Reduced Myofilament Contraction in Human Heart Failure. Insights from Electromechanical Simulations

Maria T Mora, Sofia Gutierrez, Juan F Gomez, Beatriz Trenor
Universitat Politècnica de València


Abstract

Intracellular Ca2+ is the main activator of myofilament contraction and the altered Ca2+ handling observed in failing cells, i.e. reduced systolic Ca2+ peak and elevated diastolic levels, has been established as the leading cause of reduced inotropy and lusitropy in heart failure. For this reason, electrophysiological studies usually quantify Ca2+ transients to estimate contractile effects. However, heart failure remodeling of myofilaments also occurs, modifying the correlation between Ca2+ and force. The aim of this study was to analyze myofilament tension generated by action potentials in human heart failure. We used a ventricular electromechanical model integrated with the Beta-adrenergic system to investigate cellular contraction force associated with intracellular Ca2+ during an excitation-contraction cycle. Stretch activated channels were introduced as an electromechanical feedback mechanism linked to cellular deformation. Our contribution consisted of implementing characteristic changes in the myofilament model to reproduce both heart failure remodeling and PKA-phosphorylation following Beta-adrenergic stimulation. Despite the inotropic myofilament remodeling induced in response to heart failure conditions, the maximal active tension in failing cells was one-third of the force generated in normal cells. With isoproterenol, Beta-adrenergic stimulation increased systolic Ca2+, which enhanced myofilament tension by up to 150%, but failing cells also showed a smaller contraction force compared to normal. We finally observed that myofilament contractility was very sensitive to changes in intracellular Ca2+, confirming that actions aimed at increasing systolic Ca2+ peak would improve contraction in heart failure.