Heart failure with reduced ejection fraction (HFrEF) is a multifactorial syndrome involving extensive remodeling at electrophysiological, structural, contractile, and neurohormonal levels. At the cellular scale, the hallmarks of HFrEF are action potential (AP) prolongation, Ca 2+ and Na + mishandling, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) upregulation, and T-tubules loss. To determine how these remodeling elements contribute to arrhythmogenesis and contractile dysfunction, we developed a biophysically detailed computational model of HFrEF ventricular myocytes. This was based on published experimental data from an established rabbit model where HFrEF is induced by combined pressure and volume overload. We modified the main repolarizing and depolarizing currents to reproduce the functional changes measured in patch-clamp experiments, and increased CaMKII expression based on measurements with phospho-specific antibodies. We incorporated the structural remodeling by increasing both cell volume and membrane capacitance, and by decreasing the density of L-type Ca 2+ channels (LTCC) and Na + /Ca 2+ exchanger (NCX) near ryanodine receptors (RyRs) in the cleft. The resulting model reproduced the key features of HFrEF, including prolonged AP, slowed and diminished Ca 2+ transient resulting from reduced SERCA activity, and enhanced NCX function, collectively leading to impaired contractility. The model was validated against experimental data observed across multiple conditions, including physiological pacing rates from 0.25 to 4 Hz, and isoproterenol administration. Our simulations support the role of structural remodeling (i.e., LTCC-RyR uncoupling and cell hypertrophy) in HFrEF-associated myocyte dysfunctions. Moreover, our analysis dissects the contribution of individual targets of CaMKII and β-adrenergic signaling in the generation of delayed after depolarizations. By systematically assessing the specific role of each node (or relationship) in this complex signaling network in promoting Ca 2+ and voltage instabilities, our analysis might reveal new anti-arrhythmic targets for HFrEF patients.
Mazhar et al. (Sun,) studied this question.