Abstract
The heart is able to adapt to new, often pathologic, conditions, so-called cardiac remodeling. Although initially adequate, these adaptations could can become maladaptive over time. One of the adaptations of the heart during pathology is ventricular hypertrophy, which may go hand in hand with an increased risk of fatal ventricular
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arrhythmias. Moreover, ventricular hypertrophy may deteriorate into heart failure. Both compensated ventricular hypertrophy and heart failure are accompanied by a significant risk for sudden cardiac death, attributable to ventricular arrhythmias. In this thesis, we sought to elucidate underlying molecular, cellular, and structural mechanisms leading to increased susceptibility to fatal ventricular arrhythmias during the process of cardiac remodeling, with a focus on the determinants of impulse propagation. A variety of models (see below) has been used 1) to cover various stages of remodeling and 2) to obtain a more solid basis for extrapolation to human cardiac disease. In the calcineurin mouse (MHC-CnA), a model of artificially induced hypertrophy, impairment of conduction was associated with severe diminution of Nav1.5, Cx43 and Cx40 protein expression. Downregulation of Nav1.5 and Cx40 protein expression, however, was accounted for by a transcriptional mechanism. Protein reductions were accompanied by a decreased mRNA of Nav1.5 and Cx40, but not Cx43. The latter was accounted for by a post-transcriptional mechanism. Increased collagen deposition in the heart occurs during aging. A senescent mouse model showed that prevention of fibrosis by chronic RAAS inhibition resulted in an anti?arrhythmogenic effect. In addition, in treated mice, lower arrhythmogeneity was directly correlated to a reduced amount of patchy fibrosis. Longitudinal characterization in a murine chronic pressure overload model of compensated and decompensated hypertrophy (TAC, transverse aortic constriction) showed a rapid evolution of structural and electrical remodeling. TAC mice showed an increased vulnerability to induced ventricular arrhythmias, which were related to heterogeneous expression of Cx43. In heart failure patients, a heterogeneous distribution of Cx43 was also associated with a history of serious ventricular arrhythmias. Heterogeneous Cx43 distribution may lead to functional block and unstable reentry, giving rise to polymorphic ventricular tachyarrhythmias. Detailed 3D mapping in the chronic atrioventricular block (CAVB) dog, model of compensated hypertrophy, revealed focal activity to be the dominant mechanism involved in perpetuation of ibutilide induced TdP. This was in line with the frequent observation of a focal origin of activation during TdP and scanty electrophysiological changes in favor of reentry. In TAC rats, a pressure overload model of compensated hypertrophy, transmural conduction was impaired, which was related to a decreased total amount of Cx43 combined with increased heterogeneity of Cx43 expression and partial substitution with non-phosphorylated Cx43. In this model, these alterations resulted in polymorphic VTs. Virtually all results point out that a heterogeneous distribution of Cx43 generates a major arrhythmogenic substrate, both in the animal models and in heart failure patients. Cx43 heterogeneity correlated well with dispersed impulse conduction and increased arrhythmia inducibility. Therefore, spatial distribution of Cx43 might be a novel diagnostic tool in the identification of increased arrhythmia vulnerability in patients. Additionally, spatial Cx43 distribution might provide a new therapeutic target in the diseased myocardium
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