tetano
Editor, Senior Moderator
PLoS One
. 2021 Aug 19;16(8):e0255976.
doi: 10.1371/journal.pone.0255976. eCollection 2021.
COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab
Sanzio Dimai[SUP] 1 2 [/SUP], Lukas Semmler[SUP] 1 3 [/SUP], Ashok Prabhu[SUP] 1 3 [/SUP], Harald Stachelscheid[SUP] 4 [/SUP], Judith Huettemeister[SUP] 1 [/SUP], Sandra C Klaucke[SUP] 5 [/SUP], Philipp Lacour[SUP] 1 3 [/SUP], Florian Blaschke[SUP] 1 3 [/SUP], Jan Kruse[SUP] 6 [/SUP], Abdul Parwani[SUP] 1 3 [/SUP], Leif-Hendrik Boldt[SUP] 1 3 [/SUP], Lars Bullinger[SUP] 7 [/SUP], Burkert M Pieske[SUP] 1 3 4 8 [/SUP], Frank R Heinzel[SUP] 1 3 [/SUP], Felix Hohendanner[SUP] 1 3 4 [/SUP]
Affiliations
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.
. 2021 Aug 19;16(8):e0255976.
doi: 10.1371/journal.pone.0255976. eCollection 2021.
COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab
Sanzio Dimai[SUP] 1 2 [/SUP], Lukas Semmler[SUP] 1 3 [/SUP], Ashok Prabhu[SUP] 1 3 [/SUP], Harald Stachelscheid[SUP] 4 [/SUP], Judith Huettemeister[SUP] 1 [/SUP], Sandra C Klaucke[SUP] 5 [/SUP], Philipp Lacour[SUP] 1 3 [/SUP], Florian Blaschke[SUP] 1 3 [/SUP], Jan Kruse[SUP] 6 [/SUP], Abdul Parwani[SUP] 1 3 [/SUP], Leif-Hendrik Boldt[SUP] 1 3 [/SUP], Lars Bullinger[SUP] 7 [/SUP], Burkert M Pieske[SUP] 1 3 4 8 [/SUP], Frank R Heinzel[SUP] 1 3 [/SUP], Felix Hohendanner[SUP] 1 3 4 [/SUP]
Affiliations
- PMID: 34411149
- DOI: 10.1371/journal.pone.0255976
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.