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Physiological Variations in CX43 and Fibrosis Deposition Affect Human Ventricular Electrophysiology Promoting Arrhythmia

Abstract:

Connexin 43 (Cx43), the major component of gap junctions in the ventricle, is responsible for electrical impulse transmission between ventricular cardiomyocytes. Little is known about the interindividual heterogeneity of CX43 tissue expression in the human left ventricle (LV) and its contribution to arrhythmogenecity either alone or in combination with other proarrhythmic factors like fibrosis. We processed LV fluorescent immunostaining images from living donors and characterized the population heterogeneity of CX43 expression and fibrosis deposition. The lowest CX43 expression and the highest fibrosis deposition values in the population were implemented in 2D computational models of human LV electrophysiology. We measured conduction velocity (CV) and areas of High Repolarization Gradient (HRG) from the simulated action potentials (APs), and the amplitude, duration and area of calculated unipolar electrograms (EGMs). Simulations showed that both reduced CX43 and fibrosis notably influence CV, HRG extent, EGM activation area and the dispersion of activation recovery intervals from EGMs, with a largest impact of CX43 reduction. In conclusion, decreased CX43 and increased fibrosis, to the extents measured in non-diseased human LV tissues, contribute to a substrate for the generation of reentrant arrhythmias, which can be quantified from ventricular EGMs.