Syncope in Athletes: A Prelude to Sudden Cardiac Death?

Introduction

Sudden cardiac death in an athlete is a rare, tragic, and seemingly unpredictable event. However, many patients who have survived sudden cardiac arrest recall warning symptoms, including syncope, in the weeks prior to event.¹ In addition, in patients with implantable defibrillators (ICD) who have experienced an appropriate shock, ventricular ectopy often occurs in the 30 days prior to ICD discharge.² These data suggest that sudden cardiac death might be heralded by cardiac symptoms, including syncope.

Consequently, the evaluation of syncope assumes extreme importance, particularly if these underlying cardiac conditions are present.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden death in athletes, accounting for approximately 20% of cases.³ HCM is characterized by marked left ventricular hypertrophy, usually in an asymmetric pattern, and often involving the basal interventricular septum. The asymmetric hypertrophy results in left ventricular outflow obstruction in about one-third of cases with a characteristic systolic murmur along the lower left sternal border. Another third of patients have what is called a provokable gradient detected after the administration of an inotropic agent. Some forms of HCM are not associated with obstruction which may limit the sensitivity of physical examination in diagnosing HCM.

More than 11 causative genes have been identified which encode a variety of sarcomere proteins in HCM. Abnormal sarcomere development results in disordered alignment of myocardial fibers, interstitial collagen deposition and eventual cardiac fibrosis, thought to be related to coronary microvascular-mediated flow dysfunction and ischemia. This abnormal cardiac architecture is a substrate for ventricular arrhythmias.

Approximately 60% of patients with HCM have a familial component, usually inherited in an autosomal dominant fashion. Consequently, a family history of sudden death in a first degree relative assumes importance in the evaluation of the athlete. Most patients with inherited HCM demonstrate left ventricular hypertrophy by early adulthood.⁴ However, some individuals have a delayed phenotypic expression. Hence, a normal physical examination and echocardiogram cannot rule out the possibility of developing HCM in the future.⁵

Physiological changes in an athlete’s heart include left ventricular hypertrophy that can be confused with pathological changes in HCM. Asymmetric increase in left ventricular wall thickness more than 12mm, decreased LV cavity, diastolic filling patterns, and cardiac MRI demonstrating delayed gadolinium enhancement are features less characteristic of athletic training and more likely to represent HCM.⁶

Syncope in an athlete with HCM might be due to vasovagal syncope or due to left ventricular outflow tract (LVOT) obstruction. However, in HCM neither vasovagal syncope nor a basal LVOT gradient (>30mmHg) is associated with sudden death.⁸ Although the presence of a left ventricular gradient is not considered to be a major risk factor for sudden cardiac death, it might be a target for pharmacologic modulation. Similarly, the development of hypotension during exercise might provide important clues for therapy in the athlete who experiences syncope with exertion.

A second cause of syncope in the athlete with HCM is atrial arrhythmias. Because of diastolic stiffness due to ventricular hypertrophy, patients with HCM rely on the atrial contribution to ventricular filling and atrial arrhythmias can be associated with syncope in HCM.⁹ Asystole and heart block have also been reported with HCM,¹⁰ but would be less likely in a young athlete.

Finally, syncope in a patient with HCM might be due to ventricular arrhythmias which could be a precursor to sudden death. A risk factor for sudden death in HCM include multiple and prolonged episodes of ventricular tachycardia on ECG monitoring. Other major risk factors include extreme septal thickness, or HCM-related sudden death in a first degree relative. Newer risk factors include the presence of a left ventricular apical aneurysm or extensive fibrosis seen with late gadolinium enhancement on MRI. In the presence of these risk factors, an implantable defibrillator (ICD) may be placed in the athlete with HCM which has implications for the athlete’s continued participation in sports.

The previous guidelines restricted competitive sports for persons with HCM to low intensity sports such as golf and bowling.¹¹ There were concerns that most sudden death in young athletes occurred with exertion¹² and were likely due to ventricular arrhythmias. If an ICD was implanted, shouldn’t the ICD eliminate concerns about sudden death?

Previous guidelines discouraged the implantation of an ICD in an athlete with HCM for the sole purpose of permitting high intensity sports participation.¹¹ There were several reasons for this. ICDs were implanted and tested for efficacy during the resting state. Would ICDs successfully defibrillate athletes during athletic participation with high catecholamine levels and other physiologic changes? Could there be injury as a result of a ventricular arrhythmia occurring during sports participation? There were also concerns about inappropriate shocks. Finally, could there be damage to the ICD during the physical contact of sports?

An International Registry of athletes with implantable defibrillators has revisited the question of athletic participation in patients with ICDs for HCM as well as other cardiac conditions. The Registry sampled athletes with ICDs who participated in high intensity sports. No deaths, no resuscitated arrests, and no shock-related injuries were noted in a median follow-up of 44 months.¹³ In part because of this data, many clinicians are allowing athletes with ICDs to participate in competitive athletics. A few medical and legal issues have been raised, trying to balance the desire of the athlete with the medical teams who want safety in sports participation.¹⁴

An important aspect of the use of ICD in athletes is appropriate programming. ICDs are programmed to provide protective shocks if a certain rate is achieved. Athletes often achieve extremely high heart rates which might result in an inappropriate shock. Programming ICD to higher rates to specifically detect ventricular arrhythmias, is one way to avoid inappropriate shocks. In addition, exercise often results in T wave changes which might be “double counted” by the device which results in an inappropriate shock. Adjustment of sensing algorithms can be effective in eliminating inappropriate shocks.

Myocarditis

Myocarditis is an inflammatory disease of the myocardium characterized by inflammatory infiltrates with necrosis of nearby myocytes.¹⁵ The types of cellular infiltrates seen (lymphocytes vs eosinophils) might suggest a particular etiology and help guide management.

The incidence of myocarditis has been reported to be 1–10/100,000. However, since the COVID pandemic, with the recognition of COVID-associated myocarditis, the incidence of myocarditis has increased to 20–64/100,000.¹⁶

Myocarditis can lead to cardiac arrhythmias and is associated with sudden cardiac death. In autopsy studies in young persons (<35 years) who died suddenly, myocarditis was reported to be found in 10% of the sample size.¹⁷ In athletes, the Expert Panel from the National Center for Catastrophic Injury Research reported the incidence of myocarditis in athletes to be 4%.¹⁸ The first manifestation of myocarditis might be sudden cardiac death which is often related to activity.

The gold standard for diagnosis of myocarditis has been an endomyocardial biopsy.¹⁹ However, it is an invasive procedure with significant risks. Further, there is a need for expertise in performing and interpreting the biopsy. Hence, the frequency with which this test is performed varies between institutions.

Advances in cardiac imaging have changed the standard of care in diagnosing myocarditis. Cardiac MRI, with the use of gadolinium enhancement, is a valuable tool to detect areas of cardiac dysfunction, hyperemia and edema, and excess extracellular volume. With updated criteria,²⁰ the sensitivity and specificity for the diagnosis of myocarditis has been reported to be 88% and 96% respectively.²¹ A cardiac MRI has the highest sensitivity if performed two to three weeks after initial presentation and can be repeated in six to 12 months to determine the presence of myocardial scar—an important predictor of cardiac mortality.²² However, some MRI-detected scars in athletes might be a normal finding²³ and careful interpretation of imaging studies along with good clinical judgement is required for accurate diagnosis.

Early in the COVID pandemic there were reports linking COVID with myocarditis. Because of this association, major collegiate conferences mandated that all athletes who contracted COVID be screened with high sensitivity troponin, ECG, and echocardiography. As it turns out, the frequency of myocarditis with COVID is low. Professional and collegiate registries showed the prevalence of myocarditis in athletes with COVID to range from 0.4% to 2%.²⁴ Importantly, no adverse cardiac effects were noted in these registries.

With these data, the evaluation of the athlete who contacts COVID has evolved. After a period of self-isolation, an asymptomatic patient with a new diagnosis of COVID may resume training after three days of rest. Those with mild to moderate cardiac symptoms should refrain from exercise until resolution of symptoms. Athletes with a remote history of infection (>3 months) and who are asymptomatic can exercise. For patients with acute COVID infections who have severe cardiovascular symptoms or who are hospitalized, especially those with troponin elevation, an abnormal ECG, or an abnormal echo, a cardiac MRI is recommended. Those with confirmed myocarditis should not return to competition for three to six months and then should have a gradual return to exercise.²⁴

The management and return to play recommendations for athletes who have recovered from COVID with mild symptoms, but have persistently elevated high sensitivity troponin, a low normal function on echo, or persistent scar or edema on follow-up MRI, is not clear.²⁵ These athletes might be at higher risk for sudden death; hence, accelerated monitoring or periodic exercise ECGs seems to be the reasonable thing to do as we wait for more long-term data on such individuals.

Arrhythmogenic Right Ventricular Dysplastic Syndrome

Arrhythmogenic Right Ventricular Dysplastic Syndrome (ARVD) is an inherited cardiomyopathy, characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. In the general population, the prevalence of ARVD is 1 per 1000 to 1 per 10,000 persons, with a high prevalence in Italy.²⁶ An autopsy study from Italy described the condition to be present in as high as 20% of deaths in young people, often occurring with exertion,²⁷ while a subsequent study in the United States showed fewer sudden cardiac death due to ARVD in competitive athletes²⁸. Current estimates suggest that ARVD accounts for about 6% of sudden deaths in athletes.²⁹

ARVD is due to mutations in genes which encode for desmosomal proteins which play an important role in adhesion between cells. After premature cell death, fatty deposits replace myocardial cells, and eventually fibrosis occurs. This remodeling is thought to potentially cause fatal arrhythmias, which can be aggravated by increasing pressure, afterload conditions and wall stress as in physical exertion. Hence, ARVD can present at an earlier age in a young athlete. About half the cases of ARVD are familial, inherited with an autosomal recessive pattern.

ARVD first manifests itself in the right ventricle although with advanced disease, involvement of the left ventricle is not uncommon.³⁰ Because the RV is involved early, athletes who have syncope and who have ECG findings of RV abnormalities such as diffuse T wave inversion in the anterior precordium, or terminal QRS notching in ECG lead V1, or who have PVCs or ventricular tachycardia with a left bundle configuration, might have ARVD. The sensitivity and specificity of standard screening tests including ECG and echo are relatively low and other imaging modalities are often required to make the diagnosis. Cardiac MRI is currently the preferred method. It can identify fibrofatty myocardial scarring in the RV free wall using late gadolinium enhancement. Other conditions that need to be differentiated from ARVD include sarcoidosis and congenital disease causing right ventricular volume overload.³⁰

Exercise is associated with sustained ventricular arrhythmias^32,33 and may lead to premature cardiac dysfunction in ARVD. For patients with borderline or definitive diagnosis of ARVD, AHA/ACC guidelines from 2015 recommend restriction from competitive sports.¹¹ More recent studies have suggested that some physical activity in patients with ARVD is acceptable. Patients with ARVD can exercise at up to two to four times the AHA recommendation for healthy adults without excess risk for cardiac arrhythmias.³⁴ A prior history of sudden cardiac arrest, sustained VT or syncope appear to be most important prognostic factors and are indications for ICD placement.³⁰

Coronary Artery Anomalies

Coronary artery anomalies refer to a heterogenous group of conditions that include an abnormal origin or course of any of the three epicardial coronary arteries. The prevalence of coronary anomalies is 1% to 8%.^35–38 It is the second most common cause of sudden cardiac death noted in athletes after HCM³⁹ accounting for 12–14% of cases.^29,39

Many coronary anomalies have a benign course. However, when the course of a coronary artery is between the aorta and pulmonary artery, compression of the coronary artery occurs and increases the risk of sudden death. Other high-risk features include fish mouth or slit like shaped orifice, acute angle take off, intramural course or proximal narrowing. The origin of a coronary artery from the pulmonary artery (ALCAPA) is another form of congenital disorder that is associated with high mortality.³⁷

Unfortunately, conventional cardiac testing is often insensitive in detecting these congenital abnormalities. While the transthoracic echo can view the origin and proximal course of coronary arteries, this requires good expertise on the part of the sonographer and seems to be of more value in children than adults. In a review of 27 sudden deaths in young athletes who were found to have an abnormal origin of either the left or right coronary artery, 15 had no cardiovascular manifestations or testing prior to the event. However, 12 had syncope or chest pain prior to death. All cardiac tests including ECG, stress test, and echo were normal.⁴⁰ Hence, special vigilance is required in the type of testing for the athlete with syncope. Coronary CTA has become the first-line imaging modality to visualize the origin and full course of coronary arteries, including the relationship with other major blood vessels. Younger athletes with high-risk features are often restricted from high intensity athletic competition without surgical correction.⁴¹ Asymptomatic athletes with low-risk features and no evidence of ischemia can return to athletic competition, with close surveillance.⁴¹

Other coronary artery anomalies include myocardial bridges and coronary artery aneurysms such as those seen with Kawasaki disease.

Long QT Syndrome

Long QT syndrome (LQTS) is an inherited cardiac channelopathy that is associated with sudden cardiac death. The prevalence of LQTS in the general population is about one in 2000⁴² although LQTS accounts for 5.3% of sudden deaths in athletes.²⁹

At least 700 mutations have been identified in 13 genes which encode proteins which are essential in the formation of the cardiac action potential. There are at least 16 clinical forms of LQTS with unique clinical and electrocardiographic features. For example, LQTS-1 patients typically have symptoms which occur with exercise, particularly swimming. The ECG shows a broad-based T wave. Patients with LQTS-2 often have symptoms related to auditory stimulation with notched T waves. LQTS-3 patients usually have symptoms at rest or sleep with a late appearing T wave often with a very long QT interval. Major genes that have been identified and the types of LQTS are KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), accounting for ≈90% of all genotype-positive cases of LQTS.⁴³

In an athlete with syncope, careful attention should be made to analysis of the QT interval. The QT interval is often provided by computer interpreted ECG, but should be measured manually. The QT interval should be corrected for rate (QTc). 99% of males have a QTc interval of < 470ms and 99% of females have a QTc of < 480ms. However, some genetically proven patients with LQTS have relatively normal QTc intervals. In these patients, exercise may, paradoxically, prolong the QTc interval, establishing the diagnosis, especially in LQTS-1. Scoring systems which incorporate the QTc interval as well as clinical and genetic factors can help diagnose LQTS in borderline cases.⁴⁴ Of note, a QTc interval of >500ms correlates with an increased risk of torsade des pointes.

All prescription and over-the-counter medications should be reviewed in athletes with LQTS with strict avoidance of QT prolonging drugs. CredibleMeds is an online resource that maintains and updated list of drugs that have a risk of QT prolongation. Registration to this website is free and this can serve as a great resource for physicians and patients to check medications that may be safe to prescribe in patients with LQTS.

In the past, sports participation for athletes with LQTS, especially those with syncope, was discouraged. Specific recommendations have specified that athletes with LQTS-1 syndrome should not engage in sports that require diving into cold water since this activity was associated with increased cardiac arrhythmias.⁴¹ However, with full consent of the athlete and involvement of coaches and trainers as well as availability of personal external defibrillators, more LQTS athletes are safely returning to play. A 2021 study showed a low rate of non-lethal events in athletes with LQTS over a 20-year follow-up. The minority of these patients (11%) had an ICD.⁴⁵ There are some athletes with syncope and LQTS who might be eligible for an ICD.⁴⁶

Beta blockers are standard therapy in most patients with LQTS. However, beta blockers impair exercise performance. Beta blockers are also banned, with some exceptions, by the World Doping Agency which governs sporting competition around the world. Consequently, beta blocker therapy can be met with resistance from the athlete and a discussion of the risk and benefits of the therapy must be made between the health care provider and the athlete.

Pre-Excitation Syndrome

Athletes with syncope may have evidence of ventricular pre-excitation on ECG, characterized by a short PR interval and a delta wave in the initial portion of the QRS complex. The ECG abnormality is due to a group of electrical fibers joining the atrium and ventricle, often time capable of extremely rapid conduction. It was first described in 1930 and it was 40 years later that risk of sudden cardiac death from rapid conduction through the accessory pathway was recognized. WPW accounts for about 4% of sudden cardiac arrest in athletes, although it is thought to be underrepresented as it is difficult to diagnose ventricular pre-excitation in postmortem cases with sudden cardiac arrest being the initial presentation.²⁹ The risk of sudden cardiac arrest seems to be highest in males and those younger than 18 years.⁴⁷ Some of the patients experienced sudden cardiac arrest during exercise. Many patients typically have warning symptoms prior to malignant arrhythmia.⁴⁸

Athletes who present with syncope and who have ECG evidence of WPW often undergo electrophysiologic studies with ablation, a highly successful form of therapy.⁴⁸

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a very rare inherited channelopathy characterized by ventricular tachycardia which occurs during exercise or strong emotion. Patients typically have normal resting ECG, a structurally normal heart and a reproducible bidirectional or polymorphic ventricular arrythmia which occurs during stress testing or with emotional stress. There is often a family history of syncope or sudden cardiac death. Mutation in genes encoding for RYR2 or CASQ2 is known to cause CPVT. Therapy includes beta blockers, calcium channel blockers, or flecainide and often an ICD placement or other surgical therapies.⁴⁹ The 2015 AHA guidelines recommend restriction from competitive sports for previously symptomatic CPVT or asymptomatic CPVT,⁵⁰ even though recent smaller studies show no difference in event rates with or without sports participation.⁵¹

Brugada Syndrome

The Brugada syndrome is a rare condition originally described in eight patients with recurrent episodes of sudden death, all with a RBBB and persistent ST segment elevation.⁵² Abnormalities in sodium channels in the right ventricular outflow tract have been identified, hence the typical ECG findings in the right precordial leads. The ECG finding can sometimes be found by moving ECG leads V1 and V2 up one interspace. A genetic form associated with the SCN5A gene has been described with an autosomal dominant pattern of inheritance, but other genes have been identified with Brugada syndrome and their association with cardiac events remain to be determined. Some cases seem to be acquired. Known factors which magnify the ECG abnormality are certain drugs and fever. The annual incidence of cardiac arrest is estimated to be 0.5% in patients without an ICD.

Most individuals with Brugada syndrome remain asymptomatic throughout their lives and the majority of events occur at rest, sleep or during fever. Sports participation in asymptomatic patients with Brugada syndrome could be allowed after full discussion with the patient and physician. The exception might be those sports associated with an increase in core temperature, like endurance sports under hot conditions.⁴¹

Coronary Artery Disease

Coronary artery disease should also be in the differential diagnosis in athletes presenting with syncope, especially syncope with exertion, and especially if above the age of 40 years or in athletes with a family history of premature CAD or familial hypercholesterolemia. Other risk factors include history of smoking, male sex and hypercholesterolemia. An important part of the evaluation of exertional syncope includes exercise stress testing, typically with imaging to improve on the detection of cardiac ischemia. Other causes for exertional syncope might include cardiac arrhythmias or a drop in blood pressure which might indicate cardiac dysfunction. CCTA also plays an important role in diagnosis and if needed coronary angiography. If inducible myocardial ischemia is identified, coronary angiography and PCI if indicated should be considered. Sports restriction post PCI or after acute coronary syndrome is recommended at least for the first three months. During this time graduated exercise schedule in the setting of structured cardiac rehabilitation program plays an important role in safe return to previous levels of exercise. After three months, consideration of exercise stress test prior to returning to high intensity sports competitions is advised. Close monitoring for symptoms during exercise, periodic assessment with imaging is needed to prevent any further events in addition to compliance with medications. For patients post PCI on dual anti-platelet, restriction of contact sports may be needed to prevent any major bleeding.⁵³

Conclusion

Syncope in an athlete is challenging to manage and it requires understanding of normal physiological changes that occur with physical training. Even though vasovagal syncope is the most common cause of syncope in this population, other cardiac abnormalities that can present with syncope need to be ruled out.

Timely identification and management of exertional syncope due to cardiac conditions plays a vital role in prevention of sudden cardiac arrest in athletes. Often, primary providers are the first physician contact for evaluation of syncope and they play an important role in risk stratifying and sending cardiology referral if needed.