Beyond the Virus: QTc Interval Changes in COVID-19 Survivors

doi:10.21203/rs.3.rs-4018677/v1

Download PDF

Research Article

Beyond the Virus: QTc Interval Changes in COVID-19 Survivors

https://doi.org/10.21203/rs.3.rs-4018677/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 receptors on host cells to enter the cells. These receptors are expressed on heart muscle tissue and the tissues of other major organs, which supports the primary accepted theory for the direct cardiac cell injury of coronavirus disease 2019 (COVID-19) and the associated cardiorespiratory manifestations. The SARS-CoV-2 infection leads to unstable myocardial cell membranes due to hypoxia, myocarditis, myocardial ischemia, and abnormal host immune response. This is the main reason behind arrhythmia and electrocardiogram (ECG) changes during COVID-19. However, the specific effect on QTc after Covid 19 infection has not been studied well. Therefore, this study aimed to examine the association between post COVID-19 infection and QTc changes.

Objectives:

Examine the association between post COVID-19 infection and QTc changes.

Materials and Methods:

This is a case control study conducted on middle age of either sex involves 50 adult patients with post-COVID-19 infections (eight were defaulted from the study because they were not cooperative), 23 females and 19 males with mean age (36.98 ± 12.2 years) who were non-vaccinated against Covid 19 after one month to two years of an acute episode of COVID-19 (confirmed by positive real-time reverse-transcription polymerase chain reaction (RT-PCR)) test according to the World Health Organization (WHO) selected randomly from those attending to the adult Holter and Echocardiography lab in Al-Zahraa Hospital/ Al-Hussein Medical City/ Karbala Province after being referred by Internist during the period from the 12th of October 2022 to the end of January 2024 and divided in to three groups : non hospitalize, hospitalize and admitted to intensive care while control group consisted of 40 healthy persons 23 females and 17 males with mean age (33.28 ± 9.58 years), whom referred by Internist for ECG with no Hx of the previous infection of covid 19. All of them have electrocardiographic evaluation by taking ECG.

Conclusion

That post COVID-19 patients had prolonged QT and QTc intervals increase the risk for cardiac arrhythmias.

Physiology

Cardiac & Cardiovascular Systems

SARS-CoV-2

COVID-19

ECG

QTc

QTc prolongation is a condition where the heart’s electrical activity takes longer than normal to recover after each beat, this can increase the risk of abnormal heart rhythms and sudden cardiac death. QTc prolongation is measured by the corrected QT (QTc) interval on an electrocardiogram (ECG). Some studies have suggested that QTc prolongation is more common in patients with COVID-19, especially those who receive certain antiviral drugs such as hydroxychloroquine and azithromycin. The exact mechanism of QTc prolongation in COVID-19 is not fully understood, but it may be related to the direct effects of the virus on the heart, the inflammatory response, electrolyte imbalances, or drug ´ interactions ¹´². QTc prolongation can be asymptomatic or cause symptoms such as palpitations, dizziness, fainting, or cardiac arrest. It can also trigger life-threatening arrhythmias such as torsade de pointes or ventricular fibrillation³. Therefore, post COVID QTc prolongation is a serious complication that can affect the cardiac function and prognosis of patients who have had COVID-19. Therefore, it is important to identify and manage this condition promptly and appropriately, to prevent or treat any potential arrhythmias and improve the quality of life of the patients.

The study population

At the College of Medicine- Al-Nahrain University, Iraq, conducted a case control study from October 2022 to February 2023. All procedures performed in this study involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institute Review Board (IRB) of Al-Nahrain University/ College of Medicine on October, 2022 (191/2022) and participants provided informed consent. This study included 90 cases, 50 adult patients with post-COVID-19 infections (eight were defaulted from the study because they were not cooperative) and control group consisted of forty healthy persons. The remaining 90 cases who agreed to participate in this research were selected randomly from those attending to the adult Holter and Echocardiography lab in Al-Zahraa Hospital/ Al-Hussein Medical City/ Karbala Province after being referred by Internist.

Sample Collection

Group I (Patients Group with Post Covid 19 Infection)

This group consisted of forty-two patients, 23 females and 19 males with mean age (36.98 ± 12.2 years) who were non-vaccinated against Covid 19 after one month to two years of an acute episode of COVID-19 (confirmed by positive real-time reverse-transcription polymerase chain reaction (RT-PCR)) test according to the World Health Organization (WHO). The patients were divided into three groups: non-hospitalized (mild and moderate illness who have any of the various signs and symptoms of COVID-19 but who did not require hospital admissions), hospitalized (severe illness), admitted to intensive care.

Age, gender, body mass index, heart rate, ECG were done for each study participant; ECG to assess and look for abnormalities in the QT, QTc. Inclusion Criteria include Patient aged > 18 up to 60 years old, Non vaccinated cases after 30 days till 2 years of acute episode of Covid-19 while exclusion Criteria include Any patient with any one of the following: Asymptomatic or pre-symptomatic infection (positive PCR but have no symptoms of Covid-19), Vaccinated, Less than 30 days after an acute episode of Covid − 19, < 18 years old, IHD, Valvular heart disease, Positive family history of heart disease, Diabetic mellitus, Stroke, Renal failure, Connective tissue disease.

Group II (Control Group)

This group consisted of forty healthy persons 23 females and 17 males with mean age (33.28 ± 9.58 years), whom referred by Internist for ECG and Echocardiography with no Hx of the previous infection of covid 19. On examination, it shows no underlying problem; this is proved by cardiac electrophysiological and echocardiographic investigation.

Materials and Instruments

Standard twelve leads ECG was performed for every patient in our study by Philips Pagewriter TC20 ECG device from Philips medical devices company. ECG was taken while a patient was lying in a supine position in a quiet room in the Holter and Echocardiography lab in Al-Zahraa Hospital. All ECG traces are assessed by a professional specialist closely for QT interval, Corrected QT interval. We used QTc parameters following the American Heart Association criteria for prolonged QTc as > 450 ms in men and > 460 ms in women. QTc values calculated by measuring QTc in lead II or V5 on a standard 12-lead ECG using the Bazett formula: QTc = QT/√RR. Meanwhile, heart rate outside this range (60–100 bpm) can use Framingham formula: QTc = QT + 0.154(1-RR), which are more accurate and should be used instead.

Statistical analysis

All analyses were performed by using SPSS software version 25.0 (SPSS, Chicago). Continuous data were presented as mean and standard deviation, and analyzed with Student t-test. Categorical variables were expressed as number and percentage and analyzed with Chi-square test. Receiver operating characteristic curve (ROC) was used to evaluate the value of different parameters in prediction of past COVID-19 infection or hospitalization due to infection. A p- value less than 0.05 was considered to indicate a statistically significant difference.

The mean age of the patients was 36.98 ± 12.2 years which was slightly higher than that of controls (33.28 ± 9.58 years) with no significant difference. Likewise, the two groups were comparable in terms of sex distribution, weight, height and BMI with no significant differences table 1.

Table (1) Demographic characteristics and clinical data of the study population

Variables

Patients

(n = 42)

Controls

(n = 40)

p- value

Age, years

Mean ± SD

Range

36.98 ± 12.2

19–60

33.28 ± 9.58

19–49

0.132

Sex

Male

Female

19(45.24%)

23(54.76%)

18(45%)

22(55%)

0.893

Weight, Kg

Mean ± SD

Range

75.93 ± 11.98

56–110

74.18 ± 15.58

43–115

0.568

Height, cm

Mean ± SD

Range

165.62 ± 8.0

142–181

163.35 ± 13.0

100–185

0.340

BMI, k/m²

Mean ± SD

Range

27.78 ± 4.73

20.76–42.97

28.23 ± 7.82

15.79-66.0

0.754

HR, beats/min

Mean ± SD

Range

94.24 ± 31.57

60–169

106.95 ± 32.39

65–164

0.076

The patients had higher mean QT and QTc (360.48 ± 30.11 ms and 414.98 ± 37.05 ms, respectively) than controls (341.5 ± 22.36 ms and 380.81 ± 35.63 ms, respectively with significant differences. There is a statistically significant difference in the prevalence of prolonged QTc between the COVID-19 group and the control group. Patients with COVID-19 are more likely to have prolonged QTc compared to patients without COVID-19. This means that the patient’s group had a 10.24 times higher risk of prolonged QTc than the control group table 2.

Table (2) QTc parameter in patients and controls

Cases	Total No.	QTc < 460 ms	QTc > 460 ms
Patient	42	37	5
Male	19	17	2
Female	23	20	3
Control	40	40	Zero
Male	17	17	Zero
Female	23	23	Zero

The normal range of QTc is less than 440 ms for healthy patients while QTc intervals of 440 ms to 460 ms in men and 440 ms to 470 ms in women are considered borderline. QTc intervals of more than 460 ms in men and 470 ms in women are considered prolonged.

Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the QT and QTc in anticipating postcovid-19 infection. The area under the curve (AUC) for QT was 0.684, 95% CI = 0.569-0.800, p = 0.004. The test's sensitivity and specificity were 67% and 62%, respectively, at a cut-off value of QT = 350 ms. For QTc, the AUC was 0.740, 95% CI = 0.632–0.847, p < 0.001. The sensitivity and specificity of the test were 69% and 67%, respectively, at a cut-off value of QTc = 402.15 ms Fig. 1

Some studies have reported that COVID-19 infection can cause QTc prolongation, either due to the direct effects of the virus on the heart, or due to the use of certain drugs that can affect the QTc, such as hydroxychloroquine or azithromycin⁴. However, the long-term consequences of QTc prolongation after COVID-19 recovery are not well understood so we conducted this study on the long-term effects of COVID-19 to identify the potential cardiac complications and risks of post COVID-19.

The present study found that patient’s group had significant, (p = 0.002), higher mean QT than control group and highly significant, (P < 0.001), higher mean QTc than control group, the possible explanation for this difference is that COVID-19 infection can cause cardiac complications, such as myocarditis, arrhythmias, and heart failure, which can affect the QTc interval, A prolonged QTc interval can increase the risk of ventricular arrhythmias and sudden cardiac death ⁵.

Similarly, there are emerging data that SARS-CoV-2 genes encode K + channels and may dysregulate the action potential and Ca2 + handing in cardiomyocytes, resulting in decreased cardiac contractility and increased susceptibility to arrhythmias. Excessive inflammation (IL-6, TNF α, and IL-1) can further modulate the function of several ion channels, specifically K + and Ca2 + channels, leading to inflammatory cardiac channelopathies, QT prolongation, and arrhythmias⁶. Therefore, this study suggests that Post COVID-19 patients may have a higher risk of developing these cardiac complications than the control group.

Moreover, (Romero-Duarte et al., 2021) found that 7.9% of COVID-19 survivors reported arrhythmia or palpitations as a persistent symptom during the 6 months after discharge, and that this symptom was independently associated with the return to the emergency services⁷.

This study differs to study done in Spain (Mojón-Álvarez et al.,2023), that showed a prolonged QTc on admission had no clinical impact on the long-term follow-up of patients who survived hospitalization due to COVID-19. It normalized in most patients at 7 months after hospital discharge. Few patients demonstrated a new prolonged QTc at follow-up, and it was not associated with inflammatory markers or adverse events. Patients with prolonged QTc at follow up had higher rates of atrial fibrillation at 1-year follow-up. The presence of obesity, COPD, coronary artery disease, and cancer were independently related to prolonged QTc at follow-up⁸.

Post COVID-19 patients had significantly higher QT and QTc intervals than the control group, indicating that COVID-19 infection can increase the risk of cardiac complications and arrhythmias.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding and supports

This research received no specific funding from public, commercial, or non-profit funding agencies.

Conflict of interest statement:

The authors declare that there is no conflict of interest

Author contributions

Etheridge, S.P. and Asaki, S.Y. (2021) COVID-19 infection and corrected QT interval prolongation—collateral damage from our newest enemy. JAMA Network Open, 4(4), e217192.
Pollock, A., Kumar, R., Devitt, P. et al. (2020) COVID-19 and QTc: is hydroxychloroquine worth the risk? A review of QT prolongation in hospitalized COVID-19 patients treated with hydroxychloroquine and azithromycin. Heart, 106, A1.
Al-Khatib, A., Al-Moujahed, A., Abou Hassan, O., Alameddine, R., Alameddine, A., Alameddine, M. and Alameddine, Y. (2020) ‘QTc prolongation in patients with COVID-19: a retrospective chart review’, Journal of Electrocardiology, 63, pp. 102-106.
Rubin, G.A., Desai, A.D., Chai, Z. and others, 2021. Cardiac QTc changes among patients treated for COVID-19 infection. JAMA Network Open, 4(4), p.e217192.
Block, J.P., Boehmer, T.K., Forrest, C.B. and others, 2022. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination — PCOR net, United States, January 2021–January 2022. Morbidity and Mortality Weekly Report, 71(15), pp.517-523.
Lazzerini, P.E., Laghi-Pasini, F., Boutjdir, M. and Capecchi, P.L., 2019. Cardio immunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies. Nature Reviews Immunology, 19(1), pp.63-64.
Romero-Duarte, Á., Rivera-Izquierdo, M., Guerrero-Fernández de Alba, I. and others, 2021. Sequelae, persistent symptomatology and outcomes after COVID-19 hospitalization: the ANCOHVID multicenter 6-month follow-up study. BMC Medicine, 19(1), p.129.
Mojón-Álvarez, D., Izquierdo, A., Cubero Gallego, H. and others, 2023. The natural history of QTc interval and its clinical impact in coronavirus disease 2019 survivors after 1 year. Frontiers in Cardiovascular Medicine, 10, p.1140276.

The authors declare no competing interests.

Download PDF

Version 1

posted

You are reading this latest preprint version

Beyond the Virus: QTc Interval Changes in COVID-19 Survivors

Status:

Version 1

Abstract

Figures

Introduction

Subjects and Methods

Group I (Patients Group with Post Covid 19 Infection)

Group II (Control Group)

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1