ABSTRACT

Aim

Coronavirus disease 2019 (COVID-19) has been linked to various arrhythmias, including atrial and ventricular ectopy, atrial fibrillation, and conduction disturbances. Proposed mechanisms include myocardial injury, systemic inflammation, autonomic dysfunction, and endothelial damage. This study aimed to assess arrhythmic burden and its predictors in patients with prior COVID-19 infection using 24-hour Holter monitoring.

Materials and Methods

We retrospectively analyzed 153 patients who underwent Holter electrocardiography (ECG) between January 2021 and June 2023. Participants were divided into COVID-19 positive (n=62) and control (n=91) groups. Demographic, clinical, and laboratory characteristics were compared. Ventricular ectopic beats (VES) were quantified, and ROC analysis identified 571 VES/day as the threshold for high arrhythmic burden. Patients were stratified accordingly, and predictors of high burden were determined using multivariate logistic regression.

Results

VES counts were significantly higher in the COVID positive group (p<0.001). Patients with >571 VES had a higher frequency of fragmented QRS (75.0% vs. 7.6%) and prior COVID-19 infection (60.4% vs. 31.4%) (p<0.001 for both). In multivariate analysis, fragmented QRS [odds ratio (OR): 26.99, p<0.001] and COVID-19 history (OR: 10.30, p<0.001) independently predicted high arrhythmic burden. COVID-19 vaccination was associated with a reduced risk (OR: 0.13, p=0.006).

Conclusion

COVID-19 infection is significantly associated with increased ventricular ectopy and fragmented QRS on Holter ECG, indicating persistent arrhythmic risk. Fragmented QRS and COVID-19 history independently predict high arrhythmic burden, while vaccination appears protective. Post-COVID rhythm surveillance may help identify high-risk individuals.

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 infection has been associated with a wide range of cardiovascular complications, including arrhythmias¹. Post-Coronavirus disease (COVID) cardiac manifestations are increasingly recognized, with ventricular arrhythmias being one of the concerning sequelae². The potential mechanisms underlying this increased arrhythmic burden include direct myocardial injury, systemic inflammation, and autonomic dysfunction. Emerging evidence also suggests that survivors of Coronavirus disease 2019 (COVID-19) may develop autonomic nervous system disturbances for instance, persistent sympathetic activation and reduced heart rate variability have been observed – which could facilitate post-COVID arrhythmogenesis​³. Identifying patients at higher risk of developing significant arrhythmias may help in optimizing post-COVID-19 cardiac care⁴. However, data regarding the long-term ventricular arrhythmic burden in relatively young, non-hospitalized post-COVID populations remain limited. This study aimed to evaluate the arrhythmic burden in patients with a history of COVID-19 infection and determine the clinical predictors of increased ventricular ectopic activity (VEA).

MATERIALS AND METHOD

This retrospective study included 153 patients who underwent 24-hour electrocardiography (ECG) Holter monitoring, classified into two groups: COVID-19 positive (COVID+) (n: 62) and control (n: 91). Between January 2021 and January 2022, patients were selected for inclusion if they had a confirmed COVID-19 diagnosis by positive reverse transcription polymerase chain reaction and subsequently presented with cardiac symptoms such as palpitations, presyncope, or chest pain warranting Holter monitoring. Symptoms such as presyncope, syncope, palpitations were recorded. None of the patients had complete syncope. Patients in the control group also underwent Holter monitoring for similar cardiac symptoms such as palpitations, syncope, or chest pain, despite having no history of COVID-19. Exclusion criteria comprised any history of structural heart disease, pacemaker implantation, or severe electrolyte imbalances, to avoid confounding factors that could independently affect arrhythmia propensity. Patients’ vaccination history was recorded, however, due to the heterogeneity in vaccine types (inactivated and mRNA-based) and variable dose numbers (ranging from one to four doses), vaccination status was analyzed categorically as vaccinated or unvaccinated. Baseline clinical characteristics, laboratory parameters, and ECG Holter recordings were compared between groups. A ROC curve analysis was performed to determine the optimal threshold for high arrhythmic burden based on ventricular extra systole (VES) counts. A cut-off value of 571 VES was identified. Patients were then further categorized into two subgroups: VES >571 (n: 48) and VES ≤571 (n: 105). Univariate and multivariate logistic regression analyses were conducted to identify independent predictors of high VES burden. The study was carried out in compliance with the Declaration of Helsinki and received approval from the Institutional Committee on Human Research and Ethics. All participants provided written informed consent before enrollment. Ethical approval for this research was granted by The Ethics Committee for Scientific Research, Faculty of Medicine, Trakya University (decision no: 02/17, date: 18.12.2021).

Statistical Analysis

Statistical analyses were conducted using SPSS version 25.0 (SPSS, Chicago, IL). Continuous variables were summarized as mean ± standard deviation, while categorical variables were reported as frequencies and percentages. The Shapiro-Wilk test was applied to evaluate the normality of distributions. Group comparisons for continuous variables were performed using the independent t-test, whereas categorical variables were analyzed with the Pearson’s chi-square test. Correlations were evaluated with spearman correlation test. ROC curve analysis was utilized to determine the area under the curve (AUC) and optimal cut-off values for diagnostic performance. Logistic regression analysis was employed to identify independent predictors. All statistical tests were two-sided, with a significance level set at p<0.05.

RESULTS

Baseline clinical and demographic characteristics are presented in Table 1. mean age was similar between the COVID+ and control groups (38.57±15.14 vs. 37.12±16.03 years, p: 0.903). Female patients were more prevalent in the COVID+ group (41.93% vs. 25.27%, p: 0.030). Thyroid dysfunction was significantly higher in the COVID+ group (24.19% vs. 7.69%, p: 0.030), while rates of hypertension (43.54% vs. 43.95%, p: 0.848) and diabetes mellitus (37.09% vs. 29.67%, p: 0.336) showed no significant differences (Table 1). No difference was found in terms of the medication (antihypertensive or antiarrhythmic) used by the patients (Table 1). COVID+ patients had significantly elevated high-sensitivity-C-reactive protein (hs-CRP) levels (2.47±3.33 mg/dL vs. 1.46±1.95 mg/dL, p: 0.002) and a higher incidence of fragmented QRS (46.77% vs. 10.98%, p<0.001). The COVID+ group also exhibited a significantly higher burden of VEA (VES count, p<0.001). The analysis of ECG Holter parameters is presented in Table 2. ROC curve analysis identified 571 VES as the optimal threshold for high arrhythmic burden (AUC: 0.82, 95% confidence interval: 0.76-0.88, p<0.001) (Table 3).

Figure 1. Patients with VES >571 had a higher prevalence of fragmented QRS (75.0% vs. 7.62%, p<0.001) and prior COVID-19 infection (60.41% vs. 31.42%, p<0.001). VEA, age, ejection fraction (EF) and hs-CRP were evaluated by correlation analyses (Figure 2). A weak positive correlation was found between VEA and advanced glycation end-products. There is a negative, weak and statistically significant correlation between VEA and EF (r=-0.2313, p=0.004). There was a negative, moderate and statistically significant correlation between CRP and EF variables (Figure 2). Vaccination rates were significantly lower in the high VES group (52.08% vs. 90.47%, p<0.001). Elevated hs-CRP levels correlated with high VES burden
(p: 0.002). Although the EF was slightly lower in the high VES group (54.45% vs. 55.58%, p: 0.314), the difference was not statistically significant.

The clinical characteristics of the study population in comparison with VEA count (571) are presented in Table 4. ECG Holter analysis showed that COVID+ patients had a higher burden of atrial extrasystoles (987.22±208.85 vs. 463.55±221.33, p: 0.042), prolonged QTc intervals (430.47±24.50 ms vs. 441.14±24.05 ms, p: 0.020), and increased QT dispersion (40.87±6.78 ms vs. 52.58±16.68 ms, p<0.001) compared to controls. Multivariate logistic regression analysis identified fragmented QRS [odds ratio (OR): 26.99, p<0.001] and COVID-19 infection (OR: 10.30, p<0.001) as independent predictors of high VES burden (Table 5). Vaccination was associated with a significantly lower risk of arrhythmia (OR: 0.13, p: 0.006).

DISCUSSION

COVID-19 infection has been implicated not only in acute cardiac injury but also in long-term cardiac sequelae, including inflammatory and arrhythmogenic manifestations. In a previously published case, we reported the development of constrictive pericarditis in a young individual following COVID-19 and vaccination exposure, raising awareness of the virus’s potential to induce delayed cardiac inflammation and remodeling, even in structurally normal hearts⁵​. COVID-19 infection has been linked to various cardiac arrhythmias, including atrial and ventricular ectopy, atrial fibrillation, and conduction abnormalities. Proposed mechanisms include direct myocardial injury, systemic inflammation, autonomic dysfunction, and endothelial damage, all contributing to altered cardiac electrophysiology. Recent studies indicate that post-COVID-19 patients, especially those with severe illness, have an increased risk of ventricular arrhythmias and QT prolongation, highlighting the need for long-term cardiac surveillance⁶. In a recently published review, the relationship between COVID-19 and the cardiovascular system has been thoroughly evaluated. This study discusses the mechanisms by which COVID-19 induces arrhythmias, which are associated with hypoxia, myocarditis, and secondary causes. Specifically, it highlights that hypoxia can trigger anaerobic glycolysis through cellular damage, increase cytosolic calcium levels, and facilitate arrhythmogenesis by inducing early and late depolarizations⁷. Unlike prior studies focusing on hospitalized COVID-19 patients, our study uniquely highlights the persistent arrhythmic risk even in a relatively young outpatient population.

The findings of this study highlight three key results: 1. prior COVID-19 infection is significantly associated with increased VEA and fragmented QRS, suggesting a potential link between myocardial injury and arrhythmic risk. 2. hs-CRP levels were significantly elevated in patients with high arrhythmic burden, reinforcing the role of systemic inflammation in post-COVID arrhythmogenesis. 3. vaccination was associated with a significantly lower risk of high VES burden, indicating a potential protective effect against post-COVID cardiovascular complications.

The association between COVID-19 infection and increased ventricular arrhythmic burden has been supported by previous studies. For example, Turagam et al.⁸demonstrated that post-COVID patients, particularly those with severe disease, exhibited a higher frequency of ventricular ectopy. The f-QRS pattern may have significant prognostic implications in COVID-19 patients. There are publications in the literature suggesting that this condition may exhibit temporal and mechanistic variations, and our study supports these findings⁹. Our findings align with these studies, suggesting that myocardial injury and fibrosis, as reflected by fragmented QRS patterns, may contribute to sustained arrhythmic risk¹⁰. The presence of fragmented QRS has been well-documented as a marker of myocardial scarring, which predisposes patients to malignant arrhythmia.

However, it should be noted that truly malignant ventricular arrhythmias (such as sustained ventricular tachycardia or fibrillation) appear to be relatively infrequent in post-COVID patients without critical illness. In fact, clinical data indicate that ventricular tachyarrhythmias in COVID-19 are mainly observed in the presence of severe metabolic derangements​ suggesting that profound electrolyte imbalances or other metabolic factors during acute illness are often required to precipitate life-threatening arrhythmias¹¹.

Elevated hs-CRP levels in patients with high VES burden further emphasize the role of systemic inflammation in arrhythmogenesis. Prior studies have shown that post-COVID inflammatory responses, including cytokine-mediated myocardial stress, can alter cardiac electrophysiology. In line with this, Marques et al.¹² reported that elevated inflammatory markers, particularly CRP and interleukin-6, were associated with an increased risk of ventricular arrhythmias post-COVID¹³. Our results support this concept, as heightened systemic inflammation may exacerbate myocardial excitability, leading to increased ectopic activity. The association between autonomic dysfunction and inflammation in long-COVID patients, as indicated by elevated CRP and impaired heart rate recovery, aligns with our findings of increased VEA and prolonged QT parameters in post-COVID individuals¹⁴. These results further support the hypothesis that persistent systemic inflammation and autonomic imbalance may contribute to heightened arrhythmic risk in COVID-19 survivors, underscoring the need for long-term cardiac monitoring

The observed protective effect of vaccination against high arrhythmic burden is an important finding. Previous research has demonstrated that COVID-19 vaccination reduces the severity of systemic inflammatory responses, which are known contributors to arrhythmia development. Studies such as Pari et al.¹⁵ reported a lower incidence of post-COVID cardiovascular complications among vaccinated individuals, likely due to the mitigation of endothelial dysfunction and myocardial inflammation. Our findings reinforce these observations, suggesting that vaccination may play a role in reducing post-infectious arrhythmic risk.

Beyond these primary results, certain findings warrant further discussion. The significantly prolonged QTc interval and increased QT dispersion in the COVID+ group suggest potential autonomic dysregulation or direct myocardial electrophysiological alterations post-infection¹⁶. In addition to autonomic dysregulation, potential contributors to QTc prolongation may include subclinical electrolyte imbalances or the use of QT-prolonging medications, although major disturbances were part of our exclusion criteria. These parameters are known predictors of ventricular arrhythmias and sudden cardiac death, necessitating further research on long-term QT dynamics in post-COVID populations¹⁷. Additionally, the high prevalence of thyroid dysfunction in the COVID+ group raises questions regarding the interplay between endocrine abnormalities and arrhythmic risk, as thyroid dysfunction is a known contributor to ventricular ectopy. Although thyroid dysfunction was more prevalent in the COVID+ group, this association may be incidental, and no direct causal link can be established based on our data. Future prospective studies should investigate whether these abnormalities persist over time and their potential therapeutic implications in post-COVID cardiac care¹⁸. The observed increase in atrial extrasystoles, prolonged QTc intervals, and greater QT dispersion in the COVID+ group suggests a potential impact of COVID-19 on cardiac electrophysiology. QT dispersion, a known marker of ventricular repolarization heterogeneity, has been associated with an increased risk of malignant arrhythmias and sudden cardiac death in various clinical settings. Previous studies have reported that prolonged QT dispersion in post-viral myocarditis and systemic inflammatory states may contribute to long-term arrhythmic complications, emphasizing the need for close monitoring in post-COVID-19 patients¹⁹.

Correlation analysis further supported these findings by revealing a weak but significant inverse relationship between VES burden and left ventricular EF, suggesting that even subtle reductions in systolic function may contribute to increased VEA. Additionally, the observed moderate inverse correlation between hs-CRP and EF highlights the interplay between systemic inflammation and myocardial performance, potentially linking inflammatory burden to both arrhythmic risk and subclinical cardiac dysfunction. Although the correlation between age and VES burden was weak, it may reflect an age-related increase in myocardial irritability or autonomic imbalance in post-COVID patients.

From a clinical standpoint, our results underscore the importance of vigilant cardiac follow-up in recovered COVID-19 patients. Implementing routine 24-hour Holter monitoring for post-COVID individuals with palpitations, syncope, or other worrisome cardiac symptoms could facilitate early detection of significant arrhythmias and guide timely intervention.

Study Limitations

Despite these insights, certain limitations must be acknowledged. This study is retrospective in nature, and the sample size remains relatively small. Furthermore, the long-term arrhythmic risk beyond the study period is unknown. Future research should focus on larger, prospective cohorts with longer follow-up durations to better elucidate the long-term cardiovascular effects of COVID-19. We could not classify COVID-19 positive patients according to clinical severity (e.g., asymptomatic, mild, moderate, severe) due to lack of standardized symptom documentation. This may have influenced arrhythmic outcomes. Future studies should consider subgroup analysis based on COVID-19 severity to better delineate its prognostic impact. Additionally, the exact time interval between COVID-19 infection and Holter monitoring could not be uniformly determined due to retrospective data collection. This temporal uncertainty limits the ability to distinguish between transient and persistent arrhythmic patterns.

CONCLUSION

COVID-19 infection is significantly associated with an increased burden of VEA. Fragmented QRS and a history of COVID-19 infection are independent predictors of high arrhythmic burden, whereas vaccination appears to be protective. These findings highlight the need for close cardiac monitoring and risk stratification in post-COVID-19 patients, particularly those exhibiting fragmented QRS on ECG. Vaccination appears to have a protective effect against post-COVID arrhythmias, suggesting its potential role in reducing cardiovascular complications. Larger-scale studies with extended follow-up periods are needed to better understand the long-term clinical significance of these findings.