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

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255976
Author(s):  
Sanzio Dimai ◽  
Lukas Semmler ◽  
Ashok Prabhu ◽  
Harald Stachelscheid ◽  
Judith Huettemeister ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Induced Pluripotent Stem Cell ◽  
Rat Cardiomyocytes ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Induced Pluripotent

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.

Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro

2018 ◽  
Vol 360 ◽  
pp. 88-98 ◽  
Author(s):  
Liang Guo ◽  
Sandy Eldridge ◽  
Michael Furniss ◽  
Jodie Mussio ◽  
Myrtle Davis
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Use of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes in Preclinical Cancer Drug Cardiotoxicity Testing: A Scientific Statement From the American Heart Association

2019 ◽  
Vol 125 (10) ◽  
Author(s):  
Gary Gintant ◽  
Paul Burridge ◽  
Lior Gepstein ◽  
Sian Harding ◽  
Todd Herron ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Cardiac Injury ◽  
Induced Pluripotent Stem Cell ◽  
Heart Association ◽  
Cancer Drug ◽  
Great Promise ◽  
Drug Induced ◽  
Induced Pluripotent

It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced quality of life. These effects, which may manifest in the short term or long term, are mechanistically not well understood. Research is hampered by the reliance on whole-animal models of cardiotoxicity that may fail to reflect the fundamental biology or cardiotoxic responses of the human myocardium. The emergence of human induced pluripotent stem cell–derived cardiomyocytes as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity of oncological drugs that may manifest as contractile and electrophysiological dysfunction, as well as structural abnormalities, making it possible to deliver novel drugs free from cardiac liabilities and guide personalized therapy. This article briefly reviews the challenges of cardio-oncology, the strengths and limitations of using human induced pluripotent stem cell–derived cardiomyocytes to represent clinical findings in the nonclinical research space, and future directions for their further use.

scholarly journals Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Andrea Ruiz-Velasco ◽  
Min Zi ◽  
Susanne S Hille ◽  
Tayyiba Azam ◽  
Namrita Kaur ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Cardiac Injury ◽  
Induced Pluripotent Stem Cell ◽  
Mitogen Activated Protein Kinase ◽  
Rat Cardiomyocytes ◽  
Functional Studies ◽  
Mitogen Activated Protein ◽  
Myocardial Insulin Resistance

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

Using human Pompe disease-induced pluripotent stem cell-derived neural cells to identify compounds with therapeutic potential

2019 ◽  
Vol 28 (23) ◽  
pp. 3880-3894 ◽  
Author(s):  
Hsiang-Po Huang ◽  
Wei Chiang ◽  
Lee Stone ◽  
Chun-Kai Kang ◽  
Ching-Yu Chuang ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Drug Testing ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Glycogen Storage ◽  
Neural Cells ◽  
Enzyme Replacement ◽  
Recessive Mutations ◽  
Induced Pluripotent

Abstract Pompe disease (OMIM # 232300) is a glycogen storage disease caused by autosomal recessive mutations of the gene encoding alpha-1,4-glucosidase (GAA; EC 3.2.1.20). Despite the relatively effective employment of enzyme replacement therapy, some critical medical issues still exist in patients with this disease, including the persistence of abnormalities in the central nervous system (CNS), probably because of the inability of the recombinant GAA to pass through the blood–brain barrier. To address this issue, identification of more therapeutic agents that target the CNS of patients with Pompe disease may be required. In this study, we derived neuronal cells from Pompe disease-induced pluripotent stem cells (Pom-iPSCs) and proved that they are able to recapitulate the hallmark cellular and biochemical phenotypes of Pompe disease. Using the Pom-iPSC-derived neurons as an in vitro drug-testing model, we then identified three compounds, ebselen, wortmannin and PX-866, with therapeutic potential to alleviate Pompe disease-associated pathological phenotypes in the neurons derived from Pom-iPSCs. We confirmed that all three compounds were able to enhance the GAA activity in the Pom-iPSC-derived neurons. Moreover, they were able to enhance the GAA activity in several important internal organs of GAA-deficient mice when co-injected with recombinant human GAA, and we found that intraperitoneal injection of ebselen was able to promote the GAA activity of the GAA-heterozygous mouse brain. Our results prove the usefulness of Pom-iPSC-derived neuronal populations for identifying new compounds with therapeutic potential.

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