key: cord-0732518-wc62ncsg
authors: Chimenti, Cristina; Magnocavallo, Michele; Ballatore, Federico; Bernardini, Federico; Alfarano, Maria; Della Rocca, Domenico Giovanni; Severino, Paolo; Lavalle, Carlo; Francesco, Fedele; Frustaci, Andrea
title: Prevalence and Clinical Implications of COVID-19 Myocarditis
date: 2021-11-09
journal: Card Electrophysiol Clin
DOI: 10.1016/j.ccep.2021.11.001
sha: 7e0ce4611caf0f53b9564384ad8f6427ae70a80a
doc_id: 732518
cord_uid: wc62ncsg

The clinical manifestations of COVID-19 are widely variable and may involve several districts. Although the clinical course is mostly characterized by respiratory involvement, up to 30% of hospitalized patients have evidence of myocardial injury due to acute coronary syndrome, cardiac arrhythmias, myocarditis, and cardiogenic shock. In particular, myocarditis is a well-recognized severe complication of COVID-19 and is associated with fulminant cardiogenic shock and sudden cardiac death. The pathophysiology of cardiac injury remains poorly understood and the management and outcomes of myocarditis are not yet clarified. Our aim is to present a comprehensive review about COVID-19 related myocarditis, including clinical characteristics, diagnostic workup, and management.

In December 2019 the first case of coronavirus disease 2019 (COVID- 19) was described in Wuhan, China, in a patient complaining of flu-like symptoms [1] . The pathogen has been recognized as a novel enveloped RNA β-coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The clinical manifestations of COVID-19 are widely variable ranging from asymptomatic infection to multi-organ failure and death. Although the clinical course of SARS-CoV-2 infection is mostly characterized by respiratory involvement, ranging from mild influenza-like illness to acute respiratory distress syndrome, it soon became evident that COVID-19 affects multiple organ systems, including the cardiovascular system [2] [3] [4] . Overall, up to 30% of hospitalized patients have evidence of myocardial injury which is associated with a greater need for mechanical ventilatory support and higher in-hospital mortality [5, 6] . Cardiovascular manifestations include acute coronary syndrome, atrial and ventricular arrhythmias, myocarditis, and cardiogenic shock [3] . In particular, myocarditis is a well-recognized severe complication of COVID-19 and is associated with fulminant cardiogenic shock and sudden cardiac death [7] [8] [9] . The pathophysiology of cardiac injury remains poorly understood and the management and outcomes of myocarditis are not yet clarified. Thus, we present a comprehensive review about COVID-19 related myocarditis, describing clinical characteristics, diagnostic workup, and management.

The annual incidence of acute myocarditis from all causes is approximately 22 cases per 100,000 population, with heart failure (HF) occurring in 0.5% to 4.0% of these cases [10].

The true prevalence of myocarditis among COVID-19 patients is difficult to establish, because the early reports often lacked the specific diagnostic modalities to assess myocarditis and the circulating biomarkers reflecting myocardial injury can also be related to non-primary J o u r n a l P r e -p r o o f myocardial damage (multi organ failure, hypoxia, hypo-perfusion and activation of hemostasis) [11] .

Overall, several studies report that myocardial injury occurs in 15-27.8% of severe COVID-19 pneumonia cases [12] [13] [14] . Additionally, COVID-19 related myocarditis are also described in patients without prior pneumonia indicating the probability of late onset of cardiovascular complications, even in those with mild symptoms [15, 16] . Otherwise, diffuse myocardial injury was also detected in the early stage of COVID-19 recovered patients who had no active cardiac symptoms [17] .

SARS-CoV-2 is a β-coronavirus whose genome consists of single-stranded RNA with positive polarity that belongs to the Coronaviridae family. The virus invades the human host cell by binding with high affinity to the angiotensin converting enzyme 2 (ACE 2) receptor.

ACE2 can be found on the ciliated columnar epithelial cells of the respiratory tract, type II pneumocytes, and cardiomyocytes. Therefore, this mechanism appears to be the pathway of SARS-CoV-2 infection of the human heart, especially in case of HF as ACE2 is upregulated [18] . After penetration, viral RNA enters the cell nucleus for replication inducing human immunological response to the virus [19] .

The mechanism of heart damage remains poorly understood and several mechanisms have Louise consensus criteria [53, 54] . In clinically stable patients, both CMR and coronary computed tomography could be theoretically performed for myocarditis diagnosis in a radiology section dedicated to COVID-19 patients. CMR is used in COVID-19 patients to assess biventricular function, the pattern of edema and inflammation within the myocardium, and the presence of pericardial involvement. The common imaging findings on CMR included increased T1 and T2 mapping values and edema on T2/STIR sequences [55] . Diffuse edema may be considered the only CMR hallmark of COVID-19 myocarditis because LGE may be completely absent or minimal, revealing unremarkable myocyte necrosis [56] . LGE was seen in less than half of the patients and if present, LGE was detected in the subepicardial location [55] . The presence of biventricular dysfunction, the detection of patchy, mid-wall, septal or inferior LGE enhancement, and its persistence over three months have been associated with adverse cardiac events including sudden cardiac death and heart transplantation [57-59].

In selected cases with CMR suggestive for myocarditis an EMB may be performed. The 

Patients that develop HF from COVID-19 myocarditis should be treated with guidelinedirected medical therapy, including ACE inhibitors, angiotensin receptor blockers (ARBs), or angiotensin receptor-neprilysin inhibitors (ARNi), beta blockers and diuretics [65] . Due to their mechanism of action, there was initial concern that treating COVID-19 patients with ACEi, ARB and ARNi would worsen clinical outcomes. Thus, several recent observational studies showed that there was no significant difference between patients treated with ACEi or ARB and those that discontinue these medications and, therefore, is generally recommended to initiate or continue these drugs during and beyond the disease [66, 67] .

In patients with fulminant myocarditis and cardiogenic shock, in the acute phase is recommended the administration of inotropes and/or vasopressors and in the longer-term may be required mechanical circulatory support [68] .

Appropriate management of cardiac arrhythmias related to COVID-19 myocarditis is crucial in mitigating patient's adverse health outcomes. Bradyarrhythmia may require temporary cardiac pacing, while tachyarrhythmias may respond to antiarrhythmic drugs. Beta blockers may be considered for hemodynamically stable patients whereas amiodarone is typically administered in the critically ill, although it can prompt QTc prolongation, especially when combined with azithromycin or hydroxychloroquine [69] [70] [71] . Alternatively, lidocaine infusion or oral flecainide may be considered [72] [73] [74] .

Therapies for SARS-CoV-2 have focused primarily on restoration of respiratory function and there are little data to define therapeutic options in COVID-19 myocarditis. Different antiviral therapies were expected to be effective in hospitalized patients with COVID-19:

remdesivir, hydroxychloroquine and interferon beta-1a. Unfortunately, all these drugs had little or no effect on overall mortality, initiation of ventilation, and duration of hospital stay [75, 76] . Moreover, many pharmacological agents used empirically to treat COVID-19, especially hydroxychloroquine, may expose patients to an increased risk of cardiac arrhythmias: indeed, hydroxychloroquine, may cause QTc interval prolongation and its combination therapy with macrolides should be accompanied by QTc interval monitoring

Nonsteroidal anti-inflammatory drugs are generally not indicated in myocarditis patients because they are the known cause of renal impairment and sodium retention, which could exacerbate acute ventricular dysfunction [68] .

Since cytokine release syndrome is a probable mechanism of injury in COVID-19 myocarditis, some authors suggested to use anti-inflammatory and anti-cytokine drugs like high-dose steroids and intravenous immunoglobulins (IVIG) [78] . However, the use of highdose steroids in COVID-19 patients has given conflicting results: if in a retrospective study there was an improvement of survival, another trial showed a reduction in viral clearance, increased risk of over infection and mortality for all causes [79] [80] [81] . Overall, in patients hospitalized with COVID-19 the use of corticosteroid resulted in a clinical benefit only in those who were receiving invasive mechanical ventilation and oxygen therapy [82] .

Regarding purified IVIG, they gave encouraging result in a small group of five critical COVID-19 patients without clinically suspected myocarditis but no additional evidence exists in patients with COVID-19 established myocarditis [83] . The immunomodulatory effects of J o u r n a l P r e -p r o o f IVIG are multifactorial showing not only anti-viral effects, but also anti-inflammatory effects by suppressing inflammatory cytokines [84] . Currently, the evidence does not support the routine use IVIGs alone.

Several immune therapies have also been investigated and agents targeting IL-6, such as tocilizumab, have also been evaluated the REMAP-CAP study showing promising results in critically ill patients [85] .

In summary, in patients with isolated SARS-CoV-2 myocarditis who are hospitalized, or hypoxemic, high-dose steroids may be reasonable while should be avoided in patients with less severe illness. Regarding targeted immunomodulatory therapy with IL-6 antagonists, additional data are needed to establish whether it can be recommended for SARS-CoV2myocarditis.

Although there are very limited data about the clinical outcomes of COVID-19 myocarditis, it seems that most patients have a favorable prognosis [56, 86] . It should also be underlined the complexity of the COVID-19 and the possibility to die for other reasons than cardiac involvement (acute severe respiratory distress, systemic embolism, multiorgan failure).

Overall, Shi et al. reported that patients with myocardial injury presented higher mortality rate than those without myocardial injury (51.2% vs. 4.5%; p < 0.001), being an independent risk factor for mortality [12] . In addition, myocardial injury was associated with a higher incidence of severe respiratory distress (58.5% vs. 14.7%), need of non-invasive (46.3% vs.

3.9%) or invasive ventilation (22.0% vs. 4.2%), and complications such as acute kidney injury (8.5% vs. 0.3%) and coagulopathy (7.3% vs. 1.8%) [12] . Also, patients with an increase of troponin present higher levels of leukocytes, D-dimer, ferritin, and IL-6, portraying an important correlation between myocardial injury and inflammatory hyperactivity triggered by J o u r n a l P r e -p r o o f the viral infection. Raised troponin levels in COVID-19 are associated with worse outcome, but the specific prognostic role of myocarditis is unknown [87] .

In general, myocardial involvement in COVID-19 is associated with an increased mortality, but isolated myocarditis is not necessarily a marker of poor prognosis. However, given the paucity of published data and the inhomogeneity of the cases, conclusive assertion on prognosis cannot be made. 

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