Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study

Abstract

BackgroundHeart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression.ObjectiveIn this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation.MethodsTwo different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias.ResultsSimulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+/Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure.ConclusionAn extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.

Intermittent Failure Dynamics Characterization

“…This is where computational studies are of great help by performing mechanistic analyses using mathematical models of disease-specific APs in the human heart, and revealing mechanisms for arrhythmogenesis. In this way, a simulation study by Gomez et al revealed increased APD dispersion under HF conditions assuming transmural homogeneous ion channel remodeling with respect to control, regardless of the presence or absence of M cells, but decreased TDR values were found when transmural heterogeneous remodeling was considered [53] and only in the absence of M cells. This computational study explained the above mentioned experimental controversial findings for TDR in HF, showing that the absence of M cells in the human failing heart is important but not sufficient to bring TDR values below those of nonfailing hearts.…”

“…The consideration of I NaL in computational models of heart failure is crucial in simulating the activity of failing ventricular cells because of its important role in repolarization abnormalities, such as EAD generation [31,32,34,35,41,53]. Model predictions have suggested I NaL as a novel [38] Dog ↓66% ↑75% ↓33% ↓68% Puglisi et al [25] Rabbit ↓36% ↑100% ↓49% ↓24% Shannon et al [26] Rabbit ↑100% ↓50% Morita et al [39] Rabbit ↑200% ↑200% ↓20% Priebe and…”

“…Gomez et al used computational models to describe various ways by which fibrotic content and structural remodeling modulates the arrhythmogenic substrate of the failing heart, increasing repolarization gradients and leading to abnormal impulse propagation [53]. The fibrotic content ranged from 4 to 40%, measured as a percentage of nodes assigned to the fibroblast ionic model, which would correspond to the experimental ranges in terms of fibrotic area.…”

Population-Based Mechanistic Modeling Allows for Quantitative Predictions of Drug Responses across Cell Types

“…5f). 23 a variant of the O'Hara model was constructed to reproduce molecular and physiological alterations observed in heart failure (HF). Altered parameters (see Table S5) reflected well-described changes in HF such as reduced SERCA pump activity, upregulation of NCX, and downregulation of I Ks .…”

Intracellular Calcium Regulation in Canine Ventricular Myocytes: a Simulation Study

“…These computational studies rely on detailed and comprehensive mathematical models of action potentials for different animal species [6][7][8], including human [9]. Using this models, different studies have attempted to characterize the influence of the different sarcolemmal and SR ionic currents in AP and intracellular Ca 2+ preclinical biomarkers [10,11], but none of them has been carried out in dog, an animal that has widely been used in the past for drug and mutation effect studies [12,13].In this study, we have used a well-known existing model of the action potential and ionic currents of a dog ventricular myocyte [7] to perform a sensitivity analysis to elucidate the ionic mechanisms that affect intracellular Ca 2+ regulation. …”