Implications of SARS-CoV-2-Associated Myocarditis in the Medical Evaluation of Athletes

Abstract

Context:

Myocarditis is a known cause of death in athletes. As we consider clearance of athletes to participate in sports during the COVID-19 pandemic, we offer a brief review of the myocardial effects of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) through the lens of what is known about myocarditis and exercise. All athletes should be queried about any recent illness suspicious for COVID-19 prior to sports participation.

Evidence Acquisition:

The PubMed database was evaluated through 2020, with the following keywords: myocarditis, COVID-19, SARS-CoV-2, cardiac, and athletes. Selected articles identified through the primary search, along with position statements from around the world, and the relevant references from those articles, were reviewed for pertinent clinical information regarding the identification, evaluation, risk stratification, and management of myocarditis in patients, including athletes, with and without SARS-CoV-2.

Study Design:

Systematic review.

Level of Evidence:

Level 3.

Results:

Since myocarditis can present with a variety of symptoms, and can be asymptomatic, the sports medicine physician needs to have a heightened awareness of athletes who may have had COVID-19 and be at risk for myocarditis and should have a low threshold to obtain further cardiovascular testing. Symptomatic athletes with SARS-CoV-2 may require cardiac evaluation including an electrocardiogram and possibly an echocardiogram. Athletes with cardiomyopathy may benefit from cardiac magnetic resonance imaging in the recovery phase and, rarely, endocardial biopsy.

Conclusion:

Myocarditis is a known cause of sudden cardiac death in athletes. The currently reported rates of cardiac involvement of COVID-19 makes myocarditis a risk, and physicians who clear athletes for participation in sport as well as sideline personnel should be versed with the diagnosis, management, and clearance of athletes with suspected myocarditis. Given the potentially increased risk of arrhythmias, sideline personnel should practice their emergency action plans and be comfortable using an automated external defibrillator.

The novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2), has characteristics that have influenced the practice of sports medicine, including the return of athletes to sports participation. Of patients hospitalized with COVID-19, the disease caused by SARS-CoV-2, 10% to 27.8% have evidence of myocardial injury with mortality as high as 69.4%.¹⁶ Even after recovery clinically, patients are found to have abnormal cardiac magnetic resonance imaging (MRI). These abnormalities include water sensitive sequences (up to 54%) and late gadolinium enhancement (31%), which is used to detect scar formation.¹⁹ Arrhythmia is a known clinical phenotype of COVID-19, with palpitations reported in about 7% of patients²⁸ with ventricular arrhythmias seen up to 78% of patients with myocarditis.³⁹ Because the risks of arrhythmias during active SARS-CoV-2 infection are not known, both screening for COVID-19 before and during the athletic season, especially in symptomatic athletes, seem reasonable.

To date, those less than 18 years old account for less than 5% of diagnosed cases of COVID-19 with 27% of the cases in those 10 to 14 years old and 32% in those 15 to 17 years old.^6,31 This is subject to significant bias since testing priorities have evolved and focus on hospitalized patients and those at the highest risk for complications.²³ While community testing is available, those who live in urban and suburban areas have had more access to it. Numerous studies document disproportionate rates of infection among racial and ethnic minority groups, raising concern for the safety of those with poor access to medical care. Besides commercially available polymerase chain reaction (PCR) tests, the US Food and Drug Administration also allows each state to authorize laboratories to test for SARS-CoV-2. The tests have a reported sensitivity of just 70% early in the disease⁴³ and with reported false negative rates between less than 5% and 40%,^29,53 highlighting that the results of molecular testing by PCR do not identify all infected patients.^27,43,53 Furthermore, the detection of viral RNA using PCR is dependent on the location of sample collection, with the largest viral concentration found in the nasopharynx, when compared with the saliva or blood. Serological tests that identify antibodies may document prior exposure; however, little is known about the sensitivity and the specificity of the various serological tests available,⁵¹ and it is unknown if prior exposure confers immunity.³ Recent studies show that antibody levels are positive in symptomatic individuals by days 11 to 24.^27,56 Asymptomatic or mildly symptomatic individuals may be less likely to develop detectable antibodies,⁵⁴ which have a half-life of about 36 days.^20,30 Antibody levels fall, sometimes dramatically after infection, and up to 40% of asymptomatic patients test negative for antibodies at 8 weeks.³⁰

Infected children typically report less severe symptoms, and when they do report symptoms, the most common are fever (35%), cough (41%), and myalgia (30%).^6,48 The rate of cardiac involvement in infected children who are not hospitalized, or among those who are not tested or diagnosed with COVID-19, is unknown at this time. However, the appearance of myocardial damage in the young can be abrupt and without respiratory symptoms and can result in cardiac dysfunction, arrhythmias, and even death.^13,37 Injury in the young seems to be related to viral infiltration,^7,22,42 resulting in myocarditis and reduced systolic function. A resultant systemic cytokine release leads to inflammation, necrosis, and cardiomyopathy.¹ Autopsies of select patients with COVID-19 infection have revealed infiltration of the myocardium by interstitial mononuclear inflammatory cells,^44,55 and cardiac biopsies in patients diagnosed with myocarditis have found that the virus affects macrophages and cardiac myocytes.¹⁷

In previous reports of idiopathic or viral myocarditis, the risk of arrhythmias and sudden death did not correlate with the degree of myocardial inflammation.^{5,9,15,21,26,52} Myocarditis accounts for 5% to 22%^10,11,32,33 of sudden cardiac deaths in athletes younger than 35 years, with an increased incidence during exercise,^11,32 which has been shown to aggravate myocarditis.¹⁵ Unfortunately, death can occur without any preceding symptoms.¹²

Myocarditis was the most common cause of sudden cardiac death among US Air Force recruits during a 20-year period,⁴⁰ with the most common etiology of myocarditis being a viral infection.¹⁴ Before the COVID-19 pandemic, 1% to 5% of acute viral infections involved the myocardium,²⁴ but in patients who recovered from COVID-19, 78% had abnormal findings on cardiac MRI with 60% showing cardiac inflammation, independent of preexisting conditions.^41,46 The relevance of these prior reports to the present pandemic is not yet known. The rate of myocarditis seems to be lower in SARS-CoV-2 than in Coxsackie viral infection.¹⁸

Diagnosis and Management during the Acute Sars-Cov-2 Exposure

There are 3 phases of myocarditis that overlap, each with its own risk of death: the active inflammatory phase of the infection, the body’s response to the infection, and the resulting scar tissue and/or cardiomyopathy that is present after the infection and inflammation have resolved.⁸

During the active phase of infection, patients with myocarditis can present within a broad range of symptoms, including chest pain, exertional dyspnea and fatigue, exercise intolerance, overtly decompensated heart failure, and/or cardiogenic shock.⁴ However, observational studies of sudden cardiac deaths in the pre-COVID-19 era shows that many patients did not endorse symptoms and were discovered to have myocarditis on autopsy.¹³ The initial electrocardiogram (ECG), which often remains a firstline test in patients in whom myocarditis is suspected, can also show variable and nonspecific findings, including ST segment deviations, ectopy, conduction abnormalities, sustained arrhythmias, or low voltages. However, these ECG changes are found only 47% of the time.⁸

In patients in whom myocarditis is considered, the American Heart Association (AHA) scientific statement on the management of cardiomyopathies² recommends cardiac imaging, such as echocardiogram or cardiac MRI. Transthoracic echocardiography may show increased wall thickness, global left ventricular dysfunction, or localized wall motion abnormalities with a pericardial effusion. Diagnostic cardiac MRI findings include edema, irreversible cell injury and capillary leak or hyperemia.⁴⁷ The gold standard means to establish a diagnosis of myocarditis is an endomyocardial biopsy; however, this test is limited by inherent risk and low sensitivity, as inflammation is often patchy in distribution and is not recommended in patients infected with SARS-CoV-2.^25,49

Those with a probable or definitive diagnosis of recent myocarditis are restricted from participating in sports because during the acute phase of viral myocarditis, there is an unstable myocardial substrate leading to necrosis, fibrosis, and potentially a pro-arrhythmic myocardium. As MRI does not uniformly detect the resolution of the inflammation, it is recommended that clearance of patients with confirmed myocarditis involve ECG, echocardiogram, and Holter monitoring.³³ In the United States, this clearance occurs no less than 3 to 6 months after the initial diagnosis of myocarditis (Class 1 Level of Evidence C),³⁴ while in Europe, there is a standard 6-month restriction from activity before investigation is commenced to assess for resolution of inflammation.³⁸

The cardiomyopathy and pro-arrhythmic potential of the myocardium may last from 6 to 12 months postinfection.³⁹ While the literature is limited regarding the consequences of scar formation in athletes, one study using cardiac MRI with late gadolinium enhancement (LGE) showed that in 27 athletes with stria pattern of scarring on the lateral wall of the left ventricle, 6 had malignant arrhythmias within 38 months,⁵⁷ with 5 of the 6 events occurring during exercise. These findings were reproduced in another study that prospectively followed 7 athletes with lateral wall LGE over 3 years, where again, 6 of 7 athletes experienced ventricular arrhythmias or progressive left ventricular dysfunction that led to withdrawal from participation in competitive sports.^{45 These findings on MRI were not confirmed to be myocarditis by endomyocardial biopsy and their relevance to the MRI features seen after recovery from COVID-19 remain uncertain.}

The long-term consequences of myocarditis due to SARS-CoV-2 are unknown. Until we know the unique characteristics of SARS-CoV-2 on cardiac muscle, previous studies of viral myocarditis cannot be translated to patients during the current pandemic.⁵⁰ Autopsy studies of elderly patients found cardiac histopathological findings are common, while myocarditis is rare.¹⁹ In the absence of COVID-19 specific clinical data, it is reasonable to consider screening for cardiac dysfunction in patients who recover from COVID-19, especially those who exhibit near syncope, exercise intolerance, or palpitations.³⁵ A prospective study investigating the outcomes of asymptomatic patients with confirmed myocarditis (history including chest pain, palpitations, or dyspnea; elevated high-sensitivity troponin, angiographic exclusion of obstructive coronary artery disease >50% stenosis, and characteristic findings on cardiac MRI) after return to sporting activities found that patients who were restricted from activity for 3 months did not demonstrate any new cardiac events or worsening left ventricular function. During this period of exercise restriction, 1 of the 30 patients did have an episode of nonsustained ventricular tachycardia.³⁶ The potential for arrhythmias in the exercising athlete due to myocarditis stresses the importance of clinicians and sideline personnel to be well-versed with their emergency action plan and to regularly practice using the automated external defibrillator.

As research regarding the cardiac effects of SARS-CoV-2 is rapidly growing, many groups have been created to help safely return the athlete to competitive sport. Given the lack of objective markers of myocarditis, it is prudent that those involved with clearing athletes maintain a high index of suspicion. We highlight some areas where further research can help guide recommendations, and until these are further investigated, a conservative protocol as outlined to return athletes to play is encouraged.