Interplay between variability in intrinsic cellular properties and heart failure-associated remodeling in a simulated...

Heart failure (HF) is the presentation of mechanical pump dysfunction, with HF patients facing increased risk of sudden cardiac death predominantly driven by ventricular arrhythmias. At the cellular level, HF is associated with remodeling of ionic currents and fluxes, as well as chronic activation of β-adrenergic signaling pathways, ultimately resulting in pathological changes in action potential and intracellular calcium transient characteristics. However, it is challenging to understand the mechanistic underpinnings of HF and associated arrhythmias across diverse populations, due to both inter-individual variability and variability in disease-associated remodeling. In this study, we perform numerical simulations of a model of human ventricular myocytes, utilizing a novel population approach to distinctly represent the variability in both intrinsic cellular properties and properties of HF-associated ionic and β-adrenergic signaling remodeling, to predict key outcomes of arrhythmia susceptibility and the presentation of the HF phenotype. We highlight the cellular properties and remodeling leading to both arrhythmia and the HF phenotype, noting key similarities and differences. Critically, we find that the relationship between intrinsic cellular properties and outcome (i.e., arrhythmia susceptibility or the HF phenotype) can be different than the relationship between remodeling severity and outcome, with the expression levels and remodeling severity of inwardly rectifying potassium current (I_K1) and the sodium-calcium exchanger (I_NaCa) as notable examples. Finally, we find that upregulation of specific β-adrenergic signaling molecules are predicted to be protective against arrhythmia. Overall, our study presents a novel approach to investigate inter-individual and disease variability and identifies how the interplay between the intrinsic variability in electrophysiology and heart failure-associated remodeling influences arrhythmias in the setting of human heart failure.