Ventricle-specific fibrotic cardiac remodeling in the progression of heart failure with preserved ejection fraction
Abstract
Heart failure with preserved ejection fraction (HFpEF) is currently the most prominent form of heart failure (HF). Despite the rising prevalence over the last few years, the pathogenesis of this disease is still unknown. Therefore, the focus of this dissertation is to investigate the molecular pathogenesis of fibrotic cardiac remodeling in swine models of HFpEF as cardiac fibrosis is a hallmark feature of this disease and hypothesized to be involved in its pathogenesis. Fibrotic cardiac remodeling can occur when there is a dysregulation between the synthesis and degradation of extracellular matrix (ECM) proteins. Additionally, the focus of this dissertation is to evaluate fibrosis in the left and right ventricles as right ventricle (RV) dysfunction can increase the risk of mortality up to 80 percent in individuals with HFpEF. Overall the goals of this dissertation are two-fold. First, to evaluate RV remodeling in a cardio-metabolic swine model of HFpEF. Second, to investigate the differences between the regulation of cardiac fibrosis in left ventricle (LV) and RV in a swine model subject to chronic pressure overload and/or the loss of female sex hormones. With the cardio-metabolic swine model, RV transcriptome analysis identified MAPK8/JNK1 as a hub gene associated with ECM remodeling that included an increase in fibronectin in the right coronary artery (RCA). This increase in fibronectin was potentially due to a regulatory imbalance between JNK and matrix metalloproteinase-14 (MMP-14). Additionally, this increase in fibronectin was associated with an increase in vascular stiffness. With the second goal of this study, it was demonstrated that the regulation of cardiac fibrosis occurs in a chamber-specific manner. In the LV, there was an increase in total collagen levels due to the loss of sex hormones but this increase in fibrosis was not a result of linear alterations in synthesis or degradation. In the RV, though, there was an increase in total collagen levels due to chronic pressure overload and independent of the loss of sex hormones. This increase in fibrosis was due to an increase in synthesis associated with increases in JNK activation and myofibroblast activation. Taken together, these results demonstrate differences in the regulation of ECM remodeling that occur in the LV, RV, and RCA in two swine models with relevance to HFpEF. This emphasizes the need to further explore the regulation of ECM remodeling at multiple levels of the heart in order to fully understand the pathogenesis of HFpEF.
Degree
Ph. D.