2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play

 [bib_ref] Cardiac troponin for assessment of myocardial injury in COVID-19: JACC review topic..., Sandoval [/bib_ref] [bib_ref] Electrocardiographic findings in coronavirus disease-19: insights on mortality and underlying myocardial processes, Mccullough [/bib_ref] [bib_ref] Thrombosis in hospitalized patients with COVID-19 in a New York City health..., Bilaloglu [/bib_ref] [bib_ref] Persistent symptoms in patients after acute COVID-19, Carfi [/bib_ref] [bib_ref] Sequelae in adults at 6 months after COVID-19 infection, Logue [/bib_ref] [bib_ref] Myocarditis with COVID-19 mRNA vaccines, Bozkurt [/bib_ref] 

# Methods

# Background
On May 26, 2021, the ACC's Cardiovascular Conundrums in the COVID-19 Era Roundtable was convened to bring together expert clinicians along with a broad set of stakeholders, including representatives from patient advocacy groups, professional societies, and content experts, to discuss ongoing questions faced by cardiovascular clinicians caring for individuals with COVID-19.
Participants in this ACC Heart House Roundtable identi-

## Process
Guidance issued in this document was informed by scientific evidence presented and expert opinions considered during the Heart House Roundtable, with additional review and deliberation by the writing committee.
Although practical approaches and ongoing gaps in knowledge were discussed during the Roundtable meeting, this document is a separate and independent endeavor that specifically aims to address some of the most common questions that were raised. duration; and echocardiogram with ventricular wall motion abnormalities, often in a noncoronary distribution, and/or abnormal ventricular strain. Informed by the presentation and may include coronary angiography for suspected acute coronary syndrome or CT pulmonary angiography for suspected pulmonary embolism (see [fig_ref] FIGURE 3: Evaluation and Management of Patients With Suspected Myocarditis or Myocardial Involvement [/fig_ref]. Includes other laboratory testing (eg, complete blood count, basic metabolic panel, C-reactive protein), an ambulatory rhythm monitor, a chest X-ray or CT imaging, and pulmonary function tests, along with additional testing for suspected PASC-CVD or PASC-CVS (see [fig_ref] FIGURE 7: Evaluation of Cardiovascular Symptoms Suggestive of PASC *Consideration should be given to... [/fig_ref]. For patients with myocarditis, medical therapy may include immunosuppressive drugs (eg, corticosteroids); for patients with pericardial involvement, medical therapy may include nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids (see [fig_ref] FIGURE 3: Evaluation and Management of Patients With Suspected Myocarditis or Myocardial Involvement [/fig_ref]. kSee [fig_ref] FIGURE 7: Evaluation of Cardiovascular Symptoms Suggestive of PASC *Consideration should be given to... [/fig_ref]. For patients with PASC-CVS, empiric medical therapy may include a beta-blocker, a non-dihydropyridine calcium-channel blocker, ivabradine, fludrocortisone, and/or midodrine.
#Includes maximal-effort exercise testing and/or an ambulatory rhythm monitor (see [fig_ref] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP... [/fig_ref].

## Incidence and prevalence
Historically, viral infection has been regarded as the most common cause of myocarditis. Its reported prevalence is variable and has been estimated at 10 to 106 cases per 100,000 people worldwide, with an annual incidence of 1.8 million. [bib_ref] Global, regional, and national burden of myocarditis and cardiomyopathy, Dai [/bib_ref] With COVID-19, the true incidence of myocarditis has proven challenging to assess because of ambiguous definitions, evaluation of nonrepresentative populations, and lack of systematic data collection.
Although a recent population-based study of young adults (aged <20 years) from 48 U.S. health care organizations estimated the incidence of myocarditis with COVID-19 at about 450 per million,prospective and retrospective studies of hospitalized patients, autopsy data, and CMR suggest that the overall incidence is higher. Fortunately, fulminant myocarditis appears to be quite rare. [bib_ref] Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19), Inciardi [/bib_ref] [bib_ref] COVID-19 and myocarditis: a systematic review and overview of current challenges, Castiello [/bib_ref] [bib_ref] COVID-19-associated myocarditis presenting as new-onset heart failure and atrial fibrillation, Gaine [/bib_ref] Echocardiographic data from prospective, crosssectional studies of patients hospitalized for COVID-19
suggest that myocardial dysfunction may be present in up to 40%. [bib_ref] Spectrum of cardiac manifestations in COVID-19: a systematic echocardiographic study, Szekely [/bib_ref] [bib_ref] Incremental prognostic value of biventricular longitudinal strain and high-sensitivity troponin I in..., Sun [/bib_ref] This can range from abnormal ventricular strain to overt left and right ventricular systolic dysfunction. [bib_ref] Echocardiographic manifestations in COVID-19: a review, Carrizales-Sepulveda [/bib_ref] Although the latter may be global, wall motion abnormalities with myocarditis are classically segmental in a noncoronary distribution. Pericardial effusion and thickening may also be seen (especially in cases of myopericarditis); however, data on their frequency and degree of overlap with myocarditis are limited. [bib_ref] Pericardial diseases in COVID19: a contemporary review, Furqan [/bib_ref] In selected studies, these echocardiographic findings correlate with cTn levelsand risk of mortality. [bib_ref] Incremental prognostic value of biventricular longitudinal strain and high-sensitivity troponin I in..., Sun [/bib_ref] 

## Evaluation
Cognizant of 1) the spectrum of myocardial involvement that may be seen with COVID-19; 2) the timing of evaluation relative to SARS-CoV-2 infection; and 3) the range of diagnostic tests available, the writing committee proposes a multiparametric approach to help guide decision-making (see [fig_ref] FIGURE 3: Evaluation and Management of Patients With Suspected Myocarditis or Myocardial Involvement [/fig_ref]. This is limited, however, In those with a rising cTn, ECG abnormalities con- In those with suspected myocardial involvement, CMR is recommended if the patient is hemodynamically stable.
In symptomatic patients, CMR is the most sensitive method to exclude ischemia and preexisting cardiomy-
[formula] opathies [/formula]

## Asymptomatic (subclinical) myocardial involvement
Asymptomatic myocardial involvement has been reported following SARS-CoV-2 infection (eg, following CMR screening of athletes as part of a RTP protocol).
Because most asymptomatic individuals do not undergo cardiac testing, however, this group is likely to be quite small. Recognizing that the long-term consequences of this condition are not known, it is still reasonable to manage these individuals expectantly, with instruction to share any worrisome symptoms or signs (eg, chest pain, shortness of breath, syncope, edema) should they occur. For those interested in resuming physical activity, further recommendations are provided in the RTP section.

## Symptomatic myocardial involvement and myocarditis
The treatment approach for symptomatic myocardial Green boxes 14 cardiac testing for evaluation of myocarditis/myocardial involvement. Orange box 14 other cardiac/noncardiac testing. Purple boxes 14 management.
*Informed by symptoms suggestive of cardiac involvement, including chest pain/pressure, dyspnea, palpitations, and syncope. Includes diffuse T-wave inversion, ST-segment elevation without reciprocal ST-segment depression, and prolongation of the QRS complex duration. Often in a noncoronary distribution; may also include abnormal ventricular strain. Includes hypotension, cardiogenic shock, sustained ventricular arrhythmias, and/or advanced atrioventricular block.
kThis is an incomplete list of potential etiologies. Testing for viral genomes should be performed on frozen heart tissue to exclude other causes of myocarditis, if possible.
#Assumes chest pain is the only symptom, LV systolic function is preserved, and there are no ventricular arrhythmias.
**Includes an ECG, echocardiogram, ambulatory rhythm monitor, and CMR. patients with myocarditis to: 1) gauge recovery of cardiac function and inflammation; 2) guide heart failure management; and 3) assess prognosis.

## Postvaccination myocarditis

## Clinical presentation
Myocarditis following COVID-19 mRNA vaccination is an entity separate from but related to myocarditis following SARS-CoV-2 infection.In case reports and case series of vaccine-associated myocarditis, chest pain has been noted in the vast majority, [bib_ref] Myocarditis with COVID-19 mRNA vaccines, Bozkurt [/bib_ref] occurring most commonly 2-3 days after the second mRNA vaccine dose. [bib_ref] Myocarditis with COVID-19 mRNA vaccines, Bozkurt [/bib_ref] Much less often, it has been observed after the first dose. [bib_ref] Myocarditis with COVID-19 mRNA vaccines, Bozkurt [/bib_ref] 

## Mechanism
Although the exact mechanism of vaccine-associated myocarditis is not currently known, it has been hypothesized that molecular mimicry (between the spike protein of SARS-CoV-2 and self-antigens), autoantibody formation, triggered immune dysregulation with activation of natural killer cells, and a dysregulated cytokine and immune response to mRNA may all play a role. [bib_ref] Myocarditis with COVID-19 mRNA vaccines, Bozkurt [/bib_ref] [bib_ref] Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance, Caforio [/bib_ref] [bib_ref] Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms, Heymans [/bib_ref] The observed male predominance may also be related to sex hormone differences in immune response. [bib_ref] The quest for new approaches in myocarditis and inflammatory cardiomyopathy, Heymans [/bib_ref] Endomyocardial biopsy has been reported in only a small number of cases of postvaccination myocarditis. In 2 cases, specimens showed inflammatory infiltrates largely consisting of T cells and macrophages, admixed with eosinophils, B cells, and plasma cells. [bib_ref] Myocarditis after COVID-19 mRNA vaccination, Verma [/bib_ref] In other cases, biopsy has failed to demonstrate myocardial infiltrates 132 and evidence of myocarditis. [bib_ref] Myocarditis temporally associated with COVID-19 vaccination, Rosner [/bib_ref] [fig_ref] FIGURE 4 Favorable: Benefit-to-Risk Ratio for COVID-19 mRNA Vaccination Among Those at Highest Risk for... [/fig_ref]. [bib_ref] Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients:..., Gargano [/bib_ref] In addition, beyond helping to mitigate the risk [bib_ref] Striking similarities of multisystem inflammatory syndrome in children and a myocarditis-like syndrome..., Most [/bib_ref] and PASC. [bib_ref] Myocarditis with COVID-19 mRNA vaccines, Bozkurt [/bib_ref] [bib_ref] Long COVID-19 or post-acute sequelae of SARS-CoV-2 infection in children, adolescents, and..., Hageman [/bib_ref] Evaluation and Management
In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection (see Patients with this condition commonly experience wide-ranging symptoms, including fatigue, cognitive dysfunction, sleep disturbance, and exercise intolerance.
Reported symptoms encompass nearly every organ system, with varying impacts on quality of life (see [fig_ref] FIGURE 5: Symptoms of PASC and Potential Mechanisms COVID-19 14 novel coronavirus disease 2019 [/fig_ref].

## Pasc-cvd
PASC-CVD refers to a broad group of cardiovascular conditions that manifest $4 weeks after SARS-CoV-2 infection. Timing, however, may vary depending upon initial illness severity. PASC-CVD includes, but is not limited to,

## Myalgic encephalomyelitis/chronic fatigue syndrome
The clustering of exercise intolerance with symptoms of fatigue, postexertional malaise, and brain fog has prompted comparison of PASC to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 168 ME/CFS is defined by a triad of symptoms: 1) substantial impairment in the ability to function at home or at work, lasting for more than 6 months, accompanied by profound fatigue of new or definite onset (but not lifelong) that is not appreciably alleviated by rest; 2) postexertional malaise;
and 3) unrefreshing sleep. [bib_ref] Beyond myalgic encephalomyelitis/ chronic fatigue syndrome: an IOM report on redefining an..., Clayton [/bib_ref] Patients must also have either orthostatic intolerance or cognitive impairment. [bib_ref] Beyond myalgic encephalomyelitis/ chronic fatigue syndrome: an IOM report on redefining an..., Clayton [/bib_ref] Although ME/CFS has been reported after infection (eg, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6 and 8, Borrelia burgdorferi), a direct link between infection and prolonged symptoms is usually lacking.
Even though some have suggested that ME/CFS and PASC share a common pathophysiology (including immune and metabolic system dysregulation), ME/CFS still remains poorly understood, with relatively few practitioners experienced in diagnosing and treating it.

## Epidemiology
Data suggest that as many as 10%-30% of individuals may experience prolonged symptoms following SARS-CoV-2 infection, a subset of which may relate to the cardiovascular system. [bib_ref] Sequelae in adults at 6 months after COVID-19 infection, Logue [/bib_ref] In a community sample of >500,000 U.K.
residents participating in the REACT-2 (Real-Time Assessment of Community Transmission-2) study, onethird of those self-reporting a history of COVID-19 noted at least one symptom (such as shortness of breath, chest pain, or tiredness) and nearly 15% experienced 3 or more symptoms lasting 12 weeks or longer. [fig_ref] FIGURE 6: Downward Spiral of Deconditioning [/fig_ref]. [bib_ref] Postural orthostatic tachycardia syndrome: JACC focus seminar, Bryarly [/bib_ref] In fact, this is considered to be one of the key mechanisms underlying POTS. [bib_ref] Cardiac origins of the postural orthostatic tachycardia syndrome, Fu [/bib_ref] Importantly, although exercise therapy is essential to recovery, standard exercise involving upright activity (eg, walking, jogging) may worsen symptoms of PASC-CVS, further prolonging recovery. This is because upright activity perpetuates the physiology of bedrest deconditioning, [bib_ref] Deconditioning as main mechanism of impaired exercise response in COVID-19 survivors, Rinaldo [/bib_ref] including decreased blood volume, decreased venous return, and cardiac atrophy, with accompanying vagal withdrawal and sympathetic activation. Acknowledging that other mechanisms for fatigue, exercise intolerance, and excessive tachycardia likely exist, the construct of bedrest deconditioning provides a unifying explanation for these symptoms, as well as a paradigm to focus recovery. inflammation may also increase the potential for coronary vasospasm. [bib_ref] Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group..., Evans [/bib_ref] [bib_ref] Endothelial dysfunction in patients with chest pain and normal coronary arteries, Quyyumi [/bib_ref] [bib_ref] An EAPCI expert consensus document on ischaemia with nonobstructive coronary arteries in..., Kunadian [/bib_ref] In a study of 11 PASC patients with angina and suspected ischemia, invasive coronary vasomotion testing revealed abnormal endothelial-dependent responses to acetylcholine in 82%; this was driven by a mix of endothelial-dependent and endothelialindependent (smooth muscle) effects. [bib_ref] Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal..., Espejo [/bib_ref] Other potential contributors include myocardial and/or pericardial disease that may have gone undetected with initial testing. Finally, chest pain is a common feature of POTS and ME/CFS; the underlying mechanisms for this, however, remain poorly understood.

## Dyspnea
Shortness of breath, cough, and pleuritic chest pain represent commonly reported symptoms with PASC.
Some may also note inability to take a full breath or air hunger with exertion, prompting interruption of ambulation on flat ground and/or basic activities of daily living.
Although dyspnea is common in patients with myocardial ischemia, heart failure, and arrhythmia, it may also be seen in those with pulmonary complications following SARS-CoV-2 infection. These include: 1) pulmonary embolism, especially if dyspnea is accompanied by exercise-induced oxygen desaturation, tachycardia, and/or presyncope/syncope; 2) pneumonia; 3) impaired diffusion capacity for carbon monoxide; 4) pulmonary fibrosis; 5) neuromuscular weakness; 6) new or worsening asthma; and 7) bronchial hyperreactivity due to pulmonary vascular inflammation. Among patients hospitalized for COVID-19, lung function impairment is common 6 months after discharge. [bib_ref] Respiratory and psychophysical sequelae among patients with COVID-19 four months after hospital..., Bellan [/bib_ref] [bib_ref] Lung function deficits and symptom burden in survivors of COVID-19 requiring mechanical..., Finney [/bib_ref] Unexplained dyspnea (in the absence of cardiopulmonary abnormalities) may also be seen with PASC and may Ultimately, for those with persistent symptoms but without PASC-CVD, additional evaluation for PASC-CVS should be performed, dictated by: 1) the most prominent symptom(s); 2) the patient's baseline characteristics; and
3) the pretest probability of cardiovascular disease (see [fig_ref] FIGURE 7: Evaluation of Cardiovascular Symptoms Suggestive of PASC *Consideration should be given to... [/fig_ref].

## Tachycardia and exercise intolerance
While other potential causes of tachycardia (eg, [bib_ref] Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal..., Espejo [/bib_ref] Invasive coronary vasomotor testing can help with evaluation of the latter; however, referral to a specialized center may be needed.

## Dyspnea
Given the proclivity of SARS-CoV-2 infection to involve the lungs, initial diagnostic testing should focus on exclusion of pulmonary processes. Most commonly, this involves a chest X-ray and/or a noncontrast CT scan of the lungs, along with pulmonary function testing. If

## Management

## Most treatment recommendations related to pasc-cvd
should be based on current guidelines; those related to PASC-CVS largely depend on the underlying symptom(s).

## Tachycardia and exercise intolerance
For those with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, interventions normally used for POTS should be considered. The benefits of exercise training following bedrest deconditioning [bib_ref] Response to exercise after bed rest and after training, Saltin [/bib_ref] [bib_ref] Effect of rowing ergometry and oral volume loading on cardiovascular structure and..., Hastings [/bib_ref] and that resulting from POTS [bib_ref] Cardiac origins of the postural orthostatic tachycardia syndrome, Fu [/bib_ref] [bib_ref] Short-term exercise training improves the cardiovascular response to exercise in the postural..., Shibata [/bib_ref] [bib_ref] The international POTS registry: evaluating the efficacy of an exercise training intervention..., George [/bib_ref] However, not all exercise is problematic. [bib_ref] What are the recommendations for returning athletes who have experienced long term..., Lindsay [/bib_ref] Instead of upright exercise, recumbent or semi-recumbent exercise (eg, rowing, swimming, or cycling) is recommended initially (see [fig_ref] FIGURE 8: Sample Recumbent Exercise Therapy Prescription*For a more precise prescription for exercise therapy... [/fig_ref] , with transition to upright exercise over time as orthostatic intolerance resolves. [bib_ref] Short-term exercise training improves the cardiovascular response to exercise in the postural..., Shibata [/bib_ref] [bib_ref] Effect of rowing ergometry and oral volume loading on cardiovascular structure and..., Hastings [/bib_ref] [bib_ref] Exercise and non-pharmacological treatment of POTS, Fu [/bib_ref] In addition, exercise duration should be short initially, increasing gradually as functional capacity increases.
Exercise intensity should also be at a submaximal level, sustained for the duration of exercise, with natural increases as tolerance improves. For example, patients should generally start with daily recumbent exercise for only w5-10 minutes at a level that allows them to speak in full sentences; thereafter, gradual increases in exercise (eg, 2 additional minutes of exercise per day each week) are recommended (see [fig_ref] FIGURE 8: Sample Recumbent Exercise Therapy Prescription*For a more precise prescription for exercise therapy... [/fig_ref]. These principles help to avoid worsening fatigue or setbacks and usually can be applied to all patients with deconditioning, regardless of age and whether POTS is present. [bib_ref] Reversing the cardiac effects of sedentary aging in middle age-a randomized controlled..., Howden [/bib_ref] This type of program has also been shown to support long-term cardiovascular health. [bib_ref] Impact of lifelong exercise "dose" on left ventricular compliance and distensibility, Bhella [/bib_ref] Ultimately, a formalized exercise program should be initiated. For some patients, this may be best done in a supervised setting with a physical therapist;
alternatively, specific instructions may be provided on how to implement such a program at home or in a gym. [bib_ref] Postural orthostatic tachycardia syndrome: JACC focus seminar, Bryarly [/bib_ref] [bib_ref] The international POTS registry: evaluating the efficacy of an exercise training intervention..., George [/bib_ref] Given the reduction in plasma volume that follows deconditioning, [bib_ref] Cardiac atrophy after bed-rest deconditioning: a nonneural mechanism for orthostatic intolerance, Levine [/bib_ref] 

## Dyspnea
For patients with dyspnea unrelated to cardiovascular disease, consideration should be given to pulmonary consultation to guide further evaluation and management. Importantly, low preload states can result in dyspnea, underscoring the importance of volume loading and recumbent exercise, as described in the tachycardia and exercise intolerance section. [bib_ref] Dyspnea in chronic low ventricular preload states, Tooba [/bib_ref] Physical therapy that incorporates aerobic training and diaphragmatic breathing exercises can be a helpful adjunct to address underlying ventilatory abnormalities and muscle dysfunction, [bib_ref] Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease, Mancini [/bib_ref] [bib_ref] Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological..., Gea [/bib_ref] as noted with other pulmonary diseases.

## Future directions
Both PASC-CVD and PASC-CVS may be encountered after SARS-CoV-2 infection, with varying effects on quality of life. Because much remains to be learned about these conditions, [bib_ref] The longterm sequelae of COVID-19: an international consensus on research priorities for..., Adeloye [/bib_ref] substantial opportunities exist to better understand their epidemiology, underlying mechanisms, and best approaches for evaluation and management. [bib_ref] The longterm sequelae of COVID-19: an international consensus on research priorities for..., Adeloye [/bib_ref] In addition, little is also currently known about the incidence of PASC in children, those with vaccine breakthrough infection, and those affected by newer SARS-CoV-2 variants (eg, Delta, Omicron). All of this underscores the need to conduct studies that leverage rigorous data collection and precise enrollment to define best practices for distinct phenotypes. Given that the total cost of PASC to patients and their families, the health care system, payers, and society at large is likely to be substantial, there is a critical need to identify ways to better meet the needs of those with this condition. evidence-based framework to guide RTP evaluation.

## Epidemiology
Multiple studies have affirmed that myocarditis is a common cause of sudden cardiac death in athletes. [bib_ref] Myocarditis in athletes is a challenge: diagnosis, risk stratification, and uncertainties, Eichhorn [/bib_ref] Unfortunately, early RTP recommendations related to COVID-19 were limited by: 1) an uncertain prevalence of Abnormal ECG: 3 (5%) Abnormal cTn: 1 (2%) Abnormal echocardiogram: 6 (11%) Any CMR abnormality (of 8 tested): 2 (25%) *Studies included standard triad testing (ECG, cTn, and echocardiogram) or standard triad testing along with mandated CMR.
CMR 14 cardiac magnetic resonance imaging; cTn 14 cardiac troponin; ECG 14 electrocardiogram; LGE 14 late gadolinium enhancement; NA 14 not available; RV 14 right ventricle. myocarditis with SARS-CoV-2 infection; 2) unknown rates of adverse outcomes with exercise resumption; and 3) reports of significant myocardial injury and poor outcomes among some hospitalized patients. 10,11

## Case series
Initial reports detailing the prevalence of myocardial involvement in athletes with COVID-19 were largely single-center studies using CMR as an additional screening tool. In the first published case series of largely asymptomatic U.S. collegiate athletes who underwent triad testing along with screening CMR, [bib_ref] Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection, Rajpal [/bib_ref] [bib_ref] High prevalence of pericardial involvement in college student athletes recovering from COVID-19, Brito [/bib_ref] It is noteworthy that no other COVID-19 athlete study has reported similar degrees of pericardial involvement.
Additional small, single-center case series have followed [bib_ref] Evaluation for myocarditis in competitive student athletes recovering from coronavirus disease 2019..., Starekova [/bib_ref] [bib_ref] Cardiac magnetic resonance findings in patients recovered from COVID-19: initial experiences in..., Vago [/bib_ref] [bib_ref] Cardiac involvement in consecutive elite athletes recovered from Covid-19: a magnetic resonance..., Malek [/bib_ref] [bib_ref] Cardiovascular evaluation after COVID-19 in 137 collegiate athletes: results of an algorithm-guided..., Hendrickson [/bib_ref] [bib_ref] Findings from cardiovascular evaluation of National Collegiate Athletic Association Division I collegiate..., Hwang [/bib_ref] (see , all limited by: 1) lack of appropriate controls as well as independent and blinded review of imaging studies; 2) heterogeneity in CMR abnormalities; and 3) lack of a standardized approach to timing of CMR acquisition (ranging from 10-40 days after testing positive for COVID . Data from these studies, along with well-publicized cases in the media,have nonetheless led some organizations to mandate the use of CMR to screen all competitive athletes following SARS-CoV-2 infection.

## Registries
Throughout 2020, multiple large registries were created to track U.S. professional and collegiate athletes who had recovered from COVID-19. Both the U.S. professional cohort (N 14 789) [bib_ref] Prevalence of inflammatory heart disease among professional athletes with prior COVID-19 infection..., Martinez [/bib_ref] Most recently, the Big Ten Conference published data on 1,597 athletes who underwent universal screening with CMR in addition to triad testing, irrespective of symptom status 68 (see . Abnormalities on CMR consistent with myocarditis 29 were reported in 2.3% of athletes.
Similar to data from single-center studies, however, there was marked heterogeneity in the prevalence (0%-7.6%) and type of CMR abnormalities among the 13 programs Clinical myocarditis: 9 (0.6%) *N 14 62 with moderate COVID-19 symptoms or abnormal baseline cardiac testing. Myocardial involvement defined as: 1) definite: T1 abnormality  LGE and T2 abnormality, or T2 abnormality  additional supportive criteria (LVEF #45%, pericardial effusion or enhancement, or cTn level above the 99th percentile upper reference limit); 2) probable: T1 abnormality  LGE and 1 or more supportive criterion; or 3) possible: isolated T1 abnormality or LGE. Myocarditis defined as clinical or subclinical (CMR-defined myocardial inflammation in the absence of symptoms suggestive of clinical myocarditis and elevated cTn).
CMR 14 cardiac magnetic resonance imaging; cTn 14 cardiac troponin; ECG 14 electrocardiogram; LGE 14 late gadolinium enhancement; LVEF 14 left ventricular ejection fraction; NA 14 not available. that participated. Results were also remarkably comparable to those of the Outcomes Registry for Cardiac Conditions in Athletes and the professional athlete registries, as only 9 athletes (0.6%) had findings consistent with clinical myocarditis. athletes. [bib_ref] Myocardial fibrosis in athletes-Current perspective, Malek [/bib_ref] A recent study also noted comparable rates of focal LGE at RV insertion points among athletes with SARS-CoV-2 (22%) and noninfected athlete controls (24%).Third, parametric mapping requires a high level of expertise. Accordingly, marked heterogeneity in reported CMR results from different centers may relate to regional variations in CMR performance and interpreter bias, given the lack of blinded review by an independent core laboratory. Fourth, the absence of an appropriate control group limits the interpretation of clinical significance and application of these CMR findings in a testing algorithm. Finally, cost, limited availability, and equi- Historically, an athlete has been defined as an individual who places a high premium on exercise training, competition, and sports achievement. [bib_ref] Sports cardiology: core curriculum for providing cardiovascular care to competitive athletes and..., Baggish [/bib_ref] Individuals who self-identify as athletes extend across the age spectrum, from youth sports (aged <18 years) to masters-level (aged >35 years) exercise enthusiasts. [bib_ref] Sports cardiology: core curriculum for providing cardiovascular care to competitive athletes and..., Baggish [/bib_ref] Previous recommendations were given to individual athletic populations recovering from COVID-19, with encouragement to observe younger athletes (aged <21 years) for several weeks to monitor for the development of MIS-C. [bib_ref] Multisystem inflammatory syndrome in U.S. children and adolescents, Feldstein [/bib_ref] [bib_ref] Pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): clinical presentation, infectivity, and..., Yonker [/bib_ref] Masters-level athletes may also have traditional risk factors for cardiovascular disease, [bib_ref] Prevalence of subclinical coronary artery disease in Masters Endurance Athletes with a..., Merghani [/bib_ref] 

## Return to exercise and athletic training
For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms concerning for myocarditis or myocardial involvement (chest pain or tightness, dyspnea, palpitations, lightheadedness, or syncope) and/or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation should be performed before resuming exercise (see [fig_ref] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP... [/fig_ref]. For all others who are asymptomatic or with symptoms less suggestive of a cardiopulmonary etiology (eg, fever [temperature $100.4 F], chills, lethargy, myalgias), additional cardiac testing is not recommended.
Current CDC guidelines stipulate at least 5 days of selfisolation from symptom onset or upon testing positive for COVID-19.Past consensus RTP guidance recommended that individuals abstain from exercise throughout a 10-day self-isolation period, in part, because of the potential for clinical deterioration. [bib_ref] A game plan for the resumption of sport and exercise after coronavirus..., Phelan [/bib_ref] [bib_ref] Coronavirus disease 2019 and the athletic heart: emerging perspectives on pathology, risks,..., Kim [/bib_ref] Studies demonstrating a lack of clinically significant myocardial involvement among athletes with mild COVID-19 43,69 suggest that such activity restriction is no longer necessary (see [fig_ref] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP... [/fig_ref]. For athletes with cardiopulmonary symptoms, initial evaluation should ideally be with an ECG, cTn (highsensitivity assay preferred), and an echocardiogram (see [fig_ref] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP... [/fig_ref]. The presence of abnormal findings with triad testing or persistence of cardiopulmonary symptoms (specifically chest pain or tightness, palpitations, or syncope) after initial testing suggest that additionalCardiopulmonary symptoms include chest pain/tightness, dyspnea, palpitations, and lightheadedness/syncope; this also includes symptoms occurring #1 week following COVID-19 mRNA vaccination. Strategies to minimize transmission of SARS-CoV-2 to other athletes 3-10 days following a positive COVID-19 test include 1) training in isolation, 2) participating in socially-distanced outdoor training, 3) training with a face mask in a well-ventilated facility with appropriate social distancing, and 4) participating in group training after a single negative NAAT (eg, RT-PCR test) or 2 negative rapid antigen tests 24-48 hours apart. Excludes prolonged, isolated anosmia/ageusia, which should not delay return to training.
kMaximal-effort exercise testing should be deferred until myocarditis has been excluded. Use of CMR to screen athletes who are asymptomatic or with non-cardiopulmonary symptoms is likely to be low yield. Such testing may, however, be considered in those with abnormal triad testing along with increased concern of cardiac involvement or in those with either persistent or new cardiopulmonary symptoms. Importantly, further research is needed to better understand the significance of other forms of myocardial involvement detected by CMR, [bib_ref] Prevalence of clinical and subclinical myocarditis in competitive athletes with recent SARS-CoV-2..., Daniels [/bib_ref] [bib_ref] Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection, Rajpal [/bib_ref] particularly in the absence of symptoms.

## Remote history of covid-19
It is likely that clinicians will increasingly see asymp- infection (see [fig_ref] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP... [/fig_ref].

## Nonspecific and isolated screening abnormalities
In general, routine surveillance monitoring and/or addi- Myocarditis and other myocardial involvement n Myocarditis is defined by: 1) cardiac symptoms (eg, chest pain, dyspnea, palpitations, syncope); 2) an elevated cTn; and 3) abnormal electrocardiographic, echocardiographic, CMR, and/or histopathologic findings on biopsy or postmortem evaluation in the absence of flow-limiting coronary artery disease. n When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cTn (preferably using a high-sensitivity assay), and an echocardiogram. n Cardiology consultation is recommended for those with a rising cTn and/or ECG or echocardiographic abnormalities concerning for myocarditis. n CMR is recommended in hemodynamically stable patients with suspected myocarditis. n Hospitalization is recommended for patients with definite myocarditis that is either mild or moderate in severity, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies. n Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. n For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. n Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A. Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk. n As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge. n Myocarditis following COVID-19 mRNA vaccination is rare. The highest observed rates have been in young male individuals (aged 12-17 years) after the second vaccine dose. n COVID-19 vaccination is associated with a very favorable benefit-to risk ratio for all age and sex groups evaluated thus far. n In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection.
PASC n PASC is defined as a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after SARS-CoV-2 infection. n PASC-CVD refers to a broad group of cardiovascular conditions that include, but are not limited to, myocarditis and other forms of myocardial involvement, pericarditis, new or worsening myocardial ischemia, microvascular dysfunction, nonischemic cardiomyopathy, thromboembolism, cardiovascular sequelae of pulmonary disease, and arrhythmia. n PASC-CVS is a heterogeneous disorder that includes widely-ranging cardiovascular symptoms, without objective evidence of cardiovascular disease using standard diagnostic testing. Common symptoms include tachycardia, exercise intolerance, postexertional malaise, palpitations, chest pain, and dyspnea. n For patients with cardiovascular symptoms and suspected PASC, a reasonable initial testing approach includes: 1) basic laboratory testing (including cTn); 2) an ECG; 3) an echocardiogram; 4) an ambulatory rhythm monitor; 5) chest imaging (X-ray and/or CT); and/or 6) pulmonary function tests. n Cardiology consultation is recommended for patients with PASC that have: 1) abnormal cardiac test results; 2) known cardiovascular disease with new or worsening symptoms or signs; 3) documented cardiac complications during SARS-CoV-2 infection; and/or 4) persistent cardiopulmonary symptoms that are not otherwise explained. n Recumbent or semi-recumbent exercise (eg, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves. n Salt and fluid loading represent nonpharmacological interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension. Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
RTP n Athletes who are asymptomatic after recent SARS-CoV-2 infection may resume exercise training after 3 days of exercise abstinence during self-isolation. n Athletes with mild or moderate non-cardiopulmonary symptoms after recent SARS-CoV-2 infection may resume exercise training after their symptoms have resolved. n Athletes with remote infection ($3 months) without ongoing cardiopulmonary symptoms may resume exercise training without the need for additional testing. n Athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain/tightness, palpitations, or syncope) and/or those requiring hospitalization with increased suspicion for cardiac involvement should undergo triad testing (ECG, cTn, and echocardiogram). Triad testing should also be performed in those developing new cardiopulmonary symptoms after resumption of exercise training. n CMR is recommended if triad testing is abnormal or cardiopulmonary symptoms persist. n Athletes with myocarditis should abstain from exercise for 3-6 months. n Maximal-effort exercise testing and/or an ambulatory rhythm monitor may be helpful in the evaluation of athletes with: 1) persistent cardiopulmonary symptoms and 2) either normal CMR or CMR that demonstrates other forms of myocardial (or pericardial) involvement. Maximal-effort exercise testing should only be performed, however, after myocarditis has been excluded with CMR. n CMR to screen athletes who are asymptomatic or with non-cardiopulmonary symptoms is likely to be low yield. n Repeat cardiac testing is not warranted in athletes with recurrent COVID-19 in the absence of cardiopulmonary symptoms.

## Pasc and return to exercise
Decision-making regarding RTP in PASC should be informed by whether cardiopulmonary symptoms are present. If they are, a similar approach to that recommended above should be pursued, using: 1) triad testing;
2) CMR (if appropriate); and 3) limitation of strenuous physical activity (see [fig_ref] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP... [/fig_ref]. If PASC-CVD is excluded, further evaluation with CPET and pulmonary function testing may be considered as part of the PASC-CVS evaluation. Although individuals with PASC may be unable to readily resume their prior activity levels, structured and individualized graded exercise, as recommended in the PASC section, should be performed throughout the recovery process.

## Future directions
As our understanding of the cardiovascular effects of COVID-19 evolves, it is anticipated that RTP guidance for athletes will change as well. Several areas of future investigation are noteworthy. First, although it is extremely reassuring that adverse events among infected athletes have been rare, further study is needed to determine how long recovery takes after documented abnormalities and the role that imaging can play in guiding this. Second, the risks and benefits of exercise resumption among patients with PASC remains to be rigorously defined. Given the therapeutic role of training in this population, further investigation into associated risks will be particularly important. Third, our current knowledge stems largely from study of those infected with early variants of SARS-CoV-2. Further research is needed to understand whether the extent and severity of cardiac involvement is different with Delta, Omicron, and other variants. It will also be important to define the temporal pattern of myocardial involvement, along with predictors of myocarditis progression and resolution with SARS-CoV-2 and other common respiratory viral pathogens. Finally, widespread resumption of competitive sports will come with rare but devastating adverse events, including sudden cardiac death, that well predate COVID-19. Accordingly, it will be important to limit automatic attribution of such events to COVID-19 without further detailed evaluation.

## Implication of pathway
This ECDP provides a framework for evaluation and management of adults with cardiovascular sequelae following SARS-CoV-2 infection. Guidance provided is based on expert consensus, with multiple key takeaways (see . Importantly, it is intended to help clinicians understand not only when testing may be warranted, but also when it is not. Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves.
For both myocarditis and PASC, there exist significant opportunities to better understand their epidemiology, underlying mechanisms, predisposing risk factors, and preferred approaches for evaluation and management.
For RTP, there is a need to more rigorously define how long cardiovascular abnormalities persist and the relative benefits of exercise training in those with PASC.
Beyond the indirect effects and undesirable consequences that COVID-19 has had on care delivery, it also remains to be seen how new variants and vaccine breakthrough infection will affect cardiovascular health.
Improved understanding of the associated near-and longterm consequences will be key in helping to improve clinical outcomes.
[fig] 1720, Figure 1 1721, Figure 2 1725, Figure 3: OF CONTENTS PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719 1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719 2. METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719 2.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719 2.2.Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1720 3. RATIONALE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 1720 3.1. Scope of the Document . . . . . . . . . . . . . . . . . . . . . Scope of the Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1720 3.1.1. Myocarditis and Other Myocardial Involvement . . . . . . . . . . . . . . . . . . . . . . . . . 1721 3.1.2. Post-acute Sequelae of SARS-CoV-2 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1721 3.1.3. Return to Play . . . . . . . . . . . . . . . . . . . . . . . . 1721 4. ASSUMPTIONS AND DEFINITIONS . . . . . . . . . . . . . 1721 5. PATHWAY SUMMARY GRAPHIC . . . . . . . . . . . . . . . Framework for Evaluating and Managing Cardiovascular Sequelae of COVID-19 in Adults . . 1722 6. DESCRIPTION OF PATHWAY . . . . . . . . . . . . . . . . . . 1721 6.1. Section 1: Myocarditis and Other Myocardial Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1721 6.1.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1721 6.1.2. Definitions and Clinical Presentation . . . . 1723 6.1.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . 1724 6.1.4. Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . 1724 6.1.5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation and Management of Patients With Suspected Myocarditis or Myocardial Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1726 6.1.6. Management . . . . . . . . . . . . . . . . . . . . . . . . 1726 6.1.7. Postvaccination Myocarditis . . . . . . . . . . . 1727 [/fig]
[fig] Figure 4 1730, Figure 5 1733, Figure 6 1735, Figure 7 1737, Figure 8 1741, Figure 9: Favorable Benefit-to-Risk Ratio for COVID-19 mRNA Vaccination Among Those at Highest Risk for Postvaccination Myocarditis . . 1729 6.1.8. Future Directions . . . . . . . . . . . . . . . . . . . . 1730 6.2. Section 2: Post-acute Sequelae of SARS-CoV-2 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1730 6.2.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . Symptoms of PASC and Potential Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1730 6.2.2. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . 1731 6.2.3. Framework . . . . . . . . . . . . . . . . . . . . . . . . . . 1731 6.2.4. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . 1732 6.2.5. Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . Downward Spiral of Deconditioning: A Potential Mechanism of Exercise Intolerance and Excessive Tachycardia in COVID-19 . . . . . . . . . . 1734 6.2.6. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation of Cardiovascular Symptoms Suggestive of PASC . . . . . . . . . . . . . . . . . . . . . . . 1736 6.2.7. Management . . . . . . . . . . . . . . . . . . . . . . . Sample Recumbent Exercise Therapy Prescription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1737 6.2.8. Future Directions . . . . . . . . . . . . . . . . . . . . 1738 6.3. Section 3: Return to Play . . . . . . . . . . . . . . . . . . . 1739 6.3.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . 1739 6.3.2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . 1739 6.3.3. Case Series . . . . . . . . . . . . . . . . . . . . . . . . 1740 6.3.4. Registries . . . . . . . . . . . . . . . . . . . . . . . . . . 1740 6.3.5. Limitations of Screening With CMR . . . . 1741 6.3.6. Evaluation and Management . . . . . . . . . . 1741 6.3.7. Return to Exercise and Athletic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP and/or Intense Training . . . . . . . . . . . . 1742 PREFACE The American College of Cardiology (ACC) has a long history of developing documents (eg, decision pathways, health policy statements, appropriate use criteria) to provide members with guidance on both clinical and nonclinical topics relevant to cardiovascular care. In most circumstances, these documents have been created to complement clinical practice guidelines and to inform clinicians about areas where evidence may be new and evolving or where sufficient data may be more limited. Despite this, numerous care gaps continue to exist, highlighting the need for more streamlined and efficient processes to implement best practices in service to improved patient care. Central to the ACC's strategic plan is the generation of "actionable knowledge"-a concept that places emphasis on making clinical information easier to consume, share, integrate, and update. To this end, the ACC has evolved from developing isolated documents to developing inte-grated "solution sets." Solution sets are groups of closely related activities, policy, mobile applications, decision support, and other tools necessary to transform care and/ or improve heart health. Solution sets address key questions facing care teams and attempt to provide practical guidance to be applied at the point of care. They use both established and emerging methods to disseminate information for cardiovascular conditions and their related management. The success of the solution sets rests firmly on their ability to have a measurable impact on the delivery of care. Because solution sets reflect current evidence and ongoing gaps in care, the associated content will be refined over time to best match changing evidence and member needs. Expert Consensus Decision Pathways (ECDPs) represent a key component of solution sets. The methodology for ECDPs is grounded in assembling a group of clinical experts to develop content that addresses key questions facing our members across a range of high-value clinical topics. 1 This content is used to inform the development of various tools that accelerate real-time use of clinical policy at the point of care. They are not intended to provide a single correct answer; rather, they encourage clinicians to ask questions and consider important factors as they define treatment plans for their patients. Whenever appropriate, ECDPs seek to provide unified articulation of clinical practice guidelines, appropriate use criteria, and other related ACC clinical policy. In some cases, covered topics will be addressed in subsequent clinical practice guidelines as the evidence base evolves. In other cases, these will serve as stand-alone policy. Ty J. Gluckman, MD, MHA, FACC Chair, ACC Solution Set Oversight Committee 1. INTRODUCTION The novel coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact worldwide. In the United States alone, more than 78 million cases have been reported, with greater than 948,000 deaths attributed directly to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as of the writing of this ECDP. 2 Among patients hospitalized for COVID-19, various abnormalities in cardiac testing (eg, electrocardiographic abnormalities, elevated cardiac biomarkers) 3-5 and a wide range of cardiovascular complications (eg, myocardial [/fig]
[fig] Myocarditis: This condition is defined by the presence of 1) cardiac symptoms (eg, chest pain, dyspnea, palpitations, syncope); 2) an elevated cTn; and 3) abnormal electrocardiographic (eg, diffuse T-wave inversion, STsegment elevation without reciprocal ST-segment depression, prolongation of the QRS complex duration), echocardiographic (eg, left ventricular [LV] wall motion abnormalities, often noted in a noncoronary distribution), CMR (eg, nonischemic late gadolinium enhancement [LGE] pattern with prolonged native T 1 and T 2 relaxation times), and/or histopathologic findings on biopsy or postmortem evaluation (eg, inflammatory myocardial infiltrates associated with myocyte degeneration and necrosis) in the absence of flow-limiting epicardial coronary artery disease. It is further categorized into levels of certainty (possible, probable, and definite) based on the number of features present. n Possible myocarditis: This includes individuals with: 1) cardiac symptoms; 2) an elevated cTn; and 3) abnormal electrocardiographic and/or echocardiographic findings but a) absence of acute myocarditis by endomyocardial biopsy or CMR or b) circumstances where neither biopsy nor CMR were performed. Ideally, flow-limiting coronary artery disease would have been excluded in men older than 50 years and women older than 55 years. n Probable myocarditis: This condition is defined by all features of possible myocarditis, but follow-up CMR and/or biopsy within 6 months of SARS-CoV-2 infection demonstrates abnormalities consistent with previous myocarditis. n Definite myocarditis: This condition is defined by all features of possible myocarditis, but CMR and/or biopsy performed at the time of SARS-CoV- [/fig]
[fig] 106: while confirming cardiac changes due to SARS-CoV-2 infection, including myocardial inflammation, nonischemic epicardial scar, and pericardial effusion/enhancement, all of which are demonstrable after 4 weeks. 106,107 For patients who are unstable or exhibit high-risk features (eg, hypotension, ventricular arrhythmias), evaluation at an advanced heart failure center is recommended. Endomyocardial biopsy should be considered in those with clinical deterioration, particularly if heart block or ventricular arrhythmias are present and obstructive coronary artery disease has been excluded. 83,108-110 of patients with myocardial involvement in the setting of COVID-19 is primarily dictated by the clinical presentation and course. Because myocarditis is associated with a heightened risk of cardiac complications early in the disease course, 34,111 a proactive management plan should be in place. [/fig]
[fig] FIGURE 3: Evaluation and Management of Patients With Suspected Myocarditis or Myocardial Involvement [/fig]
[fig] FIGURE 4 Favorable: Benefit-to-Risk Ratio for COVID-19 mRNA Vaccination Among Those at Highest Risk for Postvaccination Myocarditis *Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19)-associated hospitalization surveillance network (COVID-NET). 12,141 COVID-19 14 novel coronavirus disease 2019; ICU 14 intensive care unit, mRNA 14 messenger RNA. incidence, risk factors, mechanisms, preferred diagnostic and therapeutic approaches, and prognosis for viral-mediated and mRNA vaccine-associated myocarditis remain incompletely understood. Because of this, additional systematic, cross-sectional data are needed to describe the frequency, type, and severity of myocarditis and myocardial involvement observed. Randomized trials are also needed to better understand the preferred means to test and treat patients with myocarditis related both to SARS-CoV-2 infection and mRNA vaccination. Although randomized trials in myocarditis have been challenging historically, the current pandemic has created unique opportunities for further investigation. [/fig]
[fig] 6. 2: Section 2: Post-acute Sequelae of SARS-CoV-2 Infection 6.2.1. Overview PASC is a term used to describe a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after SARS-CoV-2 infection. 15 [/fig]
[fig] FIGURE 5: Symptoms of PASC and Potential Mechanisms COVID-19 14 novel coronavirus disease 2019; ENT 14 ear, nose, and throat; GI 14 gastrointestinal; PASC 14 post-acute sequelae of SARS-CoV-2 infection; PTSD 14 posttraumatic stress disorder; SARS-CoV-2 14 severe acute respiratory syndrome coronavirus [/fig]
[fig] FIGURE 6: Downward Spiral of Deconditioning: A Potential Mechanism of Exercise Intolerance and Excessive Tachycardia in COVID-19 COVID-19 14 novel coronavirus disease 2019. [/fig]
[fig] FIGURE 7: Evaluation of Cardiovascular Symptoms Suggestive of PASC *Consideration should be given to additional laboratory testing (eg, D-dimer, B-type natriuretic peptide/N-terminal pro-B-type natriuretic peptide, thyroid function tests) based on the clinical presentation. BMP 14 basic metabolic panel; BP 14 blood pressure; CAD 14 coronary artery disease; CBC 14 complete blood count; CCTA 14 coronary computed tomography angiography; CM 14 cardiomyopathy; CMR 14 cardiac magnetic resonance imaging; CPET 14 cardiopulmonary exercise test; CRP 14 C-reactive protein; CT 14 computed tomography; cTn 14 cardiac troponin; CV 14 cardiovascular; ECG 14 electrocardiogram; GI 14 gastrointestinal; HR 14 heart rate; MVD 14 microvascular dysfunction; PASC 14 post-acute sequelae of SARS-CoV-2 infection; PASC-CVD 14 PASC-Cardiovascular Disease; PASC-CVS 14 PASC-Cardiovascular Syndrome; PET 14 positron emission tomography; PFTs 14 pulmonary function tests; POTS 14 postural orthostatic tachycardia syndrome; SARS-CoV-2 14 severe acute respiratory syndrome coronavirus 2; SCD 14 sudden cardiac death; VHD 14 valvular heart disease. consideration should be given to CPET with flow-volume loops (if available) to characterize cardiac and pulmonary reserve. A CT pulmonary angiogram or ventilation-perfusion (V/Q) scan should also be considered if pulmonary embolism is suspected. Finally, an ischemia evaluation should be pursued if obstructive coronary artery disease or microvascular dysfunction is suspected. [/fig]
[fig] FIGURE 8: Sample Recumbent Exercise Therapy Prescription*For a more precise prescription for exercise therapy with heart rate targets and patient exercise logs, see appendix to Bryarly et al. [/fig]
[fig] FIGURE 9: Evaluation of the Athletic Patient Convalesced From COVID-19 and Guidance on RTP and/or Intense Training *CDC Guidelines: COVID-19 Quarantine and Isolation. [/fig]
[fig] CMR: 14 cardiac magnetic resonance imaging; COVID-19 14 novel coronavirus disease 2019; CT 14 computed tomography; cTn 14 cardiac troponin; ECG 14 electrocardiogram; MIS-A 14 multisystem inflammatory syndrome in adults; mRNA 14 messenger RNA; NSAID 14 nonsteroidal anti-inflammatory drug; PASC 14 post-acute sequelae of SARS-CoV-2 infection; PASC-CVD 14 post-acute sequelae of SARS-CoV-2 infection-cardiovascular disease; PASC-CVS 14 post-acute sequelae of SARS-CoV-2 infection-cardiovascular syndrome; RTP 14 return to play; SARS-CoV-2 14 severe acute respiratory syndrome coronavirus 2. clinical myocarditis <3 months since testing positive for COVID-19, especially if they have had rapid resolution of symptoms and prior demonstration of normal LV systolic function or in those with subclinical myocarditis identified with screening. The best time for this reassessment should likely be individualized, but no sooner than 1 month from the time of initial diagnosis of clinical or subclinical myocarditis. For asymptomatic athletes with complete resolution of myocardial inflammation and no spontaneous arrhythmias, a RTP approach using conservative, graded exercise should be pursued. Finally, screening for myocarditis in the absence of suggestive symptoms following receipt of the COVID-19 mRNA vaccine is not recommended. In addition, although selflimited side effects following vaccination (eg, fatigue, headache, fever, muscle pain) may lead some individuals to stop exercising until symptoms resolve, vaccination per se does not require a set time away from exercise training. [/fig]
[table] 31: Nagel E, Kwong RY, Chandrashekhar YS. CMR in nonischemic myocardial inflammation: solving the problem of diagnosing myocarditis or still diagnostic ambiguity? J Am Coll Cardiol Img. 2020;13:163-166. 32. Cornelissen A, Kutyna M, Cheng Q, et al. Effects of simulated COVID-19 cytokine storm on stent thrombogenicity. Cardiovasc Revasc Med. Published online April 8, 2021. https://doi.org/10.1016/j.carrev.2021. 03.023 33. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.34. Lala A, Johnson KW, Januzzi JL, et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol. 2020;76: 533-546. 35. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan, China. JAMA. 2020;323: 1061-1069. 36. Meyer P, Degrauwe S, Van Delden C, et al. Typical takotsubo syndrome triggered by SARS-CoV-2 infection. Eur Heart J. 2020;41:1860. 37. Nguyen D, Nguyen T, De Bels D, et al. A case of Takotsubo cardiomyopathy with COVID 19. Eur Heart J Cardiovasc Imaging. 2020;21:1052. 38. Alvarez-Garcia J, Jaladanki S, Rivas-Lasarte M, et al. New heart failure diagnoses among patients hospitalized for COVID-19. J Am Coll Cardiol. 2021;77: 2260-2262. 39. Goyal P, Reshetnyak E, Khan S, et al. Clinical characteristics and outcomes of adults with a history of heart failure hospitalized for COVID-19. Circ Heart Fail. 2021;14:e008354. 40. Kirkegaard C, Falco-Roget A, Sanchez-Montalva A, et al. Incidence and risk factors for early readmission after hospitalization for SARS-CoV-2 infection: results from a retrospective cohort study. Infection. Published online July 30, 2021. https://doi.org/10.1007/s15010-021-01662-1 41. Yoo J, Grewal P, Hotelling J, et al. Admission NT-proBNP and outcomes in patients without history of heart failure hospitalized with COVID-19. ESC Heart Fail. 2021;8:4278-4287. 42. Wei ZY, Geng YJ, Huang J, et al. Pathogenesis and management of myocardial injury in coronavirus disease 2019. Eur J Heart Fail. 2020;22:1994-2006. 43. Moulson N, Petek BJ, Drezner JA, et al. SARS-CoV-2 cardiac involvement in young competitive athletes. Circulation. 2021;144:256-266. 44. Pellegrini D, Kawakami R, Guagliumi G, et al. Microthrombi as a major cause of cardiac injury in COVID-19: a pathologic study. Circulation. 2021;143: 1031-1042. 45. Basso C, Leone O, Rizzo S, et al. Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur Heart [/table]