COVID-19, Arrhythmic Risk, and Inflammation

Abstract

oronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). 1Besides direct tissue invasion, SARS-CoV-2 can also elicit an exaggerated host immune response, frequently leading to a cytokine storm, which significantly contributes to multiorgan dysfunction. 1 Indeed, high levels of circulating cytokines, particularly interleukin (IL)-6, are commonly found in patients with COVID-19, also associating with in-hospital death. 1 Accumulating data point to an increased cardiovascular disease morbidity and mortality in these patients. 1In particular, growing evidence suggest that COVID-19 is burdened by a higher risk of arrhythmic events, with important implications for survival. 1Heart palpitations were reported as one of the most common initial symptom of the disease (7.3%). 1 In 138 hospitalized patients with COVID-19, arrhythmias represented the leading complication (19.6%) after acute distress respiratory syndrome, particularly in those admitted to intensive care unit where the prevalence rose to 44.4%. 1 Specifically, malignant ventricular arrhythmias (ie, ventricular tachycardia/fibrillation) were found in 5.9% of cases. 1 It is currently believed that myocardial damage might represent a main driver of enhanced arrhythmic risk in these patients. 1Cardiac myocyte injury, reflected by increased troponin levels, was demonstrated in many individuals, particularly in those with severe disease.Accordingly, higher incidence of ventricular tachycardia/fibrillation was reported in patients with elevated troponin-T levels. 1 Although the mechanisms of myocardial involvement are still under investigation, they probably include direct viral infection, hypoxia-induced apoptosis, and cytokine storm-related cell damage (Figure ). 1 However, the evidence presented that in intensive care unit patients, despite the high frequency of arrhythmias (≈50% of cases), only half showed acute cardiac injury (with median troponin-I levels falling in the normal range), which suggests that factors other than myocardial damage are also involved in enhancing the arrhythmic risk in COVID-19.In this regard, the potential role of pharmacological treatments in enhancing the susceptibility to QT-related life-threatening ventricular arrhythmias, particularly Torsades de Pointes (TdP), is increasingly recognized. 1 In fact, some off-label drugs used to counteract the virus invasion and replication may promote corrected QTinterval (QTc) prolongation.This is the case of chloroquine/hydroxychloroquine, antimalarial agents blocking infection by increasing the endosomal pH required for virus/cell fusion, and lopinavir/ritonavir, protease inhibitors interfering with the virus RNA replication.Notably, in both cases, the impact on ventricular repolarization is direct, via inhibition of the hERG-K + channel, and also indirect by increasing circulating levels of other concomitant QT-prolonging drugs. 1 In fact, chloroquine and hydroxychloroquine inhibit CYP2D6 (cytochrome P450 2D6), which metabolizes several antipsychotics, antidepressants, and antihistamines,

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