all strokes is attribuited to this arrhythmia. Ischemic stroke associated with AF is often fatal, and those patients who survive are left more disabled by their stroke and more likely to suffer a recurrence than patients with other causes of stroke. Due to the foregoing, the basic and the only therapy that has proven to reduce mortality in patients with AF is the stroke prevention by using anticoagulant therapy 5,6. Another great advancement with catheter ablation in the treatment of patients with AF which has been present in the last few years in our region is the availability of new oral anticoagulants (NOAC) 6,7. In Croatia, two NOACs are currently available: dabigatran and rivaroxaban, and this year the registration of apixaban is expected. NOACs are divided into two groups: direct thrombin inhibitors (dabigatran), which has been added to the supplemental list of Croatian Health Insurance Fund since June 2013 and inhibitors of activated factor X (rivaroxaban and apixaban). Unlike vitamin K antagonists (VKA) which have an effect on a number of factors of the coagulation cascade, NOACs block the activity of one single step in coagulation. Large randomized trials and meta-analyses have demonstrated non-inferiority of NOACs compared with VKA in reducing thromboembolic events and a better safety profile in terms of reducing the incidence of bleeding, especially intracranial bleeding. The main problems that still limit a greater penetration of NOACs among patients with AF are a higher price than the price of VKA, non-coverage or partial coverage of the costs by health insurance in the Republic of Croatia and still insufficient education of physicians and patients in respect to the efficacy and safety of this type of anticoagulant therapy. Given the aforementioned advancements in the treatment of AF, the availability of new European guidelines, the need has arisen for systematic collection of contemporary data on the treatment and management of patients with AF in ESC member countries. For this reason, ESC has launched a program of creating a AF registry in order to collect contemporary data as to determine whether the diagnostic and therapeutic procedures in patients with AF are in compliance with contemporary guidelines, to evaluate the use of rhythm control strategies such as catheter ablation AF, symptoms, quality of life, morbidity and mortality in patients with AF. As well as the ESC, the Working Group on Arrhytmias and Cardiac Pacing of the Croatian Cardiac Society has launched a project of a national AF registry in order to obtain suitable data on incidence, prevalence, morbidity and mortality of patients with AF, treatment trends, pharmacoeconomics, all in order to develop better treatment strategies in patients with AF in the Republic of Croatia. Cardiac pacing Progress in the field of electrostimulation is reflected not only in reducing the cost of devices for electrotherapy, but also the availability of more quality data from large randomized clinical trials that better show what patients can benefit from the above therapy compared to the groups of patients who are not likely to have much benefit from such a therapy (while harmful consequences can be significant). In that respect, once relatively rare treatment methods such as cardiac resynchronization therapy (CRT) devices and implantable cardioverter defibrillators (ICD) have become ubiquitous in the Republic of Croatia, where the most significant difference compared to most European countries re- 2014;9(1-2):5. Cardiologia CROATICA

6 razlika u odnosu na veêinu europskih zemalja i dalje relativno nedostatan broj ugraappleenih ureappleaja u odnosu na stvarne potrebe naπe populacije. Glavni ograniëavajuêi Ëimbenik, naæalost, i dalje predstavljaju nedostatna financijska sredstva koja su dostupna za primjenu ovog naëina lijeëenja. Olakotni Ëimbenici, poput entuzijazma i interesa kolegica i kolega, stalno prisutnu edukaciju i rastuêi broj centara gdje je navedene postupke moguêe provesti, imali su samo ograniëeni uëinak na broj ovih postupaka (podaci o najëeπêim tipiënim postupcima u elektroterapiji su pregledno prikazani u Tablici 2). Nadalje, kako bi se postojeêe stanje u Republici Hrvatskoj moglo usporediti sa stanjem od prije nekoliko godina, skreêemo pozornost Ëitatelja na Ëlanak objavljen u Cardiologia Croatica godine, Ëime Êe steêi potpuni uvid u trenutno stanje, ali i trendove 4. mains relatively insufficient number of implanted devices compared to the real needs of our population. The main limiting factor, unfortunately, is still a lack of financial resources available for the use of this treatment option. Mitigating factors, such as the enthusiasm and interest of colleagues, constantly present education and a growing number of centers where these procedures can be performed, had only a limited effect on the number of these procedures (data on the most typical procedures in electrotherapy are detailed in Table 2). Furthermore, in order to be able to compare the existing situation in the Republic of Croatia with the situation we faced a few years ago, we draw the reader s attention to an article published in Cardiologia Croatica in 2011, which will give you a complete insight into the current situation and trends as well 4. Table 2. Overview of cardiac pacing in Croatia from 2011 to Procedure Pacemaker units implanted 2,532 2,515 New implants 2,147 2,191 Replacement Implanting centers CRT units implanted CRT-P CRT-D Implanting centers 8 10 ICD units implanted Implanting centers Loop recorder units implanted 15 7 Lead extraction 7 7 Perfoming centers 1 3 Iz prikazanih podataka razvidno je da je doπlo do odreappleenog platoa u broju ugraappleenih elektrostimulatora, pri Ëemu bi se, s obzirom na evoluciju nekih dijagnostiëkih metoda, ipak oëekivao daljnji porast. Meappleutim, zbog gore navedenih razloga, do tog porasta nije doπlo. Odreappleen porast prisutan je u ugradnji CRT i ICD ureappleaja, no naæalost taj porast je joπ uvijek nedostatan u odnosu na veêinu zemalja u regiji, πto je takoappleer zabiljeæeno i godine 2,3. Svakako je najznaëajnija novost u podruëju elektrostimulacije objava dugo oëekivanih novih Smjernica za elektrostimulaciju i srëanu resinkronizacijsku terapiju ESC koje su objavljene tijekom Europace kongresa u lipnju godine 8. S obzirom na to da su prijaπnje Smjernice objavljene joπ (uz dodatno osvjeæenje u podruëju lijeëenja CRT ureappleajima godine), jasno je zaπto je dobrodoπlo novo izdanje 9,10. Glavne novosti u tim Smjernicama rezultat su brojnih istraæivanja u podruëju primjene srëane resinkronizacijske terapije kod bolesnika sa zatajivanjem srca. Nakon objave rezultata nekoliko velikih randomiziranih kontroliranih kliniëkih studija u kojima je pokazano da primjena CRT ureappleaja donosi znatnu korist bolesnicima s ozbiljnim zatajivanjem srca u smislu boljeg preæivljenja, ali i poboljπanja simptoma uslijedio je niz studija u kojima je naglasak stavljen na definiranje varijabli koje odreappleuju pobliæe podskupine bolesnika za koje je The presented data shows that a certain maximum in the number of implanted pacemakers has been achieved, whereas we still expect a further increase considering the evolution of some diagnostic methods. However, this increase has not occurred for the above reasons. There is a certain increase in the implantation of CRT and ICD devices, but unfortunately, this increase is still insufficient compared to the most of countries in the region, which was also recorded in ,3. Certainly the most significant innovation in the field of cardiac pacing is publishing of long awaited ESC Guidelines for pacing and cardiac resynchronization therapy published during Europace Congress in June Considering the fact that the previous Guidelines were published in 2007 (with additional update in the field of treatment by using CRT devices in 2010), it is clear why the new edition is welcome 9,10. The main novelty in these Guidelines is the result of numerous studies in the field of applying cardiac resynchronization therapy in patients with heart failure. The publication of the results of several large randomized controlled clinical studies which showed that the use of CRT devices brings substantial benefit to patients with severe heart failure in terms of better survival, but also improvement of symptoms was followed by a series of studies in which emphasis was placed on defining the variables that closely determine Cardiologia CROATICA 2014;9(1-2):6.

7 najveêa vjerojatnost da Êe imati koristi od navedene terapije. Navedeno se ponajviπe odnosi na prikladan odabir bolesnika kod kojih se razmatra lijeëenje CRT ureappleajem, kao i na odreappleivanje kliniëkih karakteristika koje vode k povoljnom odgovoru na takvo lijeëenje. Nova saznanja iz tih studija ugraappleena su u nove Smjernice, a odnose se ponajviπe na varijable za odabir bolesnika koji imaju najveêu vjerojatnost koristi od primjene CRT ureappleaja i predviappleanje odgovora na primjenu CRT. Sve viπe paænje posveêuje se i infekcijama sustava za elektrostimulaciju, buduêi da je broj takvih infekcija u znatnom porastu. S obzirom na sve veêi broj bolesnika koji su nositelji takvih sustava, navedeno ne predstavlja iznenaappleenje, meappleutim ima znatne implikacije na zdravstveni sustav, buduêi da su takve infekcije znaëajan uzrok morbiditeta, mortaliteta i znatnog poveêanja troπkova lijeëenja. Takoappleer, s obzirom na sve veêi broj bolesnika koji Êe trebati zamjenu postojeêeg sustava za elektrostimulaciju (ponajprije zbog iscrpljenja generatora, ali i zbog revizija elektroda), za oëekivati je i sve veêi broj takvih infekcija. Prema podacima pokazanim u Tablici 2 postupci ekstrakcije sustava za elektrostimulaciju poëeli su se provoditi i u Republici Hrvatskoj. U novim smjernicama za ugradnju CRT ureappleaja, po prvi puta donesene su jasne preporuke za perioperativno postupanje u bolesnika s antitrombocitnom i/ili antikoagulantnom terapijom. Hematomi su Ëesta komplikacija, javljaju se u oko 2,9-9,5% sluëajeva, a najëeπêe se lijeëe konzervativno. Evakuacija je potrebna u oko 0,3-2% sluëajeva i 15 puta povisuje rizik za nastanak infekcije. VeÊina hematoma i krvarenje moæe se izbjeêi pravilnom preoperativnom pripremom bolesnika i adekvatnom regulacijom antitrombocitne i antikoagulantne terapije. Nove smjernice preporuëuju da se u ve- Êine bolesnika na antitrombocitnoj terapiji moæe perioperativno obustaviti terapija u trajanju od 5 do 7 dana, osobito ako su navedeni lijekovi uvedeni radi primarne prevencije. U bolesnika viπeg rizika s dvostrukom antitrombocitnom terapijom, preporuëa se ukidanje klopidogrela u trajanju od 4 dana prije implantacije. U bolesnika niskog tromboembolijskog rizika na antikoagulantnoj terapiji preporuëuje se smanjenje doze uz postizanje INR-a 1,5 do 2 ili obustavljanje antikoagulantne terapije 3 do 5 dana prije implantacije. U bolesnika visokog tromboembolijskog rizika preporuëuje se ugradnja ureappleaja uz INR izmeappleu 2 do 2,5. Uporaba heparina perioperativno kao most za antikoagulantnu terapiju se viπe ne preporuëuje zbog znaëajnog poviπenja rizika za razvoj hematoma loæe (uëestalost 15-20%) 8. Nagla srëana smrt Iako je priprema novih Smjernica iz podruëja lijeëenja ventrikulskih aritmija i sprjeëavanja nagle srëane smrti u tijeku (s oëekivanom objavom istih tijekom godine), vaæno je napomenuti da su i u tom podruëju prisutne brojne nove spoznaje, koje su dobrim dijelom ugraappleene u ove Smjernice za elektrostimulaciju i srëanu resinkronizacijsku terapiju, buduêi da su prijaπnje Smjernice iz ovog podruëja objavljene joπ godine 11. Jedna od znatnih novosti je i dodatni prikaz uloge pretrage MR srca, koja se u nekoliko centara moæe uëiniti i u Republici Hrvatskoj. Nove spoznaje iz ovog podruëja odnose se na bolje razumijevanje pojavnosti i uzroka ventrikulskih aritmija i nagle srëane smrti, kao i odabir bolesnika koji bi trebali imati najviπe koristi od ugradnje ICD ureappleaja. subgroups of patients which are most likely to benefit from this therapy. The foregoing primarily applies to the appropriate selection of patients who are considered to undergo the treatment by a CRT device as well as to determination of clinical characteristics that lead to a favorable response to such a treatment. New insights from these studies are incorporated in the new Guidelines, which primarily relate to the variables for the selection of patients who are most likely to benefit from the use of CRT devices and predicting the response to CRT application. Ever greater attention is paid to the infection of electrical stimulation system, since the number of such infections is constantly in rise. Considering the increasing number of patients who are the carriers of such systems, the foregoing is not surprising; however, it has significant implications for the healthcare system, since such infections are a significant cause of morbidity, mortality and a significant increase in medical costs. Also, considering an increasing number of patients who will need a replacement of the existing pacemaker (primarily due to the generator depletion, but also due to inspection of electrodes), we can expect an increasing number of such infections. According to the data shown in Table 2, the methods of extraction of the pacing systems started to be implemented in the Republic of Croatia. The new guidelines for the implantation of a CRT device include for the first time the clear recommendations for the perioperative treatment of patients with antiplatelet and/or anticoagulant therapy. Pocket hematomas are a common complication, occurring in about 2.9% to 9.5% of cases and are usually treated conservatively. Evacuation is required in about 0.3% to 2% of cases and increases risk for occurrence of infection by 15 times. Most of the hematoma and bleeding can be avoided by proper preoperative patient preparation and adequate regulation of antiplatelet and anticoagulant therapy. The new guidelines recommend that in the majority of patients on antiplatelet therapy, the therapy may be discontinued perioperatively for a period of 5-7 days, especially if these drugs were introduced for primary prevention. In higher-risk patients with dual antiplatelet therapy, discontinuation of clopidogrel in a length of 4 days prior to implantation is recommended. Dose reduction of VKA is recommended in patients on anticoagulant therapy with low thromboembolic risk, achieving an INR of or discontinuation of anticoaganticoagulant therapy for 3-5 days prior to implantation. In high thromboembolic risk patients implantation of devices with an INR between is recommended. The use of heparin perioperatively as a "bridge" for anticoagulant therapy is no longer recommended due to a significant increase in the risk for the development of hamstring hematoma (incidence 15-20%) 8. Sudden cardiac death Although the preparation of the new Guidelines in the area of treatment of ventricular arrhythmias and prevention of sudden cardiac death (SCD) is in progress (where the publishing of these guidelines is expected in 2015), it is important to note that a number of new insights are present in this area, which are mostly incorporated in the Guidelines for cardiac pacing and cardiac resynchronization therapy, since the previous guidelines in this area were published in One of the significant novelties is an additional presentation of the role of heart MRI scan, which can be performed in a few centers in the Republic of Croatia. New insights in this area are related to a better understanding of the incidence and causes of ventricular arrhythmias and SCD, as well as the selection of patients that are benefit the most from ICD therapy. 2014;9(1-2):7. Cardiologia CROATICA

8 Na kraju, valja spomenuti i pomake vezane uz postupke kardiopulmonalne reanimacije. U Republici Hrvatskoj se niz godina provodi viπe vrsti teëajeva iz kardiopulmonalne reanimacije sukladno Smjernicama Europskog druπtva za resuscitaciju (ALS, ILS, EPLS, AED; zadnje Smjernice su iz godine), a u organizaciji Hrvatskog druπtva za reanimatologiju Hrvatskog lijeëniëkog zbora 12. Tijekom godine uëinjeni su znatni pomaci u dostupnosti defibrilatora na javnim mjestima, kako u Gradu Zagrebu, tako i diljem Republike Hrvatske; sve s ciljem kako bi se πto veêem broju laika omoguêilo uspjeπno provoappleenje postupka reanimacije i, u sluëaju potrebe, vanjske defibrilacije primjenom AED ureappleaja. Pri tome se mora naglasiti uloga Hrvatskoga kardioloπkog druπtva i Zaklade Hrvatska kuêa srca. Glavni izazov u ovom podruëju svakako predstavlja potreba za kontinuiranom i sveobuhvatnom edukacijom πto veêeg broja laika, ali i zdravstvenog osoblja. Genetsko testiranje Nasljedne aritmogene bolesti srca predstavljaju vaæan uzrok malignih poremeêaja srëanog ritma. Javljaju se preteæito u mlaapplee populacije, a manifestiraju se najëeπêe u vidu palpitacija, omaglica i sinkopa te u najgorem sluëaju, naglom srëanom smrti (NSS). Karakterizirane su poveêanom uëestaloπ- Êu supraventrikulskih i ventrikulskih poremeêaja srëanog ritma te se smatraju najëeπêim uzrokom NSS u mladih sportaπa. U skupinu nasljednih aritmogenih bolesti ubrajamo sindrom dugog (LQTS) i kratkog QT intervala (SQTS), Brugadin sindrom (BrS), kateholaminergiënu polimorfnu ventrikulsku tahikardiju (CPVT), aritmogenu kardiomiopatiju desne klijetke (ARVC) te hipertrofijsku kardiomiopatiju (HCM) (vidi Slike 1-4). Nasljeappleuju se preteæito autosomno dominantno, a bliæi su srodnici pod poviπenim rizikom za obolijevanje od istih bolesti 13,14. Finally, we should mention the breakthroughs made in regard to the cardiopulmonary resuscitation procedures. Several types of cardiopulmonary resuscitation courses have taken place in the last few years in the Republic of Croatia in accordance with the Guidelines of the European Society for Resuscitation (ALS, ILS, EPLS, AED; the latest guidelines date back to 2010), organized by the Croatian Society of Resuscitation of the Croatian Medical Association 12. During the year 2013, major breakthroughs have been made in the availability of defibrillators in public places, not only in the City of Zagreb, but also throughout the Republic of Croatia; with an aim to help as many lay persons to successfully perform resuscitation and, if necessary, external defibrillation using the AED devices. The role of the Croatian Cardiac Society and the Croatian Heart House foundation is to be emphasized. The main challenge in this area is certainly the need for continuous and comprehensive education of as many lay persons as possible, but also the medical staff. Genetic testing Inherited arrhythmogenic heart diseases are an important cause of malignant cardiac arrhythmias. They often occur in young people, and usually manifest in the form of palpitations, syncopes, and at worst, SCD. They are characterized by an increased incidence of supraventricular and ventricular cardiac rhythm disorders and are considered the most common cause of SCD in young athletes. The group of congenital arrhythmogenic diseases include long QT syndrome (LQTS) and short QT syndrome (SQTS), the Brugada syndrome (BrS), catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM) (Figures 1-4). They are inherited predominantly autosomally, while closer relatives are at increased risk of developing the same disease 13,14. Figure 1. ECG of a 33 year old female patient with LQTS after resuscitation because of ventricular fibrillation. See the characteristic QT prolongation in lead III. U Republici Hrvatskoj trenutno ne postoji moguênost sustavnog genetskog testiranja nasljednih aritmogenih bolesti srca. U lipnju godine u sklopu zajedniëkog projekta zapoëeta je suradnja izmeappleu Zavoda za kardiovaskularne bolesti KBC Rijeka i Statens Serum Instituta (Kopenhagen, Danska) u cilju sustavnog istraæivanja svih bolesnika s kli- At the moment, there is no possibility of a systematic genetic testing of congenital arrhythmogenic heart disease in the Republic of Croatia. In June 2012, the cooperation was established between the Institute for Cardiovascular Diseases University Hospital Centre Rijeka and Statens Serum Serum Institute (Copenhagen, Denmark) as part of the joint project Cardiologia CROATICA 2014;9(1-2):8.

9 Figure 2. ECG of a 23 year old male patient with Brugada syndrome. See the characteristic coved ST elevation i lead V1 and V2. Figure 3. ECG of a 47 year old patient with fully expressed ARVC. See the characteristic Epsilon wave and negative T-waves in lead V2 and V3 (arrow) and ventricular extrasystoles. Figure 4. ECG of a 17 year old patient with HCM. See the characteristic left ventricular hypertrophy with diffuse negative T wave. niëki postavljenom dijagnozom nasljedne aritmogene bolesti i njihovih bliæih srodnika 15,16. Cilj ovog istraæivanja bilo je sustavno genetski analizirati bolesnike s nasljednim aritmogenim bolestima i njihovih bliæih srodnika, kako bi se po prvi puta na naπim prostorima dobila genetska karakterizacija in order to conduct a systematic trial of all the patients with a clinical diagnosis of congenital arrhythmogenic diseases and their close relatives 15,16. The aim of this trial was to conduct a systematic genetic analysis of patients with congenital arrhythmogenic diseases and their close relatives, in 2014;9(1-2):9. Cardiologia CROATICA

10 populacije te pokuπalo identificirati bolesnike pod poveêanim rizikom za NSS i omoguêilo njihovo pravovremeno savjetovanje i lijeëenje. Genetski je analizirano 85 bolesnika i njihovih srodnika, a genetska mutacija je ustanovljena 35 bolesnika (41%). Kontrolna skupina bila je saëinjena od 200 zdravih hrvatskih dobrovoljaca, Ëiji Êe genetski materijal ostati pohranjen kako bi se i ubuduêe mogao koristiti za daljnja istraæivanja te isklju- Ëile eventualne karakteristiëne i uëestale mutacije za naπu populaciju. order to obtain genetic characterization of populations for the first time in our region, to attempt to identify patients at an increased risk for SCD and providing them with prompt advice and treatment. 85 patients and their relatives were genetically analyzed, and genetic mutation was detected in 35 patients (41%). The control group was composed of 200 healthy Croatian volunteers whose genetic material will be deposited, so that it could be used for further trials in the future and to exclude any characteristic and frequent mutations in our population. Table 3. Population charachteristics of genetic inhereted disease in Croatia. ARVC HCM BrS LQTS Total No (%) No. of individuals No. of new mutations (48%) Sex male / female 4/4 11/8 3/2 1/2 19/16 Mean age at diagnosis ARVC = arrhythmogenic right ventricular cardiomyopathy; HCM = hypertrophic cardiomyopathy; BrS = Brugada syndrome; LQTS = long QT syndrome. U Tablici 3 prikazane su karakteristike bolesnika u kojih je ustanovljena genetska mutacija. Najzanimljiviji rezultat je 17 dosad novo opisanih mutacija (48%), πto je i za oëekivati s obzirom na dosad vrlo slabo genetski karakteriziranu populaciju 17,18. Genetsko istraæivanje aritmoloπkih bolesnika i otkrivanje novih mutacija vaæan je doprinos za bolje razumijevanje raznolikosti aritmija te nam omoguêuje raniju dijagnostiku, kvalitetnije lijeëenje i preventivno djelovanje. Osnovne problemi su visoke cijene ovih pretraga, nemoguênost obavljanja navedenih testiranju u Hrvatskoj, nemoguênost refundacije troπkova od zdravstvenog osiguranja i nedostatak educiranosti iz podruëja genetskog savjetovanja. ZakljuËak ZakljuËno, moæe se reêi da se najveêi napredak u podruëju aritmologije u Republici Hrvatskoj u zadnjih nekoliko godina desio u podruëju elektrofiziologije i kateterske ablacije FA prvenstveno zahvaljujuêi velikom entuzijazmu lijeënika koji se bave ovim podruëjem medicine. Prisutni su i znatni pomaci u novim spoznajama u podruëju elektrostimulacije, u Republici Hrvatskoj prisutan je daljnji porast u brojnu centara gdje se takvi postupci provode, kao i u broju uëinjenih postupaka, pri Ëemu edukacija u tom podruëju prati nove spoznaje i trendove, sve s ciljem kako bi naπim bolesnicima omoguêili dulje preæivljenje i bolju kvalitetu æivota. Meappleutim, glavni izazovi koji ostaju pred nama nisu se bitno promijenili u odnosu na prijaπnje godine, a osnovno je pronalazak dodatnih sredstava koji bi osigurali bolju prevenciju nagle srëani smrti neophodnim poveêanjem broja ugradnje implantabilnih kardioverter defibrilatora i ureappleaja za resinhronizacijsku terapiju. Prostor za poboljπanje je znatan, pri Ëemu se ne moæe dovoljno naglasiti vaænost ustrajne aktivnosti struënog druπtva u ovom podruëju. Received: 22 nd Jan 2014; Accepted: 30 th Jan 2014 *Address for correspondence: KliniËki bolniëki centar Rijeka, Tome StriæiÊa 3, HR Rijeka, Croatia. Phone: sandro.brusich@gmail.com Table 3 shows the characteristics of patients with established genetic mutation. The most interesting result is 17 new mutations described so far (48%), which is to be expected taking into account the population that has been so poorly genetically characterized in the past 17,18. Genetic trial of arrhythmologic patients and discovery of new mutations is an important contribution necessary for a better understanding of the diversity of arrhythmia, and allows us earlier diagnosis, better quality treatment and preventive action. The basic problems are high prices of these tests, the inability to perform the above tests in Croatia, the inability to refund the costs from the health insurance and lack of education in the field of genetic counseling. Conclusion To conclude, we can say that the greatest advancement in the area of arrhythmology has been made in the field of electrophysiology and AF catheter ablation in the Republic of Croatia in recent years, primarily due to the great enthusiasm of physicians that engage in this area of medicine. There are also significant advancements in new insights in the field of electrical stimulation. A further increase in a number of centers where such procedures are performed has been recorded in the Republic of Croatia, and there is also an increasing number of performed procedures where education keeps up with new insights and trends, all with an aim to enable our patients prolonged survival and a better quality of life. However, some major challenges we are facing have not significantly changed compared to the previous years, and the basic one is finding additional resources to ensure better prevention of SCD by a necessary increase in the number of ICD and CRT implantats. The room for improvement is great, whereas we can not sufficiently emphasize the importance of persistent activities of the professional society in this area. Cardiologia CROATICA 2014;9(1-2):10.

11 Literature 1. Liew R. Almanac 2013: cardiac arrhythmias and pacing. Cardiol Croat. 2014;9(1-2): Auricchio A, Kuck KH, Hatala P, Arribas F. The current status of cardiac electrophysiology in ESC member countries. EHRA White book 2012: fifth edition. 3. Auricchio A, Kuck KH, Hatala P, Arribas F. The current status of cardiac electrophysiology in ESC member countries. EHRA White book 2013: sixt edition. 4. Bernat R. Arrhythmology in the Republic of Croatia. Cardiol Croat. 2011;6(12): European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19): Camm AJ, Lip GY, De Caterina R, et al focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21): Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013;34(27): European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA), Brignole M, Auricchio A, Baron-Esquivias G, et al ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace. 2013;15(8): Vardas PE, Auricchio A, Blanc JJ, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy. The Task Force for Cardiac Pacingand Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Europace. 2007;9(10): Dickstein K, Vardas PE, Auricchio A, et al Focused Updateof ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Eur Heart J. 2010;31(21): Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace. 2006;8(9): Nolan JP, Soar J, Zideman DA, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation. 2010;81(10): Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29(13): Ranthe MF, Carstensen L, Oyen N, et al. Family history of premature death and risk of early onset cardiovascular disease. J Am Coll Cardiol. 2012;60(9): Brusich S, DembiÊ M, Hedley P, et al. Genetic analysis of hereditary heart diseases: the Danish - Croatian collaboration. Cardiol Croat. 2012;7(Suppl 1): DembiÊ M, Brusich S, Hedley P,»ubraniÊ Z, ZaputoviÊ L, Christiansen M. Genetic testing, incidence and prevention of sudden cardiac death in Croatia. Cardiol Croat. 2012;7(Suppl 1): DembiÊ M, Brusich S, Hedley P, et al. Novel arrhythmia-related mutations in Croatian arrhythmia patients. Europace. 2013;15(suppl 2):ii119-ii Brusich S, DembiÊ M, ubraniê Z. First results of genetic testing in Croatian arrhythmia patients. Cardiol Croat. 2013;8(9): ;9(1-2):11. Cardiologia CROATICA

12 Pregledni rad / Review article Almanac 2013.: aritmije i elektrostimulacija srca Almanac 2013: cardiac arrhythmias and pacing Reginald Liew 1,2 * 1 Duke-NUS Graduate Medical School, Singapur, Republika Singapur 2 Gleneagles Hospital, Singapur, Republika Singapur 1 Duke-NUS Graduate Medical School, Singapore, Singapore 2 Gleneagles Hospital, Singapore-Singapore SAÆETAK: U posljednjih nekoliko godina uëinjen je zna- Ëajan napredak u podruëju kliniëke elektrofiziologije i elektrostimulacije srca. Znanstvenici i lijeënici bolje razumiju patofizioloπke mehanizme fibrilacije atrija (FA) πto je rezultiralo poboljπanjem dijagnostiëkih metoda, stratifikaciji rizika i lijeëenja. Uvoappleenje novih oralnih antikoagulansa omoguêilo je lijeënicima alternativne moguênosti zbrinjavanja bolesnika s FA kod umjerenog ili visokog rizika tromboembolije te su dostupni i novi podaci za uporabu kateterske ablacije u lijeëenju bolesnika sa simptomatskom FA. Drugo podruëje intenzivnog istraæivanja aritmija i elektrostimulacije srca vezano je uz primjenu kardijalne resinkronizacijske terapije (CRT) u lijeëenju bolesnika sa zatajivanjem srca. Po objavi najznaëajnijih randomiziranih kontroliranih istraæivanja koja dokazuju da CRT poboljπava πanse za preæivljavanje kod bolesnika s teπkim stupnjem zatajivanja srca te da ublaæava simptome, provedene su mnoge studije vezane uz probir bolesnika za lijeëenje primjenom CRT i evaluirani su kliniëki znaci povezani s povoljnom reakcijom na terapiju. Takoappleer, nastavljeno je aktivno istraæivanje podruëja iznenadne srëane smrti i implatibilnih kardioverter defibrilatora s vaænim novim epidemioloπkim i kliniëkim podacima poglavito o metodama izbora, stratifikacije rizika i skrbi bolesnika. Ovaj pregledni rad prikazuje najznaëajniji napredak na podruëjima aritimija i elektrostimulacije srca. FIBRILACIJA ATRIJA Epidemiologija fibrilacije atrija Brojne velike epidemioloπke studije koje koriste podataka iz registara i prospektivne kohorte podatka ponovno su ukazale na povezanost izmeappleu fibrilacije atrija (FA) i ostalih netradicionalnih Ëimbenika rizika za FA. To ukljuëuje poveêani rizik od pojave FA kod bolesnika s visokom razinom HbA1c i loπom kontrolom glikemije 1, celijaklijom 2, reumatoidnim artritisom 3 i psorijazom 4, s uporabom nesteroidnih antireumatika 5 i visokih ljudi 6. Druga zanimljiva veza je otkriêe iz pod- SUMMARY: Important advances have been made in the past few years in the fields of clinical cardiac electrophysiology and pacing. Researchers and clinicians have a greater understanding of the pathophysiological mechanisms underlying atrial fibrillation (AF), which has transpired into improved methods of detection, risk stratification, and treatments. The introduction of novel oral anticoagulants has provided clinicians with alternative options in managing patients with AF at moderate to high thromboembolic risk and further data has been emerging on the use of catheter ablation for the treatment of symptomatic AF. Another area of intense research in the field of cardiac arrhythmias and pacing is in the use of cardiac resynchronisation therapy (CRT) for the treatment of patients with heart failure. Following the publication of major landmark randomised controlled trials reporting that CRT confers a survival advantage in patients with severe heart failure and improves symptoms, many subsequent studies have been performed to further refine the selection of patients for CRT and determine the clinical characteristics associated with a favourable response. The field of sudden cardiac death and implantable cardioverter defibrillators also continues to be actively researched, with important new epidemiological and clinical data emerging on improved methods for patient selection, risk stratification, and management. This review covers the major recent advances in these areas related to cardiac arrhythmias and pacing. CITATION: Cardiol Croat. 2014;9(1-2): ATRIAL FIBRILATION Epidemiology of atrial fibrillation A number of large scale epidemiological studies using registry databases and prospective cohort data have reported novel associations between atrial fibrillation (AF) and other non-traditional risk factors for AF. These include an increased risk of incident AF in patients with high glycosylated haemoglobin (HbA1c) and poor glycaemic control 1, coeliac disease 2, rheumatoid arthritis 3 and psoriasis 4, use of non-aspirin, non-steroidal antiinflammatory drugs (NSAID) 5, and The article was first published in Heart. 2013;99(19): doi: /heartjnl Epub 2013 Aug 1. and is republished with permission Cardiologia CROATICA 2014;9(1-2):12.

13 studije SAFETY (Standard versus Atrial Fibrillation SpecificManagement Study) u kojoj je kod 260 bolesnika s kroniënom FA otkrivena visoka zastupljenost blagih kognitivnih poremeêaj kod starijih, visoko riziënih bolesnika hospitaliziranih s FA 7. U podstudiji Cardiovascular Health Study otkrivena je povezanost poviπenih koncentracija ukupnih dugolanëanih n-3 polunezasiêenih masnih kiselina (PUFA) u cirkulaciji s niskim rizikom od pojave FA 8. Druge nedavne epidemioloπke studije o FA ukazuju na poveêanje incidencije FA u bolesnika s poveêanim rizikom od razvoja terminalne faze kroniëne bubreæne bolesti kod preegzistirajuêe kroniëne bolesti bubrega 9. Studija provedena kod bolesnika je pokazala da je novonastala FA kod bolesnika s infarktom miokarda bez prethodnih anamnestiëkih podataka o FA povezana s poveêanom smrtnosti 10. U velikoj πvedskoj studijii s podacima od bolesnika s FA ukljuëenih u registar, Friberg i sur. 11 su utvrdili da su ishemijski moædani udari bili ËeπÊi u æena nego u muπkaraca, Ëime se podræava stav da se æenski spol treba uzeti u razmatranje prilikom donoπenje odluke o antikoagulacijskom lijeëenju. Nadalje, kod starijih bolesnika primljenih s nedavno dijagnosticiranom FA, rizik od moædanog udara se Ëini veêim kod æena nego kod muπkaraca, bez obzira na uporabu varfarina 12, a meappleu zdravim æenama novonastala FA se smatra neovisnim Ëimbenikom povezanim s ukupnom kardiovaskularnom i ne-kardiovaskularnom smrtnosti 13. Medikamentozno lijeëenje fibrilacije atrija Podaci iz meappleunarodne, opservacijske, presjeëne studije RealiseAF s bolesnicima s anamnestiëkim podatkom o FA tijekom prethodne godine, ukazuju da su bolesnici kod kojih je FA bila kontrolirana (definirana kao sinusni ritam ili FA s frekvencijom srca u mirovanju 80/min) imali bolju kvalitetu æivota i manje simptoma nego oni kod kojih je FA bila nekontrolirana 14. Ipak, Ëak i bolesnici s kontroliranom FA imaju Ëesto simptome poput nepodnoπljivosti napora, promjene kvalitete æivota i kardiovaskularne dogaappleaje, pa su stoga vaæni kontinuirani napori u razvoju novog i boljeg lijeëenja kod FA. Registar RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation) je bila svjetska, prospektivna opservacijska studija o lijeëenju FA temeljena na neselektivnoj kohorti tijekom razdoblja od 12 mjeseci 15. Kod bolesnika, Ëiji su podaci bili dostupni, terapijski uspjeh (kontrola FA) ostvaren je u 54% svih bolesnika (kontrola ritma u 60% nasuprot kontrole frekvencije u 47%). Na kliniëke ishode (koji su uglavnom bili potaknuti hospitalizacijama zbog aritmije i drugih kardiovaskularnih uzroka) nije utjecao izbor strategije kontrole srëane frekvencije ili ritma, iako je izbor kontrole ritma smanjio vjerojatnost napredovanja FA. Studija RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation) je bila prva sluæbena procjena drugaëijih ciljeva u kontroli frekvencije u FA te je po prvi put pokazano da strategija blaæe kontrole frekvencije (ciljna srëana frekvencija u mirovanju <110/min) nije inferiorna u odnosu na strategiju stroge kontrole frekvencije (ciljna srëana frekvencija u mirovanju <80/min i tijekom umjerenog vjeæbanja <110/min) 16. Dvije naknadne pod-studije istraæivanja RACE II su dokazale da stroga kontrola frekvencije nije imala znaëajan uëinak na kvalitetu æivota u bolesnika s trajnom FA 17 te da blaæa kontrola frekvencije nije imala negativan utjecaj na atrijsko i ventrikulsko remodeliranje u usporedbi sa strogom kontrolom frekvencije (iako je æenski spol bio neovisno povezan sa znaëajnim negativnim srëanim remodeliranjem) 18. U drugoj increased height 6. Another interesting association is the finding from a substudy of 260 patients with chronic AF from the SAFETY trial (Standard versus Atrial Fibrillation Specific Management Study) that mild cognitive impairment is highly prevalent among older, high risk patients hospitalised with AF 7. In another substudy of the Cardiovascular Health Study, investigators found that higher baseline circulating concentrations of total long chain n-3 polyunsaturated fatty acids (PUFA) were associated with a lower risk of incident AF 8. Other interesting recent epidemiological studies on AF include the association of incident AF with an increased risk of developing end stage renal disease in patients with chronic kidney disease 9, and a community based study of 3,220 patients which showed that new AF in patients with no history of AF before a myocardial infarction increased mortality in patients with myocardial infarction 10. In a large Swedish registry study of 100,802 patients with AF, Friberg et al. 11 found that ischaemic strokes were more common in women than in men, supporting the notion that female gender should be taken into consideration when making decisions about anticoagulation treatment. Furthermore, among older patients admitted with recently diagnosed AF, the risk of stroke appears to be greater in women than in men, regardless of warfarin use 12, and among healthy women new onset AF was found to be independently associated with all cause cardiovascular and non-cardiovascular mortality 13. Medical management of atrial fibrillation Data from the RealiseAF study, an international, observational, cross-sectional survey of patients with any history of AF in the previous year, suggested that patients in which their AF was controlled (defined as sinus rhythm or AF with a resting heart rate 80 beats/min) had a better quality of life and fewer symptoms than those whose AF was uncontrolled 14. Nonetheless, even patients with controlled AF experienced frequent symptoms, functional impairment, altered quality of life and cardiovascular events hence the importance of ongoing efforts to develop novel and better treatments for AF. The RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation) registry was a worldwide, prospective observational survey of AF management in an unselected, community based cohort over a 12 months period 15. The investigators found that in 5,171 patients whose data were available, therapeutic success (driven by control of AF) was achieved in 54% overall (rhythm control 60% vs rate control 47%). The choice of rate or rhythm strategy did not affect clinical outcomes (which were driven mainly by hospitalisations for arrhythmia and other cardiovascular causes), although the choice of rhythm control reduced the likelihood of AF progression. The RACE (Rate Control Efficacy in Permanent Atrial Fibrillation) II trial was the first formal assessment of alternative rate control goals in AF and demonstrated for the first time that a lenient rate control strategy (target resting heart rate <110 beats/min) was non-inferior to a strict rate control strategy (target resting heart rate <80 beats/ min and heart rate during moderate exercise <110 beats/min) 16. Two subsequent sub-studies of the RACE II trial showed that the stringency of rate control had no significant effect on the quality of life in patients with permanent AF 17 and that lenient rate control did not have an adverse effect on atrial and ventricular remodelling compared with strict rate control (although female gender was independently associated with significant adverse cardiac remodelling) 18. In another sub- 2014;9(1-2):13. Cardiologia CROATICA

14 podstudiji iz AFFIRM istraæivanja (Atrial Fibrillation Follow- Up Investigation of Rhythm Management) u kojoj su razmatrani kardiovaskularni ishodi, istraæivaëi su otkrili da je ukupna smrtnost ili bolniëko lijeëenje radi kardiovaskularnih dogaappleaja bilo bolje prilikom odabira kontrole frekvencije nego kontrole ritma (uporabom amiodarona ili sotalola) 19. Nekardiovaskularna smrt i boravak u jedinici intenzivne skrbi su bili uëestaliji kod bolesnika na terapiji amiodaronom uz kraêe vrijeme boravka u bolnici zbog kardiovaskularnog dogaappleaja. U prospektivnoj, randomiziranoj, otvorenoj studiji, Yamase i sur. 20 su u bolesnika s perzistentnom FA usporeappleivali farmakoloπku kardioverziju amiodaronom nasuprot bepridilom u 40 uzastopnih ispitanika. Bepridil je bio superioran u odnosu na amiodaron kod konverzije u sinusni ritam (85% naspram 35%; p< 0,05) i odræavanja sinusnog ritma nakon prosjeënog praêenja od 14,7 mjeseci (75% naspram 50%). Pitanje ima li PUFA pozitivan uëinak na FA i dalje ostaje jedno od tema. U velikoj meta-analizi koja ukljuëuju bolesnika iz 10 randomiziranih kontroliranih istraæivanja utvrappleeno je da dodatak PUFA nije imao znaëajan uëinak na prevenciju FA 21. U istraæivanju FORWARD (Randomised Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) 586 ambulantnih ispitanika s dokazanom simptomatskom paroksizmalnom FA koja je zahtijevala kardioverziju ili koji su imali najmanje dvije epizode FA u prethodnih 6 mjeseci je nasumiëno, podijeljeno na lijeëenje placebom ili PUFA (1 g/dan) tijekom 12 mjeseci 22. Dodatak PUFA nije smanjio recidive FA niti je bilo dobrobiti kod drugih prethodno definiranih zajedniëkih ishoda (ukupna smrtnost, ne-fatalni moædani udar, ne-fatalni akutni infarkt miokarda, sistemske embolije ili zatajivanje srca). U velikom placebo kontroliranom, randomiziranom kliniëkom istraæivanju koje je ukljuëivalo bolesnika u 28 centara, perioperativni dodatak PUFA nije dokazao smanjenje rizika od postoperativne FA, iako se dobro podnosio 23. Nasuprot tome, u drugom randomiziranom dvostruko slijepom placebom kontroliranom istraæivanju koje je ukljuëilo 199 bolesnika koji su primali PUFA (2 g/dan) ili placebo tijekom razdoblja od 4 tjedna prije elektrokardioverzije, utvrappleeno je tijekom jednogodiπnjeg praêenja da Êe se u sinusnom ritmu vjerojatnije zadræati bolesnici koji su primali PUFA 24. PraÊenje i procjena fibrilacije atrija Dijagnosticiranje paroksizmalne FA dostupnim dijagnostiëkim metodama i tehnologijom i danas moæe biti oteæano te se Ëine stalni napori u cilju poboljπanja metoda za detekciju i dijagnosticiranje. Paæljivijim praêenjem bolesnika i uporabom invazivnih i neinvazivnih metoda postoji sve znaëajnija povezanost subkliniëke FA i moædanog udara nejasne etiologije. U studiji provedenoj kod bolesnika u dobi od 65 godina ili viπe, s nedavno ugraappleenim elektrostimulatorom ili defibrilatorom i bez anamnestiëkog podatka o FA, otkrivene su subkliniëke atrijske tahiaritmije kod 261 bolesnika (10,1%) 25. Tijekom prosjeënog praêenja od 2,5 godine, otkriveno je da bolesnici sa subkliniëkim atrijskim tahiaritmijama imaju poveêan rizik od razvoja kliniëke FA, ishemijskog moædanog udara ili sistemske embolije (HR 2.49, 95% CI 1.28 do 4.85; p=0,007). Kod bolesnika bez elektrostimulatora ili defibrilatora koji su razvili moædani udar nejasne etiologije, trebalo bi razmotriti dugoroëno ambulantno praêenje elektrokardiograma vanjskim ili implantabilnim ureappleajima radi dijagnosticiranja subkliniëke FA 26,27. U studiji provedenoj kod 100 pacijenata radi detekcije FA, istraæivaëi su usporeappleivali uëinkovitost primjene 7-dnevnog study looking at cardiovascular outcomes in subjects from the original AFFIRM trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management), investigators found that the composite outcome of mortality or cardiovascular hospital stays was better in rate compared with rhythm control strategies (using amiodarone or sotalol) 19. Non-cardiovascular death and intensive care unit hospital stay were more frequent in patients on amiodarone, and time to cardiovascular hospital stay was shorter. In a prospective, randomised, open label trial of pharmacological cardioversion in patients with persistent AF, Yamase et al. 20 compared amiodarone with bepridil in 40 consecutive subjects. The investigators found that bepridil was superior to amiodarone in achieving sinus conversion (85% vs 35%; p<0.05) and maintaining sinus rhythm after an average follow-up of 14.7 months (75% vs 50%). The issue of whether PUFA have any beneficial effects on AF remains a topical one. A large meta-analysis of 10 randomised controlled trials involving 1,955 patients found that PUFA supplementation had no significant effect on AF prevention 21. In the FORWARD trial (Randomised Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation), 586 outpatient participants with confirmed symptomatic paroxysmal AF who required cardio-version or had at least two episodes of AF in the preceding 6 months were randomly assigned to receive placebo or PUFA (1 g/day) for 12 months 22. The investigators found that PUFA supplementation did not reduce the recurrence of AF or have any beneficial effects on the other prespecified end points (all cause mortality, non-fatal stroke, non-fatal acute myocardial infarction, systemic embolism or heart failure). In a large placebo controlled, randomised clinical trial involving 1,516 patients in 28 centres, perioperative supplementation of PUFA, although well tolerated, was not shown to reduce the risk of postoperative AF 23. In contrast, another randomised, double blind, placebo controlled trial involving 199 patients who received either PUFA (2 g/day) or placebo for 4 weeks before direct current (DC) cardioversion found that patients who received PUFA were more likely to be in sinus rhythm at 1 year follow-up compared with control patients 24. Monitoring and assessment of atrial fibrillation The detection of paroxysmal AF can be difficult with current methods and technology; hence ongoing efforts are being made to improve methods for detection and diagnosis. The association between subclinical AF and cryptogenic stroke has gained increasing prominence with more careful monitoring of patients using invasive and non-invasive methods. In a nice study of 2,580 patients aged 65 years or older with a pacemaker or defibrillator recently implanted and no history of AF, investigators detected subclinical atrial tachyarrhythmias in 261 patients (10.1%) 25. Over a mean follow-up of 2.5 years, patients with subclinical atrial tachyarrhythmias were found to have an increased risk of clinical AF and of ischaemic stroke or systemic embolism (HR 2.49, 95% CI 1.28 to 4.85; p=0.007). In patients who do not have pacemakers or defibrillators who present with cryptogenic stroke, longer term ambulatory ECG monitoring using external or implantable devices may be worth considering to help confirm a diagnosis of subclinical AF 26,27. In a study of 100 patients being screened for AF, investigators compared the effectiveness of using 7-day triggered ECG monitoring with 7-day continuous Holter ECG monito- Cardiologia CROATICA 2014;9(1-2):14.

15 dogaappleajima uvjetovanog praêenja elektrokardiorama sa 7- dnevnim kontinuiranim praêenjem holterom EKG 28. Aritmija je zabiljeæena u 42 ispitanika (42%) na holteru u odnosu na 37 ispitanika (32%) s dogaappleajima uvjetovanim praêenjem elektrokardiograma (p=0,56). Osjetljivost dogaappleajima uvjetovanog praêenja elektrokardiograma je niæa od one praêenjem holterom, uglavnom zbog kraêeg trajanja praêenja, iako je kvalitativna analiza dogaappleajima uvjetovanog praêenja zahtjevala manje vremena. U drugoj studiji od 647 bolesnika s implantabilnim ureappleajima za kontinuirano praêenje, utvrappleeno je da je isprekidano praêenje inferiornije u odnosu na kontinuirano praêenje i nije u stanju prepoznati recidiv FA kod velikog broja riziënih bolesnika 29. U zanimljivoj studiji u kojoj se istraæuje uporaba NT-proBNP radi ocijene nedavnog nastupa FA i sigurnosti kardioverzije, istraæitelji su podijelili 86 bolesnika s pretpostavljenim nedavnim nastupom FA u dvije skupine (43 u svakoj skupini) na temelju vrijednosti NTproBNP iznad i ispod graniëne vrijednosti te su svi ispitanici bili pregledani transezofagealnom ehokardiografijom 30. Normalne vrijednosti NT-proBNP bile su najjaëi prediktor prisutnosti tromba, πto ukazuje da bi kratkoroëni porast NTproBNP nakon poëetka FA mogao biti koristan u ocjeni nedavnog nastupa epizode FA, ako je nepoznat, a moæe se potencijalno koristiti radi utvrappleivanja sigurnosti kardioverzije. Kateterska ablacija fibrilacije atrija Iako su antiaritmici i kateterska ablacija izbori lijeëenja dostupni za odræavanje sinusnog ritma kod simptomatskih bolesnika s FA, mnogi lijeënici i bolesnici ipak inicijalno pribjegavaju konzervativnom pristupu i razmatraju katetersku ablaciju tek nakon πto isprobaju jedan ili viπe antiaritmika te utvrde njihovu neuëinkovitost. Pitanje je li kateterska ablacija FA uëinkovita kao poëetna terapija paroksizmalne FA je ispitana u maloj randomiziranoj studiji u kojoj je 294 bolesnika (bez da su prethodno koristili antiaritmike) randomizirano te je zapoëeto lijeëenje radiofrekventnom kateterskom ablacijom ili antiaritmicima I.c ili III. skupine 31. Nisu ustanovljene znaëajne razlike izmeappleu skupina u kumulativnom optereêenju FA (90. centila optereêenja aritmije 13% i 19%, odnosno, p=0,10) u prvih 18 mjeseci. Meappleutim, nakon 24 mjeseca optereêenje FA je bilo znaëajno niæe u skupini s ablacijom u usporedbi s onom na antiaritmicima (9% naspram 18%; p=0,007) te je manje bolesnika u skupini s ablacijom imalo simptomatsku FA (93% naspram 84%; p=0,01). U skupini koja je lijeëena lijekovima, 54 bolesnika (36%) je naknadno podvrgnuto ablaciji. U maloj randomiziranoj studiji ablacije FA kod bolesnika s perzistentnom FA, uznapredovalim zatajivanjem srca i teπkom sistoliëkom disfunkcijom lijeve klijetke (LV), MacDonald i sur. su otkrili su da je kateterska ablacija bila uspjeπna u uspostavi sinusnog ritma u 50% bolesnika, iako je postupak bio povezan sa znaëajnom stopom komplikacija (15%) 32. Kateterska ablacija takoappleer nije poboljπala sistoliëku funkciju lijeve klijetke (mjereno kardiovaskularnom magnetskom rezonancijom) ili neke druge sekundarne ishode te je dovela u pitanje omjer rizik/korist za ablaciju kod bolesnika s perzistentnom FA i disfunkcijom lijeve klijetke. U Euro Heart Survey (meappleunarodni multicentriëni registar) je kod bolesnika podvrgnutih ablaciji FA uspostava sinusnog ritma kateterskom ablacijom bila povezana s niæim rizikom od moædanog udara i smrti u usporedbi s kontrolnom skupinom lijeëenom farmakoloπki 33. ring for detection of AF 28. An arrhythmia was recorded in 42 subjects (42%) with continuous ECG recordings versus 37 subjects (32%) with triggered monitoring (p=0.56). The sensitivity of triggered ECG monitoring was found to be lower than that of continuous ECG monitoring, mainly due to a shorter effective monitoring duration, although qualitative triggered ECG analysis was less time consuming than continuous ECG analysis. In another larger study of 647 patients with implantable continuous monitoring devices, intermittent rhythm monitoring was found to be significantly inferior to continuous monitoring for the detection of AF and was not able to identify AF recurrence in a great proportion of patients at risk 29. In an interesting study investigating the use of N-terminal pro B-type natriuretic peptide (NT-proBNP) values to estimate the recency of AF onset and safety of cardioversion, investigators separated 86 patients presenting with presumed recent onset AF into two groups (43 in each group), based on NTproBNP concentrations above and below a cut-off value, and subjected all subjects to transoesophageal echocardiography 30. NT-proBNP concentrations below the cut-off value were found to be the most powerful predictor of the presence of thrombus, suggesting that a short term increase in NT-proBNP after AF onset might be useful in assessing the recency of onset of the AF episode, if unknown, and might be potentially used to help determine the safety of cardioversion. Catheter ablation of atrial fibrillation Although antiarrhythmic drugs (AADs) and catheter ablation are the main treatment options available to maintain sinus rhythm in symptomatic patients with AF, many clinicians and patients still opt for an initial conservative strategy and consider catheter ablation only after one or more AADs have been tried and found to be ineffective. The question of whether catheter ablation of AF is an effective initial therapy for paroxysmal AF was addressed in a small randomised study in which 294 patients (with no history of AAD use) were randomly assigned to an initial strategy with radiofrequency catheter ablation or therapy with a class 1c or III AAD 31. The investigators found no significant difference between the ablation and drug therapy groups in the cumulative burden of AF (90 th centile of arrhythmia burden 13% and 19%, respectively; p=0.10) in the initial 18 months. However, at 24 months, AF burden was significantly lower in the ablation group compared with the drug therapy group (9% vs 18%; p=0.007) and more patients in the ablation group were free from symptomatic AF (93% vs 84%; p=0.01). In the drug therapy group, 54 patients (36%) subsequently underwent ablation. In another small randomised study of AF ablation in patients with persistent AF, advanced heart failure and severe left ventricular (LV) systolic dysfunction, MacDonald et al. 32 found that catheter ablation was successful at restoring sinus rhythm in 50% of patients, although the procedure was associated with a significant complication rate of 15%. In addition, catheter ablation did not improve LV ejection fraction (LVEF) (as measured using cardiovascular magnetic resonance) or other secondary outcomes, calling into question the risk/benefit ratio of performing AF ablation in patients with persistent AF and LV dysfunction. An international multicentre registry study of 1,273 patients undergoing AF ablation suggested that maintenance of sinus rhythm through catheter ablation was associated with a lower risk of stroke and death compared with a control group consisting of medically treated patients with AF in the Euro Heart Survey ;9(1-2):15. Cardiologia CROATICA

16 Nekoliko nedavno objavljenih studija je unaprijedilo naπe razumijevanje Ëimbenika povezanih s uspjehom ili neuspjehom nakon ablacije FA. Miyazaki i sur. su dodano naglasili vaænost metode izolacije pluênih vena (PV) u bolesnika s paroksizmalnom i perzistentnom FA i povezanosti s dugoroënim kliniëkim ishodima kod 83,6% (480 od 574) bolesnika tijekom prosjeënog praêenja od 27±14 mjeseci 34. Kasni recidivi (6-12 mjeseci nakon prvog postupka ablacije FA) su bili povezani u svih bolesnika s ponovnom rekonekcijom PV, dok su vrlo kasni recidivi (>12 mjeseci nakon zahvata) bili nevezani s PV kod njih 85,7%. Prednost izvoappleenja dodatnih linearnih ablacijskih linija nakon izolacije PV na poboljπanje ishoda ablacije dodatno je ispitano u prospektivnoj, randomiziranoj studiji od 156 bolesnika s paroksizmalnom FA koji su randomizirani na izolaciju PV, izolaciju PV i krovne linije ili izolaciju PV, krovne i straænje inferiorne linije 35. Nije registrirana dodatna dobrobit mjerena kliniëkim ishodom kod bolesnika s uëinjenom izolacijom dodatnih linija, koja je znaëajno produæila vrijeme trajanja postupka. Veliki broj istraæivaëa utvrdio je da su mnogi Ëimbenici predvidivi i utjeëu na negativan ishod nakon ablacije pored veê poznatih Ëimbenika: vrste FA (paroksizmalna ili perzistentna), veliëine lijeve pretklijetke te prisustva disfunkcije lijeve klijetke. Od novih Ëimbenika to su oni povezani sa srcem atrijski elektromehaniëki interval mjeren pulsnim doplerom i ehokardiografski nalaz fibroze lijevog atrija mjeren kalibriranim integriranim povratnim rasprπenjem (cib) 37, perikardijalno masno tkivo 38, biomarkeri plazme (npr. B-tipa natriuretskog peptida) 39, disfunkcija bubrega 40 i metaboliëki sindrom 41. Prisutnost disociranih potencijala PV, Ëesto koriπten pokazatelj uspjeπne izolacije PV, nije predviappleao recidiv FA u studiji s ukljuëenih 89 uzastopnih bolesnika prosjeëno praêenih 21±8 mjeseci 42. U maloj randomizirano kontroliranoj studiji sa 161 bolesnika utvrappleeno je da tromjeseëno uzimanje kolhicina (2 x 0,5 mg) smanjuje rani recidiv FA nakon izolacije PV, vjerojatno zbog smanjenja upalnih medijatora, ukljuëujuêi interleukin 6 i C reaktivni protein 43. U multicentriënom dvostruko slijepom randomiziranom istraæivanju s 336 bolesnika utvrappleeno je da kolhicin (2 x 1 mg na poëetku, potom doza odræavanja od 2 x 0,5 mg tijekom mjesec dana) smanjuje uëestalost postoperativne FA i skraêuje duljinu hospitalizacije 44. U interesantnoj randomiziranoj studiji izolacije PV s i bez popratne denervacije renalne arterije kod 27 bolesnika s refraktornom simptomatskom FA i perzistentnom arterijskom hipertenzijom, Pokushalov i sur. su dokazali da je denervacija renalne arterije smanjila sistoliëki i dijastoliëki arterijski tlak te recidiv FA tijekom praêenja od godine dana 45. Drugo polje istraæivanja u podruëju ablacije FA bili su Ëimbenici povezani s poveêanim komplikacijama zbog postupka. Analizom podataka iz bolniëke baze podataka dræave Kalifornije, Shah i sur. su otkrili da je meappleu bolesnika koji su bili podvrgnuti poëetnom postupku ablacije FA, 5% imalo periproceduralne komplikacije (najëeπêe vaskularne), a 9% ih je ponovno primljeno u roku od 30 dana 46.»imbenici koji su bili povezani s poveêanim rizikom od komplikacija i/ili ponovnim prijemom u roku od 30 dana nakon ablacije FA su starija dob, æenski spol, prethodne hospitalizacije radi FA te nedavni bolniëki postupci. Prema rezultatima retrospektivne studije s ukljuëenih 565 bolesnika ljestvice CHADS2 i CHA2DS2-VASc predstavljaju korisne prediktore nuspojava nakon ablacije FA 47. Prvo randomizirano kliniëko istraæivanje u kojem se usporeappleivala uëinkovitost i sigurnost kateterske ablacije s kirurπkom ablacijom je ukljuëivalo 124 bolesnika s FA refraktornom na lijekove 48. IstraæivaËi su otkrili da je primarni ishod (bez aritmije dulje od 30 sekundi porijekla iz lijeve pretkli- Several studies have recently been reported which increase our understanding of the factors associated with success or failure following AF ablation. The importance of pulmonary vein (PV) isolation was further reinforced by Miyazaki et al. who reported long term clinic outcomes of 83.6% (480 out of 574 patients) with a mean follow-up of 27±14 months using an extensive PV isolation approach in patients with both paroxysmal and persistent AF 34. Late recurrences (defined as 6-12 months following the initial AF ablation procedure) was associated with PV reconnection in all patients, while very late recurrences (>12 months after the procedure) were associated with non-pv triggers in 85.7% of cases. The added benefit of performing additional linear ablation lines after PV isolation on improving outcomes following AF ablation has been further questioned in a prospective, randomised study of 156 patients with paroxysmal AF who were randomly assigned to undergo PV isolation only, PV isolation and a roof line, or PV isolation, roof line and a posterior inferior line 35. The investigators found no improvement in clinical outcome in the patients who received the additional lines while, unsurprisingly, the addition of the linear ablations significantly prolonged procedure times. A number of investigators have found that many factors are predictive of or adversely related to outcome following AF ablation in addition to well established factors, such as type of AF (paroxysmal or persistent), left atrial size, and presence of LV dysfunction. These novel factors include cardiac related factors, such as atrial electromechanical interval on pulse wave Doppler imaging 36 and left atrial fibrosis as assessed by measuring echo-cardiograph derived calibrated integrated backscatter 37, pericardial fat 38, plasma biomarkers (such as plasma B-type natriuretic peptide values 39, renal dysfunction 40, and the metabolic syndrome 41. Interestingly, the presence of dissociated PV potentials, often used as a marker of successful PV isolation, was not found to predict AF recurrence in a study of 89 consecutive patients over a mean follow-up of 21±8 months 42. In a small randomised controlled study of 161 patients, a 3 month course of colchicine (0.5 mg twice daily) was found to decrease early AF recurrence after PV isolation, probably due to a reduction in inflammatory mediators, including interleukin 6 (IL-6) and C reactive protein (CRP) 43. Colchicine (1.0 mg twice daily initially followed by a maintenance dose of 0.5 mg twice daily for 1 month) was also found to reduce the incidence of postoperative AF and decrease in-hospital stay in a multicentre, double blind, randomised trial of 336 patients 44. In an interesting small randomised study of PV isolation with and without concomitant renal artery denervation in 27 patients with refractory symptomatic AF and resistant hypertension, Pokushalov et al showed that renal artery denervation reduced systolic and diastolic blood pressure and reduced the recurrence of AF during 1 year follow-up 45. Another area of research in the field of AF ablation has been on the factors associated with increased complications from the procedure. Using data from the California State Inpatient Database, Shah et al. found that among 4,156 patients who underwent an initial AF ablation procedure, 5% had periprocedural complications (most commonly vascular) and 9% were readmitted within 30 days 46. Factors associated with a higher risk of complications and/or 30-day readmission following an AF ablation were older age, female sex, prior AF hospitalisations, and recent hospital procedure experience. In another retrospective study of 565 patients, both the CHADS2 and CHA2DS2-VASc scores were found to be useful predictors of adverse events following AF ablation 47. The first randomised clinical trial comparing the efficacy and safety of catheter ablation of AF with surgical ablation involved 124 patients with drug refractory AF 48. The investigators found that the primary end point (freedom from left at- Cardiologia CROATICA 2014;9(1-2):16.

17 jetke u osoba bez antiaritmika nakon 12 mjeseci) bio 36,5% za skupinu s kateterskom ablacijom i 65,6% za skupinu koja se podvrgava operaciji (p=0,0022). U skupini bolesnika podvrgnuti operaciji registirrano je znatno viπe nuspojava (uglavnom zbog komplikacija tijekom postupka operacije) u odnosu na skupinu s kateterskom ablacijom. Pison i sur. su kod 26 bolesnika s FA objavili relativno visoke stope uspjeha u prvoj godini (93% za paroksizmalnu i 90% za perzistentnu FA) primjenom kombiniranog transvenoznog endokardijalnog i transtorakalnog epikardijalnog pristupa za prvi postupak ablacije FA 49. Strategije smanjenja tromboembolije U posljednjih nekoliko godina je u porastu primjena novih oralnih antikoagulansa u bolesnika s FA s ciljem smanjenja rizika od moædanog udara i sistemske tromboembolije te se poveêava njihova prihvaêenost nakon objavljivanja brojnih znaëajnih multicentriënih randomiziranih kliniëkih studija u kojima se usporeappleuje njihova uëinkovitost s uobiëajenim antagonistima vitamina K Meta-analiza 12 studija s ukupno ukljuëenih ispitanika je pokazala znaëajno smanjenje intrakranijskog krvarenja s novim antikoagulansima u usporedbi s antagonistima vitamina K, kao i trend smanjenja velikih krvarenja 54. Novi oralni antikoagulansi mogu imati odreappleenu ulogu kod bolesnika podvrgnutih elektrokardioverziji. Podstudija istraæivanja RE-LY (Randomised Evaluation of Long-Term AnticoagulationTherapy) u kojoj su bolesnici s FA bili podvrgnuti kardioverziji je pokazala da je dabigatran (u dozama od 2 x 110 ili 2 x 150 mg) razumna alternativa varfarinu, s niskim zastupljenoπêu moædanog udara i velikih krvarenja u roku od 30 dana nakon kardioverzije 55. Novi oralni antikoagulansi takoappleer mogu imati odreappleenu ulogu u periproceduralnoj antikoagulaciji bolesnika podvrgnutih radiofrekventnoj ablaciji FA. Nekoliko studija dokazalo je da je dabigatran periproceduralno u bolesnika podvrgnutih ablaciji FA jednako siguran kao i varfarin 56-58, iako je jedna studija pokazala poveêan rizik od krvarenja i tromboembolijskih komplikacija 59. Da bi se definitivno razjasnilo pitanje mogu li se novi oralni antikoagulansi koristiti umjesto varfarina za periproceduralnu antikoagulaciju bolesnika podvrgnutih ablaciji FA potrebno je prospektivno randomizirano kontrolirano istraæivanje. Ekonomska evaluacija novih oralnih antikoagulansa ukazuju na to da mogu biti isplativi kao prva linija lijeëenja za prevenciju moædanog udara i sistemske embolije 60, osobito u bolesnika s visokim rizikom od krvarenja ili moædanog udara, osim u sluëaju da je kontrola INR s varfarinom bila izvrsna 61. Druga opcija za smanjenje uëestalosti tromboembolijskih dogaappleaja u bolesnika s FA koja sve viπe postaje znaëajnom je uporaba mehaniëkih okluzijskih ureappleaja za zatvaranje aurikule lijevog atrija (LAA). U analizi 14 studija, implantacija okluzijskih ureappleaja za zatvaranje LAA u bolesnika s FA bila je uspjeπna u 93% sluëajeva, s periproceduralnom smrtnoπêu i uëestalosti moædanog udara od 1,1% i 0,6%; ukupna uëestalost moædanog udara meappleu svim studijama je bila 1,4% godiπnje 62. Podstudija studije PROTECT AF (Percutaneous Closure of the LAA versus Warfarin Therapy for Prevention of Stroke in Patients with AF) objavila je da je 32% bolesnika s ugraappleenim ureappleajima na transezofagijskoj ehokardiografiji imalo odreappleeni stupanj protoka oko ureappleaja u razdoblju od 12 mjeseci, iako se ne Ëini da je to povezano s poveêanim rizikom od tromboembolije u odnosu na one bez protoka nakon ugradnje ureappleaja koji su prekinuli uzimanje varfarina 63. Analiza 34 studije paænju je usmjerila na utvrrial arrhythmia >30 s without AADs after 12 months) was 36.5% for the catheter ablation group and 65.6% for the surgical group (p=0.0022), but patients in the surgical group experienced significantly greater adverse effects (driven mainly by procedural complications) compared to the catheter ablation group. Pison et al reported relatively high 1 year success rates (93% for paroxysmal AF and 90% for persistent AF) with a combined transvenous endo-cardial and thorascopic epicardial approach for a single AF ablation procedure in a small cohort of 26 patients with AF 49. Strategies to decrease thromboembolism The use of novel oral anticoagulants to decrease the risk of stroke and systemic thromboembolism in patients with AF has gained increasing use and acceptance over the past several years following the publication of a number of landmark multicentre, randomised clinical trials comparing their efficacy with conventional vitamin K antagonists A metaanalysis of 12 studies totalling 54,875 patients showed a significant reduction of intracranial haemorrhage with these novel anticoagulants compared with vitamin K antagonists, and a trend toward reduced major bleeding 54. These novel oral anticoagulants may also have a role in patients undergoing DC cardioversion. A sub-study of patients with AF who underwent cardioversion in the RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) trial showed that dabigatran (at two doses of 110 and 150 mg twice daily) is a reasonable alternative to warfarin, with low frequencies of stroke and major bleeding within 30 days of cardioversion 55. These novel oral anticoagulants may also have a role to play in the periprocedural anticoagulation of patients undergoing radiofrequency ablation for AF. Several registry and observational studies have suggested that dabigatran is as safe as periprocedural warfarin in patients undergoing AF ablation 56-58, although one study suggested an increased risk of bleeding and thromboembolic complications with dabigatran compared with warfarin 59. A prospective randomised controlled trial is required to definitively address the issue as to whether these novel oral anticoagulants can be used in place of warfarin for periprocedural anticoagulation in patients undergoing AF ablation. Economic evaluation of these novel oral anticoagulants suggest that they may be cost effective as a first line treatment for the prevention of stroke and systemic embolism 60, especially in patients at high risk of haemorrhage or stroke, unless international normalised ratio (INR) control with warfarin is already excellent 61. Another strategy to decrease thromboembolic events in patients with AF that is gaining favour involves the use of mechanical left atrial appendage (LAA) occlusion devices. In a systematic review of 14 studies, implantation of LAA occlusion devices in patients with AF was successful in 93% of cases, with periprocedural mortality and stroke rates of 1.1% and 0.6%, respectively; the overall incidence of stroke among all studies was 1.4% per annum 62. A substudy of the PROTECT AF (Percutaneous Closure of the LAA versus Warfarin Therapy for Prevention of Stroke in Patients with AF) study reported that 32% of implanted patients had some degree of peridevice flow at 12 months on transoesophageal echocardiography, although this did not appear to be associated with an increased risk of thromboembolism compared to patients with no peridevice flow who discontinued warfarin 63. A systematic review aimed at determining which subgroups of patients would benefit most from LAA closure devices looked at the location of atrial thrombi in patients with 2014;9(1-2):17. Cardiologia CROATICA

18 appleivanje koje podskupine bolesnika bi imale najviπe koristi od ureappleaja za zatvaranje LAA analizirajuêi lokalizaciju atrijskih tromba kod bolesnika s FA 64. ZakljuËili su da bolesnici s nevalvularnom FA mogu imati veêu dobrobit od zatvaranja LAA; 56% bolesnika s valvularnom FA su imali trombe u atriju smjeπtene izvan LAA, 22% u mjeπovitim kohortama i kod 11% bolesnika s nevalvularnom FA. RESINKRONIZACIJSKA TERAPIJA I ELEKTROSTIMULACIJA Resinkronizacijska terapija U nedavnom istraæivanju iz podruëja resinkronizacijske terapije (CRT) prouëavali su se dugoroëni uëinci CRT elektrostimulacije na funkciju lijeve klijetke (LV) i desne klijetke (DV) i koje podskupine bolesnika mogu imati najveêu dobrobit od lijeëenja primjenom CRT.»ini se da je povoljni odgovor DV na CRT povezan s veêom uëestalosti preæivljavanja kod bolesnika s CRT ureappleajima; a i utvrdilo se u studiji od 848 bolesnika koji su primili CRT da je funkcija DV neovisan prediktor dugoroënog ishoda 65. Nakon vaæne MADIT-CRT studije (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronisation Therapy) koja je pokazala da je CRT u kombinaciji s implantabilnim kardioverter-defibrilatorom (ICD, CRT-D) smanjio rizik od zatajivanja srca kod relativno asimptomatskih bolesnika s niskom sistoliëkom funkcijom i πirokim QRS kompleksom 66, veliki broj naknadnih analiza je donio dodatne zanimljive informacije. To ukljuëuje podatke o utjecaju CRT na smanjenje broja epizoda srëanog zatajivanja 67 i atrijskih aritmija 68, utvrappleivanje dodatnih Ëimbenika koji su povezani s poboljπanim odgovorom na CRT 69,70 i s izvrsnim odgovorom (definiranog gornjim kvartilom promjene sistoliëke funkcije LV) 71, Ëimbenike povezane s najboljim poboljπanjem kvalitete æivota 72, kao i informacije o optimalnom pozicioniranju elektrode u LV 73,74. U prospektivnoj, randomiziranoj kontroliranoj studiji Diab i sur. 75 su utvrdili da bolesnici s prisustvom ehokardiografski utvrappleene disinkronije klijetki imaju najbolji terapijski odgovor na CRT, iako su i bolesnici bez disinkronije s ugraappleenim CRT takoappleer imali veêu korist u odnosu na one bez ugradnje. Autori su zakljuëili da se posljednje spomenutoj skupini bolesnika CRT takoappleer ne bi trebao uskratiti.»ini se da CRT dovodi do odreappleenog poboljπanja kod bolesnika sa zatajivanjem srca i normalnim trajanjem QRS kompleksa, pri Ëemu bolesnici navode poboljπanje simptoma, bolju toleranciju napora i kvalitetu æivota, iako nije bilo razlike u ukupnoj ili kardiovaskularnoj smrtnosti izmeappleu skupina s CRT i onih s optimalnom medikamentoznom terapijom 76. Meappleu bolesnicima sa zatajivanjem srca i produljenim trajanjem QRS kompleksa koji su dobili CRT ureappleaj, veêu su korist (manji rizik od ventrikulskih aritmija i smrti te poboljπane ehokardiografske varijable) imali bolesnici s morfologijom bloka lijeve grane u usporedbi s onima koji nisu imali takav oblik QRS kompleksa (blok desne grane ili poremeêaje intraventrikularnog provoappleenja) 77. U prospektivnoj randomiziranoj multicentriënoj studiji provedenoj sa 186 bolesnika ispitivalo se da li je u bolesnika s permanentnom FA i ablacijom atrioventrikularnog Ëvora (AV) terapija primjenom CRT superiorna u odnosu na konvencionalnu elektrostimulaciju DV u smanjenju epizoda zatajivanja srca 78. Tijekom prosjeënog praêenja od 20 mjeseci (IQR 11 do 24 mjeseci) u skupini sa CRT manje je bolesnika (11%) razvilo primarni ishod (smrt, hospitalizacija ili pogorπanje zatajivanja srca) u usporedbi sa skupinom na elek- AF in a total of 34 studies 64. The investigators concluded that patients with non-valvular AF may derive greater benefit from LAA closure devices 56% of patients with valvular AF had atrial thrombi located outside the LAA, 22% in mixed cohorts and 11% in non-valvular AF patients. CARDIAC RESYNCHRONISATION THERAPY AND PACING Cardiac resynchronisation therapy Recent research in the area of cardiac resynchronisation therapy (CRT) has looked at the long term effects of CRT pacing on LV and right ventricular (RV) function and further into which subgroups of patients may derive greatest benefit from CRT pacing. A favourable RV functional response to CRT appears to be associated with improved survival in patients with CRT devices, and RV function was found to be an independent predictor of long term outcome after CRT insertion in a study of 848 CRT recipients 65. Following the landmark MADIT-CRT (Multi-center Automatic Defibrillator Implantation Trial-Cardiac Resynchronisation Therapy) study, which demonstrated that CRT combined with implantable cardioverter defibrillator (ICD, CRT-D) decreased the risk of heart failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complexes 66, a number of subsequent analyses have provided further interesting information. This includes data on the benefits of CRT in reducing the risk of recurring heart failure events 67 and atrial arrhythmias 68, identification of additional factors that are associated with improved response to CRT 69,70 and with a super-response (defined by patients in the top quartile of LVEF change) 71, factors associated with greatest improvement in quality of life 72, and information on optimal lead positioning of the LV lead 73,74. In a prospective, randomised controlled study to address whether ventricular dyssynchrony on echocardiography predicted response to CRT, Diab et al 75 found that the presence of echocardiographic dyssynchrony identified patients who derived the most improvement from CRT, although patients without dyssynchrony also showed more benefit and less deterioration with CRT than without. The authors concluded that the latter group of patients should not be denied CRT. CRT appeared to produce some benefits in patients with heart failure and a normal QRS duration, with patients experiencing an improvement in symptoms, exercise capacity and quality of life, although there was no difference in total or cardiovascular mortality in patients who received CRT compared with those receiving optimal pharmacological management 76. Among patients with heart failure and prolonged QRS duration who received a CRT device, those with a left bundle branch block (LBBB) morphology derived greater benefit (lower risk of ventricular arrhythmias and death and improved echocardiographic parameters) compared with patients who had a non-lbbb QRS pattern (right bundle branch block (RBBB) or intraventricular conduction disturbances) 77. The issue of whether CRT in patients undergoing atrioventricular (AV) junction ablation for permanent AF was superior to conventional RV pacing in reducing heart failure events was addressed in a prospective, randomised, multicentre study involving 186 patients 78. Over a median follow-up of 20 months (IQR months) fewer patients in the CRT group (11%) experienced primary end point events (death from heart failure, hospitalisation due to heart failure or worsening Cardiologia CROATICA 2014;9(1-2):18.

19 trostimulaciji DV (26%; CRT naspram DV skupine: SHR 0.37, 95% CI ; p=0,005). Ukupna smrtnost je bila sliëna u obje skupine. U analizi praêenja koja se bavila prediktorima kliniëkog poboljπanja nakon strategije ablirati i elektrostimulirati, viπe je bolesnika u CRT skupini reagiralo na lijeëenje (83% naspram 63% u DV skupini) 79. Utvrappleeno je su CRT mod i eho-optimizirani CRT ureappleaj jedini nezavisni protektivni Ëimbenici protiv loπeg odgovora (HR=0.24, 95% CI , p=0.001 i HR=0.22, 95% CI , p=0,018). U istraæivanju PACE (Pacing to Avoid Cardiac Enlargement), elektrostimulacija DV je u bolesnika s bradikardijom i oëuvanim sistoliëkom funkcijom LV bila povezana s nepovoljnim remodeliranjem LV i pogorπanjem sistoliëke funkcije u drugoj godini, πto se sprjeëavalo biventrikularnom elektrostimulacijom 80. SrËani blokovi i elektrostimulatori U retrospektivnoj kohortnoj studiji s 299 bolesnika ispitivalo se preæivljavanje bolesnika starije æivotne dobi (prosjeëna dob 75±9 godina) s AV blokom II. stupnja tip Mobitz I. 81. Tijekom razdoblja praêenja srëani implantabilni elektroniëki ureappleaji (CIED) bili ugraappleeni u 141 bolesnika (47%), od Ëega je bilo 17 ICD. Bolesnici s CIED su imali veêi kardioloπkii komorbiditet u odnosu na one bez, iako je ugradnja CIED bila povezana s 46% smanjenjem smrtnosti (HR 0.54, 95% CI ; p=0,004). Van Geldrop i sur. 82 su u opservacijskoj studiji o utjecaju mjesta ventrikulske elektrostimulacije na funkciju LV u djece s AV blokom, otkrili da je frakcija skra- Êenja LV veêa kod elektrostimulacije LV nego DV 82. Daljnja istraæivanja na temu da li je elektrostimulacija srca korisna u bolesnika s neuroloπki posredovanom sinkopom upuêuju na to da dvokomorna elektrostimulacija moæe biti korisna u bolesnika s teπkim asistolijom. U randomiziranom multicentriënom istraæivanju ISSUE-3 (Third International Study on Syncope of Uncertain Aetiology) bolesnici sa sinkopom zbog asistolije dokumentirane implantabilnim loop rekorderom nasumiëno su raspodjeljeni u skupine s dvokomornim elektrostimulatorom reprogramiranim na program za nagli pad frekvencije ili samo na osjeêanje (engl. sensing) 83. Oni s dvokomornom elektrostimulacijom su imali manji broj epizoda sinkopa tijekom razdoblja praêenja (32% apsolutno i 57% relativno smanjenje sinkopa). Pokazalo se da pozitivan test s intravenozno primjenjenim adenozin 50- trifosfatom korelira s podskupinom bolesnika s neuroloπki posredovanom sinkopom 84. Randomizirano multicentriëno istraæivanje potencijalne koristi testa adenozin 50-trifosfatom u starijih bolesnika (prosjeëna dob 75,9±7,7 godina) sa sinkopom nepoznatog podrijetla pokazalo je da je aktivna dvokomorna elektrostimulacija kod onih s pozitivnim testom smanjila rizik od recidiva sinkope za 75% (95% CI 44%- 88%) 85. Podaci na malom uzorku od 18 bolesnika s recidivirajuêim sinkopama o dugoroënom ishodu (praêenje do 14 godina) glede razliëitih tipova AV blokova, pri Ëemu niti jedan bolesnik nije imao stalni ili paroksizmalni AV blok koji se ne moæe objasniti trenutno poznatim mehanizmima, ukazuju na to da ovi bolesnici mogu imati koristi od elektrostimulacije srca 86. Na temelju podataka danskog nacionalnog registra koji je ukljuëio bolesnika sa sinkopom i kontrola usklaappleenih prema dobi i spolu, prouëavani su ishodi kod zdravih osoba primljenih zbog prve epizode sinkope 87. Bolesnici koji su bili primljeni zbog sinkope su imali znaëajno veêu ukupnu smrtnost, uëestalije kardiovaskularne hospitalizacije, recidive sinkopa i moædane udare te su im kasnije ËeπÊe ugraappleivani elektrostimulatori ili ICD. heart failure) compared with patients in the RV group (26%; CRT vs RV group: sub-hazard ratio (SHR) 0.37, 95% CI 0.18 to 0.73; p=0.005). Total mortality was similar in both groups. In a follow-up analysis looking at the predictors of clinical improvement after the ablate and pace strategy, more patients in the CRT group responded to treatment (83% vs 63% in the RV group) 79. CRT mode and echo-optimised CRT were found to be the only independent protective factors against nonresponse (HR=0.24, 95% CI 0.10 to 0.58, p=0.001 and HR=0.22, 95% CI 0.07 to 0.77, p=0.018, respectively). In the PACE (Pacing to Avoid Cardiac Enlargement) trial, RV pacing in patients with bradycardia and preserved LVEF was associated with adverse LV remodelling and deterioration of systolic function at the second year, which was prevented by biventricular pacing 80. Heart block and pacemakers The long term survival of older patients (average age 75±9 years) with Mobitz I second degree AV block was examined in a retrospective cohort study of 299 patients 81. The investigators found that 141 patients (47%) had a cardiac implantable electronic device (CIED) inserted during the follow-up period, of which 17 were ICDs. Patients with a CIED had greater cardiac comorbidity than those without a CIED, although CIED implantation was associated with a 46% reduction in mortality (HR 0.54, 95% CI 0.35 to 0.82; p=0.004). In another observational study of the impact of the ventricular pacing site on LV function in children with AV block, van Geldrop et al. found that LV fractional shortening was significantly higher with LV pacing than with RV pacing 82. Further research on the topic of whether cardiac pacing is beneficial in patients with neurally mediated syncope suggests that dual chamber pacing may be useful in patients with severe asystolic forms. In the randomised multicentre ISSUE-3 trial (Third International Study on Syncope of Uncertain Aetiology) patients with syncope due to documented asystole on an implantable loop recorder were randomly assigned to dual chamber pacing with rate drop response or to sensing only 83. Those assigned to dual chamber pacing had fewer syncopal episodes during follow-up (32% absolute and 57% relative reduction in syncope). A positive test with intravenous adenosine 50-triphosphate has been shown to correlate with a subset of patients with neurally mediated syncope 84. A randomised, multicentre trial of the potential benefit of the ATP test in elderly patients (mean age 75.9±7.7 years) with syncope of unknown origin reported that active dual chamber pacing in those with a positive ATP test reduced syncope recurrence risk by 75% (95% CI 44% to 88%) 85. Long term outcome data on a distinct form of AV block, paroxysmal AV block, which cannot be explained by currently known mechanisms, suggest that these patients have a long history of recurrent syncope and may benefit from cardiac pacing, although in a small series of 18 patients (followed up for up to 14 years), no patient had permanent AV block 86. The prognosis among healthy individuals admitted with their first episode of syncope was studied in a Danish nationwide registry involving 37,017 patients with syncope and 185,085 age and sex matched controls 87. Patients who were admitted with syncope had significantly increased all cause mortality, cardiovascular hospitalisation, recurrent syncope and stroke event rates and were more likely to have a pacemaker or ICD inserted later. 2014;9(1-2):19. Cardiologia CROATICA

20 Infekcija povezana sa srëanim implantabilnim elektroniëkim ureappleajima Infekcije povezana sa CIED su prepoznate kao znaëajan uzrok morbiditeta, mortaliteta i poveêanih zdravstvenih troπkova. Prospektivno kohortno istraæivanje International Collaboration on Endocarditis-Prospective Cohort Study (ICE- PCE) ukljuëilo je 61 centar u 28 zemalja, a analizirane su kliniëke znaëajke, ishod i utjecaj infekcija povezanih sa CIED i endokarditisa 88. BolniËke i jednogodiπnje stope smrtnosti su bile 14,7% (95% CI 9.8%-20.8%) i 23,2% (95% CI 17,2%-30,1%). UËestalost istodobne infekcije zaliska je bila visoka (kod 66 bolesnika, 37.3%, 95% CI 30.2%-44.9%), a rano uklanjanje ureappleaja je bilo povezano s poboljπanjem preæivljavanja u razdoblju od jedne godine. U pokuπaju da se ocjene dugoroëni ishodi i prediktori smrtnosti kod bolesnika lijeëenih prema vaæeêim preporukama za infekciju povezanu s CIED, Deharo i sur. 89 su proveli kohortnu studiju na dvije podudarne skupine sa 197 sluëajeva infekcije povezane s CIED. DugoroËna uëestalost smrtnosti su bile sliëne meappleu skupinama (14,3% naspram 11,0% u razdoblju od jedne godine i 35,4% naspram 27,0% u petogodiπnjem razdoblju; obje p=ns). Neovisni prediktori dugoroëne smrtnosti su starija dob, CRT, trombocitopenija i bubreæno zatajenje. U drugoj studiji u kojoj se istraæivalo da li je vrijeme novog postupka ugradnje CIED utjecalo na kliniëku sliku i ishod endokarditisa povezanog s implantiranom elektrodom, istraæivaëi su otkrili da je rani endokarditis povezan s elektrodom popraêen znacima i simptomima lokalne infekcije dæepa, dok je udaljeni izvor bakteremije bio prisutan u 38% kasnih endokarditisa povezanih s elektrodom, ali samo 8% ranih 90. BolniËka smrtnosti je bila niska (rana 7%; kasna 6%). VENTRIKULSKE ARITMIJE I IZNENADNA SR»ANA SMRT Epidemiologija iznenadne srëane smrti Iznenadna smrt je Ëest i dobro poznat rizik u bolesnika nakon infarkta miokarda. U studiji u kojoj su se analizirali podaci bolesnika iz istraæivanja VALIANT (Valsartan in Acute Myocardial Infarction Trial) koji su doæivjeli iznenadnu smrt, istraæivaëi su otkrili da se visok udio smrtnih sluëajeva dogodio kod kuêe, iako su se bolniëki ishodi deπavali ranije 91. Bolesnici koji su zaspali najverojatnije su imali ovakve neosvjedoëene dogaappleaje. Iako iznenadna srëana smrt (SCD) i koronarna bolest srca (KBS) imaju mnogo zajedniëkih Ëimbenika rizika, neki kliniëki i elektrokardiografski parametri mogu biti korisni u izdvajanju ova dva stanja. Primjerice, iz podataka studije ARIC (Atherosclerosis Risk in Communitiesi) i Cardiovascular Health Study s sudionika, Soliman i sur. 92 su utvrdili da su, nakon prilagodbe uobiëajenih Ëimbenika rizika za KBS, hipertenzija, poviπena srëana frekvencija, produljenje QTc intervala i abnormalno invertirani T valovi znaëajniji prediktori visokog rizika SCD. U usporedbi s tim, poviπena visina ST-segmenta (mjereno na toëci J i 60 ms nakon J toëke) jaëi prediktor visokog rizika za KBS. Viπe istraæivanja o SCD je takoappleer bilo provedeno u drugim podskupinama. U francuskom prospektivnom nacionalnom istraæivanju SCD u sportu provedenom od do godine, koje je ukljuëivalo ispitanike od 10 do 75 godine æivota, istraæivaëi su utvrdili da je ukupno optereêenje od iznenadne smrti u godinu dana iznosi 4.6 na milijun osoba, sa Cardiac implantable electronic device related infection CIED infection is recognised as a significant cause of morbidity, mortality, and increased healthcare costs. The clinical characteristics, outcome, and health care implications of CIED related infections and endocarditis was analysed in a prospective cohort study using data from the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCE) involving 61 centres in 28 countries 88. CIED infection was diagnosed in 177 out of 2760 patients (6.4%). In-hospital and 1 year mortality rates were 14.7% (95% CI 9.8% to 20.8%) and 23.2% (95% CI 17.2% to 30.1%), respectively. The rate of concomitant valve infection was high (found in 66 patients, 37.3%, 95% CI 30.2% to 44.9%) and early device removal was associated with improved survival at 1 year. In an attempt to assess the long term outcomes and predictors of mortality in patients treated according to current recommendations for CIED infection, Deharo et al. 89 conducted a two-group matched cohort study of 197 cases of CIED infection. Long term mortality rates were similar between cases and matched controls (14.3% vs 11.0% at 1 year and 35.4% vs 27.0% at 5 years, respectively; both p=ns). Independent predictors of long term mortality were older age, CRT, thrombocytopenia, and renal insufficiency. In another study examining whether the timing of the most recent CIED procedure influenced the clinical presentation and outcome of lead associated endocarditis (LAE), investigators found that early LAE presented with signs and symptoms of local pocket infection, whereas a remote source of bacteraemia was present in 38% of late LAE but only 8% of early LAE 90. In-hospital mortality was low (early 7%; late 6%). VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH Epidemiology of sudden cardiac death Sudden death is a frequent and well recognised risk in patients following myocardial infarction. In a study analysing data from 1,067 patients from VALIANT (Valsartan in Acute Myocardial Infarction Trial) who had sudden death, investigators found that a high proportion of the deaths occurred at home, although in-hospital events were more common early on 91. Patients who were asleep were more likely to have unwitnessed events. Although sudden cardiac death (SCD) and coronary artery disease (CAD) have many risk factors in common, certain clinical and electrocardiographic parameters may be useful to help separate out the two risks. For example, in a study of 18,497 participants from the ARIC (Atherosclerosis Risk in Communities) study and the Cardiovascular Health Study, Soliman et al. 92 found that after adjusting for common CAD risk factors, hypertension, increased heart rate, QTc prolongation, and abnormally inverted T waves were found to be stronger predictors of high SCD risk. In comparison, elevated ST segment height (measured at both the J point and 60 ms after the J point) was found to be more predictive of high incident CAD risk. More research has also been performed on SCD in other subgroups. In a prospective, national survey of sports related sudden death performed in France from 2005 to 2010, involving subjects years of age, investigators found that the overall burden of sudden death was 4.6 per million population per year, with 6% of cases occurring in young Cardiologia CROATICA 2014;9(1-2):20.

21 6% sluëajeva kod mladih profesionalnih sportaπa. Viπe od 90% sluëajeva se javlja u rekreativnom sportu 93. PoËetna kardiopulmonalna reanimacija (CPR) od strane prolaznika i defibrilacija bili su najjaëi neovisni prediktori za preæivljavanje do otpusta iz bolnice, iako je CPR od prolaznika pokrenut tek u jednoj treêini sluëajeva. U retrospektivnoj studiji u kojoj su provedene obdukcije na 902 mlade osobe (prosjeëne dobi 38±11 godina) koji su preboljeli netraumatsku iznenadnu smrt, uzrok iznenadne smrti se pripisao srëanoj patologiji kod 715 (79,3%) i neobjaπnjivom uzroku kod 187 osoba (20,7%) 94. U drugoj nacionalnoj studiji o uëestalosti SCD kod osoba u dobi od 1 do 35 godina, 7% svih smrtnih ishoda se pripisivalo SCD 95. Pojava SCD kod mladih procijenjena na 2,8% na osobagodina i viπa je nego πto se je ranije navodilo.»imbenici rizika za SCD kod æena u postmenopauzi mogu ukljuëivati viπe novih varijabli, kao πto su viπi puls, viπi omjer struk-bokovi, poviπen broj leukocita i etniëka pripadnost (afriëki Amerikanci imaju veêi rizik), kao i tradicionalne Ëimbenike rizika 96. Provedeno je intenzivnije istraæivanje u razliëitim okruæenjima o sindromu rane repolarizacije buduêi da su znaëajne studije pokazale vezu s idiopatskom ventrikularnom fibrilacijom i iznenadnom smrti 97,98. One su ukljuëivale studije o sindromu rane repolarizacije kod preæivjelih sa srëanim zastojem i oëuvanom sistoliëkom funkcijom 99, u obiteljima sa sindromom iznenadne aritmogene smrti 100 i drugim obiteljima s obrascem rane repolarizacije u EKG 101 te u azijskim populacijama 102. Meappleutim, joπ uvijek postoje kontroverze o toënom kliniëkom znaëaju i posljedicama tih EKG nalaza 103,104. Nasljedna srëana stanja i Ëinjenica kako odreappleeni genotipovi mogu dovesti do kliniëkih manifestacija bolesti i dalje privlaëe veliki interes te utjeëu na zbrinjavanje i shvaêanje rizika SCD Rezultati studije DARE (Drug-induced Arrhythmia Risk Evaluation), u kojoj je ispitano 167 pojedinaënih polimorfizma nukleotida koji obuhvaêaju gen NOS1AP, kod 58 ispitanika bijele rase koji su imali QT prolongaciju induciranu lijekovima i 87 kontrolnih ispitanika bijele rase, pokazali su da su uobiëajene varijacije gena NAS1AP bile povezane sa znaëajnim poveêanjem uëestalosti sindroma dugog QT induciranog lijekovima 109. To Êe imati kliniëke posljedice za buduêe farmakogenomsko testiranje kod bolesnika koji imaju rizik od lijekovima induciranog sindroma produljenja QT intervala. U drugoj studiji u kojoj se ocjenjuje da li su nekardiovaskularni herg (human Ether a go-go-related Gene) blokatori kanala povezani s poveêanim rizikom od SCD u opêoj populaciji, istraæitelji su usporedili sluëajeva SCD sa sluëaja u kontrolnim skupinama 110. Utvrappleeno je da je koriπtenje herg blokatora kanala bilo povezano s poveêanim rizikom od SCD; lijekovi s visokom sposobnoπêu inhibiranja herg kanala su imali viπi rizik za SCD nego oni za niskom sposobnoπêu inhibiranja. Impantibilni kardioverter defibrilatori U retrospektivnoj studiji s 900 bolesnika ocjenjivani su kliniëki parametri povezani uz smrt bolesnika s ishemijskom bolesti srca prije terapije ICD s onima kojima je implantiran ICD zbog primarne prevencije 111. IstraæivaËi su utvrdili da su znaëajni nezavisni prediktori smrti bolesnika bez odgovarajuêe terapije s ICD; funkcijska klasa NYHA III, poodmakla dob, πeêerna bolest, istisna frakcija LV 25% i prethodno puπenje, uz napomenu da ove informacije mogu olakπati procjenu rizika kod bolesnika. Drugi algoritam za predviappleanje akutnih proceduralnih komplikacija ili smrti nakon ugradnje ICD koristi 10 dostupnih varijabli dobivenih nakon competitive athletes and more than 90% of cases occurring in the context of recreational sports 93. Bystander cardiopulmonary resuscitation (CPR) and initial use of cardiac defibrillation were the strongest independent predictors for survival to hospital discharge, although bystander CPR was only initiated in one third of cases. In a retrospective autopsy study of 902 young adults (mean age 38±11 years) who had suffered non-traumatic sudden death, the cause of sudden death was attributed to a cardiac condition in 715 (79.3%) and unexplained in 187 (20.7%) 94. In another nationwide study on the incidence of SCD in persons aged 1-35 years, 7% of all deaths were attributed to SCD 95. The incidence of SCD in the young, estimated to be 2.8% per 100,000 person-years, was higher than previously reported. Risk factors for SCD in post-menopausal women may include more novel parameters, such as higher pulse, higher waist-to-hip ratio, elevated white blood cell count, and ethnicity (African Americans having a higher risk) as well as traditional risk factors 96. More intense research has been conducted in a variety of settings on the early repolarisation syndrome (ERS) since landmark studies showed a link with idiopathic ventricular fibrillation and sudden death 97,98. These include studies on ERS on cardiac arrest survivors with preserved ejection fraction 99, in families with sudden arrhythmic death syndrome 100 and other families with an early repolarisation pattern on the ECG 101, and in Asian populations 102. However, there is still some controversy over the exact clinical significance of these ECG findings and what the implications are 103,104. The genetics of inherited cardiac conditions and how specific genotypes can lead to clinical manifestations of disease, affect SCD risk or guide management continues to attract intense interest Results from the DARE (Drug-induced Arrhythmia Risk Evaluation) study, in which 167 single nucleotide polymorphisms spanning the NOS1AP gene, were evaluated in 58 Caucasian patients who had experienced drug induced QT prolongation and 87 Caucasian controls, demonstrated that common variations in the NOS1AP gene were associated with a significant increase in drug induced long QT syndrome 109. This may have clinical implications for future pharmacogenomics testing in patients at risk of drug induced long QT syndrome and safer prescribing. In another study assessing whether non-cardiovascular herg (human Ether a go-go-related Gene) channel blockers are associated with an increased risk of SCD in the general population, investigators compared 1,424 cases of SCD with 14,443 controls 110. Use of herg channel blockers was found to be associated with an increased risk of SCD and drugs with a high herg channel inhibiting capacity had a higher risk of SCD than those with a low herg channel inhibiting capacity. Implantable cardioverter defibrillators The clinical parameters associated with death before appropriate ICD therapy in patients with ischaemic heart disease who had an ICD inserted for primary prevention were assessed in a retrospective cohort study of 900 patients 111. The investigators found that New York Heart Association (NYHA) functional class III, advanced age, diabetes mellitus, LVEF 25%, and a history of smoking were significant independent predictors of death without appropriate ICD therapy, and suggested that this information may facilitate a more patient tailored risk estimation. Another risk score for predicting acute procedural complications or death after ICD 2014;9(1-2):21. Cardiologia CROATICA

22 implantacija te je napravljen kako bi se osigurale korisne informacije lijeënicima u selekciji bolesnika i odreappleivanju intenziteta skrbi nakon ugradnje 112. U studiji MADIT- II 113 kod bolesnika je primijenjena procjena rizika usmjerena na predviappleanje dugoroëne (8 godiπnje) koristi ugradnje ICD-a u primarnoj prevenciji. Bolesnici s niskim i srednjim rizikom (0 ili 1-2 Ëimbenika rizika) imali su viπe koristi od ugradnje ICD u usporedbi s bolesnicima s visokim rizikom ( 3 Ëimbenika rizika) koji su imali viπestruke komorbiditete i kod kojih nije bilo znaëajne razlike u osmogodiπnjem preæivljavanju izmeappleu onih s implantiranim ICD i onima bez njega. Izraappleen je algoritam za predviappleanje smrtnosti kod bolesnika kojima je implantiran ICD u primarnoj prevenciji na korisnicima Medicare od bolesnika uz potvrdu na skupini od bolesnika 114. Tijekom prosjeënog praêenja od 4 godine, (37,5%) bolesnika u kontrolnoj i (30,8%) bolesnika u promatranoj skupini je umrlo. Sedam kliniëkih relevantnih prediktora smrtnosti je utvrappleeno i koriπteno za izradu modela kod odreappleivanja onih bolesnika s najveêim rizikom od smrti nakon ugradnje ICD. Odabir bolesnika za implantaciju ICD u primarnoj prevenciji se u buduênosti stoga mora promijeniti te se osobno prilagoditi omjer rizik/koristi za pojedinog bolesnika, a ne se prema preporukama vaæeêih smjernica uglavnom voditi sistoliëkom funkcijom LV. Ostala istraæivanja, poput oslikavanja srca magnetskom rezonancom (CMR) radi utvrappleivanja i definiranja oæiljka na miokardu mogu biti koristan dodatak u buduêem odabiru bolesnika za ugradnju ICD u primarnoj prevenciji. U studiji od 55 bolesnika s ishemijskom kardiomiopatijom kojima je ugraappleen ICD u primarnoj prevenciji ispitivana je moguênost predviappleanja ventrikulskih aritmija na temelju karakteristika oæiljka utvrappleenog pomoêu CMR i primjene gadolinija prije ugradnje ureappleaja 115. Utvrappleeno je da se sve utvrappleene karakteristike oæiljaka oslikavanjem CMR mogu smatrati prediktorima nastanka ventrikulskih aritmije, potvrappleujuêi potencijalnu korist ovih slikovnih modaliteta u stratifikaciji rizika i boljoj selekciji bolesnika za ugradnju ICD. Ovaj rezultat je dodatno podræan prospektivnom studijom od 137 bolesnika evaluiranih CMR prije ugradnje ICD za primarnu prevenciju 116. Utvrappleeno je da je oæiljak miokarda vidljiv primjenom CMR neovisan prediktor negativnih ishoda. Bolesnici sa znaëajnim oæiljkom (>5% lijeve klijetke) s ejekcijskom frakcijom LV >30% su imali sliëan rizik kao i oni s 30%, dok je u onih s EF 30% minimalni oæiljak ili bez oæiljka bio povezan s manjim rizikom, sliëno onima s EF >30%. Dodatna je paænja usmjerena na uporabu intrakardijalnih ICD varijabli u procjeni rizika. U prospektivnoj multicentriënoj studiji sa 63 bolesnika s implantiranim ICD, utvrappleeno je da su varijabilnosti alterirajuêeg i ne-alterirajuêeg T vala (TWA/V) statistiëki znaëajnije prije epizoda ventrikulske tahikardije/ventrikulske fibrilacije nego li tijekom baziënog ritma 117. IstraæivaËi su zakljuëili da kontinuirano mjerenje TWA/V na intrakardijalnom elektrogramu ICD moæe biti koristan parametar u otkrivanju predstojeêe VT/VF te omoguêiti da ureappleaj pokrene terapijsku elektrostimulaciju radi sprje- Ëavanja ventrikulskih aritmija. Nasuprot tome, rana analiza prospektivne jednocentriëne studije o koriπtenju ICD u pra- Êenju ishemije u kliniëkoj skrbi i zbrinjavanju bolesnika ukazala je na to da ovaj parametar nije bio kliniëki koristan i zapravo je poveêao broj nepredviappleenih ambulantnih posjeta kod bolesnika s ovom opcijom na ICD naspram onih bez te opcije 118. IzvjeπÊa o komplikacijama i negativnim aspektima ICD ukljuëuju probleme povezane s Sprint Fidelis ICD elektroda- implantation using 10 readily available variables from ICD implants was developed to provide useful information in guiding physicians on patient selection and determining the intensity of post-implant care required 112. A risk score aimed at predicting the long term (8 years) benefit of primary prevention ICD implantation was applied to 11,981 patients from the MADIT-II trial 113. The investigators found that patients with low and intermediate risk (0 or 1-2 risk factors, respectively) benefitted more from ICD implantation, compared with patients with high risk ( 3 risk factors) who had multiple comorbidities, in which there was no significant difference in 8 years survival between ICD and non-icd recipients. Another risk score for the prediction of mortality in Medicare beneficiaries receiving ICD implantation for primary prevention was developed from a cohort of 17,991 patients and validated in a cohort of 27,893 patients 114. Over a median follow-up of 4 years, 6,741 (37.5%) patients in the development cohort and 8595 (30.8%) patients in the validation cohort died. Seven clinically relevant predictors of mortality were identified and used to develop a model for determining those patients at highest risk for death after ICD implantation. Future selection of ICD recipients for primary prevention ICDs may therefore be refined and more personalised to the individual patient s risk/benefit profile with the use of such models, rather than being based predominantly on LVEF, as is recommended by current guidelines. Other investigations, such as cardiac magnetic resonance (CMR) imaging to identify and characterise myocardial scar, may be a useful addition to future risk stratification of patients for primary prevention ICD implantation. The ability of scar characteristics assessed on CMR to predict ventricular arrhythmias was evaluated in a study of 55 patients with ischaemic cardiomyopathy who received an ICD for primary prevention and in whom CMR with late gadolinium enhancement had been performed before ICD implantation 115. All CMR derived scar tissue characteristics were found to be predictive for the occurrence of ventricular arrhythmias, supporting the potential use of this imaging modality to help refine risk stratification of patients and improve selection for ICD implantation. This finding was further supported by a prospective study of 137 patients evaluated with CMR before ICD implantation for primary prevention 116. Myocardial scarring on CMR was found to be an independent predictor of adverse outcomes. Patients with significant scarring (>5% of the left ventricle) with LVEF >30% had a similar risk to those with LVEF 30%, while in patients with LVEF 30%, minimal or no scarring was associated with low risk, similar to those with LVEF >30%. The use of intracardiac ICD parameters to assess risk has also received further attention. In a prospective, multicentre study of 63 ICD patients, T wave alternans and non-alternans variability (TWA/V) was found to be significantly greater before ventricular tachycardia/ventricular fibrillation (VT/VF) episodes than during baseline rhythm 117. The investigators suggested that continuous measurements of TWA/V from the intracardiac ICD electrograms may be a useful parameter to detect impending VT/VF and allow the device to initiate pacing therapies to prevent the ventricular arrhythmias from occurring. In contrast, an early analysis of a prospective, single centre study on the use of ICD based ischaemia monitoring on clinical care and patient management reported that this parameter was not clinically useful and actually increased the number of unscheduled outpa- Cardiologia CROATICA 2014;9(1-2):22.

23 ma i potencijalnim psiholoπkim uëinkom i pojavom anksioznosti meappleu primateljima ICD 122. IstraæivaËi su u studiji provedenoj u 117 talijanskih centara na bolesnika koji su podvrgnuti de novo implantaciji CRT-D ureappleaja, utvrdili su da su dogaappleaji povezani uz ureappleaje ËeπÊi u primatelja CRT-D nego kod onih koji su primili samo ICD (jednokomorni ili dvokomorni), iako ti dogaappleaji nisu bili povezani s loπijim kliniëkim ishodom 123. U multicentriënoj longitudinalnoj kohortnoj studiji sa bolesnika koji su primili jednokomorne ili dvokomorne ICD, ugradnja dvokomornog ureappleaja je bila ËeπÊa, ali je bila povezana s poveêanim periproceduralnim komplikacijama i bolniëkom smrtnoπêu u usporedbi s jednokomornim ICD 124. U retrospektivnoj jednocentriënoj kohortnoj studiji kod 334 bolesnika s hipertrofiënom kardiomiopatijom je objavljeno da je skupina bolesnika s ICD imala znaëajnu kardiovaskularnu smrtnost i bila izloæena Ëestim neprimjerenim πokovima i komplikacijama implantata 125. Nepovoljni dogaappleaji vezani za ICD (neprimjereni πokovi i/ili komplikacije impantanta) su zabiljeæeni kod 101 bolesnika (30%; 8,6% godiπnje), bolesnici s CRT-D imali veêu vjerojatnost za razvoj komplikacija vezanih uz implantante u odnosu na one s jednokomornim ICD te su imali viπu stopu kardiovaskularne smrtnosti u 5-godiπnjem razdoblju. Strategije za smanjenje komplikacija vezanih uz ICD i neprimjerenih πokova ukljuëuju koriπtenje posebnih dijagnostiëkih ICD algoritama za utvrappleivanje potencijalnih ranih problema 126 s elektrodom te promjene u programiranju ICD s produljenom odgodom u terapiji tahiaritmije s 200/min ili viπe, kao πto je prikazano u studiji MADIT-RIT (MADIT-Reduction in Inappropriate Therapy) 127. Sve veêe kliniëko iskustvo se stjeëe i u uporabi subkutanog ICD koji ima veliki potencijal u smanjenju nekih vrsta komplikacija povezanih s ICD, iako se prvo treba prevladati poëetna krivulja uëenja 128,129. KliniËki podaci o ugradnji ICD i koriπtenju pokazuju da bolesnici koje zbrinjavaju operateri s malim brojem zahvata (lijeënici koji ugraappleuju 1 ICD godiπnje) imaju veêu vjerojatnost od smrtnog ishoda ili srëanih komplikacija u usporedbi s operatorima koji imaju veêi volumen 130. Druga strategija smanjenja komplikacija vezanih s ICD je unaprijediti proces odabira onih bolesnika koji bi doista imali koristi od tih ureappleaja. U opservacijskoj studiji ishoda kod uzastopnih ispitanika upu- Êenih u regionalnu ambulantu za naslijeappleena srëana stanja zbog nekog roappleaka koji je imao naglu neoëekivanu smrt, utvrappleeno je da je broj ugraappleenih ICD kao rezultat pregleda specijaliste bio vrlo mali (2%) 131. VanbolniËki srëani zastoj»ini se da je preæivljavanje vanbolniëkog srëanog zastoja poraslo u posljednjih nekoliko godina, vjerojatno kao posljedica bolje vanbolniëke skrbi (rano prepoznavanje, uëinkovitija kardiopulmonalna reanimacija (CPR), bræa reakcija hitne sluæbe) i napredka u bolniëkom zbrinjavanju bolesnika nakon zastoja Podaci iz Londonskog registra hitne sluæbe od do godine su pokazali poboljπanje u preæivljavanju osoba s vanbolniëkim srëanim zastojem tijekom razdoblja od pet godina 134. U opservacijskoj studiji πvedskog registra sa bolesnika s vanbolniëkim srëanim zastojem tijekom razdoblja od 18 godina, utvrappleeno je da je CPR od strane prolaznika porasla sa 46% na 73% (95% CI za OR 1,060-10,081 godiπnje), rano preæivljavanje se poveêalo sa 28% na 45% (95% CI 1,044-1,065) te jednomjeseëno preæivljavanje s 12% na 23% (95% CI 1,058-1,086) 135. ZnaËajni prediktori ranog i kasnog preæivljavanje su bili kratak interval od kolapsa do defibrilacije, CPR od strane prolaznika, æenski spol i mjesto kolapsa. Velika prospektivna kohortna studitient visits in patients with this feature on their ICD compared with patients with ICDs without this capability118. Reports on the complications and negative aspects of ICDs include problems associated with the Sprint Fidelis ICD leads and potential psychological impact and phobic anxiety among ICD recipients 122. In a study of 3,253 patients from 117 Italian centres who underwent de novo implantation of a CRT-D device, investigators found that device related events were more frequent in patients who received CRT-D devices compared with those who received ICDs only (single or dual chamber), although these events were not associated with a worse clinical outcome 123. In a multicentre, longitudinal cohort study of 104,049 patients receiving single and dual chamber ICDs, dual chamber device implantation was more common, but was associated with increased periprocedural complications and in-hospital mortality compared with single chamber ICDs 124. A retrospective, single centre cohort study of 334 hypertrophic cardiomyopathy patients with ICDs reported that this group of patients had significant cardiovascular mortality and were exposed to frequent inappropriate shocks and implant complications 125. Adverse ICD related events (inappropriate shocks and/or implant complications) were seen in 101 patients (30%; 8.6% per year), and patients with CRT-D were more likely to develop implant complications than those with single chamber ICDs and had a higher 5-year cardiovascular mortality rate. Strategies to reduce ICD complications and inappropriate shocks include using special diagnostic ICD algorithms to identify potential lead problems early 126, and changes in ICD programming with a prolonged delay in therapy for tachyarrhythmias of 200 beats/min or higher, as demonstrated in the MADIT-RIT (MADIT-Reduction in Inappropriate Therapy) trial 127. Increasing clinical experience is also being gained in the use of subcutaneous ICDs 128,129, which holds great potential in reducing some types of ICD related complications, although an initial learning curve needs to be overcome first. Real world data of ICD implantation and use show that patients treated by very low volume operators (physicians who implanted 1 ICDs per year) were more likely to die or experience cardiac complications compared with operators who frequently performed ICD implantation 130. Another strategy to reduce ICD complications is to improve the selection process of those patients who would truly benefit from these devices. In an observational outcome study of consecutive subjects referred to a regional inherited cardiac conditions clinic because of a relative who had sudden unexpected death, the number of ICDs inserted as a result of specialist assessment was found to be very small (2%) 131. Out-of-hospital cardiac arrest Survival from out-of-hospital cardiac arrest (OHCA) appears to have increased over the past several years, probably as a result of better pre-hospital care (early recognition, more effective CPR, faster emergency services response) and advances in the hospital management of patients following OHCA 132,133. Data from the London Ambulance Service s cardiac arrest registry from 2007 to 2012 showed an improvement in OHCA survival over the 5 year study period 134. In an observational Swedish registry study of 7,187 patients with OHCA over an 18 year period, bystander CPR was found to increase from 46% to 73% (95% CI for OR to per year), early survival increase from 28% to 45% (95% CI to 1.065), and survival to 1 month increase from 12% to 23% (95% CI to 1.086)135. Strong predictors of 2014;9(1-2):23. Cardiologia CROATICA

24 ja vanbolniëkih srëanih zastoja kod odraslih u Sjevernoj Americi koja je ukljuëivala ispitanika (2.042 na javnom mjestu, kod kuêe) je pokazala da je preæivljavanje do otpusta iz bolnice bilo bolje za zastoje koji su se dogodili na javnim mjestima s dostupnim automatskim vanjskim defibrilatorima (AED) koje primjenjuju prolaznici u odnosu na preæivljavanja kod kuêe (34% naspram 12%; prilagoappleeni OR 2,49, 95% CI 1,03-5,99, p=0,04) 136. BolniËke karakteristike povezane s poboljπanim ishodima bolesnika nakon vanbolniëkog srëanog zastoja bili su analizirani u Registru srëanog zastoja hitne sluæbe Victoria kod bolesnika tijekom razdoblja od 8 godina 137. Utvrappleeno je da je ishod bio znatno poboljπan u bolnicama s 24-satnim kardioloπkim intervencijskim sluæbama (OR 1,40, 95% CI 1,12-1,74; p=0,003) i prijmom bolesnika izmeappleu 8 i 17 sati (OR 1,34, 95% CI 1,10-1,64, p=0,004). VanbolniËki srëani arest u djece je bio evaluiran u prospektivnoj studiji temeljenoj na podacima mlaappleih od 21 godina æivota 138. Incidencija pedijatrijskog vanbolniëkog srëanog zastoja je bila 9,0 na pedijatrijskih osoba-godina (95% CI 7,8-10,3), dok je incidencija srëanog zastoja zbog srëanih uzroka iznosila 3,2 (95% CI 2,5-3,9 ). Autori su zakljuëili da vanbolniëki srëani zastoj Ëini znaëajan udio u pedijatrijskoj smrtnosti, iako je velika veêina onih koji su preæivjeli imala nepromijenjen neuroloπki status. Studije o optimalnom slijedu CPR mjera za uporabu kod bolesnika s vanbolniëkim srëanim zastojem su objavile razliëite rezultate. U meta-analizi Ëetiri randomizirana kontrolirana kliniëka istraæivanja s ispitanika, nije utvrappleena znaëajna razlika u uspostavi spontane cirkulacije, preæivljavanja do otpusta iz bolnice ili povoljnih neuroloπkih ishoda izmeappleu po- Ëetne kompresije prsnog koπa u odnosu na defibrilaciju. Analize podskupina ukazale su da poëetak s kompresijom prsnog koπa moæe donijeti dobrobit kod zastoja s produljenim vremenom reakcije 139. U novijoj, japanskoj opservacijskoj studiji s bolesnicima s vanbolniëkim srëanim zastojem koji su imali doæivjeli zastoj i bili defibrilirani sa javno dostupnim AED, utvrappleeno je da je CPR sa samo kompresijama prsnog koπa povezana sa znaëajno viπim jednomjeseënim preæivljavanjem i povoljnijim neuroloπkim ishodima u usporedbi s konvencionalnim CPR (kompresija prsnog koπa i disanje usta na usta) 140. Meappleutim, za djecu i mlaapplee osobe s vanbolniëkim srëanim zastojem zbog nekardijalnih uzroka, kao i osoba kod kojih je doπlo do odgode u zapoëinjanju CPR, ostale studije su pokazale da je konvencionalna CPR povezana s boljim ishodima od samih kompresija prsnog koπa 141,142. ZakljuËci U posljednjih nekoliko godina postignut je vaæan napredak u naπem razumijevanju osnovne i kliniëke elektrofiziologije srca Ëime je unaprijeappleeno i poboljπano zbrinjavanje bolesnika s poremeêajima srëanog ritma. Veliki broj studija su ukazale na povezanost izmeappleu FA i razliëitih sistemskih stanja te novih Ëimbenika rizika. U ovim studijama se naglaπava vaænost i sloæenost ove vaæne aritmije te se ukazuje da je FA sistemsko stanje. Iako se pokazalo da mnogi Ëimbenici nisu uzrok, mogu biti kliniëki korisni u buduêim alatima za stratifikaciju rizika za dijagnosticiranje i lijeëenje FA. Potrebno je provesti viπe istraæivanja kako bi poboljπali naπe razumijevanje temeljnih mehanizama odgovornih za razvoj i napredovanje FA te kod kojih podskupina bolesnika Êe biti najviπe koristi od odreappleenih oblika lijeëenja ili razliëitih opcija antikoagulacije. early and late survival were a short interval from collapse to defibrillation, bystander CPR, female gender, and place of collapse. A large prospective cohort study of OHCA in North American adults involving 12,930 subjects (2,042 occurring in a public place and 9,564 at home) also found that the rate of survival to hospital discharge was better for arrests in public settings with automated external defibrillators (AEDs) applied by bystanders compared to those that occurred at home (34% vs 12%, respectively; adjusted OR 2.49, 95% CI 1.03 to 5.99; p=0.04) 136. Hospital characteristics associated with improved patient outcomes following OHCA were analysed from the Victorian Ambulance Cardiac Arrest Registry of 9,971 patients over an 8 year period 137. Outcome following OHCA was found to be significantly improved in hospitals with 24 h cardiac interventional services (OR 1.40, 95% CI 1.12 to 1.74; p=0.003) and patient reception between 8.00 and h (OR 1.34, 95% CI 1.10 to 1.64; p=0.004). OHCA in children was assessed in a prospective, population based study of victims younger than 21 years of age 138. The incidence of paediatric OHCA was 9.0 per 100,000 paediatric person-years (95% CI 7.8 to 10.3), whereas the incidence of paediatric OHCA from cardiac causes was 3.2 (95% CI 2.5 to 3.9). The authors concluded that OHCA accounts for a significant proportion of paediatric mortality, although the vast majority of OHCA survivors have a neurologically intact outcome. Studies on the optimal sequence of CPR measures to use in OHCA patients have reported varying results. In a metaanalysis of four randomised controlled clinical trials enrolling 1,503 subjects with OHCA, no significant difference was found between chest compression first versus defibrillation first in the rate of return of spontaneous circulation, survival to hospital discharge or favourable neurologic outcomes, although subgroup analyses suggested that chest compression first may be beneficial for cardiac arrests with a prolonged response time 139. In a more recent, nationwide, population based observational study involving OHCA patients in Japan who had a witnessed arrest and received shocks with public access AED, compression only CPR was found to be associated with a significantly higher rate of survival at 1 month and more favourable neurological outcomes compared with conventional CPR measures (chest compression and rescue breathing) 140. However, for children and younger people who have OHCA from non-cardiac causes, and in people in whom there was a delay in starting CPR, other studies have suggested that conventional CPR is associated with better outcomes than chest compression only CPR 141,142. Conclusions Important progress has been made over the past few years in our understanding of basic and clinical cardiac electrophysiology which have advanced and improved the management of patients with heart rhythm disorders. Multiple studies have demonstrated an association between AF and various systemic conditions and novel risk factors. These studies highlight the importance and complexity of this complex arrhythmia and further support the notion that AF is a systemic condition. Although many of these associations have not been shown to play a causal role, they may nonetheless prove useful clinically in future risk stratification scores for the diagnosis or treatment of AF. More research is still needed to increase our understanding of the underlying mechanisms responsible for the development and progression of AF and which patient subgroups will benefit most from specific treatments or the different options for anticoagulation. Cardiologia CROATICA 2014;9(1-2):24.

25 U posljednjih nekoliko godina takoappleer je je vrlo brzo napredovalo podruëje implantacije CRT i elektrostimulacije s naglaπenim interesom za definiranjem optimalnih kliniëkih parametara u odabiru bolesnika, predviappleanja reakcije i nepovoljnog remodeliranja. Takoappleer, odabir podobnih kandidata za implantaciju ICD postaje precizniji kako se naπe razumjevanje patoloπkog supstrata za ventrikulske aritmije i iznenadnu srëanu smrt poboljπalo. Istraæivanje komplikacija povezanih s implantabilnim kardijalnim ureappleajima, poput infekcije povezanih s ureappleajem i neprimjereni πokovi iz ICD postaju znaëajnim, jer se indikacije za implantaciju ureappleaja i dalje πire i sve se viπe bolesnika s postojeêim ureappleajima podvrgava postupcima zamjene ureappleaja. The field of CRT and pacing has also progressed rapidly over the past few years with a lot of interest in the optimal clinical parameters for selection of patients, prediction of response, and adverse remodelling. 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28 StruËni rad / Professional article Kardiomiopatija inducirana ventrikulskim ekstrasistolama Ventricular extrasystole induced cardiomyopathy Vedran VelagiÊ* KliniËki bolniëki centar Zagreb, Zagreb, Hrvatska University Hospital Centre Zagreb, Zagreb, Croatia SAÆETAK: Ventrikulske ekstrasistole (VES) Ëesta su i naëelno benigna pojava, osobito ako se radi o bolesniku sa strukturno zdravim srcem godine objavljena je prva studija u kojoj je dokazano da medikamentozna supresija ekstrasistolije rezultira oporavkom funkcije lijeve klijetke u dilatacijskoj karidomiopatiji te je razvijen koncept VES inducirane kardiompatije (CMP). Sama pojavnost VES vrlo je velika u populaciji, raste s dobi, no toëne podatke o incidenciji VES inducirane kardiomiopatije nemamo. Najvaæniji Ëimbenik u razvoju ovog entiteta je VES optereêenje no joπ se vode polemike oko toëne definicije istog. Razvijeno je nekoliko æivotinjskih modela za rasvjetljavanje patofiziologije ove bolesti te se najvjerojatnije radi o funkcijskom poremeêaju koji je u velikoj mjeri reverzibilan. U obradi ovih bolesnika potrebno je na sve dostupne naëine detektirati sekundarne uzroke ekstrasistolije i kardiomiopatije, jer je VES inducirana CMP dijagnoza do koje dolazimo iskljuëivanjem. Od terapijskih opcija na raspolaganju nam je medikamentozna terapija antiaritmicima te kateterska radiofrekventna (RF) ablacija. Randomizirane studije koje bi dale prednost jednoj od ovih opcija ne postoje. U posljednje vrijeme preferira se RF ablacija s vrlo dobrim razultatima u reverziji kardiomiopatije i s malom uëestalosti komplikacija. U ovom trenutku, VES inducirana CMP joπ je prerijetko prepoznata kao uzrok neishemijske kardiomiopatije. KLJU»NE RIJE»I: ventrikulske ekstrasistole, kardiomiopatija, antiaritmici, radiofrekventna ablacija. SUMMARY: Ventricular extrasystoles (PVC, Premature Ventricular Contraction) are a common and generally a benign phenomenon, especially in a patient with a structurally normal heart. The first study was published in 1998 which proved that medical suppression of extrasystole results in the recovery of the left ventricular function in dilatation cardiomyopathy, whereas the concept of PVC-induced cardiomyopathy (CMP) was developed. The incidence of PVCs itself is very large in population, rises with age, but we have no accurate data on the incidence of PVC-induced cardiomyopathy. The most important factor in the development of this disease is PVC burden, but the exact definition thereof is still being discussed. Several animal models have been developed for elucidating the pathophysiology of this disease and it is probably a functional disorder that is largely reversible. In the treatment of these patients it is necessary to detect secondary causes of extrasystole and cardiomyopathy in all available ways; because the PVC-induced CMP is diagnosis of exclusion. Out of therapeutic options we have antiarrhythmic drug therapy and catheter radiofrequency (RF) ablation at disposal. There are no randomized studies that would prefer one of these options. RF ablation, with very good results in the reversion of cardiomyopathy and with a low incidence of complications, has been preferred lately. At this point, PVC-induced CMP is still too seldom recognized as a cause of non-ischemic cardiomyopathy. KEYWORDS: premature ventricular contraction, cardiomyopathy, antiarrhythmic drug therapy, catheter radiofrequency ablation. CITATION: Cardiol Croat. 2014;9(1-2): V entrikulske ekstrasistole (VES) su jedna od najëeπêih aritmija u radu kardiologa kliniëara. Prije smatrane kao benigna pojava bez kliniëkog znaëaja 1, VES se sada povezuju s entitetom nazvanim VES inducirana kardiomiopatija. Svakodnevno raste koliëina dokaza koja povezuje ventrikulske ekstrasistole u inaëe strukturno zdravom srcu, s razvojem dilatacije lijeve klijetke (LV) i sniæenjem vrijednosti ejekcijske frakciji (EF) LV 2-4. Ovo stanje moæe se uspjeπno lijeëiti medikamentozno 5 ili kateterskom ablacijom, πto rezultira normalizacijom dimenzija i funkcije LV 6-8. ToËna patofiziologija ove bolesti ostaje nerazjaπnjena. Postoje neke spekulacije koje povezuju VES induciranu disinkroniju i V entricular extrasystoles (premature ventricular contraction, PVC) are one of the most common arrhythmia in the practice of cardiologic clinicians. Although it was considered to be a benign phenomenon without clinical significance 1, PVC is now associated with the entity called the PVC-induced cardiomyopathy. The scope of evidence is growing on a daily basis linking the ventricular extrasystoles in the structurally normal heart to the development of left ventricular (LV) dilatation and the reduction in LV ejection fraction (EF) 2-4. This condition can be successfully treated by drugs 5 or catheter ablation resulting in the normalization of the LV dimensions and functions 6-8. The exact pathophysio- Cardiologia CROATICA 2014;9(1-2):28.

29 VES induciranu kardiomiopatiju, sliëno kao kod veê dobro poznatog negativnog utjecaja elektrostimulacije desne klijetke. Nadalje, promjene u ionskim kanalima i unutarstaniënom prometu kalcija predloæeni su mehanizmi nastanka disfukcije LV, sliëno kao πto se dogaapplea u tahi-kardiomiopatiji 9. Do sada su razvijena dva modela za istraæivanje ove bolesti koja su koristila pse mjeπance te je jasno pokazana povezanost izmeappleu ekstrasistola i disfunkcije lijeve klijetke. Meappleutim, u ovim modelima nisu detektirane veêe histopatoloπke promjene, tako da toëni mehanizmi ove bolesti ostaju nepoznati 10,11. Epidemiologija Prevalencija VES ovisna je o dobi, tako da se nalazi u rasponu od <1% u djece pa do >60% u osoba starije æivotne dobi 12.»ak do 75% ispitanika u standarnom snimanju holter elektrokardiograma (do 48 sati), imaju VES, dok u standardnom 12-kanalnom elektrokardiogramu uëestalost iznosi samo 1% 13. Dugo su se vremena VES u strukturno zdravom srcu smatrale kao sasvim benigna pojava, sve dok godine nije opisan povoljan uëinak medikamentozne supresije VES na dilatacijsku kardiomiopatiju te je razvijen koncept VES inducirane kardiomiopatije 5. ToËna prevalencija ove bolesti nije poznata, no sigurno je da ovaj entitet premalo dijagnosticiran kao uzrok kardiomiopatije (CMP). Dominantno se javlja u osoba starije æivotne dobi, vjerojatno zbog Ëinjenice da je potrebno mnogo vremena da uëestale VES izazovu sniæavanje funkcije LV 14. Osim duæine trajanja VES, vrlo je vaæna i uëestalost VES koja se mjeri udjelom (%) ili samim brojem tijekom 24 sata, takozvani PVC burden VES optereêenje. Patofiziologija VES inducirana kardiomiopatija ima neke sliënosti s drugim kliniëkim entitetima kao πto su tahi-kardiomiopatija i kardiomiopatija inducirana desno-ventrikulskom elektrostimulacijom. Prije se smatralo da je ona u biti samo jedna podvrsta tahi-kardiomipatije, koja je dobro poznat fenomen u sklopu brze fibrilacije ili undulacije atrija, drugih supraventrikulskih poremeêaja ritma ili ventrikulske tahikardije. Ovaj patofizioloπki mehanizam brzo je naiπao na kritike jer su prosjeëne frekvencije kod VES inducirane CMP sliëne onima u sinusnom ritmu. MoguÊe je da uëestale i usko vezane VES uzrokuju promjene u unutarstaniënom metabolizmu kalcija, transmembranskom prometu iona te na taj naëin iscrpljuju energetske zalihe miocita. Uz to, dolazi do promjena u hemodinamici te u dinamici srëanog pulsa uz vezane promjene u tonusu vaskulature 15. Navedeni fenomen veê je prije opisan kao postekstrasistoliëka potencijacija 11. SliËnost sa CMP kod stimulacije desne klijetke (RV) oëituje se ekscentriënom aktivacijom ventrikulskog miokarda uzrokovanog VES πto dovodi do disinkronije. Kompenzatorne pauze nakon VES mijenjaju dinamiku punjena i praænjenja klijetke. Disinkronija rezultira s smanjenom globalnom efikasnoπêu klijetki, asimetriënom hipertrofijom stijenki, promjenama u perfuziji miokarda te na kraju poveêanom potroπnjom kisika 6. Do sada su objavljena dva modela koja bi trebala rasvjetiliti toëne mehanizme ove bolesti, oba na psima mjeπancima. Akum i sur. su koristili dvokomorski elektrostimulator (obje elektrode u RV, jedna za sensing, druga za stimulaciju) kojim su simulirali VES bigeminiju iz RV. VeÊ nakon 4 tjedna doπlo je do razvoja dilatacije LV i znaëajnog pada u sistoliëkoj funkciji (EF sa 60% na 46%) 10. SliËan model koristili logy of this disease remains unclear. There are some speculations linking PVC-induced dyssynchrony to the PVC-induced cardiomyopathy, similar to the well-known negative effect of the right ventricular electrostimulation. Besides, changes in ion channels and intracellular transport of calcium are the proposed mechanisms of occurrence of the LV dysfunction, similar to what happens in case of tachycardiomyopathy 9. Two models for studying this disease using mongrel dogs have been developed so far and the correlation between extrasystoles and the LV dysfunction has been clearly shown. However, no greater histopathological changes have been detected in these models, so that the exact mechanisms of these diseases remain unknown 10,11. Epidemiology The prevalence of PVC is age dependent, so that it ranges from <1% in children up to >60% in the elderly persons 12. Up to 75% of subjects in standard Holter ECG recording (up to 48 hours) have PVC, while in standard 12-lead electrocardiogram the incidence is only 1% 13. PVC had been long regarded as an entirely benign phenomenon in structurally normal heart until 1998 when the beneficial effect of PVC suppressive drugs on dilated cardiomyopathy was described and when the concept of PVC-induced cardiomyopathy was developed 5. The exact prevalence of the disease is unknown, but it is certain that this entity is underdiagnosed as a cause of cardiomyopathy (CMP). It predominantly occurs in elderly people, probably due to the fact that it takes a long time for frequent PVCs to cause reduction of LV function 14. In addition to the duration of PVCs, the incidence of PVC measured as the ratio (%) or the absolute number during 24 hours, the so-called PVC burden is very important. Pathophysiology PVC-induced cardiomyopathy has some similarities to other clinical entities such as tachycardiomyopathy and cardiomyopathy induced by right ventricular electrostimulation. In the past, it was thought to be just one subtype of tachycardiomyopathy, which is a well-known phenomenon within the fast atrial fibrillation or undulation, other supraventricular arrhythmias or ventricular tachycardia. This pathophysiological mechanism soon faced criticism, because the average incidence in PVC-induced CMP is similar to that in sinus rhythm. It is possible that frequent and short-coupled PVCs cause changes in intracellular calcium metabolism and transmembrane ion transport thus depleting the energy supplies of myocytes. In addition, changes are made to the hemodynamics and heart rate dynamics with the associated changes in the vasculature tonus 15. The above mentioned phenomenon has been previously described as a postextrasystolic potentiation 11. The similarity to CMP in the right ventricular (RV) stimulation is reflected in eccentric activation of the ventricular myocardium caused by PVCs which leads to dyssynchrony. Compensatory pauses after PVC change the ventricular filling and discharging dynamics. Dyssynchrony results in reduced global efficiency of ventricles, asymmetric wall hypertrophy, changes in myocardial perfusion and ultimately in an increased consumption of oxygen 6. Two models that should elucidate the exact mechanisms of this disease have been published so far, both on mongrel dogs. Akum et al. used dual chamber pacemaker (the both electrodes in the RV, one for sensing, the other for stimulation) used for simulating PVC bigeminy from the RV. Only after four weeks LV dilatation developed followed by a significant decline in systolic function (EF from 60% to 46%) 10. A similar model was used by Ellenbogen et al., where dila- 2014;9(1-2):29. Cardiologia CROATICA

30 su Ellenbogen i sur. gdje je nakon 12 tjedana takoappleer doπlo do dilatacije i znaëajnog pada u funkciji LV. Nadalje, veê 2-4 tjedna nakon prestanka stimulacije doπlo do oporavka funkcije LV. U tom radu napravljene su i histoloπke studije koje nisu naπle znakova upale, fibroze, promjena u apoptozi ili u oksidativnoj fosforiliaciji u mitohondrijima kod subjekata s CMP, πto govori u prilog da je VES inducirana kardiomiopatija reverzibilno stanje bez veêih patohistoloπkih i mitohondrijskih anomalija. Do promjene je doπlo u efektivnom refrakternom periodu klijetke, πto je znak elektriënog remodeliranja. Radi se dakle, dominantno o funkcijskoj, a ne strukturnoj abnormalnosti koja je uzrok CMP 11.»injenica da je kod pseêeg modela, tako malo vremena bilo potrebno za razvoj CMP, baca sumnju na adekvatnost istog u sluëaju interpolacije na ljude gdje je poznato da su potrebne godine za deterioraciju funkcije LV. Grupa autora iz Michigena razvila je ovëji model s vrlo sliënom metodologijom (dvokomorski elektrostimulator i inducirana VES bigeminija), no ovdje su se promjene u parametrima funkcije LV javile mnogo kasnije te su bile mnogo suptilnije. Na staniënoj razini, zabiljeæene su tek neke promjene u unutarstaniënom prometu kalcija koje bi mogle barem djelomiëno objasniti patofiziologiju ove bolesti (joπ neobjavljeni podaci). Karakteristike ventrikulskih ekstrasistola Ne postoje strogo definirane granice uëestalosti VES koje bi sigurno uzrokovale pad u funkciji LV. Neki bolesnici s vrlo visokim optereêenjem ne dobiju CMP, dok je drugi s mnogo manjim optereêenjem razviju, no to se ipak dogaapplea mnogo rjeapplee. Sigurno je da i drugi parametri osim VES optereêenja igraju vaænu ulogu u razvoju ove bolesti. Ipak, bolesnici sa sniæenom EF imaju znaëajno viπe optereêenje od sliënih bolesnika s normalnom EF. RazliËiti autori postavljaju drugaëije granice kojima definiraju visoko optereêenje, /dan, >10.000/dan, >10% QRS, >10/sat, itd. 6,16,17. Vaæno je za napomenuti da tek jedna treêina bolesnika s visokim VES optereêenjem razvije CMP. Pitanje je da li se radi o greπki u metodologiji (uobiëajeni 24 satni Holter) ili su odgovorni drugi, nepoznati momenti. Jedna studija pokazuje da granica od 24% VES dnevno ima zadovoljavajuêu specifiënost (79%) i senzitivnost (78%) u razgraniëavanju bolesnika s i bez CMP 18. Velika veêina idiopatskih VES proizlazi iz izlaznog trakta RV (oko 2/3), no znaëajan udio aritmijskih fokusa nalazi se u muskularnim traëcima iznad pulmonalne i aortne valvule (vidjeti Ëlanak dr. AniÊa u ovom broju Ëasopisa 18 ). Neπto su rijeapplei fokusi u LV slobodnoj stijenci, papilarnim miπiêima ili fasciklima lijeve grane. Ventrikulska ektopija, dakako moæe biti i multifokalna πto rezultira polimorfnim VES, no Ëesto su one iz izlaznog trakta dominantne. Zanimljivo je da je u jednoj studiji bila potrebna mnogo veêa uëestalost VES iz LV (>20%) naspram RV (>10%) za razvoj CMP πto bi moglo govoriti u prilog VES inducirane disinkronije kao patofizioloπkog mehanizma. Osim toga, VES πirokog QRS-a (>150 ms) ili one epikardijalnog podrijetla nezavisan su prediktor razvoja CMP 19. VeÊ prije smo napomenuli da je i trajanje ekstrasistolije vaæan prediktor razvoja CMP. Potrebne su godine, a ne samo mjeseci vrlo uëestalih VES da bi doπlo do razvoja CMP. Pacijenti bez ikakvih simptoma (kasnije se javljaju lijeëniku) ili oni s trajanjem palpitacija >60 mjeseci ËeπÊe razvijaju kardiomiopatiju 20. Pitanje utjecaja VES coupling intervala i VES interpolacije na razvoj CMP joπ nema jednoznaëan odgovor. tion and a significant decline in the LV function occurred after 12 weeks. Besides, already 2-4 weeks the cessation of stimulation was followed by the recovery of LV function. In this article, some histological studies were performed finding no signs of inflammation, fibrosis, changes in apoptosis or oxidative phosphorylation in mitochondria in subjects with cardiomyopathy, which confirms the thesis that PVC-induced cardiomyopathy is a reversible condition with no major pathohistological and mitochondrial anomalies. The change occurred in the effective refractory period of the ventricle, which is the sign of the electric remodelling. So, the most probably, it is predominantly the functional rather than structural abnormality that causes CMP 11. The fact that in canine models it took so little time for CMP to develop, casts doubt on the appropriateness of the same in case of interpolation on people where we know that it takes years for the LV function to deteriorate. A group of authors from Michigan developed a sheep model with a very similar methodology (dual chamber pacemaker and induced PVC bigeminy), but here the changes in the parameters of LV function were detected much later and were much more subtle. At the cellular level, there were only a few changes in the intracellular transport of calcium which could at least partially explain the pathophysiology of this disease (still unpublished data). Characteristics of ventricular extrasystoles There are no strictly defined limits of incidence of PVC, which would certainly cause a decline in LV function. Some patients with very high burden do not develop CMP, while the other with a much smaller burden develop it, however, it still happens a lot less often. It is certain that the other parameters except for PVC burden play an important role in the development of this disease. However, patients with lowered EF have significantly greater burden than similar patients with normal EF. Various authors have set different boundaries which define high burden, 20,000/day, >10,000/day, >10% QRS, >10/hour, etc. 6,16,17. It is important to note that only one third of patients with high PVC burden develop CMP. The question is whether an error in the methodology is concerned (the usual 24- hour Holter) or whether some other unknown moments are accountable. One study shows that the limit of 24% PVC a day is sufficiently specific (79%) and sensitive (78%) in dividing patients in those with and without CMP 18. The vast majority of idiopathic PVC arises from the RV outflow tract (around 2/3), but a significant proportion of arrhythmic foci is positioned in the muscular extension above the pulmonary and aortic valve (see the article by AniÊ in this issue 18 ). Foci in LV the free wall, papillary muscles or fascicles of the left bundle branch are somewhat rarer. Ventricular ectopia, can of course be multifocal resulting in polymorphic PVC, but often those coming from the outflow tract are dominant. It is worth noting that one study showed that much higher prevalence of LV from PVC (>20%) versus RV (>10%) was required for the development of CMP that might indicate PVC-induced dyssynchrony as a pathophysiological mechanism. In addition, PVCs of wide QRS (>150 ms) or the ones of epicardial origin are an independent predictor of the development of the CMP 19. We noted earlier that the duration of the extrasystoles is an important predictor of the development of CMP. It takes years, not only months for very frequent PVCs to cause the development of CMP. Patients without any symptoms (they visit a doctor later) or those with a length of palpitations >60 months develop cardiomyopathy more often 20. There is still no unambiguous answer to the question concerning the Cardiologia CROATICA 2014;9(1-2):30.

31 KliniËka evaulacija i terapija VES inducirana karidomiopatija joπ je uvijek dijagnoza do koje se dolazi iskljuëivanjem. Potrebno je detektirati sve eventualne podleæeêe strukturne bolesti srca koje bi mogle biti uzrok Ëestim ekstrasistolama. Nekada je vrlo teπko utvrditi πto Ëemu prethodi, odnosno koji je primarni poremeêaj, ekstrasistolija koja vodi strukturnoj bolesti ili obrnuto. U veêine bolesnika nije moguêe utvrditi poëetak uëestale ekstrasistolije u odnosu na razvoj CMP 21. Kako je VES inducirana CMP reverzibilna bolest, vaæno je pronaêi primarni uzrok. Raspon simptoma kojima se bolesnici prezentiraju proteæe se od palpitacija (tipiëna preskakanja, probadanja, nespecifiëne prekordijalne opresije), presinkopalnih epizoda, sinkopa pa sve do manifestnog srëanog zatajivanja u sluëaju veê razvijene karidomiopatije. Kod dijagnoze veêina bolesnika ima strukturno zdravo srce 1, no potrebno je uëiniti standardnu kardioloπku obradu. AnamnestiËki je vaæno ispitati obiteljsku anamnezu (obiteljske neishemijske CMP) te osobnu anamnezu koja moæe rasvijetliti uzrok eventaulne CMP (toksiëna, ishemijska riziëni faktori, infektivna itd.). Fizikalnim pregledom najëeπêe se detektira aritmiëan rad srca, ako su VES izrazito Ëeste. U 12-kanalnom elektrokardiogramu mogu se zabiljeæiti VES πto pomaæe u lociranju fokusa (najëeπêe izlazni trakt RV). Isto tako, u EKG treba traæini naznake aritmogene displazije RV, hipertrofijske kardiomiopatije, itd. Bez 24-, odnosno 48-satnog holter EKG dijagnoza je nemoguêa, vrlo je vaæno odrediti optereêenje bolesnika ekstrasistolijom. Kako je dnevno optereêenje varijabilno, potrebno je ËeπÊe ponavljati holterski monitoring. Ehokardiografija je nezaobilazna, kako u verificiranju strukturno zdravog srca, tako i u detektiranju najëeπêih poremeêaja u sklopu ove CMP dilatacije LV i sniæenje EF uz najëeπêe globalnu redukciju kontraktiliteta 22. Ehokardiografija nam je takoappleer vaæna u iskljuëivanju drugih eventualnih uzroka CMP te u daljnjem praêenju bolesnika. Joπ se ne znaju Ëimbenici rizika za razvoj CMP u sklopu uëestalih VES, tako da ne postoje jasne smjernice za uëestalost ehokardiografskih kontrola i holterskog monitorniga. Ako postoje Ëimbenici rizika za koronarnu bolest srca uz regionalne smetnje kontraktiliteta, potrebno je uëiniti i koronarografiju. Nadalje, magnetska rezonanca srca moæe nam dati najbolje podatke ako sumnjamo na aritmogenu displaziju, preboljeli miokarditis ili infiltrativne bolesti srca. Generalni je konsenzus da je terapija VES potrebna kada je zabiljeæena disfunkcija LV te postoji temeljita sumnja na VES induciranu CMP, odnosno ako je VES optereêenje izrazito visoko. Terapija je indicirana i u sluëaju neπto niæeg VES optereêenja u sluëaju izraæenih simptoma koji naruπavaju kvalitetu æivota. Postoje dvije terapijske opcije, konzervativno medikamentozno (antiaritmici) lijeëenje te kateterska radiofrekventna (RF) ablacija. VeÊina bolesnika s uëestalim ekstrasistolama ima strukturno zdravno srce i nakon πto smo to utvrdili, ponajprije je potrebno savjetovanje i smirivanje zabrinutog bolesnika, odnosno obrazlaganje da se radi o apsolutno benignom poremeêaju s odliënom prognozom 1. Ne treba æuriti s farmakoterapijom koja je u ovom sluëaju indicirana samo ako simptmi ograni- Ëavaju bolesnikov æivot. Prva linija farmakoterapije obiëno su beta-blokatori ili nedihidropiridinski kalcijski blokatori 23. U sluëaju da oni nemaju efekta mogu se uprotrijebiti sotalol ili antiaritmici I.b (meksiletin) ili I.c (propafenon) skupine koji su inaëe kontrainidicirani ako je veê razvijena CMP 24. U ovom sluëaju, uvijek treba odvagnuti eventulano proaritmogeno impact of PVC coupling interval and PVC interpolation on the development of CMP. Clinical evaluation and therapy PVC-induced cardiomyopathy is still a diagnosis of exclusion. It is necessary to detect all potential underlying structural heart diseases that could be a cause for frequent extrasystoles. Sometimes it is very difficult to determine what precedes what, and what a primary disorder is, whether it is extrasystole causing a structural disease or vice versa. In most patients, it is not possible to determine the start of frequent extrasystoles in relation to the development of CMP 21. As PVC-induced CMP is a reversible disease, it is important to find the primary cause. The range of symptoms that patients present with, extends from palpitations (typical heart skipping, pricking pains, unspecified precordial oppressions), presyncopal episodes, syncopes to manifest heart failure in the case of already developed CMP. At the time of diagnosis, most of the patients have structurally normal heart 1, but a standard cardiac workup should be performed anyway. It is important to examine family medical history (familiar non-ischemic CMP) and the personal medical history that may help explain the cause of any potential CMP (toxic, ischemic risk factors, infectious, thyroid etc.). Physical examination usually detects arrhythmic heart rate if PVCs are extremely common. The 12-lead electrocardiogram can record PVC which helps locate the focus (most commonly the RV outflow tract). Likewise, the ECG should search for signs of arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, etc. The diagnosis is impossible without 24-, or 48-hour Holter ECG, because it is very important to determine the patient s PVC burden. As the daily burden varies, Holter monitoring is to be repeated more often. Echocardiography is unavoidable not only in verifying structurally normal heart, but also in diagnosing the most common disorders within this CMP LV dilatation and global reduction of contractilities 22. Echocardiography is also important to us to exclude any other potential causes of CMP and for further follow-up of patients. The risk factors for the development of CMP as a part to frequent PVC are still unknown, so that there are no clear guidelines for the frequency of echocardiographic follow-ups and Holter monitoring. If there are risk factors for coronary artery disease with regional wall motion abnormalities, then coronary angiography is to be performed. Furthermore, heart magnetic resonance imaging can give us the best information if you suspect the arrhythmogenic dysplasia, the history of myocarditis or infiltrative cardiac diseases. The general consensus is that the PVC therapy is required when LV dysfunction is recorded, and there is a thorough suspicious of PVC-induced CMP, or if the PVC burden is extremely high. The therapy is indicated in case of a slightly lower PVC burden in case of pronounced symptoms that impair the quality of life. There are two treatment options, conservative medical (antiarrhythmic drugs) treatment and catheter radiofrequency (RF) ablation. Most patients with frequent extrasystoles have structurally normal heart and once we determine it, it is primarily necessary to advise and comfort a concerned patient and explain that this it is a completely benign disorder with an excellent prognosis 1. No need to rush with pharmacotherapy, which is in this case indicated only if the symptoms limit the patient s life. Beta blockers or non-dihydropyridine calcium channel blockers are the first line of pharmacotherapy 23. In case they have no efficacy, we can use sotalol or I.b antiarrhythmics (mexiletine) or I.c (propafenone) groups which are otherwise 2014;9(1-2):31. Cardiologia CROATICA

32 djelovanje antiarimtika, kao i ostale moguêe nuspojave naspram potencijalne koristi. U sluëaju da lijeëimo bolesnika kod kojeg je doπlo do pada u funkciji LV tada nam, od antiaritmiëke farmakoterapije, preostaje jedino amiodaron. Terapija amiodaronom se u viπe studija pokazala kao uëinkovita u supresiji VES uz posljediënu normalizaciju funkcije LV 5,25. S obzirom na razvoj novih metoda i opcija invazivnog lije- Ëenja aritmija, ukljuëujuêi 3D navigacijske sustave (koje drastiëno reduciraju vrijeme fluroskopije), alternativne izvore ablativne energije (krioablacija), usavrπavanje epikardijalnog pristupa itd, kateterska ablacija postaje sve privlaënija opcija lijeëenja ove bolesti. Joπ uvijek ne postoje randomizirane kliniëke studije koje bi usporeappleivale medikamentozno i invazivno lijeëenje. UnatoË tome postoje brojni izvjaπtaji o uspjeπnosti RF ablacije u lijeëenju ove aritmije. Prva grupa koja je izvjestila o uspjeπnosti RF ablacije u normalizaciji funkcije LV bila je ona od Yarlagadde godine 14. Vrlo brzo uslijedilo je viπe izvjeπtaja sa sliënim rezultatima, na manjim brojevima bolesnika. NajveÊe serije bolesnika imala je grupa iz Michigena, takoappleer s vrlo povoljnim rezultatima RF ablacije. Bogun i sur. opisali su 60 bolesnika od kojih je 48 zadovoljavalo kriterije uspjeπnosti ablacije, a od 22 bolesnika s kompromitoranom funkcijom njih 18 uspjeπno abliranih imalo je znaëajan oporavak funkcije LV (EF 34% na 59%, LVIDd 59 mm na 51 mm) 6. Baman i sur. su izvjestili o 80% smanjenju VES optereêenja na 174 bolesnika uz zna- Ëajno poboljπanje funkcije LV (EF 35% na 54%) i redukciju dimenzija LV (LVIDd 59 mm na 54 mm) kod 57 bolesnika koji su imali razvijenu CMP 17. Kao i svaki invazivni zahvat, RF ablacija aritmija ima i svoje komplikacije koje se u starijim publikacijama javljaju u do 3% sluëajeva, a ukljuëuju moædani udar, AV blok koji zahtjeva elektrostimulaciju, perforaciju, tamponadu, lokalne vaskularne komplikacije, infarkt miokarda, itd 26. U novijoj literaturi koja se odnosi na ablacije VES, uëestalost komplikacija je znaëajno manja. Zbog navedenog potrebno je dobro razmisliti i odvagnuti potencijalnu korist naspram rizika same intervencije. Ne treba zaboraviti da i medikamentozno lijeëenje ima svojih negativnih strana, tako da moderne tehnike kateterske ablacije s boljim omjerom rizika i koristi postaju sve primamljivije i ËeπÊe koriπtene opcije lijeëenje VES inducirane karidomiopatije. ZakljuËak Ventrikulske ekstrasistole su u naëelu benigna pojava, osobito ako se radi o strukturno zdravom srcu, no Ëesto su previappleeni uzrok CMP. S obzirom da se najizglednije radi o dominantno funkcijskom poremeêaju koji je u velikoj mjeri reverzibilan, prepoznavanje ovog entiteta je vrlo vaæno za lijeëenje dijela bolesnika s neishemijskom CMP. Kateterska radiofrekvenctna ablacija sve je sigurnija i privlaënija metoda lijeëenja ovih pacijenata kojom izbjegavamo dugotrajno, moguêe i doæivotno uzimanje antiarimtika. Stoga, preporu- Ëamo da se ovakvi bolesnici referiraju u neki od elektrofizioloπkih centara. Recived: 15 th Jan 2014; Accepted: 19 th Jan 2014 *Address for correspondence: KliniËki bolniëki centar Zagreb, KiπpatiÊeva 12, HR Zagreb, Croatia. Phone: vvelagic@gmail.com contraindicated if CMP has already developed 24. In this case, you should always weigh any pro-arrhythmogenic effects of antiarrhythmics, as well as any possible side effects against the potential benefits. In case that we treat a patient who has experienced a decline in LV function, then the only one which is left from the antiarrhythmic drug therapy is amiodarone. In a number of studies amiodarone therapy has proved to be efficient in suppressing PVCs which resulted in normalization of LV function 5,25. Considering the development of new methods and options of invasive treatment of arrhythmias, including 3D navigation systems (which drastically reduce the time of fluoroscopy), the alternative sources of ablative energy (cryoablation), the advancement of epicardial access etc. the catheter ablation is becoming an increasingly attractive option of treating this disease. There are still no randomized clinical trials that compared the medical and invasive treatment. Nevertheless, there are numerous reports on the success of RF ablation in the treatment of this arrhythmia. The first group which reported on the success of RF ablation in normalizing the LV function was the one from Yarlagadde in It was followed by some more reports with similar findings on a smaller numbers of patients. The group from Michigan had the largest series of patients, also with very favorable results on RF ablation. Bogun et al. have described 60 patients, of whom 48 met the criteria for successful ablation, whereas out of 22 patients with compromised function there were 18 of them successfully ablated who experienced a significant recovery of the LV function (EF 34% to 59%, LVIDd from 59 mm to 51 mm) 6. Baman et al. have reported on 80% reduction of PVC burden in 174 patients with a significant improvement on the LV function (EF 35% to 54%) and reduction in LV dimensions (LVIDd from 59 mm to 54 mm) in 57 patients who had developed CMP 17. As in case of any invasive procedure, the RF ablation of arrhythmias is followed by its complications which according to previous publications appear in up to 3% of cases and include stroke, AV block requiring electrostimulation, perforation, tamponade, local vascular complications, myocardial infarction, etc 26. In the recent literature relating to the ablation of PVC, the incidence of complications is significantly lower. For this reason, it is necessary to think it through and weigh the potential benefits and risks of the procedure. We should not forget that the medical treatment also has its disadvantages, so that modern techniques of catheter ablation with a better risk-benefit ratio are becoming increasingly attractive and more commonly used treatment options for PVC-induced cardiomyopathy. Conclusion Ventricular extrasystoles are a common and generally a benign phenomenon, especially if a structurally normal heart is concerned, but they are frequently an overlooked cause of CMP. Given that the most likely scenario is a predominantly functional disorder that is largely reversible, it is very important to recognize this entity for the treatment of one portion of patients with non-ischemic CMP. Catheter radiofrequency ablation is becoming safer and more attractive method of treatment of these patients, where we avoid lengthy, and possibly lifetime antiarrhythmic therapy. Therefore, we recommend that such patients should be referred to some of the available electrophysiology centers. Cardiologia CROATICA 2014;9(1-2):32.

33 Literature 1. Gaita F, Giustetto C, Di Donna P, et al. Long-term follow-up of right ventricular monomorphic extrasystoles. J Am Coll Cardiol. 2001;38: Chugh SS, Shen WK, Luria DM, et al. First evidence of premature ventricular complex-induced cardiomyopathy: a potentially reversible cause of heart failure. J Cardiovasc Electrophysiol. 2000;11: Shiraishi H, Ishibashi K, Urao N, et al. A case of cardiomyopathy induced by premature ventricular complexes. Circ J. 2002;66: Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart. 2009;95: Duffee DF, Shen WK, Smith HC. Suppression of frequent premature ventricular contractions and improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy. Mayo Clin Proc. 1998;73: Bogun F, Crawford T, Reich S, et al. Radiofrequency ablation of frequent, idiopathic premature ventricular complexes: Comparison with a control group without intervention. Heart Rhythm. 2007;4: Takemoto M, Yoshimura H, Ohba Y, et al. Radiofrequency catheter ablation of premature ventricular complexes from right ventricular outflow tract improves left ventricular dilation and clinical status in patients without structural heart disease. J Am Coll Cardiol. 2005;45: Redfearn DP, Hill JD, Keal R, et al. Left ventricular dysfunction resulting from frequent unifocal ventricular ectopics with resolution following radiofrequency ablation. Europace. 2003;5: Del Carpio Munoz F, Syed FF, Noheria A, et al. Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs. J Cardiovasc Electrophysiol. 2011;22: Akoum NW, Daccarett M, Wasmund SL, et al. An animal model for ectopy-induced cardiomyopathy. Pacing Clin Electrophysiol. 2011;34: Huizar JF, Kaszala K, Potfay J, et al. Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol. 2011;4: Messineo FC. Ventricular ectopic activity: prevalence and risk. Am J Cardiol. 1989;64:53J-56J. 13. Ng GA. Treating patients with ventricular ectopic beats. Heart. 2006;92: Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation. 2005;112: Sekiguchi Y, Aonuma K, Yamauchi Y et al. Chronic hemodynamic effects after radiofrequency catheter ablation of frequent monomorphic ventricular premature beats. J Cardiovasc Electrophysiol 2005;16: Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart. 2009;95: Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm. 2010;7: AniÊ A, BakotiÊ Z, BiπtirliÊ M, JoviÊ M. Ablation of ventricular arrhythmias above semilunar valves. Cardiol Croat. 2014;9(1-2): Yokokawa M, Kim HM, Good E, et al, Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy, Heart Rhythm. 2012;9: Yokokawa M, Kim HM, Good E, et al. Relation of symptoms and symptom duration to premature ventricular complex-induced cardiomyopathy. Heart Rhythm. 2012;9: Wilber DJ. Ventricular ectopic beats: not so benign. Heart. 2009;95: Shanmugam N, Chua TP, Ward D. Frequent ventricular bigeminy-a reversible cause of dilated cardiomyopathy. How frequent is frequent? Eur J Heart Fail. 2006;8: Krittayaphong R, Bhuripanyo K, Punlee K, et al. Effect of atenolol on symptomatic ventricular arrhythmia without structural heart disease: a randomized placebo-controlled study. Am Heart J. 2002;144:e Echt DS, Liebson PR, Mitchell LB, wt al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324: Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med. 1995;333: Wellens HJ. Catheter ablation of cardiac arrhythmias: usually cure, but complications may occur. Circulation. 1999;99: ;9(1-2):33. Cardiologia CROATICA

34 Pregledni rad / Review article Ablacija ventrikularnih aritmija iznad semilunarnih valvula Ablation of ventricular arrhythmias above semilunar valves Ante AniÊ*, Zoran BakotiÊ, Marin BiπtirliÊ, Albino JoviÊ OpÊa bolnica Zadar, Zadar, Hrvatska Zadar General Hospital, Zadar, Croatia SAÆETAK: Aritmije iz izgonskog trakta desne ili lijeve klijetke mogu imati svoje ishodiπte u supravalvularnim miokardnim ekstenzijama. Medikamentozna terapija je tradicionalno neuspjeπna pa se kod simpomatskih slu- Ëajeva ili onih kod kojih se razvije aritmijom inducirana kardiomiopatija treba odluëiti za interventno rjeπenje. Za njihovu uspjeπnu eliminaciju ablacijom mapiranje i primjena radiofrekventne energije mora se uëiniti iznad semilunarnih valvula, u regijama koje imaju specifiëne anatomske osobitosti. U ovom preglednom radu donosimo kratak osvrt na anatomsku podlogu ovih aritmija i intraproceduralne korake koji vode uspjeπnoj i sigurnoj ablaciji, kao i pregled vlastitog iskustva. KLJU»NE RIJE»I: ablacija ventrikularnih aritmija, idiopatske ventrikularne tahikardije, ventrikularna tahikardija iz koronarnih kuspisa, preferentna kondukcija, potencijal velikih arterija. SUMMARY: Arrhythmias from the right and left ventricular outflow tract may stem from supravalvular myocardial extensions. Medical therapy has traditionally been unsuccessful, so in symptomatic cases or those in which arrhythmia-induced cardiomyopathy develop we should opt for an intervention. Mapping and use of radiofrequency energy has to be performed above semilunar valves for their successful elimination by ablation, in the regions that have specific anatomical features. This review article provides a brief overview of the anatomical substrate of these arrhythmias and intraprocedural steps that lead to successful and safe ablation, as well as an overview of our own experience. KEYWORDS: ablation of ventricular arrhythmias, idiopathic ventricular tachycardias, ventricular tachycardia from coronary cusps, preferential conduction, great arterial potential. CITATION: Cardiol Croat. 2014;9(1-2): I diopatske ventrikularne aritmije Ëine dobro opisani entitet u elektrofiziologiji. Prvi prikazi serija pacijenata su pokazali predilekcijsku sklonost za izlazni trakt desne klijetke (RVOT). Razvojem elektrofiziologije shvatilo se da znaëajan dio tih aritmija moæe dolaziti i iz izlaznog trakta lijeve klijetke (LVOT), a u tim sluëajevima je supstrat dominantno smjeπten supravalvularno 1. Suvremeni prikazi serija pacijenata s ovim entitetom upuêuju da supravalvularne ventrikularne aritmije Ëine Ëak oko 16% od ukupnog broja pacijenata s idiopatskim ventrikularnim aritmijama, πto daje naslutiti da je ovaj entitet bio u proπlosti nedovoljno shvaêen i u veêine pacijenata previappleen 2. Anatomska i patofizioloπka podloga supravalvularnim aritmijama Koncept ekstenzija ventrikularnog ili atrijskog miokarda u velike krvne æile je poznat veê dugo. Proπla su puna tri desetljeêa od prvog sistematskog opisa ekstenzija atrijskog miokarda u pluêne vene do spoznaje da su ti izolirani traëci tkiva elektriëki nestabilni i mogu biti okidaë aritmije, u ovom sluëaju fibrilacije atrija 3. Dva razloga su u podlozi, prvo, izoli- I diopathic ventricular arrhythmias are a well described entity in electrophysiology. The first presentations of a series of patients showed a predilection for the right ventricular outflow tract (RVOT). With the development of electrophysiology it was found that a significant proportion of these arrhythmias can stem from the left ventricular outflow tract (LVOT), and in these cases the substrate is predominantly located in the supravalvular region 1. Modern presentations of a series of patients with this entity suggest that supravalvular ventricular arrhythmias even make for 16% of the total number of patients with idiopathic ventricular arrhythmias, which suggests that this entity was not sufficiently understood in the past and it was overlooked in the majority of patients 2. Anatomical and pathophysiological substrate for supravalvular arrhythmias The concept of ventricular or atrial myocardium extension in large blood vessels has already been known for a long time. It has been full three decades since the extensions of atrial myocardium in the pulmonary veins were systematically described for the first time until we realized that these isolated tissue fibers are electrically unstable and may trigger arrhy- Cardiologia CROATICA 2014;9(1-2):34.

35 rani miokard gubi elektriënu stabilnost jer nije dio sincicija. Gubi se komunikacija izmeappleu stanica i stvara podloga autonomnoj elektriënoj aktivnosti. Kao drugi razlog se opisuje heterogenost u brzini provoappleenja impulsa (anizotropija) πto stvara uvjete za lokalizirani reentry. Za idiopatske ventrikularne aritmije supravalvularnog ishodiπta se smatra da je izoliranost tih vlakana od ostalog miokarda osnovna podloga njihovoj autonomnoj aktivnosti. Bitan koncept za objaπnjenje ovog entiteta je i razumijevanje povezanosti ovih vlakana s miokardom. Ako se promotre intimni anatomski odnosi LVOT, RVOT te koronarnih kuspisa postaje jasno zaπto naprimjer fokus iz lijevog koronarnog kuspisa moæe imati viπestruke regije izlaza impulsa, najëeπêe prema LVOT, ali i prema septalnom RVOT πto onemoguêava koriπtenje elektrokardiografskih kriterija za lokalizaciju ishodiπta aritmije 4 (Slika 1). Razumijevanje ovog fenomena, tzv. preferentne kondukcije impulsa, vrlo je vaæno jer objaπnjava zaπto u istog pacijenta moæemo imati ventrikularne aritmije razliëitih QRS morfologija, a sve se mogu ablirati u istom fokusu (Slika 2). Tradicionalno bi viπestruke QRS thmias, in the case the atrial fibrillation 3. Two reasons lie in the substrate, first, the isolated myocardium loses electrical stability because it is not a part of the syncytium. The cell to cell coupling is lost, thus creating the foundation for autonomous electrical activity. The second reason is described as heterogeneity of the rate of impulse conduction (anisotropy) providing thus the conditions for localized reentry. For idiopathic ventricular arrhythmias of supravalvular origin it is considered that the isolation of such fibers from the remaining myocardium is the basic foundation of their autonomous activities. An important concept for the explanation of this entity is the understanding of association of these fibers with myocardium. Looking at the intimate anatomical relations LVOT, RVOT and coronary cusps, it becomes clear why for example, the focus from the left coronary cusp can have multiple exit sites, usually towards the LVOT, but also to the septal RVOT which makes the use of electrocardiographic criteria for the localization of the origin of arrhythmias unreliable 4 (Figure 1). Understanding this phenomenon, the so-called Figure 1. Cross section through the heart at the level of semilunar valves. Aortic valve is behind and below the pulmonary. Left coronary cusp faces the superoposterior aspect of right ventricular outflow tract and pulmonary artery. Right coronary cusp is in intimate relation to His bundle, while non-coronary cusp is in intimate relation to interatrial septum. Figure lead electrocardiogram in patient with idiopathic non-sustained ventricular tachycardia originating in left coronary cups. Both nonsustained ventricular tachycardia episodes demonstrate first QRS complex having different morphology when comparing to the rest of complexes, pointing to a preferential conduction being the operative mechanism. Since pattern is reproducible, it proves the preferential conduction and excludes some other possible explanations for this phemonenon, such as fusion. 2014;9(1-2):35. Cardiologia CROATICA

36 morfologije obeshrabrile pokuπaj ablacije te rezultirale ekstenzivnom kardioloπkom obradom, neinvazivnom i invazivnom, u smislu traæenja organskog supstrata za takav obrazac ventrikularnih aritmija. KliniËka slika i medikamentozno lijeëenje Kao i kod drugih tipova idiopatskih ventrikularnih aritmija u pojedinaënog pacijenta se moæe registrirati cijeli spektar, od izoliranih ventrikularnih ekstrasistola, Ëesto u obliku bigeminija ili trigeminija, preko nepostojanih ventrikularnih tahikardija (NSVT) do dugotrajnije VT. Ovisno o optereêenju ektopijskom aktivnoπêu entitet moæe predstavljati godinama samo simptomatski fenomen, no nerijetko se razvija i aritmijom inducirana kardiomiopatija. Tradicionalno se ove aritmije kao lijekom izbora lijeëe betablokatorima, no vlastito i iskustvo drugih centara ukazuje da ove aritmije uglavnom nisu inducirane adrenergiënim tonusom, tj. razlikuju se od klasiënih RVOT tahikardija koje su trigerirane, posredovane intracelularnim camp. Dokaz za to je da prilikom testa optereêenja u pravilu dolazi do supresije ektopijske aktivnosti, toënije bi bilo reêi ipak da dolazi do dominacije sinusnog ritma zbog duæine ciklusa. Antiaritmici skupine I.c (u Hrvatskoj propafenon) mogu u pojedinaënim sluëajevima dovesti do znaëajne supresije ektopijske aktivnosti, no doista je nuæno prije lijeëenja iskljuëiti strukturnu bolest srca. Ablacija u supravalvularnim regijama Zbog neuspjeha medikamentozne terapije, ali i Ëinjenice da se uglavnom radi o mladim, aktivnim pacijentima, ablaciju treba rano ponuditi kao terapijsko rjeπenje. Bilo da je fokus u pluênoj arteriji ili Valsalvinim aortnim sinusima (u i iznad koronarnih kuspisa) ne radi se o posebno zahtjevnim ablacijskim manevrima. DapaËe, mapiranje aorte retrogradnim pristupom je vrlo lako, no primjena radiofrekventne (RF) energije mora biti diskretna zbog blizine koronarnih arterija. Naprimjer, kako je pulmonalna valvula oko 1-2 cm iznad aortne, ablacija fokusa tik iznad pulmonalne valvule moæe biti udaljena svega 5-6 mm od debla lijeve koronarne arterije, dok je jasna, intrinziëna, opasnost za ozljedu uπêa koronarnih arterija za ablacije u aorti pa se primjena RF energije obvezno mora kontrolirati nekom od slikovnih metoda prikaza, bilo direktnom koronarnom angiografijom (Slika 3) preferential conduction of impulses, is very important because it explains why the same patient can have ventricular arrhythmias of different QRS morphologies, and all of them can be ablated in the same focus (Figure 2). Traditionally, multiple QRS morphologies would discourage the attempts of ablation and result in an extensive diagnostic cardiac work up, both non-invasive and invasive, in terms of seeking an organic substrate for such a form of ventricular arrhythmias. Clinical manifestations and medical treatment As in other types of idiopathic ventricular arrhythmias, the entire spectrum can be recorded in an individual patient from isolated ventricular extrasystoles, often in the form of bigeminies or trigeminies through non-sustained ventricular tachycardia (NSVT) to sustained VT. Depending on the ectopic activity burden, the entity can make for only symptomatic phenomenon for years, however, arrhythmia induced cardiomyopathy often develops. Traditionally, these arrhythmias are treated by beta-blockers as the drugs of choice, but our own experience and experience of other centers suggests that these arrhythmias are generally not induced by adrenergic tone, that is, they differ from traditional RVOT tachycardias which are triggered, mediated by intracellular camp. The proof for this is that the suppression of ectopic activity typically occurs during the exercise stress test, to be more precise, that the dominance of sinus rhythm occurs due to the length of the cycle. Group 1c antiarrhythmics (propafenone in Croatia) can in particular cases lead to significant suppression of ectopic activity, but it is really necessary to exclude structural heart disease before the treatment is initiated. Ablation in supravalvular regions Due to the failure of the medical therapy, but also the fact that these are mainly young, active patients, the ablation should be early offered as a therapeutic solution. No matter whether the focus is in the pulmonary artery or aortic sinuses of Valsalva (and above the coronary cusps), no particularly demanding ablation maneuvers are concerned. On contrary, the mapping by applying retrograde aortic approach is straightforward, but the use of radiofrequency (RF) energy has to be discreet because of the proximity of the coronary Figure 3. Left coronary angiography during the ablation in aortic cusps, left anterior oblique 30 view. Ablation catheter is introduced through the right femoral artery and positioned at the left coronary cusp. Catheter for left coronary angiography is introduced via right radial artery. Another ablation catheter is also shown, introduced through right femoral vein for right ventricular outflow tract and pulmonary artery mapping to allow simultaneous right and left sided mapping as per standard institutional protocol. Intimate relation of superoposterior right ventricular outflow tract to left main coronary artery can easily be appreciated. Cardiologia CROATICA 2014;9(1-2):36.

37 ili pod monitoriranjem poloæaja ablacijskog katetera putem intrakardijalne ehokardiografije (ICE) (Slika 4). Za ablacije u desnom koronarnom kuspisu postoji opasnost ozljede Hisovog snopa koja se moæe izbjeêi paæljivim praêenjem signala i stimulacijom s velikom izlaznom energijom koja ne smije postiêi His stimulaciju. arteries. For example, since the pulmonary valve is about 1-2 cm above the aorta, the ablation of the focus just above the pulmonary valve may be only 5-6 mm distant from the left main coronary artery, while the danger of an injury to the orifice of the coronary arteries for aortic ablation is clear and intrinsic, so the use of RF energy must necessarily be controlled by some imaging method, either by direct coronary angiography (Figure 3) or by monitoring the position of ablation catheter via intracardiac echocardiography (ICE) (Figure 4). As for ablations in the right coronary cusp, there is a danger of an injury to the bundle of His that can be avoided by careful monitoring of signals and stimulation with a high power output that can not achieve the stimulation of His. Figure 4. Intracardiac echocardiography imaging during the ablation in aortic cusps. Left panel shows native images of aortic valve and root before putting in the ablation catheter (longitudinal view-up; cross sectional view-down). Right panel shows ablation catheter positioned in left aortic cups, as imaged by intracardiac echocardiography Using this techique one can perform safe ablation at these sites since it allows clear catheter tip visualization therefore enabling assesment of cathetertissue contact and its relation to left main coronary artery. Furthermore it helps assesing for complications such as valvular insufficiency. Zadnjih godina se naglaπava nuænost registracije vrlo tipiënih elektrograma za pronalaæenje toënog ishodiπta aritmije. Naime izolirani traëci miokarda u aorti ili pulmonalnoj arteriji daju vrlo specifiëan potencijal koji je istovjetan onom koji se moæe snimiti u pluênim venama ili na Hisovom snopu 5. Taj potencijal, nazvan potencijal velikih arterija, tijekom ektopijske aktivnosti pada vrlo rano ispred QRS kompleksa πto dokazuje da je taj miokardni traëak ishodiπte aritmije i ozna- Ëava primjeren cilj za ablaciju 6. Ti signali imaju vrlo veliku prediktivnu vrijednost za trajni uspjeh RF ablacije, a ablacija voappleena tim signalima tipiëno rezultira gotovo trenutnim nestankom ventrikularne ektopijske aktivnosti. Uspjeh i komplikacije radiofrekventne ablacije supravalvularnih aritmija Uspjeh ablacije supravalvularnih aritmija je bolji nego za klasiëne intramiokardijalne fokuse, jer je regija iz koje dolazi ventrikularna aktivnost dobro definirana πto ne mora biti slu- Ëaj kod klasiënih RVOT aritmija gdje je u pravilu nuæna primjena viπekratnih radiofrekventnih lezija za eliminaciju aritmije. Ablacija voappleena potencijalima velikih arterija predstavlja suvremeni standard i nudi 95% vjerojatnost dugotrajne neprisutnosti aritmije. Od komplikacija su opisane ozljede koronarnih arterija ili kuspisa s posljediënom valvularnom insuficijencijom. Oboje su In recent years we highlight the necessity of registering very typical electrograms to find the exact origin of arrhythmia. Specifically isolated myocardial fibers in the aorta or pulmonary artery provide a very specific potential which is identical to that which can be recorded in the pulmonary veins or on the bundle of His 5. This potential, called the great arterial potential drops during the ectopic activity very early before the QRS complex, which proves that this myocardial fiber of the origin of arrhythmias marks an appropriate target for ablation 6. These signals have a very high predictive value for the long-term success of RF ablation, and ablation guided by these signals typically results in almost immediate disappearance of ventricular ectopic activity. Success and complications of radiofrequency ablation of supravalvular arrhythmias The success of ablation of supravalvular arrhythmias is better than the classical intramyocardial focuses, because the region that the ventricular activity comes from is well defined which needs not be the case in classical RVOT arrhythmias where the application of multiple radiofrequency lesions for the elimination of arrhythmias is required. Ablation guided by great arterial potential is the modern standard and provides a 95% probability of long-term absence of arrhythmias. Regarding the complications, the injuries to coronary arteries and cusps with consequential valvular insufficiency 2014;9(1-2):37. Cardiologia CROATICA

38 na razini anegdotalnih opisa i uz danaπnju dostupnost slikovnih metoda, osobito primjenom ICE se ne bi smjele dogaappleati. Iskustva iz OpÊe bolnice Zadar U razdoblju od travnja do prosinca godine uëinjena ablacija u supravalvularnim regijama u 13 pacijenata (10 u aortnim kuspisima, 3 u pluênoj arteriji) πto predstavlja 25% od ukupnog broja pacijenata kod kojih je raappleena ablacija idiopatske ventrikularne aritmije. U 8 od 10 pacijenata s uspjeπnom ablacijom u aortnim kuspisima su registrirani arterijski potencijali te u svih pacijenata s fokusom u pluênoj arteriji (Slika 5). have been described. They are both at the level of anecdotal descriptions, and with today s availability of imaging methods, particularly ICE, they should not occur. Experience from the Zadar General Hospital During the period from April 2011 to December 2013, the ablation was performed in supravalvular regions in 13 patients (10 in the aortic cusps, 3 in the pulmonary artery), which accounts for 25% of the total number of patients who underwent the ablation of idiopathic ventricular arrhythmias. Arterial potentials were registered in 8 out of 10 patients with successful ablation in the aortic cusps, and in all patients with the focus in the pulmonary artery (Figure 5). Figure 5. Signals from the ablation catheter positioned at the left aortic cusp (same patient as at Figure 4). Upper panel shows 12-lead electrocardiogram, ABLd-bipolar electrogram from the distal part of the tip of the catheter, ABLp-bipolar electrogram from the proximal part of the catheter s tip, ABL U-unipolar electrogram from the ablation catheter. During premature ventricular complex, discreet, sharp potential is reproducibly registered that precedes QRS by 96 ms. This signal represents isolated myocardial fiber potential and stems out of myocardial exstension into aorta thus the designation-great arterial potential. During sinus QRS complexes this signal comes after the local ventricular electrogram, pattern is reversed during premature ventricular complex. Za ablaciju je koriπtena samo konvencionalna oprema za elektrofiziologiju (elektrofizioloπke stanice EP Tracer 70, Cardiotek, Netherlands i EP Med 3, SJM, USA), bez pomoêi sustava za elektroanatomski mapping. Raspon uranjenosti signala pred QRS-om je bio ms za ablacije u koronarnim kuspisima te ms za fokuse u pluênoj arteriji.»ak u 4 pacijenta se radilo o ponovljenim procedurama te se u svim tim sluëajevima opisivala ranija neuspjeπna ablacija u subvalvularnom RVOT. Akutni uspjeh u smislu kompletne eliminacije ektopijske aktivnosti je bio zabiljeæen u svih 13 pacijenata, a postproceduralno je u dosadaπnjem praêenju (1-30 mjeseci) zabiljeæen povrat aritmije u samo jednog. Ablacija u koronarnim kuspisima je u svih pacijenata bila monitorirana direktnom koronarnom angiografijom ili primjenom ICE. Nije zabiljeæena ikakva komplikacija u smislu ozljede koronarnih arterija ili valvularne insuficijencije. Only conventional equipment for electrophysiology (electrophysiological stations EP Tracer 70, Cardiotek, Netherlands and EP Med 3, SJM, USA) was used for the ablation, without the help of the electroanatomical mapping system. The early signal range before QRS was ms for the ablations in coronary cusps and ms for foci in the pulmonary arteries. 4 patients were redo cases and in all these cases the earlier unsuccessful ablation in subvalvular RVOT was described. Acute success in terms of the complete elimination of ectopic activity was observed in all 13 patients, and recurrence of arrhythmia was recorded in only one patient in the postprocedural follow up (at 1-30 months). The ablation in coronary cusps was monitored in all patients by direct coronary angiography or ICE. Not a single complication was observed in terms of an injury to coronary arteries or valvular insufficiency. Cardiologia CROATICA 2014;9(1-2):38.

39 Received: 30 th Dec 2013; Accepted 5 th Jan 2014 *Address for correspondence: OpÊa bolnica Zadar, Boæe PeriËiÊa 5, HR Zadar, Croatia. Phone: anteanic@gmail.com Literature 1. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Ventricular tachycardias arising from the aortic sinus of valsalva: an under-recognized variant of left outflow tract ventricular tachycardia. J Am Coll Cardiol. 2001;37: Yamada T, McElderry HT, Doppalapudi H, et al. Idiopathic ventricular arrhythmias originating from the aortic root prevalence, electrocardiographic and electrophysio- logic characteristics, and results of radiofrequency catheter ablation. J Am Coll Cardiol. 2008;52: AniÊ A. Catheter ablation for atrial fibrillation. Cardiol Croat. 2010;5(3-4): Yamada T, Platonov M, McElderry HT, Kay GN. Left ventricular outflow tract tachycardia with preferential conduction and multiple exits. Circ Arrhythm Electrophysiol. 2008;1: Tada H, Naito S, Ito S, et al. Significance of two potentials for predicting successful catheter ablation from the left sinus of Valsalva for left ventricular epicardial tachycardia. Pacing Clin Electrophysiol. 2004; 27: Tabatabaei N, Asirvatham S. J. Supravalvular arrhythmia: identifying and ablating the Substrate. Circ Arrhythm Electrophysiol. 2009;2: ;9(1-2):39. Cardiologia CROATICA

40 Prikaz sluëaja / Case report Pristup bolesniku s poremeêajem provoappleenja uzrokovan Lyme boreliozom Approach to a patient with conduction disturbance caused by Lyme borreliosis Ena KurtiÊ 1, Ivica PremuæiÊ MeπtroviÊ 2 *, Hrvojka Marija Zeljko 2, Stjepan KranjËeviÊ 2, Darko PoËaniÊ 2, Helena JerkiÊ 2 1 Dom zdravlja Zagreb Centar, Zagreb, Hrvatska 2 KliniËka bolnica Merkur, Zagreb, Hrvatska 1 Public Health Centre Zagreb Centar, Zagreb, Croatia 2 Clinical Hospital Merkur, Zagreb, Croatia SAÆETAK: U muπkarca s kliniëkom slikom Lyme borelioze i atrioventrikulskim blokovima svih stupnjeva indicirano je elektrofizioloπko ispitivanje, a po nalazu i ugradnja dvokomornog elektrostimulatora srca. Smatramo da je elektrofizioloπko ispitivanje indicirano kod te grupe bolesnika radi donoπenja odluke o potrebi ugradnje privremenog ili trajnog elektrostimulatora srca. KLJU»NE RIJE»I: Lyme borelioza, poremeêaj provoappleenja, elektrofiziologija, elektrostimulator. SUMMARY: In a man presented with Lyme disease and atrioventricular blocks of all grades, electrophysiology study is indicated followed by the implantation of the two chamber permanent pacemaker upon obtaining the findings. We consider electrophysiology study indicated in that group of patients for the purpose of making a decision to implant a temporary or a permanent pacemaker. KEYWORDS: Lyme boreliosis, conduction disturbance, electrophysiology, pacemaker. CITATION: Cardiol Croat. 2014;9(1-2): Uvod U Europi se Lyme borelioza kardioloπki manifestira u oko 0,5% do 4,0% sluëajeva, meappleutim neke studije navode razvoj kardijalnih komplikacija i do 10% nelijeëenih bolesnika s infekcijom koju uzrokuje Borrelia burgdorferi 1,2. Lajmska bolest se javlja sa sliënom prevalencijom u oba spola te zahvaêa ljude sve dobi, meappleutim, neki autori navode drugaëiju prevalenciju lyme karditisa ovisno o spolu 3,4. Lyme karditis se prezentira najëeπêe kao poremeêaj atrioventrikulskog (AV) provoappleenja, pri Ëemu se najëeπêe javlja prolongacija PR intervala, koji progredira u oko 50% tih bolesnika u totalni AV blok 5. Napominje se da se u istog bolsnika mogu intermitentno javiti razliëiti stupnjevi AV provoappleenja 6. Totalni AV blok tipiëno spontano prolazi (u viπe od 90% bolesnika) unutar tjedan dana, a manje teπki poremeêaji provoappleenja unutar πest tjedana 7. Postavljanje dijagnoze lyme karditisa moæe biti veoma zahtjevno, a kada se naglo razvije AV blok nepoznate etiologije potrebni je uzeti u obzir lyme karditis, posebice u mladih ljudi 6. Eritema migrans, kao izrazito specifiëan simptom akutne faze bolesti Ëesto nije prisutan u svim sluëajevima 8, zbog Ëega postoji potreba za jasnim testom potvrde kliniëke sumnje seroloπka pretraga kao πto je imunoapsorpcijski Introduction While some studies showed that cardiac manifestations in Lyme borreliosis occur in 0.5% to 4.0% of cases in Europe, some other studies have suggested incidences as high as 10% of untreated patients infected with Borrelia burgdorferi as having cardiac complications 1,2. Lyme disease has a similar prevalence in both males and females and affects people of all ages, while some studies have shown slightly different Lyme carditis predominance depending on a sex 3,4. It is tipically presented as conduction disturbances, the most common of which is the 1 st degree atrioventricular (AV) block, with up to 50% of these patients progressing to complete heart block 5. Also, different forms of block can occur intermittently in a single patient 6. Complete AV block typically spontaneously (in >90% patients) resolves within one week, and more minor conduction disturbances within six weeks 7. Diagnosis Lyme carditis can be very challenging. When AV block of unkown origin develops suddenly, Lyme carditis must be considered, especially in younger patients 6. Although erytema migrans is a very specific symptom in the acute phase, it may not be present in all cases 8. Therefore, there is a need of readily clinical testing serologic examination, such as enzyme-linked immunosorbent assay Cardiologia CROATICA 2014;9(1-2):40.

41 enzimski test (ELISA) 9. Tijekom Ëekanja rezultata pretrage, opravdano je kod bolesnika s poremeêajem provoappleenja, uëiniti elektrofizioloπko ispitivanje radi donoπenja odluke o potrebi ugradnje trajnog ili privremenog elektrostimulatora. Prikaz sluëaja Hospitaliziran je prethodno zdrav 32-godiπnjak zbog umora, muënine i razvoja AV bloka nepoznatog trajanja. Kod prijema bolesnik je bio priseban, afebrilan te bez patoloπkog nalaza u statusu osim sistoliëkog πuma nad aortalnom valvulom maksimalnog intenziteta II/IV. Bolesnik nije uzimao nikakve lijekove, ilegalnu drogu ili je imao promjenu u prehrani koji bi mogli utjecati na navedene simptome. Po zanimanju je poljoprivrednik, a bavi se i pëelarstvom te uzgojem krava i svinja. Navodi uëestale ubode krpelja, posljednji put prije mjesec dana kada je primijetio i osip u podruëju glutealne regije, zbog navedenoga se nije javio lijeëniku obiteljske medicine. Kod bolesnika nisu utvrappleeni sistemski znakovi infekcije ili simptomi sliëni gripi karakteristiëni za poëetnu fazu. Nakon prijema uëinjeno je rutinsko laboratorijsko testiranje pri Ëemu nisu utvrappleena patoloπka odstupanja. Elektrokardiogram je pokazao sinusni ritam, urednog trajanja PR intervala, bez drugih poremeêaja provoappleenja. DinamiËkim elektrokardiogramom se utvrdi intermitentna pojava AV bloka svih stupnjeva. NajËeπÊi patoloπki nalaz bili su prolongacija PR intervala do 320 ms i Mobitz tip I. Manje uëestalo su se javljali AV blok II stupnja Mobitz tip II i totalni AV blok s uskim QRS kompleksom i s najduljim RR intervalom od 3 sekunde. Tijekom Ëekanja nalaza uëinjene seroloπke pretrage za B. burgdorferi uëinili smo elektrofizioloπko (EF) ispitivanje. Rezultati EF ispitivanja (Figure 1) su ukazali na rascijepani i prolongirani His (35 ms), atrio-hisalna provodljivost (AH interval) je bila normalna (75 ms), a his-ventrikularna (HV) provodljivost je bila oπteêena (65 ms). Tijekom kateterske (kvadripolarni) stimulacije iz podruëja desnoga atrija izazove se Wenckebach kod 660 ms. Na temelju rezultata elektrofizioloπkog ispitivanja koje je ukazalo na intra- i infrahisalni poremeêaj provoappleenja indicira se ugradnja dvokomornog elektrostimulatora srca. Tri mjeseca kasnije na kontroli rada (ELISA) 9. While awaiting the results, the electrophysiological examination should be done in patients with conduction disturbances to localize the origin of the block in order to estimate the need of implantation of a permanent or a temporary pacemaker. Case presentation A 32-year old previously healthy man was admitted for fatigue, nausea and AV block of undetected origin. On examination, the patient was conscious, afebrile and responsive with no abnormalities in physical examination except for a systolic heart murmur II/VI, punctum maximum above aortic valve. Based on the patient s reliable account, he did not use any medications, illegal drugs and made no changes in diet which could be attributed to reported symptoms. The patient is a farmer, he is engaged in beekeeping and breeds cows and pigs. He recalls a tick bites, many of them, the last one occurred a month ago, and he noticed rash on his gluteal region, but he did not consult the family physician. There were no systemic signs of an infection or flu-like symptoms as commonly observed in the initial stage. After admission, we did routine laboratory blood testing and there were no pathological aberrations. A resting electrocardiogram showed sinus rhythm, normal length of PR interval and without other aberrations. Holter ECG revealed AV block of all grades, intermittently. Most common pathological findings was PR prolongation up to 320 ms and AV block second degree Mobitz type I. Atrioventricular block second degree Mobitz type 2 and total AV block occurred less frequently, with narrow QRS complexes and the longest RR interval of up to 3 seconds. While waiting for serological findings for B. burgdorferi, we approached to electrophysiological examination (EPS). Results of the EPS (Figure 1): Electrophysiological study showed a spitted and prolonged His potential (35 ms), the atrio- Hisial conduction (AH interval) was normal (75 ms) and Hisventricular (HV interval) conduction was disturbed (65 ms). During the catheter stimulation from the site of the right atrium, Wenckebach appears at 660 ms. Considering the results of the electrophysiology studies, which revealed the intra- and infra-hisian conduction disturbance, implantation of permanent double-chamber pacemaker is indicated. Figure 1. I, II, V1 extracardiac records; RA 1-4 quadripolar catheter in the area of His; RA 5-8 quadripolar catheter in the are of right atrium; AH atrio-hisial interval; HV his-ventricular interval. 2014;9(1-2):41. Cardiologia CROATICA

42 elektrostimulatora utvrdi se ventrikulska stimulacija u 8% vremena, a u preostalom vremenu je bio prisutan ventrikulski sensing. Rasprava Lajmska bolest je multisistemska bolest uzrokovana s Borrelia burgdorferi. ZahvaÊenost srca kod ove bolesti je izrazito rijetko i nastaje tijekom rane faze bolesti, u prosjeku unutar 3-10 dana od inicijalnog izlaganja. Kao i bolesnici prezentirani u drugim sluëajevima, naπ bolesnik nije imao ranije zdravstvene tegobe, ali je navodio osip te se prezentirao sa steëenim AV blokovima svih stupnjeva zbog Ëega smo se odluëili uëiniti elektrofizioloπko ispitivanje uslijed postavljene sumnje na Lyme boreliozu. KliniËka manifestacija lymske bolesti je izrazito varijabilna, pri Ëemu se najëeπêe kod zahvaêenosti srca javljaju AV blokovi Naime, Van der Linde je u preglednom Ëlanku o kliniëkim karakteristikama lyme karditisa kod 66 sluëajeva u Europi i 39 sluëajeva u SAD-u zakljuëio da je totalni AV blok bio najëeπ- Êi oblik AV bloka u obje skupine. On se javio u 49% bolesnika, u usporedbi s pojavnoπêu AV blokom kod 16% te prolongacije PR intervala kod 12% bolesnika. Prema istome, vjerojatnost razvoj kompletnog AV bloka je znatno ËeπÊa kod produljenja PR intervala >300 ms 6. Elektrofizioloπko ispitivanje provedeno na 19 bolesnika s Lyme karditisom je pokazalo da je u 68% bolesnika blok nastao na supraventrikulskoj razini, pri Ëemu je jedna treêina ispitanika imala difuzno zahvaêen provodni sustav zaklju- Ëeno na temelju produljenih AA, AH i HV intervala 14. U drugom Ëlanku stoji da je 98% bolesnika s poremeêajima provoappleenja tijekom bolesti imalo PR prolongaciju, dok se Wenckebachova periodika javila u 40% i AV blok u 50% bolesnika 7. McAlister i sur. su godine proveli elektrofizioloπko ispitivanje na 4 bolesnika s lajmskom bolesti pri Ëemu su 3 pacijenta imala blok iznad His-a. Preostali pacijent je imao blok ispod razine His-a te je zahtijevao implantaciju trajnog elektrostimulatora srca 7. Van der Linde je takoappleer izvijestio o 4 bolesnika s AV blokom izazvanim lyam-boreliozom, pri Ëemu je uëinio elektrofizioloπko ispitivanje na trojici od njih. Ispitivanjem se kod dvoje bolesnika verificirao suprahisalni blok, a kod treêeg normalni AH interval, bez terminalne negativne defleksije His-ovog signala uz razvoj totalne disocijacije signala Hisovog snopa i ventrikla 15. Studija je pokazala da se poreme- Êaj provoappleenja takoappleer moæe javiti u distalnom segmentu His-ova snopa ostavljajuêi proksimalni dio His-a netaknutim. U tom izvjeπêu, unatoë ekstenzivnoj primjeni antibiotika i kortikosteroida kod bolesnika je perzistirao totalni AV blok te je pacijentu implantiran trajni elektrostimulator Naπ pacijent, baπ kao i veê navedeni iz primjera, prikazao se klasiënom slikom poremeêaja provoappleenja kod Lyme borelioze u smislu da su zabiljeæeni intermitentno svi tipovi AV blokova. S obzirom na postavljenu sumnju, kasnije seroloπki potvrappleenu, uëini se EF ispitivanje. Istim se utvrdi fragmentacija His-a i njegova prolongacija πto ukazuje da je boleπêu zahvaêen i His (intrahisalno). Takoappleer, zabiljeæi se produljen HV interval koji ukazuje na bolest provodne strukture distalnije od AV Ëvora (infrahisalni blok). VodeÊi se time i ranije objavljenim radovima McAllistera i van der Linde 6,7, odluëili smo se za ugradnju trajnog elektrostimulatora srca. U daljnjem praêenjem, pacijent je bio subjektivno bez tegoba te se na prvoj kontroli rada elektrostimulatora, kao dodatna potvr- Three months later, on control checkup, we verified ventricular stimulation during the 8% of the time, whereas ventricular sensing was present during the remaining time. Discussion Lyme disease is a multisystem disease caused by Borrelia burgdorferi. Cardiac involvement with Lyme disease is extremely rare and occurs during the early disseminated phase of the disease, typically within 3-10 days of initial exposure. Our patient, just like many other presented patients in other cases, is young, with no health problems, with the history of rash and acquired AV block of all types, so we decided to do electrophysiology study, based on suspected Lyme borreliosis. The clinical expression of Lyme disease is highly variable, but the most common cardiac manifestation is AV block Van der Linde, in a review of the clinical characteristics of 66 cases of Lyme carditis in Europe and 39 cases from the US, found that complete heart block was the most common form of AV block in the both groups. It was present in 49% of patients, compared to 16% with second-degree and 12% with first degree AV blocks. According to him, the risk of complete atrioventricular block is much higher when the PR interval is >300 ms 6. Electrophysiology studies, performed in 19 patients with Lyme carditis, showed a supraventricular origin of the block in 68% of patients. One third of patients studied were believed to have had diffuse conduction system disease based upon simultaneously prolonged AA, AH and HV interval 14. Another report suggests that 98% of the patients with AV conduction disturbances had at some time during the course of the disease the first degree AV block, while Wenckebach periodicity occurred in 40% and complete AV block in 50% 7. McAlister et al. performed an electrophysiology studies on 4 patients with Lyme disease in 1989 and 3 of them had block above the His bundle. The remaining patient who had block at or below the His bundle, required a permanent pacemaker 7. Van der Linde also reported four cases of Lyme borreliosis induced AV block and, also, did electrophysiology studies on three of them. The studies showed that 2 of them had a suprahisal origin of the block and the third one had no terminal negative deflection of the His spike, a normal AH interval and no relation between His bundle activity and ventricular complexes 15. This shows that the site of the atrioventricular block may also lie in the distal part of the His bundle, leaving the proximal part undisturbed. In this report, despite extensive treatment with antibiotics and corticosteroid, complete AV block persisted in this patient and a permanent pacemaker had to be implanted Our patient, like many other from the examples above, presented with classic conduction disturbances like intermittently recorded AV blocks of all degrees, due to Lyme borreliosis. Considering the suspected Lyme disease, what was later serological confirmed, we did the electrophysiology study. It revealed His fragmentation and its prolongation which indicates a sickness of a His. We also recorded a prolongation of HV interval which reveals a sickness of conduction structure distal of AV node (intra- and infra Hisian block). Considering to early published articles of Mc Allister and van der Linde 6,7, we decided to implant a permanent doublechamber pacemaker. In further monitoring, the patient had Cardiologia CROATICA 2014;9(1-2):42.

43 da valjanosti terapijskom postupku, verificira povremena potreba za ventrikulskom stimulacijom (AS-VP je 8%, AS-VS je 92%). Na temelju naπeg iskustva i dostupne literature relativno starijeg datuma, stava smo da bi se kod svih mladih ljudi sa steëenim AV blokovima s riziënom profesijom, odnosno endemskom lokalizacijom, trebalo uëiniti EF ispitivanje u jednom od postojeêih centara radi donoπenja odluke o potrebi implantacije trajnog ili zaπtite pacijenta s privremenim elektrostimulatorom tijekom aktivne bolesti (prosjek unutar 6 tjedana). no subjective complaints and at the first pacemaker operation control, as further validation of the therapeutic procedure, we verified the occasional need for ventricular stimulation (AS-VP 8%, AS-VS 92%). Based on our experience and the available literature, that is relatively older, we consider reasonable in all young people with acquired AV block with a risky profession, respectively endemic localization, EP study is to be done in one of the existing centers, in order to make a decision on the need for implantation of a permanent pacemaker or care of the patient with a temporary pacemaker during active disease (mean within 6 weeks). Received: 7 th Feb 2014; Accepted 8 th Feb 2014 *Address for correspondence: KliniËka bolnica Merkur, ZajËeva 19, HR Zagreb, Croatia. Phone: premuzici@yahoo.com Literature 1. Wang G, van Dam AP, Schwartz I, Dankert J. Molecular typing of Borrelia burgdorferi sensu lato: taxonomic, epidemiological, and clinical implications. Clin Microbiol Rec. 1999;12: Ciesielski CA, Markowitz LE, Horsley R, Hightower AW, Russel H, Broome CV. Lyme disease surveillance in the United States, Rev Infect Dis. 1989;11(Suppl6):S Hengge UR, Tannapfel A, Tyring SK, et al. Lyme borreliosis. Lancet Infect Dis. 2003;3: Xanthos T, Levolas P, Kantsos H, et al. Lyme carditis: complete AV dissociation with need for temporary pacing. Hellenic J Cardiol. 2006;47: Heckler AK, Shmorhun D. Asymptomatic, transient complete heart block in a pediatric patient with Lyme disease. Clin Pediatr (Phila). 2010;49: van der Linde M.R. Lyme carditis: clinical characteristics of 105 cases. Scand J Infect Dis Suppl. 1991;77: McAlister HF, Klementowicz PT, Andrews C, Fisher JD, Feld M, Furman S. Lyme carditis: an important cause of reversible heart block. Ann Intern Med. 1989;110(5): Dh te R, Basse-Guerineau AL, Beaumensil V, Christoforov B, Assous MV. Full spectrum of clinical, serological and epidemiological features of complicated forms of Lyme borreliosis in Paris, France, area. Eur J Clin Microbiol Infect Dis. 2000;19: Magnarelli LA. Current status of laboratory diagnosis for Lyme disease. Am J Med. 1995;98:10S-12S. 10. Steere AC, Bartenchagen NH, Craft JE, et al. Clinical manifestation of Lyme disease. Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263(1-2): Goldings EA, Jericho J. Lyme disease. Clin Rheum Dis. 1986;12: Schned ES, Williams DN. Lyme disease. The tick bite, the rash and the sequelae. Postgrad Med 1985;77:303-8, Hechemy KE, Lyme disease: a review. Bull Soc Pathol Exot Filiales. 1986;79: Haddad FA, Nadelman RB. Lyme disease and the heart. Front Biosci. 2003;8:s van der Linde MR, Crijns HJGM, Koning J, et al. Range of atrioventricular conduction disturbances in Lyme borreliosis: a report of four cases and review of other published reports. Br Heart J. 1990;63: Meyer LK, Swenson DB. Lyme carditis: high-grade heart block in Lyme disease. Minn Med. 1987;70: Dattwyler RJ, Halperin JJ, Pass H, Luft BJ. Ceftriaxone as effective therapy in refractory Lyme disease. J Infect Dis. 1987;155: ;9(1-2):43. Cardiologia CROATICA

44 Prikaz sluëaja / Case report Double fire rijetka, a joπ ËeπÊe neprepoznata aritmija Double fire a rare and commonly unrecognized arrhythmia Zoran BakotiÊ*, Ante AniÊ, Marin BiπtirliÊ, Albino JoviÊ OpÊa bolnica Zadar, Zadar, Hrvatska Zadar General Hospital, Zadar, Croatia SAÆETAK: Dvojna fiziologija provoappleenja atrioventrikularnim (AV) Ëvorom, odnosno prisutnost tzv. sporog puta, prema raznim studijama, elektrofizioloπkim ispitivanjem se moæe dokazati u do Ëak 35% ljudi. Meappleutim, kod samo manjeg broja on ima i kliniëki znaëaj. Prikazujemo sluëaj pacijentice s vrlo rijetkom elektrofizioloπkom manifestacijom aktivnog sporog puta, dvostrukog odgovora ventrikula na jedan atrijski kompleks. Problem je uspjeπno rjeπen radiofrekventnom ablacijom. Ovakav naëin provoappleenja AV Ëvorom vjerovatno je i znatno ËeπÊi nego πto se opisuje u literaturi, ali se na æalost rijetko prepoznaje te je uglavnom refraktoran na medikamentoznu terapiju. KLJU»NE RIJE»I: dualna fiziologija atrioventrikulranog Ëvora, double fire fenomen, radiofrekventna ablacija. SUMMARY: Dual atrioventricular node (AV) pathway physiology or the presence of so-called slow conduction pathway is according to various studies demonstrable in up to 35% of normal people during electrophysiology study. In only a small number of them, it has a clinical significance. We present a case of a patient with a very rare electrophysiological manifestation of active slow pathway, double ventricular response to one atrial complex. The problem was successfully treated with radiofrequency ablation. This form of conduction via AV node is probably much more common than it was previously described in the literature, but unfortunately it is rarely recognized and is generally refractory to medical therapy. KEWWORDS: dual atrioventricular node physiology, double fire phenomenon, radiofrequency ablation. CITATION: Cardiol Croat. 2014;9(1-2): Prikaz sluëaja Prikazujemo sluëaj 62 godiπnje pacijentice naruëene na invazivnu kardioloπku obradu zbog uëestalih palpitacija te intolerancije napora praêene opresijama u prekordiju. Od ranije se lijeëi zbog arterijske hipertenzije i hiperlipidemije, a zbog palpitacija u terapiji ima i propafenon 2x150 mg te verapamil 180 mg. VeÊ na rutinskom 12-kanalnom elektrokardiogramu kod prijema prepoznat je potencijalni uzrok tegoba. Naime, prisutni su brojni ventrikularni kompleksi koji po morfologiji odgovaraju supraventrikulnim ekstrasistolama (SVES), bez vidljive atrijske aktivnosti, a u uskoj vezi s prethodno uredno provedenim sinusnim kompleksom (Slika 1). U 24-satnom kontinuranom snimanju EKG zabiljeæeno je viπe od takvih SVES. Ehokardiografski se radi o strukturno zdravom srcu oëuvane sistoliëke funkcije, a koronarografijom je iskljuëena okluzivna bolest epikardijalnih arterija. Case study We present a case of a 62 year-old woman admitted for further evaluation because of frequent palpitations and effort intolerance accompanied by precordial oppressions. She has been treated for arterial hypertension and hyperlipidemia since earlier, and takes propafenone 2x150 mg, and verapamil 180 mg in her therapy for palpitations. A potential cause of problems was recognized already on a routine 12-lead electrocardiogram at the time of admission. In fact, there are numerous ventricular complexes that according to their morphology correspond to supraventricular extrasystoles (SVES), with no visible atrial activity, and are closely related to the previously duly conducted sinus complex (Figure 1). More than 10,000 such SVES were recorded in the 24-hour continuous ECG recording. Echocardiography showed that it is a structurally normal heart with preserved systolic function, and coronary angiography excluded coronary artery disease. Cardiologia CROATICA 2014;9(1-2):44.

45 Figure 1. Sinus rhythm with lot of narrow QRS extra beats, without preceding P wave. It is difficult to differentiate whether it is ectopic activity from the AV junction (His region) or dual conduction of one P wave through both fast and slow pathway to ventricle. OdluËili smo se za elektrofizioloπko ispitivanje (EPS). BaziËnim intrakardijalnim elektrogramima potvrappleena je sumnja da se radi o tzv. double fire fenomenu, odnosno dvostrukom atrioventrikularno (AV) provoappleenju. Na jedan atrijski kompleks dolaze dva ventrikularna od kojih je prvi proveden brzim, a drugi sporim putem (Slika 2a i 2b). Standardnim EPS protokolom dokazana je dualna fiziologija AV Ëvora, iskljuëeno je retrogradno provoappleenje, a nije inducirana tahikardija niti ev. eho udari. U regiju sporog puta postavljen je ablacijski kateter te se nakon nekoliko kraêih aplikacija energije u potpunosti eliminira dvojna AV fiziologija s iskljuëivim provoappleenjem kroz brzi put (Slika 3a i 3b). Aritmija se ne javlja niti nakon primjene izoproterenola. Otpuπtena je kuêi bez antiaritmika. Electrophysiology study (EPS) was performed. Basic intracardiac elektrograms confirmed the suspicion that this is the so-called double fire phenomenon, or dual atrioventricular (AV) conduction. Two ventricular complexes come to one atrial complex, of which the first is conducted by the fast and the second by the slow pathway (Figure 2a and 2b). Standard EPS protocol proved dual AV node pathway physiology, excluded retrograde conduction, and induced no tachycardia or echo beats. After a few short energy applications in the region of the slow pathway, dual AV node physiology was completely eliminated, only with conduction via the fast pathway (Figure 3a and 3b). Arrhythmia was not inducible even after the application of isoproterenol. She was discharged home without antiarrhythmics. Figure 2a. Intracardiac recording during electrophysiology study. 2014;9(1-2):45. Cardiologia CROATICA

46 Figure 2b. Schematic presentation of pulse propagation from atrium to ventricle: First atrial (sinus) impulse is conducted through both fast and slow pathway to the region of His, and down to the ventricle (1:2 conduction). Second atrial stimulus is blocked in the atrioventricular node which is still refractory from the previous depolarization by slow pathway. Third atrial impulse is conducted only by fast pathway. (HRAd high right atrium; HISd region of His with its potential; RVd apex of the right ventricle). Figure 3a. ECG after successful ablation in the slow pathway region intracardiac recording. ZakljuËak Dvojna fiziologija provoappleenja AV Ëvorom, odnosno prisutnost tzv. sporog puta, prema raznim studijama, elektrofizioloπkim ispitivanjem se moæe dokazati u do Ëak 35% ljudi 1-2. Fenomen dvostrukog ventrikularnog odgovora na jedan atrijski kompleks prvi je opisao Csapo godine i nazvao Conclusion Dual AV node pathway physiology or the presence of socalled slow conduction pathway is according to various studies present in up to 35% of people during EPS 1-2. The phenomenon of dual ventricular response to a single atrial complex was first described by Csapo in 1979 and cal- Cardiologia CROATICA 2014;9(1-2):46.

47 Figure 3b. ECG after successful ablation in the slow pathway region standard 12-lead ECG. ga je double fire ili non-reentrant tahikardija 3. Rijedak je jer zahtjeva posebne karakteristike oba puta anterogradnu provodljivost i retrogradni blok, a spori put mora biti dovoljno spor da dopusti His-Purkinjeovom tkivu da oporavi podraæljivost nakon prethodne stimulacije 4-6. Zbog toga fenomen provodljivosti 1:2 nije konstantan, AV Ëvor se neujednaëeno depolarizira, pa su Ëesto prisutni i razliëiti oblici funkcionalnog AV bloka (PR prolongacija ili Wenckebach). Na vanjskom elektrokardiogramu to se manifestira nepravilnim ventrikularnim ritmom, a odnos s P valom je ponekad teπko pratiti. Zato i nije neobiëno da se ova aritmija teπko prepozna, a kod bræe frekvencije i niæe voltaæe P vala lako zamjeni za npr. fibrilaciju atrija. Dominantan simptom su palpitacije, a u literaturi su opisani sluëajevi tahikardiomiopatije uzrokovani ovom aritmijom, uspjeπno rjeπeni ablacijom sporog puta 7-9. Ovi pacijenti u pravilu nemaju kruæne tahikardije koje su tipiëne za aktivni spori put, kao πto je atrioventrikularna nodalna kruæna tahikardija. Loπ odgovor na medikamentoznu terapiju (zbog rezistencije sporog puta na veêinu klasiënih antiaritmika) i moguênost izljeëenja radiofrekventnom ablacijom, nameêe potrebu da razmiπljamo o ovom tipu aritmije koja se moæe prepoznati veê iz standardnog 12-kanalnog elektrokardiograma. Naravno, za dokaz je ipak potrebna elektrofizioloπka studija. Received: 12 th Jan 2014; Updated 19 th Jan 2014; Accepted 30 th Jan 2014 *Address for correspondence: OpÊa bolnica Zadar, Boæe PeriËiÊa 5, HR Zadar, Croatia. Phone: zbakotic@gmail.com led it a double fire or non-reentrant tachycardia 3. It is rare because it requires special characteristics of the both pathways anterograde conduction and retrograde block, while the slow pathway must be slow enough to allow the His- Purkinje tissue to recover excitability after previous stimulation 4-6. For this reason, the conductivity phenomenon 1:2 is not constant, the AV node is inconsistently depolarized, so different forms of functional AV block (PR prolongation or Wenckebach) are often present. It is manifested by irregular ventricular rhythm on the external electrocardiogram, and the relation with the P wave is sometimes hard to follow. So it was not surprising that this arrhythmia is hard to recognize, and at faster frequency and low voltage of the P wave it can be easily confused for e.g. atrial fibrillation. The dominant symptom are palpitations, and literature has described the cases of tachycardiomyopathy caused by this arrhythmia, successfully treated with radiofrequency (RF) ablation of the slow pathway 7-9. These patients typically have no reentrant tachycardia typical for active slow pathway, such as atrioventricular nodal reentrant tachycardia (AVNRT). A poor response to medical therapy (due to resistance of the slow pathway to most classic antiarrhythmics) and the possibility of the treatment with RF ablation, forces us to think about this type of arrhythmia that can be recognized already from the standard 12-lead electrocardiogram. Of course, electrophysiology study is required to prove it. Literature 1. Lee KW, Badhwar N, Scheinman MM. Supraventricular Tachycardia - Part I. Curr Probl Cardiol. 2008;33: Brooks R, Goldberger J, Kadish A. Extended protocol for demonstration of dual AV nodal physiology. Pacing Clin Electrophysiol. 1993;16(2): Csapo G. Paroxysmal nonreentrant tachycardias due to simultaneous conduction in dual atrioventricular nodal pathways. Am J Cardiol. 1979;43(5): Francis J, Krishnan M.Dual ventricular response or 1:2 atrioventricular conduction in dual atrioventricular nodal physiology. Indian Pacing Electrophysiol J. 2008;8(2): Germano JJ, Essebag V, Papageorgiou P, Josephson ME. Concealed and manifest 1:2 tachycardia and atrioventricular nodal reentrant tachycardia: manifestations of dual atrioventricular nodal physiology. Heart Rhythm. 2005;2: Fraticelli A, Saccomanno G, Pappone C, Oreto G. Paroxysmal supraventricular tachycardia caused by 1:2 atrioventricular conduction in the presence of dual atrioventricular nodal pathways. J Electrocardiol. 1999;32: Josephson ME. Tachycardia-mediated cardiomyopathy. Card Electrophysiol Clin. 2010; 2: Clementy N, Casset-Senon D, Giraudeau C, Cosnay P. Tachycardiomyopathy secondary to nonreentrant atrioventricular nodal tachycardia: recovery after slow pathway ablation. Pacing Clin Electrophysiol. 2007;30: Anselm F, Frederiks J, Boyle NG, Papagerorgiou P, Josephson ME. An unusual cause of tachycardia-induced myopathy. Pacing Clin Electrophysiol. 1996;19: ;9(1-2):47. Cardiologia CROATICA

48 Pregledni rad / Review article Inhibitori ADP-om ovisne agregacije trombocita Inhibitors of ADP-dependent platelet aggregation Aleksandar KneæeviÊ* Radna skupina za kliniëku kardiovaskularnu farmakologiju, Hrvatsko kardioloπko druπtvo, Hrvatska Working Group on Clinical Cardiovascular Pharmacology, Croatian Cardiac Society, Croatia SAÆETAK: Trombociti imaju srediπnju ulogu u patogenezi aterotromboze. Trombocitni ADP (adenozindifosfatazni) receptori (P2Y12) imaju kljuënu ulogu u agregaciji potencirajuêi uëinak brojnih drugih faktora koji pri njoj sudjeluju. Inhibitori ADP ovisne agregacije trombocita (tiklopidin, klopidogrel, prasugrel, tikagrelor) su skupina lijekova koja poveêava antiagregacijski uëinak, poglavito u inicijalnoj fazi aktivacije trombocita te time daju znaëajan doprinos u lijeëenju aterotrombotskih bolesti, posebice ACS (akutnog koronarnog sindroma). Tiklopidin je prvi uveden u kliniëku praksu, no hematoloπke nuspojave i spor poëetak uëinka brzo su ograniëile kliniëku primjenu. Klopidogrel uz acetilsalicilatnu kiselinu brzo postaje zlatni standard u antiagregacijskoj terapiji nakon PCI (perkutane koronarne intervencije) i u ACS. No, njegova farmakokinetska i farmakodinamska ograniëenja dovode do razvoja novih lijekova. Prasugrel ima jaëi i bræi antiagregacijski uëinak, ali uz cijenu viπe krvarenja. Tikagrelor je zadnji iz ove skupine lijekova s prednoπêu snaæne, efikasne, brze i reverzibilne blokade P2Y12 receptora u odnosu na klopidogrel. Time je prema vaæeêim smjernicama preferirani lijek za PCI u ACS, ali njegov status na Listi lijekova Hrvatskog zavoda za zdravstveno osiguranje za sada ograniëava njegovu πiru primjenu u Hrvatskoj. KLJU»NE RIJE»I: antiagregacijska terapija, tiklopidin, klopidogrel, prasugrel, tikagrelor. SUMMARY: Platelets play a central role in the pathogenesis of atherothrombosis. Platelet adenosine diphosphate (ADP) receptors (P2Y12) have a key role in the aggregation potentiating the effect of many other factors involved in it. Inhibitors of ADP-dependent platelet aggregation (ticlopidine, clopidogrel, prasugrel, ticagrelor) are a group of drugs that increase antiaggregation effect, especially in the initial phase of platelet activation and thereby make a significant contribution to the treatment of atherothrombotic disease, especially ACS (acute coronary syndrome). Ticlopidine was the first that was introduced into clinical practice, but hematologic side-effects and the slow start of effects have quickly limited the clinical application. Clopidogrel with acetylsalicylic acid is fast becoming the gold standard in antiaggregation therapy after PCI (percutaneous coronary intervention) even in ACS. But its pharmacokinetic and pharmacodynamic limitations lead to the development of new drugs. Prasugrel has a more potent and faster antiaggregation effect, but at the expense of more extensive bleeding. Ticagrelor is the last from this group of drugs with the advantage of a potent, efficient, rapid and reversible P2Y12 receptor antagonist over clopidogrel. According to the applicable guidelines, it is a preferred drug for PCI in ACS and its status in the List of the Croatian Health Insurance Fund limits its wider use in Croatia at the moment. KEYWORDS: antiaggregation therapy, ticlopidine, clopidogrel, prasugrel, ticagrelor. CITATION: Cardiol Croat. 2014;9(1-2): T rombociti imaju srediπnju ulogu u patogenezi aterotromboze. Acetilsalicilatna kiselina (ASK) je temeljni standardni antitrombocitni lijek. Djelovanjem na nastajanje tromboksana A2 dovodi do trajnjeg smanjenja agregacijskih moguênosti trombocita. Ipak, zbog ograniëene uloga tromboksana A2 u agregaciji, ASK je nedostatno djelotvorna u visokoriziënim stanjima kao πto su akutni koronarni sindrom (ACS) ili perkutana koronarna intervencija (PCI). Trombocitni ADP (adenozindifosfatazni) receptori (P2Y12) imaju kljuënu ulogu u agregaciji potencirajuêi uëinak brojnih drugih faktora koji pri njoj sudjeluju. Inhibitori ADP ovisne agregacije trombocita su skupina lijekova koja poveêava antiagregacijski uëinkak, poglavito u inicijalnoj fazi aktivacije trombocita te time daju znaëajan doprinos u lijeëenju ate- P latelets play a central role in the pathogenesis of atherothrombosis. Acetylsalicylic acid (ASA) is the basic standard antiplatelet drug. Its action on the formation of thromboxane A2 leads to a permanent reduction in platelet aggregation capabilities. However, due to the limited role of thromboxane A2 in the aggregation, ASA is insufficiently potent in high-risk conditions such as acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). Platelet adenosine diphosphate (ADP) receptors (P2Y12) have a key role in the aggregation potentiating the effect of many other factors involved in it. Inhibitors of ADPdependent platelet aggregation are a group of drugs that increase antiplatelet effect, especially in the initial phase of the platelet activation and thereby make a significant contri- Cardiologia CROATICA 2014;9(1-2):48.

49 rotrombotskih bolesti, posebice ACS. Intravenski antagonisti GP IIb/IIIa receptora djeluju u zavrπnoj fazi trombocitne agregacije. U inhibitore P2Y12 receptora spadaju tienopiridinski lijekovi (tiklopidin, klopidogrel i prasugrel) te tikagrelor koji je netienopiridinski lijek. Tiklopidin Prvi tienopiridinski lijek koji se poëeo koristiti u kliniëkoj primjeni je tiklopidin. U poëetku se je pokazao uëinkovitim u dugotrajnoj terapiji nakon ishemijskog moædanog udara i kod klaudikacija, a u placebo kontroliranom ispitivanju u terapiji nestabilne angine pektoris (AP) postignuta je za 46% redukcija u kardiovaskularnoj smrtnosti i infarktu miokarda (IM) u prvih 6 mjeseci 1. Kombinacija ASK i tiklopidina je olakπala uporabu koronarnih stentova, a u jednoj usporednoj studiji s klopidogrelom nakon elektivnog stenta pokazao je bolji uëinak u prvih mjesec dana nakon PCI 2. Takoappleer, to je jedini P2Y12 inhibitor koji ima odobrenu indikaciju primjene nakon elektivnog stenta. Ipak, njegov kasni poëetak djelovanja (24 do 48 sati nakon primjene) Ëini ga nepogodnim u ACS, kao i hematoloπke nuspojave (osobito trombotiëna trombociteopeniëna purpura i aplastiëna anemija) koje se najëeπêe javljaju u prva tri mjeseca primjene te zahtjevi za Ëestom kontrolom krvne slike, ograniëili su primjenu ovog lijeka te je on istisnut iz πire uporabe uvoappleenjem klopidogrela u terapiju. Kako nije dokazana genetska varijabilnost u metabolizmu tiklopidina, a uëinkovit je u 96,5% bolesnika s dokazanom rezistencijom na klopidogrel, ostaje kao alterantiva za bolesnike s nepodnoπljivoπêu i neuëinkovitoπêu klopidogrela 3,4. Klopidogrel Nakon tiklopidina u terapiju je uveden slijedeêi tienopiridin klopidogrel kome je glavna prednost u odnosu na prethodnika bio puno bræi farmakodinamski uëinak (dva sata nakon loading doze od mg) πto ga je Ëinilo superiornim pri PCI u ACS, a takoappleer je imao manje hematoloπkih nuspojava u odnosu na tiklopidin te bolju gastrointestinalnu toleranciju. Monoterapija klopidogrelom pokazala se neπto uëinkovitija ASK u sekundarnoj prevenciji ishemijskog dogaappleaja u bolesnika s perifernom vaskularnom boleπêu, ishemijskim moædanim udarom i IM u CAPRIE studiji 5. Ipak, nije zamjenio ASK zbog visoke cijene u odnosu na njega te se u monoterapiji primjenjuje kao alternativa ASK kod njegova nepodnoπenja. Brojna ispitivanja u ACS i nakon PCI pokazala su superiornost kombinacije klopidogrela i ASK u odnosu na samu ASK tijekom jednogodiπnje primjene tako da je to postala standardna terapija u bolesnika s ACS te nakon implantacije stenta Glavne mane klopidogrela su joπ uvijek relativno sporiji nastup djelovanja, velike interindividualne razlike u uëinku te ireverzibilan uëinak na agregaciju trombocita. Za prve dvije odgovoran je proces aktivacije klopidogrela koji se provodi u dvije faze, a ukljuëuje velik broj citokrom P450 enzima koji su osjetljivi na interakcije lijekova te genski polimorfizam. Bolesnici s genskim polimorfizmom nemaju ili imaju ograni- Ëen metabolizam klopidogrela te time i rezistenciju na njegov uëinak 11. bution to the treatment of atherothrombotic disease, especially ACS. Intravenous GP IIb/IIIa receptor antagonists have an action in the final stage of platelet aggregation. The P2Y12 receptor inhibitors include thienopyridine drugs (ticlopidine, clopidogrel and prasugrel) and ticagrelor which is a non-thienopyridine drug. Ticlopidine Ticlopidine is the first thienopyridine drug that started to be used in the clinical practice. It first proved to be efficient in the long-term therapy after ischemic stroke even in case of claudication and a 46% reduction was achieved in cardiovascular mortality and myocardial infarction (MI) in the first six months in the placebo-controlled study for the treatment of unstable angina pectoris (AP) 1. The combination of ASA and ticlopidine has facilitated the use of coronary stents, and in one comparative study with clopidogrel after elective stenting, it showed a better effect in the first month after PCI 2. It is also the only P2Y12 inhibitor that has an approved indication for application after the elective stent. However, its delayed onset of action (24 to 48 hours after administration) makes it unsuitable in ACS, as well as hematological side-effects (especially thrombotic thrombocytopenic purpura and aplastic anemia), which usually occur in the first three months of application and requirements for frequent blood count control have limited the administration of this drug, and it has been squeezed out from the wider use at the time of introducing clopidogrel in the therapy. Since genetic variability has not been proved in the metabolism of ticlopidine and it is effective in 96.5% of patients with proved resistance to clopidogrel, it remains to be an alternative for patients who do not tolerate clopidogrel and in whom it is inefficent 3,4. Clopidogrel After ticlopidine, the following thienopyridine clopidogrel was introduced in the therapy which had a major advantage over its predecessor which was much faster pharmacodynamic effect (two hours after the loading dose of mg) which made it superior when performing PCI in ACS, and it also had less hematological side effects than ticlopidine and better gastrointestinal tolerance. Clopidogrel monotherapy proved to be somewhat more effective ASA in secondary prevention of ischemic events in patients with peripheral vascular disease, ischemic stroke and MI in the CAPRIE study 5. However, it has not replaced ASA due to the high cost compared to it, and it is used as an alternative to ASA in the monotherapy in case of its intolerance. Numerous tests in ACS and after PCI have shown the superiority of the combination of clopidogrel and ASA compared to ASA alone during one-year application, so that it has become a standard therapy in patients with ACS and after stent implantation The main disadvantages of clopidogrel are still relatively slow onset of action, high inter-individual differences in the effect of the irreversible effect on platelet aggregation. Clopidogrel activation process is responsible for the first two ones that is carried out in two phases, and includes a large number of cytochrome P450 enzymes that are susceptible to drug interactions and genetic polymorphisms. Patients with the genetic polymorphism have no or limited metabolism of clopidogrel and thus resistance to its effect ;9(1-2):49. Cardiologia CROATICA

50 Pokuπaji da se predvidi uëinak klopidogrela mjerenjem agregacije trombocita nisu se do sada pokazali uëinkovitim (npr. nedavno ARCTIC ispitivanje 12 u kome je prilagoappleena antiagregacijska terapija usporeappleivana sa standardnom nakon PCI) tako da nema smisla odreappleivati agregaciju trombocita za odreappleivanje djelotvornosti klopidogrela, a u ovom trenutku i ostalih antiagregacijskih lijekova 13. Takoappleer pitanje interakcije klopidogrela s inhibitorima protonske pumpe (o Ëemu je puno diskutirano zadnjih godina), ima viπe teoretsko, nego praktiëno znaëenje 14,15. Prasugrel Najnoviji u klasi tenopiridina je uëinkovitiji od tiklopidina i klopidogrela, primarno zbog bræeg i uëinkovitijeg metabolizama (samo u jednoj fazi) tako da na trombocit djeluje viπe aktivnog metabolita. Ima bræi poëetak djelovanja i jaëi antiagregacijski uëinak od klopidogrela. U usporedbi s njim pokazuje manju varijabilnost u uëinku, a nema dokaza da genski polimorfizam u CYP izoenzimima utjeëe na njegov metabolizam. U TRITON TIMI 38 ispitivanju u bolesnika s AKS pokazao se superiornijim klopidogrelu u smanjenju ishemijskih dogaappleaja (posebice u bolesnika sa STEMI ili dijabetesom), ali uz cijenu neπto veêeg rizika od krvarenja, poglavito fatalnog (21 prasugrel: 4 klopidogrel). UËinak je bio vidljiv svih 15 mjeseci koliko je trajalo prosjeëno praêenje bolesnika u studiji. Takoappleer je za 50% smanjena in-stent tromboza, kako kod BMS tako i kod DES. Rizik krvarenja bio je poveêan u bolesnika starijih od 75 godina, manje tjelesne mase te preboljelim moædanim udarom, tako da se tim bolesnicima ne preporuëa primjena lijeka (CVI kontraindikacija), odnosno ako je primjena neophodna treba im dati reduciranu dozu od 5 mg. Takoappleer je rizik krvarenja bio viπi za 4 puta u bolesnika koji su bili podvrgnuti aortokoronarnom premoπtenju (CABG) nego u skupini koja je primala klopidogrel, a pove- Êan je i kod drugih operacija prvih tjedan dana nakon prestanka uzimanja lijeka 16. U TRILOGY studiji usporeappleivan je prasugrel u odnosu na klopidogrel u bolesnika s AKS, ali koji su bili lijeëeni medikamentozno. Tu se nije pokazala statistiëki znaëajna razlika izmeappleu dva lijeka, ali u skupini bolesnika s angiografski dokumentiranom koronarnom bolesti srca prasugrel je bio bolji od klopidorela u smanjenju ishemijskih dogaappleaja (12,8 naspram 16,5%, p=0,001) 17. Tikagrelor Tikagrelor je prvi predstavnik nove skupne inhibitora P2Y12 receptora tzv. ciklopentiltrazolpirimidina. Nastao je u procesu traæenja mimetika oralno aktivnog ATP, prirodnog antagonista P2Y12 receptora. Tikagrelor se reverzibilno veæe uz receptor uz jaëi i bræi antitrombocitni uëinak od klopidogrela. U PLATO studiji pokazao je u odnosu na klopidogrel relativnu redukciju za 16% rizika primarnog cilja studije (zbir kardiovaskularne smrtnosti, MI i moædanog udara) uz nesignifikantno poveêanje rizika od velikih krvarenja 18. U podstudiji PLATO-INVASIVE dokazana je statistiëki znaëajna redukcija ishemijskih dogaappleaja (ukljuëivo tromboza stenta), ali bez poveêanja velikih krvarenja u odnosu na klopidogrel 19. Takoappleer je bio sigurniji u bolesnika koji su bili podvrgnuti CABG, premda su krvarenja u bolesnika koji nisu operirani bila neπto ËeπÊa. Dok klopidogrel i prasugrel nisu pokazali redukciju mortaliteta, tikagrelor je imao za 22% manji mortalitet usprkos snaænom antitrombocitnom uëinku 20. Cardiologia CROATICA The attempts to predict the effect of clopidogrel by measuring platelet aggregation have not proved effective so far (e.g. the recent ARCTIC trial 12 in which the adjusted antiplatelet therapy was compared to standard therapy after PCI), so there is no sense to determine platelet aggregation for determining the efficacy of clopidogrel, and other antiplatelet drugs at this moment 13. The question as to the interaction of clopidogrel with proton pump inhibitors (which has been much discussed in recent years), has more theoretical than practical significance 14,15. Prasugrel Being most recent one in the thienopyridine class, it is more effective than ticlopidine and clopidogrel, primarily due to a faster and more efficient metabolism (only in one phase), so that the platelets are affected by several active metabolites. It has a faster onset of action and a stronger antiaggregation effect than clopidogrel. Compared to it, it shows less variability in effect, and there is no evidence that genetic polymorphism in the CYP isoenzymes affects its metabolism. In TRITON TIMI 38 trial in patients with ACS it has proven to be superior to clopidogrel in reducing ischemic events (particularly in patients with STEMI or diabetes), but at the expense of a slightly higher risk of bleeding, especially fatal one (21 prasugrel versus 4 clopidogrel). The effect was visible in all 15 months as long as an average follow-up of patients lasted in the study. The in-stent thrombosis was reduced by 50%, both in BMS and DES. The risk of bleeding was increased in patients over 75 years of age, with less weight and previous stroke, so administration of the medicine was not recommended in these patients (stroke contraindication), or if the administration is necessary, they should be given a reduced dose of 5 mg. The risk of bleeding was higher by four times in patients who underwent the coronary artery bypass grafting than in the group receiving clopidogrel and it was also increased in other operations in the first week after they stopped taking the medicine 16. The study TRILOGY compared prasugrel vs. clopidogrel in patients with ACS, but who were treated pharmacologically. There was no statistically significant difference between the two drugs, but in patients with angiographically documented coronary artery disease, prasugrel was superior to clopidogrel in reducing ischemic events (12.8% vs. 16.5%, p = 0.001) 17. Ticagrelor Ticagrelor is the first representative of a new group of P2Y12 receptor inhibitors, the so-called cyclopen-tyltriazolo-pyrimidines. It was created in the process of searching orally active mimetic ATP, the natural P2Y12 receptor antagonist. Ticagrelor reversibly binds with the receptor with a more potent and more rapid antiplatelet effect of clopidogrel. In the PLATO study it showed, compared to clopidogrel, a relative reduction by 16% of risk-primary endpoint (the composite of cardiovascular mortality, myocardial infarction and stroke) with an insignificant increase in the risk of major bleeding 18. A statistically significant reduction of ischemic events (including stent thrombosis) was proved in the substudy PLATO- INVASIVE, but with no increase in major bleeding as compared to clopidogrel 19. It was also safer in patients who underwent coronary artery bypass grafting, although bleeding was more extensive in patients who did not undergo the surgery. While clopidogrel and prasugrel showed no reduction in mortality, ticagrelor 2014;9(1-2):50.

51 Relativno kratak poluæivot lijeka te uzimanje dvaput dnevno zahtjeva dobru suradljivost bolesnika na kojoj treba trajno inzistirati. Takoappleer treba biti oprezan u bolesnika s velikim rizikom od krvarenja i komorbiditetom. Premda je lijek joπ registriran u EU i SAD te uvrπten u smjernice za lijeëenje AKS Europskog kardioloπkog druπtva i engleskog NICE, serija Ëlanaka objavljenih dovode u pitanje rezultate i metodologiju PLATO studije, tako da je u rujnu god. Ministarstvo pravosuapplea SAD zapoëelo istragu o provoappleenju studije (Ëije rezultate joπ Ëekamo). Interesantno je spomenuti da je regulatorni status lijek usprkos toj istrazi, nepromjenjen 21,22. KliniËka istraæivanja novih antiagregacijskih lijekova U kliniëkim ispitivanjima je joπ nekoliko antiagregacijskih lijekova koji djeluju razliëitim mehanizmima,a od njih je najbliæi kliniëkoj uporabi voraksapar koji inhibira aktivaciju trombocita preko trombinskih PAR-1 receptora. U ovom trenutku je u tijeku njegova registracija u indikaciji sekundarne prevencije IM, dok je negativan sigurnosni profil (nepovoljan odnos prevencije ishemijskih dogaappleaja u odnosu na krvarenja) iskljuëio ovaj lijek u lijeëenju AKS 23. Antiagregacijski lijekovi u smjernicama Smjernice ESC za lijeëenje AKS, poglavito u bolesnika koji idu na PCI, preferiraju tikagrelor i prasugrel nad klopidogrelom, gdje je lijek prvog izbora tikagrelor. Klopidogrel se navodi kao moguênost lijeëenja ako su prva dva lijeka nedostupna ili kontraindicirana. Dualnu terapiju treba provoditi 12 mjeseci nakon PCI 24,25. AmeriËke smjernice za PCI u AKS u istu razinu preporuke stavljaju: klopidogrel, prasugrel i tikagrelor uz preporuku da ih se daje u dvojnoj terapiji s ASK joπ 12 mjeseci. Kod PCI koja nije povezana s AKS, jedini blokator P2Y12 receptora koji se preporuëa je klopidogrel uz preporuku da se nakon BMS daje minimalno u dvojnoj terapiji mjesec dana (optimalno godinu), a nakon DES obvezno godinu dana uz moguênost daljnjeg produæenja 26. Engleske NICE smjernice za sekundarnu prevenciju infarkta miokarda preporuëavaju klopidogrel za dvojnu antiagregacijsku terapiju u onih bolesnika kojima je indicirana trajna antikoagulacijska terapija. Duæina primjene dvojne antikoagulacije terapije nakon AKS i PCI, odnosno elektivne PCI je sukladna veê navedenim smjernicama. IzriËito navode da se tikagrelol i prasugrel ne preporuëaju davati uz varfarin, a takoappleer ne preporuëaju niti primjenu novih oralnih antikoagulansa (dabigatran, rivaroksoban i apiksaban) uz dvojnu antiagregacijsku terapiju 27,28. ZakljuËak U nas su registrirana sva Ëetiri inhibitora P2Y12 receptora koji se spominju u ovom Ëlanku,a sva Ëetiri su i na Listi lijekova HZZO. Od toga dva nova (Efient prasugrel i Brilique tikagrelor) s relativno velikom nadoplatom od 214 i 324 kune po kutiji lijeka. To bitno ograniëava njihovu primjenu sukladno hrvatskim smjernicama za lijeëenje AKS. Premda u literaturi postoje miπljenja da njihova prednost nad klopidogrelom i nije tako velika da bi opravdala razliku u cijeni 29, ipak bi njihovo uvrπtenje na Osnovnu Listu lijekova HZZO-a (bez nadoplate) omoguêilo bolje lijeëenje naπih had a 22% lower mortality despite the potent antiplatelet effect 20. The relatively short half-life of the drug and taking the drug twice a day requires good patient compliance which should be permanently insisted on. You should be cautious in patients with a high risk of bleeding and comorbidity. Although the drug was registered in the European Union and the United States of America in 2011, and is included in the guidelines of the European Society of Cardiology (ESC) for the treatment of ACS, as well as in the British NICE guidelines, a series of articles published in 2013 has raised doubts about the results and methodology of the PLATO study, so that in September 2013 the U.S. Department of Justice began an investigation on the implementation of the study (which results are still awaited). It is interesting to note that the regulatory status of the drug has remained unchanged in spite of that investigation 21,22. New antiplatelet drugs in clinical trials There are several antiplatelet drugs included in the clinical trials whose action is enabled by various mechanisms, whereas voraxapar is one of them being closest to the clinical use and inhibiting activation of platelets via thrombin PAR-1 receptors. At this point, its registration in the indication of secondary prevention of myocardial infarction is underway, while the negative safety profile (negative ratio of prevention of ischemic events vs. bleeding) excluded this drug in the treatment of ACS 23. Antiplatelet drugs in the guidelines ESC Guidelines for the treatment of ACS, especially in patients undergoing PCI, prefer ticagrelor and prasugrel to clopidogrel, where ticagrelor is the drug of choice. Clopidogrel is mentioned as a treatment option, if the first two drugs are unavailable or contraindicated. Dual therapy should be conducted 12 months after PCI 24,25. American guidelines for PCI in ACS place the below specified drugs in the same level of the recommendation: clopidogrel, prasugrel and ticagrelor thereby recommending that they should be administered in the dual therapy with ASA in the further 12 months period. In case when PCI is not associated with ACS, the only P2Y12 receptor antagonist that is recommended is clopidogrel with a recommendation, that after BMS it should be administered in dual therapy for at least one month (one year optimally), and after DES it should be administered mandatory for one year with the possibility of further extension of this term 26. The English NICE guidelines for secondary prevention of myocardial infarction recommend clopidogrel for dual antiplatelet therapy in those patients with indicated permanent anticoagulation therapy. The length of administering dual antiplatelet therapy after ACS and PCI, that is, elective PCI, is consistent with mentioned guidelines. They explicitly state that ticagrelol and prasugrel are not to be administered together with warfarin, and also do not recommend the administration of new oral anticoagulants (dabigatran, rivaroxoban and apixaban) with dual antiplatelet therapy 27,28. Conclusion All four P2Y12 receptor inhibitors discussed in this article are registered in Croatia, and all four of them are listed in the 2014;9(1-2):51. Cardiologia CROATICA

52 koronarnih bolesnika, poglavito u AKS, ali je pitanje koliko je to u ovom ekonomskom trenutku realno. Received: 21 st Jan 2014; Accepted 30 th Jan 2014 *Address for correspondence: OpÊa bolnica Zadar, Boæe PeriËiÊa 5, HR Zadar, Croatia. Phone: aleksandar.knezevic@zd.t-com.hr List of the Croatian Health Insurance Fund. Out of these new drugs, there are two new ones (Efient prasugrel and Brilique ticagrelor) with a relatively high surcharge ranging from HRK 214 to HRK 324 per box of the drug. This is the reason why their use is greatly limited in accordance with Croatian guidelines for the treatment of ACS. Although the literature mentions some opinions according to which their advantage over clopidogrel is not so great to justify the difference in price 29, their listing in the List of Essential Medicines of the Croatian Health Insurance Fund (without a surcharge) would allow a better treatment for our coronary patients, especially in ACS, but the question is how viable it is in this hard economic situation. Literature 1. Balsano F, Rizzon P, Violi F, et al. Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio Della Ticlopidina nell Angina Instabile Group. Circulation. 1990;82: Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation. 2000;102: Maeda A, Ando H, Asai T, et al. Differential impacts of CYP2C19 gene polymorphisms on the antiplatelet effects of clopidogrel and ticlopidine. Clin Pharmacol Ther. 2011;89: Campo G, Valgimigli M, Gemmati D, et al. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol. 2007;50: CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348: Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: Sabatine MS, Cannon CP, CLARITY-TIMI 28 Investigators, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with Stsegment elevation. N Engl J Med. 2005;352: Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366: Steinhubl SR, Berger PB, CREDO Investigators, et al. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288: Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376: Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability to individual responsiveness to clopidogrel; clinical implication, management, and future perspectives. J Am Coll Cardiol. 2007;49: Collet JP, Ciusset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367: Zeymer U. Oral antiplatelet therapy in acute coronary syndromes: recent developments. Cardiol Ther. 2013;2: KneæeviÊ A. Interaction between clopidogrel and proton pump inhibitors. Cardiol Croat. 2009;4(8-9): Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363: Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs. clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357: Roe MT, Armstrong PW, Fox KA, et a. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367: Wallentin L, Becker R, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375: Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass surgery: results from PLATO trial. J Am Coll Cardiol. 2011;57: DiNicolantonio JJ, Tomek A. Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: Serious concerns over the reliability of the PLATO trial. Int J Cardiol. 2013;168: US Department of Justice Investigating PLATO Ticagrelor Trial, Medscape ( ). 23. FDA Advisory Panel Recommends Approving Vorapaxar. Medscape ( ). 24. Hamm CW, Bassand JP, Agewall S, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23): Steg G. James SK, Atar D, et al. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012:33: Levine GN, Bates ER, Blankenship JC, et al ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124: Myocardial infarction - secondary prevention: NICE guideline. ( ) 28. KneæeviÊ A. Guidelines and evidence-based medicine. Cardiol Croat. 2012;7(5-6): Curzen N. Antiplatelet therapy in acute coronary syndromes: beyond aspirin and clopidogrel. Heart 2012;98: Cardiologia CROATICA 2014;9(1-2):52.

53 Pregledni Ëlanak / Review article Almanah 2014.: stabilna koronarna bolest srca Almanac 2014: stable coronary artery disease Viktor PerπiÊ*, Marko Boban Thalassotherapia Opatija Klinika za lijeëenje, rehabilitaciju i prevenciju bolesti srca i krvnih æila, Opatija, Hrvatska Thalassotherapia Opatija Clinic for treatment, rehabilitation and prevention of cardiovascular disease, Opatija, Croatia SAÆETAK: Stabilna koronarna bolest karakterizirana je tranzitornim anginoznim tegobama kao posljedice reverzibilnog i relativnog nesklada u opsrkrbi miokarda oksigeniranom krvi prema potrebama u trenucima tjelesnog napora, emocionalnog ili drugog stresa, no moæe se javiti i u mirovanju. KroniËna ishemijska bolest srca Ëini znaëajan izazov u globalnom zbrinjavanju kardiovaskularnih bolesti. U opêoj populaciji ima oëekivanu prevalenciju od 1 do 4%, odnosno ona je nekoliko puta ËeπÊa od akutnog koronarnog sindroma. U preglednom radu prikazane su osnove kliniëke dijagnostike i lijeëenja stabilne koronarne bolesti srca u naπoj sredini te u okrilju recentnih smjernica Europskog kardioloπkog druπtva. KLJU»NE RIJE»I: koronarna bolest srca, dijagnoza, lijeëenje, smjernice. SUMMARY: Stable coronary artery disease is characterized by transient angina symptoms as a result of reversible and relative inequality of myocardial oxygenated blood supply as per needs at the moments of physical exertion, emotional or other stress, but it can also occur at rest. Chronic ischemic heart disease poses a significant challenge in the global management of cardiovascular diseases. In the general population, it shows expected prevalence of 1-4%, that is several times more common than acute coronary syndromes. The review article shows the basics of clinical diagnosis and treatment of stable coronary artery disease in the Republic of Croatia and within the scope of the recent guidelines of the European Society of Cardiology. KEYWORDS: coronary artery disease, diagnosis, treatment, guidelines. CITATION: Cardiol Croat. 2014;9(1-2): Uvod Kardiovaskularne bolesti predstavljaju jedan od najvaænijih javnozdravstvenih problema danaπnjice u Republici Hrvatskoj 1. Radi se o najëeπêim kroniënim bolestima, uz znaëajnu prevalenciju u opêoj populaciji. Navedena grupa odgovorna je za oko polovinu ukupne godiπnje smrtnosti. Epidemioloπki podaci pokazuju varijabilnost, koja se moæe tumaëiti starenjem populacije, opadanjem broja ukupne populacije, dugoroëno negativnim socioekonomskim trendovima, nivou i kontinuitetu preventivnih aktivnosti te djelatnosti zdravstvenog sektora. ZnaËajni pomaci u sustavnom smislu pratili su razvoj aktivnosti oko primarne prevencije, dominantno institucionalnog u domovima zdravlja te mreæi akutne skrbi u bolnicama. Vjerojatno najznaëajniji organizacijski doseg predstavlja stvaranje prve mreæe ranog zbrinjavanja akutnog infarkta miokarda, odnosno tzv. mreæe primarnih perkutanih koronarnih intervencija (PCI-mreæa) 2. Takoappleer se u zadnjih nekoliko godina u Republici Hrvatskoj razvila djelatnost kardiokiruπkih centara, koji ukupno djeluju u okviru pet kliniëkih bolnica te jedne specijalne bolnice. Osobito se mora naglasiti djelatnost Hrvatskog kardioloπkog druπtva te pridruæenih druπtava koje su takoappleer poduzimale brojne javnozdravstvene mjere i sveobuhvatne principe aktivnosti u lijeëenju i kroniënom zbrinjavanju kardiovaskularnih bolesti. Konkordantno s razvojem kardiologije u Republici Hrvatskoj razvija- Introduction Cardiovascular diseases represent one of the most important public health problems of nowadays in Croatia 1. These are commonly chronic diseases, with significant prevalence in the general population. The aforementioned group is accountable for about a half of the total annual mortality. Epidemiological data shows variability, which can be interpreted by aging of the population, by a decline in the number of the total population, the long-term negative socioeconomic trends, the level and continuity of prevention activities and the activities of the health sector. Significant progress in organizational terms was in line with the development of the activities relating to primary prevention, predominantly institutional development in the community health centers and a network of acute care in hospitals. The most significant organizational success was probably the establishment of the first network of early management of acute myocardial infarction, that is, the network of primary percutaneous coronary interventions (PCI-network) 2. In the last few years the activity of cardiac surgery centers has developed in Croatia, being active in the 5 university hospitals and one specialty hospital in total. We must specifically stress the activity of the Croatian Cardiac Society and affiliated associations that have also undertaken a number of public health measures and comprehensive principles of activities in the treatment 2014;9(1-2):53. Cardiologia CROATICA

54 ju se dva stacionarna i jedan ambulantni centar za rehabilitaciju kardiovaskularnih bolesnika. U novije vrijeme, unatoë suboptimalnim resursima zdravstvenog sustava postiæe se dodatne uspjehe zahvaljujuêi dostupnosti i poveêanju primjene suvremenih metoda neinvazivne dijagnostike, izmeappleu ostalog u vidu primjene viπeslojne kompjutorizirane tomografije srca i krvnih æila (MSCT koronarografija), kao i magnetske rezonancije srca. Nadalje, veêim izborom dostupnosti testova optereêenja, takoappleer se pribliæavamo standardu poboljπane individualizacije dijagnostiëkog pristupa i kasnijeg terapijskog zbrinjavanja sindroma grudne boli u odnosu na oëekivanu vjerojatnost prileæeêe koronarne bolesti srca (KBS) 3. Stabilna koronarna bolest srca ZnaËajan izazov u zbrinjavanju kardiovaskularnih bolesti predstavlja kroniëna ishemijska bolest srca koja u opêoj populaciji ima oëekivanu prevalenciju od 1 do 4%, odnosno ona je nekoliko puta veêa od akutnog koronarnog sindroma 4. Stabilna KBS karakterizirana je tranzitornim anginoznim tegobama kao posljedice reverzibilnog nesklada u opskrbi miokarda oksigeniranom krvi prema potrebama u trenucima tjelesnog napora, emocionalnog ili drugog stresa, no moæe se javiti i u mirovanju 5. DijagnostiËka obrada stabilne koronarne bolesti srca Osnovne pretrage u prvoj liniji dijagnostiëke obrade stabilne KBS Ëine: elektrokardiogram (EKG) u mirovanju, standardne laboratorijske nalaze, po potrebi telemetrijsko praêenje EKG ili holter EKG, ultrazvuk srca i ovisno o indikaciji rendgensku sumacijsku snimku torakalnih organa. U sluëaju da pomoêu standardnog transtorakalnog ehokardiografskog pregleda i uz primjenu kontrasta zbog suboptimalne tehniëke dostupnosti nismo u moguênosti uëiniti dobru procjenu srëanih struktura, funkcije ili segmentalnih poremeêaja kontraktiliteta, moæe se uëiniti slikovnu dijagnostiku primjenom magnetske rezonancije (MR srca) 6. Temeljem kliniëke prosudbe potrebno je uëiniti Bayesovu analizu (statistiëka vjerojatnost) odnosa predtestne vjerojatnosti (PTV) prisutnosti KBS, o Ëemu u potpunosti ovisi tijek buduêih dijagnostiëko-terapijskih intervencija. Glavni Ëimbenici koje se pri tom uzima u obzir su: dob, spol i karakteristike simptoma, uz standardnu obradu izraæenosti Ëimbenika kardiovaskularnog rizika. U sluëaju obrade osoba s niæim ili umjerenim omjerom PTV prisutnosti KBS osobito se povoljna Ëini dijagnostika primjenom MSCT koronarografije koja ima dobru negativnu prediktivnu vrijednost (optimalnije za iskljuëenje bolesti), a prednost joj u navedenim okolnostima Ëini obrada mlaappleih osoba s oëekivanim niæim udjelom kalcija u koronarnim arterijama. U Tablici 1 prikazani su osnovni dijagnostiëki testovi za procjenu koronarne bolesti srca. Dodatna obrada osoba s niæom PTV prisutnosti KBS (<15%) ukljuëuje dijagnostiku nekoronarnih uzroka sindroma grudne boli. U sluëaju ponavljanih tegoba, uz pojavu anginoznih tegoba u mirovanju vrijedi u obzir uzeti moguênost vazospastiëke angine 5. Kod ispitanika s intermedijarnom PTV prisutnosti KBS (15-85%) potrebna je dodatna obrada primjenom dostupne neinvazivne dijagnostike. Za sluëaj da se Cardiologia CROATICA and management of chronic cardiovascular diseases. Concordantly with the development of cardiology in the Republic of Croatia, there are two in-patient centers and one out-patient center for the rehabilitation of cardiovascular patients that have been established. In recent times, despite suboptimal resources of the health system, additional success was achieved owing to the availability and increased use of modern methods of non-invasive diagnostics, in the form of using cardiac and blood vessel multi-slice computed tomography (MSCT coronary angiography) and magnetic resonance imaging of the heart. Furthermore, a greater diversity of available diagnostic tests has also resulted in our getting closer to the standard of improved individualization of a diagnostic approach and subsequent therapeutic management of chest pain syndrome compared to the expected probability of the underlying coronary artery disease (CAD) 3. Stable coronary artery disease A significant challenge in the management of cardiovascular disease is a chronic ischemic heart disease that in the general population has an expected prevalence of 1-4%, and it is several times greater than the acute coronary syndrome 4. Stable CAD is characterized by transient angina problems as a result of reversible inequality of myocardial oxygenated blood supply as per needs at the moments of physical exertion, emotional or other stress, but it can also occur at rest 5. Diagnostic evaluation of stable coronary artery disease The basic tests in the first line diagnostic evaluation of stable CAD include: electrocardiogram (ECG) at rest, standard laboratory values, telemetric monitoring ECG or Holter ECG if necessary, echocardiography, and depending on the indication, chest X-ray. In case technical difficulties occur due to suboptimal transthoracic echocardiographic analysis of cardiac structures, function or segmental contractility disorders by applying a standard transhoracic echocardiographic examination and by using the contrast due to suboptimal technical availability, imaging diagnostics can be done by using magnetic imaging resonance (cardiac MRI) 6. Based on clinical judgment, it is necessary to do a Bayesian analysis (statistical probability) of a relationship of pretest probability (PTP) of presence of CAD, which is entirely dependent on the progress of the future diagnostic and therapeutic interventions. The main factors to be taken into consideration are: age, gender, symptom characteristics, along with the standard treatment of pronounced cardiovascular risk factors. In case of treatment of persons with lower or moderate ratio of PTP of CAD, the diagnostics by using MSCT coronary angiography seems to be particularly beneficial, due to an excellent negative predictive value (more optimal for excluding the disease), whereas the treatment of young people with an expected lower proportion of calcium in the coronary arteries makes it more beneficial in the given circumstances. Table 1 shows basic diagnostic tests for the evaluation of coronary artery disease. Additional treatment of persons with lower PTP of CAD (<15%) include the diagnostics of non-coronary causes of chest pain syndromes. In the case of recurring problems along with the occurrence of angina pain at rest, it is worth considering the possibility of vasospastic angina5. In pa- 2014;9(1-2):54.

55 Diagnostic test Sensitivity (%) Specificity (%) Table 1. Common diagnostic tests for diagnosing the presence of coronary artery disease (modified from European Society of Cardiology 2013 guidelines 5 ). Exercise electrocardiogram Exercise stress echocardiography Exercise stress SPECT Dobutamine stress echocardiography Dobutamine stress MRI Vasodilatator stress echocardiography Vasodilatator stress SPECT Vasodilatator stress MRI Coronary computerized tomography Vasodilatator stress PET SPECT = single photon emission computerized tomography; MRI = magnetic resonance imaging; PET = positron emission tomography. radi o visokom stupnju PTV prisutnosti KBS (>85%), uz kliniëke simptome koji jasno odgovaraju anginoznim dodatna testiranja neinvazivnom dijagnostikom nisu nuæno potrebna te se bolesnika moæe uputiti na invazivnu koronarografiju5. U potonjem navedenom sluëaju primjena dodatnih neinvazivnih dijagnostika oëekivano ne dovodi do preciznijeg odgovora o prisutnosti KBS, no u sluëaju procijenjene kliniëke opravdanosti primjena dodatnih testova pomaæe u dodatnoj diferencijaciji rizika pojave glavnih neæeljenih kardiovaskularnih dogaappleaja. U pogledu ispitanika s intermedijarnim stupnjem PTV prisutnosti KBS primjena MSCT za procjenu kalcifikata koronarnih arterija prema Agastonu, kada su iznosi kalcija >400 dovodi do znaëajnog poveêanja udjela pozitivnih nalaza (laæno i stvarno pozitivnih). Obrada MSCT-kalcijskim skoringom moæe se tada dijelom i smatrati pouzdanim ekvivalentom konvencionalnih stres testova, no odluka o daljoj obradi, odnosno invazivnoj koronarografiji u smislu æurnosti obrade donosi se temeljem ostalih karakteristika kliniëke procjene 7. Stres testovi primjenom tjelesnog optereêenja predstavljaju metodu prvog izbora u dijagnostiëkoj obradi, jednostavno zbog veêe reprezentativnosti patofizioloπkih promjena u kontroliranom testiranju koje su bliske naporima u svakodnevnom æivotu. Nadalje, primjena tjelesnog optereêenja donosi nam vrijedne kliniëke podatke poput objektivnije procjene stupnja podnoπenja tjelesnih napora, dinamiku vrijednosti arterijskog tlaka i pulsa, uz monitoriranje elektrokardiografskih promjena. Primjena farmakoloπkih oblika stresa osobito je pogodna za dodatnu obradu veê poznatih segmentalnih poremeêaja kontraktiliteta miokarda, ili kod osoba koji ne mogu uspjeπno izvesti test uz primjenu tjelesnog optereêenja. Dobutaminski stres test pokazao se osobito korisnim za izazivanje nesklada u opskrbi i potrebama miokarda za kisikom. Osobito su velike moguênosti otkrivanja segmentalnih ispada u kontraktilitetu nakon primjene dobutamina, u smislu detekcije vijabilnosti / omamljenosti miokarda na MR srca 8. Vaæno je napomenuti da je sigurnosni profil primjene dobutaminskog stresa podjednak kod MR srca i ehokardiografije 9. Primjena vazodilatatorskih testova poput adenozina, odnosno tzv. MRI-perfuzije znaëajno se ËeπÊe koristi u kliniëkoj praksi, uz zadovoljavajuêi sigurnosni profil i dobar stupanj dijagnostiëke toënosti, podjednak SPECT i PET testiranjima 10. Ukoliko se za procjenu ispada perfuzije primjenjuju kvalitativne metode analize protoka, dijagnostiëka toëtients with intermediate PTP of CAD (15-85%) additional treatment by using the available non-invasive diagnostics is required. In case that a high degree of PTP of CAD (>85%) along with clinical symptoms that clearly resembles angina chest pain, additional tests by noninvasive diagnostics are not necessarily taken, and a patient may well be referred for invasive coronary angiography5. In the latter case, the application of additional noninvasive diagnostics does not, as expected, lead to a more precise answer about the presence of CAD, but if it is clinically justified, the application of additional tests helps in additional differentiation of risks for occurrence of major adverse cardiovascular events. Regarding the subjects with intermediate degree of PTV of CAD, the use of MSCT to evaluate coronary artery calcification based on Agaston score, when the amounts of calcium >400 leads to a significant increase in the proportion of positive results (falsely and truly positive ones). The evaluation based on MSCT-calcium scoring can then partly be considered to be a reliable equivalent to conventional stress tests, but the decision on further treatment or invasive coronary angiography in terms of the urgency of the treatment is to be made on the basis of other characteristics of the clinical evaluation 7. Stress tests by using the physical stress represent the first choice method in the diagnostic evaluation, simply because of the greater representativeness of pathophysiological changes in the controlled environment that are as close to the everyday life stress. Furthermore, the use of physical stress brings us valuable clinical data such as objective evaluation of a degree of endurance of physical stress, dynamics of blood pressure and pulse, accompanied by the monitoring of changes in the ECG. The application of pharmacological stress types is particularly suited for additional evaluation of already known segmental myocardial contractility disorders, or in patients who are unable to successfully perform the test with physical load. Dobutamine stress test is established as particularly useful for inducing of mismatch of myocardial oxygen supply and myocardial oxygen demands. There are particularly great possibilities of identifying segmental deficits in the contractility after the administration of dobutamine, in terms of detection of viability/numbness of myocardium to MRI 8. It is important to note that the safety profile of the application of dobutamine stress is equal in MRI and echocardiography 9. The vasodilatator tests such as adenosine, or the so-called 2014;9(1-2):55. Cardiologia CROATICA

56 nost MR srca odgovara pribliæno invazivnoj koronarografiji uz primjenu frakcione analize protoka/rezerve (FFR) 11. Procjena vijabilnosti miokarda pomoêu MR srca pruæa morfoloπke detalje visoke rezolucije, ukljuëujuêi i funkcionalnu procjenu lijeve klijetke u svega 30-ak minuta oslikavanja. Princip oslikavanja gadolinijem temelji se na veêoj brzini ispiranja gadolinija iz normalnog miokarda naspram onog zamijenjenog fibrozom ili oæiljkom. Na tim osnovama odgoappleeno oslikavanje, 5 do 20 minuta nakon ubrizgavanja kontrastnog sredstva, jasno Êe prikazati fibrozu ili oæiljak. U kliniëkim ispitivanjima na ljudima, MR srca uz primjenu gadolinija kao kontrastnog sredstva je predstavljena kao precizna metoda odreappleivanja vijabilnosti miokarda u kojoj je oporavak funkcije miokarda nakon koronarne premosnice predstavljen kao referentni standard. U 52 bolesnika koji su bili podvrgnuti koronarnoj revaskularizaciji, uoëena je bolja regionalna funkcija u 82% segmenata u kojih nije ustanovljena preoperativna imbibicija kontrastom, u 64% segmenata s 1% do 25% zahvaêenosti miokarda, a svega 37% u segmentima s 26% do 50% zahvaêenosti miokarda. 12 Meta analizom ranijih studija primjena MSCT koronarografije u dijagnostici KBS pokazuje visoke stope senzitivnosti (98-99%) i negativne prediktivnu vrijednost (99-100%), no uz neπto manju specifiënost (82-89%) i pozitivnu prediktivnu vrijednost (91-93%) 13. Na drugoj strani, veêa multicentriëna studija na bolesnicima s poznatom KBS, ranijim perkutanim koronarnim intervencijama i preboljelim infarktom, dijagnostiëka toënost je neπto niæa (senzitivnost 85%, specifiënost 90%) 14. Tahikardija, artitmije i poveêan udio kalcifikata koronarnih arterija zbog mineralnih artefakata oteæavaju analizu MSCT koronarografije te smanjuju dijagnostiëku toënost 15. Procjena dugoroënog kliniëkog rizika stabilne koronarne bolesti srca Procjena dugoroënog kliniëkog rizika stabilne KBS ukljuëuje analizu veêeg broja Ëimbenika iz sfere kliniëkog pregleda i obrade Ëimbenika rizika, relevantnih ranijih anamnestiëkih podataka te nalaza aktualne dijagnostiëke obrade uz podrazumijevanje primjene kliniëkog zbrinjavanja u skladu s vaæe- Êim smjernicama kliniëke prakse, odnosno medicine utemeljene na dokazima. Posljednje smjernice Europskog kardioloπkog druπtva (ESC) iz godine podrazumijevaju visok kliniëki rizik, odnosno opravdanost za dodatnom invazivnom obradom, uz pruæanje moguênosti adekvatnog oblika revaskularizacijskog lijeëenja (gdje je to moguêe) za bolesnika s oëekivanom stopom jednogodiπnjih komplikacija i velikih neæeljenih dogaappleaja od 3% 5. DijagnostiËko-terapijsko kliniëko pitanje, odnosno obrada stope rizika ukljuëuje kliniëku reevaluaciju, procjenu rizika temeljem istisne frakcije lijeve klijetke, odgovora na stres testiranje i morfoloπkog nalaza koronarnih arterija. U Tablici 2 prikazane su stope rizika, temeljem dijagnostiëke obrade, prema vaæeêim smjernicama ESC. MRI-perfusion are significantly more commonly used in clinical practice, with a satisfactory safety profile and a sufficient degree of diagnostic accuracy, equaling to SPECT and PET tests 10. If qualitative methods of flow analysis are applied for the evaluation of perfusion deficit, the diagnostic accuracy of MRI approximately corresponds to invasive coronary angiography accompanied by using fractional flow reserve (FFR) analysis 11. The evaluation of myocardial viability by using MRI provides high-resolution morphological details, including functional evaluation of the left ventricle in only 30 minutes of imaging. The principle of gadolinium-based imaging is based on a delayed wash out of gadolinium from normal myocardium compared to the one replaced by fibrosis a scar. A delayed imaging from 5 to 20 minutes after the injection of a contrast agent will clearly show fibrosis or a scar. In clinical trials on human subjects, cardiac MRI accompanied by the use of gadolinium as a contrast agent is introduced as an accurate method of identifying myocardial viability where the recovery of the myocardial function after coronary artery bypass surgery is presented as a reference standard. In 52 patients who underwent coronary revascularization, we observed a better regional function in 82% of segments in whom preoperative imbibition by the contrast agent was not established, in 64% of segments where myocardium was affected from 1% to 25%, and only 37% in segments where myocardium was affected from 26% to 50%. 12 In a meta-analysis of of MSCT coronary angiography in the diagnostics of CAD shows a high rate of sensitivity (98-99%) and negative predictive value (99-100%), but with slightly lower specificity (82-89%) and positive predictive value (91-93%) 13. A larger multi-centric study on patients with a history of CAD, previous percutaneous coronary interventions and previous myocardial infarction shows that the diagnostic accuracy is slightly lower (sensitivity 85%, specificity 90%) 14. Tachycardia, arrhythmia and an increased frequency of calcification of the coronary arteries due to mineral artifacts make the performance of the analysis of MSCT coronary angiography more difficult and reduce diagnostic accuracy 15. Evaluation of long-term clinical risk of stable coronary artery disease The evaluation of the long-term clinical risk of stable CAD involves an analysis of a large number of factors in the field of clinical examination and processing of risk factors, relevant previous history data and findings of the current diagnostic workup assuming the application of the clinical management in accordance with applicable clinical practice guidelines or evidence-based medicine. The latest guidelines of the European Society of Cardiology (ESC) of 2013 suggest a high clinical risk, or the justification for additional invasive workup, accompanied by providing an adequate form of revascularization treatment (where possible) for patients with an expected rate of annual complications and major adverse events of 3% 5. Diagnostic and therapeutic clinical question or evaluation of risk rate involves clinical re-evaluation, risk assessment based on the left ventricular ejection fraction, the response to stress test and morphological findings of coronary arteries. Table 2 shows the risk level, based on the diagnostic workup, according to the applicable ESC guidelines. Cardiologia CROATICA 2014;9(1-2):56.

57 Table 2. Definitions of risk by diferent testing modalities according to the European Society of Cardiology 2013 guidelines 5. High risk Cardiovascular mortality 3%/year Exercise stress electrocardiogram Intermediate risk Cardiovascular mortality 1-3%/year Low risk Cardiovascular mortality <1%/year Ischaemia imaging High risk Intermediate risk Low risk Area of ischaemia >10% (>10% SPECT; >2/16 segments MRI; >3 dobutamine-induced dysfunctional segments; >3 dysfunctional segments by stress echocardiography) Area of ischaemia 1-10% and any ischaemia less than high risk by MRI or stress echocardiography No ischaemia Significant lesions of high risk category (three-vessel disease High risk with proximal stenoses, left-main and proximal stenosis Multislice computed of left anterior descendent artery) tomography coronary Intermediate risk Significant lesion(s) in large and proximal coronary artery(ies) angiography but not high risk category. Low risk Normal coronary artery or plaques only. Adapted from ESC 2013 guidelines 5 Mikrovaskularna angina Primarna mikrovaskularna bolest kliniëki se prezentira kao tipiëne ponavljajuêe anginozne tegobe. Navedeni entitet ËeπÊe se javlja uz πeêernu bolest, hipertrofiënu kardiomiopatiju ili aortnu stenozu te se podrazumijeva pod sekundarnom mikrovaskularnom bolesti, za razliku od stabilne KBS. Dugogodiπnja arterijska hipertenzija takoappleer ponekad dovodi do pojave grudne boli uz uredan morfoloπki nalaz epikardijalnih koronarnih arterija, no iz ranijih istraæivanja poznati su sluëajevi koronarografski utvappleene smanjene koronarne priëuve (FFR), Ëak i u uvjetima bez znaëajnije hipertrofije lijeve klijetke. Nasuprot tome, uz hipertenzivnu hipertrofiju lijeve klijetke dolazi do hipertrofije kardiomiocita, umnaæanja veziva, kao i perivaskularnih promjena u intramuralnom toku koronarne cirkulacije uz poremeêaje dijastoliëke funkcije 16. Dodatna obrada potrebna je kada su slikovne ili EKG metode stres testiranja postavile sumnju na KBS, no nalaz koronarografije je iskljuëio fiksnu ili dinamiëku koronarnu stenozu u epikardijalnom tijeku koronarnih arterija 17. Dijagnostika, obrada i prognostiëki Ëimbenici vazospastiëke angine, koja takoappleer suπtinski ne spada u oblike stabilne KBS prikazani su u odgovarajuêim smjernicama ESC. Zbrinavanje stabilne koronarne bolesti srca Moramo napomenuti da sveukupno zbrinjavanje ishemijske bolesti srca ukljuëuje aktivnosti oko rane dijagnostike i prevencije te kontinuiranih sveobuhvatnih mjera koje moraju osigurati Ëim povoljniju podlogu u vidu kroniënog zbrinjavanja Ëimbenika rizika. U naπoj dræavi i dalje je prisutna relativno velika zastupljenost puπenja, suboptimalne kontrole arterijske hipertenzije, dislipidemije i pretilosti te nepovoljan socioekonomski profil koji su bitan izazov u javnozdravstvenom smislu 18. U suπtinskom smislu lijeëenje stabilne KBS u okrilju medicine utemeljene na dokazima podrazumijeva optimizaciju medikamentozne terapije kombiniranu s mjerama interven- Microvascular angina Primary microvascular disease clinically presents as a typical recurring angina symptoms. The above said disease commonly occurs with diabetes, hypertrophic cardiomyopathy or aortic stenosis, and is understood to be secondary microvascular disease, unlike the stable CAD. Long-term hypertension can sometimes lead to chest pain with normal morphology of epicardial coronary arteries, but the previous studies suggest the well-known case of determined reduced fractional flow reserve (FFR), even without significant left ventricular hypertrophy. Unlike this, hypertensive left ventricular hypertrophy is accompanied by hypertrophy of cardiomyocytes, proliferation of connective tissues, as well as perivascular changes in the intramural flow of coronary circulation with diastolic function disorders 16. Additional evaluation is required when the imaging or ECG stress test methods suggest CAD, but the result of coronary angiography has excluded fixed or dynamic coronary stenosis in the flow of epicardial coronary arteries 17. Diagnostics, treatment and prognostic factors of vasospastic angina, which also essentially is not considered as stable CAD are presented in the relevant ESC guidelines. Management of stable coronary artery disease We have to note that the overall management of ischemic heart disease includes the activities involving early diagnostics and prevention as well as continuous comprehensive measures which must provide a favorable base in the form of chronic risk factor management. In our country, a relatively high prevalence of smoking, suboptimal control of hypertension, dyslipidemia and obesity and adverse socioeconomic profile that are essential challenge in public health terms are still present 18. The treatment of stable CAD within the scope of evidencebased medicine basically involves the optimization of medical therapy combined with measures of intervention treat- 2014;9(1-2):57. Cardiologia CROATICA

58 cijskog lijeëenja perkutanim koronarnim intervencijama i/ili kardiokiruπkim zahvatima. Medikamentozna terapija stabilne koronarne bolesti Ciljevi medikamentozne terapije stabilne KBS podrazumijevaju: 1. kontrolu simptoma (angina) 2. prevenciju neæeljenih kardiovaskularnih dogaappleajaa 3. dobru kontrolu Ëimbenika kardiovaskularnog rizika. U pogledu antiaterosklerotske terapije ciljevi lijeëenja ukljuëuju stabilizaciju i regresiju poznatih plakova, smanjenje sistemske upalne reakcije blagog intenziteta i spreëavanje aterotrombotskih komplikacija. Optimalna medikamentozna terapija stabilne KBS ukljuëuje viπe grupa lijekova poput: antitrombocitnih, inhibiotora 3-hidroksi-3-metilglutarilkoenzim-A-reduktaze (statini), blokatore beta adrenergiëkih receptora, nitrate, inhibitore enzima angiotenzinogenske konvertaze, kalcijske antagoniste te grupu novijih antiishemijskih lijekova poput ranolazina, trimetazidina i ivabradina 19. U pogledu opêih terapijskih napomena vaæno je istaknuti da u okrilju dobre medicinske prakse lijeëenje stabilne KBS podrazumijeva primjenu barem 2 grupe lijekova (antiishemijsko i preventivno lijeëenje neæeljenih kardiovaskularnih dogaappleaja), bolesnike kontinuirano treba poduëavati o stanju bolesti, pridruæenim rizicima te na svakoj kontroli uëiniti procjenu pridræavanja terapije kao i terapijske uëinkovitosti (rezistencija). Uz statin, mandatorna terapija spreëavanja neæeljenih kardiovaskularnih dogaappleaja ukljuëuje acetilsalicilatnu kiselinu, odnosno klopidrogel u sluëaju nepodnoπenja acetilsalicilata. Iako su se noviji P2Y antagonisti prasugrel i tikagrelor u dosadaπnjim studijama pokazali i terapijski uëinkovitijim od klopidrogela, adekvatne studije primarno u pogledu stabilne KBS joπ nisu dostupne. Takoappleer vrijedi napomenuti, da primjena dvojne antitrombocitne terapije u okrilju stabilne koronarne ili aterosklerotske bolesti uz poviπen kardiovaskularni rizik (studija CHARISMA) nije dovodila do bolje prevencije velikih neæeljenih kardiovaskularnih dogaappleaja, a izlaæe bolesnika dodatnim rizicima komplikacija, odnosno krvarenja 20. Nasuprot tome, kod poznatih aterotrombotskih komplikacija i akutnog koronarnog sindroma primjena dvojne antiagregacijske terapije je vrijedna i korisna te opisana u nadleænim smjernicama. Revaskularizacijsko lijeëenje Revaskularizacijsko lijeëenje, kao πto je ranije spomenuto, treba imati na umu kod bolesnika sa stabilnom KBS i oëekivanom procijenjenom stopom rizika kardiovaskularnih dogaappleaja 3% na godinu. Dodatna kliniëka reevaluacija preporuëa se u intermedijarnim razredima rizika ( 1 do 3%/godina) 5. Odluku o vremenu i opsegu optimalnog oblika revaskularizacijskog lijeëenja uputno je donijeti na struënom konziliju koji ukljuëuje intervencijskog kardiologa i kardijalnog kirurga te ostale subspecijalnosti u okrilju kliniëkog pitanja. Dodatne stratifikacije rizika opisane su u ranijem tekstu o dijagnostiëkoj obradi te nadleænim smjernicama ESC. ment by percutaneous coronary interventions and/or surgical interventions. Medical therapy of stable coronary artery disease The goals of medical therapy of stable CAD include: 1. the control of symptoms (angina) 2. prevention of adverse cardiovascular events 3. good control of cardiovascular risk factors. Regarding the antiatherosclerotic therapy, the treatment goals include stabilization and regression of known plaques, reduction of systemic inflammatory response of mild intensity and prevention of atherothrombotic complications. Optimal medical therapy of stable coronary artery disease includes several groups of drugs such as: antiplatelet, 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins), beta adrenergic receptor antagonists, nitrates, angiotensin-converting enzyme inhibitors, calcium antagonists, and a group of new anti-ischemic drugs such as ranolazine, trimetazidine and ivabradine 19. Regarding general therapeutic notes, it is important to stress that within the scope of good medical practice, the treatment of stabile CAD involves the administration of at least two groups of drugs (anti-ischemic and preventive treatment of adverse cardiovascular events). Besides, the patients should be continually studied as to the state of the disease, associated risks, and the evaluation of therapy compliance and the therapeutic efficacy (resistance) should be made at the time of every follow-up. In addition to statin, the mandatory therapy for prevention of cardiovascular adverse events includes acetylsalicylic acid or clopidogrel in case of intolerance of acetylsalicylates. Although the more recent P2Y antagonists prasugrel and ticagrelor proved in the previous studies to be more therapeutically effective than clopidogrel, the relevant studies primarily in terms of stable CAD are not yet available. The use of dual antiplatelet therapy for stable coronary or atherosclerotic diseases with increased cardiovascular risk (CHARIS- MA study) did not result in better prevention of major adverse cardiovascular events, but it exposed patients to additional risks of complications, i.e. bleeding 20. On contrary, in case of atherothrombotic complications and acute coronary syndrome the use of dual antiplatelet therapy is beneficial and useful, and is described in the relevant guidelines. Revascularization treatment Revascularization treatment, as mentioned earlier, should be taken into consideration in patients with stable CAD and the expected estimated risk rate for cardiovascular events 3% per year. Additional clinical re-evaluation is recommended in the intermediate risk classes ( 1 to 3%/year) 5. The decision on the timing and extent of the optimal form of revascularization treatment is to be analyzed by multiprofessional teamwork involving intervention cardiologists, cardiac surgeons and other subspecialties with regard to the clinical issue. Additional risk stratifications have been described in the ESC relevant guidelines considering acute and postacute care settings. Cardiologia CROATICA 2014;9(1-2):58.

59 Received: 5 th Feb 2014; Accepted: 8 th Feb 2014 *Address for correspondence: Thalassotherapia Opatija, Marπala Tita 188/1, HR Opatija, Croatia. Phone: ; Fax: viktor.persic@ri.t-com.hr Literature 1. Kralj V, oriê T, TomiÊ B, Hrabak-ÆerjaviÊ V. Sources of information for indicators of mortality and morbidity of cardiovascular diseases. Cardiol Croat. 2011;6(1-2): NikoliÊ Heitzler V, Babic Z, Milicic D, et al. Results of the Croatian Primary Percutaneous Coronary Intervention Network for patients with ST-segment elevation acute myocardial infarction. Am J Cardiol. 2010;105: Fihn SD, Gardin JM, Abrams J, et al.; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; American College of Physicians; American Association for Thoracic Surgery; Preventive Cardiovascular Nurses Association; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons. ACCF/AHA/ACP/AATS/PCNA/SCAI/STS. Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60:e Hemingway H, McCallum A, Shipley M, Manderbacka K, Martikainen P, Keskimaki I. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006;295: Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34: Hendel RC, Patel MR, Kramer CM, et al. ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness CriteriaWorking Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. J Am Coll Cardiol. 2006;48: Genders TS, Meijboom WB, Meijs MF, et al. CT coronary angiography in patients suspected of having coronary artery disease: decision making from various perspectives in the face of uncertainty. Radiology. 2009;253: Wahl A, Paetsch I, Gollesch A, et al. Safety and feasibility of high-dose dobutamine-atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: experience in 1000 consecutive cases. Eur Heart J. 2004;25: Selvanayagam JB, Kardos A, Francis JM, et al. Value of delayed-enhancement cardiovascular magnetic resonance imaging in predicting myocardial viability after surgical revascularization. Circulation. 2004;110: Nagel E, Lehmkuhl HB, BockschW, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation. 1999;99: Schwitter J, Wacker CM, Wilke N, et al. MR-IMPACTII: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial. Eur Heart J. 2012;34: Lockie T, Ishida M, Perera D, et al. High-resolution magnetic resonance myocardial perfusion imaging at 3.0-Tesla to detect hemodynamically significant coronary stenoses as determined by fractional flow reserve. J Am Coll Cardiol. 2011;57: Paech DC,Weston AR. A systematic review of the clinical effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of suspected coronary artery disease. BMC Cardiovasc Disord. 2011;11: Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Eng J Med. 2008;359: Brodoefel H, Burgstahler C, Tsiflikas I, et al. Dual-source CT: effect of heart rate, heart rate variability, and calcification on image quality and diagnostic accuracy. Radiology. 2008;247: Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. 2009;54: Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation. 2010;121: Reiner Z, Mihatov S, Milicic D, Bergovec M, Planinc D. Treatment and secondary prevention of ischemic coronary events in Croatia (TASPIC-CRO study). Eur J Cardiovasc Prev Rehabil. 2006;13: Henderson RA, O Flynn N. Management of stable angina: summary of NICE guidance. Heart. 2012;98: Bhatt DL, Fox KA, HackeW, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Eng J Med. 2006;354: ;9(1-2):59. Cardiologia CROATICA

60 Pregledni Ëlanak/Review article Almanac 2013.: stabilna koronarna bolest srca Almanac 2013: stable coronary artery disease Shahed Islam, Adam Timmis* Barts and the London School of Medicine and Dentistry, London Chest Hospital, London, Ujedinjeno Kraljevstvo Barts and the London School of Medicine and Dentistry, London Chest Hospital, London, United Kingdom KORONARNA BOLEST SRCA SE SMANJUJE Epidemioloπki podaci iz Europe, SAD i drugdje u razvijenom svijetu pokazuju nagli pad smrtnosti od koronarne bolesti srca (KBS) tijekom posljednjih 40 godina. 1 Zabrinutost zbog izjednaëavanja stope smrtnosti u mlaappleih odraslih 2 donekle je ublaæena podacima iz Nizozemske koji pokazuju da su se kod muπkaraca u dobi <55 godina stope smanjivanja ponovno ubrzale, poveêanjem od samo 16% u razdoblju od do na 46% u razdoblju od do SliËno je uoëeno kod mladih æena sa stopama smanjivanja 5% i 38% u istom vremenskom razdoblju. To je ohrabrujuêe, osobito u kontekstu podataka iz Danske i Velike Britanije koji ukazuju na smanjivanje smrtnosti, kao i nagli pad standardizirane stope incidencije akutnog infarkta miokarda koji ukazuju da su koronarna prevencija, kao i lijeëenje akutnih faza bolesti pridonijele nedavnim trendovima pada mortaliteta. 4,5 U meappleuvremenu nas australska studija podsjeêa da je infarkt miokarda jedna od nekoliko manifestacija kardiovaskularne bolesti, pri Ëemu ukazuje na to da su se smanjenja uëestalosti i stope recidiva hospitaliziranih KBS od do godine takoappleer odnosile na cerebrovaskularne i bolesti perifernih arterija. 6 Meappleutim, nisu sve epidemioloπke vijesti dobre, a podaci iz Velike Britanije pokazuju da se poguban odnos izmeappleu socioekonomskog statusa (SES) i KBS u posljednjih nekoliko godina ne umanjuje, gradijenti izmeappleu gornjih i donjih skupina kvintila SES za bolniëke prijeme su u naëelu ostali nepromijenjeni u rasponu starosne dobi. 7 Da li to pridonosi gotovo trostrukom riziku od infarkta miokarda povezanog s mrtvoroappleenima i deveterostrukom riziku povezanog s ponovljenim spontanim pobaëajima u novijoj njemaëkoj studiji je nejasno, jer istraæivaëi nisu pratili SES. 8 Isto tako nije jasno da li SES pridonosi trajnim etniëkim razlikama u obje ameriëke i britanske studije o smrtnosti od KBS iako se i drugi Ëimbenici smatraju bitnim. Dakle, afroameriëki muπkarci imaju veêu izloæenost Ëimbenicima rizika za KBS nego bijelci, a kada se podaci obrade nevezano, njihova sklonost za KBS nije veêa, iako su stope smrtnosti dvostruko viπe. 9 Za afroameriëke æene, uëestalosti i stope smrtnosti su viπe nego kod æena bijelkinja. Ovi rezultati, koji ukazuju da izloæenost Ëimbenicima rizika doprinosi etniëkim razlikama u pojavnosti KBS, se u odreappleenoj mjeri prikazuju i u nedavnom CORONARY HEART DISEASE IN DECLINE Epidemiological data from Europe, the USA and elsewhere in the developed world show a steep decline in coronary heart disease (CHD) mortality during the last 40 years. 1 Concern about levelling of mortality rates in younger adults 2 has been somewhat alleviated by data from The Netherlands showing that in men aged <55 years, rates of decline have again accelerated, increasing from only 16% in to 46% in A similar pattern was observed in young women with rates of decline of 5% and 38% during the same time periods. This is encouraging, particularly in the context of data from Denmark and the UK showing declining mortality and also a sharp fall in standardised incidence rates for acute myocardial infarction indicating that coronary prevention, as well as acute treatments, has contributed to recent mortality trends. 4,5 Meanwhile an Australian study reminds us that myocardial infarction is but one of several manifestations of cardiovascular disease by reporting that decreasing incidence and recurrence rates for hospitalised CHD from 2000 to 2007 have also been seen for cerebrovascular and peripheral arterial disease. 6 However, the epidemiological news is not all good, and data from the UK show that the pernicious relationship between socioeconomic status (SES) and CHD has shown no tendency to go away in recent years, the gradients between top and bottom SES quintile groups for hospital admissions remaining essentially unchanged across the age range. 7 Whether this has contributed to the almost 3-fold risk of myocardial infarction associated with stillbirth and 9-fold risk associated with recurrent miscarriage in a recent German study is unclear because the investigators made no adjustment for SES. 8 Nor is it clear if SES has contributed to the persistent ethnic differences in both US and UK studies of CHD mortality although other factors appear also to be important. Thus, African-American men have greater exposure to CHD risk factors than Caucasians and, when adjustment is made for this, their susceptibility to CHD is no greater, although mortality rates are twice as high. 9 For African- American women, incidence and mortality rates are higher than their Caucasian counterparts. These findings suggesting that exposure to risk factors contributes to ethnic differences in the incidence of CHD are to some extent reflected in a recent report from the Health Survey for England in The article was first published in Heart. 2013;99(22): doi: /heartjnl Epub 2013 Sep 5. and is republished with permission. Cardiologia CROATICA 2014;9(1-2):60.

61 izvjeπêu Zdravstvenog istraæivanja za Englesku u kojoj je bijelaca i azijata pristalo na praêenje smrtnosti. 10 Tjelesna neaktivnost je ËeπÊe kod azijata u odnosu na bijelce (47% naspram 28%) Ëime smo objasnili >20% viπe njihove smrtnosti od KBS. U svakom sluëaju novije miπljenje je da je poveêana smrtnost meappleu britanskim azijatima gotovo u cijelosti proizlazi iz njihove poveêane osjetljivosti za bolest, a ne poveêanim stopama smrtnosti oboljelih. 11 DIJAGNOZA STABILNE KORONARNE BOLESTI SRCA U najnovijim smjernicama AHA/ACC 12 naglaπena je vaænost individualiziranja dijagnostiëkog protokola na temelju procijenjene vjerojatnosti KBS. U tom smislu, one preslikavaju ranije objavljene smjernice Nacionalnog instituta za kliniëku izvrsnost (NICE) o pristupu dijagnosticiranja boli u prsima, 13 ali postoji znaëajna razlika u preporukama za neinvazivno testiranje. U novim smjernicom AHA/ACC daje se prednost ergometriji kao poëetnom dijagnostiëkom postupku za veêinu bolesnika, (NICE se ranije zalagao protiv koriπtenja ergometrije zbog relativno slabih dijagnostiëkih dometa), a dijagnostika s famakoloπkim radionuklidima, srëanom magnetskom rezonancom (MRI) ili ehokardiografskim stres testom su opcije za bolesnike koji su nepodobni za test optereêenja. Preporuke za CT koronarografiju (CTCA) su oprezne, a klasiëna koronarografija se preopruëuje u dijagnostiëke svrhe samo ako su rezultati neinvazivnih testiranja ukazuju na veliku vjerojatnost teπke troæilne bolesti ili bolesti glavnog debla lijeve koronarne arterije, a bolesnik je spreman podvrêi se revaskularizaciji. OpÊenito, stoga, najnovije smjernice AHA/ACC nisu strogo definirane kao ranije smjernice NICE, moæda dijelom i zato πto je stavljen i manji naglasak na odnos troπkovne uëinkovitosti preporuka. LIJE»ENJE STABILNE KORONARNE BOLESTI SRCA U novim NICE smjernicama 14 preporuëeno je poëetno lije- Ëenje kratkodjelujuêim nitratima i beta-blokatorom i/ili blokatorom kalcijevog kanala za kontrolu angiozinih tegoba uz acetilsalicilatnu kiselinu (ASK) i statin za sekundarnu prevenciju. Naglaπene su i mjere koje se odnose na æivotne navike. Za bolesnike koji i dalje imaju angiozne tegobe preporuëuje se koronarografija uz eventalnu revaskularizaciju, dok se dodatno medikamentozno lijeëenje za suzbijanje angine (dugodjelujuêi nitrati ili jedan od novijih lijekova) preporuëuje samo bolesnicima koji su procijenjeni nepodobni za revaskularizaciju. NaËin revaskularizacije (perkutana koronarna intervencija (PCI) ili aortokoronarne premosnice (CABG) se odreappleuje na multidisiplinarnom timu, a ta preporuka je takoappleer naglaπena i u smjernicama europskog udruæenja, 15 imajuêi na umu povoljniji uëinak CABG u bolesnika s kompleksnom viπeæilnom koronarnom bolesti i bolesti debla lijeve koronarne arterije, a posebno kod dijabetiëara. 16 Za simptomatske bolesnike koji su prihvatljivo kontrolirani farmakoloπkom terapijom, u smjernicama se preporuëuje prikaz i rasprava o potencijalnom prognostiëkom poboljπanju s CABG. Onim bolesnicima koji bi naknadno pristali na CABG, mogla bi se ponuditi dijagnostiëka koronarografija radi iskljuëenja kompleksne viπeæilne bolesti i bolesti glavnog debla lijeve koronarne arterije o kojoj je izvijeπteno u meta-analizi kod Ëak 36% (18,5-48,8%) sluëajeva stabilne koronarne bolesti odabranih za kateterizaciju srca. 17 which 13,293 Caucasian and 2,120 S Asians consented to mortality follow-up. 10 Physical inactivity was more frequent in S Asians compared with Caucasians (47% vs 28%) and explained >20% of their excess CHD mortality. Certainly, the emerging consensus is that the excess CHD mortality among UK S Asians is driven almost entirely by their increased susceptibility to disease and not by increased casefatality rates. 11 DIAGNOSIS OF STABLE CORONARY ARTERY DISEASE The recent AHA/ACC guideline update 12 emphasised the importance of individualising the diagnostic workup based on the estimated probability of coronary artery disease. In this respect, it mirrored an earlier National Institute of Clinical Excellence (NICE) guideline on chest pain diagnosis, 13 but there were important differences in the recommendations for non-invasive testing, the new AHA/ACC guideline preferring the exercise ECG as the initial diagnostic approach for most patients, (NICE had previously counselled against use of the exercise ECG based on its relatively poor diagnostic performance) with pharmacologic radionuclide, cardiac MRI or stress echocardiography testing in reserve for patients unable to exercise. Recommendations for cardiac CT coronary angiography (CTCA) were cautious, and invasive angiography was recommended for diagnostic purposes only if the results of non-invasive testing suggested a high likelihood of severe 3-vessel or left main coronary artery disease, and the patient was willing to undergo revascularisation. In general, therefore, the AHA/ACC guideline update was less prescriptive than the earlier NICE guideline, perhaps partly because it put less emphasis on the cost effectiveness of its recommendations. MANAGEMENT OF STABLE CORONARY ARTERY DISEASE The recent NICE guideline 14 recommended initial treatment with a short-acting nitrate and a beta-blocker and/or a calcium channel blocker for control of angina plus aspirin and a statin for secondary prevention. Lifestyle measures were also emphasised. For patients with continuing symptoms cardiac catheterisation with a view to revascularization was recommended, additional antianginal treatment (long-acting nitrates or one of the newer agents) only being indicated for patients unsuitable for revascularisation. It was further recommended that the mode of revascularisation (percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG)) should best be determined by a multidisciplinary group, a recommendation that has also been emphasised by European guideline groups, 15 bearing in mind the potential for prognostic benefit from CABG in patients with complex multivessel and left main stem disease, particularly those with diabetes. 16 For patients with symptoms adequately controlled with medical treatment, the guideline recommended discussion of the potential for prognostic improvement with CABG. Those patients prepared to proceed to CABG might then be offered diagnostic cardiac catheterisation to rule out complex multivessel and left main stem disease, which a recent meta-analysis reported in as many as 36% ( %) of cases of stable coronary disease selected for cardiac catheterization ;9(1-2):61. Cardiologia CROATICA

62 SEKUNDARNA PREVENCIJA STABILNE KORONARNE BOLESTI SRCA Dodatni prostor za poboljπanje sekundarne prevencije u bolesnika sa stabilnom KBS je naglaπen u dva nedavna izvjeπêa. U multinacionalnom registru REACH, simptomatskih bolesnika su analizirani su radi dobre kontrole kardiovaskularnih Ëimbenika rizika, koja je definirana kao tri do pet Ëimbenika: sistoliëki arterijski tlak <140 mmhg, dijastoliëki arterijski tlak <90 mmhg, glikemija nataπte <110 mg/dl, ukupni kolesterol <5,17 mmol/l, nepuπenje. 18 Samo 59,4% imalo je dobru kontrolu Ëimbenika rizika na poëetku, a to je bilo povezano s niæim mortalitetom (OR 0,89; 95% CI 0,79-0,99) u 36. mjesecu, u usporedbi s loπom kontrolom Ëimbenika. U britanskom istraæivanju ASPIRE-2-PREVENT, 676 bolesnika s KBS (25,6% æena) su imali sljedeêu uëestalost glavnih Ëimbenika rizika: puπenje 14,1%, pretilost 38%, tjelesna neaktivnost 83,3%, arterijski tlak 130/80 mmhg, ukupni kolesterol 4 mmol/l i dijabetes 17,8% πto je autore navelo na zakljuëak da postoji znaëajan potencijal za smanjenje kardiovaskularnog rizika kod ovih bolesnika, a time i poboljπanje prognoze. 19 Klopidogrel Dostupnost jeftinog generiëkih klopidogrela je potaknuo reviziju NICE-a u smislu njegove isplativosti te je preporuka dovela do istiskivanja ASK u pojedinim visokoriziënim skupinama, odnosno kod bolesnika s viπestrukom vaskularnom bolesti, perifernom vaskularnom bolesti i infarktom miokarda. 20 Meappleutim, klopidogrel se metabolizira enzimima u sustavu jetrenog citokroma P450 (CYP), a promjenjivost u antiagregacijskom djelovanju se moæe pojaviti zbog djelovanja ovih enzima te se na nju utjeëe uobiëajenim genetskim varijacijama, kao i velikim brojem Ëesto koriπtenih lijekova. U nekoliko studija se navodi smanjenje aktivacije alela u CYP2C 19 πto za posljedicu ima smanjenu aktivaciju klopidogrela 21 i umjerno sniæenje antiagregacijskog djelovanja, 22 πto je povezano s poveêanim rizikom od kardiovaskularnih bolesti kod nekih meta-analiza. 23 Obrnuto, pojaëana aktivacija alela je povezano sa smanjenjem kardiovaskularnog rizika kod bolesnika lijeëenih klopidogrelom. 24 Nedavna metaanaliza se meappleutim nije osvrnula na tendenciju malih studija, koje mogu biti optereêene biasom o naëinu kako genetske varijante utjeëu na kliniëke ishode, dok u veêim studijama terapije klopidogrelom s 200 krajnih ishoda nije naappleen uëinak smanjene aktivacije alela na kardiovaskularni rizik. 25 Trenutno se dakle Ëini da nema niti jednog uvjerljivog pokazatelja za genetsko testiranje pri voappleenju terapije klopidogrelom, iako je ova tema i dalje predmet stalnih rasprava. Takoappleer se raspravlja o interakciji klopidogrela s nekim Ëesto koriπtenim lijekovima, osobito inhibitorima protonske pumpe (IPP) i amlodipinom. Nedavnom metaanalizom studija IPP u bolesnika lijeëenih klopidogrelom naappleen je jasan dokaz smanjene aktivnosti trombocita, ali iako se Ëini da je na kliniëke ishode interakcija negativno utjecala, autori su pozvali na oprezno tumaëenje, istiëuêi heterogenost uzrokovane retrospektivnim studijama. Kada je analiza ograniëena na prospektivne studije IPP i klopidogrela, πtetne kliniëke posljedice se viπe ne bi mogle dokazati (OR 1,13 (0,98-1,30)). 26 SliËno tome, kliniëki uëinak amlodipina na reakciju na klopidogrel i dalje ostaje nejasan. Dakako, postoje dokazi o interakciji, a u jednoj studiji od bolesnika koji su primali klopidogrel, primjena amlodipina je povezano s viπom reaktivnoπêu trombocita u tijeku terapije samo u onih bolesnika sa smanjenom aktivacijom genotipa P450 (CYP) SECONDARY PREVENTION OF STABLE CORONARY DISEASE The scope for improving secondary prevention in patients with stable coronary artery disease has been emphasised in two recent reports. In The multinational REduction of Atherothrombosis for Continued Health (REACH) Registry, 20,588 symptomatic patients were analysed for good control of cardiovascular risk factors, defined as three to five of systolic blood pressure <140 mmhg, diastolic blood pressure <90 mmhg, fasting glycaemia <110 mg/dl, total cholesterol <200 mg/dl, non-smoking. 18 Only 59.4% had good control of risk factors at baseline, but this was associated with lower mortality (OR 0.89; 95% CI ) at 36 months, compared with poor control. In the UK ASPIRE-2-PREVENT survey, 676 patients with CHD (25.6% women) had the following rates of major risk factors: smoking 14.1%, obesity 38%, physical inactivity 83.3%, blood pressure 130/80 mmhg, total cholesterol 4mmol/l and diabetes 17.8%, leading the authors to conclude that there is considerable potential for reducing cardiovascular risk in these patients and thereby improve prognosis. 19 Clopidogrel The availability of low-cost generic clopidogrel prompted a NICE review of its cost effectiveness which recommended it should now supersede aspirin in certain high-risk groups, namely patients with multivascular disease, peripheral vascular disease and myocardial infarction. 20 However, clopidogrel is metabolised by enzymes in the hepatic cytochrome P450 (CYP) system, and variability in its antiplatelet activity may occur because the activity of these enzymes is influenced by common genetic variations, and also by a number of commonly used drugs. Several studies have reported loss-of-function alleles in CYP2C 19 that result in reduced activation of clopidogrel 21 and a modest lowering of antiplatelet activity 22 which have been associated with an increased risk of cardiovascular events in some meta-analyses. 23 Conversely, gain-of-function alleles have been associated with reduced cardiovascular risk among clopidogrel-treated patients. 24 A recent meta-analysis, however, has commented on the tendency of small studies to bias conclusions about the way genetic variants influence clinical outcomes, and in larger studies of clopidogrel therapy with 200 outcome events found no effect of loss-of-function alleles on cardiovascular risk. 25 At present, therefore, there seems to be no compelling indication for genetic testing to guide clopidogrel treatment although the topic remains a subject of ongoing debate. Also debated is the interaction of clopidogrel with some commonly used drugs, particularly proton pump inhibitors (PPI) and amlodipine. A recent meta-analysis of studies of PPIs in patients treated with clopidogrel found clear evidence of reduced platelet activity but although clinical outcomes appeared adversely affected by the interaction, the authors urged cautious interpretation, pointing out the heterogeneity caused by retrospective studies. When analysis was restricted to prospective studies of PPIs and clopidogrel, adverse clinical consequences could no longer be demonstrated (OR 1.13 ( )). 26 Similarly, the clinical impact of amlodipine on responsiveness to clopidogrel remains uncertain. Certainly, there is evidence of interaction, and in one study of 1,258 patients receiving clopidogrel, amlodipine administration was associated with higher on-treatment platelet reactivity only in those patients with a loss-offunction P450 (CYP) genotype (249±83 vs 228±84 P2Y12 Cardiologia CROATICA 2014;9(1-2):62.

63 (249±83 naspram 228±84 P2Y12 reakcijskih jedinica), i to je bilo povezano s veêom uëestaloπêu kardiovaskularnih dogaappleaja (4,6% naspram 0,6%). 27 Meappleutim, u novijem randomiziranom istraæivanju, funkcija trombocita u 98 bolesnika sa stabilnom KBS koji su uzimali klopidogrel je bila sliëna bez obzira na terapiju amlodipina. 28 Trenutno, dakle ne postoje smjernice za preporuku o istovremenom propisivanju ovih lijekova kod bolesnika koji uzimaju klopidogrel. Statini, nijacin i inhibitori kolesteril-ester transfer proteina (CETP) Prednosti statina za sekundarnu prevenciju kod bolesnika s stabilnom KBS su dobro utvrappleene. Kardiovaskularni zajedniëki ishodi se smanjuju razmjerno stupnju smanjenja LDLkolesterola, vjerojatno kao odgovor na stabilizaciji i regresiju ateromatoznog plaka. Kapacitet za regresiju plaka je nedavno potvrdilo i serijsko ispitivanje primjenom IVUS kod bolesnika sa stabilnom KBS randomiziranih na rosuvatatin 40 mg dnevno ili atorvastatin 80 mg dnevno. 29 Volumen ateroma tijekom razdoblja praêenja od 2 godine se smanjio u prosjeku za oko 1% u obje skupine, viπe nego πto se prethodno objavljeno s manje intenzivnim reæimima statina. Meappleutim, dodatne kliniëke koristi niacina sada nisu nedvosmisleno odbaëene u istraæivanju AIM-HIGH u kojem je bolesnika sa stabilnom kardiovaskularnom boleπêu koji uzimaju statine randomizirano za niacin (n = 1.718) ili placebo (n = 1.696). 30 Iako je niacin znaëajno poveêao HDLkolesterol i snizio trigliceride, razlike u primarnim zajedniëkim ishodima (broj nepovoljnih koronarnih dogaappleaja, moædanih udara i revaskularizacije ) su bili zanemarivi, i javili su se kod 16% bolesnika u svakoj skupini. Istraæivanje je zaustavljeno nakon prosjeënog praêenja od 3 godine, kada je postalo jasno da je terapija podizanja HDL s niacinom bila kliniëki nedjelotvorna. Sve nade za poviπenje razine HDL su sada usmjerene prema CETP inhibitorima, unatoë problemima vezanim za sigurnost nakon istraæivanja ILLUMINATE o torcetrapibu, 31 u kojem je lijeëenje bilo povezano s poveêanom smrtnoπêu unatoë znaëajnim poviπenjima HDL, a ostali inhibitori CETP sada ulaze u III fazu istraæivanja. Nedavno randomizirano istraæivanje dalcetrapiba u bolesnika s akutnim koronarnim sindromom je bilo razoëaravajuêe bez smanjenja rizika ponovljenih koronarnih dogaappleaja unatoë pove- Êanju razina HDL od >30% u skupinama lijeëenja. 32 UËinkovitost i sigurnost istraæivanja anacetrapiba u bolesnika sa visokim rizikom stabilne koronarne bolesti je bilo povoljno, iako nisu bili zajamëeni kliniëki ishodi, 33 a evacetrapib je sada ukljuëen u nedavno istraæivanje u kojem se prikazuje uëinkovito podizanje HDL bez πtetnih uëinaka na arterijski tlak πto je zabiljeæeno kod torcetrapiba i, u manjoj mjeri, dalcetrapiba. 34 Ostaje nepoznato hoêe li bilo koji od ovih inhibitora CETP poboljπati kliniëke ishode. Novi lijekovi za sniæavanje vrijednosti lipida u kliniëkim studijama Konvencionalne terapije sniæavanja lipida Ëak i u kombinaciji sa LDL-aferezom su Ëesto nedovoljne za lijeëenje bolesnika prema ciljnim vrijednostima u smjernicama kod bolesnika s obiteljskom hiperkolesterolemijom (FH), autosomnom dominantnom poremeêaju metabolizma lipida povezanog s ubrzanom KBS. 35 Postoji, prema tome, znaëajan interes za novim terapijama koje se trenutno istraæuju, naroëito lomitapid, oralni inhibitor mikrosomalnog transfer proteina i monoklonska antitijela protiv PCSK9. Faza II studije o lomitapireaction units), and this was associated with a higher incidence of cardiovascular events (4.6% vs 0.6%). 27 However, in a more recent randomised trial, platelet function in 98 patients with stable coronary artery disease taking clopidogrel was similar regardless of amlodipine therapy. 28 At present, therefore, there is no guideline recommendation about concomitant prescription of these drugs in patients taking clopidogrel. Statins, niacin and cholesteryl ester transfer protein (CETP) inhibitors The benefits of statins for secondary prevention in patients with stable coronary artery disease are well established. Cardiovascular end-points are reduced in proportion to the degree of LDL-cholesterol reduction, probably in response to stabilisation and regression of atheromatous plaque. The capacity for plaque regression has recently been confirmed by serial IVUS examination in 1,039 patients with stable coronary disease randomised to rosuvastatin 40 mg daily or atorvastatin 80 mg daily. 29 Atheroma volume during the 2- year monitoring period decreased by an average of about 1% in both groups, more than previously reported with less intensive statin regimens. However, additional clinical benefits of niacin have now been unequivocally ruled out in the AIM-HIGH trial in which 3,414 patients with stable cardiovascular disease taking statins were randomised to receive niacin (n = 1,718) or placebo (n = 1,696). 30 Although niacin significantly increased HDL cholesterol and lowered triglycerides, differences in the primary endpoints (a composite of adverse coronary events, strokes and revascularisation) were negligible, occurring in 16% of patients in each group. The trial was stopped after an average follow-up of 3 years when it became clear HDL raising therapy with niacin was clinically ineffective. All hopes for HDL raising therapy are now invested in CETP inhibitors, and despite safety concerns following the ILLUMINATE trial of torcetrapib, 31 in which treatment was associated with increased mortality despite substantial HDL elevations, other CETP inhibitors are now entering phase III trials. A recent randomised trial of dalcetrapib in patients with acute coronary syndromes was disappointing with no reduction in the risk of recurrent coronary events despite a >30% increase in HDL levels in the treatment group. 32 An efficacy and safety trial of anacetrapib in patients with, or at high risk of, stable coronary disease was favourable, although not powered for clinical outcomes 33, and evacetrapib has now entered the arena with a recent study showing effective HDL raising without the adverse effects on blood pressure seen with torcetrapib and, to a lesser extent, dalcetrapib. 34 Whether any of these CETP inhibitors will improve clinical outcomes, however, remains unknown. Novel lipid-lowering drugs in clinical translation Conventional lipid-lowering therapies, even when combined with LDL-apheresis, are often insufficient to treat to guideline targets patients with familial hypercholesterolaemia (FH), an autosomal dominant disorder of lipid metabolism associated with accelerated coronary disease. 35 There is, therefore, considerable interest in novel therapies currently under investigation, particularly lomitapide, an oral inhibitor of microsomal transfer protein and monoclonal antibodies against PCSK9. A phase II study of lomitapide in homozy- 2014;9(1-2):63. Cardiologia CROATICA

64 du u homozigotnom FH je pokazala smanjenje od 50% LDLkolesterola i, iako su gastrointestinalne nuspojave bile Ëeste, korisna uloga za lijek se Ëinila vjerojatnom kod ovih homozigotnih bolesnika. 36 Inhibitori PCSK9 su takoappleer doveli do 50-60% smanjenja vrijednosti LDL-kolesterola u kliniëkim studijama kada se dodaju statinima i ezetimibima, ali za razliku od lomitapida, vjerojatno su uglavnom uëinkoviti kod heterozigotnih FH, jer oni djeluju preko intereferencije s LDL receptorima, koji su disfunkcionalni ili u potpunosti odsutni kod homozigota. 37,38 OËekuje se da Êe primjena tih novih lijekova omoguêiti veêini bolesnika s FH postizanje ciljnih koncentracija LDL kolesterola. Vaæna komponenta zbrinjavanja FH ukljuëuje utvrappleivanje ostalih zahvaêenih Ëlanova obitelji, a kaskadni probir koristeêi gensko testiranje se pokazalo troπkovno uëinkovitim. 39 Meappleutim, nedavni dokazi upuêuju da poligenski poremeêaji Ëine znaëajan dio sluëajeva FH, 40 a time Êe se uëinkovitost kaskadnog probira ograniëiti na roappleake mutacijskih-pozitivnih (monogenskih) sluëajeva. Kod drugih bolesnika sa razinama kolesterola koji je u skladu s genotipom FH, uobiëajene primarne mjere zbrinjavanja 41 bi trebale ostati metoda izbora probira, barem zasada. REVASKULARIZACIJA KOD STABILNE KORONARNE BOLESTI SRCA Perkutana koronarna intervencija Studija COURAGE je donijela obrat pokazavπi da stentiranje koronarnih arterija u bolesnika sa stabilnom anginom ne pospjeπuje kardiovaskularne ishode u usporedbi s optimalnom farmakoloπkom terapijom (OMT), dok su koristi u pogledu kvalitete æivota bile kratkog trajanja. 42,43 Sada je dostupna metaanaliza u kojoj se usporeappleuje najnovija medikamentozna terapija i PCI u osam randomiziranih istraæivanja koja ukljuëuju bolesnika sa stabilnom KBS. 44 Ponovno, kardiovaskularni ishodi izmeappleu skupina su bili sliëni tijekom praêenja od prosjeëno 4,3 godine, bez znaëajne kliniëke koristi za PCI, rizika od smrti (8,9% naspram 9,1%) i nefatalnog infarkta miokarda (8,9% naspram 8,1%) πto je gotovo istovjetno medikamentoznoj terapiji, dok su razlike u neplaniranoj revaskularizaciji (21,4% naspram 30,7%) i perzistentnoj angini (29% naspram 33%) bile male i neznaëajne. Podaci podræavaju nedavne preporuke iz smjernica za lije- Ëenje stabilne angine (vidi gore) te su koriπteni kao poziv za preispitanje miπljenja lijeënicima koji i dalje preporuëaju PCI bolesnicima koji se ne lijeëe pomoêu OMT. 45 Meappleutim, studija FAME-II je sada omoguêila potporu ranom intervencijskom pristupu u randomiziranoj usporedbi OMT i PCI uz uporabu DES i intervenciju voappleenu nalazom frakcije priëuvnog protoka (FFR). 46 Studija je zaustavljena 17 mjeseci prije nego πto je planirano, jer se primarni zbirni ishod (smrtnost od svih uzroka, nefatalni infarkt miokarda, hitna revaskularizacija) dogodio u 4,3% u skupini na PCI u usporedbi s 12,7% u skupini na OMT. Ublaæavanje angine takoappleer je bilo uëinkovitije u skupini lijeëenoj primjenom PCI. Metoda PCI voappleena FFR-om postala je veê preporuëena strategija kod stabilne KBS, ali neki smatraju da je to prerano za zakljuëke. 47 Tako je razlika u uëinku lijeëenja u studiji FAME-II proizaπla iskljuëivo smanjenjem hitne revaskularizacije (49 samo u OMT skupini; 7 u FFR-PCI skupini (HR = 0,13; 95% CI 0,06-0,30), dok su 33 smrti i nefatalni infarkti miokarda bili ravnomjerno rasporeappleeni izmeappleu skupina. toviπe, veêina bolesnika koji su podvrgnuti æurnoj revaskularizaciji nisu imali objektivne nalaze visoko riziëne ishemije ili porasta biomarkera te se time postavlja pitanje bias-a u odabiru bolegous FH showed a 50% reduction in LDL-cholesterol and, although gastrointestinal side effects were common, a useful role for the drug seems likely in these homozygous patients. 36 PCSK9 inhibitors have also produced 50-60% reductions in LDL-cholesterol values in clinical studies when added to statins and ezetimibe, but unlike lomitapide, are probably mainly effective in heterozygotic FH because they act through interference with LDL receptors which are dysfunctional or completely absent in homozygotes. 37,38 The expectation is that application of these new drugs will allow most patients with FH to achieve target concentrations of LDL cholesterol. An important component of FH management involves identification of other affected family members, and cascade screening using genetic testing has been reported as cost effective. 39 However, recent evidence suggests that polygenic disorders account for an appreciable proportion of FH cases, 40 and this will limit the effectiveness of cascade screening to relatives of mutation-positive (monogenic) cases. In other patients, with cholesterol levels consistent with an FH genotype, more conventional primary care strategies 41 should remain the screening tool of choice, at least for the time being. REVASCULARISATION IN STABLE CAD Percutaneous coronary intervention The COURAGE trial was a game-changer, showing that coronary stenting in patients with stable angina did not improve cardiovascular outcomes compared with optimal medical therapy (OMT) while quality-of-life benefits were shortlived. 42,43 Now available is a meta-analysis comparing contemporary medical therapy and PCI in eight randomised trials involving 7,229 patients with stable CAD. 44 Again, cardiovascular outcomes between the groups were similar during follow-up for an average 4.3 years with no significant clinical benefit for PCI, risks of death (8.9% vs 9.1%) and non-fatal MI (8.9% vs 8.1%) being nearly identical with medical therapy, while differences in unplanned revascularisation (21.4% vs 30.7%) and persistent angina (29% vs 33%) were small and insignificant. The data support recent guideline recommendations for treatment of stable angina (see above), and have been used to challenge those clinicians who continue to offer PCI to patients not receiving OMT. 45 However, FAME-II has now provided some support for an early interventional approach in a randomised comparison of OMT and PCI using drug-eluting stents guided by fractional flow reserve (FFR). 46 The study was stopped 17 months earlier than planned because the composite endpoint (all-cause mortality, non-fatal MI, urgent revascularisation) occurred in 4.3% of the PCI group compared with 12.7% of the non-pci (OMT) group. Relief of angina was also more effective in the PCI group. Already, PCI guided by FFR has become a recommended strategy in stable coronary artery disease but some feel this is premature. 47 Thus, the treatment difference in FAME-II was driven solely by a reduction in urgent revascularisation (49 in the OMT alone group; 7 in the FFR-PCI group (HR = 0.13, 95% CI ), while the 33 deaths and non-fatal MIs were distributed fairly evenly between the groups. Moreover, the majority of patients undergoing urgent revascularisation lacked objective findings of high-risk ischaemia or threshold biomarker elevations, raising concerns of biased selection of patients for invasive management during follow-up. Nevertheless, the argument in favour of interventional management as an initial strategy in stable angina has undoubtedly been strengthened by FAME-II, but Cardiologia CROATICA 2014;9(1-2):64.

65 snika za invazivni pristup tijekom razdoblja praêenja. Ipak, dokazi u korist intervencijskog zbrinjavanja kao poëetne strategije kod stabilne angine nesumnjivo su se osnaæili u studiji FAME-II, no, konaëni odgovori na temu Êe moæda morati priëekati rezultate istraæivanja ISCHEMIA, u kojem se usporeappleuju uëinci revaskularizacije (PCI ili CABG) u kombinaciji s OMT, samo s OMT na kardiovaskularnu smrtnost ili infarkt miokarda kod bolesnika sa stabilnom KBS i objektivnim dokazima ishemije miokarda. Aortokoronarno premoπtenje Aktualne ameriëke smjernice 48 podræavaju preporuka NICE smjernica o multidisciplinarnom timskom pristupu pri donoπenju odluka o revaskularizaciji kod bolesnika s kompleksnom KBS, potiëuêi primjenu SYNTAX i drugih alata/ljestvica za donoπenje odgovarajuêe odluke. 49 MoguÊnost za CABG u usporedbi s PCI za poboljπanje prognoze kod bolesnika s boleπêu debla lijeve koronarne arterije i viπeæilne KBS je podræana u nedavno objavljenim kohortnim studijama, 50,51 a sada su dostupni podaci petogodiπnjeg praêenja iz studije SYNTAX u kojoj su glavni nepovoljni srëani i cerebrovaskularni dogaappleaji (MACCE) bili 26,9% u skupini na CABG i 37,3% u skupini na PCI, uglavnom zahvaljujuêi niæim stopama nefatalnog infarkta miokarda i ponovljene revaskularizacije za CABG, bez znaëajne razlike u smrtnosti od svih uzroka i moædanog udara u usporedbi s PCI. 52 Prednosti CABG su posebno bile vidljive kod bolesnika sa srednjim i visokim rezultatima primjene SYNTAX ljestvice, bez da postoji znaëajna razlika u ishodima meappleu strategijama revaskularizacije za bolesnike s niskim rezultatima SYNTAX ljestvice. Sva pitanja o strategiji izbora revaskularizacije kod bolesnika s dijabetesom i viπeæilnom KBS sada su odgovorena u studiji FREEDOM u kojoj je randomizirano bolesnika na OMT za PCI sa DES ili CABG. 53 Nakon prosjeënog praêenja od 3,8 godina, primarni ishod, koji se sastoji od smrti od bilo kojeg uzroka, nefatalnog infarkta miokarda, odnosno nefatalnog moædanog udara, dogodio se u 26,6% PCI skupine i 18,7% u skupini CABG. Autori su zakljuëili da je CABG superioran u odnosu na PCI u bolesnika s dijabetesom i viπeæilnom KBS. Odluka o strategiji izbora revaskularizacije debla lijeve koronarne arterije manje je odreappleena, pri Ëemu su SYNTAX istraæitelji izvijestili o sliënim ishodima za PCI i CABG, a rezultat je u skladu s ostalim suvremenim studijama u kojima se ugradnja stenta smatra razumnom strategijom kod dobro odabranih sluëajeva, iako je potreba za ponovnom revaskularizacijom gotovo uvijek veêa nego kod CABG. 54,55 Kirurπka tehnika se u zadnje vrijeme poëela detaljno istraæivati. Zabrinutosti zbog moguêih nuspojava endoskopske metode vaappleenja vene safene naspram otvorenog kirurπkog zahvata uklanjanja vene safene se u velikoj mjeri temelje na nerandomiziranoj kohortnoj studiji od bolesnika kod kojih je uëestalost neuspjeha presaappleivanja vene u 1. godini bili 47% naspram 38%, a stope smrti, infarkta miokarda ili revaskularizacije u 3. godini su bile 20,2% naspram 17,4 % za endoskopsku naspram otvorene metode vaappleenja vene safene. 56 Zbog toga se NICE smjernice preporuëile oprez u koriπtenju endoskopske tehnike, 57 ali ta zabrinutost se sada smanjuje zbog rezultata dviju velikih kohortnih studija. U ameriëkoj studiji kod Medicare bolesnika s CABG stope smrtnosti iz nacionalne baze podataka su bile sliëne bez obzira na tehniku vaappleenja, dok su stope komplikacija lokacije vaappleenja bile niæe za endoskopsku tehniku. 58 Britanska studija sa bolesnika s CABG je izvijestila o sliënim rezultatima, bez razlika u bolniëkoj smrtnosti (0.,9% vs 1,1%, p = 0.71 i srednjoroënoj smrtnosti (HR 1,04; 95% CI final answers to the debate may have to await the findings of the ongoing International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (IS- CHEMIA Trial; ClinicalTrials.gov number, NCT ), comparing effects of revascularisation (PCI or CABG) combined with OMT, with OMT alone on cardiovascular death, or MI in patients with stable CAD, and objective evidence of myocardial ischaemia. Coronary artery bypass surgery Updated US guidelines 48 have endorsed the NICE recommendation of a multidisciplinary team approach to adjudicating revascularisation decisions in patients with complex coronary disease, encouraging application of SYNTAX and other scoring systems in arriving at an appropriate decision. 49 The potential for CABG compared with PCI to improve prognosis in patients with left main and multivessel CAD is supported by recent cohort studies, 50,51 and now available are the 5-year follow-up data from SYNTAX in which major adverse cardiac and cerebrovascular events (MACCE) were 26.9% in the CABG group and 37.3% in the PCI group, driven largely by lower rates of non-fatal myocardial infarction and repeat revascularisation for CABG, with no significant difference in all-cause mortality and stroke compared with PCI. 52 The benefits of CABG were particularly evident in patients with intermediate and high SYNTAX scores, there being no significant difference in outcomes between revascularisation strategies for patients with low SYNTAX scores. Any question about the preferred revascularisation strategy in patients with diabetes and multivessel coronary artery disease has now been answered by the FREEDOM TRIAL which randomised 1,900 patients on OMT to either PCI with drug-eluting stents or CABG. 53 After a median follow-up of 3.8 years, the primary outcome, a composite of death from any cause, non-fatal myocardial infarction, or non-fatal stroke, occurred in 26.6% of the PCI group and 18.7% of the CABG group. The authors concluded that CABG is superior to PCI in patients with diabetes and multivessel disease. There is less certainty about the preferred revascularisation strategy in left main coronary disease, the SYNTAX investigators reporting similar outcomes for PCI and CABG, a finding consistent with other contemporary studies that identify stenting as a reasonable strategy in appropriately selected cases, even though the need for repeat revascularisation is almost invariably higher compared with CABG. 54,55 Surgical technique has come under considerable scrutiny recently. Concerns about the potential adverse effects of endoscopic versus open saphenous vein harvesting have been based largely on a non-randomised cohort study of 1,817 patients in whom rates of vein graft failure at 1 year were 47% vs 38%, and rates of death, myocardial infarction or revascularisation at 3 years were 20.2% vs 17.4% for endoscopic versus open saphenous vein harvesting. 56 This led NICE to recommend caution in use of the endoscopic technique, 57 but such concerns have now been allayed by the results of two large cohort studies. In the US study of 235,394 Medicare CABG patients in the Society of Thoracic Surgeons (STS), national database mortality rates were similar regardless of harvesting technique, while rates of harvest site complications were lower for the endoscopic technique. 58 A UK study of 4,702 CABG patients reported similar findings with no differences in in-hospital mortality (0.9% vs 1.1%, p = 0.71) or midterm mortality (HR 1.04; 95% CI ) for endoscopic versus open vein harvesting ;9(1-2):65. Cardiologia CROATICA

66 1.66) za endoskopsku u odnosu na otvorenu metodu vaappleenja vene. 59 Takoappleer se iscrpno istraæuju relativne prednosti zahvata kardiokirurπke revaskularizacije bez ili uz potporu stroja za vantjelesnu cirkulaciju. Svaki ima svoje zagovornike, 60,61 ali rezultati randomiziranih istraæivanja nisu uspjeli pokazati jasnu prednost CABG bez potpore stroja za vantjelesnu cirkulaciju, pri Ëemu su trogodiπnji rezultati studije Best Bypass Surgery Trial pokazali da nema znaëajne razlike u primarnom sloæenom ishodu MACCE u odnosu na CABG s kardiopulmonalnim premoπtenjem, nego tendenciju veêe smrtnosti. 62 Time se barem djelomiëno mogu prikazati razlike u stopama prohodnosti favorizirajuêi postupke koriπtenja kardiopulmonalnog premoπtenja, pri Ëemu je istraæivanje ROOBY objavilo stope od 91,4% naspram 85,8% za arterijske transplantate i 80,4% naspram 72,7% za transplantate vene safene kod bolesnika kod kojih se primjenjuje postupak koriπtenja kardiopulmonalnog premoπtenja u odnosu na bolesnike kod kojih se ne primjenjuje kardiopulmonalno premoπtenje. 63 Osobito je bio razoëaravajuêi neuspjeh operacije bez koriπtenja kardiopulmonalnog premoπtenja za smanjenje cerebralne ozljede, ali randomizirana usporedba minimalne (MECC) u odnosu na konvencionalnu (CECC) izvantjelesnu cirkulaciju u 64 bolesnika podvrgnutih CABG je viπe obeêavajuêa. 64 MECC je povezana s poboljπanom opskrbom mozga kisikom tijekom operacije, a neurokognitivni rezultat u 3 mjeseca je bio bolji u usporedbi s CECC. ISHEMIJSKO PREDKONDICIRANJE UDALJENIH ORGANA ILI TKIVA ZA LIJE»ENJE STABILNE KORONARNE BOLESTI SRCA Zagovornici smatraju ishemijsko predkondiciranje udaljenih organa (RIPC) korisnim i jeftinim naëinom za poboljπanje ishoda u πirokom nizu kardiovaskularnih bolesti. Za njih je stoga frustrirajuêi neuspjeh proboja tehnike u kliniëku praksu, uz proturjeëna izvjeπêa o njegovoj uëinkovitosti, a neuvjerljivost mehanizma uëinka potkopava povjerenje u kliniëku korisnost RIPC. Neka novija randomizirana istraæivanja su bila povoljna, u jednom se izvijestilo o zaπtiti od kontrastom inducirane nefropatije tijekom kateterizacije srca, 65 a drugom o smanjenju oπteêenja miokarda tijekom operacije srëanih zalistaka. 66 Moæda je najpovoljnije bilo randomizirano istraæivanje predbolniëkog RIPC kod 333 bolesnika sa STEMI koji subili lijeëeni primarnom PCI. 67 Skupina s RIPC je pokazala znaëajno poboljπanje u indeksu spaπavanja miokarda u usporedbi s skupinom bez RIPC (0,75 naspram 0,55), iako istraæivanje nije ukljuëilo dovoljno ispitanika za praêenje koronarnih dogaappleajia. Nasuprot toga se mora prikazati negativno istraæivanje RIPC u skupini bolesnika podvrgnutih CABG, 68 ali je malo vjerojatno da Êe to biti posljednja rijeë, jer se veê metaanalizom od devet studija koje su ukljuëivale 704 bolesnika zakljuëilo da RIPC znaëajno smanjuje otpuπtanje troponina tijekom CABG. 69 Studije u kojima se pratio mehanizam djelovanja ukljuëuju kriænu studiju u bolesnika sa stabilnom KBS, a u toj studiji RIPC je smanjio djelovanje trombocita tijekom testiranja pod optereêenjem, bez zaπtite od ishemijskih elektrokardiografskih promjena. 70 U drugoj studiji u kojoj se koristila venska pletizmografija krvotoka podlaktice kod zdravih dobrovoljaca, RIPC je πtitio od oπte- Êenja vazomotorne funkcije endotela, koja nastaje pri ishemiji. 71 Meappleutim, na tu zaπtitu nije utjecala infuzija antagonista bradikinin B2 receptora, navodeêi autore na zakljuëak da bradikinin nije medijator RIPC. Also under scrutiny have been the relative benefits of offpump and on-pump CABG. Each has its proponents, 60,61 but the results of randomised outcome trials have failed to show any clear advantage for off-pump CABG, the 3-year results of the Best Bypass Surgery Trial showing no significant difference in the primary composite outcome of MACCE compared with on-pump CABG, but a tendency towards higher mortality. 62 This may reflect, at least in part, differences in graft patency rates favouring on-pump procedures, the ROOBY trial reporting rates of 91.4% vs 85.8% for arterial grafts and 80.4% vs 72.7% for saphenous vein grafts in onpump compared with off-pump patients. 63 Particularly disappointing has been the failure of off-pump surgery to reduce cerebral injury, but a randomised comparison of minimal (MECC) versus conventional (CECC) extracorporeal circulation in 64 patients undergoing CABG has been more promising. 64 MECC was associated with improved cerebral oxygen delivery during surgery, and neurocognitive performance at 3 months was better when compared with CECC. REMOTE ISCHAEMIC PRECONDITIONING FOR TREATMENT OF STABLE CORONARY DISEASE Its proponents see remote ischaemic preconditioning (RIPC) as a useful and inexpensive means of improving outcomes across a range of cardiovascular disorders. They must be frustrated, therefore, by the technique s failure to penetrate clinical practice, conflicting reports of its efficacy and mechanistic uncertainty combining to undermine clinical confidence in the utility of RIPC. Some recent randomised trials have been favourable, reporting protection against contrast-induced nephropathy during cardiac catheterization 65 and reduction in myocardial injury during heart valve surgery. 66 Perhaps the most favourable has been a randomised trial of prehospital RIPC in 333 patients with STEMI who underwent primary PCI. 67 The group with RIPC showed a significant improvement in myocardial salvage index compared with the group without (0.75 vs 0.55) although the trial was not powered for coronary events. Against this must be set a negative trial of RIPC in a group of patients undergoing CABG, 68 but this is unlikely to be the last word, and already a meta-analysis of nine studies including 704 patients has concluded that RIPC significantly reduces troponin release during CABG. 69 Mechanistic studies of interest include one crossover study in patients with stable coronary artery disease in which RIPC reduced platelet activation during exercise testing without protecting against ischaemic ECG changes. 70 In another study of forearm blood flow using venous plethysmography in healthy volunteers, RIPC protected against impaired endothelium-dependent vasomotor function induced by ischaemia. 71 However, this protection was unaffected by infusion of a bradykinin B2 receptor antagonist, leading the authors to conclude that bradykinin is not a mediator of RIPC. PROGNOSTIC BIOMARKERS IN STABLE CAD Circulating biomarkers Interest in circulating cardiovascular biomarkers has never been higher, and methodological papers have been developed to alert researchers to the standards necessary for proper evaluation of their prognostic utility. 72,73 However, a systematic review of 83 CRP studies was critical of their ge- Cardiologia CROATICA 2014;9(1-2):66.

67 PROGNOSTI»KI BIOMARKERI KOD STABILNE KORONARNE BOLESTI SRCA Biomarkeri u cirkulaciji Interes za biomarkere u kardiovaskularnoj cirkulaciji nikada nije bio veêi, a metodoloπki radovi su izraappleeni kako bi upozorili istraæivaëe o standardima potrebnim za pravilno vrednovanje njihove prognostiëke koristi. 72,73 Meappleutim, sistematski pregledni Ëlanak o 83 CRP studija je bio kritiëan prema njihovoj opêoj kvaliteti te se zakljuëilo da viπe vrsta pristranosti u izvjeπêivanju i objavama Ëine vaænost bile koje veze izmeappleu CRP i prognoze meappleu bolesnicima s stabilnom KBS dovoljno neizvjesnom da se ne mogu dati nikakve preporuke kliniëke prakse. 74 Isti autori su bili jednako kritiëni prema 19 BNP studijama u bolesnika sa stabilnom KBS, pri Ëemu su izvijestili da su kliniëki korisne mjere za predviappleanje i diskriminaciju uglavnom bile nedostupne te zakljuëili da je nije jasno dokazana nepristrana veza BNP s prognozom kod stabilne KBS. 75 DostupnoπÊu visokoosjetljivih reagenasa obnovljen je interes za troponine kao markera rizika kod stabilne KBS, pri Ëemu ameriëka studija od 984 bolesnika u Heart and Soul Study navodi da je svako udvostruëenje hsctni razine povezano s 37% viπom stopom kardiovaskularnih dogaappleaja. 76 U meappleuvremenu istraæivaëi PEACE studije su objavili da je meappleu bolesnika sa stabilnom KBS hs-ctni neovisno povezan s kardiovaskularnom smrêu ili zatajivanjem srca (HR 1,88 (1,33-2,66; p <0,001)), a veza s nefatalnim infarktom miokarda je bila slabija (1,03-2,01; p = 0,031). 77 Dokazi iz CTCA upuêuju na to da je kliniëki nezamjetna ruptura nekalcificiranog plaka s naknadnom mikroembolizacijom vjerojatno patofizioloπki mehanizam poviπenja troponina, 78 ali je joπ uvijek prerano procijeniti da li Êe imati kliniëku ulogu u prognostiëkoj procjeni stabilne KBS. Isto vrijedi i za dio proadrenomedulina iz srednje regije i drugih biomarkera koji se trenutno istraæuju. 79 Vaskularni biomarkeri Debljina intime-medije karotidnih arterija (cimt) je utvrappleena kao prediktor kardiovaskularnih dogaappleaja u opêoj populaciji, a slabije u bolesnika sa stabilnom KBS. 80 Njegova prediktivna vrijednost se moæe poveêati dodatnim razmatranjem veli- Ëine karotidnog plaka omoguêavajuêi dobivanja ukupnog zbroja optereêenja koji je bio prikazan od strane kineskih istraæitelja radi poboljπanja predviappleanja petogodiπnjeg rizika od kardiovaskularnih primarnih ishoda u usporedbi sa samim cimt. 81 Dakako, vrijednost samog cimt za predviappleanje kardiovaskularnog rizika u opêoj populaciji je pod znakom pitanja nakon velike metaanalize podataka na razini sudionika kod osoba u kojoj cimt nije dodao gotovo niπta ocjeni rizika po Framinghamskoj ljestvici. 82 Drugom metaanalizom podataka na razini sudionika su postavljena ostala pitanja, a koja je ukljuëivala ljudi koji su praêeni u prosjeku od 7 godina. 83 IstraæivaËi su pokazali da nema povezanosti izmeappleu progresije cimt i rizika od kardiovaskularnih dogaappleaja, pri Ëemu su preispitali valjanost koriπtenja promjene u cimt kao surogata primarnih ishoda u istraæivanjima kardiovaskularnog rizika. Kalcij i paratiroidni hormon Studije koje su ukazale na to da ljudi koji uzimaju kalcijeve dodatke mogu poveêati svoj rizik od infarkta miokarda 84,85 su izazvale interes za serumski kalcij i njegov odnos prema kardiovaskularnim dogaappleajima u bolesnika s KBS. Nedavna neral quality and concluded that multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. 74 The same authors were equally critical of 19 BNP studies in patients with stable coronary disease, reporting that clinically useful measures of prediction and discrimination were generally unavailable, and concluding that the unbiased strength of association of BNP with prognosis in stable coronary disease is unclear. 75 The availability of high-sensitivity assays has seen renewed interest in troponins as markers of risk in stable coronary disease, a US study of 984 patients in the Heart and Soul Study reporting that each doubling in hs-ctnt level is associated with a 37% higher rate of cardiovascular events. 76 Meanwhile the PEACE investigators have reported that among 3,623 patients with stable coronary artery disease, hs-ctni is independently associated with cardiovascular death or heart failure (HR 1.88 ( ; p < 0.001)), the association with non-fatal myocardial infarction being weaker ( ; p = 0.031). 77 Evidence from CTCA suggests that clinically silent rupture of non-calcified plaque with subsequent microembolisation is a likely pathophysiological mechanism of troponin elevation 78 but it is too soon to know whether it will have a clinical role in the prognostic assessment of stable coronary artery disease. The same applies to the mid-regional portion of proadrenomedullin and other biomarkers currently under investigation. 79 Vascular biomarkers Carotid intimamedia thickness (cimt) is well established as a predictor of cardiovascular events in the general population and, more weakly, in patients with stable coronary artery disease. 80 Its predictive value may be enhanced by additional consideration of the extent of carotid plaque allowing derivation of the total burden score which was shown by Chinese investigators to improve the prediction of the 5-year risk of cardiovascular endpoints compared with cimt alone. 81 Certainly, the value of cimt alone for cardiovascular risk prediction in the general population is under question following a large meta-analysis of participant-level data in 45,828 individuals in which cimt added almost nothing to the Framingham Risk Score. 82 Further questions have been raised by another meta-analysis of participant-level data which included 36,984 individuals followed-up for an average of 7 years. 83 The investigators showed no association between progression of cimt and risk of cardiovascular events, questioning the validity of using changes in cimt as a surrogate endpoint in trials of cardiovascular risk. Calcium and parathyroid hormone Studies suggesting that people who take calcium supplements may be increasing their risk of myocardial infarction 84,85 have stimulated interest in serum calcium and its relation to cardiovascular events in patients with CHD. A recent study has confirmed that vitamin D, parathyroid hormone and calcium show association with cardiovascular risk factors in US adolescents, 86 and now we have data in 1,017 patients with stable coronary artery disease followed-up for a median of 8.1 years, suggesting that high calcium levels, but not high phosphate levels, might be associated with allcause and cardiovascular mortality (HR ). 87 The 2014;9(1-2):67. Cardiologia CROATICA

68 studija je potvrdila da vitamin D, paratiroidni hormon i kalcij pokazuju povezanost s kardiovaskularnim Ëimbenicima rizika kod ameriëkih adolescenata 86 i sada imamo podatke kod bolesnika sa stabilnom KBS praêenih prosjeëno 8,1 godina, koji ukazuju na to da bi visoke razine kalcija, ali ne i visoke razine fosfata mogle biti povezane s ukupnom i kardiovaskularnom smrtnoπêu (HR 2,39 do 4,66). 87 Mehanizam ove povezanosti je nejasan, ali dokaz sliëne povezanosti visokog paratireoidnog hormona i kardiovaskularne smrtnosti u istoj kohorti moæe upuêivati na mobilizaciju kalcija iz kostiju kao uzroëno-posljediëni put djelovanja. 88 mechanism of this association is unclear, but the demonstration in the same cohort of a similar association between high parathyroid hormone and cardiovascular mortality may implicate calcium mobilisation from bone on the causal pathway. 88 Contributors: SI and AT contributed equally to the preparation and writing of this review article. 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71 Prikaz sluëaja / Case report Cor triatriatum sinister u trudnice A case of cor triatriatum sinister during pregnancy Stanko BioËiÊ, Josip Vincelj, Mario UdoviËiÊ* KliniËka bolnica Dubrava, Zagreb, Hrvatska University Hospital Dubrava, Zagreb, Croatia SAÆETAK: Cor triatriatum sinister rijetka je priroappleena sr- Ëana greπka, koja obiëno biva otkrivena u djetinjstvu. Donosimo prikaz sluëaja mlade bolesnice kojoj je cor triatriatum sinister otkriven u odrasloj dobi te njegovo pra- Êenje tijekom trudnoêe i uspjeπno konzervativno lijeëenje sve do poroda. Obzirom na sliënu patofiziologiju odluëili smo se bolesnicu pratiti kao umjereno teπku asimptomatsku mitralnu stenozu. KliniËko praêenje i redoviti ehokardiografski pregledi zauzimaju pri tome centralno mjesto. Prema naπem saznanju, ovaj sluëaj pacijentice predstavlja prvi sluëaj majëinskoga cor triatriatum sinister u trudnoêi u Hrvatskoj. KLJU»NE RIJE»I: cor triatriatum sinister, trudnoêa, ehokardiografija. SUMMARY: Cor triatriatum sinister is a rare congenital cardiac malformation, usually diagnosed in childhood. We describe a case of maternal cor triatriatum diagnosed in adult age and its successful conservative management throughout pregnancy until postpartum. Due to hemodynamic similarities, we decided to treat the cor triatriatum sinister like a moderate asymptomatic functional mitral stenosis in this case. Clinical controls, regular echocardigraphic controls have a central place in the follow up of gravida with congenital cardiac anomalies. To the best of our knowledge, this case is the first case of maternal cor triatriatum sinister in Croatia. KEYWORDS: cor triatriatum sinister, pregnancy, echocardiography. CITATION: Cardiol Croat. 2014;9(1-2): Uvod Cor triatriatum sinister rijetka je priroappleena srëana greπka, koja obiëno biva otkrivena u djetinjstvu. Dijagnoza i praêenje cor triatriatum sinister u potpunosti je moguêe s minimalno invazivnim metodama, kao πto su transtorakalna i transezofagusna 2D te 3D ehokardiografija. Ove metode su stupovi praêenja ove rijetke priroappleene srëane greπke, Ëija rijetkost moæe doprinijeti njezinom neprepoznavanju, no kada je ispravno prepoznata i lijeëena, ishod je izvrstan 1. Donosimo prikaz sluëaja mlade bolesnice kojoj je cor triatriatum sinister otkriven u odrasloj dobi te njegovo praêenje tijekom trudnoêe i uspjeπno konzervativno lijeëenje sve do poroda. Prikaz sluëaja Trudnica u dobi od 30 godina s nedavno otkrivenim asimptomatskim cor triatriatum sinister upuêena je u ustanovu radi kardioloπke reevaulacije. Od djetinjstva je znala za πum na srcu, no sve do nedavno nije bila kardioloπki obraappleena. Napore je dobro tolerirala. U statusu je na srcu dominirao holosistoliëki πum s punctum maximum nad apeksom te fiksno rascjepljenim drugim srëanim tonom bez naglaπenog P2. Laboratorijski nalazi bili su neupadljiv, kao i zapis 12-kanalnog EKG. Transtorakalnom i transezofagusnom 2D te 3D ehokardiografijom prikazana je fibromuskularna membrana lijevog atrija, koja ga dijeli na dvije komore, od kojih proksimalna prima pluêne vene. Ko- Introduction Cor triatriatum sinister is a rare congenital cardiac malformation, usually diagnosed in childhood. Diagnosis and follow up of cor triatriatum sinister is entirely possible by minimally invasive methods such as transthoracic and transesophageal 2D and 3D echocardiography. These methods are the mainstay of the follow up of this rare cardiac anomaly, whose rarity can contribute to its misdiagnosis, but when correctly diagnosed and managed, it has an excellent outcome 1. We describe a case of maternal cor triatriatum diagnosed in an adult age and its successful conservative management throughout pregnancy until postpartum. Case report A 30-year-old gravida with an asymptomatic, recently diagnosed, cor triatriatum sinister was referred to our institution for cardiac re-evaluation. She has had a history of heart murmur since childhood, but she has never been properly evaluated because she tolerated effort well. On physical examination she had regular pulse and normal blood pressure. Cardiac auscultation revealed fixed splitting of the 2nd heart sound without accentuation of P2 and a pansystolic murmur at the apex. Blood test results as well as ECG recording were both unremarkable. Transthoracic and transesophageal 2D and 3D echocardiogram documented a fibromuscular membrane across the left atrium, dividing it into two compartments, with the proximal one receiving the 2014;9(1-2):71. Cardiologia CROATICA

72 more komuniciraju preko otvora povrπine 1,41 cm 2. Kontinuiranim je doplerom u dijastoli izmjeren srednji intraatrijski gradijent od 6 mmhg. Svi drugi ehokardiografski nalazi bili su uredni. Nije bilo ni indirektnih znakova poviπenog pluênog tlaka kao niti eventulanih drugih pridruæenih srëanih anomalija (Slike 1-4). pulmonary venous flow. The two chambers communicated via an orifice with an area of 1.41 cm 2. The continuous wave Doppler across the membrane showed a diastolic intraatrial mean gradient of 6 mmhg. All other echocardiographic findings were also normal, without any indirect signs of elevated pulmonary pressures. There were no other associated cardiac anomalies (Figures 1-4). Figure 1. Transesophageal echocardiography presenting left atrium with intraatrial membrane (M). Legend: LA1 and LA2 compartments of left atrium, LAA left atrial appendage, MV mitral valve, LV left ventricle. Figure 2. Transthoracic echocardiography showing left atrial membrane. Obzirom da nije bilo simptoma ili znakova srëanog popuπtanja, u suradnji s ginekologom, odluëili smo se za konzervativni pristup. Bolesnici je u terapiju uveden beta-blokator u niskoj dozi te preporuëeno mirovanje i redukcija unosa teku- Êine. TrudnoÊa je uz redovite kontrole protekla bez problema, bolesnica cijelo vrijeme nije imala nikakve simptome ili tegobe. Redovite rutinske transtorakalne ultrazvuëne kontrole srca bile su uredne, kao i vrijednosti NT-proBNP u seru- Since there were no persisting symptoms or signs of heart failure, in cooperation with a gynecologist, we decided to continue the conservative approach. The patient was put on a low dosage of beta blocker, while prescribing bedrest and reduction of water intake. Close surveillance throughout the pregnancy was maintained, which was uneventful. Routine transthoracic echocardiography repeatedly showed normal findings without development of pulmonary hypertension Cardiologia CROATICA 2014;9(1-2):72.

73 Figure 3. Continuous wave Doppler recording across the membrane. Figure 4. 3D transthoracic echocardiography showing left atrial membrane (otvor: orifice). mu. U 38. tjednu trudnoêe pacijentica je vaginalnim putem rodila zdravu djevojëicu. Rasprava Cor triatriatum sinister rijetka je srëana greπka, prvi put opisana godine 2 s incidencijom od 0,1% meappleu srëanim greπkama i omjerom incidencije u muπkaraca naspram æena 1,5:1. 3 Cor triatriatum sinister biva najëeπêe otkriven u djetinjstvu, no u nekim sluëajevima dijagnoza se postavlja u odrasloj dobi 4,5, tada najëeπêe sluëajno 6. KliniËka slika i patofi- and NT-proBNP levels remained normal. A healthy baby girl was successfully delivered by a normal vaginal birth at 38 weeks gestation, without any complications. Discussion Cor triatriatum sinister is a rare congenital cardiac abnormality first described by Church in with an estimated incidence of 0.1% of all congenital heart diseases with a ratio of men to women 1.5:1. 3 Cor triatriatum is most commonly diagnosed in infancy or childhood, but in some cases it is not 2014;9(1-2):73. Cardiologia CROATICA

74 zioloπke osobine odgovaraju mitralnoj stenozi. Zbog opstruktivne prirode intraatrijske membrane dolazi do stvaranja tlaënog gradijenta s posljediënim porastom pluênog venskog i arterijskog tlaka te su najëeπêi simptomi i znakovi zaduha i hemoptiza. Kao i mitralna stenoza, cor triatriatum sinister moæe predstavljati veliki izazov u voappleenju trudnoêe i poroda 7. Tijekom trudnoêe, dolazi do hormonalno uvjetovanog porasta mase eritrocita, srëane frekvencije 8 πto je povezano s 40% porastom volumena krvi te srëanog minutnog volumena 9. U ovom sluëaju, obzirom na sliënu patofiziologiju odluëili smo se bolesnicu pratiti kao umjereno teπku asimptomatsku mitralnu stenozu. Bolesnica je rutinski kontrolirana jednom mjeseëno, kada smo radili i ultrazvuëne kontrole, kojima su u prvom redu kontrolirani tlakovi u pluênoj cirkulaciji i gradijent nad orificijem membrane. Cijelo vrijeme je bila bez simptoma, bez znakova srëanog popuπtanja, uz uredne razine NT-proBNP. S jedne strane poveêan afterload lijeve klijetke, a s druge limitiran preload predstavljaju kliniëki izazov. U takvoj situaciji izrazito je vaæno sprijeëiti tahikardiju i fibrilaciju atrija, kako bi se odræao adekvatan preload. U isto vrijeme postoji prijetnja nastupa pluêne kongestije i edema, naroëito tijekom poroda. Potrebno je stoga izbjegavati poveêavanje cirkulirajuêeg volumena primjenom intravenskih infuzija. U terapiju smo uveli beta-blokator radi produljenja dijastoliëkog punjenja, no obzirom na relativno nizak sustavni arterijski tlak nismo se odluëili na uvoappleenje diuretika, veê samo kontrolu unosa tekuêine. U literaturi se kod maternalne mitralne stenoze preporuëa porod carskim rezom, no u ovom sluëaju ginekolog se u dogovoru s trudnicom odluëio za vaginalni porod koji je protekao uredno. ZakljuËak Uz kliniëko praêenje redoviti ehokardiografski pregledi zauzimaju centralno mjesto kod praêenja trudnica s priroappleenim srëanim greπkama. Prema naπem saznanju, sluëaj ove bolesnice predstavlja prvi sluëaj majëinskoga cor triatriatum sinister u trudnoêi u Hrvatskoj. Received: 3 rd Jan 2014; Updated 7 th Jan 2014; Accepted 15 th Jan 2014 *Address for correspondence: KliniËka bolnica Dubrava, Avenija Gojka uπka 6, HR Zagreb, Croatia. Phone: mario.udovicic@gmail.com diagnosed until later 4,5 and then mostly incidentally 6. The clinical features mimic those of mitral stenosis. Pathophysiologically the obstructive nature of the membrane leads to the creation of a pressure gradient with an associated rise in pulmonary arterial and venous pressures and the most common symptoms present in adults are dyspnea, hemoptysis, and orthopnea. Like mitral stenosis, cor triatriatum may represent a great challenge in management of pregnancy and delivery 7. During the course of pregnancy, hormonally mediated changes result in an increase in red blood cell mass and heart rate 8, and are thus associated with a 40% increase in blood volume and cardiac output 9. In this case, due to hemodynamic similarities, we decided to treat the cor triatriatum sinister like a moderate asymptomatic functional mitral stenosis. The patient routinely underwent controls once a month, when an echocardiogram was performed with measurements of pulmonary pressures and the gradient across the membrane orifice. She remained asymtomatic all the time, without any signs of heart failure and with normal NT-proBNP levels. In this setting the left ventricle has increased afterload and limited preload due to cor triatriatum a combination that tends to worsen the cardiac output. Prevention of tachycardia and atrial dysrhythmias is vital to ensure adequate left ventricular preloading along with avoiding sudden decrease in systemic vascular resistance, while the pulmonary capillary bed is extremely prone to pulmonary edema, especially during delivery. It is also important to avoid any increase in the central blood volume by extraneous administration of fluids. We decided to introduce a beta-blocker in order to extend the diastolic filling, but due to a relatively low systemic blood pressure, we also decided to refrain from giving a diuretic; instead we focused on water intake control. Literature also prefers cesarean section to vaginal delivery in such circumstances, but the gynecologist in charge chose the latter approach in agreement with the gravida, which took a normal course. Conclusion Along with clinical controls, regular echocardigraphic controls have a central place in the follow up of gravida with congenital cardiac anomalies. To the best of our knowledge, this case is the first case of maternal cor triatriatum sinister in Croatia. Literature 1. Nassar PN, Hamdan RH. Cor triatriatum sinistrum: classification and imaging modalities. Eur J Cardiovasc Med. 2011;1(3): Church WS. Congenital malformation of the heart: abnormal septum in the left auricle. Trans Pathol Soc Lond. 1868;19: Su CS, Tsai IC, Lin WW, Lee T, Ting CT, Liang KW. Usefulness of multidetector-row computed tomography in evaluating adult cor triatriatum. Tex Heart Inst J. 2008;35: Chen Q, Guhathakurta S, Vadalapali G, et al. Cor triatriatum in adults: three new cases and a brief review.tex Heart Inst J. 1999;26(3): Hamdan R, Mirochnik N, Celermajer D, Nassar P, Iserin L. Cor triatriatum sinister diagnosed in adult life with three dimensional transesophageal echocardiography. BMC Cardiovasc Disord. 2010;10: Tanaka F, Itoh M, Esaki H, Isobe J, Inoue R. Asymptomatic cor triatriatum incidentally revealed by computed tomography. Chest. 1991;100(1): Mathew PJ, Subramaniam R, Rawat RS, Kulkarni A. A case of cor triatriatum with pregnancy: an anaesthetic challenge. J Postgrad Med. 2004;50: Siu SC, Colman JM. Heart disease and pregnancy. Heart. 2001;85: Robson SC, Hunter S, Boys RJ, Dunlop W. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol. 1989;256(4 Pt 2):H Cardiologia CROATICA 2014;9(1-2):74.

75 Ostalo / Other Uputa autorima Guidelines for authors Cardiologia Croatica (ISSN tiskanog izdanja X; ISSN mreænog izdanja ) je dvojeziëni Ëasopis Hrvatskoga kardioloπkog druπtva koji izlazi kao dvomjeseëno izdanje. Svim zainteresiranim Ëitateljima omoguêen je otvoreni pristup objavljenim Ëlancima na hrvatskom i engleskom jeziku. Uredniπtvo Cardiologia Croatica putem elektroniëke poπte na adresu kardio@kardio.hr prima sljedeêe kategorizirane ili razne priloge iz podruëja kardiologije na hrvatskom i/ili engleskom jeziku: znanstvene i struëne radove, pregledne radove, kratka i prethodna priopêenja, izlaganja i saæetke sa skupova, vijesti, prikaze knjiga, pisma uredniku i ostale priloge. 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PreporuËa se grafove poslati kao Excel dokument. Uredniπtvo ima pravo kraêenja tekstova. Svi objavljeni Ëlanci predstavljaju stavove i miπljenje njihovih autora koji preuzimaju punu odgovornost za sve πto je izneπeno u radu, neovisno o recenziji. Objavljeni materijal smije biti reproduciran uz pisanu suglasnost izdavaëa. Oglaπeni promotivni materijal sadræi bitne podatke o lijeku koji su istovjetni cjelokupnom odobrenom saæetku opisa svojstava lijeka te cjelokupnoj odobrenoj uputi o lijeku sukladno Ëlanku 15. Pravilnika o naëinu oglaπavanja o lijekovima i homeopatskim proizvodima (Narodne novine br. 118/2009). Samo za zdravstvene djelatnike. Uredniπtvo i izdavaë ne snose odgovornost niti jamëe za bilo koji od proizvoda ili oglaπenih usluga. Uputa za pisanje referencija Za pisanje referencija u Cardiologia Croatica koristi se Vancouverski naëin citiranja. 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76 StruËni rad / Professional article STRANICA SPONZORA / SPONSOR S PAGE Smanjenje tereta koronarne bolesti srca na dokazima utemeljenim principima lijeëenja Evidence-based treatment approaches in reducing the burden of coronary heart disease Jasna Meπko, Veronika Hribar, Sanja Brus, Mateja Groπelj, Breda BarbiË-Æagar* Krka, d. d., Novo Mesto, Slovenija Krka, d. d., Novo mesto, Slovenia SAÆETAK: Koronarna bolest srca (KBS) predstavlja vodeêi uzrok smrti diljem svijeta. Naæalost, iznenadna srëana smrt je za mnoge pojedince prva manifestacija KBS. Prevencija idealno poëinje primarnom intervencijom u osoba s poveêanim rizikom od kardiovaskularnih bolesti (KVB), ali bez kliniëki manifestne bolesti. Usmjerena je na zbrinjavanje Ëimbenika rizika, koji ukljuëuju dislipidemiju i artrijsku hipertenziju, koji su odavno utvrappleeni kao vaæni promjenjivi kardiovaskularni (KV) Ëimbenici rizika. Meappleutim, postupci primarne prevencije su joπ uvijek nedovoljni i ne mogu pruæiti optimalnu zaπtitu od razvoja KBS. Napori u sekundarnoj prevenciji, gdje zbrinjavanje KV Ëimbenika rizika postaje joπ vaænije, usmjereni su na prevenciju daljnje progresije bolesti koja moæe dovesti do ponovne pojave KV dogaappleaja, pa Ëak i smrti. Tijekom proteklog desetljeêa, kliniëka dobrobit hipolipemika i antihipertenzivnih lijekova u smislu smanjenja KV rizika je utvrappleena u brojnim randomiziranim kontroliranim istraæivanjima. Statini su jedina skupina hipolipemika koji poboljπavaju kliniëke ishode u bolesnika sa i bez KVB. Oni dokazano smanjuju KV pobol i smrtnost, kao i potrebu za intervencijama na koronarnim arterijama. Dokazi o djelotvornosti perindoprila u smanjenju pojavnosti KV dogaappleanja su dobro utemeljeni. Rezultati studije EUROPA u bolesnika sa stabilnom KBS pruæaju jasne dokaze o djelotvornosti perindoprila u sekundarnoj prevenciji bolesnika sa stabilnom KBS. MoguÊnosti lijeëenja zasnovane na dokazima, poput statina i inhibitora angiotenzin konvertirajuêeg enzima bi mogle pomoêi u smanjenju faktora rizika kod bolesnika sa KVB, a time i osigurati odgovarajuêu zaπtitu od daljnje progresije ove bolesti. KLJU»NE RIJE»I: koronarna bolest srca, arterijska hipertenzija, hiperlipidemija, statini, perindopril. SUMMARY: Coronary heart disease (CHD) is the leading cause of death worldwide. Unfortunately, sudden cardiac death is for many individuals the first manifestation of CHD. Prevention ideally begins with primary interventions in persons at increased risk for cardiovascular disease (CVD) but without clinically manifested disease. It is aimed at managing risk factors, including dyslipidemia and hypertension, which have long been established as important modifiable cardiovascular (CV) risk factors. However, primary prevention practices are still inadequate and may provide suboptimal protection against the development of CHD. Efforts in secondary prevention, where the management of CV risk factors becomes even more crucial, are focused on the prevention of further progression of the disease which can result in recurrence of the CV event or even death. Over the past decade, the clinical benefit of lipid-lowering and antihypertensive medicines in terms of CV risk reduction has been established in numerous randomised controlled trials. Statins are the only lipid-lowering medicines which improve clinical outcomes in patients with and without CVD. They have been shown to reduce CV morbidity and mortality as well as the need for coronary artery interventions. Evidence of the efficacy of perindopril in reducing the incidence of CV events is well established. The findings of the EUROPA study in patients with stable CHD provided clear evidence of the efficacy of perindopril in secondary prevention in patients with stable CHD. Evidence-based treatment options, such as statins and angiotensin-converting enzyme inhibitors, could help reduce risk factors in CHD patients and, consequently, provide adequate protection against further progression of the disease. KEYWORDS: coronary heart disease, hypertension, hyperlipidemia, statins, perindopril. CITATION: Cardiol Croat. 2014;9(1-2): Koronarna bolest srca (KBS) predstavlja vodeêi uzrok smrti dijljem svijeta, a kako je u porastu postala je istinska pandemija koja nema granica. 1 KBS je i glavni uzrok smrti u Europi, gdje je odgovorna za 1.8 milijuna smrti svake godi- Coronary heart disease (CHD) is the leading cause of death worldwide; it is on the rise and has become a true pandemic that respects no borders. 1 It is also the main cause of death in Europe where it accounts for 1.8 million deaths Cardiologia CROATICA 2014;9(1-2):76.

77 ne. 2 Naæalost, iznenadna srëana smrt za mnoge je pojedince prvi znak da se radi o KBS. 1 Prevencija KVB idealno poëinje primarnim intervencijama u osoba s poveêanim rizikom od kardiovaskularnih bolesti (KVB), ali bez kliniëke manifestne bolesti. Uloga lijeënika u primarnoj prevenciji je procijeniti kardiovaskularne (KV) Ëimbenike rizika, savjetovati promjenu naëina æivota i pokrenuti lijeëenje u bolesnika s poveêanim rizikom od KVB. Meappleutim, postupci primarne prevencije su joπ uvijek nedovoljni te ateroskleroza temeljni uzrok bolesti Ëesto napreduje tiho desetljeêima dok se konaëno ne manifestiraju simptomi KBS. 1 Osobe s veê utvrappleenom KBS imaju pet do sedam puta veêi rizik od ponovljenih manifestacija KBS te stoga imaju veêe apsolutne prednosti od intervencijskih strategija. 3 Doprinos razliëitih Ëimbenika za KV rizik prikazan je u multicentriënoj, kontroliranoj studiji provedenoj u 52 zemlje. Studija je pokazala da abnormalne razine lipida i hipertenzija Ëine pribliæno 70% rizika od infarkta miokarda (IM) u populaciji. 4 Tijekom proteklog desetljeêa, kliniëka dobrobit hipolipemika i antihipertenzivnih lijekova u smislu smanjenja KV rizika je utvrappleena u brojnim randomiziranim kontroliranim istraæivanjima. Obzirom na Ëinjenicu da su od svih hipolipemika jedino statini poboljπali kliniëke ishode kod bolesnika s i bez KVB, ova skupina predstavlja prvu liniju farmakoterapije u lijeëenje hiperlipidemije. 1 Statini dokazano smanjuju kardiovaskularni pobol i smrtnost, kao i potrebu za intervencijama na koronarnim arterijama. 5-8 Scandinavian Simvastatin Survival Study (4S) po prvi puta je dokazala da lijeëenje statinima dovodi do promjene uëestalosti KV dogaappleaja u bolesnika s KBS, pa predstavlja prekretnicu u kardiologiji i medicini utemeljenoj na dokazima. Tijekom razdoblja od 5,4 godine prosjeënog praêenja, statini su smanjili rizik velikih koronarnih dogaappleaja za 34%, kao i rizik od ukupne smrtnosti za 30%. Nije bilo razlike u nekardiovaskularnoj smrti u lijeëenim skupinama i skupinama koje su primale placebo. Ova studija je jasno utvrdila da je terapija statinima sigurna i da smanjuje pobol i smrtnost u bolesnika s KBS. Glavni rezultati studije 4S su saæeto prikazani u Tablici 1. 5 each year. 2 Unfortunately, sudden cardiac death is for many individuals the first manifestation of CHD. 1 Prevention of CHD ideally begins with primary interventions in persons at increased risk for cardiovascular disease (CVD) but without clinically manifested disease. The physician s role in primary prevention is to assess the cardiovascular (CV) risk factors, urge lifestyle changes and initiate medical treatment in patients at increased CV risk. However, primary prevention practices are still inadequate and atherosclerosis the underlying cause of the disease is often progressing silently for decades until CHD symptoms finally manifest. 1 Individuals with already established CHD have a five- to seven-fold increased risk for recurrent CHD events and, hence, derive greater absolute benefits from the intervention strategies. 3 The contribution of different risk factors to CV risk was demonstrated in a multicenter, case-control study conducted in 52 countries. The study has shown that abnormal lipid levels and hypertension account for approximately 70% of the attributable risk for myocardial infarction (MI) in the population. 4 Over the past decade, the clinical benefit of lipid-lowering and antihypertensive medicines has been, in terms of CV risk reduction, established in numerous randomised controlled trials. Given the fact that lipid-lowering medicines other than statins have failed to improve clinical outcomes in patients with and without CVD, statins are the first-line pharmacotherapy in the treatment of hyperlipidemia. 1 They have been proven to reduce CV morbidity and mortality as well as the need for coronary artery interventions. 5-8 The Scandinavian Simvastatin Survival Study (4S), which has demonstrated for the first time that treatment with statins changes the incidence of CV events in patients with CHD, turned out to be a milestone in cardiology and evidence-based medicine. Over the 5.4 years of median follow-up of the treatment, statins reduced the risk for major coronary events by 34% and the risk for mortality from all-causes by 30%. There was no difference in non-cardiovascular deaths in the treated and placebo groups. This study has clearly established that statin therapy is safe and that it reduces morbidity and mortality in patients with CHD. The main results of the 4S study are summarised in Table 1. 5 Table 1. Summary of the main results of the 4S study 5. Number of patients Causes of death Placebo group Statin group (n=2223) (n=2221) All coronary All cardiovascular All deaths Events Any major coronary event Coronary surgery or angioplasty Non-MI acute CHD Any cerebrovascular Other cardiovascular ;9(1-2):77. Cardiologia CROATICA

78 Uslijedio je niz drugih velikih randomiziranih kliniëkih studija koje su utrle put πirokoj primjeni statina u prevenciji kardiovaskularnih bolesti. U studiji CTT analizirani su i saæeti rezultati 14 randomiziranih kontroliranih istraæivanja koji uklju- Ëuju oko ispitanika, od kojih je 47% imalo prethodno postojeêu KBS. Statini dokazano smanjuju rizik od komplikacije KBS i poveêavaju duljinu æivota. 6 SliËan uëinak bio je uoëen u studiji CARE u bolesnika s utvrappleenom KBS, u kojoj se pokazalo da se sniæavanjem kolesterola statinima u bolesnika s preboljelim IM smanjuje rizik od fatalne KBS ili nefatalnog IM za 24%, fatalnog IM za 37% i aortokoronarnog premoπtenja za 26%. 7 Promatrane kliniëke dobrobiti se mogu pripisati anti-anterogenom djelovanju statina, koji je ocijenjen u studijama pomoêu koronarne angiografije ili ultrazvuënih tehnika. Studija u kojoj se istraæuje intenzivna terapija statinima i regresija plaka je bilo ispitivanje SATURN u kojem je usporeappleeno djelovanje rosuvastatina (40 mg dnevno) i atorvastatina (80 mg dnevno) kod bolesnika s KBS u 104 tjedna. Rezultati su pokazali da smanjenje razina LDL kolesterola za viπe od 50% rezultira znaëajnom regresijom koronarne ateroskleroze. 8»injenica da se mnogi bolesnici u sekundarnoj prevenciji ne lijeëe viπim dozama statina, ostaje jedan od izazova za sekundarnu prevenciju. 1 Hiperlipidemija se Ëesto pojavljuje zajedno s arterijskom hipertenzijom. 9 Dokazi ukazuju da lijeëenje usmjereno na oba spomenuta Ëimbenika KV rizika dovode do veêeg smanjenja KV rizika. 10,11 Pokazalo se da smanjenje sistoliëkog arterijskog tlaka za 15 mmhg uzrokuje 10% smanjenje KV rizika. Osim toga, smanjenje ukupnog kolesterola za 0,6 mmol/l je bilo povezano s 10% smanjenja KV rizika. Meappleutim, isto smanjenje oba Ëimbenika rizika je bilo daleko korisnije i imalo je za rezultat 45% smanjenje KV rizika. 10 Stoga, ne Ëudi da je izraëunato da bi se gotovo polovica KBS dogaappleaja koji se dogode kod hipertenzivnih bolesnika mogla sprijeëiti istodobnom kontrolom arterijskog tlaka i lipida. 11 Inhibitori angiotenzin konvertirajuêeg enzima (ACEI) su se pokazali djelotvornima u sekundarnoj prevenciji KBS. Dokaz o djelotvornosti perindoprila u smanjenju pojavnosti KV dogaappleaja je veê dobro utvrappleen. 12 Rezultati studije EUROPA donijeli su jasne dokaze o djelotvornosti perindoprila u sekundarnoj prevenciji bolesnika sa stabilnom KBS. 13 Perindopril u dozi kojom se smanjuje visoki arterijski tlak (8 mg/dan) rezultirao je 20% smanjenjem primarnog KV krajnjeg ishoda (KV smrtnosti, ne-fatalnog IM, ili reanimiranog srëanog zastoja) u usporedbi s placebom, a ta je dobrobit uoëena kod bolesnika niskog, srednjeg i visokog rizika te u populaciji istodobno lijeëenoj hipolipemicima (koja je primijenjena kod 69% bolesnika). Pored toga, perindoprilom su smanjeni KV dogaappleaji kod normotenzivnih i hipertenzivnih bolesnika, a to smanjenje je potencijalno bilo veêe nego πto bi se oëekivalo od promatranog smanjenja od poëetne vrijednosti arterijskog tlaka (prosjeëno smanjenje 5/2 mmhg). To ukazuje na izravno vaskularno i antiaterosklerotsko djelovanje perindoprila. Poznata korisna djelovanja perindoprila na vaskularnu strukturu ukljuëuju smanjenje hipertrofije arterijske stjenke i krutosti arterija te poboljπanje elastiënosti arterija. 12 Korisna djelovanja perindoprila mogu biti povezana s njegovim djelovanjima koja dovode do poboljπanja funkcije endotela i prekida patofizioloπkog kontinuuma. Time se usporava brzina napredovanja KBS i, sukladno tome, poboljπava prognoza bolesnika. 13 Kako je prevencija KVB jedan od najvaænijih podruëja suvremene medicine, Krka je ponudila πirok spektar lijekova koji se koriste u primarnoj i sekundarnoj prevenciji KBS. Asortiman proizvoda takoappleer ukljuëuje dva najpotentnija statina na træiπtu atorvastatina (Atoris ) i rosuvastatin (Roswera ), A host of other large randomised clinical trials followed, which paved the way to widespread use of statins in the CVD prevention. A study by the Cholesterol Treatment Trialists (CTT) collaboration analysed and summarised the results of 14 randomised controlled trials involving about 90,000 subjects, of whom 47% had pre-existing CHD. Statins were proven to lower the risk of CHD complications and increase life expectancy. 6 A similar effect was observed in the Cholesterol and Recurrent Events (CARE) study in patients with established CHD, which has shown that cholesterol lowering with statins in patients with previous MI reduces the risk for fatal CHD or nonfatal MI by 24%, fatal MI by 37% and coronary artery bypass surgery by 26%. 7 The observed clinical benefits may be attributed to the antiatherogenic effect of statins, which was assessed in studies using coronary angiography or ultrasound techniques. A study investigating intensive statin therapy and plaque regression was the SATURN trial which compared the effect of rosuvastatin (40 mg daily) and atorvastatin (80 mg daily) in 1,039 patients with CHD for 104 weeks. The results have shown that a reduction of LDL cholesterol levels by more than 50% results in a significant regression of coronary atherosclerosis. 8 Due to the fact that many patients in secondary prevention are not being treated with higher doses of statins, this remains one of the challenges in secondary prevention. 1 Hyperlipidemia often occurs together with hypertension. 9 Consequently, evidence suggests that therapies targeted at both these CV risk factors lead to greater reductions in the CV risk. 10,11 A reduction of the systolic blood pressure by 15 mmhg was shown to lead to a 10% CV risk reduction. In addition, a reduction of the total cholesterol by 0.6 mmol/l was associated with a 10% CV risk reduction. However, the same reduction of both risk factors was far more beneficial and resulted in a 45% reduction in the CV risk. 10 Therefore, it s not surprising that it has been calculated that almost half of the CHD events occurring in hypertensive patients could be prevented by controlling blood pressure and lipids at the same time. 11 Angiotensin-converting enzyme inhibitors (ACEI) have been shown to be effective in secondary prevention of CVD. Evidence of the efficacy of perindopril in reducing the incidence of CV events is already well established. 12 The findings of the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) provided clear evidence of the efficacy of perindopril in secondary prevention in patients with stable CHD. 13 Perindopril given at a dose that reduces high blood pressure (8 mg/day) resulted in a 20% reduction in the primary CV endpoint (CV mortality, non-fatal MI, or resuscitated cardiac arrest) when compared with placebo, and this benefit was observed across low-, medium-, and high-risk patients and in a population treated with concomitant lipid-lowering therapy (administered to 69% of patients). Additionally, perindopril reduced CV events in both normotensive and hypertensive patients and, overall, this reduction was potentially greater than it would be expected from the observed decrease from baseline in blood pressure (mean reduction of 5/2- mmhg). This suggests a direct vascular and antiatherosclerotic effect of perindopril. Well-known beneficial effects of perindopril on the vascular structure include reductions in arterial wall hypertrophy and arterial stiffness, and improvements in arterial elasticity. 12 The beneficial effects of perindopril can be linked to its effects leading to an improvement of the endothelial function and breaking the pathophysiological continuum. This slows the rate of progression of CVD and, consequently, improves patient prognosis. 13 Cardiologia CROATICA 2014;9(1-2):78.

79 koji su dostupni u dvije dodatne doze, atorvastatin 30 mg i 60 mg te rosuvastatin 15 mg i 30 mg. Atorvastatin 60 mg ili rosuvastatin 30 mg posebno mogu pruæiti odgovarajuêu dozu odræavanja u bolesnika s KBS, koji obiëno trebaju intenzivnije zbrinjavanje lipida. Krka je trenutno jedna od malobrojnih farmaceutskih tvrtki koja nudi cjelokupni portfelj perindoprila perindopril (Perineva ), kombinaciju fiksne doze perindoprila i indapamida (Co-Perineva ) i kombinaciju fiksne doze perindoprila i amlodipina (Dalneva ), πto omoguêuje prilagoappleeni terapeutski pristup kod velikog broja hipertenzivnih bolesnika. UËinkovitost i sigurnost Krkinih kardiovaskularnih lijekova se kontinuirano prati u kliniëkim studijama. Do sada je viπe od bolesnika sudjelovalo u ovim studijama ukljuëujuêi bolesnike s KBS. Rezultati kliniëkih ispitivanja predstavljaju vaæan doprinos poboljπanju zbrinjavanja hiperlipidemije i arterijske hipertenzije u razliëitim skupinama bolesnika. MoguÊnostima lijeëenja zasnovanim na dokazima, poput statina i inhibitora angiotenzin konvertirajuêeg enzima moæemo smanjiti Ëimbenike rizika kod bolesnika sa KVB kako bi osigurali odgovarajuêu zaπtitu od daljnje progresije bolesti. Received: 30 th Jan 2014; Accepted 7 th Feb 2014 *Address for correspondence: Krka d. d., Dunajska 65, SLO-1000 Ljubljana, Slovenija. Phone: ; breda.zagar@krka.biz As the prevention of CVD is being one of the most important fields of modern medicine, Krka has made available a wide range of medicines used in the primary and secondary prevention of CVD. Its range of products also includes two most potent statins on the market atorvastatin (Atoris ) and rosuvastatin (Roswera ), which are available in two additional strengths, atorvastatin 30 mg and 60 mg and rosuvastatin 15 mg and 30 mg. Atorvastatin 60 mg or rosuvastatin 30 mg in particular can provide a suitable maintenance dose for patients with CHD, who usually need a more intensive lipid management. Krka is also one of the few companies offering the entire perindopril portfolio perindopril (Perineva ), fixed-dose combination of perindopril and indapamide (Co-Perineva ) and fixed-dose combination of perindopril and amlodipine (Dalneva ), which enables a tailored therapeutic approach in a broad range of hypertensive patients. The efficacy and safety of Krka's cardiovascular medicines are continuously monitored in clinical studies. Till now, more than 110,000 patients have participated in these studies, including patients with CHD. The results of clinical studies are an important contribution towards improving the management of hyperlipidemia and hypertension in different groups of patients. With evidencebased treatment options, such as statins and ACEI, we could reduce risk factors in CHD patients in order to provide adequate protection against further progression of the disease. Literature 1. Perk J, De Backer G, Gohlke H, et al. 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