There is compelling evidence for an association between influenza epidemics and major adverse cardiovascular events like Myocardial infarction (MI), stroke, and SCD. These all may be prevented by influenza vaccination . 10,11 Influenza epidemics is also associated with higher risk of out-of-hospital cardiac arrest (OHCA). 12
Although the direct causal association of SCD and COVID-19 remain unproven, analysis of the present data suggests a plausible association. Increase incidence of SCD has been reported both in community and hospital settings.
Data from the Houston Fire Department shows a 45% jump during this COVID-19 pandemic, in the number of cardiac arrest calls that ended with patient dead. 13 Data from Italy suggests a significant positive association with spread of COVID-19 and an increase number of OHCA. There is 58% rise in OHCA as compared to the previous year's. 14, 15 A total of 103 patients out of 362 who had OHCA arrest were suspected or confirmed diagnosis of Covid-19 and were responsible for 77.4% of increase in cases of OHCA. 14 A two-fold rise in OHCA has also been noticed concurrent with COVID-19 pandemic in the registry data from Paris. 16 Although OHCA may be partly related to direct COVID-19 deaths, indirect effects like lockdown, behaviour changes, and health system issues may also be contributing.
Hospital data from China revealed that 27.8% of admitted COVID-19 patients had myocardial injury. Patients with elevated troponin levels had more frequent malignant arrhythmias (11.5% vs 5.2%). Overall mortality was much higher in elevated troponin levels (59.6% vs 8.9%) 17 A study of 146 hospitalized COVID-19 patients in China reported a cardiac injury incidence of 20% and a much higher mortality of 51.2% compared with 4.5% in patients with cardiac injury versus no cardiac injury. 18 Study from Philadelphia reported 1.3% incidence of cardiac arrest amongst 700 patients admitted for COVID- 19 . Notably, all cardiac arrest occurred in patients admitted to intensive care unit (ICU) and the reported rhythm in 8 of the 9 patients was asystole or pulseless electrical activity with only 1 patient having Torsades des pointes (TdP). 19 J o u r n a l P r e -p r o o f
In a global survey carried out by Heart Rhythm Society Atrial fibrillation (21%) was the most commonly reported tachyarrhythmia, whereas severe bradycardia (8%) and complete heart block (8%) were the most common bradyarrhythmias. Respondent reported incidence of 4.8% for ventricular tachycardia/ventricular fibrillation arrest and 5.6% of pulseless electrical activity amongst hospitalized COVID-19 patients. 19 All of this evidence point out some association of increase mortality and SCD with COVID-19 infection.
The mechanism of SCD in COVID-19 can be multifactorial. (Table 1 ). However, due to lack of data, it remains difficult to ascertain the most common mechanism involved. Both tachyarrhythmia and bradyarrhythmia have been reported in COVID-19. 19 Life threatening arrhythmias have been variably reported from 10-16% of patients hospitalized for severe COVID-19, more commonly in the setting of elevated troponin indicating myocardial injury. 5, 11, 17, 19 The arrhythmias and SCD often cluster in the ICU setting in patients with more severe systemic illness. 5 Multiple factors play an important role in such a setting, including hypoxia, acidosis, dyselectrolytemia, drug interactions, and importantly direct cardiac involvement in the form of myocarditis and acute coronary syndrome. Up to one third of patients admitted to ICU with COVID-19 have been shown to develop concurrent myocarditis or stress cardiomyopathy. 6, 7, 17, 21 Arrhythmias in the acute setting of myocarditis may be due to a direct cytopathic effect, causing electrical imbalance, ischemia and gap junction dysfunction from impaired myocardial expression of connexins, or due to impairment of various ion channels.
Because of this electrophysiological remodelling there is abnormal calcium handling and down-regulation of potassium channels which leads to prolonged repolarization and abnormal conduction. This may lead to triggered activity or either circus-type re-entry or phase 2 re-entry. 22 In the post inflammatory stage, arrhythmia can be seen, due to variable degrees of myocardial scaring which promotes re-entrant. 23 In an observational study of patients who have recently recovered from COVID-19 and underwent cardiac magnetic resonance (CMR) with a median duration of 71 days from infection, 78% were found to have some cardiac involvement and 60% had ongoing inflammation, followed by regional scar and pericardial enhancement. This is irrespective of preexisting conditions, the severity of illness and overall course of the COVID-19 presentation. 24 In a retrospective study of twenty-six patients recovered from COVID-19 and reported cardiac symptoms, 58% had abnormal CMR findings on conventional CMR sequences: myocardial edema was found in 54% and late gadolinium enhancement was found in 31% . 25 case-control analysis of symptomatic healthcare workers receiving pre-exposure HCQ prophylaxis revealed no increased risk of adverse reactions or arrhythmias. 27 Despite using a higher dose of HCQ (800 mg od, followed by 600 mg in 6-8 hours, then 600 mg od for 4 additional days), no arrhythmias or deaths were noted. 28 The
Incidence of QTc prolongation in COVID patients treated with HCQ /CQ ranges from 7% to as high as 36% depending upon doses. However no ventricular arrhythmia, including torsades de pointes, were recorded. [27] [28] [29] [30] .
Other drugs including azithromycin and lopinavir/ritonavir have also been implicated to confer a higher risk of SCD, when used alone or in combination with other QTc prolonging drugs. Rosenberg 35 QTc prolongation was commonly observed in subjects with elevated C-reactive protein from different inflammatory conditions, also robustly correlating with IL-6 concentrations. 36 In the setting of a viral infection, pre-existing chronic cardiovascular diseases can become unstable due to increased metabolic demand, reduced cardiac reserve, acute inflammatory responses. 18 It has been shown that the inflammatory activity within coronary atherosclerotic plaques is exacerbated during systemic inflammatory response due to acute infection, making them prone to rupture and causes acute coronary syndrome. 37 Fatal arrhythmias in COVID-19 may also result due to hypoxia because of, direct viral lungs involvement, cardiac dysfunction, or severe systemic inflammatory state, electrolyte derangements, intravascular volume imbalances, and drug side effects. 19 Hypoxia can lead to fatal arrhythmias by several ways. It increases cytosolic calcium levels leading to early and late depolarizations and temporal alterations in the action potential duration. It also increase the extracellular potassium levels, which decreases the threshold for depolarization, accelerating electrical conduction. 38 Hypoxemia can also cause reduced electrical coupling and tissue anisotropy due to dephosphorylation of connexin 43 in the gap junctions. 39 Clinically significant heart blocks have also been reported in COVID-19. 19 Acute thrombosis can manifest into SCD through acute pulmonary embolism and in situ pulmonary thrombosis or coronary thrombosis with subsequent myocardial infarction. 42 Up to 50% of the patients admitted in ICUs with COVID-19 pneumonia develop thrombotic events. 43, 44 Pulmonary thromboembolism has been indeed most common thrombotic complication. 42, 43, 44, 45 It is commonly reported from ICU setting, affecting up to one third of all critically ill patients. 43, 44, 45, 46 Acute pulmonary embolism is a major concern that can act as a perpetuator of SCD. The high risk of thrombotic events has already prompted a widespread routine prophylaxis in the form of heparin in all hospitalized COVID-19 patients.
Acute coronary syndrome (ACS) because of coronary thrombosis (type I myocardial infarction) due to SARS-CoV-2 infection seems a real possibility, but has been limited to very few case reports. 47 Type II myocardial infarctions secondary to persistent hypoxia and consequent demand-supply mismatch are more common and lead to myocardial injury. Antiplatelet therapies according to guidelines must be instituted once a diagnosis of ACS is made. Close monitoring is warranted as COVID-19 patients as they are also at high risk of bleeding due to consumption coagulopathy/ disseminated intravascular coagulation, commonly seen in critically ill patients. 48 Other mechanisms have been also been reported to predispose to SCD in COVID patients on a case to case basis. These include coronary artery dissection, 49 Most do not recommend to do CPR in this situation.
The exact arrhythmic risk related to COVID-19 patients with less severe illness or those who recover from the acute phase of the severe illness is currently unknown. Improved understanding of this is critical, primarily in guiding decisions on whether additional arrhythmia monitoring is needed after discharge or whether an implantable cardioverter defibrillator or wearable cardioverter defibrillator will be needed in those with impaired left ventricular function.
To conclude, an increasing trend of SCD concurrent with SARS-CoV-2 pandemic has been observed. SCD is often multifactorial with interlinked mechanisms. Keeping a high index of suspicion with active risk stratification followed by suitable preventive measures hold the key towards reducing SCD incidence. 