A major global health concern has emerged from the rapid spreading of coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first reported in Wuhan, Hubei Province, China, on December 2019. Millions of cases have been reported worldwide, impacting global health and economy. Although it primarily affects the respiratory tract, other organs are concurrently involved such as the cardiovascular system, significantly affecting cardiac function and conduction system, which is associated with increased disease severity and adverse outcomes. As new data emerge, our knowledge about the impact of COVID-19 on cardiac arrhythmias continues to evolve and further studies are required for better understanding of its pathophysiology and management strategies.
One aspect of cardiac injury among COVID-19 patients and overall critical illness is an increased risk for cardiac arrhythmias. These were first described by Wang and colleagues, reporting a 17% (23/138) incidence of arrhythmias; 16 patients were admitted to the intensive care unit (ICU), accounting for 44% of the total number of ICU patients. A recent study revealed normal 12-lead ECGs on only 26% of the patients. Lei and associates reported 24% of arrhythmias in COVID-19 patients, and 33% of ICU admitted patients had developed arrhythmias. (1) In fatal cases of COVID-19, 60% developed arrhythmias, and additionally, cardiac arrhythmias were independently associated with an increased risk of in-hospital mortality (11.5% vs. 5.6% among those patients without arrhythmia; odds ratio, 1.95; 95% confidence interval [CI], 1.33-2.86). In clinically stable patients, a low prevalence of arrhythmias was noted.
In the United States, the data on arrhythmia characterization in COVID-19 patients are now emerging. Recent published cases from New York observed several manifestations of arrhythmias varying from bradyarrhythmias including transient complete heart block (CHB) and high-degree atrioventricular (AV) block, to tachyarrhythmias including supraventricular tachycardia (SVT) and atrial fibrillation/flutter (AF/flutter), as well as ventricular arrhythmias such as monomorphic or polymorphic ventricular tachycardia (VT) and sudden cardiac arrest (SCA) with pulseless electrical activity (PEA).
QTc prolongation leading to torsades de pointes (TdP) was commonly reported in association with various conditions such as electrolyte and metabolic derangements, certain drugs used in the treatment of COVID-19 disease, myocarditis toxicity, and inherited arrhythmia syndromes. Furthermore, a case of Brugada-type pattern 12-lead ECG was present that later resulted in a brief episode of AV nodal reentrant tachycardia (AVNRT).
These manifestations suggest various potential mechanisms for arrhythmogenesis.
The specific cause of arrhythmias among COVID-19 patients has not been specified, but potential mechanisms include not only the direct viral effect but also systemic illness including hypoxia, abnormal host immunologic response, myocarditis, myocardial strain, myocardial ischemia, drug interactions and side effects, electrolyte disorders, and intravascular volume imbalance.
The effects of these mechanisms can cause an exacerbation of a previous underlying cardiomyopathy and conduction disorder or induce new electrophysiological abnormalities in patients without any previous history of cardiac disease.
Lung injury from COVID-19 leads to acute respiratory failure and hypoxemia, which is known to cause hypoxia-induced cellular damage activating anaerobic glycolysis, reducing intracellular pH, and increasing intracellular calcium levels and extracellular levels facilitating early and late depolarization and alterations in the action potential (AP) duration.
Abnormal host immune response
Several cytokines including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 can modulate the expression and function of calcium and potassium channels (inflammatory cardiac channelopathies) causing prolongation of ventricular APs, along with direct myocardial injury. These cytokines cause overactivation of the cardiac sympathetic system using the hypothalamus-mediated inflammatory reflex and peripheral-mediated activation of the stellate ganglion pathway, which can lead to QTc interval prolongation. Cytokines are well known arrhythmogenic triggers, especially in patients with underlying long QT syndrome (LQTS). Furthermore, IL-6 increases the bioavailability of QTc interval–prolonging drugs by inhibition of cytochrome P450 (CYP450).
The pathophysiology of myocarditis can be explained by a possible mechanism that includes direct myocardial injury due to direct viral tissue involvement or due to extrapulmonary migration of infected alveolar macrophages. It can potentially predispose a patient to enhanced arrhythmogenic risk by disrupting electrical conduction. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors on the myocardial cell membrane by utilizing the spike protein. In theory, when SARS-CoV-2 attaches to the ACE2 receptors found on the myocardium, there is downregulation of ACE2 receptors, causing unopposed angiotensin II accumulation, which leads to adverse myocardial remodeling by its action on angiotensin II type 1 receptors.
Another possible mechanism is via cell-mediated cytotoxicity in which primed CD8+ T lymphocytes migrate to the cardiomyocytes and cause myocardial inflammation. Via cytokine storm or cytokine release syndrome, proinflammatory cytokines are released into the circulation, augmenting T-lymphocyte activation that further releases more cytokines and results in a positive feedback loop of immune activation and myocardial injury.
Myocarditis may cause arrhythmia in the acute stage as a consequence of the direct cytopathic effect, producing electrical imbalances, ischemia from microvascular dysfunction, and dysfunction of gap junctions from impaired myocardial expression of connexins. It also may cause ion-channel impairment, which is especially seen in patients with overlapping inflammatory channelopathies.
In viral myocarditis, factors from the host and virus can cause structural as well as electrophysiological remodeling, causing abnormal calcium handling and downregulation of potassium channels, leading to prolonged repolarization and abnormal conduction. Prolonged repolarization can induce triggered activity, whereas in combination with abnormal conduction (which involves reduced conduction velocity, decreased refractoriness, and increased diffusion of conduction in the myocardium) can cause either circus-type reentry or phase 2 reentry without an obstacle. Arrhythmias can also be seen in the postinflammatory stage, promoted by the presence of variable degrees of myocardial scarring.
Myocardial injury with ST-segment elevation has been reported in patients with COVID-19 infection. Microvascular dysfunction and hyperinflammatory state are potential causes for myocardial ischemia by leading to activation of inflammatory cells and a cytokine surge within a preexisting atherosclerotic plaque. This causes vasoconstriction due to dysregulation of the coronary vascular endothelium, which can result in acute coronary syndrome (ACS). IL-6 and TNF-α can both cause depletion of the coagulation and fibrinolytic system, leading to bleeding as well as thrombosis, and promote microvascular dysfunction in the form of disseminated intravascular coagulation (DIC). Another possible mechanism of microvascular dysfunction causing myocardial ischemia is infection-mediated vasculitis triggered as a result of a hypersensitivity reaction induced by direct viral entry in the myocardial endothelial cells or due to indirect immunological response.
The most common reported thrombotic complication in COVID-19 patients is pulmonary embolism and, along with pulmonary hypertension, causes severe acute respiratory distress syndrome (ARDS), heart failure (HF), or sepsis. They can result in an increase of right-sided cardiac filling pressures leading to right myocardial strain. In these patients, there is an increased risk of atrial tachyarrhythmias as a result of increased right atrial pressure and an increased sympathetic tone. A case was reported in a patient who was found to have a temporary occurrence of S1Q3T3 12-lead ECG pattern who later developed transient CHB suggested to be caused by pulmonary arterial hypertension.
Several antimicrobial drugs that are currently being used as potential “off-label” therapeutic agents for COVID-19 have uncertain benefits, yet they are either known to induce or may induce QTc interval prolongation with potential ventricular proarrhythmic effects such as TdP. These agents are chloroquine (CQ), HCQ, azithromycin, and lopinavir/ritonavir. Recent evidence indicates significant QTc interval prolongation in COVID-19 patients receiving HCQ alone or concomitantly with azithromycin. Advanced AV conduction block was also observed. HCQ and azithromycin inhibit the hERG-K+ channel causing prolongation of the AP, and with unopposed inward Na+ and Ca2+ currents they trigger early after depolarization (EAD) leading to TdP. The cardiac effects with other therapies used in COVID-19 including ribavirin, remdesivir, and tocilizumab remain uncertain because there are no sufficient data.
It has been well studied that the effect of electrolyte abnormalities including hypokalemia, hypomagnesemia, and hypophosphatemia is a precipitant for preexistent or new-onset arrhythmias. Electrolyte disturbances were observed in 7.2% of 416 hospitalized patients with COVID-19 infection reported in a case series, and they were attributed to COVID-19–associated acute renal injury or diarrhea.
Intravascular volume imbalance
Intravascular volume imbalance is commonly encountered in critically ill patients as well as in COVID-19 due to either sepsis caused from ARDS, HF, or a combination of both. AF appears to be the most commonly encountered arrhythmia in the critical care setting.
The majority of patients present with a systemic illness consistent with COVID-19, rather than specific signs or symptoms of arrhythmias or conduction system disease. The patients may be tachycardic (with or without palpitation) in the setting of other illness-related symptoms (e.g., fever, pain, shortness of breath, etc.)
Physicians should be cognizant of potential rhythm disturbances in COVID-19 patients. Therefore, it is necessary to have a baseline examination and to determine essential clinical information, such as a history of palpitation, dizziness, arrhythmias, unexplained syncope, family history of premature sudden cardiac death (SCD), and a detailed medication history, especially medications that might cause 12-lead ECG QTc interval prolongation, to evaluate those patients who may be at higher risk for cardiac arrhythmias.
A baseline 12-lead ECG showed be performed at the time of admission on most patients suspected of COVID-19. Although nonessential testing, including serial ECGs, should be avoided to reduce exposure of front-line medical workers and other patients to infectious risk, the ECG should be closely monitored for early warning, intervention and especially in patients with cardiac comorbidities and in whom QTc interval prolonging medications are planned to be used. Physicians should identify any ST-T wave changes accompanied by continuous dynamic changes in two or more leads with R wave domination, abnormal Q waves, continuous, coupled, polymorphic or multifocal premature ventricular contractions (PVCs); new-onset sinus, AV conduction block, complete left or right bundle branch block (LBBB or RBBB), sinus arrest; AF/flutter, AVNRT and low-voltage or wide QRS complexes.
Continuous ECG monitoring and transthoracic echocardiography
These modalities are not required for all patients unless there is a development of cardiac manifestations, documented cardiac arrhythmias, suspected myocardial ischemia or other standard indications.
The management of any bradyarrhythmia or tachyarrhythmia in the setting of COVID-19 infection is no different from the routine management of these conditions without COVID-19 infection and should include optimization of supportive treatments, identifying and correcting secondary causes such as electrolyte or metabolic imbalances, myocardial ischemia, hypoxia, fever and pro-arrhythmic effects of drugs. The goal is to safely treat by limiting exposure and focusing on the transient nature of arrhythmias and drug-drug interactions (Table 5-2).
TABLE 5-2Covid and Cardiac Arrhythmias ||Download (.pdf) TABLE 5-2 Covid and Cardiac Arrhythmias
|Arrhythmias || |
|Mechanism || |
Drug interactions and side effects
Abnormal host immune response
|Diagnostic || |
Clinical history and physical examination
±Continuous cardiac monitoring
|Management || |
Generalized management like non–COVID-19 patients.
Identify and treat secondary causes (electrolyte or metabolic imbalances, myocardial ischemia, hypoxia, fever, and proarrhythmic effects of drugs).
Monitor baseline ECG, QTc interval, K+, Mg2+, Ca2+, and PO42–.
Bradyarrhythmia: atropine, isoprenaline, temporary pacemaker. Need for permanent pacemaker should be reassessed after recovery.
Atrial tachyarrhythmias: rate control or rhythm control.
Ventricular arrhythmias: antiarrhythmic drugs and/or electrical defibrillation.
Special management for patient with inherited conduction disorders.
Minimize healthcare and patient exposure.
Triaging EP procedures.
Isoprenaline and atropine can be used in patients with persistent bradycardia and should be considered prior to the implantation of a temporary transvenous pacemaker. Given the transient nature of bradyarrhythmias, nature of critical illness, risk of bacterial superinfection, and risk of device infection, prior to implanting a permanent device, temporary pacemaker implantation is considered reasonable. The evaluation of a permanent pacemaker should be reassessed after recovery from COVID-19 infection.
For acute termination in patients with SVT, intravenous adenosine can be used and synchronized electrical cardioversion can be considered in patients with refractory cases; it should be postponed in asymptomatic and stable patients. Maintenance therapy with β-adrenoceptor (BBs) or calcium-channel antagonists (CCBs) may be initiated if there are no contraindications. Drug-drug interactions with antiviral agents must be evaluated prior to initiation of these medications to avoid the risk of bradycardia and QTc interval prolongation.
Similarly, patients with new-onset of AF/flutter with a stable rhythm can be treated with rate control. Rhythm-control strategy should be reserved for patients with hemodynamically unstable patients or in HF patients. It can be achieved with synchronized electrical cardioversion or antiarrhythmic drugs (AADs) such as amiodarone. There is a high risk of immediate arrhythmia recurrence without the use of any AAD as maintenance therapy, which can be minimized by treating secondary causes of arrhythmias prior to attempting rhythm-control strategy. Once hemodynamically stable, discontinuation of AADs should be considered given serious drug-drug interactions with antiviral drugs and rate-controlling medications started with BBs or CCBs unless contraindicated, with or without digoxin. In terms of anticoagulation, there are data suggesting that COVID-19 infection might be associated with a hypercoagulable state, increasing the risk for thromboembolism. After recovering from COVID-19 infection, a rate- versus rhythm-control strategy should be reassessed along with the need for anticoagulation.
If the patient develops sustained VT, intravenous infusion of amiodarone and other antiarrhythmic medications may be administered, but external defibrillation can be used if necessary. If ventricular fibrillation (VF) occurs, then advanced cardiac life support (ACLS) protocol must be implemented with immediate defibrillation.
The Heart Rhythm Society COVID-19 Task Force has created a consensus document that divides electrophysiological procedures into urgent or emergent, semi-urgent, and nonurgent or elective procedures. Emergent procedures are considered if they reduce the risk of clinical deterioration, hospitalization, or death. Elective and nonurgent procedures should be postponed until a later date to minimize the potential exposure of healthcare personnel. Conversely, urgent and semi-urgent procedures should be performed if the perceived benefits of the procedure to the patient outweigh the risks of resource utilization and healthcare personnel exposure. (1-5)
It is recommended to obtain a pretreatment baseline 12-lead ECG, QTc interval measurement, and baseline electrolytes (K+, Ca2+, and Mg2+) to determine high-risk cardiovascular and comorbid conditions.
A dynamic discussion with the patient about the benefits and risks of receiving any QTc interval–prolonging medications should be ongoing based on the baseline risk perceived or actual benefit of therapy and development of significant QTc interval prolongation or TdP.
Reevaluation of the risk of TdP, discontinuation of other QTc interval–prolonging medications, and correction of all electrolyte abnormalities is recommended, as well as placing the patient on continuous telemetry or mobile 12-lead ECG devices, with consideration of a wearable defibrillator (LifeVest) or placement of external defibrillator patches.
After recovery from COVID-19 infection, evaluation of a permanent pacemaker and automatic implantable cardioverter defibrillator therapies should be reassessed.