Quantification of the effects of electrical remodeling due to hypertrophic cardiomyopathy on human ventricular electromechanical activity and energetics

Hypertrophic cardiomyopathy caused by mutations in genes coding for sarcomeric proteins leads to electrical remodeling, oxidative stress and energetic impairment. This study combines recently published models of each component to investigate the mechanisms by which the hypertrophic cardiomyopathy-induced electrical remodeling, oxidative stress and energetic malfunction affect cardiac electrical activities. A current electrophysiological model was updated with recent experimental data for both control and disease. A metabolite sensitive myofilament model was incorporated alongside a model of mitochondrial energetics and reactive oxygen species production. It was shown that electrical remodeling leads to a substantial prolongation of action potential duration, an increase in both systolic and diastolic Ca²⁺ levels and concomitant increase in levels of active Ca²⁺/calmodulin kinase II. A positive inotropic effect was seen with hypertrophic cardiomyopathy due to increased Ca²⁺ concentration and Ca²⁺ sensitivity of the myofilament. Greater mitochondrial reactive oxygen species production was observed in the diseased cell and energetic buffering capacity by phosphocreatine was found to be diminished.