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| Item Type: | Article |
|---|---|
| Title: | COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab |
| Creators Name: | Dimai, S., Semmler, L., Prabhu, A., Stachelscheid, H., Huettemeister, J., Klaucke, S.C., Lacour, P., Blaschke, F., Kruse, J., Parwani, A., Boldt, L.H., Bullinger, L., Pieske, B.M., Heinzel, F.R. and Hohendanner, F. |
| 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 Ca(2+) transient amplitudes and altered baseline [Ca(2+)] 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 Ca(2+) release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca(2+) release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca(2+) release or Ca(2+) 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 Ca(2+) signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca(2+) imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein. |
| Keywords: | Cardiac Arrhythmias, Cardiac Myocytes, COVID-19, Calcium, Calcium Signaling, Humanized Monoclonal Antibodies, Induced Pluripotent Stem Cells, Left Ventricular Dysfunction, Preclinical Drug Evaluation, SARS-CoV-2, Sprague-Dawley Rats, Animals, Rats |
| Source: | PLoS ONE |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Volume: | 16 |
| Number: | 8 |
| Page Range: | e0255976 |
| Date: | 19 August 2021 |
| Official Publication: | https://doi.org/10.1371/journal.pone.0255976 |
| PubMed: | View item in PubMed |
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