Simulation study of the electrophysiological mechanisms for heart failure phenotype

Prolongation of action potential duration (APD) and altered calcium (Ca²⁺) handling in ventricular myocytes are commonly observed in heart failure (HF). This study describes a mathematical model of human HF, using a modified version of the Grandi et al. formulation for human ventricular action potential, which includes the late Na⁺ current (I_NaL). A sensitivity analysis is performed to investigate how the reported variability in HF remodeling might modulate the main electrophysiological (EP) characteristics in HF. Our simulations reproduced experimental observations in failing myocytes and the APD₉₀ was increased in 24% in HF versus normal ones, diastolic [Ca²⁺]_i was slightly increased, whereas peak systolic [Ca²⁺]_i was reduced to 41% of its normal value. From the sensitivity analysis it could be extracted that APD is particularly sensitive to I_NaL and I_NaK. The most impactful parameters on Ca²⁺ handling are the SERCA function, I_NaL, I_NaK, I_leak, I_{Ca, b} and I_NCX.