The COVID-19 pandemic caused by SARS-CoV-2 has demonstrated a broad spectrum of presentations ranging from asymptomatic disease to severe respiratory failure, myocardial injury, and death. Up to 20-30% of patients hospitalized with COVID-19 have evidence of myocardial involvement manifested by elevated troponin levels [1] [2] [3] [4] [5] [6] . The prevalent cardiac expression of angiotensin I converting enzyme 2 (ACE2) 7 , the target for SARS-CoV-2's spike protein, is implicated in the pathophysiology of the associated myocardial injury. There are multiple pathways to myocardial injury (Fig 1) , including Type 1 or 2 myocardial infarction, myocarditis, vasculitis or other mechanisms related to inflammation, thrombosis, and/or stress. Depending on the type of myocardial injury, there may be important sequelae if residual inflammation or fibrosis exists. As SARS-CoV-2 is a new pathogen, there are no long-term data on cardiovascular abnormalities or dysrhythmias that may occur in the convalescent phase.
In patients with COVID-19, it is plausible that myocardial involvement can be the initiator of a pathway of inflammation and subsequent fibrosis 8 . If the extent and distribution of fibrosis produces electrophysiologic abnormalities that predispose to atrial fibrillation and ventricular arrhythmias, early detection and intervention could improve long-term outcomes. Patients with asymptomatic but overt clinical cardiac disease would benefit from standard therapy. Patients with subclinical disease may be at risk for cardiac arrhythmias. Therefore, identification of survivors of COVID-19 infections with subclinical myocardial disease and/or arrhythmias creates a rationale to consider agents with demonstrated cardioprotective properties such as mineralocorticoid antagonists, beta-blockers, and statins 9 . Given the large number of COVID-19 survivors, enhanced surveillance and treatment for those with significant electrophysiologic abnormalities could substantially lower the burden of subsequent morbidity and mortality.
Treatment for COVID-19 infections has included standard, novel, and experimental therapies. Specific antiviral, anti-inflammatory, immunosuppressive, and cell-based therapies continue to evolve 5, 10 . Nevertheless, we hypothesize that a substantial number of patients who survive COVID-19 and have evidence for myocardial injury at the time of initial presentation, may have long-term overt or subclinical myocardial and/or electrophysiologic abnormalities. It is unknown whether the severity of cardio-pulmonary injury, the type of treatment or other host factors influences long term sequelae. Heightened surveillance is therefore warranted in these patients with consideration of primary prevention approaches. Despite the novelty of COVID-19
infections, there have been numerous case reports, case series, editorials and review articles on cardiovascular complications during acute COVID-19 infection 1, [3] [4] [5] [11] [12] [13] [14] [15] . In this review, we highlight potential cardiovascular or arrhythmia complications that may occur during convalescent phase in survivors of COVID-19 infection.
SARS-CoV-2 has caused a global COVID-19 pandemic with serious infections, major morbidity and mortality 1, 2, 4, 5, 11, [16] [17] [18] . This virus attaches to ACE2, which is found extensively in alveolar tissue and myocardial tissue 7 . Numerous studies have shown that ACE2 is a cardioprotective transmembrane protein whose expression is downregulated with SARS-CoV-2 virus infection 5 including macrophage infiltration. This suggests a direct causal effect from viral infiltration and the associated inflammation. It was also noted in this study that patients with SARS-CoV infection in the heart suffered significantly more aggressive illness and succumbed to earlier death compared to those with SARS-CoV without myocardial infiltration 19 Cardiac involvement in patients with COVID-19 (Table 1) has been attributed to multiple mechanisms and patterns of injury (Fig 1) 4, 15 . Up to 20-30% of patients hospitalized with COVID-19 have evidence of myocardial involvement manifested by elevated troponin levels which is associated with worse short-term outcomes (Table 1) [1] [2] [3] 6, 12, 20 . In a case series of 187 patients with COVID-19, elevated troponins, with or without a history of cardiovascular disease, were associated with malignant arrhythmias, acute respiratory failure, and higher mortality.
Interestingly, patients with known CVD but without elevated troponins had a more favorable outcome 12 . Acute cardiac injury portends a worse prognosis, greater need for mechanical ventilation, and higher mortality. Shi and colleagues 3 reported that cardiac injury was associated with acute respiratory distress syndrome (ARDS), acute kidney injury, and coagulation disorders.
Coagulation disorders and metabolic derangements with acute kidney injury can also contribute to cardiac injury. Other mechanisms of cardiac injury (Fig 1) Up to 20-30% of patients hospitalized with COVID-19 have evidence of myocardial involvement manifested by elevated troponin levels which is associated with worse short-term outcome ( Table 1) Acute cardiac injury portends a worse prognosis, greater need for mechanical ventilation, and higher mortality. Shi and colleagues 3 reported that cardiac injury was associated with acute respiratory distress syndrome, acute kidney injury, and coagulation disorders. Coagulation disorders and metabolic derangements with acute kidney injury can also contribute to cardiac injury.
Acute ST-segment elevation myocardial infarction has been well recognized in viral respiratory illnesses 24 . A study by Kwong et al. showed that the incidence of acute coronary syndrome is 5-10 times as high within the first seven days of influenza diagnosis 25 .
Recommendations from experts suggest that these patients should be preferentially treated with fibrinolytic therapy 26 . Therefore, patients with acute ST-segment myocardial infarction and COVID-19 may be expected to have larger infarcts if fibrinolytic therapy does not result in timely and complete reperfusion.
Given the high prevalence of cardiac injury, it is reasonable to expect that a spectrum of heart disease is present with some residual post-myocarditis abnormalities. In fact, media recent reports have already suggested some patients suffer new onset cardiomyopathy during the convalescent phase after COVID-19 infection (https://www.nbcnewyork.com/news/coronavirus/coronavirus-after-effects-ny-doctor-developsheart-disease-after-recovery/2397699/).
As there are no current data on long-term COVID-19 cardiovascular complications, it would be instructive to review recovery from other types of myocardial injury. For patients with acute coronary syndrome, or Type I MI, standard follow-up and care are warranted. Chapman and colleagues studied consecutive hospital in-patients with elevated troponins 27 . Patients with Type II MI (supply/demand mismatch with evidence for ischemia), and cardiac injury (elevated troponin and no evidence for ischemia) were compared with patients with Type I MI during 5 years follow-up. Patients with Type II MI and/or cardiac injury had significantly higher rates of major cardiovascular events (after adjustment for clinical co-variates) and higher rates of noncardiovascular death 27 . These data would be relevant for patients recovered from COVID-19 associated cardiac injury.
For patients with stress induced myocardial injury, the long-term follow-up of patients with Takotsubo cardiomyopathy may be relevant. In one recent small study, the patients recovered from Takotsubo cardiomyopathy demonstrated long-term symptomatic and functional impairment despite normalized ejection fraction 28 . However, MRI study did not reveal late gadolinium enhancement. Although atrial and ventricular arrhythmias are common during the acute phase, there does not appear to be significant risk of ventricular arrhythmias in the convalescent phase after recovery from Takotsubo cardiomyopathy 29 .
Microemboli and/or microvascular coronary dysfunction has been posited to be one of the mechanisms of acute coronary injury during COVID-19. Pre-clinical studies on microemboli demonstrated vasoconstriction and inflammation, with increase in tumor necrosis factor α 30 .
Microemboli have been described during acute percuatenous coronary interventions and may lead to microvascular dysfunction and heart failure 30 .
with COVID-19 myocarditis and/or fibrosis due to inflammation (regional or local) associated with their acute illness. In one study of 502 patients with biopsy proven inflammatory carditis, up to 6.6% of patients developed aborted or actual sudden cardiac death and/or appropriate ICD shocks 31 . In a recent study on inpatients with symptomatic active or prior myocarditis, there was an increased prevalence of atrial and ventricular arrhythmias 32 . Moreover, the arrhythmic burden was not different among patients with active versus previous myocarditis, although the type of arrhythmias differed. In the 62 patients with previous myocarditis with mean ejection fraction 47 ± 14%, atrial fibrillation was present in 34% and ventricular tachycardia was present in 47%.
Late gadolinium enhancement in a nonischemic pattern was observed on cardiac MRI in all 62 patients with prior myocarditis. Ventricular arrhythmias occurred even among patients with left ventricular ejection fraction > 50% 32 .
In a long-term follow-up study of 1142 patients who recovered from acute myocarditis (mean age 40.2 years), the authors noted heart failure hospitalizations between 6-8% 33 .
Currently, there are no studies that have specifically evaluated the burden of arrhythmias post-myocarditis in follow-up, particularly in patients whose ventricular function has recovered.
In one study of long-term survival of 112 patients with biopsy proven myocarditis, ejection fraction ≤40% was only a borderline predictor of mortality (p=0.052), suggesting that a substantial number of patients with preserved left ventricular function died in follow-up 34 . Other series of patients with myocarditis also show diminished survival and sudden cardiac death 35 . A case report describes a patient with myocarditis who had a monitored ventricular fibrillation event 2 months later when left ventricular function was normal 36 . Autopsy series 37,38 of patients with sudden cardiac death have identified myocarditis as a potential explanation in a significant number of cases, even with a grossly normal appearing heart. The finding of myocarditis as a significant cause of sudden death in the young is notable and relevant to survivors of COVID- 19. 39 While myocarditis is typically considered for its manifestations on the ventricle, the atrium is also involved 40 . Endomyocardial biopsies in patients with "idiopathic" atrial fibrillation has shown a high incidence of myocarditis on both atrial septal and right ventricular biopsy specimens 41 . A Taiwanese study found an adjusted odds ratio of 1.182 (p =0.03) for developing atrial fibrillation in individuals who had had influenza versus those who did not 42 .
Obesity has been observed to be a risk factor for worse outcomes during COVID-19
infections. ACE2 is also expressed in adipose tissue. Recent publications point to a pathophysiologic link between COVID-19 and obesity 43 . Obesity modulates inflammatory response through secretion of pro-and anti-inflammatory adipokines, modulation of IL-6; therefore, COVID-19 infection and its interaction with adipocytes may contribute to deleterious outcomes 43 . Inflammation involving the epicardial adipose tissue (EAT) may be impacted by myocarditis due to the contiguity of the myocardium and EAT. Epicardial fat has been linked with atrial fibrillation and coronary artery disease 44, 45 . Hence, COVID-19 interaction with epicardial fat may provide a plausible link to acute or long-term atrial fibrillation and coronary artery disease.
There is much unknown about COVID-19 infection. Just like other entities with acute cardiac injury, there is likely to be a diverse response, depending on the mechanism of myocardial injury, severity of the acute illness, therapy delivered, hemodynamic response, host factors, immune-mediated factors, and post recovery care and follow-up. Based on other studies of patients with recovered myocarditis, Type II MI or other cardiac injury, it is expected that some patients will have subclinical and possibly overt cardiovascular abnormalities. Patients with ostensibly recovered cardiac function may still be at risk for coronary artery disease, atrial fibrillation or ventricular arrhythmias.
While current paradigms for treatment appropriately focus on acute recovery, it is unknown whether the treatment given during the acute illness may affect future cardiovascular pathology. Given the size of the pandemic, it is important to determine whether acute delivery of antifibrotic therapy, anti-inflammatory therapy, cell-based therapy, or antiviral therapy impacts long-term as well as short-term outcomes.
The optimal screening for patients following recovery from COVID-19 is unknown. One paradigm (Fig 2) would be to define the population at highest risk, by identifying patients with COVID-19 infection with elevated high-sensitivity troponin and/or BNP, as this has already been shown to provide important short-term prognostic information. These patients should be followed to monitor and assess the long-term prognostic impact of COVID-19 myocardial involvement.
Screening for residual cardiac involvement in the convalescent phase is needed to establish the population burden of long-term cardiac disease contributed to by COVID-19. If a significant burden of disease is identified, trials of prophylactic therapies to prevent long-term complications may be appropriate. The type of testing, and cost-effectiveness of screening tests for post COVID-19 myocardial dysfunction/arrhythmias will need to be determined. We recommend standard ECG and echocardiogram and possibly a cardiac monitor 2-6 months post recovery, with the recognition that even these tests may not detect very subtle clinical abnormalities. Consideration should be given for advanced imaging (ie. MRI with gadolinium enhancement, or echocardiographic strain) when initial testing reveals abnormalities or, as clinically indicated. Future studies will clarify whether there will be a "post-COVID-19 Cardiac Syndrome" and how best to manage patients recovering from COVID-19 cardiac involvement.
We are currently facing a pandemic unseen in our lifetime with potential long-term cardiovascular complications. Now is the time for action to plan appropriate registries, such as the American Heart Association COVID-19 registry, and clinical studies to assess the incidence and significance of potential mid-and long-term cardiac abnormalities and dysrhythmias, with the hope and promise to mitigate these long-term sequelae. Central Illustration. Flow chart with recommendations to identify patients with cardiac injury during the acute phase-obtain troponin (TN) and brain natriuretic peptide (BNP). Following identification of patients with potential cardiac injury, the recommendation is to screen patients with electrocardiogram (ECG) and echocardiogram (ECHO). Depending on symptoms, a cardiac monitor may be considered Further testing and treatment would be guided by the patient's symptoms, cardiac risk factors, and findings from initial testing. 