The Effect of Structural Microheterogeneity on the Initiation and Propagation of Ectopic Activity in Cardiac Tissue

Abstract

Cardiac arrhythmias triggered by both reentrant and focal sources are closely correlated with regions of tissue characterized by significant structural heterogeneity. Experimental and modeling studies of electrical activity in the heart have shown that local microscopic heterogeneities which average out at the macroscale in healthy tissue play a much more important role in diseased and aging cardiac tissue which have low levels of coupling and abnormal or reduced membrane excitability. However, it is still largely unknown how various combinations of microheterogeneity in the intracellular and interstitial spaces affect wavefront propagation in these critical regimes. This thesis uses biophysically realistic 1-D and 2-D computer models to investigate how heterogeneity in the interstitial and intracellular spaces influence both the initiation of ectopic beats and the escape of multiple ectopic beats from a poorly coupled region of tissue into surrounding well-coupled tissue. An approximate discrete monodomain model that incorporates local heterogeneity in both the interstitial and intracellular spaces was developed to represent the tissue domain. The results showed that increasing the effective interstitial resistivity in poorly coupled fibers alters the distribution of electrical load at the microscale and causes propagation to become more like that observed in continuous fibers. In poorly coupled domains, this nearly continuous state is modulated by cell length and is characterized by decreased gap junction delay, sustained conduction velocity, increased sodium current, reduced maximum upstroke velocity, and increased safety factor. In inhomogeneous fibers with adjacent well-coupled and poorly coupled regions, locally increasing the effective interstitial resistivity in the poorly coupled region reduces the size of the focal source needed to generate an ectopic beat, reduces dispersion of repolarization, and delays the onset of conduction block that is caused by source-load mismatch at the boundary between well-coupled and poorly-coupled regions. In 2-D tissue models, local increases in effective interstitial resistivity as well as microstructural variations in cell arrangement at the boundary between poorly coupled and well-coupled regions of tissue modulate the distribution of maximum sodium current which facilitates the unidirectional escape of focal beats. Variations in the distribution of sodium current as a function of cell length and width lead to directional differences in the response to increased effective interstitial resistivity. Propagation in critical regimes such as the ectopic substrate is very sensitive to source-load interactions and local increases in maximum sodium current caused by microheterogeneity in both intracellular and interstitial structure.