QTc prolongation in COVID-19 Patients: Pathophysiology and Considerations for Prevention and Treatment

A 46-year-old male was admitted to the hospital for an episode
of syncope from non-infectious diarrhea...

subsequently found to be positive for SARS-CoV-2. He was stable and discharged home with instructions to self-isolate. Five days later he presented to the Emergency Department with complaints of light-headedness with exertion and hypoxia with an oxygen saturation of 51% on room air. He was quickly intubated for hypoxic respiratory failure and started on peripheral vasopressors for persistent hypotension. An arterial blood gas indicated severe acute respiratory distress syndrome (ARDS), prompting paralyzation and proning. He received initial treatment with azithromycin 500 mg for three days and piperacillin/tazobactam for presumed concomitant pneumonia. His hospital course was complicated by prolonged ARDS and delirium requiring Quetiapine. Given his prolonged Intensive Care Unit (ICU) admission he was started on Remdesivir on day 13 of hospitalization. On day 16, he developed pulseless polymorphic ventricular tachycardia.

Past Medical History
The patient had a history of hypertension that was treated with amlodipine 10 mg daily and labetalol 200 mg twice a day

Differential Diagnosis
The patient had severe sepsis and hypoxic respiratory failure

Follow-Up
Our patient remained in normal sinus rhythm throughout his hospitalization and was transferred out of the ICU to the medical floors where he still resides. He is undergoing evaluation for inpatient rehabilitation.

Discussion
SARS-CoV-2 is the underlying virus causing the global pandemic known as COVID-19. Patients with preexisting cardiovascular disease (CVD) who contract SARS-CoV-2 appear to have an increased risk of severe disease, morbidity and mortality. Furthermore, infection with SARS-CoV-2 has been associated with myocardial injury, defined as an increased serum troponin level, and arrhythmias [1,2]. The exact pathophysiology of myocardial injury has not yet been determined. Studies have shown that the SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2) protein for entry into cells [1]. ACE2 is a membrane-bound aminopeptidase found predominantly in cardiac and pulmonary alveolar cells. Viral entry into cardiac myocytes may be directly related to the ACE2 protein leading to myocardial injury [3]. Myocardial injury likely increases the risk of developing arrhythmias which represented a leading complication (19.6%) in a study of 138 hospitalized COVID-19 patients. Patients with COVID-19 who have myocardial injury have an increased risk of developing ventricular arrhythmias [1].

Volume 29-Issue 4
It is important to recognize that myocardial injury may play a role in the development of arrhythmias in COVID-19 patients.  [6]. IL-6 has been proven to negatively modulate the hERG channel thus prolonging action potential duration in ventricular myocytes. IL-6 also inhibits cytochrome p450 which can increase the bioavailability of several medications including those known to prolong the QT interval, like azithromycin which is being used to treat COVID-19 patients [4].
Several medications being used to treat COVID-19 including hydroxychloroquine, chloroquine and azithromycin are known to be QT prolonging agents and increase a patient's risk of developing acquired LQTS. Although the risk is low, it is likely exacerbated by elevated levels of IL-6 and the use of other sedative medications. A recent cohort study showed that patients who received hydroxychloroquine for COVID-19 were at high risk of QTc prolongation and concurrent treatment with azithromycin was associated with greater changes in QTc [7]. Similar findings were seen in 40 ICU patients treated with hydroxychloroquine with or without azithromycin with larger increases in QTc in the group treated with azithromycin [8,9]. Hydroxychloroquine, chloroquine and azithromycin are known to prolong QTc however little is known about Remdesivir and its effects on the QT interval.
It is certainly possible that Remdesivir contributed to TdP in our patient, however, it remains unclear. Measures must be used to decrease the incidence of TdP in COVID-19. In a case study from Mitra, intravenous lidocaine was used to successfully shorten the QTc interval from 620 ms to 550 ms.9 It may be beneficial as well to block the IL-6 pathway with an anti-IL-6 receptor monoclonal-antibody like tocilizumab which has shortened QTc in patients with rheumatoid arthritis [4].

Conclusion
Factors that contribute to the development of LQTS from a hyperacute immune response with CRS and medications known to prolong the QT interval should all be taken into account when trying to prevent TdP in COVID-19 patients. Ultimately, QTc should be monitored with these patients to help prevent TdP and, if experimental drugs prove efficacious, methods should be implemented to help shorten the QTc if it is prolonged.

I.
The large inflammatory response in COVID-19 patients makes them more susceptible to acquiring LQTS and TdP II. Experimental medications for the treatment of COVID-19 should be used with caution as they increase the risk of LQTS and TdP