Abstract
BackgroundHeart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure.ObjectiveIn this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations.MethodsThe electrical activity of human transmural ventricular tissue (5 cm×5 cm) was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW) for reentry was evaluated following cross-field stimulation.ResultsNo reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components.ConclusionStructural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity.
Highlights
Ventricular arrhythmias in patients with congestive heart failure (HF), contribute to the high incidence of sudden cardiac death associated with HF [1,2]
The principal findings and insights from our work are (i) demonstration that HF electrophysiological remodeling delays the limits of the vulnerable window for reentry but does not alter the width of the VW, so that the likelihood of reentrant activity is not enhanced; (ii) confirmation that fibrosis is determinant for reentry generation; intermediate fibrotic levels increase the VW and favor reentry generation, while high levels hamper it; (iii) evidence that intermediate intercellular uncoupling enhances the VW; (iv) understanding how the active interaction between fibroblasts and failing myocytes increases the presence of phase singularities in ventricular tissues and alters the spiral wave dynamics in reentrant circuits
Repolarization is delayed in HF and premature stimulation can lead to reentry if applied at later instants of time Moreno et al [16] evaluated the effects of drugs on reentry generation in a virtual human ventricular tissue with HFinduced electrophysiological remodeling and observed that conduction block occurred at slower frequencies with HF remodeling, delaying the limits of the vulnerable window for reentry generation
Summary
Ventricular arrhythmias in patients with congestive heart failure (HF), contribute to the high incidence of sudden cardiac death associated with HF [1,2]. Afterdepolarization-induced trigger activity has a high tendency to develop in the failing myocardium. Conditions favoring reentrant arrhythmias have been described in failing hearts [2]. Reentrant activity is generated by wave interaction with anatomical or functional obstacles combined with specific excitability conditions [3]. In diseased hearts, preexisting electro anatomic tissue heterogeneity is amplified considerably, increasing vulnerability to reentrant arrhythmias [3,4]. Heart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure
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