In this series on cardiac screening in athletes we delve into the issues surrounding the current practice of pre-participation cardiac screening. In the first part, we explored the question of whether athletes are truly at an increased risk of sudden cardiac death (SCD) and whether they should be preferentially screened compared to their non-athletic counterparts (a link can be found here). In this section, we address the current guidelines on how to perform a pre-participation cardiac evaluation (PPE), with particular reference to the utility of an electrocardiogram (ECG).

There is a general consensus that a PPE should be performed on all competitive athletes. Given that non-traumatic sudden death in a young person is almost always due to an underlying cardiac abnormality,^1-3 screening provides an opportunity to detect and subsequently treat the underlying disease before it causes a fatal event.^4,5 There is, however, considerable debate regarding the optimal method of performing such an evaluation. The most notable difference is between the European Society of Cardiology (ESC)⁶ and the American Heart Association/American College of Cardiology (AHA/ACC)⁷ guidelines, published in 2005 and 2007 respectively, which rests on the use of a 12-lead ECG. The European Society of Cardiology (ESC) endorses the use of an ECG as an initial screening tool, while the AHA/ACC does not. The question is, ten years on, are we any closer to reconciling this complex issue?

The Italian versus Israeli experience of ECG Screening in Young Athletes

The most compelling evidence for the integration of a 12-lead ECG in a PPE is derived from large Italian trials.^4,5 Corrado et al. explored the trends in cardiovascular death in athletes prior to and after implementation of a mandatory nationwide systematic ECG PPE program.⁴ After initiating the program, the annual incidence of SCD in athletes decreased by 89% (from 3.6/100,000 person-years in 1979-1980 to 0.4/100,000 person-years in 2003-2004; P for trend <.001). This reduction was driven by fewer deaths attributable to cardiomyopathies, notably arrhythmogenic right ventricular cardiomyopathy (ARVC). Accordingly, the number of athletes disqualified because of ARVC concomitantly increased. Overall, 2% of all athletes screened were ultimately prohibited from competitive sports. Whilst this study provides important data on the effectiveness of an ECG screening program to reduce SCD events, a number of limitations were identified in the accompanying editorial by Thompson and Levine.⁸ The authors note that ARVC was only recognized as a cause of exercise-related SCD in the 1980s; therefore, the low detection rate of ARVC prior to – and subsequent increase in ARVC detection following ECG screening – may have been due to an increase in the awareness of ARVC, together with the addition of an ECG. Without a randomized study with two arms, one arm screening with history and physical examination only and a separate arm using an additional ECG, we are unable to discern whether all of the reduction in ARVC deaths were due to the addition of an ECG. The incidence of ARVC is also far higher in the Veneto region of Italy than in the US and therefore the relevance and applicability of this data to inform healthcare policy in the US is questionable. Furthermore, a greater awareness of SCD, and possible better availability of automated external defibrillators at sports grounds may also have contributed to the reduction in SCD during the post-screening period. Finally, Thompson and Levine comment on the high incidence rate of SCD in athletes, prior to the screening program, as a contributing factor to the reduction in SCD over the course of the study. However, recent collected data from the UK supports this high incidence rate of SCD in athletes.⁹ Malhotra et al. report the incidence rate of SCD in UK adolescent soccer players to be 6.8 deaths per 100,000 person years, despite comprehensive screening with ECG and echocardiogram.⁹

The reduction in incidence of SCD in athletes following a mandated ECG screening program have not yet been replicated elsewhere in the world. Despite the 1997 implementation of a mandatory ECG program in Israel, there was no significant difference in the yearly incidence of SCDs between the pre-screening and post-screening period (2.54 versus 2.66 per 100,000 persons).¹⁰ There were, however, notable weaknesses in the methodology compared to the Italian study. First, while the Italian data was collected from a national prospective registry, the number of SCD in Israel was derived from two newspapers, which is likely to have missed a number of cases (particularly in those engaged in sport at a non-elite level). Second, the certainty of the number of competitive athletes undergoing pre-participation screening in Israel has been questioned.¹¹ Under the circumstances, the reliability of both the numerator and denominator from which incidence rates are calculated may be questioned. When the number of SCD events in athletes are low, such uncertainty regarding the reliability of the data collection is likely to undermine the value of the study.

False-Positive Rate of ECG Screening in Young Athletes

While the presence of at least one positive cardiac symptom or family history is reported as 33% in a large college screening program,¹² a major criticism of a mandatory ECG in addition to the history and physical examination PPE is the high false-positive rate. Indeed, in the seminal Italian study, 9% of the screened athletes were referred for further examination because of positive findings, but only 2% were ultimately diagnosed with a condition associated with SCD.⁴ In the context of a US nationwide screening program, this represents an unacceptably high false-positive rate, the consequences of which would result in undue anxiety, cost and inappropriate sports restriction. To rectify this issue, several observational studies have examined the electrical adaptations unique to athletes,^7,13-19 and the significant ethnic and age-related variations in the athlete's ECG.^11,12 These findings have helped differentiate physiological adaptations from changes suggestive of cardiac pathology and are reflected in the most recent guidelines for the interpretation of an athlete's ECG.²⁰ Following these updates, the positive rate when performing ECG screening in athletes has reduced.^21,22 A retrospective analysis of nearly 5000 athletes screened from 2011-2014, using the latest international recommendations, showed that 3% of athletes would be deemed to have an abnormal ECG. This represented an 86%, 50%, and 30% relative reduction compared with the 2010 ESC,¹³ Seattle,²³ and refined²⁴ criteria, respectively (all 2-tail p < 0.0001).²²

False Negative Rate of ECG Screening in Young Athletes

As well as concerns regarding the false-positive rate, there is also apprehension for the false-negative rate when using a resting 12-lead ECG to detect underlying cardiomyopathy in athletes. A recent study by Malhotra et al. highlights this important, but nuanced issue.⁹ In their study of elite adolescent soccer players in England who all underwent cardiac screening with a history, physical examination, ECG and echocardiogram, there were eight cases of SCD over a 20-year period. Six of the eight were undetected by screening; yet, autopsy examination revealed cardiomyopathy or idiopathic left ventricular hypertrophy in all but one athlete. On the face of it, this may suggest that screening with ECG does not adequately identify those at risk of SCD. However, among the athletes who died from cardiac disorders, the mean time between screening and sudden death was 6.8 years. Therefore, an argument may be made for serial ECG screening to overcome the false-negative results due to the age-related penetrance of these inherited conditions.

Unexplained sudden cardiac death/Sudden arrhythmic death syndrome

Malhotra et al. identified one SCD event where the athlete had a normal initial ECG, echocardiogram, as well as a normal autopsy examination, an entity deemed unexplained SCD or sudden arrhythmic death syndrome. Over the last decade our understanding of the etiology of SCD in young athletes has been questioned and we recognize that unexplained SCD is an important and, possibly, the most common cause of SCD in young athletes. While traditionally we have considered hypertrophic cardiomyopathy to be the most common cause of SCD in athletes in the US, recent studies indicate that 30-40% of cases of sudden cardiac death among children and young adults have no evidence of pathology after a comprehensive autopsy examination that includes toxicologic and histologic studies.^24-27 While genetic testing increases the diagnostic yield of autopsy examinations by >25%,²⁷ it is unknown how many of these individuals would have an abnormal resting 12-lead ECG. Using a local Canadian registry of all young persons who had out-of-hospital cardiac arrest, Landry et al. recorded 16 cases of sudden cardiac arrests that occurred during competitive sports.²⁸ Of these, the authors conclude that only three may have been detected by pre-participation screening with an ECG.

The ECG screening undoubtedly increases the diagnostic yield of athletes with cardiac condition associated with SCD – but are we able to modify these athletes' risk of SCD?

There is a general consensus that an ECG as part of a PPE detects considerably more cases of cardiac disease associated with SCD than history and physical examination alone. But herein lies an issue that is at the crux of the ECG screening debate: if an asymptomatic athlete with no family history of disease is diagnosed with a cardiac condition from the screening ECG, are we able to reduce his/her risk of SCD? Returning to the study by Malhotra et al., out of 11,168 athletes, the authors identified 36 cases of conditions associated with SCD detected by ECG only. Twenty-six athletes had a Wolff-Parkinson-White (WPW) ECG pattern, of whom, 24 underwent ablation before returning to play. While it is likely all these asymptomatic individuals underwent appropriate exercise and electrophysiological studies to determine the need for ablation, an examination of the natural history of asymptomatic WPW ECG pattern indicates that the risk of SCD is exceedingly low (0.015 per patient-year).²⁹ It is important to note this data is derived from the general population and as such, we are unaware whether this risk changes through competitive sports participation.

The next largest group of athletes Malhotra et al. detected by screening ECG was hypertrophic cardiomyopathy (5 out of 36 athletes). The Tufts experience has provided an important insight into our understanding of SCD risk stratification of hypertrophic cardiomyopathy (HCM).³⁰ Using the 2011 American College of Cardiology Foundation/American Heart Association HCM guidelines³¹ we are able to accurately identify those that will not experience SCD.³⁰ It is likely that the vast majority of athletes with HCM identified incidentally by a screening ECG would not meet criteria for implantable cardioverter-defibrillator (ICD) implantation. Being identified only incidentally by screening ECG, they would be asymptomatic, without syncope or palpitations and without any significant family history. Therefore, these athletes would either require a left ventricular (LV) thickness of 30mm, an apical aneurysm or >15% of scar on late gadolinium enhancement (LGE). This paper suggests that absent these identifiable risk factors, the risk is of SCD in HCM is very low. However, akin to the WPW data, the Tufts experience is derived from the general population and whether the risk of SCD in HCM is modified by competitive sports is unclear. While the professional society recommendations advise athletes with HCM against playing competitive sport, as new data emerge, this may be an overly cautious approach. The risk of SCD in an HCM athlete is not zero, but we do not know whether competitive sports increase that risk. Indeed there is an ongoing prospective study (Exercise in Genetic Cardiovascular Conditions (LIVE-HCM/LQT) to address this very question.

Despite the apparent limitations in altering the natural course of asymptomatic/negative family history WPW and HCM, ECG screening programs often detect cases of asymptomatic long QT syndrome (LQTS). Out of the >11,000 adolescent athletes screened, Malhotra et al. identified three individuals with LQTS. It is entirely plausible that early detection and subsequent appropriate management of this disease does reduce the risk of future cardiac arrest.

Financial Implications of ECG Screening in Young Athletes

A nationwide cardiac screening program involving initially only a history and physical examination is estimated to cost $250 million, excluding the additional testing required for positive screens (10 million high-school and middle school athletes x $25 for each personal and family history).⁷ The addition of a $50 ECG for each screened individual would increase this initial cost to $750 million. These calculations formed part of the rationale in 2007 for the AHA/ACC to oppose a mandatory nationwide ECG integrated cardiac screening program. The authors of the guideline state that, assuming a 15% positive rate on the initial screen and the secondary investigations subsequently required, the annual total cost of the overall program would reach $2.0 billion. Based on the prevalence for cardiac conditions associated with SCD in the US, approximately 10,000 of the 10 million athletes would harbor sinister cardiac pathology, of which 9,000 would be identified during the screening process. In this setting, the cost of each diagnosis is $330,000. However, not all athletes diagnosed with a cardiac condition associated with SCD experience a fatal event. The authors of the guideline position that if only 10% of the diagnosed at-risk athletes experience SCD, the cost of preventing each theoretical death would be $3.4 million. However, our recent understanding of SCD in athletes require a revision of these calculations. It is likely that the number of individuals with a condition associated with SCD that go on to develop SCD lies between 2-5% rather than 10%. When an ECG screening program is performed in capable hands, we now know that the rate of abnormal ECGs is 3-5%. Considering both a 5% positive ECG rate and 2-5% of individuals with disease experiencing SCD, crude calculations suggest that the cost per diagnosis would be $74,000 and the cost per preventing each theoretical death would be $1.5-3.7M.

Beyond cost implications, the AHA/ACC recognize the need for appropriate medical resources to run an efficient nationwide program in the US. For example, pre-participation cardiac screening typically occurs in the office of a primary care physician or volunteers with varying levels of cardiology exposure. Despite the development of sports cardiology online modules to improve one's understanding of athlete's ECG interpretation, it is likely that individuals not well versed in the nuances of the athlete's ECG may misinterpret findings. This in turn could lead to erroneous diagnoses, unnecessary work-up and anxiety. Even if the correct diagnosis is made, complications can still occur from an elective procedure to treat a disease that may not have clinically manifest as SCD in one's lifetime. While sports cardiologists have anecdotally come across these devastating and tragic cases, the screening ECG has also identified disease where appropriate treatment may have subsequently prevented SCD, particularly in LQTS. We are yet unsure which of these anecdotes garners more media attention.

Conclusion

Following the publication of the PPE guidelines over ten years ago, the issue of whether to use an ECG as part of the PPE continues to be fiercely debated. Those who support the use of an ECG in the PPE unequivocally emphasize increases in the diagnostic yield of conditions associated with SCD. This, together with the near three-fold reduction in the rate of abnormal ECGs forms the central thesis for the implementation of an ECG screening program.²² Conversely, those opposing the incorporation of an ECG in the PPE have legitimate concerns regarding the significant resource allocation required for its implementation, its false positive and negative rate, and with the uncertainties surrounding risk modification in an asymptomatic athlete without a family history of disease.

Yet, we should base our decisions on Bayes' theorem and be conscious of our own biases when contemplating new information gathered from a screening ECG. While the relative risk of SCD in asymptomatic athletes diagnosed with cardiac disease is higher than the general population, when taken together with the a priori risk of SCD in an athlete, the absolute risk of SCD in these individuals remains low. To date, there are no randomized data to clearly show the efficacy of ECG screening in athletes to prevent SCD due to difficulties in achieving adequate power and resource implications of long-term follow-up. Designing such a study would inevitably require a robust collaboration among various stakeholders, including a possible joint partnership between American and European experts. In the meantime, however, we may have to look to the best available evidence to inform our decision-making for future healthcare policies.

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Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Sports and Exercise Cardiology, Vascular Medicine, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Quality Improvement, Novel Agents, Echocardiography/Ultrasound, Sports and Exercise and Congenital Heart Disease and Pediatric Cardiology, Sports and Exercise and Imaging

Keywords: Athletes, Sports, Adaptation, Physiological, Aneurysm, Anxiety, American Heart Association, Arrhythmogenic Right Ventricular Dysplasia, Autopsy, Cardiomyopathy, Hypertrophic, Cicatrix, Defibrillators, Defibrillators, Implantable, Death, Sudden, Cardiac, Echocardiography, Electrocardiography, Hypertrophy, Left Ventricular, Genetic Testing, Gadolinium, Consensus, Long QT Syndrome, Out-of-Hospital Cardiac Arrest, Incidence, Midazolam, Parkinson Disease, Physicians, Primary Care, Prevalence, Prospective Studies, Reproducibility of Results, Registries, Physical Examination, Risk Factors, Penetrance, Retrospective Studies, Syncope, Wolff-Parkinson-White Syndrome

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