key: cord-0919150-xhum1ykr
authors: Kochi, Adriano Nunes; Tagliari, Ana Paula; Forleo, Giovanni Battista; Fassini, Gaetano Michele; Tondo, Claudio
title: Cardiac and arrhythmic complications in patients with COVID‐19
date: 2020-04-13
journal: J Cardiovasc Electrophysiol
DOI: 10.1111/jce.14479
sha: e5299832eede854a8cb2f95e45b0a4cddee12ec4
doc_id: 919150
cord_uid: xhum1ykr

In December 2019, the world started to face a new pandemic situation, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Although coronavirus disease (COVID‐19) clinical manifestations are mainly respiratory, major cardiac complications are being reported. Cardiac manifestations etiology seems to be multifactorial, comprising direct viral myocardial damage, hypoxia, hypotension, enhanced inflammatory status, ACE2‐receptors downregulation, drug toxicity, endogenous catecholamine adrenergic status, among others. Studies evaluating patients with COVID‐19 presenting cardiac injury markers show that it is associated with poorer outcomes, and arrhythmic events are not uncommon. Besides, drugs currently used to treat the COVID‐19 are known to prolong the QT interval and can have a proarrhythmic propensity. This review focus on COVID‐19 cardiac and arrhythmic manifestations and, in parallel, makes an appraisal of other virus epidemics as SARS‐CoV, Middle East respiratory syndrome coronavirus, and H1N1 influenza.

SARS-CoV-2 infection is associated with a variety of proinflammatory mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications. In a single center study 1 cardiac injury was observed in 19% of hospitalized patients with COVID-19, and it was associated with higher risk of inhospital mortality. Therefore, it is plausible that these patients have an even higher risk of cardiac arrhythmias.

Abbreviations: ATP, antitachycardia pacing; CHF, congestive heart failure; CO, cardiac output; COVID-19, coronavirus disease-2019; CRT-D, cardiac resynchronization therapy defibrillator; HCQ, hydroxychloroquine; HF, heart failure; HR, hazard ratio; hs-cTnI, high-sensitivity cardiac troponin I; ICD, implantable cardiac defibrillator; ICU, intensive care unit; LVEF, left ventricular ejection fraction; MERS-CoV, Middle East respiratory syndrome coronavirus; NHC, National Health Commission of China; OR, odds ratio; RBBB, right bundle branch block; SARS, severe acute respiratory syndrome; SARS-CoV, severe acute respiratory syndrome-coronavirus; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2; SCD, sudden cardiac death; SVT, supraventricular tachycardia; TnT, troponin T; VA, ventricular arrhythmias; VF, ventricular fibrillation; VT, ventricular tachycardia.

Aiming to shed some light in this issue, we performed this review focused on COVID-19 cardiac manifestations not only by analyzing   the preliminary available evidence about the virus, but also by   making comparative considerations with SARS-CoV, MERS-CoV, and   H1N1 influenza.

Much of our present knowledge of SARS-CoV-2 comes from previous historical epidemics that preceded the current outbreak, as SARS-CoV, MERS-CoV, and H1N1 influenza syndromes. It was observed, during these outbreaks, a significant association between underlying cardiovascular disease, myocardial injury, and worse outcomes. 4 The first human infection by a new strain of coronavirus, the SARS-CoV, was reported in 2002. At that time it was known that, at least in rabbits, coronavirus infections could induce cardiomyopathy resulting in cardiac chambers dilatation and systolic function impairment, simulating other dilated cardiomyopathies. 5 In humans, hypotension, cardiac arrhythmias, and even sudden cardiac death (SCD) were described as possible SARS-CoV manifestations. 6 In a cohort of 121 patients, Yu et al demonstrated that sinus tachycardia was the commonest cardiovascular SARS-CoV finding with an overall incidence of 72%. Persistent tachycardia mean duration was 12.7 days with a mean heart rate of 117 beats/min (range: 102-150 beats/min) and the tachycardia remained persistent in nearly 40% of patients within 30 days after hospital discharge. The incidence of tachycardia during the third hospitalization week, when most patients were afebrile, could be related to drug treatment, such corticosteroid and ribavirin. However, corticosteroid therapy was not associated with persistent tachycardia during follow-up. Hence, longstanding tachycardia could eventually be due to autonomic tone changing. Or, alternatively, sinus tachycardia secondary to cardiopulmonary or peripheral deconditioning since this disease resulted in prolonged bed rest. 7 Besides these findings, significant sinus bradycardia was seen in 18 (14.9%) patients. Unlike tachycardia, which was persistent, bradycardia was somewhat transient with a mean heart rate of 43 beats/min (range: 38-49 beats/min) and a mean duration of 2.6 days. Reversible cardiomegaly was also reported in 13 (10.7%), with no clinical evidence of heart failure (HF). Transient atrial fibrillation was observed in one patient. 7 Lau et al additionally described that palpitation, in the form of tachycardia at rest or mild exertion, was noted amongst patients recovering from SARS. Possible causes, according to them, were deconditioning, impaired pulmonary function, impaired cardiac function, cardiac arrhythmia, thyroid dysfunction, anemia, autonomic dysfunction, and anxiety state. In the setting of the 2012 MERS-CoV syndrome, despite some similarities with SARS-CoV, the early mortality rate for the former achieved 60%, 10 remaining higher than 35% during the overall outbreak period, while for SARS-CoV the mortality rate was about 10%. 11 A meta-analysis suggested that MERS-CoV infection was more likely to occur in patients with underlying cardiovascular diseases. 12 In terms of overall complications, renal failure (40.9%), F I G U R E 1 Mechanisms and consequences of COVID-19 myocardial damage. COVID-19, coronavirus disease cardiac arrhythmias (15.7%), hepatic dysfunction (31.4%), 13 besides pericarditis, and hypotension were the most commonly reported. 14 In a case report published by Alhogbani, he describes an acute myocarditis caused by MERS-CoV; a 60-year-old presenting with respiratory symptoms, chest pain, and persistent tachycardia (120 bpm). Echocardiogram demonstrated severe left ventricular function impairment, cardiac magnetic resonance showed typical findings of acute myocarditis, and sputum was positive for MERS-CoV. The patient was intubated and required hemodialysis.

After 6 weeks of intensive care unit (ICU) and 1 month of ward hospitalization, he was discharged in stable condition. 15 Last but not least, influenza virus infection is well-known to aggravate plenty of cardiovascular disorders, being associated with myocarditis, myocardial infarction, and HF exacerbation. 16 The multivariate generalized linear model showed that during high influenza activity, patients were more likely to have a VA treated with shock (odds ratio [OR]: 1.06; P < .001) or ATP (OR: 1.06; P < .0001). 17 Multiple mechanisms have been proposed to explain influenza triggering arrhythmias, among them severe systemic, arterial, and myocardial inflammatory reaction seems to be one of the most plausible. Moreover, influenza is known to exacerbate congestive heart failure (CHF) and increase CHF-related hospital admissions. 18 Decompensated CHF, besides leading to hospitalization, is related to electrical myocardial homeostasis impairment, causing ventricular tachycardias (VTs) treated with shock or ATP therapy. In patients with underlying ischemic cardiomyopathy, the worsening of ischemia by increased oxygen demand and potential acute coronary syndromes led by influenza can also have a role in the increase of arrhythmic events. 17 These concepts were strengthened by a nationwide Denmark studied, which showed a strong relationship between yearly influenza vaccination and mortality in patients with HF. In this study, annual influenza vaccination was associated with 18% reduction in the adjusted risk of all-cause death and 18% reduction in the adjusted risk of cardiovascular death (P < .001, for both). Remarkably, those who received more than one seasonal vaccination also had a more pronounced reduction in atrial fibrillation incidence (hazard ratio [HR]: 0.94; P = .009). According to this study, influenza infection may result in increased metabolic demand, hypoxia, and adrenergic surges, which may lead to acute decompensation or exacerbation of HF.

Additionally, the infection may induce a hypercoagulable state and trigger acute coronary syndromes, resulting in further left ventricular function deterioration, or it could cause direct myocardial depression. Based on these results, the authors advocated that influenza vaccination may be a valuable treatment strategy to improve survival in patients with HF. 19 

Despite not being particularly lethal, SARS-CoV-2 is very contagious. In a published clinical cohort of patients with COVID-19, they observed that acute cardiac injury, shock, and arrhythmias were present in 7.2%, 8.7%, and 16.7% of patients, respectively, with higher prevalence amongst patients requiring intensive care. 2 In this report, myocardial injury biomarkers levels were significantly higher in patients requiring ICU admission than in those not treated in the ICU (median creatine kinase-MB level 18 U/l vs 14 U/l; P < .001; and high-sensitivity cardiac troponin I [hs-cTnI] level 11.0 pg/mL vs 5.1 pg/mL; P = .004), suggesting that patients with severe symptoms often have complications involving acute myocardial injury. 2 Overall, arrhythmia rate was also more frequent in ICU patients (44.4% vs 6.9%; P < .001). Despite the relevance of these initial data, the authors did not provide any arrhythmia classification or definition Table 1 . Another relevant aspect of COVID-19 infection is that early diagnosis can be confounded in patients with chronic cardiac conditions, once the most frequent symptoms, like fatigue (51%, 95% CI: 34%-68%), dyspnea (30%, 95% CI: 21%-40%), and cough (67%, 95% CI: 59%-76%) 25 can also be manifestations of decompensated HF or arrhythmic syndrome. Corroborating this concern, the National Health Commission of China (NHC) reported that among SARS-CoV-2 infection confirmed cases, cardiovascular symptoms were the first presentation in some patients. The problem behind these atypical presentations is that patients suffering from heart palpitations and chest tightness rather than respiratory symptoms, such as fever and cough, had a delayed COVID-19 diagnosis. 26 Still T A B L E 1 Cohorts that evaluated cardiac manifestations in SARS-CoV, MERS-CoV, H1N1, and SARS-CoV-2 Al-Albdallat et al 14 9 Chest pain (44%) ND 22%

Pericarditis (1 pt Regarding hypoxemia caused by COVID-19, it is relevant to highlight that this condition can trigger atrial fibrillation, which is the most common arrhythmia among elderly individuals, and that atrial fibrillation can become persistent even before pulmonary improvement. Furthermore, the systemic inflammatory response would make anticoagulation therapy for atrial fibrillation very complex. 30 

Another essential aspect to be discussed is about chloroquine cardiovascular side effects since this is one of the promising drugs that have been tested in patients with COVID-19. It is well-reported that long-term chloroquine use may increase depolarization length duration and Purkinje fiber refractory period, 31-34 ultimately leading to atrioventricular nodal and/or His system malfunction. 31 As an antimalarial drug, both chloroquine and hydroxychloroquine (HCQ) are accumulated in lysosomes, directly inhibiting phospholipase activity, inducing cytoplasmic inclusion body formation, increasing lysosomal pH, and causing protein inactivity. 31, 35 Due to these properties, drug-induced atrial and VAs have been associated with their use. [31] [32] [33] [34] [35] The most usual electrocardiographic alteration is fascicular block, which can lead to advanced types of atrioventricular block, generally associated with syncope. 36 HCQ can also induce QT interval prolongation, an extremely rare but potential fatal side effect, due to the risk of induced polymorphic VT and SCD. The proposed mechanism by which HCQ causes QT interval prolongation is not well understood. In 2015, Capel et al demonstrated, in guinea pig sinoatrial node myocytes, an inhibitory effect of the HCQ on the hyperpolarization-activated current ion channels (also known as "funny current" channels), along with delayed rectifier potassium currents, and L-type calcium ion currents. 37 Inhibitory effects on pacemaker cells were shown to cause delayed rates in depolarization leading to decreased heart rates. These findings may correlate with a proposed mechanism by which refractory action potentials in cardiac myocytes may lead to prolongation of QT interval due to delayed depolarization and repolarization from abnormal ion currents. 38 QT prolongation in individual medical therapy is not always predictable, dose adjustments and/or additional monitoring with electrocardiograms may be appropriate in some cases. HCQ proarrhythmic risk must be monitored in patients with underlying cardiovascular or renal disorders, and high caution should be posed in the case of electrolyte imbalance, dysrhythmias or concurrent use of QTc-prolonging drugs. 38 

Acute lung injury is a common problem in patients with COVID-19

and results in significant morbidity and mortality. However, increasing clinical and epidemiological evidence suggests that COVID-19 infection is associated with myocardial injury and arrhythmic complications.

Even though the prevalence of COVID-19 arrhythmogenic effects has yet not been reported, close cardiovascular surveillance is advisable, particularly in patients with more severe presentation and in those with increased baseline risk due to previous cardiac comorbidities. Since many medications are being used empirically to treat the infection and/or symptoms, there is a need to increase awareness to possible drug interactions and close monitoring in atrioventricular conduction and QT interval.

ORCID

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, China

Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin

The hidden burden of influenza: a review of the extra-pulmonary complications of influenza infection. Influenza Other Respir Viruses

An experimental model for dilated cardiomyopathy after rabbit coronavirus infection

Coronaviruses and the cardiovascular system: acute and long-term implications

Cardiovascular complications of severe acute respiratory syndrome

Tachycardia amongst subjects recovering from severe acute respiratory syndrome (SARS)

Cardiac arrest in severe acute respiratory syndrome: analysis of 15 cases

Update: severe respiratory illness associated with Middle East respiratory syndrome coronavirus (MERS-CoV)-worldwide

Vaccines for emerging infectious diseases: lessons from MERS coronavirus and Zika virus

Prevalence of comorbidities in the Middle East respiratory syndrome coronavirus (MERS-CoV): a systematic review and meta-analysis

Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia

Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description

Acute myocarditis associated with novel Middle East respiratory syndrome coronavirus

Seasonal influenza infections and cardiovascular disease mortality

Effect of high influenza activity on risk of ventricular arrhythmias requiring therapy in patients with implantable cardiac defibrillators and cardiac resynchronization therapy defibrillators

Influenza-associated hospitalizations for cardiovascular diseases in the tropics

Influenza vaccine in heart failure

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Cardiovascular implications of fatal outcomes of patients with coronavirus disease

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Left ventricular performance in patients with severe acute respiratory syndrome: a 30-day echocardiographic follow-up study

Frequency of troponin elevations in patients with influenza infection during the 2017-2018 influenza season

Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis

COVID-19 and the cardiovascular system

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SAR

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Human immunopathogenesis of severe acute respiratory syndrome (SARS)

An acute respiratory infection runs into the most common noncommunicable epidemic-COVID-19 and cardiovascular diseases

Chloroquine-induced cardiomyopathy

Ventricular tachycardia in a patient on dehydroemetine and chloroquine for amoebic liver abscess

Drug-induced ventricular tachycardia. Arch Mal Coeur Vaiss

Chloroquine and cardiac arrhythmia: case report

Antiarrhythmic potential of chloroquine: new use for an old drug

Heart conduction disorders in long-term treatment with chloroquine: two new cases

Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current if: novel electrophysiological insights and therapeutic potential

Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine

A major outbreak of severe acute respiratory syndrome in Hong Kong

Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area

Middle East respiratory syndrome coronavirus: a case-control study of hospitalized patients

Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19)

Cardiac and arrhythmic complications in patients with COVID-19

http://orcid.org/0000-0002-7839-2054Giovanni Battista Forleo http://orcid.org/0000-0001-8895-8915