key: cord-0705203-ci6ygllt
authors: Anupama, B K; Adhikari, Soumya; Chaudhuri, Debanik
title: Prolonged QT Interval in a Patient With Coronavirus Disease-2019: Beyond Hydroxychloroquine and Azithromycin
date: 2020-08-07
journal: J Investig Med High Impact Case Rep
DOI: 10.1177/2324709620948407
sha: edfcdbaa04c5ea94769ed0b88620d4a1885be492
doc_id: 705203
cord_uid: ci6ygllt

Recent reports have suggested an increased risk of QT prolongation and subsequent life-threatening ventricular arrhythmias, particularly torsade de pointes, in patients with coronavirus disease-2019 (COVID-19) treated with hydroxychloroquine and azithromycin. In this article, we report the case of a 75-year-old female with a baseline prolonged QT interval in whom the COVID-19 illness resulted in further remarkable QT prolongation (>700 ms), precipitating recurrent self-terminating episodes of torsade de pointes that necessitated temporary cardiac pacing. Despite the correction of hypoxemia and the absence of reversible factors, such as adverse medication effects, electrolyte derangements, and usage of hydroxychloroquine/azithromycin, the QT interval remained persistently prolonged compared with the baseline with subsequent degeneration into ventricular tachycardia and death. Thus, we highlight that COVID-19 illness itself can potentially lead to further prolongation of QT interval and unmask fatal ventricular arrhythmias in patients who have a prolonged QT and low repolarization reserve at baseline.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 infection, has resulted in significant morbidity and mortality globally. 1 Accumulating evidence has demonstrated an increased frequency of cardiovascular complications, including cardiac arrhythmias, with possible implications for prognosis and survival. 1 In a Chinese cohort of 138 hospitalized COVID-19 patients, 16.7% of the patients had cardiac arrhythmias, which were more common in the intensive care unit than in non-intensive care unit patients (44.4% vs 6.9%). 2 Although the data on arrhythmogenic events are anecdotal, the most commonly reported arrhythmias in COVID-19 patients include atrial fibrillation (AF), atrial flutter, monomorphic or polymorphic ventricular tachycardia, atrioventricular heart block, and pulseless electrical activity. 3 Several recent reports have suggested an increased risk of QT prolongation and subsequent risk of life-threatening ventricular arrhythmias, particularly torsade de pointes (TdP), in COVID-19 patients who received pharmacologic treatment with hydroxychloroquine/chloroquine and azithromycin. 1 We report the case of a 75-year-old patient with a baseline prolonged QT interval in whom the COVID-19 illness resulted in further remarkable prolongation of QT interval (>700 ms), leading to fatal ventricular arrhythmias and death, in the absence of pharmacological treatment with hydroxychloroquine/ azithromycin.

A 75-year-old female with a past medical history of paroxysmal AF, nonischemic cardiomyopathy with recovered ejection fraction, type 2 diabetes mellitus, hypertension, chronic kidney disease stage IV, and hypothyroidism presented with a worsening cough and shortness of breath for 3 days and was diagnosed with COVID-19. Initial vital signs were blood pressure 148/76 mm Hg, heart rate 120 beats per minute, respiratory rate 32 breaths per minute, temperature 36.2 °C, and oxygen saturation 96% on 2 liters oxygen. Physical examination revealed respiratory distress, scattered bilateral lung crackles, and no peripheral edema. Initial electrocardiogram (ECG) demonstrated AF with premature ventricular complexes and a corrected QT (QTc) interval of 473 ms ( Figure 1 ). The patient was found to have prolonged QTc at baseline ranging from 460 to 510 ms on reviewing several ECGs from previous admissions ( Figure 2 ). Chest X-ray showed diffuse bilateral patchy opacities ( Figure 3 ). Clinical laboratory findings at admission were white blood cell count 2400 cells/µL, creatinine 2.51 mg/dL (baseline creatinine = 2.5 mg/dL), bicarbonate 17 mmol/L, potassium 4.9 mmol/L, magnesium 2.9 mmol/L, corrected calcium 9.2 mg/dL, thyroid-stimulating hormone 0.923 µ/mL, ferritin 2242 ng/mL, erythrocyte sedimentation rate 74 mm/h, D-dimer 1.24 µg/mL, lactate dehydrogenase(LD) 599 U/L, C-reactive protein (CRP) 91.5 mg/L, troponin T 0.06 ng/mL, N-terminal pro-Btype natriuretic peptide 8216 pg/mL, and interleukin-6 (IL-6) 14 pg/mL ( Table 1 ). The patient's home medications, including insulin, metoprolol, levothyroxine, and losartan, were continued along with supportive care. She did not receive hydroxychloroquine and azithromycin due to prolonged QTc. On hospital day 2, the patient developed worsening hypoxia, requiring intubation and mechanical ventilation. Computed tomography scan of the thorax demonstrated worsening diffuse bilateral ground-glass opacities ( Figure 4 ). Repeat ECG showed sinus bradycardia with first-degree heart block, deep T-wave inversions in the inferolateral leads, and markedly prolonged QTc of 718 ms ( Figure 5 ). Arterial blood gas obtained immediately after intubation showed hypoxemia and acidosis. A repeat metabolic panel showed normal serum electrolytes (Table 1) . Intravenous magnesium was administered, home metoprolol was discontinued due to bradycardia, and close cardiac monitoring was instituted. The patient continued to have persistently prolonged QTc, ranging from 600 ms to 720 ms along with intermittent bradycardia and deep T-wave inversions on telemetry monitoring, despite the correction of hypoxemia, acidosis, and aggressive electrolyte replacements. Head computed tomography head showed no acute intracranial pathology. Transthoracic echocardiogram showed an estimated left ventricular ejection fraction of 50% with no regional wall motion abnormalities. On hospital day 5, the patient developed recurrent self-terminating episodes of TdP without hemodynamic collapse ( Figure 6 ). After loading with 2 g of intravenous magnesium, isoproterenol infusion was started. A temporary transvenous pacemaker was inserted with a Figure 1 . Electrocardiogram on admission demonstrates atrial fibrillation with premature ventricular complexes, a ventricular rate of 95 beats per minute, and corrected QT of 473 ms. Bazett formula is used to correct the QT interval (QTc) for heart rate. There is no consensus regarding the measurement of QT interval in patients with atrial fibrillation. Some suggest averaging the measured QT interval over 10 beats or averaging the QT intervals with the shortest and longest preceding RR intervals. 7 In the above electrocardiogram, it is difficult to discern the QT interval for 10 successive beats. Hence the QT interval is calculated by averaging the shortest and longest QT interval.

pacing rate of 100/min to induce tachycardia and improve QTc duration. On hospital day 10, the pacemaker was removed, as the patient's intrinsic heart rate was maintained around 80 to 90 beats per minutes. With initially improved respiratory function, the patient was extubated on hospital day 14. However, the repeat COVID-19 test remained positive, and the patient experienced worsening respiratory distress. The patient and family decided on a do not resuscitate/ do not intubate order. Unfortunately, on hospital day 20, the patient had several runs of ventricular tachycardia/ventricular fibrillation with underlying prolonged QTc of >600 ms, culminating in cardiac arrest and death (Figures 7 and 8 ).

Long QT syndrome (LQTS) is characterized by prolongation of QTc intervals on surface ECG >440 ms. QTc intervals of 440 to 460 ms in men and 440 to 470 ms in women are considered borderline; the risk of arrhythmias increases with values ≥500 ms. 4 LQTS is associated with risk of TdP, a life-threatening polymorphic ventricular tachycardia that is usually self-limited but may degenerate into ventricular fibrillation and cause sudden cardiac death. Acquired LQTS is a disorder of cardiac repolarization characterized by pathologic excessive prolongation of the QT interval that occurs on exposure to the external trigger and reverts to normal following the trigger's removal. 4 Acquired LQTS is mostly secondary to adverse effects of medications and electrolyte abnormalities, such as hypokalemia, hypomagnesemia, and hypocalcemia. 4,5 Phase 3 of the ventricular myocyte action potential is characterized by efflux of potassium ions predominantly through 2 subtypes of delayed rectifier potassium current, IKr (rapid), and IKs (slow), leading to myocardial repolarization. 4, 5 IKr current proteins are encoded by the human ether-a-go-go-related gene (hERG). The blockade IKr or interaction with hERG by specific drugs characterize acquired LQTS and TdP, causing a delay in phase 3 rapid repolarization of the action potential and subsequent QT prolongation. 4,5 Pharmacologic treatments for COVID-19, such as hydroxychloroquine/chloroquine and lopinavir/ritonavir, have been shown to prolong QT directly through inhibition of the hERG-potassium channel and indirectly by increasing circulating levels of other concomitant QT-prolonging drugs by cytochrome 450 enzyme inhibition. 6 Cardiac arrhythmias are likely multifactorial in COVID-19 patients and may be attributable to acute myocardial injury or secondary to hypoxia, metabolic derangements, neurohormonal/catecholaminergic stress, antiviral drugs, and severe systemic inflammation in the acute viremia context. 1,6 Acute cardiac injury characterized by elevated cardiac biomarkers is a frequently reported cardiac complication and likely a potential trigger for heightened arrhythmic risk in COVID-19 patients. Accordingly, a new-onset malignant arrhythmia in COVID-19 patients associated with elevated cardiac markers should raise the possibility of underlying myocarditis. 1, 6 However, another potentially essential trigger for arrhythmias is a high-grade systemic inflammatory state characteristic of COVID-19. 6 Increasing evidence strongly suggests systemic inflammation as a significant risk factor for QT prolongation and TdP via inflammatory cardiac channelopathies. 4, 6 Cytokines such as IL-6, tumor necrosis factor-α, and interleukin-1 can directly modulate the expression and function of several cardiomyocyte ion channels and prolong the ventricular action potential duration. 4,6 IL-6 has been shown to prolong QT directly by inhibiting the hERG-potassium channel and indirectly by inhibiting CYP3A4, increasing the bioavailability of QT-prolonging agents. 6 Systemic inflammation can also induce cardiac sympathetic system hyperactivation through direct stimulation of the autonomic nervous system and hence increase the heart's electrical instability. 6 QTc prolongation has commonly been seen in patients with elevated CRP due to other inflammatory conditions. 4, 6 Severe COVID-19 illness is associated with a hyperinflammatory state similar to cytokine storm syndrome, characterized by an uncontrolled dysfunctional host immune response, resulting in elevated pro-inflammatory markers (serum ferritin, CRP, D-dimer, and LD) and cytokines such as IL-6 that manifest clinically as rapid progression to acute respiratory distress syndrome, shock, and multiorgan failure. 1 Studies have shown higher prevalence of cardiovascular complications, including cardiac arrhythmias, when these biomarkers are elevated. 1 The baseline prolonged QT interval in our elderly female patient with multiple medical comorbidities may be secondary to undiagnosed inherited ionchannel disorders, or the previous cardiomyopathy. In the setting of prolonged baseline QT and low repolarization reserve, the COVID-19 illness-associated severe systemic inflammation (as evidenced by high serum concentration of ferritin, LD, CRP, erythrocyte sedimentation rate, D-dimer, and IL-6) likely led to further severe prolongation the QT interval. In our patient, QTc remained persistently prolonged despite the correction of hypoxemia and metabolic derangements. There was no evidence of myocardial infarction, myocarditis, or heart failure, based on modest troponin elevation and no regional/global wall motion abnormalities in echocardiography. Our patient was not treated with hydroxychloroquine/azithromycin or other common medications associated with QTc prolongation. Thus, severe systemic inflammation in the context of acute viremia due to persistent SARS-CoV-2 infection is the most plausible explanation for markedly prolonged QTc and subsequent TdP and malignant ventricular arrhythmias in our patient. Further studies are required in the future to elucidate the predominant mechanisms and treatment strategies for COVID-19 related cardiac arrhythmias. 

We report an elderly female COVID-19 patient who developed worsening pathologic and excessive prolongation of QTc from baseline degenerating to TdP and malignant ventricular arrhythmias. Although COVID-19-related cardiac arrhythmias are multifactorial in etiology, we suggest that a robust systemic inflammatory response associated with severe COVID-19 is likely the predominant mechanism for severe QT interval prolongation and subsequent TdP in our patient.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Our institution does not require ethical approval for reporting individual cases or case series.

Informed consent for patient anonymized information to be published in this article was not obtained from the patient's family because our institution does not require informed consent for individual case reports.

Anupama B K https://orcid.org/0000-0002-6345-8153

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