Meital Ben-Ari1,2,3, Revital Schick1,2,3, Lili Barad1,2,3, Atara Novak1,2,3, Erez Ben-Ari4, Avraham Lorber3,5, Joseph Itskovitz-Eldor1,3,6, Michael R Rosen7, Amir Weissman3,6, Ofer Binah1,2,3. 1. The Sohnis Family Stem Cells Center, Technion, Haifa, Israel. 2. The Rappaport Institute, Technion, Haifa, Israel. 3. Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. 4. Department of Electrical Engineering, Technion, Haifa, Israel. 5. Department of Pediatric Cardiology, Rambam Medical Center. 6. Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel. 7. Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, USA.
Abstract
BACKGROUND: We previously reported that induced pluripotent stem cell-derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now hypothesized the BRV-HRV continuum originates in pacemaker cells. OBJECTIVE: To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node. METHODS: We measured BRV/HRV properties in single pacemaker cells, induced pluripotent stem cell-derived contracting embryoid bodies (EBs), and electrocardiograms from the same individual. RESULTS: Pronounced BRV/HRV was present at all 3 levels. The coefficient of variance of interbeat intervals and Poincaré plot indices SD1 and SD2 for single cells were 20 times greater than those for EBs (P < .05) and the in situ heart (the latter two were similar; P > .05). We also compared BRV magnitude among single cells, small EBs (~5-10 cells), and larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number (P < .05). Disrupting intracellular Ca(2+) handling markedly augmented BRV magnitude, revealing a unique bimodal firing pattern, suggesting that intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm. CONCLUSION: The decreased BRV magnitude in transitioning from the single cell to the EB suggests that the HRV of in situ hearts originates from the summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca(2+) handling determine HRV in humans and cardiomyocyte networks.
BACKGROUND: We previously reported that induced pluripotent stem cell-derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now hypothesized the BRV-HRV continuum originates in pacemaker cells. OBJECTIVE: To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node. METHODS: We measured BRV/HRV properties in single pacemaker cells, induced pluripotent stem cell-derived contracting embryoid bodies (EBs), and electrocardiograms from the same individual. RESULTS: Pronounced BRV/HRV was present at all 3 levels. The coefficient of variance of interbeat intervals and Poincaré plot indices SD1 and SD2 for single cells were 20 times greater than those for EBs (P < .05) and the in situ heart (the latter two were similar; P > .05). We also compared BRV magnitude among single cells, small EBs (~5-10 cells), and larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number (P < .05). Disrupting intracellular Ca(2+) handling markedly augmented BRV magnitude, revealing a unique bimodal firing pattern, suggesting that intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm. CONCLUSION: The decreased BRV magnitude in transitioning from the single cell to the EB suggests that the HRV of in situ hearts originates from the summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca(2+) handling determine HRV in humans and cardiomyocyte networks.
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