Investigating the Effects of Automaticity on Cardiac Propagation Restricted; Files Only

Abstract

The orchestration of the human heart’s rhythmic contraction and relaxation relies on a complex network of chambers and electrophysiological elements. Interruption of any element of the cardiac conduction pathway can generate arrhythmia, a condition that contributes significantly to global cardiac morbidity and mortality. The advent of induced pluripotent stem cell technology has facilitated the study of arrhythmogenesis through iPSC differentiated cardiomyocytes. As such, development of this model is imperative in the continued characterization of cardiac pathologies.

To this end, our study utilized automaticity inhibitors ivabradine and SEA0400 on iPSC-cardiomyocytes in order to understand the effects of inhibition of automaticity on cardiac propagation through an iPSC-CM syncytium. Utilizing field potential traces and action potentials, we identified the presence of a cardiac automaticity hierarchy in syncytium, as well as a potential protective compensatory mechanism that rescues iPSC-CMs from proarrhythmic propagative patterns through increases in conduction velocity. These findings establish novel parallels between the iPSC-CM syncytium and the human heart, indicating that iPSC-CMs can serve as an invaluable platform for simulating irregularities in automaticity for translational cardiac research.

Table of Contents

Table of Contents

Page

Introduction 1

Specific aims 5

Methods 6

iPSC reprogramming 6

Cell thawing 6

Culture and maintenance of iPSCs 7

Differentiation of iPSC-CMs 8

Purification of beating iPSC-CMs 8

Electrophysiological assay 9

MEA plating 9

Electrophysiological recording of iPSC-CM monolayers 10

Drug-induced automaticity blockade 11

Results 11

Modeling whole heart automaticity by using/developing a simplified human-based iPSC-CMs monolayer tissue model 11

The effects of Ivabradine and SEA0400 on iPSC syncytium automaticity: 13

Proarrhythmic morphologies in propagation following insult to leading pacemaker: 15

Establishment of hierarchical organization of latent pacemakers in iPSC syncytium: 17

Acute compensatory mechanisms following automaticity inhibition: 18

Discussion 20

Figures 26

Figure 1 26

Figure 2 28

Figure 3 29

Figure 4 30

Figure 5 32

Figure 6 34

Figure 7 35

References: 36

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell
Parola chiave	Conduction Velocity iPSC Stem Cell Cardiomyocyte Automaticity
Committee Chair / Thesis Advisor	Arri Eisen, Emory University Ilanit Ronen Itzhaki, Emory University Keith Easterling, Emory University

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