Preventing atrial fibrillation in COVID-19: exploring the role of interleukin-6 receptor antagonists

KEYWORDS:

• COVID-19
• atrial fibrillation
• anticoagulant
• IL-6
• tocilizumab

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In response to: preventing atrial fibrillation in COVID-19: exploring the role of interleukin-6 receptor antagonists

We read with utmost interest the prospective cohort study conducted and reported by Gupta et al. [1], which rigorously investigates the landscape of arrhythmias in patients hospitalized with coronavirus disease 2019 (COVID-19). This study fills a critical knowledge gap by examining the types and prevalence of arrhythmias in both mild/moderate and severe COVID-19 cases, offering valuable insights into this aspect from a prospective standpoint.

The study enrolled 305 consecutive hospitalized COVID-19 patients and conducted continuous electrocardiograms, alongside multiple ECGs, to comprehensively assess arrhythmias. The findings reveal that arrhythmias occurred in 6.8% of the studied population, with a distinct incidence pattern noted between patients with severe and mild/moderate COVID-19 illness. Notably, 9.2% of patients with severe illness experienced arrhythmias, compared to 3.3% in the mild/moderate group, although statistical significance was not reached (p = 0.063). Importantly, all observed arrhythmias were new-onset in this study, further underscoring their relevance in the context of COVID-19. Atrial arrhythmias were predominant, accounting for 95% of all arrhythmias, with atrial fibrillation being the most prevalent subtype, comprising 71.4% of cases. This study’s findings hold considerable clinical relevance, emphasizing the importance of vigilance for atrial fibrillation in COVID-19 patients. Further exploration of preventive strategies to manage and mitigate atrial fibrillation in this population is warranted, and this study serves as a valuable foundation for such endeavors.

Developing effective preventive measures for atrial fibrillation in patients with COVID-19 requires accurately identifying individuals at high risk. Several risk factors have been hypothesized to increase the propensity for atrial fibrillation in this population, including mitral valve disease, heart failure, history of myocardial infarction, renal failure, COPD, obesity, diabetes, hypertension, peripheral vascular disease, hyperlipidemia, smoking, and history of stroke [2]. However, applying preventive approaches to all patients with these risk factors may not be practical or efficient. To overcome this challenge, integrating predictive tools becomes crucial in identifying patients at risk. Numerous risk-scoring tools considering instrumental and laboratory factors have been established to predict incident AF. The C2HEST score (C2, coronary artery disease or chronic obstructive pulmonary disease [1 point each]; H, hypertension [1 point]; E, elderly [age ≥75 years, 2 points]; S, systolic heart failure [2 points]; T, thyroid disease [hyperthyroidism, 1 point]) is an easy-to-use and straightforward risk scoring system that was initially introduced and validated through large population-based cohorts of healthy individuals and patients with chronic diseases [3]. We recommend validating this risk score in patients with COVID-19 to assess its usability and effectiveness in this population. By identifying high-risk patients using validated risk-scoring tools like C2HEST, targeted preventive interventions can be implemented, potentially mitigating the development of atrial fibrillation and improving overall outcomes.

Additionally, early identification and intervention in individuals at risk for atrial fibrillation could significantly improve management and potentially reduce the incidence of this arrhythmia, ultimately reducing the need for lifelong anticoagulation therapy, which is notoriously associated with bleeding risk. It has been suggested that the cytokine storm observed in patients with COVID-19, particularly the release of interleukin-6 (IL-6), as a potential mechanism underlying the occurrence of atrial fibrillation. One of the arrhythmogenic effects of IL-6 is its ability to stimulate the production of fibroblasts, cells that are involved in forming scar tissue (fibrosis) in the heart [4]. Excessive fibrosis in the atrial tissue can disrupt the normal electrical conduction of the heart, creating conditions conducive to the development of atrial fibrillation. Moreover, IL-6 has been shown to disrupt calcium handling in cardiac cells. Specifically, it increases calcium release from intracellular stores, resulting in an excessive influx of calcium ions into the cytosol of cardiac cells [5]. This abnormal calcium leak can disrupt the normal electrical activity of the heart and contribute to the occurrence of arrhythmias, including atrial fibrillation. Indeed, by cumulatively including over 4,000 patients from 31 studies, a meta-analysis [6] found that circulating IL-6 concentration was associated with the risk of atrial fibrillation in the general population.

The involvement of IL-6 in developing new-onset atrial fibrillation prompts a logical investigation into the potential preventive role of IL-6 receptor antagonists, such as tocilizumab, in COVID-19-induced atrial fibrillation. Notably, the World Health Organization Rapid Evidence Appraisal for COVID Therapies (REACT) Working Group conducted a meta-analysis [7] of 27 randomized trials, revealing the mortality benefits of IL-6 receptor antagonists in patients hospitalized for COVID-19. The analysis showed a reduction in all-cause mortality in patients treated with IL-6 receptor antagonists compared to those receiving placebo or usual care (summary odds ratio = 0.86; 95% confidence interval 0.79 to 0.95). Although the direct efficacy of IL-6 receptor antagonists in preventing the development of atrial fibrillation was not explicitly demonstrated in the meta-analysis, it is plausible that the observed mortality benefits could be indirectly linked to the prevention of atrial fibrillation. As atrial fibrillation is a known risk factor for mortality in COVID-19 patients, its prevention may improve survival rates. Supporting this notion, a multicenter cohort study [8] reported a reduced risk of atrial fibrillation in COVID-19 patients treated with tocilizumab compared to those not receiving the treatment (9.0% versus 14.5%). This finding suggests that tocilizumab administration may positively impact atrial fibrillation incidence, potentially contributing to the observed mortality benefits.

The evidence highlights the potential dual benefit of IL-6 receptor antagonists, such as tocilizumab, in managing COVID-19. While their primary focus is on mitigating the hyperinflammatory response associated with severe COVID-19, these drugs may also play a role in preventing the development of atrial fibrillation. This condition can further exacerbate the clinical outcomes of COVID-19 patients. To fully leverage these potential benefits, further research and clinical trials are crucial to understand better how to identify COVID-19 patients at risk of atrial fibrillation using risk-scoring tools. This will enable us to determine the appropriateness of IL-6 receptor antagonists for these patients and potentially optimize their treatment outcomes.

Conflict of interest

All authors declare that they have no potential conflicts of interest that might be relevant to the contents of this article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded. No external funding was used in the preparation of this article.