Subthreshold Parameters of Cardiac Tissue in a Bi-Layer Computer Model of Heart Failure

Abstract

Current density threshold and liminal area are subthreshold parameters of the cardiac tissue that indicate its susceptibility to external and internal stimulations. Extensive experimental and theoretical research has been conducted to quantify these two parameters in normal conditions for both animal and human models. Here we employed a 2D numerical model of human cardiac tissue to assess these subthreshold parameters under the pathological conditions of heart failure and fibrosis. Stimuli were applied over an area ranging from 0.04 to 1 mm² using various pulse durations. The current density threshold decreased with increasing stimulation area or pulse duration. No significant changes were found in both parameters between control conditions and heart failure in the atrial tissue, while in the ventricular tissue, heart failure resulted in significantly reduced excitability with higher stimulation current magnitudes needed for excitation and larger liminal areas. This results from the specific ionic remodeling in ventricular heart failure that affects both subthreshold active currents such as I(K₁) and connexin 43 conductance. In fibrosis, increased fibroblast to myocyte coupling coefficient had a non-linear influence on current density thresholds, with an initial increase of current magnitude followed by a relaxation phase down to the current magnitude threshold for the control condition with no fibrosis. The results show that subthreshold excitation properties of the myocardium are influenced in a complex, non-linear manner by cardiac pathologies. Such observations may contribute to our understanding of impulse capturing properties, relevant, for example, for the generation of ectopic foci-originated arrhythmias and for the efficient design of cardiac stimulating electrodes.

Intermittent Failure Dynamics Characterization

“…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…”

“…Narayan et al [40] Human ↓25-200% ↓25-200% Zlochiver [32] Human ↓34% ↓36% ↓50% ↑36% ↓43% Moreno et al [41] Human ↑250% ↓36% ↑65% ↓25% ↓36% ↓31% Lu et al [30] Human ↓40% ↓64% ↓50% ↑65% ↓20% ↓42% ↓45% = ↑53%…”

“…Zlochiver et al [32] used a numerical model of human cardiac tissue to quantify the current threshold for atrial and ventricular tissues under diffuse fibrosis conditions. They concluded that subthreshold excitation properties of the myocardium, such as current threshold and stimulation area, are influenced in a non-linear manner by cardiac pathologies such as heart failure.…”

“…This resulted in conduction block at slower frequencies and lower concentrations of both flecainide and lidocaine compared to normal tissue. In the work of Zlochiver and colleagues [32] an analysis of excitability under HF remodeling was performed. They observed a non-linear influence of increased fibroblast to myocyte coupling coefficient on current density thresholds, with an initial increase of current magnitude followed by a relaxation phase down to the current magnitude threshold for the control condition with no fibrosis.…”

“…Zlochiver et al [32] employed the ten Tusscher et al [33] model to demonstrate that higher stimulation current magnitudes were needed for excitation of the failing tissue, as well as larger stimulation areas. This reduction of excitability was attributed to I K1 remodeling in HF.…”