טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentMandel Ya-El
SubjectCharacterization and Analysis of the Spontaneous Electrical
Activity over Time of Cardiomyocytes Derived from
Human Embryonic Stem Cells and from
Induced Pluripotent Stem Cells
DepartmentDepartment of Medicine
Supervisors Professor Emeritus Ofer Binah
Clinical Professor Amir Weissman
Full Thesis textFull thesis text - English Version


Abstract

The Sinoatrial (SA) node is the main impulse-generating tissue in the heart. Arrhythmias and conduction blockage caused by SA node dysfunction are a widespread phenomenon, for which electronic pacemakers are a common therapy. However, whilst providing an excellent solution, electronic pacemakers pose several physiological limitations. For this purpose, research for a biological pacemaker is necessary. Heart rate variability (HRV) is a physiological phenomenon where the time interval between successive heart beats varies. Studies have shown that reduced HRV may predict cardiac mortality after myocardial infarction (MI). In addition, several other conditions, including congestive heart failure and arrhythmias, may also be associated with decreased HRV. HRV is conventionally analyzed with time domain and frequency domain methods, which measure the overall magnitude of interbeat intervals (IBI) and the underlying rhythms composing the variability. In addition, heart rate dynamics, which describe the complexity and randomness of IBI behavior, are analyzed using methods derived from nonlinear systems.

In this thesis we characterized and analyzed the spontaneous electrical activity of two potential biological pacemakers: human embryonic stem cells derived cardiomyocytes (hESCs-CM) and induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM) derived from human hair keratinocytes. Their electrical activity was analyzed in terms of QRS-T like complex behavior and beat rate variability (BRV), to study their suitability as future biological pacemakers. In addition, the cells’ response to the If blocker zatebradine was studied.

The main findings of our study were: (1) hESCs-CM exhibited higher QRS amplitude and longer QRS and Q-T intervals than iPSCs-CM. (2) The beat rate remained steady during the 25 days of the study period, and with no significant differences between culture types. (3) Nonlinear dynamics methods revealed intrinsic self-similarity properties of IBI time series and complexity similar to that in humans. (4) The cell cultures presented intrinsic fractal-like behavior and BRV dynamics, similar to the findings in NRVM cultures. (4) Mean beat rate decreased in a dose dependent manner in response to If blocker. (5) Self-similarity and IBI series complexity properties were not affected significantly by If blocker.

Our study showed for the first time in human cardiomyocytes that these cultures are capable of displaying beat rate variability similar to that observed in humans that are due to intrinsic physiological mechanisms of the cultures. This may suggest that HRV properties found in humans are not originated from extrinsic factors only, but that they are also influenced by intrinsic mechanisms of the cardiac tissue.