COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

PLoS One. 2021 Aug 19;16(8):e0255976. doi: 10.1371/journal.pone.0255976. eCollection 2021.

Abstract

Background: Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive.

Aims and methods: We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1β antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy.

Results: Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity.

Conclusion: Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Arrhythmias, Cardiac* / etiology
  • Arrhythmias, Cardiac* / metabolism
  • Arrhythmias, Cardiac* / pathology
  • COVID-19* / complications
  • COVID-19* / drug therapy
  • COVID-19* / metabolism
  • COVID-19* / pathology
  • Calcium / metabolism
  • Calcium Signaling / drug effects*
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Middle Aged
  • Myocytes, Cardiac* / metabolism
  • Myocytes, Cardiac* / pathology
  • Rats
  • Rats, Sprague-Dawley
  • SARS-CoV-2 / metabolism*
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / pathology

Substances

  • Antibodies, Monoclonal, Humanized
  • canakinumab
  • Calcium

Grant support

This study was supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) as well as by the Else-Kröner-Fresenius Foundation and the Berlin Institute of Health (FH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.