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

Abstract

Background We previously reported that induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CM) manifest beat rate variability (BRV) resembling heart rate variability (HRV) in human sinoatrial node (SAN). 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 three-levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells and (3) in situ SAN. Methods We measured BRV/HRV properties in single pacemaker cells, iPSC-derived contracting embryoid bodies (EBs) and electrocardiograms from the same individual. Results Pronounced BRV/HRV were present at all three levels. Coefficient of variance (COV) of inter-beat intervals (IBI) and Poincaré plot SD1 and SD2 in single cells were 20x > EBs (P<0.05) and in situ heart (the latter two were similar, P>0.05). We also compared BRV magnitude among single cells, small (~5-10 cells) and larger EBs (>10 cells): BRV indices progressively increased (P<0.05) as cell number decreased. Disrupting intracellular Ca2+ handling markedly augmented BRV magnitude, revealing a unique bi-modal firing pattern, suggesting intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm. Conclusions The decreased BRV magnitude in transitioning from single cell to EB suggests HRV of hearts in situ originates from summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca2+ handling determine HRV in humans and isolated cardiomyocyte networks.

Beat Rate Variability in Murine Embryonic Stem Cell-Derived Cardiomyocytes: Effect of Antiarrhythmic Drugs

“…The importance of intracellular calcium pathways for the generation of BRV has recently been investigated in human ESC derived cardiomyocytes [6]. Consequently, the augmented BRV as a response to Verapamil in our in vitro model is consistent with clinical observations as well as in vitro studies in other species.…”

“…At the same time, an in vitro study, using human ESC-derived cardiomyocytes, concluded that 10 -6 M Ivabradine does not affect BRV [6]. In contrast to the experimental study, we detected a significant increase of all time domain measures when 10 -6 M Ivabradine was applied.…”

“…Not only basic electrophysiological properties such as stable spontaneous beating frequency, but also the response to cardioactive drugs was similar in electrocardiogram (ECG)-like recordings of extracellular field potentials (FPs) that have been the subject of in vitro studies [1][2][3][4]. In line with these approaches, it has recently been demonstrated that ESC-derived cardiomyocytes show beat rate variability (BRV) that is similar to heart rate variability (HRV) in humans [5,6].…”

Optophysiology of cardiomyocytes: characterizing cellular motion with quantitative phase imaging

“…Our data supports this conclusion and enables observation of their development over time. One particularly useful measure of cells' health is regularity of their beating cycle [34,37]. This measure is quantified by the Beating Regularity Index (BRI) histogram, which can be easily extracted from QPI data, and used for assessment of the cell viability and drug testing.…”

“…6(a). Irregular beating of single nodal hPSC-CMs has been linked to irregularity in the heart beat [37], and is an important indicator of drug toxicity [35]. The Beat Regularity Index (BRI), defined as the standard deviation of the beat period divided by the mean beat period, was calculated for 90 cells and its histogram is shown in Fig.…”