Journal Article

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

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

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Arrhythmia / Automation / Biology and Life Sciences / Calcium imaging / Calcium ions / Calcium signalling / Cardiology / Cardiomyocytes / Cardiomyopathy / Contraction / Coronaviruses / Coupling / COVID-19 / Cytokines / Excitation / Excitation-contraction coupling / Experiments / Health aspects / Heart cells / Hospitals / IL-1β / In vitro methods and tests / Incubation / Inflammation / Inflammatory response / Intensive care / Internal medicine / Kinases / Mechanical properties / Medicine / Medicine and Health Sciences / Monoclonal antibodies / Mortality / Oxygenation / Patients / Physiological aspects / Pluripotency / Precision medicine / Respiratory distress syndrome / Risk factors / Sepsis / Severe acute respiratory syndrome coronavirus 2 / Signaling / Stem cells / Ventricle / Viral diseases / Viral infections