A comprehensive, multiscale framework for evaluation of arrhythmias arising from cell therapy in the whole post-myocardial infarcted heart

Yu, Joseph Kwong-Leung; Franceschi, William H.; Huang, Qinwen; Pashakhanloo, Farhad; Boyle, Patrick; Trayanova, Natalia A.

doi:10.1038/s41598-019-45684-0

Cited by 24 publications

(19 citation statements)

References 107 publications

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“…Studies in large animals have demonstrated long-term efficacy but also defined a significant safety signal of generally transient but potentially fatal arrhythmias. As demonstrated in earlier studies ( Liu et al., 2018 ; Romagnuolo et al., 2019 ; Shiba et al., 2016 ), EA is a predictable complication of cardiac remuscularization therapy for MI ( Yu et al., 2019 ). In the NHPs, EA typically presents as a wide complex tachycardia with a variable electrical axis ( Chong et al., 2014 ; Liu et al., 2018 ), and this was reproduced in the minipig recently by the Laflamme laboratory ( Romagnuolo et al., 2019 ).…”

Section: Discussionsupporting

confidence: 54%

Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes

et al. 2021

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Summary Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0–0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy.

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Section: Discussionsupporting

confidence: 54%

Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes

et al. 2021

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“…Studies in large animals have demonstrated long-term efficacy but also defined a significant safety signal of generally transient but potentially fatal arrhythmias. As demonstrated in earlier studies (12)(13)(14), EA is a predictable complication of cardiac remuscularization therapy for myocardial infarction (22). In the NHP, EA typically presents as a wide-complex tachycardia with a variable electrical axis (11,12), and this was reproduced in the minipig recently by Laflamme laboratory (14).…”

Section: Discussionmentioning

confidence: 72%

Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes

Nakamura

Neidig

Yang

et al. 2021

Preprint

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Background: Engraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation. Objectives We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. Methods: hPSC-CM were transplanted into the infarcted porcine heart by surgical or percutaneous delivery to induce EA. Following a screen of antiarrhythmic agents, a prospective study was conducted to determine the effectiveness of amiodarone plus ivabradine in preventing cardiac death and suppressing EA. Results: EA was observed in all subjects, and amiodarone-ivabradine treatment was well-tolerated. None of the treated subjects experienced the primary endpoint of cardiac death, unstable EA or heart failure compared to 5/8 (62.5%) in the control cohort (hazard ratio 0.00; 95% confidence interval, 0-0.297; p = 0.002). Overall survival including two deaths in the treated cohort from immunosuppression-related infection showed borderline improvement with treatment (hazard ratio 0.21; 95% confidence interval, 0.03-1.01; p = 0.05). Without treatment, peak heart rate averaged 305 +/- 29 beats per min (bpm), whereas in treated subjects peak daily heart rate was significantly restricted to 185+/-9 bpm (p = 0.006). Similarly, treatment reduced peak daily EA burden from 96.8 +/- 2.9% to 76.5 +/- 7.9% (p = 0.003). Antiarrhythmic treatment was safely discontinued after approximately one-month of treatment without recrudescence of arrhythmia. Conclusions: The risk of engraftment arrhythmia following hPSC-CM transplantation can be reduced significantly by combined amiodarone and ivabradine drug therapy.

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“…1 ) [ 159 ]. Indeed, multiscale 3D whole-heart modeling has recently been developed to determine how varying parameters of cell delivery and transdifferentiation could result in focal ectopy, heart block, and reentry [ 20 ••].…”

Section: Mathematical Models For Addressing the Mechanisms Of Arrhythmogenesismentioning

confidence: 99%

“…The hiPSC-derived cardiomyocytes (hiPSC-CMs) can be obtained from healthy or diseased individuals, and provide the inexhaustible source for human disease modeling. Finally, recent development in multiscale computational studies provides yet another powerful tool to quantitatively test the mechanisms of cardiac arrhythmias in cardiac repair [ 20 ••].…”

Section: Introductionmentioning

confidence: 99%

Model Systems for Addressing Mechanism of Arrhythmogenesis in Cardiac Repair

et al. 2021

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Purpose of Review Cardiac cell-based therapy represents a promising approach for cardiac repair. However, one of the main challenges is cardiac arrhythmias associated with stem cell transplantation. The current review summarizes the recent progress in model systems for addressing mechanisms of arrhythmogenesis in cardiac repair. Recent Findings Animal models have been extensively developed for mechanistic studies of cardiac arrhythmogenesis. Advances in human induced pluripotent stem cells (hiPSCs), patient-specific disease models, tissue engineering, and gene editing have greatly enhanced our ability to probe the mechanistic bases of cardiac arrhythmias. Additionally, recent development in multiscale computational studies and machine learning provides yet another powerful tool to quantitatively decipher the mechanisms of cardiac arrhythmias. Summary Advancing efforts towards the integrations of experimental and computational studies are critical to gain insights into novel mitigation strategies for cardiac arrhythmias in cell-based therapy.

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A comprehensive, multiscale framework for evaluation of arrhythmias arising from cell therapy in the whole post-myocardial infarcted heart

Cited by 24 publications

References 107 publications

Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes

Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes

Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes

Model Systems for Addressing Mechanism of Arrhythmogenesis in Cardiac Repair

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