Arthur A M Wilde, Connie R Bezzina

1352 Eletrophysiology GENETICS OF CARDIAC ARRHYTHMIAS Take the online multiple hoie questions assoiated with this artile (see page 1374) CARDIAC See end of artile for authors affiliations Correspondene to: Dr Arthur A M Wilde, Experimental & Moleular Cardiology Group, Aademi Medial Center, Amsterdam, the Netherlands; a.a.wilde@ am.uva.nl O Arthur A M Wilde, Connie R Bezzina Heart 2005; 91:1352 1358. doi: 10.1136/hrt.2004.046334 ver the last deade, we have witnessed a revolution in the understanding of primary ardia arrhythmia syndromes. These remarkable advanes stemmed from the disovery of mutations, primarily in ion hannel genes, underlying a number of these disorders. Only 10 years ago the long QT syndrome (LQTS) was onsidered one disease entity, the Brugada syndrome had just been desribed, and the short QT syndrome (SQTS) had never been heard of. Moreover, it immediately beame obvious that geneti heterogeneity in these disorders is not the exeption but the rule. The reognition of the geneti substrate underlying the inherited arrhythmia syndromes has provided remarkable insight into the moleular basis of ardia eletrophysiology, inluding the role of the various ion hannels and mehanisms of arrhythmias. The availability of a geneti diagnosti test has added an important diagnosti tool, providing new opportunities for patient management suh as early (presymptomati) identifiation and treatment of individuals at risk of developing fatal arrhythmias. Studies into genotype phenotype relationships, arried out mostly for the LQTS, have unovered important gene speifi aspets of disease and indiated that patient management must take the nature of the gene affeted into onsideration. Initial thoughts that the geneti dissetion of these disorders would failitate therapeuti management of these patients have, however, not been substantiated. On the ontrary, the heterogeneous (geneti, pathophysiologial) harater of all primary arrhythmia syndromes preludes uniform treatment. Herein we review these developments at large, with emphasis on the issues that are relevant for understanding the pathophysiology of these syndromes and daily management of affeted individuals. ION CHANNELS AND THE ECG The ardia ation potential is mediated by the exeptionally well orhestrated ativity of a diversity of ion hannels (fig 1). Cardia ion hannels 1 are protein omplexes in the sarolemma of ardiomyoytes whih, via highly regulated opening and losing (gating), ondut a seletive and rapid flow of ions through a entral pore. Spatial heterogeneity of ion hannel expression underlies the different ation potential morphology of the different parts of the heart whih in turn ensures a oordinated ontration. The maintenane of normal ardia rhythm is dependent on the proper movement of ions mediating the ation potential in eah ardia ompartment. The ECG is the result of the travelling eletrial impulse as measured at the body surfae. The width of the QRS omplex is determined by the time interval between the depolarisation of the first and last ventriular ells, and the ST-T segment results from an inhomogeneous repolarisation in the speifi layers (endoardial, mid myoardial, epiardial) of the ventriular wall. Abnormalities in ion hannel funtion an have disastrous onsequenes that manifest themselves as ECG abnormalities and arrhythmias. These disorders of ion hannels, ommonly referred to as ardia hannelopathies, have been brought into fous in reent years as mutations in genes oding for speifi ion hannels were shown to underlie speifi forms of heritable arrhythmogeni disorders ourring in the struturally normal heart. These inlude the LQTS, SQTS, Brugada syndrome, ateholaminergi polymorphi ventriular tahyardia (CPVT), and idiopathi atrial fibrillation. These disorders fall under the ategory of monogeni disorders that is, disorders that follow a lear mendelian pattern of inheritane and are lassified as autosomal dominant (usual), autosomal reessive (rare), or X linked (not desribed in inherited primary arrhythmia disorders). LONG QT SYNDROMES The long QT syndrome, estimated to affet 1 per 5000 individuals, is a repolarisation disorder identified by prolongation of the QT interval on the ECG. It has long been reognised as a familial disorder, frequently presenting in hildhood with synopal episodes and potentially lethal torsades de pointes tahyarrhythmias whih our in a signifiant proportion of untreated patients. An autosomal dominant form (Romano-Ward syndrome) and an autosomal reessive Heart: first published as 10.1136/hrt.2004.046334 on 14 September 2005. Downloaded from http://heart.bmj.om/ on 9 May 2018 by guest. Proteted by opyright. www.heartjnl.om

Figure 1 Ioni urrents ontributing to the ventriular ation potential (A) and shemati representation of a ardiomyoyte displaying (only) those proteins involved in the pathogenesis of inherited arrhythmia syndromes (B). In panel A, the ation potential is aligned with its approximate time of ation during the ECG. In panel B, ankyrin-b, an adapter protein involved in the long QT syndrome type 4, is not depited. form (Jervell and Lange-Nielsen syndrome, also assoiated with deafness) have been linially reognised. Repolarisation is a deliate proess depending on an intriate balane between inward urrents (sodium, Na +,or alium, Ca 2+ ) and outward urrents (potassium, K + ) (fig 2). Shifts in the balane of these inward and outward urrents an either inrease or derease the ation potential duration with resultant QT interval prolongation or shortening, respetively. Inhomogeneous repolarisation ensues, predisposing the heart to potentially lethal ventriular arrhythmias. The ommon pathophysiologial mehanism underlying QT interval prolongation in the LQTS is a net redution in repolarising (that is, outward) urrent leading to an inrease in ation potential duration. 2 Sine K + hannels are the primary ontributors to the repolarisation proess it was no surprise that loss of funtion mutations in genes enoding for pore forming a-subunits (KCNQ1, KCNH2) of these hannels and for their regulatory proteins (KCNE1, KCNE2) appeared to underlie LQTS (fig 2, left panel). 2 Surprisingly, the SCN5A gene enoding the Na + hannel also appeared to be involved; gain of funtion defets in this hannel lead to an inreased inward Na + urrent during the ation potential plateau shifting the balane to prolonged repolarisation (fig 2). 2 Another gene, ANK2, linked to LQTS, however does not ode for an ion hannel protein but enodes a membrane adapter protein, ankyrin-b. 3 Mutations in ankyrin-b appear to lead to loss of funtion resulting in loss of expression and mis-loalisation of the Na + /Ca 2+ exhanger, the Na + /K + ATPase, and the InsP3 reeptor, with ensuing abnormal Ca 2+ dynamis. This finding highlighted the fat that ardia ion hannels do not funtion in isolation, but form part of omplex maromoleular assemblies (onsisting of pore forming a-subunits, modulatory subunits, ytoskeletal and extraellular matrix elements, and assoiated signalling omplexes) and that mutation in elements of this omplex other than ion hannel proteins per se ould also lead to arrhythmias. The autosomal dominant form of LQTS may be aused by mutation in any one of the above mentioned genes. However, mutations in KCNQ1, KCNH2, and SCN5A, underlying LQTS types 1, 2, and 3 (named in hronologial order of identifiation, table 1 3 5 w1 37 ), respetively, are by far the most ommon ause. The autosomal reessive form (Jervell and Lange-Nielsen syndrome) is aused by homozygosity (beause of onsanguineous parents) or ompound heterozygosity for mutations in KCNQ1 or KCNE1. These genes are expressed in marginal ells of the stria vasularis where they are thought to play a role in the homeostasis of K + in the endolymph, a K + rih fluid of the inner ear. This explains the deafness in this disorder. LONG QT SYNDROME WITH EXTRACARDIAC FEATURES. LQTS type 7, also known as Andersen syndrome, is a rare disorder with ardia manifestations that inlude mild QT interval prolongation and signifiant U waves, frequent ventriular etopy, bidiretional ventriular tahyardia (VT), and more rarely synope, reurrent polymorphi VT, and ardia arrest. The syndrome also exhibits extraardia features inluding skeletal musle periodi paralysis and developmental problems suh as left palate, low set ears, short stature, and developmental features in the limbs. 4 The different features of the phenotype are subjet to signifiant variability in expression. Loss of funtion mutations in the KCNJ2 gene, whih enodes the inward retifier K + hannel Kir2.1 in both heart and striated musle, has been linked to the disorder (fig 2). 4 This hannel onduts outward K + urrent during the terminal repolarisation phase and diastoli phase of the ation potential, thereby ontributing to repolarisation and maintenane of membrane potential lose to the resting membrane potential in both heart and striated musle. LQTS type 8 ombines severe QT prolongation with syndatyly, baldness at birth, and small teeth in 100% of 1353 Heart: first published as 10.1136/hrt.2004.046334 on 14 September 2005. Downloaded from http://heart.bmj.om/ on 9 May 2018 by guest. Proteted by opyright. www.heartjnl.om

1354 Heart: first published as 10.1136/hrt.2004.046334 on 14 September 2005. Downloaded from http://heart.bmj.om/ Figure 2 Pathophysiologi mehanisms of ion hannel mutations in long QT syndrome (LQTS) and short QT syndrome (SQTS). (A) Shemati ECG representation. The red dotted line represents QT interval prolongation (left panel) and shortening (right panel) as an be observed in the LQTS and SQTS, respetively. (B) The ventriular ation potential (AP). The red dotted line represents prolongation (left) and shortening (right) of ation potential duration (APD) as an be observed in the LQTS and SQTS, respetively. (C) Effet of mutations on urrent harateristis in LQTS (left) and SQTS (right). By onvention, upward (positive) defletions represent outward urrent, downward (negative) defletions represent inward urrent. Normal (solid grey line) and abnormal (dotted red line) urrent harateristis are aligned with their approximate time of ation during the ECG (A) and the ventriular AP (B). A redued I Ks ativity underlies APD prolongation in LQT1 and 5, while an inreased I Ks ativity underlies APD shortening in SQT2. A redued I Kr ativity underlies APD prolongation in LQT2 and 6, while an inreased I Kr ativity underlies APD shortening in SQT1. A redued I K1 ativity during the terminal phase of repolarisation underlies APD prolongation in LQT7, while an inreased I K1 ativity underlies APD shortening in SQT3. An enhaned I Na and an enhaned I Ca-L during the AP plateau prolong APD in LQT3 and LQT8, respetively. on 9 May 2018 by guest. Proteted by opyright. www.heartjnl.om

ases and less penetrant ardia strutural malformations, autism, mental retardation, and faial dysmorphi features. 5 A single mutation in CACNA1C enoding the membrane Ca 2+ hannel aounts for all 13 ases desribed so far. 5 This mutation leads to a gain of funtion defet, augmenting the depolarising urrent during the plateau phase of the ation potential (fig 2), thereby prolonging the ation potential duration. LQT8 is extremely rare and very malignant. Considering the widespread expression of the CACNA1C gene and the importane of Ca 2+ as an intraellular signalling moleule, the widespread ellular and organ defets in this disorder are not unexpeted. SHORTQTSYNDROMES The short QT syndrome is a reently desribed linial entity that presents with a high rate of sudden death and exeptionally short QT intervals (QT typially ( 300 ms). 6 So far only 30 40 patients have been desribed. Contrary to the LQTS, repolarisation is hastened by an enhaned outward urrent during repolarisation (fig 2). Gain of funtion mutations in the KCNH2 and the KCNQ1 gene, leading to an inrease in outward K + urrent through the respetive K + hannels, were identified in patients with the disorder (table 1). Gain of funtion mutations in KCNJ2 also give rise to shortening of the QT interval, although not to the extent reported for KCNH2 and KCNQ1 mutations (table 1). In this geneti subtype, the terminal part of the ST segment is shortened giving rise to a peuliar ST segment. BRUGADA SYNDROME The Brugada syndrome was first desribed in 1992 and is haraterised by ST segment elevation in the right preordial leads with or without ondution abnormalities, and a signifiant risk of sudden (noturnal) ardia death in the absene of strutural heart disease. 7 8 The eletroardiographi appearane may be variable and is under the influene of body temperature, autonomi transmitters, and drugs. The disorder is endemi in East and Southeast Asia, where it underlies the sudden unexpeted death syndrome (SUNDS). Although the average age of patients experiening arrhythmi events is 40 years, sudden death an strike at any age, even in very young hildren. Brugada syndrome is familial in about a third of patients, in whih ase an autosomal dominant mode of inheritane is observed. The SCN5A gene, whih aounts for up to 20% of ases, is the only gene linked thus far to the disorder. 8 The funtional effets of Brugada syndrome ausing SCN5A mutations are opposite to those found in LQTS. Thus, loss of funtion mutations underlie Brugada syndrome and the frequently assoiated (mild) ondution disorders. 9 The pathophysiology of the typial ECG appearane is unresolved and may be aused by transmural differenes in the ation potential morphology (partiular in the right ventriular free wall) or to loal ondution delay, or both. 10 CARDIAC CONDUCTION DEFECT Cardia ondution disease is mostly enountered as a onsequene of ardia injury (aused by ishaemia or surgery), as the major ardia manifestation of neuromusular diseases, or in assoiation with ongenital ardia abnormalities. However, isolated ardia ondution disease, with a progressive nature in some instanes (also known as Lenegre and Lev disease) has also been desribed. Three distint geneti forms have been distinguished in families displaying an autosomal dominant inheritane (table 1). One form involves mutation in SCN5A. As for those ausing Brugada syndrome, SCN5A mutations leading to ondution disease result in loss of Na + hannel funtion. This dereased Na + urrent is expeted to slow the rise time of the ardia ation potential and derease the depolarising urrent to neighbouring myoytes, thereby slowing ardia ondution. The ultimate phenotypi manifestation of redued Na + urrent (Brugada syndrome and/or ondution disease) is likely the result of a omplex interplay between yet unknown fators. Linkage to hromosome 19q13.2 q13.3 and hromosome 16q23 24 has respetively been identified in two kindreds with the disorder (table 1). The ausative gene at eah of these loi is unidentified. IDIOPATHIC SICK SINUS SYNDROME Idiopathi (ongenital) sik sinus syndrome refers to the ourrene of sinus node dysfuntion in the absene of identifiable aquired ardia onditions suh as ishaemi heart disease, ardiomyopathy, ongestive heart failure, or metaboli diseases. It is haraterised by inappropriate sinus bradyardia, sinus arrest, or hronotropi inompetene. Mutations in HCN4 have been desribed for two sporadi ases with the disorder (table 1). HCN4 enodes a hannel whih onduts one of the urrents underlying the slow diastoli depolarisation of paemaker ells. One of the HCN4 mutations leads to a trunated hannel protein laking the domain for AMP binding, whih disrupts the AMP regulation of the hannel, explaining the hronotropi inompetene during exerise observed in this patient. The other mutation involved an amino aid substitution whih led to a redued membrane expression of the hannel. Although the role of the Na + hannel enoded by SCN5A in sinoatrial node depolarisation is unlear, ompound SCN5A mutations have been identified in five patients from three families with sinus node dysfuntion. The phenotype in these individuals omprised bradyardia that progressed to atrial inexitability during the first deade of life, as well as prolonged QRS intervals and delayed His ventrile ondution. CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA Arrhythmias in the setting of ateholaminergi polymorphi ventriular tahyardia (CPVT) are typially bidiretional and polymorphi VT exlusively triggered by adrenergi stimuli. The phenotype often presents in early hildhood but asymptomati patients until their mid 30s have been desribed. In the majority of ases, CPVT displays an autosomal dominant mode of inheritane and is aused by a mutation in the gene enoding the ryanodine reeptor hannel (RYR2) (table 1, fig 1). This is an intraellular Ca 2+ release hannel on the saroplasmi retiulum (SR) that releases Ca 2+ in response to Ca 2+ entry through the membrane L-type Ca 2+ hannels during the ation potential plateau. A reessive form of CPVT has also been reognised. This is aused by homozygous mutation in the CASQ2 gene (table 1), whih enodes alsequestrin, a protein that serves as the major Ca 2+ reservoir within the lumen of the SR. Symptoms are apparently more severe in CASQ2 related CPVT, inluding an earlier age of onset. Furthermore, diagnosis is 1355 Heart: first published as 10.1136/hrt.2004.046334 on 14 September 2005. Downloaded from http://heart.bmj.om/ on 9 May 2018 by guest. Proteted by opyright. www.heartjnl.om

Table 1 Summary of genes and hromosomal loi for inherited ardia arrhythmia syndromes 1356 Subtype1 Gene Protein/aliases Chromosomal lous more diffiult beause of the absene of a positive family history, due to the reessive nature of the disease. Spontaneous SR Ca 2+ release as a onsequene of Ca 2+ overload in the SR during diastole auses a depolarising transient inward urrent leading to defletions in the sarolemmal membrane potential known as delayed after depolarisations (DADs). If DADs have amplitude greater than the threshold potential, depolarisation will our, and an arrhythmia an be triggered. DAD mediated triggered ativity is believed to be the prinipal mehanism for CPVT assoiated exerise indued arrhythmias. Although the preise pathophysiologial mehanism(s) remains to be resolved, an enhaned SR Ca 2+ release appears to underlie the pathogenesis of CPVT ausing RYR2 and CASQ2 mutations. 11 ATRIAL FIBRILLATION Atrial fibrillation is the most frequent arrhythmia and ours in partiular at older age in the presene of strutural heart disease. However, familial forms of atrial fibrillation ourring in the struturally normal heart, known as lone atrial fibrillation, have long been reognised. Reently two genes and two hromosomal loi, ontaining yet unknown genes (table 1), have been identified. A mutation in the KCNQ1 gene was identified in a large kindred with the disorder. The other gene thought to be involved is KCNE2, with mutations being identified in two probands. However, sine some family members arrying the gene defet did not have atrial fibrillation, the signifiane of KCNE2 mutation in ausality Inheritane Ioni urrent affeted Effet on urrent Referenes OMOMô Long QT syndrome LQT1 KCNQ1 KvLQT1 11p15.5 Dominant I Ks Q w1 w2 192500 LQT2 KCNH2 HERG 7q35 q36 Dominant I Kr Q w3 w4 152427 LQT3 SCN5A Nav1.5 3p21 Dominant I Na q w3 w5 603830 LQT4 ANK2 Ankyrin-B 4q25 q27 Dominant miltiple 3 w6 600919 LQT5 KCNE1 mink, Isk 21q22.1 q22.2* Dominant I Ks Q w7 176261 LQT6 KCNE2 MiRP1 21q22.1* Dominant I Kr Q w8 603796 LQT7 KCNJ2 kir2.1, IRK1 17q23.1 q24.2 Dominant I K1 Q 4 170390 LQT8 CACNA1C Cav1.2 12p13.3* De novo` I Ca-L q 5 601005 JLN1 KCNQ1 KvLQT1 11p15.5 Reessive I Ks Q w9 12 220400 JLN2 KCNE1 mink, Isk 21q22.1 q22.2* Reessive I Ks Q w13 15 220400 Short QT syndrome SQT1 KCNH2 HERG 7q35 q36* Dominant I Kr q w16 SQT2 KCNQ1 KvLQT1 11p15.5* UnknownÀ I Ks q w17 SQT3 KCNJ2 Kir2.1, IRK1 17q23.1 q24.2* Dominant I K1 q w18 Brugada syndrome BS1 SCN5A Nav1.5 3p21 Dominant I Na Q w19 601144 BS2 Unknown 3p25 22 Dominant w20 Cateholaminergi polymorphi VT CPVT1 RYR2 1q42.1 q43 Dominant SR Ca 2+ release q w21 25 604772 CPVT2 CASQ2 1p13.3 p11 Reessive SR Ca 2+ release q w26 w27 604772 Sik sinus syndrome SSS1 HCN4 15q24 q25* UnknownÀ I f Q w28 SSS2 SCN5A Nav1.5 3p21* Reessive I Na Q w29 608567 Cardia ondution disease Familial atrial fibrillationô CCD1 Unknown 19q13 Dominant w30 113900 CCD2 SCN5A Nav1.5 3p21 Dominant I Na Q w31 w32 113900 CCD3 Unknown 16q23 q24 Dominant w33 FAF1 Unknown 10q22 q24 Dominant w34 608583 FAF2 KCNQ1 KvLQT1 11p15.5 Dominant I Ks q w35 607554 FAF3 Unknown 6q14 q16 Dominant w36 608988 FAF4 KCNE2 MiRP1 21q22.1* Dominant I K, bakground q w37 607554 *Although mutations have been desribed in this gene in individuals with this disorder, geneti linkage to this lous has not yet been demonstrated. ÀAlthough desribed only in sporadi patients, in vitro funtional studies provide evidene for a dominant effet for the mutation. `All probands desribed arried the same de novo mutation with the exeption of two siblings who inherited the mutation from their unaffeted mother who was mosai for the mutation. 1Subtypes numbered aording to date of publiation of finding. ôonline Mendelian Inheritane in Man, Johns Hopkins University, http://www.nbi.nlm.nih.gov/entrez/query.fgi?db = OMIM (aessed Marh 2005). SR, saroplasmi retiulum; VT, ventriular tahyardia. of atrial fibrillation awaits further studies. For both genes, mutation results in gain of hannel funtion. Potentially, the geneti dissetion of lone atrial fibrillation will enable researh into new therapeuti options for the management of the more ommon forms of atrial fibrillation. CLINICAL IMPLICATIONS OF IDENTIFICATION OF GENETIC DEFECTS IN THESE DISORDERS The lassifiation of the long QT syndromes into various geneti lasses has led to a number of genotype phenotype studies that have demonstrated that the underlying geneti defet impats on ECG morphology, trigger and onset of symptoms, prognosis and, most importantly, treatment. In fat, soon after the reognition of different geneti subtypes, typial ECG features were desribed for LQT1, 2, and 3. 12 Adrenergi stimuli proved to be the most prevalent triggers in LQT1, 13 in addition to diving and swimming whih are almost exlusive to this patient group. w38 w39 Patients with LQT3 are at partiularly high risk at rest or during sleep sine their QT interval is prolonged exessively at slow heart rates but shortens adequately during inrease in rate. LQT2 patients share aspets of both LQT1 and LQT3 that is, they tend to suffer events both at rest and during exerise. Auditory stimuli, suh as an alarm lok or a ringing telephone, our almost exlusively in patients with LQT2. w38 The age of onset seems also to depend on the gene involved. At age 10 almost 40% of LQT1 hildren have beome symptomati, whereas only 10% of LQT2 and hardly any LQT3 patients have symptoms. 14 Heart: first published as 10.1136/hrt.2004.046334 on 14 September 2005. Downloaded from http://heart.bmj.om/ on 9 May 2018 by guest. Proteted by opyright. www.heartjnl.om

These gene speifi features form the rationale for tailored therapeuti management of genotyped LQT patients. Lifestyle adjustments to avoid genotype speifi triggers are pertinent. In onordane with the predominant adrenergi triggers, b bloking treatment is most effetive in LQT1 and to some extent in LQT2. 13 15 In LQT3 patients b blokers seem of no use. In individual patients/families, Na + hannel blokers have been used suessfully to shorten the QT interval. w40 It is important to note that long term effiay studies with this treatment are not available. Paing might be important in this latter patient group to avoid bradyardia related tahyarrhythmia. w41 For both these treatment strategies however, failures have been desribed, suh that an implantable ardioverter-defibrillator (ICD) as a bakup treatment appears a must. The genotype speifi age of onset of symptoms has as yet not led to variable onset of treatment. Besides this, the identifiation of the moleular basis for these diseases opens new avenues for researh into new forms of treatment for the future (for example, therapy diretly opposing the moleular defet, or gene therapy). For all arrhythmia syndromes the identifiation of the mutation within an affeted family allows diagnosis in other family members independently from the ECG features and the arrhythmi manifestations. As for many other mendelian disorders, redued penetrane and variable expression are more rule than exeption. Hene, not all mutation arriers are linially affeted to the same degree by the disorder. Thus, extensive phenotypi variability is observed among family members arrying an idential mutation in a single ion hannel gene, with far reahing impliations for diagnosis and treatment. Clinial examples are partiularly observed in kindreds with LQTS or Brugada syndrome where some individuals arrying the mutation may exhibit overt ECG abnormalities or suffer fatal arrhythmias, while others arrying the same primary geneti mutation might not have the ECG hanges or may never develop any arrhythmias. In general, the more prominent the phenotype the higher the risk for affeted patients, but data from LQTS patients show that also silent mutation arriers (that is, with QT intervals within the normal range) are suseptible to develop arrhythmias. Moreover, these individuals have a 50% hane of transmitting the geneti defet to their offspring, who in turn might be symptomati at an earlier age. Hene, the identifiation of suh silent mutation arriers is important. Within the field of ardia arrhythmias geneti aberranies, in partiular in the ardia Na + hannel, have been observed to ause a variety of phenotypes (pleiotropy) inluding QT prolongation (LQT3), right preordial ST elevation (Brugada syndrome), ondution disease at various levels within the heart, sinus node dysfuntion, and even dilated ardiomyopathy (table 1). 16 More and more families are desribed with different ombinations of these features. The first example of suh an overlap syndrome is the large family that we desribed in 1999 in whih a malignant phenotype was assoiated with generalised ondution abnormalities, bradyardia dependent QT prolongation, ST segment elevation in V1 V3, and bradyarrhythmias partly based on intrinsi sinus node dysfuntion. 17 Extensive studies on the biophysial properties of the mutant hannels revealed a satisfatory explanation for the diversity in phenotype. w42 w43 However, this pleiotropy also provides evidene that geneti modifiers play an important role in determining the ultimate phenotype and severity of disease in ardia hannelopathies. Genetis of primary ardia arrhythmia syndromes: key points Several ardia arrhythmia syndromes that for long were onsidered idiopathi are now known to have a geneti basis. They are aused by mutations in genes primarily enoding ion hannels The geneti basis for most arrhythmia syndromes is heterogeneous that is, a given disorder may be aused by mutations in different genes, and evidene for further geneti heterogeneity exists Mutations in ardia ion hannels lead to abnormal ioni urrent harateristis via mehanisms suh as defetive hannel gating or redution in sarolemmal hannel expression. This leads to the ECG features and/or arrhythmogenesis in the inherited arrhythmia syndromes It is beoming inreasingly lear that treatment should take the type of gene affeted into onsideration (gene speifi therapy) The identifiation of a proband with a primary ardia arrhythmia should trigger sreening of family members to identify all affeted relatives (presymptomatially) In the long QT syndrome, information on ECG morphology and triggers for arrhythmia (to be sought in the proband as well as family members) an indiate the gene likely affeted, enabling initiation of the most appropriate treatment even before results from the geneti test beome available Considerable heterogeneity may exist in disease manifestation (both in severity as well as differenes in disease features) among family members arrying the same mutation. In this respet, a geneti test is vital in unovering all arriers of the geneti defet within a family A good example of the importane of modifier genes is a family desribed with the rare arrhythmia familial atrial standstill. 18 In this family a Na + hannel mutation with mild biophysial effets (D1275N) o-segregated with a disrete ondution phenotype. However, in the presene of homozygosity for two losely linked single nuleotide polymorphisms (SNPs) in the promoter region of the onnexin 40 gene (Cx40), whih are potentially assoiated with redued expression of Cx40, atrial standstill was observed. Hene, the SCN5A mutation leads to an atrial phenotype only in the presene of the Cx40 modifier whih exlusively ats at the level of the atria. Of note, in another family the same SCN5A mutation was assoiated with dilated ardiomyopathy, in partiular when assoiated with atrial arrhythmias. 16 The onept that ion hannel disorders an lead to strutural heart disease is of great interest. In a previously desribed small nulear family, ompound heterozygosity for two SCN5A mutations was assoiated with severe ondution disease and proven fibrosis in the ondution system. 19 In the years to ome we will ertainly learn more about this intriguing assoiation between eletrial and strutural heart disease. FUTURE RESEARCH While the identifiation of genes assoiated with primary eletrial disease has progressed at a rapid momentum, insight into the genetis of aquired arrhythmias suh as in ishaemi heart disease, hypertrophy, heart failure or during the use of (QT interval prolonging) mediations, is still in its infany and examples of suh studies are very sparse in the literature. The identifiation of suseptibility genes for 1357 Heart: first published as 10.1136/hrt.2004.046334 on 14 September 2005. Downloaded from http://heart.bmj.om/ on 9 May 2018 by guest. Proteted by opyright. www.heartjnl.om

1358 aquired arrhythmias, together with the identifiation of geneti modifiers of primary eletrial disease, atually represents an antiipated hallenging next step in our understanding of the genetis of arrhythmias. Here, polymorphisms that is, ommon variants that are present (in relevant genes) throughout the genome are expeted to influene the suseptibility to arrhythmias. Evidene for suh an effet has been provided by the finding that a variant leading to an amino aid substitution in SCN5A (S1103Y), found primarily in individuals of Afrian desent (and absent in whites), was more prevalent in individuals being treated for arrhythmia than in the general population, suggesting that it inreases risk. 20 The identifiation of suh suseptibility genes for aquired arrhythmias neessitates the onstrution of large databases of patients phenotyped in a very standardised fashion to ensure adequate power for assoiation studies. A large number of genes are expeted to ontribute to suseptibility. Polymorphisms in genes enoding ardia ion hannels form very plausible andidates in whih to searh, but then the multitude of other players within the diverse pathways leading to arrhythmia, suh as ytoskeleton proteins, strutural proteins (suh as those linked to sudden death in familial hypertrophi ardiomyopathy) and proteins involved in proesses suh as fibrosis, inflammation, ell-to-ell ommuniation, and eletrial and strutural remodelling, are also of interest. w44 With reent advanes in genotyping tehnology, omprehensive sreening of multiple genes in different pathways is now feasible. Moreover, the availability of a high resolution genome-wide map of polymorphisms and the evolving tehnology for large sale genome-wide sreens (unbiased approah), and related bioinformatis, are also expeted to failitate the study of genetis of ommon aquired arrhythmias. This is likely to provide novel tools for risk stratifiation and open new opportunities for prevention and therapy of lethal arrhythmias in the ommon pathologies. Additional referenes appear on the Heart website http:// www.heartjnl.om/supplemental ACKNOWLEDGEMENTS Work from the author s laboratory is funded by Netherlands Heart Foundation grants: 2000B059, 2003B195 and 2003T302 and ICIN (projet 27).... Authors affiliations A A M Wilde, C R Bezzina, Experimental & Moleular Cardiology Group, Aademi Medial Center, Amsterdam, the Netherlands In ompliane with EBAC/EACCME guidelines, all authors partiipating in Eduation in Heart have dislosed onflits of interest that might ause a bias in the artile REFERENCES 1 Roden DM, Balser JR, George AL Jr, et al. Cardia ion hannels. Annu Rev Physiol 2002;64:431 75. 2 Clany CE, Kass RS. Inherited and aquired vulnerability to ventriular arrhythmias: ardia Na+ and K+ hannels. Physiol Rev 2005;85:33 47. 3 Mohler PJ, Shott JJ, Gramolini AO, et al. 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