Garrett Jensen , Xinjie Wang , Jacob Kuempel , Zhishi Chen , Wei Yu , Nicolas Palaskas , Mary Sobieski , Nghi Nguyen , Reid T. Powell , Clifford Stephan , Weijia Luo , Jiang Chang
{"title":"Modeling immune checkpoint inhibitor associated myocarditis in vitro and its therapeutic implications","authors":"Garrett Jensen , Xinjie Wang , Jacob Kuempel , Zhishi Chen , Wei Yu , Nicolas Palaskas , Mary Sobieski , Nghi Nguyen , Reid T. Powell , Clifford Stephan , Weijia Luo , Jiang Chang","doi":"10.1016/j.jmccpl.2024.100122","DOIUrl":"10.1016/j.jmccpl.2024.100122","url":null,"abstract":"<div><div>Immune checkpoint inhibitor-associated myocarditis is the most lethal side effect of immune checkpoint blockade. Myocarditis leads to persistently increased mortality and lacks effective treatments. The development of patient-relevant disease models may enable disease prediction, increased understanding of disease pathophysiology, and the development of effective treatment strategies. Here, we report a new method to model immune checkpoint inhibitor-associated myocarditis <em>in vitro</em> via a co-culture of activated primary human immune cells, human induced pluripotent stem cell-derived cardiomyocytes, and FDA-approved immune checkpoint inhibitors to recapitulate myocarditis <em>in vitro</em>. Significant cardiomyocyte necrosis, arrhythmia development, and sarcomere destruction occur, replicating clinical findings from myocarditis. This tissue culture myocarditis phenotype may rely on an induced pluripotent stem cell-derived cardiomyocyte antigen-specific CD8<sup>+</sup> T cell response. The administration of dexamethasone rescued cardiomyocyte viability, morphology, and electrophysiology and suppressed inflammatory cytokine production. In conclusion, we detail how this platform can effectively model and provide critical information about the morphological and electrophysiological changes induced by immune checkpoint inhibitor-associated myocarditis. We have also validated the ability of this platform to screen potential medications to treat immune checkpoint inhibitor-associated myocarditis. This work establishes a robust, scalable model for identifying new therapies and risk factors, which is valuable in delineating the nature of interactions between the immune system and the heart during myocarditis.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"10 ","pages":"Article 100122"},"PeriodicalIF":0.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yangpeng Li , Zhu Liu , Christopher O'Shea , Jianhong Li , Xian Luo , Tangting Chen , Xianhong Ou , Weichao Liu , Guoliang Hao , Christopher L.-H. Huang , Davor Pavlovic , Xiaoqiu Tan , Ming Lei
{"title":"Dual calcium-voltage optical mapping of regional voltage and calcium signals in intact murine RyR2-R2474S hearts","authors":"Yangpeng Li , Zhu Liu , Christopher O'Shea , Jianhong Li , Xian Luo , Tangting Chen , Xianhong Ou , Weichao Liu , Guoliang Hao , Christopher L.-H. Huang , Davor Pavlovic , Xiaoqiu Tan , Ming Lei","doi":"10.1016/j.jmccpl.2024.100121","DOIUrl":"10.1016/j.jmccpl.2024.100121","url":null,"abstract":"<div><div>Abnormal regional variations in electrical and calcium homeostasis properties have been implicated in catecholaminergic polymorphic ventricular tachycardias (CPVT) attributable to abnormal RyR2-mediated store Ca<sup>2+</sup> release, but their underlying mechanism have not been well explored in intact hearts.</div></div><div><h3>Methods</h3><div>We performed in vivo and ex vivo studies including high throughput mapping of Ca<sup>2+</sup> transients (CaT) and transmembrane voltage (V<sub>m</sub>) in murine wild-type (WT) and heterozygous <em>RyR2</em>-R2474S/+ hearts, before and during isoprenaline (ISO) challenge.</div></div><div><h3>Results</h3><div>ISO-challenged <em>RyR2</em>-R2474S/+ showed increased incidence of arrhythmia accompanied by abnormal Ca<sup>2+</sup> transients compared to WT. CaT duration (CaTD) in the LV apex amongst regions studied both before and during ISO challenge in both WT and <em>RyR2</em>-R2474S/+ ventricles. <em>RyR2</em>-R2474S/+ ventricles showed prolonged CaTD, both before and during isoprenaline (ISO) challenge. Conversely, action potential durations (APD) were the same in WT and RyR2-R2474S/+ ventricles and identically reduced by ISO challenge. <em>RyR2</em>-R2474S/+ showed <em>V</em><sub>m</sub>-CaT latencies at time to half decay, but not rise time to peak, which were significantly prolonged compared to WT in all ventricular regions examined with ISO challenge. Following burst pacing, ventricular localized concordant alternans in CaT and APD were readily observed in <em>RyR2</em>-R2474S/+ but not in WT mice. Such CaT and APD alternans occurred mostly semiannually in specific regions of the ventricular pre-occurrence of VT.</div></div><div><h3>Conclusion</h3><div>The pro-arrhythmic <em>RyR2</em>-R2474S/+ phenotype in intact hearts thus directly parallels delayed regional CaT recovery properties and alteration of <em>V</em><sub>m</sub>-CaT latencies. Studies suggest that discordant localized calcium alternans are mechanistically responsible for action potential duration alternans and occurrence of VT in <em>RyR2</em>-R2474S/+ mice.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"10 ","pages":"Article 100121"},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The influence of the endocannabinoid system on the profibrotic profile of cardiac fibroblasts associated with Duchenne Muscular Dystrophy","authors":"Lesia Savchenko , Salwa Soussi , Davide Rovina , Martina Rabino , Giulio Pompilio , Angelo Parini , Aoife Gowran , Nathalie Pizzinat","doi":"10.1016/j.jmccpl.2024.100115","DOIUrl":"10.1016/j.jmccpl.2024.100115","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"10 ","pages":"Article 100115"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katarzyna Kmiotek , Anna Zoccarato, Rafael R. Oexner, Ravi A. Kumar, Sharwari Verma, Ajay M. Shah
{"title":"The role of phosphofructokinase P in hypertrophy of iPSC-derived human cardiomyocytes","authors":"Katarzyna Kmiotek , Anna Zoccarato, Rafael R. Oexner, Ravi A. Kumar, Sharwari Verma, Ajay M. Shah","doi":"10.1016/j.jmccpl.2024.100116","DOIUrl":"10.1016/j.jmccpl.2024.100116","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"10 ","pages":"Article 100116"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142745401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Characterization of the cardiac Osr1+ cells in normal and ischemic hearts","authors":"Marine Gandon-Renard , Lucille Deshayes , Aicha Ben Zemzem , Estelle Robidel , Camille Knosp , Jean-Sébastien Hulot","doi":"10.1016/j.jmccpl.2024.100097","DOIUrl":"10.1016/j.jmccpl.2024.100097","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"10 ","pages":"Article 100097"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Consequences of aging on the adaptative capacity of Microcebus murinus heart to stress","authors":"Manon Marrot , Yasmine Colombani , Joel Cuoq , Pascaline Fontes , Faustine Hugon , Stéphanie Barrere-Lemaire , Nadine Mestre-Frances , Matteo E. Mangoni , Angelo Torrente","doi":"10.1016/j.jmccpl.2024.100098","DOIUrl":"10.1016/j.jmccpl.2024.100098","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"10 ","pages":"Article 100098"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}