SDS Module. A tool for prevention of Sudden Cardiac Death in youth

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1 SDS Module A tool for prevention of Sudden Cardiac Death in youth

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3 Content 1 Epidemiology SCD Incidence Worldwide SCD Incidence Variability in Various Countries and in Various Time Periods SCD Incidence with Athletic and Non-Athletic Population SCD Incidence Associated with Race and Sex ETIOLOGY Cardiovascular SCD Causes versus Athlete s Heart SCD Development Associated with Age Hypertrophic Cardiomyopathy (HCM) Arrhythmogenic Right Ventricular Dysplasia (ARVD) Arrhythmogenic Disorders: Ion Channels Disorders Wolf-Parkinson-White Syndrome (WPW Syndrome) Congenital Coronary Arteries Anomalies Myocarditis Commotio Cordis PREVENTION Expectations and Recommendations of Preventive Screening Questionnaire Consulting in Preventive Screening Personal Anamnesis Family Anamnesis Physical Examination Standard 12-Lead ECG Examination Advantages and Constraints of ECG Screening Athlete s ECG Interpretation Standardised ECG Examination and its Advantages Electrocardiographic Interpretation Criteria in Sport The Way to Conducting Efficient Screening BTL CardioPoint -SDS Module Clinical Verification of the BTL CardioPoint -SDS Module

4 BTL CardioPoint -SDS Module 4 INTRODUCTION Sudden death sports activity regular medical examinations doctors misconduct hidden heart defect tragic event media. All these terms are nowadays associated with sudden cardiac death within professional sport. Sudden cardiac death (SCD) is the leading cause of death during sport. In rare cases, young trained athletes die right at the sports ground, often before the eyes of millions of spectators or even during live broadcasts. However, cardiac arrest does not only occur within professional sport, but also within recreational or performance sport. Intense sport activity and physical effort connected with mental stress markedly increase cardiac arrest risk, mainly with individuals predisposed for cardiac disorders. Incidence of SCD is low in absolute numbers. Nonetheless, we can see sudden death cases more often than in the past. They represent unpleasant tragic events, which are moreover shown in media. Sudden death without a traumatic cause with a pro athlete, who represents an idol of youth and performance, means tragedy for the impacted person as well as for their family. At the same time, it deforms the image of sport, which is generally associated with health and vigour. Every tragic sudden death event is a substantial argument for conducting screening, since most SCD cases occur due to an existing heart disorder. Worldwide opinions about screening involving an ECG examination are not unanimous. The dispute arises from a plethora of questions about how to conduct screening efficiently. The opposing side points out low incidence of SCD, high costs of screening examination and lack of specialised professionals. Nevertheless, an ECG examination is a compulsory part of screening within sport examination in many countries. Electrocardiography is an independent indicator of myocard diseases and it provides basic information for exact diagnostics. In effort to simplify, speed up and generally make screening examination more effective, BTL Industries has, in cooperation with medical facilities, developed a possible solution. The following chapters describe characteristics, more detailed functioning principle and significance of use.

5 BTL CardioPoint -SDS Module 5 Sudden Death Syndrome It is possible to define sudden cardiac death (SCD) syndrome as acute, non-traumatic, non-violent and unexpected death caused by sudden cessation of heart activity. It usually occurs up to one or several hours from appearance of symptoms with people, who up to the moment had no visible cardiovascular system disease, i.e. people with normal health condition. Sudden death syndrome is defined mainly by clinical symptoms, rather than clearly known and defined pathophysiological action. It could really be an acute state in which a patient becomes unconscious within a few seconds or minutes due to insufficient blood flow in his brain. 1 Epidemiology SUMMARY SCD incidence is a variable piece of data that depends on age, sex, ethnicity and other factors. According to ESC Guidelines 2015, average SCD incidence with women varies from 1.40 deaths per 100,000 people/year and with men 6.68 deaths per 100,000 people/year. Younger individuals are estimated with SCD incidence of deaths per 100,000 people/year, which represents a rough number of 1,100 9,000 deaths in Europe and 800 6,200 deaths in the USA every year. It is also stated that the SCD risk is higher in athletic population in comparison with non-athletic population of similar age. SCD incidence with young athletes (< 35 years) is estimated between 0.7 and 3.0 deaths per 100,000 athletes in one year. Sudden death incidence is higher with older athletes in accordance with the supposition that the higher the age, the higher the coronary arteries diseases occurrence. 1.1 SCD Incidence Worldwide SCD occurrence is broadly discussed and to a large extent unknown. Table 1 compares SCD incidence rate (IR) data in various countries of the world, in various time periods, in athletic (IRat) and non-athletic (IRnonat) population, in male and female sex, in various ethnic groups and in various kinds of sports and furthermore in various basketball divisions. The incidence recorded varies significantly with high-school athletes in the USA, Afro-American basketball players, etc., which points out the influence of respective factors. Ways of SCD record collection may not be reliable because data is often collected from insurance-event data, death-certificate inspection and from retrospective studies. Some reports were created based on information that can falsely record up to 80 % deaths. In other cases, it is not certain that data does not include incomplete heart failures. 1

6 BTL CardioPoint -SDS Module 6 Authors Country Studied period Corrado et al., 2007 Harmon et al., 2011 Holst et al., 2010 Marijon et al., 2011 Maron et al., 2009 Steinvil et al., 2011 Toresdahl et al., 2014 Age years Category Total milion IRat /100 tis. Sex ratio Total milion IRnonat /100 tis. Total milion White Black White Black male 7.7 Basket Male 14.3 Female 2.6 Division I Male 32.0 Female 4.2 Black male 18.9 Division II Division III Swimming Cross country Denmark White France White USA White + nonwhite Israel Unspec. or unknown > USA College Black + white IR at/ nonat Table 1: Incidence rate (IR) of SCD for 100,000 athletes-years in different countries: comparison between athletes (IRat) and non-athletes (IRnonat), male and female, white and black people, different divisions in basketball SCD Incidence Variability in Various Countries and in Various Time Periods IR (Incidence Rate) variable values in respective countries and time periods confirm that the exact SCD occurrence is not clear. The reason being the commonly used methodology of respective analyses. 2 For example, IR can be halved, if analyses contain post mortem data. These state cardiovascular diagnoses by comparing them with cases when the exact cause of SCD is unkown. 3 The SCD incidence rate in the United States was stated as 0.6/100,000 athletes 4 versus 1/100,000 in France, 5 1.2/100,000 in Denmark, 6 2.1/100,000 in Veneto region in Italy 7 and 2.6/100,000 in Israel. 8 After enforcing compulsory screening in Italy, the yearly incidence rate dropped from 3.6/100,000 in the years to 0.4/100,000 in the years According to Maron et al., the high incidence rate in Veneto region in years was to a large extent associated with cases of familiar arrhythmogenic cardiomyopathy. The IR in the United States was 2.2 times higher in the years compared with the years This increase was most probably caused by higher media attention and their specific cases research rather than by a real increase of IR. 9

7 BTL CardioPoint -SDS Module SCD Incidence with Athletic and Non-Athletic Population SCD incidence with athletic and non-athletic population is also a subject for discussion. SCD occurrence is stated as on average 3 to 5 times higher with athletic population than with non-athletic population. 10,11 IR is as much as 3.7 times higher in basketball than in athletic disciplines. 3 Physical exercise works mainly as a trigger of asymptomatic cardiovascular diseases. 3,4,5,7,12 The IR with athletes in Italy decreased after implementing preventive screening compared with non-athlete population (0.5/100,000 SCD cases with athletes versus 0.8 with non-athletic population). In the USA, Harmon et al. did not observe a significant difference in SCD IR without ECG screening examination while comparing athletic high-school population and common non-athletic population (2.6/100,000 SCD cases per year with athletes (aged 17 23) versus 2.5/100,000 SCD cases per year with non-athletic population of similar age (15 24 years). The biggest difference in IR between athletes and non-athletes was observed in a Danish study, which stated that athletes have 3.3 times lower sudden death risk than non-athletic population. 6 It is hard to deduce a firm conclusion from the given study, since a small number of SCD cases were reported (n = 15). In summary, it is possible to say that most studies stated higher risk with athletes (3 5 times) in comparison with non-athletic population. Sudden cardiac death occurs more often with men. The highest sudden death risk is shown with Afro-American athletes and basketball players SCD Incidence Associated with Race and Sex Regardless of age, men have a 2 20 times higher risk than women. 3,5,11,13 Potential reasons are, among others, higher participation of men in professional sport, different training requirements and higher intensity of training. Apart from this, men have higher incidence or phenotypic expression of heart disorders such as cardiomyopathy or congenital coronary arteries anomalies. white race ETHNICITY black race lower AGE higher Factors athletics TYPE OF SPORT basketball female SEX male Average incidence per cases per year.

8 BTL CardioPoint -SDS Module 8 2 ETIOLOGY SUMMARY Individual s age is a significant factor influencing SCD incidence. A substantial majority of sudden death cases occurs due to a silent form of a cardiovascular disease. The most common causes of sudden death with young athletes are congenital as well as acquired cardiovascular disorders. These are specifically congenital cardiomyopathies such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricle dysplasia (ARVD), which represent more than a third of all cases. Congenital anomalies and premature coronary arteries atherosclerosis are responsible for approximately 20 % of SCD cases. Ion channelopathies (including congenital form of long/short QT syndrome) and other possible causes of SCD are associated with formation of fatal ventricular arrhythmias. 23 The most common disorder, but not the only one, at the age of 35 is ischemic heart disease. Sudden death can be triggered by acute myocardial infarction or it can result from arrhythmia due to an already existing scar after previous heart-attack. 2.1 Cardiovascular SCD Causes versus Athlete s Heart Regular physical activity can lead to physiological heart measures adaptation. Changes include mainly thickening of the left ventricle wall and enlargement of the left ventricle cavity. Such a modification is called athlete s heart. It allows the owner more efficient filling of the left ventricle during diastole. Bigger volume generates bigger permanent heart output. The extent of the modification is regulated by several factors including age, sex, individual body measures, type of sport and ethnicity of an athlete. Changes can be detected during an ECG examination and echocardiographic examination. Due to this, a significant diagnostic dilemma arises as how to differentiate physiological adaptation with affiliated electrocardiographic and echocardiographic changes from pathological heart changes. Falsely positive result can lead to elimination of an athlete from active participation and cause him mental harm, while falsely negative evaluation can cause sudden death. 15 Regular and intense exercise within predisposed population can increase relative SCD risk in comparison with the rest of the population with sedentary lifestyle. Substantial majority of sudden death cases results from a silent form of cardiovascular disease. Heart arrest or SCD with young athletes occurs almost in all cases during or just after athletic performance. Dehydration, hyperthermia, electrolytic disequilibrium and higher aggregation of blood platelets are mechanisms driven by strain possibly affecting SCD timing. 16 The reason for this can be any cardiovascular disorder. Sport itself is not the cause, but a trigger of an acute transition of a certain heart disorder, which appears by sudden formation of malign ventricular arrhythmia during physical exercise. 1

9 BTL CardioPoint -SDS Module SCD Development Associated with Age Sudden death incidence is significantly affected by the age of an individual (Picture 1). The most common, but not the only disorder at the age of 35 is ischemic heart disease. Sudden death can be triggered by acute myocardial infarction or it can result from arrhythmia due to an already existing scar after previous heart-attack. Besides ischemic disorders, SCD can be triggered by acquired heart muscle diseases (cardiomyopathies), rarely by a congenital heart-rate disorder. A congenital group of SCD causes appears primary with children, adolescents and youth, since acquired disorders are unlikely %/Year Advanced heart disease (1 in 4 10) Increasing Risk 0.1 %/Year Usual Causes: - Myocarditis - Hypertrophic CM - LQT and SQT - RV dysplasia - Anomalous CA - Brugada syndrome - Early repolarization - Idiopathic VF, CPVT General population >35 years of age (1 per ) %/Year Adolescents/ young adults (1 per ) Transition zone for usual causes in young and middle-aged adults Usual Causes: - Coronary atherosclerosis - Dilated cardiomyopathy - Valvular heart disease - Infiltrative heart diseases Age (Years) Picture 1: SCD Association with Age. 38 The most common SCD cause with young athletes of up to 35 years of age are congenital genetic disorders. They include structural myocard disorders (hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle) and heart electric activity disorders. Their cause usually stems from ion channel abnormalities (the so-called channelopathies) or congenital arrhythmic syndromes (long QT syndrome, familiar catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome). Other congenital or acquired non-genetic disorders can also trigger SCD: Wolff-Parkinson-White syndrome, aortic stenosis. Structural abnormalities of aorta Marfan syndrome and other disorders associated with aortic dilation can lead to sudden death with predisposed individuals due to aortic rupture or dissection Hypertrophic Cardiomyopathy (HCM) HCM is characterised by pathological expansion (> 15mm) of the left ventricle wall. The basis of the disease is myocytes disorganisation, abnormal and chaotic order of muscle fibres in myocard and fibrosis layers with bad hypertrophy in the background. The hypertrophy is in most cases asymmetric. It affects mainly interventricular septum and anterolateral part of the left ventricle outflow tract, rarely the right ventricle. Most cases are genetically determined with autosomal dominant inheritance and indistinctive male predominance. About 200 mutations on approximately 10 genes are known so far. HCM occurrence frequency is comparable in various ethnicities. North American, European, Asian and African studies report prevalence of left ventricle hypertrophy between 0.02 % and 0.23 % with adults. Much lower values prevail with patients younger than 25 years.

10 BTL CardioPoint -SDS Module 10 HCM is a very heterogeneous disease. Clinical progress is without manifestations until puberty. In some cases, such symptoms as angina pectoris, dyspnoea, palpitations or syncope appear. In extreme cases, the first symptom is sudden cardiac death. 8 ECG, echocardiography and ambulatory monitoring (Holter ECG) are applied in diagnostics. It is necessary to differentiate genetically determined HCM from symmetrical left ventricle hypertrophy with arterial hypertension, aortal valve stenosis or athlete s heart hypetrophy. There are two basic forms of pathological HCM: obstructive and non-obstructive form. From the clinical diagnostics point of view, the most common and most significant symptoms are angina pectoris, dyspnoea during exercise, ejection murmurs and others. Dyspnoea is explained by left ventricle diastolic dysfunction, myocard ischemia, mitral insufficiency and formation of fibrillation in the atria. Echocardiographic examination provides a high-degree diagnostic account. It shows lowered volume of heart cavities and localises expansion of the left ventricle wall and other pathological changes of myocardium. Myocard is capable of good contractions, nonetheless, it eventually prevents normal diastolic function of the left ventricle. Pathologic myocardium can form various rhythm disorders including fatal fibrillation of the ventricles. 33 HCM phenotype does not necessarily have to be stated, if echocardiographic examination is conducted in pre-hypertrophic phase of the disease (i.e. patient younger than 14 years). ECG examination is considered as a practically and economically more efficient alternative for echocardiography within HCM screening. ECG examination results are abnormal in 95 % of HCM patients, often before typical symptoms appear. 34 During ECG examination, we find signs of ventricular overload and myocard changes (voltage criteria for left ventricle hypertrophy, slowly increasing R waves in precordial leads, ST segment depression followed by T wave inversion, sometimes branch block or fibrillation of the atria is present). 33 Picture 2: HCM suspicion with detail on T wave inversion in precordial leads with voltage left ventricle hypertrophy criteria. High voltage above left ventricle is shown by a depression in the ST T segment due to overload. HCM represents one of the most common causes of sudden cardiac death in sport. HCM prevalence is 10 to 50 times higher than in the case of other familiar diseases that affect heart and blood vessels. 18 In the case of diagnostics of a trained athlete, it is hard to differentiate physiological heart adaptation from a pathology. False diagnostics can on one hand lead to a higher risk of SCD, on the other hand, it can lead to unnecessary exclusion from sport activity, which can cause mental and economic harm for the athlete. 19 It is therefore vital to state the suspicion. Critical changes are detectable by a standard ECG examination following certain criteria.

11 BTL CardioPoint -SDS Module Arrhythmogenic Right Ventricular Dysplasia (ARVD) ARVD is a rare and dangerous type of cardiomyopathy. Essentially, it eventually substitutes myocardium in the right (or left) ventricle by fat and fibre tissue. Due to this, the ventricle is dilated with local aneurisms and shows declined systolic function. ARVD prevalence ranges from 1/2,000 and 1/5,000 cases. 20 Some areas, such as Padova in Italy, are known to have high, even endemic, occurrence of the disease. Whole families were impacted, which confirmed genetic origin of the disease. Virus infection plays a certain part in pathogenesis. It can work as a trigger of some forms of ARVD. Clinical image includes a wide range of symptoms from arrhythmic palpitations to progressive heart failure. There are also asymptomatic forms, possible to detect by screening relations of an impacted person. In many cases, the first symptom is sudden cardiac death. Diagnostics is based on patient s anamnesis and examination by device. ECG and SA-ECG (signal-averaged electrocardiogram) examination records late ventricular potentials due to non-homogeneous impulse spread (epsilon wave in leads V1 to V3), Tawara s right bundle branch block (RBBB), inverted T wave in leads V2 V3 with absence of RBBB and rarely ST segment elevation (Afro-American ethnic group). Echocardiographic examination displays right ventricle dilation and local aneurisms. Negative echocardiographic diagnosis does not eliminate ARVD, concerning its various forms and its natural development. Holter ECG monitoring and ergometric examination is mostly conducted with young and physically active individuals. A frequent diagnosis are ventricular extrasystoles (> 1,000/24 h), ventricular tachycardia left bundle branch block (LBBB) type, which is formed with athletes during exercise. Manifested sudden death contrasts with excellent physical performance of a young person. 21 Endomyocardial biopsy method with some certainty confirms fibrous-fat left ventricular wall remodelling associated with a decline of number of myocytes under 60 %, myocyte atrophy or higher amount of tissue. It is the so-called golden standard in diagnostics. It is not commonly applied due to its demanding nature. Hidden ARVD is one of the sudden death causes with young and physically active people. In the USA, it is responsible for 3 4 % of sudden deaths. The ARVD incidence is higher in Italy and it is responsible for 22.4 % of athletes sudden deaths. Altogether 25 % of sudden deaths in sport are caused by ARVD. 22 In the attempt to reduce sudden death risk, it is recommended to determine a suspicion based on which all suspected individuals should go through further necessary diagnostic examination. 21 Picture 3: ARVD suspicion with right-hand-side heart axis deviation detail 138, R (V1) + S (V5) = 11.7 mm. A negative T wave is present in the leads from right precordium.

12 BTL CardioPoint -SDS Module Arrhythmogenic Disorders: Ion Channels Disorders Channelopathies collectively represent congenital genetic ion channel defects caused by genes mutation that code ion channels proteins and their subunits. Among those that belong to this group are long QT syndrome, Brugada syndrome, which are usually clinically clearly identified by the presence of characteristic ECG abnormalities, and catecholaminergic polymorphic ventricular tachycardia (CPVT). 20 The following are considered the predictors of CPVT, as a serious arrhythmogenic disorder: syncope or cardiac arrest in anamnesis, rapid and sustained ventricular tachycardia in Holter examination or during an exercise test. 35 Long QT Syndrome (LQTS) LQTS is a ventricular cardiomyocytes repolarisation disorder characterised by prolongation of QT interval on ECG curve. Present abnormal electrophysiological changes can lead to syncope or sudden death due to formation of polymorphic ventricular tachycardia (Torsade de Pointes TdP). We differentiate normal, borderline and prolonged QTc interval. The ESC Guidelines 2015 evaluate as a pathologically prolonged QTc interval 480 ms with repeated ECG examination. With patients with QTc 460 ms and unexpected syncope in the absence of secondary causes, a suspicion of prolonged QT interval should be considered. 46 The disease has two occurrence forms: congenital and acquired. The congenital LQTS form has varied QT interval prolongation and it is often associated with U wave occurrence. Autosomal dominant inherited form is known as Romano-Ward syndrome, whilst less common autosomal recessive inherited deafness associated with prolonged QT interval is known as Jervell and Lange-Nielsen syndrome. The basis of QT interval prolongation is mutation of genes which code proteins of sodium and potassium channels. So far, 6 genotypes have been defined. These are marked as LQT1 through LQT6. Symptoms appear mostly after adrenergic stress reaction, which can be physical or mental. Inherited forms of the disease are in most cases not accompanied by a structural myocard disorder. It is estimated that % of patients have a defect in potassium channel proteins, which appears more often in childhood. In those patients serious symptoms (syncope and sudden death) are present more often, depend on adrenergic reaction (there is no normal QT interval shortening during an exercise test). Only 5 10 % of patients have a sodium channel proteins disorder, more often in adulthood. Symptoms appear in resting state and during sleep, whereby they are fatal. Congenital LQTS diagnostics is rather difficult due to high clinical manifestation variability of the disease. The most important part is the anamnesis, including family anamnesis, and ECG curve evaluation. The changes observable at ECG examination are: T wave abnormalities (notches and splits in the T wave progress, prolongation, bigger T wave amplitude), alternating T wave, prominate U wave, bradycardia, higher QT interval dispersion. Exercise and post-exercise ECG curves can help reveal abnormal QT interval behaviour. Syncope or sudden death with young individuals, especially during exercise, must lead to LQTS suspicion. 35 The acquired LQTS form occurs more often than the congenital form. It is often a response to various conditions such as bradycardia, electrolytic imbalance, chronic consumption of medication capable of prolonging repolarisation (most often taking antiarrhythmics). Structural myocard disorders are more common with acquired forms. Women are predominantly impacted (more than two thirds). Risk factors for formation of LQTS are left ventricle hypertrophy and heart failure. Diagnostics is based on prolonging QT interval itself on the ECG curve. An electrophysiological examination to modify internal environment is applied 35 as well as lifestyle adjustment, during which it is recommended for the patients with prolonged QT interval to avoid medication that prolongs QT interval ( 46

13 BTL CardioPoint -SDS Module 13 Picture 4: Long QT syndrome suspicion with detail of QT interval measured values. Brugada syndrome (BrS) It is a rare genetically determined disease with autosomal dominant inheritance caused by a primary electric heart activity disorder and variable expression. The disease represents a higher risk of sudden death even with patients without a structural heart disorder. Most patients die in resting state, often due to malign ventricular arrhythmias (sustained ventricular tachycardia, ventricle fibrillation) during sleep, which are formed due to a higher n. vagus tonus or lower sympathicus activity. A higher n. vagus tonus as a consequence of continual sport training can alternatively cause an athlete with Brugada syndrome to be more prone to die at rest, during sleep or during rest after physical exercise. Although a relationship between physical exercise and arrhythmias has never been confirmed, individuals with a clear Brugada syndrome diagnosis should not actively engage in sport activity. Patients usually include Europeans and Asians of white race. The most common cause of sudden death with young Thais without a heart disease anamnesis is Brugada syndrome. 39 In Japan and in south-east Asia, the sudden and unexpected death syndrome is also known mainly with young men in sleep due to fibrillation of the ventricles. It is probably a variant of Brugada syndrome, as also in these cases a typical ECG image is present. 35 The worldwide BrS prevalence is stated as 1/10,000. It is though much higher in Asian populations, 5/10,000 to 10/10, BrS typically manifests in adulthood, while the average age at the time of sudden death varies around 41 ± 15 years, but it can also appear during infancy and childhood. 39 Brugada image versus Brugada syndrome two terms that differ based on presence or absence of symptoms with patients with typical ECG diagnosis (pseudo right Tawara bundle branch block and continual ST segment elevation in leads V1 to V2): Patients with typical ECG features without symptoms and having no other clinical criteria or non-sustained ventricular tachycardia or ventricular extrasystoles show image without Brugada. Patients with typical ECG features with occurrence of sudden cardiac arrest, sustained ventricular tachyarrhythmia or having other clinical criteria show Brugada syndrome.

14 BTL CardioPoint -SDS Module 14 Family anamnesis is fundamental in the diagnostics, mainly in the cases of occurrence of inexplicable syncope or other quick palpitations with presyncope. It is possible to diagnose BrS based on characteristic ECG image (BPRTw and ST segment elevation > 2 mm in leads V1 V3). In the case of hidden changes with normal ECG image, the significance of an ECG examination is low. 39 Holter examination and exercise ergometry can reveal extensive ventricular ectopy and non-sustained polymorphic ventricular tachycardia Wolf-Parkinson-White Syndrome (WPW Syndrome) WPW syndrome is a disorder caused by an extra pathway between the atria and the ventricles (the bundle of Kent) that conducts stimulus avoiding the AV node (ventricular preexcitation). WPW image versus WPW syndrome two terms differentiated based on presence or absence of arrhythmias: WPW image is characteristic for patients with ventricular preexcitation visible on ECG in absence of symptomatic arrhythmias. WPW syndrome is characteristic for patients with ventricular preexcitation manifested on ECG in presence of symptomatic arrhythmias including the bundle of Kent. WPW syndrome worldwide prevalence ranges from 1 to 3/1,000 cases yearly. This syndrome is the most common cause of an arrhythmia called paroxysmal supraventricular tachycardia and it is also the most frequent cause of abnormal heart rhythm in Chinese population, where it is responsible for more than 70 % of these cases. 40 ECG examination shows shortened PQ interval and QRS complex beginning with a delta wave. In some cases, ECG abnormalities appear only intermittently, which means favourable prognoses. Impacted individuals can be asymptomatic or they can develop palpitation and state of collapse due to regular supraventricular tachycardia. Patients with WPW syndrome have a higher risk of sudden death compared with ordinary population. In this case, ventricles fibrillation can occur. The disease is often accompanied by further structural myocard disorders or hidden heart disorders. The most common defect associated with the WPW syndrome is the Ebstein s anomaly, which impacts the tricuspid valve allowing blood flow from the right atrium to the right ventricle. Picture 5: WPW syndrome suspicion with detail view of shortened PQ interval, QRS complex and delta wave.

15 BTL CardioPoint -SDS Module Congenital Coronary Arteries Anomalies Congenital coronary arteries anomalies represent a wide range of abnormalities with various clinical consequences. The following are concerned: abnormal distance of right or left coronary artery from the aorta (high distance, multiple distances, one coronary artery, abnormal distance from the pulmonary artery, abnormal distance of coronary artery from the opposite or non-coronary sinus), abnormal progress (myocardial bridge, duplicate arteries), abnormal end of coronary arteries. Prevalence is estimated at less than 0.1 %. Most patients are asymptomatic and have normal ECG examination results. Diagnostics is rather difficult and often random during echocardiographic examination or it is determined after a sudden death event. The reliable coronary anomalies diagnostic methods are invasive coronarography, computed tomography (CT), magnetic resonance (MR) and echocardiographic examination. An advantage of a CT examination is a possibility of 3D reconstructions, which enable exact display of coronary arteries distances, their progress and anatomic correlation with large arteries. The main disadvantage of this method is radiation exposure, which eventually decreases as modern devices are being used. Another option is using magnetic resonance (MR). MR is less accessible and more time demanding than a CT examination, but does not expose patients to radiation. Invasive coronarography is being connected to more difficult and more technically demanding probing of anomaly distances and does not enable 3D reconstruction. Coronary arteries anomalies also belong to causes of SCD in sport. Carriers are usually asymptomatic, without clinical symptoms and disorder detection is mostly accidental. The question of screening is vital with young athletes, as ECG and exercise ECG cannot reveal ischemia with patients with coronary anomalies. An unreliable alternative can be echocardiographic examination aimed at showing coronary arteries distance or MR examination, while this method is financially and logistically very demanding for routine screening. Thorough screening should be conducted mainly with symptomatic or suspected athletes Myocarditis Acute myocarditis (AM) is a suddenly formed non-congenital inflammatory disease of myocard with histological signs of myocytes degeneration and necrosis of a non-ischemic origin, which is accompanied by inflammatory infiltration. The inflammation can impact myocytes, interstitium, vascular elements and often pericardium at the same time. AM prevalence is not exactly known, especially due to controversy of clinical diagnostics. Maximum AM occurrence (63 %) is between December and April and the disease is 2.5 times more frequent with men and black race. Clinical image usually begins with upper airways infection or gastrointestinal symptoms, but only mild clinical symptoms can appear, such as palpitations, fatigue, dyspnoea during exercise or syncope. Among frequent symptoms are symptoms similar to flu (higher body temperature, fever, hepatomegaly) or epidemiological connections that support viral infection. Myocarditis diagnostics is difficult. The most cases progress asymptomatically. Viral AM can precede dilation cardiomyopathy with predisposed individuals. There is no specific examination that could confirm myocarditis with certainty. A complex of examinations is needed (ECG, ECHO, MR, RTG, lab examination, etc.). The most reliable method to confirm AM is biopsy. It is only conducted in serious cases. Various changes are present on an ECG curve with myocarditis. None of them is though completely typical and the diagnosis can vary on ECG. The changes can look like myocard infarction or signs of pericarditis. They include: negative T wave, ST segment elevation or depression, tachycardia (tachyarrhythmia), extrasystoles, AV blocks. 3

16 BTL CardioPoint -SDS Module 16 Picture 6: Possible myocarditis or myocard infarction suspicion with detail view of negative T wave and an ST segment depression Commotio Cordis Ventricular fibrillation and subsequent death triggered by blunt, subtle, often innocent and accidental looking impact to the chest without ribs, breastbone or heart damage (in absence of a cardiovascular disease) is called commotio cordis. Absence of structural heart damage distinguishes commotio cordis from heart contusion, whereby a hard impact causes traumatic damage of myocardial tissue and the surrounding part of chest. Most commonly, sports where fast-flying balls and pucks are used are concerned, i.e. football, ice-hockey. Such a strong impact in the chest can in a sensitive period of ventricular repolarisation cause ventricular fibrillation. In these cases, the problem is low success rate of cardiopulmonary resuscitation (15 %), even if it is immediately applied. 14 Source of Blow Hockey puck Lacrosse ball Baseball Primary determinants and triggers Precordial impact site Timed during upstroke of T wave Contributing variables Greater hardness of projectile Smaller sphere Direct orientation Thinner, more compliant chest wall Left lung Rib Chest wall Fist or elbow 20-msec window Rapid increase in intracavitary pressure Picture 7: Commotio cordis 47 Upstroke of T wave

17 BTL CardioPoint -SDS Module 17 3 PREVENTION SUMMARY One of the purposes of screening is to provide medical consent for athlete s participation in professional sport. It is conducted using standard systematic evaluations. These are used above all to identify clinically significant and congenital cardiovascular abnormalities and to lower possible risk connected with organised sport. Detection of a disorder is the first diagnostic phase. Subsequently, a recommendation to a specialist is needed for more detailed diagnostics. After stating the final diagnosis, recommendations to continue or to exclude the athlete from permanent professional sport participation should be formulated. 16 Athlete s regular and intensive physical activity and participation in competitive disciplines can lead to manifestation of so far asymptomatic heart disorders with a predisposed individual. Preventive examination has a majority position with athletes. The purpose is to evaluate adequacy of sport activity in relation to health state of the athlete and expected development of diseases. Prevention recommendation stems from broadly accepted clinical experience stating that athletes with a cardiovascular disease (also asymptomatic) have a higher risk of sudden cardiac death (SDC) or clinical worsening of their state due to regular training load compared with completely healthy individuals. The task of prevention is to reveal hidden pathologies that could be an obstacle to sport activity, increase risk of health damage or lead to progression of diseases through active exercise. Sudden death risk in association with sport activity generates two main questions: how individuals should be evaluated before starting a sports career and what limitations should be determined for individuals diagnosed with a cardiovascular disease. Answers differ based on several determining factors: individual s age, heart disease type, type of sport activity (i.e. professional versus recreational sport). Professional sports are divided into 3 degrees based on exercise intensity. Furthermore, they are divided based on the type of load - static load (mainly pressure load of the ventricle) and dynamic load (volumetric load of the left ventricle). An example of a sport with low static and dynamic load is golf. On the contrary, rowing represents high static and dynamic load for an athlete. Just as professional sports, also recreational sports are divided based on intensity of physical exercise into: low intensity exercise (speed walking), medium intensity exercise (tennis doubles) and high intensity exercise (badminton). 3.1 Expectations and Recommendations of Preventive Screening Scientific organisations such as American College of Cardiology (ACC), American Heart Association (AHA) and European Society of Cardiology (ESC), athletic associations such as International Olympic Committe (IOC), Fédération Internationale de Football Association (FIFA) and others unanimously recommend preventive screening of athletes to lower risk of SCD. European and American screening recommendations differ in the matter of preventive screening contents. Standard cardiovascular screening in association with SCD risk protocol includes detection of personal and family anamnesis (usually in the form of questionnaires) and physical examination of an athlete worldwide (USA and EU). Standard 12-lead ECG examination is recommended in European states within screening according to ESC. 9,24,25,26 AHA does not support ECG examination within screening in the USA due to several reasons: lack of specialised doctors trained in screening and interpretation of ECG of athletic population and with this fact associated high rate of false positivity, high costs of conducting screening of a high number of athletes,

18 BTL CardioPoint -SDS Module 18 a relatively low rate of SCD mortality with athletes in the USA. It is approximately at the level which was reached by Italy after twenty years of conducting screening with ECG examination, lack of standardised screening methods for ECG interpretation with athletes and lack of normative data in certain demographic and ethnic groups. 12 Apart from personal and family anamnesis (usually in the form of a questionnaire) and physical examination of an athlete, ESC recommendations include 12-lead ECG examination to increase sensitivity and particularity of screening examination. Screening examination based solely on personal and family anamnesis is not sufficient to detect some cardiovascular abnormalities. For instance, hemodynamically significant congenital aortal valve stenosis is lesion which will probably be reliably detected by standard screening, since it is accompanied by characteristic loud heart murmur. In the case of hypertrophic cardiomyopathy (HCM), detection without ECG examination is not effective. Most patients have a non-obstructive form with minimum symptoms, alternatively without clinical manifestation. Furthermore, many athletes with HCM do not feel syncope and have no cases of SCD in their family anamnesis. 16 Personal anamnesis within detection of cardiovascular abnormalities in association with SCD with young athletes does not provide significant particularity on its own. In an older age, personal anamnesis of coronary risk factors and family anamnesis of premature ischemic heart disorder are applied to identify risk-bearing individuals. 16 Young competitive athletes Family and personal history, physical examination, 12-lead ECG Negative findings Positive findings Eligible for competition No evidence of cardiovascular disease Further examinations (echo, stress test, 24-h Holter, cardiac MRI, angio/emb, EPS) Diagnosis of cardiovascular disease Management according to established protocols Picture 8: Flow diagram illustrating the proposed screening protocol for young competitive athletes. 22 The conclusion of the first screening phase is not determination of diagnosis, but expressing suspicion about a serious cardiologic disorder. In the next phase, individuals with a positive diagnosis are recommended to proceed to additional, mainly non-invasive examinations. In unclear cases with suspected diagnoses, invasive diagnostics is necessary to confirm/reject a cardiologic disorder and to determine the final diagnosis. In the first phase, it is important that the examining doctor decides about limiting or excluding the athlete from training sessions until all examinations are complete. This period can take up to several months and it could be mentally demanding for the athlete. In some cases, it is not possible to certainly confirm or reject a specific disease even after months of difficult and sometimes invasive examinations.

19 BTL CardioPoint -SDS Module Questionnaire Consulting in Preventive Screening Questionnaires of personal and family anamnesis contain primary questions about symptoms associated with sudden cardiac death risk. The short AHA questionnaire 9 is composed of 14 questions, the longer version published according to Lausanne Recommendations of the IOC (International Olympic Comittee) and ESC 14 contains 36 questions. Based on consideration of an examiner, a positive answer in one or more questions should be evaluated as a possible SCD trigger and should lead to further examination Personal Anamnesis The personal anamnesis questionnaire focuses on symptoms triggered by physical exercise: syncope, chest pain during exercise, dyspnoea, palpitation, higher blood pressure, abnormal respiration or fatigue. Personal anamnesis determination evaluates history of cardiovascular disorders with a specific individual. Among the most common risk symptoms with physically active individuals are fatigue (44 %) and syncope (30 %), which do not necessarily have to be associated with a cardiovascular disease. Syncope during a sudden collapse and symptoms occurring solely during exercise can be responsible for structural heart disorders or primary arrhythmia syndrome. In % of cases, sudden death is the first clinical symptom of a cardiovascular disease, above all with young athletes. 27 All things considered, we can claim that the probability of discovering significant cardiovascular diseases using personal anamnesis is low Family Anamnesis Family anamnesis follows SCD occurrence in family before the 50 th year of age, inherited cardiac diseases and cardiomyopathies, Marfan syndrome, short or long QT syndrome and serious arrhythmias. Each SCD occurrence in family before reaching the 50 th year of age requires responsible cardiologic examination due to possible genetic predisposition of given cardiologic disorders. 27 Wilson et al. conducted a study during which they observed 1,074 British junior athletes. They found a disease connected to SCD risk in nine of them. None of them had any significant family anamnesis. Nonetheless, with the remaining 1,065 athletes, the SCD incidence was determined at 2.9 %. Family anamnesis is therefore an important element in SCD prevention. 9 Warning signs are often overlooked, which evokes the need to increase education in the sudden death problematics among sports public and among parents of athletic adolescents Physical Examination Physical examination analyses abnormal results of auscultation heart examinations, such as heart murmur (systolic or diastolic) determined by respiration, strengthened after exercise, irregular heart rhythm or asymmetric arteries impulses (aortic coarctation), bilateral brachial blood pressure and musculoskeletal and eye features resembling Marfan syndrome clinical image. All-in-all, it is possible to state that physical exercise on its own has relatively low efficiency detecting diseases with an SCD risk. Exceptions are some disorders such as aortic coarctation and Marfan syndrome, where physical stigmas and pulse changes in arteria femoralis are present. The results of the physical examination are usually normal with coronary heart disorders, ion channelopathies and WPW syndrome. 9

20 BTL CardioPoint -SDS Module Standard 12-Lead ECG Examination Standard 12-lead ECG together with a personal and family anamnesis and individual s examination increases the potential to detect (determine suspicion) sudden death risk. ECG examination results of patients with cardiomyopathies, which are among the main sudden cardiac death causes, are in % cases abnormal. 12,29 Abnormalities that are observed the most often include: atria enlargement, pathologic Q wave, QRS complex axis deviation, ST segment depression, deep T wave inversion, complete branch block. 32 Individuals with positive ECG diagnoses should be recommended to proceed to further diagnostics, usually using non-invasive methods (echocardiography, 24-hour Holter monitoring, SA-ECG, exercise test). In some cases, invasive diagnostic methods are necessary (contrast ventriculography, coronary angiography, endomyocardial biopsy) to confirm or reject specific cardiac disorder suspicion. Individuals with a confirmed cardiovascular disease, potentially responsible for SCD in association with exercise and sport activity, should be limited/excluded from competitive sport in accordance with recommendations of Bethesda conferences 16, 26, Advantages and Constraints of ECG Screening ECG examination was considered to be a non-invasive, inexpensive, but significantly non-specific screening tool with athletic population with a high percentage of false positivity. This conclusion stemmed from a concept claiming that physiological ECG changes with trained athletes with a heart adapted to permanent physical exercise overlap with pathologic ECG abnormalities. Anatomic remodelling in the adapted athlete s heart causes ECG changes that are interpreted as abnormalities. Falsely positive results therefore usually lead to elimination of healthy athletes or to further redundant and costly diagnostic procedures. Many conducted studies confirmed that ECG results are abnormal with 95 % of patients with HCM and with most cases of other potentially lethal diseases such as coronary anomalies, etc. A rare long QT syndrome happens to be successfully identified. Recent studies suggest that certain ratio of genetically impacted relations shows minimum or no phenotype symptom on ECG. 16 A challenge with ECG interpretation with athletes remains the ability to precisely distinguish cardiovascular diagnosis from benign physiological adaptations to regular intensive training. 31 Patient s age is among limiting factors of ECG examination analysis. ECG changes are with some disorders visible only at a later age (some congenital heart disorders). They may also be not very specific and difficult to detect or completely without any clinical manifestation. It is necessary to take these facts into consideration mainly during preventive examination of athletic adolescents (younger than 18). This group has a higher SCD risk in relation to progression of the disease in adulthood. It is overall possible to claim that just as some heart disorders have no characteristic changes of resting ECG examination (myocarditis, catecholaminergic polymorphic ventricular tachycardia), with others the changes are clear regardless of age (WPW syndrome, long QT interval syndrome). 30 According to the ESC 2015 recommendations, it is suitable to focus on congenital cardiomyopathy and channelopathies with athletes younger than 35 years, as these represent the highest SCD risk out of congenital cardiovascular disorders. 46 Current studies confirm significant influence of ethnicity on physiological adaptation to regular training, mainly with athletes of African/Afro-American ethnicity. It is sensible to suppose that taking the influence of ethnicity and sex in ECG analysis into account could eliminate false positivity of results and could make the important position of the 12-lead ECG examination within screening stronger in the future. 23

21 BTL CardioPoint -SDS Module Athlete s ECG Interpretation It is difficult to correctly interpret athlete s ECG. Incorrect interpretation can lead to a high rate of falsely positive diagnoses, whose further expert diagnostics is redundant or expensive. The solution for correct athlete s ECG interpretation was a proposition of criteria whose goal was to distinguish normal athlete s ECG from abnormalities, which require further diagnostics. Criteria application is perspective to reduce a number of falsely positive results. Most sport medicine and cardiology programmes lack standard education curriculum to interpret athlete s ECG Standardised ECG Examination and its Advantages ECG examination standardisation enables physicians, sport medicine doctors, physiotherapists and in special cases even trained volunteers to conduct ECG examination and simply separate suspected individuals from the healthy ones or the ones adapted due to training. Pathology of ECG curve changes is evaluated using standardised criteria capable to identify pathological changes of heart with athletes. The most difficult is ECG interpretation with adolescent athletes. Age, sex, ethnicity together with physiological adaptation due to physical exercise significantly influence the changes. Studies confirm that standardised criteria significantly simplify ECG interpretation and significantly improve accuracy to distinguish normal diagnoses from abnormal ones, even for (non)doctors with less broad knowledge and experience. Further diagnostics of suspected patients is conducted under an expert s supervision Electrocardiographic Interpretation Criteria in Sport Historical Progression of ECG Interpretation Criteria in the Athletes Screening for HCM in young athletes. ESC 2005 ESC 2010 Seattle Criteria Refined Criteria International Criteria NEJM. 339(6) Eur Heart J. 26(5) Eur Heart J. 31(2) Br J Sports Med 47(3) Circulation. 129(16) Br J Sport Med 1 Initial presentation of formal ECG criteria for differentiation of pathology from normality in athletes First consensus document presenting quantitative ECG criteria for use in athletes Criteria update aimed at acknowledging the difference between common/ training related ECG patterns and uncommon/ training unrelated ECG patterns Criteria update aimed at refining the ESC 2010 criteria with an emphasis on the development of training modules for sports medicine practitioners. Criteria focused on further improving the specificity of athlete ECG interpretation by using primary data derived from sizeable multiethnic athlete cohorts Key Advances First published ECG criteria designed to detect occult structural disease in athletes Key Advances First published consensus document describing the rational for clinical ECG interpretation in athletes Key Advances Segregated athlete ECG patterns into Group 1 (training related) and Group 2 (training unrelated) Key Advances Provided refined quantitative definitions for numerous ECG patterns to increase specificity for the detection of occult disease Key Advances Reclassified several common isolated ECG patterns as benign including axis deviation, atrial enlargement, and right ventricular hypertrophy Picture 9: Timeline of ECG interpretation criteria in sport. 45

22 BTL CardioPoint -SDS Module 22 ESC (European Society of Cardiology) Recommendations In 2010, ESC released revised recommendations (Picture 4B) for athlete s ECG interpretation. 41 These recommendations were created due to increasing false positivity of ECG results within pre-participation cardiovascular screening that were recorded by sport management authorities. The high number of falsely positive results appeared due to inability to distinguish pathological ECG diagnoses from those of physiological heart adaptation to active sport. To confirm higher ECG examination specificity within athletes screening applying ESC recommendations, the authors reanalysed ECG examination of 1,005 highly trained previously examined athletes. 42 Originally, 402 out of them (40 %) showed abnormal ECG results, while after applying the ESC recommendations, the original percentage of abnormal results decreased to 11 %. Certain races and ethnic groups (black-african, Afro-Caribbean, Latin-American) showed a high percentage of abnormal ECG results (20 40 %) despite applying the ESC recommendations. 43 Seattle Criteria In 2012, an international expert group of sport medicine doctors and cardiologists met. They created a common statement about athlete s ECG evaluation. The challenge was to define ECG interpretation standards with athletes with the intention to correctly distinguish benign adaptive athletes ECG changes from those that could indicate hidden heart pathologies. Furthermore, to create an overview of recommendations the Seattle Criteria 2012 (Picture 4C) for initial ECG evaluation of abnormalities resembling pathologic cardiovascular disorders and to confirm or reject their further diagnostics. Another significant thing was the interest to increase specificity of the ECG as a screening tool and to decrease the rate of falsely positive results. 31 The Seattle Criteria 2012 in comparison with the ESC Recommendations 2010 achieved positive results regarding reduction of number of ECG diagnoses previously marked as abnormal (from 17 % to 14 %) within population of professional athletes along with revealing all individuals with a certain heart pathology. Last, but not least, the Seattle Criteria take ethnicity factors into account (T wave inversion in front leads V1-V4 commonly present with athletes of black race), which helps to reduce the false positivity rate. 43 Refined Criteria In 2014, Sheikh et al. 44 published the Refined Criteria (Picture 4A) for athletes ECG interpretation based on their experience with athletes screening applying the ESC Recommendations and the Seattle Criteria. Sheikh et al. proved that ECG diagnoses of the atria broadening (the right atrium and the left atrium), heart axis deviation (right, left) and right ventricle hypertrophy stated in the ESC Recommendations and the Seattle Criteria have extremely low diagnostic benefit for determining a heart pathology. The unique feature of these criteria was the reanalysis conducted in the case of 103 young athletes with diagnosed HCM, while with the Refined Criteria, 98.1 % of the cases were confirmed. The Refined Criteria have the greatest benefit in applying electrocardiographic interpretation criteria in population of adolescent athletes.

23 BTL CardioPoint -SDS Module 23 Picture 10: Determining abnormal ECG diagnoses of athletes using: A- Refined Criteria 2014, B- ESC Recommendations 2010, C- Seattle Criteria 2012

24 BTL CardioPoint -SDS Module The Way to Conducting Efficient Screening Opinions about whether to conduct screening that includes ECG examination differs around the world. The differences are significant mainly in European and American countries. There is a large number of questions about how to conduct screening efficiently. The opponents of screening mainly point out low incidence of SCD, high costliness of screening examination and lack of specialised experts. The low sudden death incidence within athletic and non-athletic population lowers efficiency of cardiovascular screening in several forms at once. It requires screening of a high number of individuals. This coincides with overload of cardiologists and an increase of costs of conducting examination. Screening conducted by a non-expert contributes to the increase of costs. False positivity or negativity rates increase. Falsely positive results increase costs for further redundant diagnostic examinations. Apart from the real costs, the overload of specialists increases again. In population of professional athletes, falsely positive cardiovascular screening results can negatively affect their athletic performance and cause mental or economic harm. Incomplete knowledge of physiological heart adaptation to regular physical activity, which is a common case with athletes, can also be the source of falsely positive results. Incorrect diagnostics leads not only to falsely positive results, but also to falsely negative results, which can result in a fatality. Regarding the obligation to screen professional athletes, we have developed a solution in cooperation with the Charles University Hospital in Prague. This solution is capable of minimising the above-mentioned problems. The BTL CardioPoint SDS (Sudden Death Screening) module conducts automatized ECG test according to standardised criteria accepted by cardiologic as well as sport public. All of the following options included in cardiovascular screening, from test automatization, through visualisation, electronic consultation and test standardisation according to the criteria, enable shortening of time needed for the specialised doctor to determine diagnosis and shortening of patient s waiting time. They efficiently minimise patient s personal visit at the cardiologist and natural doubt of the examined patient about the progress of further diagnostic examinations. Out of original 100 % of screened individuals, we can reduce the percentage of patients suspected of a certain cardiovascular pathology to the minimum, applying all the modifications and in a short time period. The first visit the person conducting screening The first effective step that makes the selection of healthy and suspected individuals easier is the automatized and standardised test with high sensitivity. Not only experts, but also trained physicians, sport doctors and paediatricians with general knowledge of ECG can conduct the test. The largest percentage of healthy individuals is simply separated from the large number of individuals who need to undergo cardiovascular screening due to low sudden death incidence. The test standardisation is very beneficial with experts who do not commonly pursue athletic population. It is applied mainly while differentiating physiological adaptation changes from pathological myocard changes. The adaptive changes, the so-called athlete s heart, are a common case with athletic population. During the second step, the option to visually check all criteria is applied. Thanks to immediate visual results, the person conducting screening is able to correct obviously incorrect diagnostics of the automatized test and separate possible falsely positive results. This again decreases the percentage of suspected individuals. In third step the person conducting screening has an option to electronically consult an expert, who can expertly evaluate unclear cases.

25 BTL CardioPoint -SDS Module 25 First step Automatized and standardised test Second step Visual validation Third step Electronic consultation with cardiologist 100 % screened 30 % questionable/suspected 30 % visually evaluated 15 % questionable/suspected 15 % consulted < 7 % questionable/suspected The second visit cardiologist, specialist The percentage of patients requiring a visit at the cardiologist in person is reduced to the minimum throughout the first screening phase. The specialists themselves expertly evaluate ECG examination or conduct further examination during the visit. They can eliminate physiologically adapted or otherwise uncertain patients from the number of unclear cases. Patients with a cardiovascular disorder are subsequently sent to further specific diagnostic examinations. < 7 % questionable/suspected further examinations needed < 7 % questionable/suspected BTL CardioPoint -SDS Module The BTL CardioPoint SDS module enables all necessary modifications that allow for efficient conducting of screening. The tool is developed so that experts as well as doctors not specialised in arrhythmology can work with it. The tool should make their work easier and quicker. Among basic priorities of the SDS module belongs implementation of automatic detection of published criteria with high sensitivity and acceptable positive predictability. The visualisation of all results with an option to manually edit the results with automatic recalculation of selected criteria and recalculation of overall test results is highly efficient. How to work with the BTL CardioPoint SDS module The user does a classic resting ECG record or opens a previously saved record in the electronic form. The BTL CardioPoint displays ECG curves in a common way, measures and displays automatic interpretation suggestion of the record. The implemented automatic sudden death risk interpretation suggestion stems from the Seattle Criteria. If at least one of the 16 criteria is Positive, the overall result is Positive/Suspected from sudden death risk. The advantages of the Seattle Criteria are its clear definition, simple and logical structure and minimised set of symptoms compared with common automatic interpretation criteria. Furthermore, the symptoms are defined by their own normality limits. The limits were determined regarding the screened population youth with various rate of heart adaptation to load (athlete s heart). It is possible to verify automatic results and at the same time correct imprecise results. The unique results visualisation implemented straight in the ECG signal enables simple results check at a glance. The measurement straight on the typical non-averaged ECG complex is also specific. Standardly used averaged complex that smoothens the signal is usually unreliable from a doctor s point of view. Most doctors measure straight in the ECG signal on non-averaged curves. The reason is simple. Natural shapes of consequent P-QRS-T complexes in the record are variable mainly due to RR interval acceleration change during inhaling and exhaling, while this case is significant above all with children and young patients.

26 BTL CardioPoint -SDS Module 26 A combination of text and colour distinction was implemented for a better focus of the person conducting screening. The colours mean the following: green means negative diagnosis, red means positive diagnosis, orange means questionable diagnosis :» The automatic tool signals this output, if the diagnosis is borderline normal or if it is unable to decide. Manual check of the given criteria by the user and their own evaluation and diagnosis classification (negative/positive) is needed in the cases of borderline normal values.» It is possible to deliberately set this state within multiple-level evaluation, whereby the person conducting screening proceeds the unclear state to a specialist for expert evaluation. Basic module views 1. Automated Criteria Review (Picture 11): Criterion Signal Marker Marking the suspectible leads directly in the ECG signal Findings Evaluation and selection of individual criteria Switching to the measurement of selected criterion The definition of the selected criterion Rhytm lead, indicating the evaluated area The overall conclusion of doctor Picture 11: Automated Criteria Review: Classic ECG view and additional components: Findings a list of all criteria with an option to edit a criterion result, Criterion Definition selected criterion definition (help), Details a numeric table with measurement results for respective criterion symptoms, Medical Findings overall doctor s conclusion Most cases are evaluated on the selected ( Typical ) contraction in the record. The selection is automatic using implemented algorithm, while the user has an option to select his own contraction. 2. Visual Criteria Evaluation (Picture 12) Signs distinguished by colour highlight suspected ECG curve shape with a borderline value (orange colour) or with an exceeded borderline value (red colour) of one of the symptoms in the Seattle Criteria. By clicking on the spots in the ECG signal marked by signs, the user can switch from the Automated Criteria Review to the Visual Criteria Evaluation view.

27 BTL CardioPoint -SDS Module 27 In Signal Measurement Overlapping interesting leads of selected contraction Overlapping similar contractions of selected lead Picture 12: Criteria Evaluation: The In Signal Measurement component. The In Signal Measurement component provides the doctor with an option to evaluate accuracy of automatic measurement and complex criteria at a glance. It also provides them with an option to evaluate the seriousness of a symptom using normal limit visualisation. The component displays a part of signal essential for evaluating the criterion. It is divided into two parts: results projection into other leads (top part), current lead measurement (bottom part). Picture 13: The InSignalMeasurement component displays enlarged ECG signal part in order to verify correctness of automatic measurement of selected criterion symptoms or in order to conduct manual correction, if needed.

28 BTL CardioPoint -SDS Module 28 The top window of the InSignalMeasurement component is used to verify correct interval measurement in the context of other leads. Simultaneous display of local and global interval borders and values is also a unique feature of the module. The bottom window displays the currently selected contraction, which is overlapped by surrounding contractions. This means that the innovative module algorithm evaluates similarity of other contractions with the selected one in this specific view. Other contractions are displayed with various rates of transparency based on similar or different morphology and dynamics. Such signal display is unique worldwide. Unlike the classic signal zoom, doctor s uncertainty about whether the shape of the curve (mainly various rays, etc.) is caused by an artefact, arrhythmia or it is natural for the given record, is supressed. A specific view helps the user to optically reduce noise. At the same time, there is no signal distortion present, unlike with the averaged complex. Picture 14: Bottom window of the InSignalMeasurement component. The Final Report The final report contains an overview with overall evaluation of all Seattle Criteria. It points out the borderline pathological criteria values using characteristic colour distinction. The user is able to intuitively focus their attention at the highlighted criteria at a glance. In every lead of a highlighted criterion, the pathology rate (from a borderline to a risk-bearing value) is graphically displayed using an arrow indicator. An automatic text and detailed results print option can be set in the final report. Overall contents of the final report are fully adjustable and their body depends on the expert s judgement.

29 BTL CardioPoint -SDS Module Clinical Verification of the BTL CardioPoint -SDS Module Efficiency of the BTL CardioPoint SDS module was verified in cooperation with the Charles University Hospital in Prague using two clinical tests. Retrospective Automatic Evaluation Success Rate Test The Aim of the Test The main aim of the test was to verify the output of automatic SDS module diagnostics against the reference database created by a consensus of two expert doctors. The following was evaluated: selection of the signal segment used for diagnostics, accuracy of interval parameters measurement in signal, accuracy of respective criteria interpretation, the conclusion of an examination, programme ergonomics. Test Description A database with 513 retrospective anonymised records was created by the clinical test partner. It was deliberately built to contain examples of all observed criteria and to have significantly higher prevalence against natural prevalence in population. There were also three pairs of expert evaluators, whereby each of them received a set of records to be evaluated individually. All the criteria were pre-set as Unknown for the evaluator. All the callipers that measure signal were placed at previously defined spots. The evaluators were forced to individually choose an optimal part of the record in signal to be evaluated. Moreover, they were forced to move callipers into the right spots and set respective criteria and the final evaluation to an adequate state. The data evaluated were then analysed, while the analysis was consisted in match evaluation. All the records with at least one-criterion mismatch of evaluators were sent to be re-evaluated, whereby a consensus had to be reached. Criterion Code Criterion Name Prevalence CT001 Profound sinus bradycardia 0.00 % CT003 Atrial tachyarrhythmia 1.17 % CT004 Premature ventricular beats 2.34 % CT005 Ventricular arrhythmias 1.36 % CT006 ST segment depression % CT007 T-wave inversion 9.94 % CT008 Pathological Q waves 5.26 % CT009 Complete left bundle branch block 1.95 % CT010 Intraventricular conduction delay 1.95 % CT011 Ventricular pre-excitation 6.82 % CT012 Left atrial enlargement 1.95 % CT013 Brugada-like ECG pattern 0.39 % CT014 Left axis deviation 5.07 % CT018 Right ventricular hypertrophy pattern 1.56 % CT019 Long QT interval 4.87 % CT020 Short QT interval 0.19 % CT021 The conclusion is POSITIVE % Table 2: Prevalence of respective criteria in the retrospective test database. The test result in percentage: The test result confirmed a hundred-percent SDS module sensitivity, but considering the fact that with device diagnostics we take a possible deviation into account, we evaluate the test result at 98 %.

30 BTL CardioPoint -SDS Module 30 Normal Operation Prospective Test The Aim of the Test The main aim of the test was to measure the time it takes to conduct an examination (to be compared with the time it takes to evaluate manually on paper) and to verify graphic interface ergonomics. The following was evaluated: usefulness of the diagnostics module tested, selection of the signal segment used for diagnostics, respective criteria, their sensitivity, positive predictability, particularity and negative predictability, accuracy of the examination conclusion, programme ergonomics. Test Description The database contained overall 397 prospectively collected records, while in 126 (38.53 %) cases the testing module was opened. In the rest of the cases the diagnosis was so normal that the operator did not feel the need to use the views Automated Criteria Review or Visual Criteria Evaluation nor to change the automatic interpretation in the main screen of the programme. Within the clinical verification, another test was conducted to compare the time it takes to examine using the CardioPoint SDS module and the time it takes to measure manually using a printed form of a record. The manual measurement of the printed form of the record on paper took the evaluating doctors about 15 to 40 minutes. The result of the tests with opened SDS module in percentage: 55 % of records were analysed in 2 minutes, 71 % of records were processed in 5 minutes, approximately 20 % of examinations are not suitable for evaluation due to various reasons (interpretation interrupted by another activity, etc.). # of records % of records Picture 15: Graph showing the evaluation results of normal operation prospective test