M.Sc Thesis

M.Sc StudentShemla Ori
SubjectAge-Related Pacemaker Deterioration Learned from SAN Tissue
DepartmentDepartment of Biomedical Engineering
Supervisors ASSOCIATE PROF. Yael Yaniv
DR. Joachim Behar
Full Thesis textFull thesis text - English Version



Because of the complexity of the interaction between the internal pacemaker mechanisms, cell interconnected signals and interaction with other body systems, study of the role of individual systems must be performed under in vivo and ex vivo conditions. The in-situ approach is valuable when exploring the mechanisms that govern the beating rate and rhythm of the sinoatrial node (SAN), the heart’s primary pacemaker. SAN beating rate changes on a beat-to-beat basis. However, to date, there are no standard methods and tools for beating rate variability (BRV) analysis from electrograms (EGM) collected from different mammals and there is no centralized public database with such recordings.


We used EGM recordings obtained from control SAN tissues of rabbits (n=9) and mice (n=30) and from mouse SAN tissues (n=6) that were exposed to drug intervention. The data were harnessed to develop a beat detector to derive the beat-to-beat interval time series from EGM recordings. We adapted BRV measures from heart rate variability and reported their range for rabbit and mouse.


The beat detector algorithm performed with 99% accuracy (F-score), sensitivity (Se), and positive predictive value (PPV) on the test (mouse) and validation (rabbit and mouse) sets. Differences in the frequency band cutoff were found between BRV of SAN tissue vs. heart rate variability (HRV) of in vivo recordings. A significant reduction in power spectrum density existed in the high frequency band and a relative increase was seen in the low and very low frequency bands. In isolated SAN, the larger animal had a slower beating rate, but with lower BRV, which contrasted the phenomena reported for in vivo analysis. Thus, the non-linear inverse relationship between the average heart rate and HRV is not maintained under in situ conditions. The beat detector, BRV measures and databases were contributed to the open-source PhysioZoo software (available at: https://physiozoo.com/).


The approach presented here will enable standardization and reproducibility of BRV analysis in mammalian. Furthermore, different trends were found between isolated SAN from mice and rabbits, implying differences in the contribution of the SAN to the BRV of each mammal. Different trends were also found between the average beating rate and BRV of isolated SAN tissue versus HRV in vivo conditions, implying a complex interaction between SAN and the autonomic nervous system in determining HRV in vivo. Finally, different BRV measures between young and aged SAN tissue emphasizing the effect of aging on the function of the pacemaker. A drug-induced increase in the pacemaker activity was observed to return aged BRV parameter to the same level as young, which suggests that the intracellular phosphorylation process is affected by aging and can be restored.