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.
【초록키워드】 coronavirus disease, SARS-CoV-2, ARDS, coronavirus, COVID19, Mortality, intensive care, intensive care unit, cytokine, ICU, arrhythmia, cardiac injury, serum, sensitivity, Microscopy, Patient, membrane, Incubation, cardiac function, canakinumab, Arrhythmias, patients, IL-1β, cellular, Signaling, Inflammatory response, RAT, In-vitro, stem cell, no effect, exposure to, dysfunction, Anti-inflammatory therapy, Precision, impaired cardiac function, severe ARDS, therapeutic potential, veno-venous extracorporeal membrane oxygenation, cytokine release, LVEF, aims, amplitude, nuclear, Co-incubation, COVID19 patients, pharmacological, Effect, mitigate, approach, Cell, event, decrease, Result, significantly, addition, investigated, evaluated, occur, had no, electrical, cytosolic, Isolated, baseline, COVID19 patient, ventricular, 【제목키워드】 arrhythmia, dysfunction,