Screening of Potential Cardiac Involvement in Competitive Athletes Recovering From COVID-19

As our understanding of the complications of coronavirus disease-2019 (COVID-19) evolve, subclinical cardiac pathology such as myocarditis, pericarditis, and right ventricular dysfunction in the absence of significant clinical symptoms represents a concern. The potential implications of these findings in athletes are significant given the concern that exercise, during the acute phase of viral myocarditis, may exacerbate myocardial injury and precipitate malignant ventricular arrhythmias. Such concerns have led to the development and publication of expert consensus documents aimed at providing guidance for the evaluation of athletes after contracting COVID-19 in order to permit safe return to play.Cardiac imaging is at the center of these evaluations. This review seeks to evaluate the current evidence regarding COVID-19-associated cardiovascular disease and how multimodality imaging may be useful in the screening and clinical evaluation of athletes with suspected cardiovascular complications of infection. Guidance is provided with diagnostic "red flags" that raise the suspicion of pathology. Specific emphasis is placed on the unique challenges posed in distinguishing athletic cardiac remodeling from subclinical cardiac disease. The strengths and limitations of different imaging modalities are discussed and an approach to return to play decision making for athletes post-COVID-19, as informed by multimodality imaging, is provided. (J Am Coll Cardiol Img 2020;13:2635-52) CMR = cardiac magnetic resonance CTA = computed tomography angiography cTn = cardiac troponin CV = cardiovascular COVID-2019 = coronavirus disease-2019 ECG = electrocardiogram ECV = extracellular volume EF = ejection fraction EICR = exercise-induced cardiac remodeling GLS = global longitudinal strain hs-cTn = high-sensitivity cardiac troponin LGE = late gadolinium enhancement LV = left ventricle/ventricular POCUS = point-of-care ultrasound PET = positron emission tomography RTP = return to play RV = right ventricle/ventricular TTE = transthoracic echocardiography Phelan et al.
infected athletes [bib_ref] Return to sports after COVID-19 infection, Schellhorn [/bib_ref] [bib_ref] Resurgence of sport in the wake of COVID-19: cardiac considerations in competitive..., Baggish [/bib_ref]. Lately, as schools, colleges, and professional organizations seek to restart competitive sports, there has been renewed focus on the potential cardiac risk to recovered athletes. This has been due, in part, to the public acknowledgment of COVID-19-induced cardiac injury in some high-profile athletes and newer data suggesting higher than expected incidences of myocardial inflammation in recovered nonathletic and athletic populations.
Myocardial injury, defined as a cardiac troponin (cTn) level greater than the 99th percentile upper reference limit, has been reported frequently in hospitalized patients with COVID-19 and is associated with progressive heart failure, arrhythmia, and death [bib_ref] Cardiac troponin for the diagnosis and risk-stratification of myocardial injury in COVID-19:..., Sandoval [/bib_ref]. There are multiple mechanisms of myocardial injury including direct myocardial invasion by the virus resulting in myocarditis [bib_ref] COVID-19 for the cardiologist: a current review of the virology, clinical epidemiology,..., Atri [/bib_ref]. Prior to the COVID-19 pandemic, myocarditis accounted for 7% to 20% of sudden cardiac death in young athletes [bib_ref] Demographics and epidemiology of sudden deaths in young competitive athletes: from the..., Maron [/bib_ref]. At present, data on the prevalence of myocardial injury, pericarditis, or myocarditis in athletes recovering from COVID-19 are limited to very small observational case series [bib_ref] Cardiac magnetic resonance findings in patients recovered from COVID-19: initial experiences in..., Vago [/bib_ref] [bib_ref] High prevalence of pericardial involvement in college student-athletes recovering from COVID-19, Brito [/bib_ref].
Athletes recovering from COVID-19 present some unique challenges. There is concern that exercise during the acute phase of viral myocarditis may exacerbate or prolong the illness or serve as a trigger for serious arrhythmias [bib_ref] Recommendations for participation in competitive and leisure time sport in athletes with..., Pelliccia [/bib_ref] [bib_ref] Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force..., Maron [/bib_ref] [bib_ref] Coxsackievirus B3 myocarditis in C3H/ HeJ mice: description of an inbred model..., Kiel [/bib_ref]. Furthermore, the diagnosis of acute myocarditis or subsequent pathological remodeling can be difficult to differentiate from the physiological exercise-induced cardiac remodeling commonly seen as part of the healthy "athletes'
heart" phenotype. This challenge requires specific knowledge of contemporary multimodality imaging in the athletic context.
The aims of this expert consensus document are to:
Define the potential latent cardiac complications of COVID-19 infection and how these are relevant for the athlete.
Provide guidance on how to differentiate potential COVID-19-related cardiac complications from athletes' heart.
Identify "red flags" in the clinical evaluation of athletes that require further testing and provide guidance on appropriate downstream imaging.
Define the utility and limitations in the various imaging modalities to assess for COVID-19-related cardiac complications (Central Illustration).

# Covid-19-related myocardial injury
Transmitted primarily via droplets but also probably aerosols, severe acute respiratory syndrome coronavirus 2 virus enters the body via human angiotensinconverting enzyme 2, a receptor expressed not only in the lungs but also in the myocardium and throughout the cardiovascular (CV) system [bib_ref] COVID-19 for the cardiologist: a current review of the virology, clinical epidemiology,..., Atri [/bib_ref]. Up to onequarter of hospitalized patients with COVID-19 exhibit myocardial injury with some developing significant cardiac complications, including biventricular heart failure, arrhythmias, and occasionally cardiogenic shock and death [bib_ref] Cardiovascular considerations for patients, health care workers, and health systems during the..., Driggin [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. A multifactorial mechanism is likely, including cytokine-mediated cardiomyopathy, endothelial inflammation and microemboli, acute coronary events, pulmonary emboli, right ventricular (RV) strain, and myocarditis [bib_ref] COVID-19 for the cardiologist: a current review of the virology, clinical epidemiology,..., Atri [/bib_ref]. Recent data from Linder et al. [bib_ref] Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases, Lindner [/bib_ref] there is concern that significant subclinical myocardial injury may be prevalent and that this may manifest as protracted malaise or, more concerningly, may represent a substrate for arrhythmias and sudden death . These concerns have guided the CV RTP recommendations in athletes who have recovered from COVID-19 [bib_ref] Return to sports after COVID-19 infection, Schellhorn [/bib_ref] [bib_ref] Cardiorespiratory considerations for return to play in elite athletes after COVID-19 infection:..., Wilson [/bib_ref].

## Current screening strategies in athletes after covid-19
Pre-participation physical evaluation is routinely practiced in many places throughout the world, but the ECG also shows diffuse ST-segment elevation (blue arrows) and also subtle PR depression (red arrow). COVID-19 14 coronavirus disease-2019. basis of minor deviations from "normal." Although multimodality clinical assessments may lead to appropriate outcomes in difficult cases, it is also essential for practitioners to appreciate the potential deleterious effects of undue, unnecessary, and excessive testing of athletes. It is important to consider that a screening program that might be the ideal fit for one group (e.g., a professional league) may be quite poorly designed for others (e.g., clublevel sport, masters athletes). The optimal screening algorithm will take consideration of the specific risk of the population to be screened, local expertise, and available resources.
Key points:
ECG is a useful adjunct in the RTP algorithm, but in isolation it lacks sensitivity for myocarditis.
Troponin assays lack standardization in athletes but are recommended as part of the RTP risk stratification algorithm. Remain cautious of unnecessary testing and appreciate that screening protocols may vary according to athletic discipline and setting.

## Imaging athletes' hearts and

## Covid-19 considerations
Intensive exercise is associated with the generation of a 5-to 6-fold increase in cardiac output that is achieved via augmentation of stroke volume through a combination of increased venous return to the ventricles, rapid ventricular filling, and a marked reduc- cavity dimensions between 60 and 70 mm [bib_ref] Physiologic left ventricular cavity dilatation in elite athletes, Pelliccia [/bib_ref]. In a small proportion of ostensibly healthy male elite endurance athletes, markedly enlarged LV volumes and mildly reduced EFs have been observed.
This is particularly relevant for post-COVID assessments when similar changes would raise concern of active or recovering myocarditis [fig_ref] FIGURE 2: Challenges year-old male elite rower presented with 3 months of exercise intolerance... [/fig_ref]. Other than elite endurance athletes, it is rare to see a reduction in EF [bib_ref] Recommendations on the use of multimodality cardiovascular imaging in young adult competitive..., Baggish [/bib_ref] [bib_ref] Systematic review and meta-analysis of training mode, imaging modality and body size..., Utomi [/bib_ref] such that an EF <50% should raise the possibility of pathology and trigger further evaluation. It may also be useful to use exercise as a means of discrimination in ambiguous cases after active myocarditis has been ruled out by other means.
Healthy athletes demonstrate good myocardial con- [bib_ref] Recommendations on the use of multimodality cardiovascular imaging in young adult competitive..., Baggish [/bib_ref]. GLS is dependent on multiple factors, including image quality, and an isolated abnormal result should result in reviewing the primary data to ensure accuracy and integration of the echocardiographic data before proceeding with additional confirmatory tests.
A value worse than -16% should raise concern for myocardial pathology. [bib_ref] Atrial enlargement in the athlete's heart: assessment of atrial function may help..., D&apos;ascenzi [/bib_ref]. In athletes, reduced reservoir function is unusual and pathology should be considered.
Key points:
Myocarditis can cause regional wall motion abnormalities, global LV systolic dysfunction, isolated diastolic dysfunction, and regional increased wall thickness due to edema. short-axis views, respectively [bib_ref] Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes, Gerche [/bib_ref] [bib_ref] Echocardiographic tissue deformation imaging of right ventricular systolic function in endurance athletes, Teske [/bib_ref] [bib_ref] Clinical differentiation between physiological remodeling and arrhythmogenic right ventricular cardiomyopathy in athletes..., Zaidi [/bib_ref]. See [fig_ref] TABLE 1: Comparison of Typical Athletic Remodeling Versus "Red Flag" Findings That Increase Suspicion... [/fig_ref] for suggested red flags to be considered in clinical decision making. Substantial challenges in recognizing subtle pathology remain. In cases in which uncertainty persists, CMR is an appropriate next step to assist with more accurate quantification of volumes, assessment of regional abnormalities, and tissue characterization.
Although assessment of enhancement of the thin RV wall is not a reliable estimation, abnormalities in the LV myocardium can assist in the clinical and risk assessment. A complementary strategy is to employ advanced echocardiographic techniques, such as exercise imaging. Given the disproportionate increase in RV work during exercise (relative to LV work), exercise testing may elucidate subtle abnormalities but should only be done after active myocarditis has been ruled out [bib_ref] Right ventricular strain rate during exercise accurately identifies male athletes with right..., Claeys [/bib_ref]. An additional technique of novel interest is "mechanical desynchrony," referring to increased temporal spread of peak deformation. In athletic studies, this has been applied not only to the LV, but also more recently to the RV (53).

## Key points:
RV pathology is frequently seen after severe COVID-19 infection.
The RV is load sensitive and EICR can be challenging to differentiate from pathology. [fig_ref] TABLE 2: Indications [/fig_ref].

## Utility, strengths, and limitations of cmr.
CMR is the gold-standard imaging modality for regional and global ventricular function and is uniquely positioned to evaluate ventricular inflammation, edema, and scarring from myocarditis due to Phelan et al. Therefore, nuclear imaging should be reserved for specific scenarios in which first-line imaging is suboptimal or contraindicated. When pursued, PET myocardial perfusion imaging may be preferred over single-photon emission CT due to more rapid acquisition and lower radiation exposure. Furthermore, in a patient with COVID-19 and suspected microvascular ischemia, quantification of myocardial blood flow with PET may aid in the diagnosis [bib_ref] Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC State-of-the-Art Review, Taqueti [/bib_ref]. Finally, 18 Ffluorodeoxyglucose PET is occasionally a useful adjunct for assessing focal myocarditis [bib_ref] Hybrid FDG-PET/MR or FDG-PET/CT to detect disease activity in patients with persisting..., Palmisano [/bib_ref].
Key point:
PET should be considered a second-line investigation in the setting of continued clinical concern when echocardiography and CMR are suboptimal or contraindicated. biomarkers, an echocardiogram, a graded exercise ECG, and a Holter monitor [bib_ref] Recommendations for participation in competitive and leisure time sport in athletes with..., Pelliccia [/bib_ref] [bib_ref] Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force..., Maron [/bib_ref]. The use of serial CMR to evaluate for residual scarring has not been well defined, but as previously discussed, residual

## Rtp considerations for athletes with
LGE after the acute phase of myocarditis may be associated with worse outcomes. The 2019 European recommendations suggest that it is reasonable to participate in competitive sports in the context of normal LV function and in the absence of arrhythmia [bib_ref] Recommendations for participation in competitive and leisure time sport in athletes with..., Pelliccia [/bib_ref]. A shared decision-making strategy should be adopted and at least annual clinical surveillance employed.

## Highlights
COVID-19 may cause potential long-term cardiopulmonary complications in athletes, raising concern regarding RTP.
Exercise induced cardiac remodeling may be misinterpreted as COVID-19-related cardiac injury.
We discuss the strengths and limitations of relevant imaging modalities and an approach to RTP decision making.
Registry data of cardiac testing and outcomes in athletes after COVID-19 are needed to guide future screening strategies.
and to precipitate recurrences [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref]. Athletes with pericarditis should avoid competitive sports during the acute phase. Current recommendations indicate that athletes may return to full activity after normalization of serum inflammatory biomarkers and resolution of any effusion on echocardiography [bib_ref] Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force..., Maron [/bib_ref].
Athletes with concomitant myocardial involvement should follow the recommendations for myocarditis.
RV DYSFUNCTION. The underlying cause of RV dysfunction usually determines RTP recommendations. If the RV dysfunction is due to myocarditis or pulmonary emboli, then the guidelines would be made based on these diagnoses and consequences of treatment (e.g., anticoagulation) on sports participation. An important consideration independent of etiology-based guidelines is that RV dysfunction can be associated with an increased risk of arrhythmias in several conditions, including an association between RV dysfunction and arrhythmias in athletes [bib_ref] The right heart in athletes. Evidence for exercise-induced arrhythmogenic right ventricular cardiomyopathy, Heidbuchel [/bib_ref].
Whether this is relevant to those convalescing from COVID-19 is yet to be determined, but it would seem sensible to exercise caution and be vigilant for palpitations, arrhythmias, and syncope when RV dysfunction is present.

## Future directions
Prospectively collected clinical and imaging data are paramount in order to provide evidenced-based care to those with prior COVID-19 and to determine the safety of return to exercise. Furthermore, the true prevalence of cardiac involvement in athletes with or without COVID-19 symptoms remains unknown.
Developing best management practices and clarifying long-term CV sequelae will not be possible without collection and scrutinization of rigorous and carefully obtained data. Athletic registry data will further define best practices for multimodality imaging in COVID-19 for diagnosis, prognosis, and management.

# Author disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
[fig] FIGURE 1: Challenges With ECG Screening in Athletes Post-COVID-19 A B Electrocardiograms (ECGs) performed on 2 athletes highlighting challenges with differentiating normal changes associated with athletic training and pathology. (A) Normal healthy endurance athlete's ECG showing diffuse ST-segment elevation because of early repolarization (blue arrows). (B) An ECG from a 23-year-old soccer player presenting with positional pleuritic chest pain, elevated high-sensitivity troponin (>5,000 ng/l) with confirmed myopericarditis on cardiac magnetic resonance; [/fig]
[fig] FIGURE 2: Challenges year-old male elite rower presented with 3 months of exercise intolerance following a mild coronavirus disease-2019 (COVID-19) illness (polymerase chain reaction confirmed). His peak oxygen consumption had reduced by approximately 20 ml/min/kg but in the setting of complete detraining. The possibility of myocardial dysfunction secondary to COVID-19 myocarditis was considered. His high-sensitivity troponin was normal. Echocardiography revealed symmetrical dilation of all 4 cardiac chambers, but low-normal function of the left ventricle (LV). (A) Global longitudinal strain was -16% and (B) LV ejection fraction was 52%. (C) Right ventricular strain was synchronous and normal (-27%) and (D) RV fractional area change of 48% was also normal. The low-normal LV functional measures are common in endurance athletes, but given the persisting clinical uncertainty, a cardiac magnetic resonance scan was performed. (E) There was no enhancement post-gadolinium contrast administration and both (F) T1 and (G) T2 mapping values were normal. The rower was reassured and encouraged to make a graduated return to training and competition. [/fig]
[fig] Balanced 4 -: chamber enlargement and symmetrical (usually eccentric) hypertrophy are common EICR findings in endurance and mixed-sport athletes.Ejection fraction is usually normal in athletes-elite endurance athletes rarely express a mild reduction in EF at rest, but this is associated with normal diastolic function and normal augmentation of EF and supranormal functional capacity with exercise.Reduced LV systolic function or the presence of diastolic dysfunction is suspicious for occult myocardial involvement.RECOMMENDATIONS FOR ECHOCARDIOGRAPHICASSESSMENT OF THE ATHLETE'S RIGHT HEART.Although there is insufficient evidence to guide strict recommendations on post-COVID RV assessment in athletes, we believe that this deserves specific comment for 2 reasons: 1) RV dysfunction is one of the more prevalent abnormalities described in COVID-19 patients; and 2) RV assessment is difficult in athletes and there is potential for physiological changes to be confused with pathology.Phelan et al. RV dysfunction is an expected complication in COVID-19 heart disease (36) due to the fact that pulmonary and pulmonary-vascular complications dominate the clinical picture of acute COVID-19 illness. Any resulting increase in pulmonary vascular resistance can promote RV dysfunction. The RV is more load dependent than the LV; thus, assessment of pulmonary artery pressures is of great importance, particularly in COVID-19 patients. The assessment of RV structure and function in athletes is complex, particularly in the endurance athlete. RV dilation combined with low-normal or mildly abnormal measures of RV systolic function are common among healthy endurance athletes (50,51). Thus, the confident diagnosis of pathology often requires a series of complementary abnormal results, identification of regional abnormalities, or association with strong clinical suspicion.Qualitative assessment should include an assessment of RV size and wall motion in parasternal shortand long-axis views as well as in apical views. This is an important start to RV assessment but should not be relied on in isolation.Reference ranges for quantification need to be tailored to the degree of athletic conditioning, ethnicity, and sex. Unfortunately, reference ranges are not established for all combinations. An alternate strategy is to reference the RV to LV size. This assumes symmetrical remodeling, a finding that has been repeatedly demonstrated to hold true. Using a ratio of basal end-diastolic diameters, the RV-to-LV internal diameter ratio has been demonstrated to be slightly greater in athletes (50) (consistent with the finding of greater RV-to-LV volume ratios), but because of the lunar shape of the RV, the linear dimensions are typically less than the LV. For the normal athlete, the RV-to-LV end-diastolic diameter is typically 0.8 AE 0.1 and 0.6 AE 0.1 in the long-and [/fig]
[fig] FIGURE 3: Pericardial year-old elite female basketball player, coronavirus disease 2019 (COVID-19) polymerase chain reaction-positive 4 weeks prior, presented for cardiovascular risk stratification. Previous symptoms included temperature to 100.1 F, chills, and positional chest tightness, now all resolved for 21 days. Current vital signs were stable and a 12-lead electrocardiogram showed normal sinus rhythm without ST-segment deviations. (A) Transthoracic echocardiography parasternal basal short-axis view (arrow; small localized posterior effusion); (B) cardiac magnetic resonance short-axis noncontrast steady-state free precession visualizing effusion (arrow); (C) cardiac magnetic resonance short-axis phase-sensitive inversion recovery late gadolinium enhancement demonstrating localized, probably healing and subacute pericarditis (arrow). its ability to provide myocardial tissue characterization (Figure 4). LGE has been an important component of CMR tissue characterization for 20 years, as it provides a precise assessment of the presence, location, and transmural extent of myocardial scarring and fibrosis (56). A mid-myocardial or subepicardial non-coronary artery disease hyperenhancement pattern on LGE is frequently observed in acute myocarditis associated with significant troponin elevation. Multiple studies have demonstrated that the presence of LGE is a powerful marker of adverse cardiac prognosis (heart failure, ventricular arrhythmic events, and mortality) in patients with myocarditis (57,58). Recently, in a subgroup of 187 patients from the ITAMY (ITAlian study in MYocarditis) registry in Italy, evidence of persistent LGE (particularly in the mid-wall septum) at 6 months was the strongest independent predictor of long-term adverse cardiac events at follow-up (median 7 years) (59 [/fig]
[fig] FIGURE 4: Cardiac -year-old woman presented 20 days after the onset of cough, fever, diarrhea, and malaise with subsequent onset of dyspnea and was diagnosed with congestive heart failure upon hospital admission. Cardiac B-type natriuretic peptide was elevated at 2,646 pg/ml, and highsensitivity troponin I was 110 ng/l. There was mild global reduction in left ventricular (54%) and right ventricular (53%) ejection fraction. Native T1, T2, and late gadolinium enhancement cardiac magnetic resonance images were obtained.(A, B) Myocardial mapping demonstrating significant diffuse elevation of native T1 (1,110 ms) and increased T2 of the lateral wall (69 ms). (C, D) Late gadolinium enhancement imaging demonstrates subepicardial hyperenhancement of the basal and mid lateral wall (blue arrows). In addition, there is a small pericardial effusion and small bilateral pleural effusions are present. COVID-19 14 coronavirus disease 2019. [/fig]
[fig] ACUTE PERICARDITIS: For most etiologies of acute pericarditis, the natural history is benign, although a small subset may progress to more serious complications, including significant pericardial effusion with tamponade, recurrent pericarditis, and pericardial constriction. The long-term effect of COVID-19related pericarditis is unknown. Treatment of pericarditis includes exercise restriction as exercise appears to exacerbate inflammation in the pericardium [/fig]
[table] TABLE 1: Comparison of Typical Athletic Remodeling Versus "Red Flag" Findings That Increase Suspicion for COVID-19-Related Myocardial Disease on See text regarding how athletic remodeling may vary based on sport, gender, ethnicity, and body size. Ensure good image quality with appropriate tracking. Normal ranges may vary-see text for further details. COVID-19 14 coronavirus disease 2019; LA 14 left atrium; LV 14 left ventricle/ventricular; LVEDD 14 left ventricular end-diastolic diameter; LVEF 14 left ventricular ejection fraction; RV 14 right ventricle/ ventricular; RVEF 14 right ventricular ejection fraction. [/table]
[table] TABLE 2: Indications: Consider Addition of CMR to the Evaluation of Athletes Post-COVID-19CMR 14 cardiac magnetic resonance; ECG 14 electrocardiogram; TTE 14 transthoracic echocardiogram; other abbreviations as inTable 1. [/table]