Abstract:
Heart failure (HF) is a leading cause of death in the developed world, and its impact is rising due to an increasing aging population (Roth et al. 2017). Despite developments in treatment, the long-term prognosis remains poor with annual mortality rates of 1-2 million (Savarese & Lund 2017). Approximately half of these mortality cases in HF are sudden and they are believed to be the result of lethal arrhythmias (Wilson et al. 2009). Of the numerous pathologies that lead to HF, more than three quarters of patients display antecedent hypertension (Benjamin et al. 2017). In light of this, the progression of hypertension to HF has been studied intensively (A. M. Gerdes et al. 1996; Doggrell 1998; Aidietis et al. 2007; Drazner 2011) and is characterised by significant structural remodelling such as fibrosis (Ma 1998; LeGrice et al. 2012). While structural remodelling is a hallmark of progression towards HF, its role in arrhythmogenesis remains an area of debate. With this in mind, the principal objectives of this study were to characterise the relationships between electrical dysfunction and multi-scale structural remodelling in the progression towards HF. To investigate the possible electrophysiological variation associated with fibrosis, Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR) image volume sets consisting of minimal fibrosis and large amounts of fibrosis, respectively were analysed and compared. The two tissue sets were structurally investigated, while computational simulations were conducted to identify any variation in electrical activation. At larger scales, the SHR volumes displayed a marked reduction in fiber rotation in the sub epicardium. In addition, significant tissue connectivity reduction associated with fibrosis was also observed. Finally, electrical activation simulations demonstrated slowing in conduction velocity (CV) in the SHR dataset. Building on this finding, the structural and electrical changes associated with the development of HF was investigated using the hypertensive heart disease (HHD) SHR model in a longitudinal (6, 12, 18 months) paired study. Structural remodelling was captured at the tissue level using multiple morphological measures. Characterisation of the cellular architectural variation was also conducted using a imaging protocol developed in this thesis. This method enabled large high resolution volumes of cardiac cellular arrangements to be acquired without the use of physical sectioning. In addition to the structural measurements, the electrical variation was also quantified using high resolution optical mapping. Furthermore, a novel optical mapping motion artifact reduction tool was developed using a non-rigid deformation technique. The relatively simple tool was able to recover action potentials (APs) from optical mapping datasets in the presence of substantial motion artifact. The majority of these methods were applied to the SHR cohorts. The outcomes of this longitudinal study demonstrated that there were significant differences in structure and electrical activity with age. The most marked changes occurred between 6 and 12 months, showing significant increase in fibrosis, cell dimension, and rate dependent CV slowing /anisotropy and repolarization dispersion. In contrast, while there was an increase in the measures noted above from 12 to 18 months, the differences were less pronounced with a considerable overlap. Arrhythmic susceptibility also increased with age and showed a similar nonlinear trend to that of the other measures. Further to these age related changes, cellular coupling exhibited a clear inverse relationship with the amount of fibrosis. Finally, comparisons of structure and electrical dysfunction demonstrated that the extent and form of fibrosis were associated with rate dependent CV slowing/anisotropy and repolarization heterogeneity. Both these features of electrical dysfunction formed the substrates for increased arrhythmic susceptibility. Overall, the increased electrical dysfunction/arrhythmic susceptibly observed with the progression of HHD towards HF was closely linked with fibrotic influence. This provides significant evidence that structural remodelling plays a major role in electrical instability.