Conductional remodeling and arrhythmias in the diseased heart

Abstract

Cardiovascular disease (CVD) is the main cause of death in Western society and it is a global public health problem, particularly taking into account the ageing of the population in many countries. An important player in CVD is heart failure, which is a complex syndrome defined by insufficient pump function of the heart due to cardiac structural and functional abnormalities. Up to 50% of deaths in heart failure patients occurs due to sudden cardiac death, caused by fatal cardiac arrhythmias. Ventricular tachyarrhythmias are responsible for the vast majority of sudden cardiac deaths, however, the underlying mechanisms that lead to these arrhythmias are insufficiently understood. The aim of this thesis was to investigate changes affecting electrical impulse conduction in the diseased heart leading to arrhythmogenesis, and whether modification of the addressed changes proved to prevent arrhythmias. Firstly, the role of the gap junction protein connexin43 (Cx43) was thoroughly reviewed in the context of different cardiomyopathies, in which Cx43 is generally downregulated, heterogeneously redistributed throughout the heart, and in some cases lateralized. This frequently results in a reduction in conduction velocity, which might increase the susceptibility to arrhythmias, especially in combination with increased fibrosis. Next, we showed that two mouse models of renal dysfunction had a markedly increased susceptibility to arrhythmias, which was correlated with decreased Cx43 expression and increased fibrosis in the heart. Furthermore, we provided evidence that acute or chronic inhibition of calmodulin/calcium-calmodulin protein kinase II (CaM/CaMKII) in different animal models leads to increased conduction velocity due to increased presence of Cx43 at the intercalated disk. Additionally, acute CaM inhibition decreased the incidence of re-entry arrhythmias in diseased rabbit hearts, while chronic CaMKII inhibition had no suppressive effect on induced arrhythmias in mice subjected to pressure overload. Since CaM is additionally involved in activation of calcineurin A (CnA), we further looked into a potential role for CnA. Using a mouse model of cardiac overexpression of continuously active CnA, we demonstrated that hypertrophy in these mice started as early as the first postnatal week, coinciding with a reduction in Cx43 and in sodium channel NaV1.5 expression. Furthermore, these changes preceded significant deposition of fibrosis, decreased phosphorylation of Cx43 and increased expression of pro-fibrotic genes amongst them connective tissue growth factor (CTGF). The effects of absence of CTGF on cardiac remodeling upon chronic pressure overload in inducible and global CTGF knockout (KO) mice were also investigated. Surprisingly, CTGF KO failed to prevent pressure overload-induced cardiac fibrosis and hypertrophy, as well as contractile remodeling and reduced Cx43 protein expression, suggesting that CTGF is not a critical player in fibrosis development. In conclusion, we have shown in this thesis that increased cardiac fibrosis and reduced Cx43 expression are strongly associated with the arrhythmogenic substrate in the diseased heart. Increased Cx43 at the intercalated disk appears anti-arrhythmic under conditions that lack the maladaptive influence of fibrosis. Furthermore, we have shown that CTGF and CaMKII are not essential players in the development of cardiac fibrosis.