title: 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 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.
  
  
  CONCLUSIONS
  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.
authors: The Sohnis Family Stem Cells Center, Technion, Haifa, Israel.|The Rappaport Institute, Technion, Haifa, Israel.|Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Meital
authors: M
authors: Ben-Ari
authors: The Sohnis Family Stem Cells Center, Technion, Haifa, Israel.|The Rappaport Institute, Technion, Haifa, Israel.|Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Revital
authors: R
authors: Schick
authors: The Sohnis Family Stem Cells Center, Technion, Haifa, Israel.|The Rappaport Institute, Technion, Haifa, Israel.|Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Lili
authors: L
authors: Barad
authors: The Sohnis Family Stem Cells Center, Technion, Haifa, Israel.|The Rappaport Institute, Technion, Haifa, Israel.|Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Atara
authors: A
authors: Novak
authors: Department of Electrical Engineering, Technion, Haifa, Israel.
authors: Erez
authors: E
authors: Ben-Ari
authors: Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Department of Pediatric Cardiology, Rambam Medical Center.
authors: Avraham
authors: A
authors: Lorber
authors: The Sohnis Family Stem Cells Center, Technion, Haifa, Israel.|Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel.
authors: Joseph
authors: J
authors: Itskovitz-Eldor
authors: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, USA.
authors: Michael R
authors: MR
authors: Rosen
authors: Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel.
authors: Amir
authors: A
authors: Weissman
authors: The Sohnis Family Stem Cells Center, Technion, Haifa, Israel.|The Rappaport Institute, Technion, Haifa, Israel.|Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Ofer
authors: O
authors: Binah
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000328:Adult; D004562:Electrocardiography; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000502:physiology*; D012849:Sinoatrial Node / Q000502:physiology*
keywords: Cardiac myocytes; Electrophysiology; Heart rate; Heart rate variability; Induced pluripotent stem cells