Details

Autor(en) / Beteiligte

• Dimai, Sanzio
• Semmler, Lukas
• Prabhu, Ashok
• Stachelscheid, Harald
• Huettemeister, Judith
• Klaucke, Sandra C
• Lacour, Philipp
• Blaschke, Florian
• Kruse, Jan
• Parwani, Abdul
• Boldt, Leif-Hendrik
• Bullinger, Lars
• Pieske, Burkert M
• Heinzel, Frank R
• Hohendanner, Felix
• Lionetti, Vincenzo

Titel

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

Ist Teil von

• PloS one, 2021-08, Vol.16 (8), p.e0255976-e0255976

Ort / Verlag

San Francisco: Public Library of Science

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. 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-1[beta] antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. 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.sup.2+ transient amplitudes and altered baseline [Ca.sup.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.sup.2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca.sup.2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca.sup.2+ release or Ca.sup.2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. 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.sup.2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca.sup.2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.