COVID-19 Management Considerations With Inherited Arrhythmia Syndromes

Introduction

Over the course of the past 2 years, there has been a continuous increase in the understanding of the various cardiovascular implications of COVID-19. Myocarditis, stress cardiomyopathy, left and right heart failure, myocardial ischemia and infarction, and vascular thromboembolism have all been documented in independent cohorts, along with pericarditis and pericardial effusion. Importantly, atrial and ventricular arrhythmia are highly prevalent.^1,2

The mechanism of arrhythmogenesis in COVID-19 is thought to be multifactorial and related to both direct myocardial injury from viral infection, as well as systemic hypoxia, ischemia, inflammation, electrolyte and metabolic derangements, and the use of antibiotic/antiviral medications. Iatrogenic injury from supportive inotropes and pressors, particularly in critically ill individuals, is another contributing agent. Arrhythmic complications, including atrial fibrillation and ventricular tachycardia (VT), are frequent in patients hospitalized with COVID-19, and correlate directly with disease severity and mortality.^3,4 Patients with inherited arrhythmia syndromes represent a particular subset that is potentially more susceptible to arrhythmic complications related to COVID-19.

In this review, we will highlight central considerations related to the identification, monitoring, and management of patients with inherited arrhythmia syndromes affected by COVID-19, with special emphasis on long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT).⁵ (Figure 1)

Long QT Syndrome

The QT interval is an important electrocardiographic representation of the cardiac depolarization and repolarization process. To ensure rhythm stability and timely electromechanical coupling, the corrected QT interval (QTc) must be maintained within a physiological range. The measurement of the QT interval is not trivial, and QT prolongation is often missed, even by expert cardiologists.⁶ This problem is further exacerbated during acute illness, where ST-T changes and tachycardia alter the typical T wave morphology and create fusion of the T and P waves. Additionally, the QT requires correction for the heart rate, most commonly performed using Bazett’s formula (QTc = QT interval/√RR interval), which overcorrects the QT at fast heart rates (frequent in COVID-19) and undercorrects at slower heart rates. Other formulas exist such as Fridericia, Hodges, Framingham, and Rautaharju, but are less commonly used in clinical practice.^7,8 Each 10 ms increase in QTc correlates with a 5%-7% increased risk of torsades de pointes (TdP).⁸ A QTc interval of >500 msec is considered an inflection point in the risk of TdP⁹ and may require urgent intervention.

Prolongation of the QT interval can result from a wide variety of triggers, many of which are frequently encountered during COVID-19 illness. These include infection, ischemia, hypokalemia, hypocalcemia, and medications—all of which may lead to acquired LQTS in those without underlying LQTS.

Congenital LQTS is a heritable channelopathy resulting in a prolonged QT interval and increased risk for TdP. Reduced repolarizing outward potassium currents or increased depolarizing inward sodium or calcium currents underlie the pathophysiological substrate for LQTS and have a strong genotype-phenotype association, with alterations in 3 genes KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) responsible for more than 80% of cases (Figure 2).^10,11 Because of these underlying genetic abnormalities, patients with congenital LQTS are particularly sensitive to secondary acquired triggers of QT prolongation.

With severe illness from COVID-19, and particularly with direct cardiac involvement as with myocarditis, the inflammatory process may result in both hERG (I_Kr) and Ito potassium channel functional impairment, mediated by tumor necrosis factor alpha (TNFa). Similarly, both IL-1b and IL-6 have been implicated in increased I_CaL currents and action potential prolongation.¹² Additionally, metabolic derangements and especially hypokalemia, with or without diarrhea or vomiting and the use of diuretics in patients with volume overload or severe respiratory dysfunction, can all potentiate marked prolongation of the QT. Indeed, QT prolongation is highly prevalent among patients admitted to the intensive care unit, reported in up to 50% of patients.^13,14 A study of over 3000 patients admitted with COVID-19 in New York City from March to May 2020 confirmed the vast presence of clinically significant QTc prolongation independent of disease severity and the use of medications.¹⁵ Thus, particular attention to QTc monitoring in patients with COVID-19 and associated myocarditis or severe illness with a high degree of inflammation is warranted, regardless of known LQTS.

Drug-induced QT prolongation is an important cause of acquired LQTS, mediated by blocking of the delayed rectifier potassium current (I_Kr). Many QT-prolonging drugs may be used in the setting of severe COVID-19 illness, including antiemetics (ondansetron), antibiotics (macrolides), antiarrhythmics (amiodarone), and others. It is important to note that those with an underlying congenital LQTS are particularly susceptible to develop marked QT prolongation and TdP upon drug exposure.

Early in the pandemic, prior to the development of effective antiviral agents and the universal adoption of vaccination, there was widespread use of chloroquine or hydroxychloroquine in combination with azithromycin for the treatment of COVID-19. These drugs are well known to have QT-prolonging properties. As many as 23% of all inpatients admitted with severe COVID-19 and treated with a combination of hydroxychloroquine and azithromycin developed extreme QTc prolongation of >500 msec.¹⁶ Additional studies have documented TdP in patients treated with this combination.¹⁷ Multiple trials have now confirmed the lack of benefit from chloroquine or hydroxychloroquine alone or in combination with azithromycin in the treatment of COVID-19.^18,19

Until recently, the only effective antiviral to treat COVID-19 was remdesivir, an inhibitor of viral RNA polymerase originally investigated for the treatment of the Ebola virus. Several case reports of bradycardia related to remdesivir were postulated to be related to an active metabolite of the drug, with similar activity to adenosine triphosphate, which may reduce sinus node automaticity. There have been no significant rhythm-related adverse events, QTc prolongation, or occurrence of TdP with remdesivir.²⁰ In December 2021, the US Food and Drug Administration (FDA) gave emergency use authorization for 2 new oral antiviral agents, ritonavir-boosted nirmatrelvir and molnupiravir, to be used for the treatment of COVID-19. The QTc-prolonging effects of ritonavir have not been studied outside of its use in combination with lopinavir; however, during clinical trials, doses of 100 mg alone have not resulted in QTc prolongation in healthy volunteers.²¹ However, ritonavir potently inactivates cytochrome P450 3A4 (CYP3A4) and increases serum concentration of the antiarrhythmics amiodarone, dronedarone, flecainide, propafenone, and quinidine, all bearing the capacity to prolong the QT.²² The novel antiviral agents nirmatrelvir-ritonavir and molnupiravir, as well the numerous novel monoclonal antibody (mAb) therapies (bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab) employed in the treatment of COVID-19 have not shown evidence for QT prolongation in animal and human studies to date.^23-25

Recommendations for QT management of COVID-19. We recommend a 12-lead electrocardiogram (ECG) as well as QTc evaluation and monitoring in all patients who are hospitalized. With QTc >500 ms, or an increase in QTc >60 ms from baseline, continuous telemetry monitoring and consultation with a cardiovascular specialist on the mitigation of risk of TdP is recommended, particularly if the use of concomitant QT-prolonging drugs is necessary.⁵ Recently, we described the use of artificial intelligence to predict drug-induced QT prolongation, which may aid in identification of patients particularly susceptible to the condition.²⁶ In all patients with LQTS, adequate repletion of potassium >4.5 and magnesium >2.0 mEq/L are encouraged. All patients with genetically positive LQTS, irrespective of their QTc interval and including those with a normal QTc, should be treated with a nonselective beta-blocker. The continuation of proven therapies for LQTS, including nonselective beta-adrenergic blockade agents such as propranolol and nadolol, is strongly encouraged unless absolutely contraindicated due to concomitant illness.

Brugada Syndrome

BrS is a familial arrhythmia syndrome with complex inheritance, which manifests as a coved ST-segment elevation pattern in precordial leads V1-V2 along with T wave inversions (type 1 pattern), and in some patients, is associated with ventricular fibrillation (VF). A type 2 BrS ECG pattern is described as a “saddle-back” ST-segment elevation and an upright or biphasic T waves in V1-V2. (Figure 2)

Loss-of-function mutations in SCN5A have been associated with BrS in up to 20% of patients.²⁷ There has been an ongoing debate with regard to the pathological mechanisms underlying both the electrocardiographic patterns and clinical arrhythmia. The “repolarization paradigm” suggests Ito-induced shortening of the epicardial action potential with concomitant dispersion in repolarization. On the other hand, the “depolarization paradigm” suggests a primary depolarization abnormality resulting in conduction delay predominantly in the epicardial right ventricular outflow tract, leading to the Brugada pattern and occurrence of VF.^28-31

Irrespective of mechanism, certain drugs may increase the risk of ventricular arrhythmia in patients with BrS; a full listing can be found at www.brugadadrugs.org. Other high-risk markers that have been suggested in BrS include history of syncope or sudden cardiac death (SCD), male gender, a family history of SCD, spontaneous type 1 Brugada pattern, presence of QRS fragmentation, S-wave pattern in lead 1 or early repolarization beyond V3 on ECG, inducible ventricular arrhythmias on EP study, and presence of a pathogenic SCN5A mutation.^32-34

Importantly, fever has been repeatedly documented to be associated with arrhythmic events in BrS. Fever is also a potent physiological “challenge” converting the ECG of patients with type 2 to type 1 pattern, confirming the diagnosis. This is thought to be mediated via a negative attenuation of the sodium channel at higher body temperatures.³⁵

Although the nature and prevalence of COVID-19 symptoms has been variable with the implementation of vaccines and occurrence of different variants, studies reported fever >38 °C to be present in as many as 78% of symptomatic patients.³⁶ In those hospitalized, prolonged fevers of >7 days occur in 12% of patients. The rates of fever after COVID-19 vaccination from mRNA vaccines is comparatively low at 11%-16% and predominantly resolves within 24 hours. Very high fever above 38.9 °C are present in <1% following vaccination.^37,38 Therefore, it is imperative that patients with known BrS are monitored for arrhythmia and treated promptly and aggressively with antipyretics. VF and arrhythmia-related events are more likely to occur in the setting of high fevers >38 °C.

In patients with type 1 BrS and fever, treatment with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) should be initiated. Higher risk patients with known spontaneous type 1 pattern without an implantable cardioverter-defibrillator (ICD), those with a history of arrhythmic syncope, and those with known pathogenic SCN5A mutations should be monitored in the inpatient setting if fevers are not controlled with antipyretics. Patients with drug-induced type 1 patterns and no prior history of syncope can generally be managed at home with supportive therapy and frequent antipyretic use unless high-risk features, arrhythmia symptoms, or severe COVID-19 illness develops.5 Because of the high prevalence of fever in COVID-19, many patients are incidentally diagnosed with atypical ECG findings, including Brugada-like pattern. We do not recommend routine, diagnostic sodium channel blocker challenge for those with non-type 1 pattern in the absence of arrhythmic symptoms or suggestive history (ie, syncope, family history of SCD).

In patients with ICDs who receive appropriate shocks in the setting of COVID-19 infection and fever, immediate hospital attention should be sought as the risk of electrical storm may continue with persistent fevers and systemic illness. Treatment of such emergencies should consist of isoproterenol infusion and quinidine at 600-1500 mg/day. Simultaneous temperature control with antipyretics and use of external or internal cooling is often necessary.^39,40 Quinidine is an effective therapy for patients with BrS,⁴¹ but special consideration should be directed to patients cotreated with nirmatrelvir-ritonavir, as it will increase the levels of quinidine and may result in potentially life-threatening side effects including severe QT prolongation.   

Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is characterized by adrenergic-induced bidirectional and polymorphic VT in patients with structurally normal hearts and resting ECGs. Mechanistically, diastolic calcium release from the sarcoplasmic reticulum leading to intracellular calcium overload and delayed after depolarization-triggered activity leads to induction of VT. The 2 most common genes associated with this disorder are pathogenic variants in the cardiac ryanodine receptor (RyR2) and the cardiac calsequestrin protein (CASQ2). Patients often present with emotional or physical stress-induced arrhythmias and syncope, with a high rate of SCD by age 30 in untreated patients.^42,43

While no specific management considerations pertain to those with COVID-19, the use of beta-blockers and/or adjunctive flecainide should be continued in patients with CPVT in the setting of acute illness. Caution should be made with flecainide dosing and antivirals containing ritonavir. In those critically ill with COVID-19 and requiring the use of vasopressor support, we recommend avoiding alpha-1 and beta-1 receptor agonists such as epinephrine, norepinephrine, isoproterenol, dopamine, and dobutamine. Acute management of VT storm in the setting of CPVT involves the use of beta-blockade and may require addition of nondihydropyridine calcium channel blockers. Stellate ganglion block may be required for incessant arrhythmia.⁴⁴

Other Arrhythmia Syndromes, General Considerations, and COVID-19 Vaccination

Inherited familial arrhythmia syndromes also include entities such as arrhythmogenic right ventricular cardiomyopathy, early repolarization syndrome, idiopathic VF, and short-QT syndrome. Although there is no robust evidence showing specific association of COVID-19 with these conditions, careful consideration should be applied when treating patients with inherited arrhythmia. Interruption of antiarrhythmic therapy during acute illness should be weighed against potential arrhythmic complications and an alternative plan should be in place for any scenario. For example, if quinidine therapy is interrupted in a patient with idiopathic VF, acute therapy with isoproterenol should be available.       

In the setting of a pandemic, changes to health care delivery have included more frequent remote monitoring, increased use of wearable and at-home ECG technology, and expansion of telehealth services. This facilitates outpatient evaluation, management, and isolation of patients with COVID-19 infection for monitoring of arrhythmia symptoms and evaluation of parameters such as increased presence of asymptomatic atrial or ventricular arrhythmias, marked prolongation of QT intervals, and other changes in electrocardiographic features.

For all inherited arrhythmia syndromes, we believe it is clear that the benefit of COVID-19 vaccination far outweighs any potential risks. The risk of VF is much higher in the setting of prolonged fevers with COVID-19 infection in BrS, as compared with a very short fever duration related to vaccination. There is no QT prolongation known to be associated with COVID-19 vaccination or any contraindication in patients with inherited arrhythmia syndromes.

Conclusion

With the advancement of medical therapy for COVID-19, expansion of vaccination efforts, increased herd immunity and evolution of weaker variants, the hope is that SARS-COV-2 infection will transition to a milder disease with predominantly outpatient clinical management. Nonetheless, patients with inherited arrhythmia syndromes are at elevated risk and require unique management considerations. In particular, the monitoring of QTc in LQTS patients, avoidance of QTc-prolonging drugs (particularly those lacking efficacy in treatment of COVID-19), and awareness of drug-drug interactions in those treated with antiarrhythmic medications is of importance. In BrS patients, highlighting the need for intensive antipyretic therapy in the setting of fevers from COVID-19 infection or vaccination is paramount. 

Correspondence: lior.jankelson@nyulangone.org

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chinitz reports consulting fees from Abbott, Biosense Webster, Biotronik, and Medtronic, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, Biosense Webster, Biotronik, Cardiva Medical (now part of Haemonetics), and Medtronic.

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