Biophysical basis of discontinuous propagation in the diseased myocardium

Carolina Vasquez, Purdue University

Abstract

Cardiac electrograms recorded at infarct border zone (IBZ) regions of the ventricles have a characteristic long duration and fractionated appearance which is consistent with slow inhomogeneous activation that forms the substrate for lethal arrhythmias. Different convoluted explanations have been proposed to explain the nature of these recordings, but the biophysical mechanisms behind them have not been clearly identified. The hypothesis of this thesis is that fibroblasts and/or other non-excitable cells, which are present in large numbers in IBZ of the ventricles, may be interconnected via gap junctions and provide a direct electrical connection between surviving myocytes. This connection may under certain conditions result in non-excitable cell mediated conduction. This thesis examines the electrical coupling between myocytes and non-excitable cells, and the characteristics of non-excitable cell mediated conduction, in an in-vitro cardiac cell network and using a mathematical modeling approach. Experiments performed using in-vitro scar models developed from monolayer cultures of neonatal mouse ventricular cells showed that non-excitable cells (endothelioid and fibroblasts) were able to sustain non-excitable cell mediated propagation over distances of up to 500μm. Non-excitable cell mediated propagation was characterized by long conduction delays and slow conduction velocities in the order of 1cm/s. Results from mathematical simulations using a biophysical model of a cardiac fiber comprising myocytes and non-excitable cells were consistent with in-vitro findings, and showed that this form of conduction results in complex source-load interactions that may account for arrhythmia vulnerability in the infarct border zone. The electrophysiological basis of the altered conduction mechanisms reside in the lack of excitability of fibroblasts and endothelioid cells, and in a reduction in the level of gap junctional communication due to the expression of different connexin isoforms. The proposed non-excitable cell mediated mechanism of conduction provides a biophysical basis for the discontinuous propagation of the electrical activation in the diseased myocardium, thus increasing the understanding of arrhythmia substrates. The study of this novel form of cardiac conduction represents a significant contribution to the development of more guided approaches to arrhythmia treatment and the prevention of sudden cardiac death.

Degree

Ph.D.

Advisors

Moreno, Purdue University.

Subject Area

Biomedical research|Anatomy & physiology

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