Diffuse fibrosis and repolarization disorders explain ventricular arrhythmias in Brugada syndrome: a computational study

Abstract

In this work, we reported a computational study to quantitatively determine the individual contributions of three candidate arrhythmic factors associated with Brugada Syndrome. In particular, we focused our analysis on the role of structural abnormalities, dispersion of repolarization, and size of the diseased region. We developed a human phenomenological model capable of replicating the action potential characteristics both in Brugada Syndrome and in healthy conditions. Inspired by physiological observations, we employed the phenomenological model in a 2D geometry resembling the pathological RVOT coupled with healthy epicardial tissue. We assessed the insurgence of sustained reentry as a function of electrophysiological and structural abnormalities. Our computational study indicates that both structural and repolarization abnormalities are essential to induce sustained reentry. Furthermore, our results suggest that neither dispersion of repolarization nor structural abnormalities are sufficient on their own to induce sustained reentry. It should be noted how our study seems to explain an arrhythmic mechanism that unifies the classic repolarization and depolarization hypotheses of the pathophysiology of the Brugada Syndrome. Finally, we believe that this work may offer a new perspective on the computational and clinical investigation of Brugada Syndrome and its arrhythmic behaviour.

A Computational Model of Brugada Syndrome in 3D Heterogeneous Cardiac Tissue

“…In our model the intensity of I T O is increased when d 0 w is decreased. The minimal d 0 w used in our simulations (d 0 w = 0.3) caused irreversible AP dome loss in the isolated myocyte model, whereas the maximal (d 0 w = 0.5) caused a delayed dome AP morphology [5].…”

“…To perform the simulations, we employed our previously published phenomenological model of ventricular myocytes [4][5][6]. With different sets of parameters, the model reproduces the electrophysiological properties of both epicardium, endocardium and midmyocardium.…”

“…With different sets of parameters, the model reproduces the electrophysiological properties of both epicardium, endocardium and midmyocardium. To replicate the phenotype of myocytes impaired by BrS, we modified the epicardial model to have slow upstroke velocity, prominent AP notch, and early repolarization (loss of AP dome) depending on the actual membrane state [5]. Loss of AP dome happens when the transient outward current I T O is strong enough to repolarize the membrane below its activation threshold.…”

Electrophysiological patterns and structural substrates of Brugada syndrome: Critical appraisal and computational analyses

“…In a previous computational work of our group regarding BrS, we related structural and electrophysiological abnormalities to a possible mechanism of arrhythmia in a computational model of BrS. 87,103 We observed that the likelihood of arrhythmia was a function of the structural alteration and electrophysiological alteration and demonstrated that the plane defined by these two parameters defines regions of low and high probability of arrhythmia. The application of this model to clinical risk stratification context requires the identification of which physiological quantities are related to the modeled structural and electrophysiological alterations (e.g., EGM fractionation as a marker of structural alteration), and how their values are related to the values modeled in the computational setup.…”

Electrophysiological Closed Loop Model of the Heart as Supporting Tool for Cardiac Pacing

“…mulation, where the diffusivity values were selected to replicate time intervals corresponding to complete atrial activation [8], atrioventricular conduction [9], and complete ventricular activation [10]. For the definition of the ionic current (I ion ), we adopted our previously published phenomenological model [11][12][13], which we fitted to the electrophysiological properties of the different types of cardiac cells. The fitting procedure is aimed at reproducing the main characteristics of experimental action potential morphology and action potential duration, and conduction velocity steady-state restitution curves.…”