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Project

The role of adipose tissue in arrhythmogenesis: an in silico study

The most common sustained cardiac arrhythmia is atrial fibrillation (AF), affecting approximately 1.5 % of the population [Lip G. et al. 2007]. AF is a progressive disease becoming more prevalent with increasing age and results in increased mortality, morbidity and impaired quality of life [Thrall G. et al. 2006].

AF is associated with important structural, electrical and mechanical (both passive and contractile) remodeling. The disease progresses from paroxysmal (with episodes of AF) to persistent AF. During atrial fibrillation, the electrical wave propagation of the atria is disturbed and could be seen as ”chaotic”. However, clear distinct mechanisms of fibrillation have been predicted by computational modeling and were observed in the clinic. AF is now commonly treated with ablation techniques, preventing re-entry to occur by scarring parts of the atrial wall, that can be guided eventually by computational techniques. Examples are Mother rotor AF, Multiple wavelet AF, non-reentrant AF and mixed focal reentrant AF [J. Weiss et al. 2016]. Therefore, computational modeling has already proven to be a powerful way of examining the mechanisms underlying cardiac arrhythmias, allowing for a controlled environment to test hypotheses [Panfilov A. 1998, ten Tusscher K. & Panfilov A. 2006, Wilhelms M. et al. 2013].

Despite the fact that the arrhythmia is common and can be successful treated with ablation techniques, less is known about the onset and the progression of AF and computational models can play a role to unravel basic mechanisms. Computational models for the atrial cellular action potential, based on ion-channel dynamics have been developed for the diseased state based on data derived from patch-clamp experiments in atrial myocytes from animal models mimicking AF [Butters T. et al. 2013], including the model developed in Leuven [Anne W. et al. 2007, Lenaerts I. et al. 2009]. However, most computational modeling studies of atrial wave propagation, have subsequently been studied on atria with normal atrial morphology and tissue structure, ignoring the changes in both morphology, with marked regionally different dilatation of the atria, and structure, i.e. the substrate for the arrhythmia.

Persistent AF is associated with structural changes on top of electrical ones [Anne W. et al. 2007] and increased myocardial fibrosis in the atria, has been proposed as the main contributor to an arrhythmogenic substrate. Recent experiments have shown also significant correlations between adipose tissue and AF [Pantanowitz L. 2001, Samanta R. et al. 2016]. Infiltrations of adipose tissue within the myocardium have been associated to arrhythmogenicity for long in arrhythmogenic right ventricular cardiomyopathy [Bauce B. et al. 2005] and more recently in ventricular fibrillation secondary to myocardial infarction, where adipocyte infiltration in the infarct border zone was found to be more arrhythmogenic [Pouliopoulos J. et al. 2013]. The presence of these adipocytes in turn modulate the electrophysiological properties of the adjacent myocytes [Lin Y. et al. 2012]. Data from our own animal model in Leuven, has shown that progression of AF shows fibrotic remodeling of adipose infiltrates in the sub-epicardial layers of the atrial wall, associated with cellular inflammation [Haemers P. et al. 2015].

To date, integrative modeling of these structural and electrophysiological changes is lacking and will be the subject of this thesis.

Date:1 Oct 2014 →  2 May 2019
Keywords:Atrial fibrillation, in silico modelling, adipose tissue
Disciplines:Cardiac and vascular medicine
Project type:PhD project