From beat rate variability in induced pluripotent stem cell-derived pacemaker cells to heart rate variability in human subjects

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 Poincare plot indices SDI. 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 (similar to 5-10 cells), and Larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number (P < .05). Disrupting intracellular Ca2+ 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 Ca2+ handling determine HRV in humans and cardiomyocyte networks.