key: cord-0996392-pvfvrwcr
authors: Akhtar, Zaki; Gallagher, Mark M.; Yap, Yee Guan; Leung, Lisa W. M.; Elbatran, Ahmed I.; Madden, Brendan; Ewasiuk, Victoria; Gregory, Louise; Breathnach, Aodhan; Chen, Zhong; Fluck, David S.; Sharma, Sumeet
title: Prolonged QT predicts prognosis in COVID‐19
date: 2021-04-13
journal: Pacing Clin Electrophysiol
DOI: 10.1111/pace.14232
sha: 1c389217561e4f3b9e413307db4eca7cd7b4c7b7
doc_id: 996392
cord_uid: pvfvrwcr

BACKGROUND: Coronavirus disease‐2019 (COVID‐19) causes severe illness and multi‐organ dysfunction. An abnormal electrocardiogram is associated with poor outcome, and QT prolongation during the illness has been linked to pharmacological effects. This study sought to investigate the effects of the COVID‐19 illness on the corrected QT interval (QTc). METHOD: For 293 consecutive patients admitted to our hospital via the emergency department for COVID‐19 between 01/03/20 ‐18/05/20, demographic data, laboratory findings, admission electrocardiograph and clinical observations were compared in those who survived and those who died within 6 weeks. Hospital records were reviewed for prior electrocardiograms for comparison with those recorded on presentation with COVID‐19. RESULTS: Patients who died were older than survivors (82 vs 69.8 years, p < 0.001), more likely to have cancer (22.3% vs 13.1%, p = 0.034), dementia (25.6% vs 10.7%, p = 0.034) and ischemic heart disease (27.8% vs 10.7%, p < 0.001). Deceased patients exhibited higher levels of C‐reactive protein (244.6 mg/L vs 146.5 mg/L, p < 0.01), troponin (1982.4 ng/L vs 413.4 ng/L, p = 0.017), with a significantly longer QTc interval (461.1 ms vs 449.3 ms, p = 0.007). Pre‐COVID electrocardiograms were located for 172 patients; the QTc recorded on presentation with COVID‐19 was longer than the prior measurement in both groups, but was more prolonged in the deceased group (448.4 ms vs 472.9 ms, pre‐COVID vs COVID, p < 0.01). Multivariate Cox‐regression analysis revealed age, C‐reactive protein and prolonged QTc of >455 ms (males) and >465 ms (females) (p = 0.028, HR 1.49 [1.04‐2.13]), as predictors of mortality. QTc prolongation beyond these dichotomy limits was associated with increased mortality risk (p = 0.0027, HR 1.78 [1.2‐2.6]). CONCLUSION: QTc prolongation occurs in COVID‐19 illness and is associated with poor outcome.

Coronavirus disease-2019 (COVID-19) causes viral pneumonia and severe illness resulting in organ dysfunction including acute respiratory distress syndrome (ARDS) and acute cardiac injury and renal injury. 1 There is also an increased incidence of arrhythmias, especially in those requiring intensive care. 2 As yet, few data are available regarding the effects of the infection on the electrophysiology of the heart. Electrocardiography (ECG) can be used to detect cardiac involvement in multisystem disorders, and often provides prognostic information. In COVID-19, left bundle branch block and ST segment deviation may be associated with increased risk of mortality. 3 The effects on repolarization remain unclear. A risk of QT prolongation was highlighted in cases of COVID-19 treated with hydroxychloroquine and Azithromycin, but the QT abnormality observed may have been more than just a pharmacological effect. 4 

We screened patients who were admitted to our institute via the emergency department with the Sars-Cov-2 virus infection at the height of the COVID-19 outbreak locally. In total, 406 patients presenting to the department tested positive for the infection between 1st March -18th May 2020. Of these, 293 patients were recruited in to the study; 106 were excluded as they did not require hospital admission and were discharged from the emergency department and seven were excluded due to the presence of a paced cardiac rhythm. Data were collected and analyzed for patient demographics, admission ECG, chest

x-ray and blood biochemical and hematological profiles. The left ventricle ejection fraction was calculated by a certified echocardiographer using the Simpson's biplane method; when this was not possible, the visual estimation was accepted. A comparison was performed of patients who succumbed to the infection ("deceased" group) and those who remained alive to the time of last accessing the hospital record at > 6 weeks after presentation ("survived" group wave to the T-wave offset, which was the point of intersection of the downward slope tangent-line with the baseline (Figure 1 ). 5 Correction was performed using Bazett's formula. 6 Corrected QT clinical limits of >450 milliseconds (ms) for males and >460 ms for females were accepted as prolonged. 7 ECGs showing an abnormal prolonged QTc were re-checked by an experienced cardiac electrophysiologist. For all patients included in the study, the pre-existing medical record was searched for a prior ECG. These pre-COVID ECGs, when available, were analyzed in the same manner as the baseline ECG.

In this study the deceased patients (n = 133) were older (82 ± 10. 

We have shown that the QTc interval lengthens during COVID-19

infection, and that the degree of lengthening is greater in those who subsequently die during the illness. This finding was based on the admitting ECG before exposure to any pharmaceutical known to prolong the QT-interval, and is suggestive of mechanisms beyond cardiotoxicity that may alter ventricular repolarisation. 4 COVID-19 associated QT-prolongation may also be a secondary feature, reflecting the severity of a multi-system illness. In our study, the deceased patients were significantly more unwell on-admission as indicated by their higher National Early Warning Score (NEWS), a United Kingdom adopted scoring system implemented to detect patients requiring critical care. 12 The intense inflammatory response characteristic of COVID-19 could produce QT prolongation both by direct and indirect mechanisms. 11 The up-regulation of angiotensin-II by Sars-Cov-2 via binding to the ACE2 receptor can result in excessive inflammation and injury 9 ; the QTc could be an expression of the degree of inflammation. This is consistent with reports which have indicated that ITU stay was associated with QT prolongation 13 and patients admitted to ITU were disposed to arrhythmias. 1, 2 The multivariate analysis revealed that prolonged QTc on presentation was independently associated with an increased risk of mortality in COVID-19 (p = 0.001). This finding has rarely been reported and could easily have been overlooked. 3, 14 Romero et al demonstrated that

new T-wave inversion in COVID-19 was associated with mortality. 14 The ECGs reproduced in their manuscript to illustrate this T-wave inversion also demonstrate marked prolongation of the QTc, although this finding was not remarked upon and the interval was apparently not measured. Lanza et al did find a prolonged QT in a small proportion (5.8%) of COVID-19 patients. 3 By treating QT prolongation as a binary variable, we believe that previous authors may have missed instances in which the interval was prolonged beyond the level that was normal for that patient, but did not exceed the range defined as normal for the population. By contrast, we measured the QTc in all patients and com- The QT-interval responds to changes in heart rate 20 and body temperature 21 and is sensitive to electrolyte disturbance, owing to its dynamic nature. All methods of QT interval correction for heart rate are vulnerable to inter-individual variation and all have proved inaccurate at extremes of the heart rate spectrum. Within our series the groups are well matched for the baseline heart rate and metabolic state, and therefore it is unlikely these factors can explain the differences in the QT interval. The association between QTc prolongation and mortality is also unlikely to be affected by the heart-rate correction formula used. 16 

Prolongation of the QTc in COVID-19 infection is a harbinger of death and may represent the severity of the illness. The findings of our study can be used to triage COVID-19 patients and tailor treatment according to their mortality risk. Our observation should also prompt more caution in the use of QTc prolongation medications for COVID-19

patients during the peak phase of the illness. The long-term effect of Sars-Cov-2 virus on the QT interval is yet to be determined although presumably it should normalize. Future risk of acquired long-QT syndrome in these patients however remains a theoretical concern. Noncardiac causes of QT prolongation are common and include circadian rhythm, age and drug-induced abnormal repolarisation. 5 Long-term QTc surveillance may be beneficial to monitor for risk of sudden cardiac death.

The ECGs analyzed in this series were recorded at the arbitrary time-point of first arrival at our hospital. Therefore, the time interval between the onset of COVID-19 and ECG measurement cannot be accurately determined which may have an implication to the QTc prolongation as it is possible that the QTc prolongation is a dynamic process, it may worsen as the condition worsens or improves when one recovers. This potential wide spectrum of disease severity is difficult to quantify and correct for statistically. Also, the Bazett's corrected QTinterval at high heart rates may be over-estimated but it is a consistent approach and the use of this formula should not affect the mortality risk associated with prolonged-QT.

Prolongation of the QTc interval is associated with mortality in COVID-

19 infection and appears to be independent of drug-toxicity. Frequent QTc monitoring on ECG is advocated in the risk stratification of COVID-19 patients. 

Zaki Akhtar has received funding for a research fellowship from Abbott

Medical.

Data is on file ORCID Zaki Akhtar MBBS https://orcid.org/0000-0002-9365-8826

Mark M. Gallagher MD https://orcid.org/0000-0002-6333-6420

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