Logo

American Heart Association

  53
  0


Final ID: MP2716

Sarcoplasmic Reticulum Ca2+ Leak Drives Arrhythmogenesis During In Vivo Maturation of Stem Cell-Derived Cardiomyocytes

Abstract Body (Do not enter title and authors here): Heart regeneration via transplantation of human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CMs) holds significant clinical potential. However, a transient, yet severe, period of ventricular arrhythmia, termed engraftment arrhythmia (EA), has limited bench-to-bedside translation. EA begins ~1-week post-transplant and persists for ~1-month, coinciding with the period when transplanted cells form intercellular connections to host myocardium but have not fully matured. Immature hiPSC-CMs display automaticity similar to sinoatrial nodal cells where pacemaker activity is regulated by sarcolemmal ion channel currents and spontaneous sarcoplasmic reticulum (SR) calcium (Ca2+) leak. In this study, we hypothesize that dysfunctional excitation-contraction (EC) coupling and aberrant SR Ca2+ leak are mechanistic drivers of EA. To test this, WTC-11 hiPSC-CMs were generated that stably express the cytosolic Ca2+ sensor jGCaMP8f and a membrane targeted RFP. hiPSC-CMs were transplanted into a rat acute myocardial infarction model to mature in-vivo. Cells were re-isolated for experiments after 1 week, coinciding with arrhythmia onset, and after 4 weeks, when arrhythmias terminate. We found hiPSC-CMs remain morphologically immature even after 4-weeks in-vivo. Surprisingly, compared to cells in-vitro, the cells re-isolated at 1-week showed significantly impaired Ca2+ dynamics including ~3-fold reduction in Ca2+ transient amplitude and slower kinetics which recovered by 4-weeks. And only ~20% of the non-transplanted or 1-week re-isolated cells adhered to 1 Hz pacing at room temperature compared to ~80% of the 4-week ex-vivo cells, suggesting more mature electrophysiology. High-spatiotemporal resolution Ca2+ imaging revealed the 1-week ex-vivo hiPSC-CMs have a significant ~2-fold surge in Ca2+ spark rate with a greater number of slowly terminating Ca2+ sparks than in the non-transplanted or 4-week re-isolated cells. Single-cell resolution spatial transcriptomics revealed heterogeneity within grafts, with progressive maturation over time. These data suggest excess SR Ca2+ leak and inefficient EC coupling promote EA early after cardiac cell therapy which improves as cells mature. Therapeutic strategies aimed at reducing SR Ca2+ leak or promoting further maturation of hiPSC-CMs could potentially reduce arrhythmogenicity.
  • Wescott, Andrew  ( University of Washington , Seattle , Washington , United States )
  • Karbassi, Elaheh  ( University of Washington , Seattle , Washington , United States )
  • Marchiano, Silvia  ( University of Washington , Seattle , Washington , United States )
  • Nimmagadda, Likitha  ( University of Washington , Seattle , Washington , United States )
  • Perrault, Nora  ( University of Washington , Seattle , Washington , United States )
  • Blakely, Leslie  ( University of Washington , Seattle , Washington , United States )
  • Maclellan, Robb  ( University of Washington , Seattle , Washington , United States )
  • Davis, Jennifer  ( University of Washington , Seattle , Washington , United States )
  • Murry, Chuck  ( University of Southern California , Los Angeles , California , United States )
  • Author Disclosures:
    Andrew Wescott: DO NOT have relevant financial relationships | Elaheh Karbassi: DO NOT have relevant financial relationships | Silvia Marchiano: DO NOT have relevant financial relationships | Likitha Nimmagadda: DO NOT have relevant financial relationships | Nora Perrault: DO NOT have relevant financial relationships | Leslie Blakely: No Answer | Robb Maclellan: No Answer | Jennifer Davis: DO NOT have relevant financial relationships
Meeting Info:

Scientific Sessions 2025

2025

New Orleans, Louisiana

Session Info:

Molecular Mechanisms in Cardiac Regeneration

Monday, 11/10/2025 , 10:45AM - 11:55AM

Moderated Digital Poster Session

More abstracts on this topic:
Assessing Trends in Disability-Adjusted Life Years (DALYs) and Age-Adjusted Mortality Rates (AAMR) of Ischemic Heart Disease: A Comparative Analysis of the United States and Global Burden of Disease

Buhadur Ali Muhammad Khan, Shahzaib Muhammad, Qureshi Muhammad Ahmad, Ammar Ur Rahman Mohammad, Munir Luqman, Khalid Amna, Hayat Malik Saad, Shoaib Muhammad Mukarram

Heart regeneration with a composite scaffold and hiPSC-derived cardiomyocytes improves regional cardiac mechanics

Dwyer Kiera, Soepriatna Arvin, Snyder Caroline, Roser Stephanie, Callanan Anthony, Coulombe Kareen

More abstracts from these authors:
You have to be authorized to contact abstract author. Please, Login
Not Available