Year of Publication

2013

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Engineering

Department

Biomedical Engineering

First Advisor

Dr. Abhijit Patwardhan

Abstract

Repolarization alternans, i.e. beat-to-beat variation of repolarization of action potential, is proposed as a predictor of life-threatening arrhythmias. Restitution relates repolarization duration with its previous relaxation time, i.e. diatstolic interval (DI), and is considered a dominant mechanism for alternans. Previously, we observed that different repolarization durations at the same DI during decelerating and accelerating pacing, i.e. restitution displays hysteresis, which is a measure of “cardiac memory”.

Objective of the current study was to investigate in the pig 1) the mechanism for a previously observed hysteresis type phenomenon, where alternans, once started at higher heart rate, persists even when heart rate decreases below its initiating rate, 2) regional differences in expression of hysteresis, i.e. memory in restitution in the heart, and 3) changes in restitution and memory during manipulation of an important repolarization current, the slow delayed rectifier, IKs.

Action potentials were recorded in pig ventricular tissues using microelectrodes. Regional differences were explored in endocardial and epicardial tissues from both ventricles. DIs were explicitly controlled in real time to separate restitution mechanism from non-restitution related effects. Stepwise protocols were used to explore the existence in hysteresis in alternans threshold, where DIs were held constant for each step and progressively decreased and then increased. Quantification of cardiac memory was achieved by sinusoidally changing DI protocols, which were used to investigate memory changes among myocytes from different regions of the heart and during IKs manipulation.

Results show that during stepwise protocol, hysteresis in alternans still existed, which indicates that restitution is not the only mechanism underlying the hysteresis. When comparing hysteresis obtained from sinusoidally oscillatory DIs among different regions, results show memory is expressed differently with endocardium expressing the most and epicardium the least memory. This provides important implications about the location where arrhythmia would initiate. Results also show that measures for hysteresis loops obtained by sinusoidal DI protocols decreased (increased) after enhancement (attenuation) of IKs, suggesting decreased (increased) hysteresis, i.e. memory in restitution. This effect needs to be considered during drug development.

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