Clinical and treatment perspectives for heart failure with preserved ejection fraction
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Heart failure with preserved ejection fraction (HFpEF) currently represents half of the ~6 million heart failure patients in the United States, and is increasing at a rate of ~1% per year. Conventional treatments commonly used for heart failure with reduced ejection fraction (HFrEF) patients have proven ineffective for HFpEF, highlighting the critical need for development of novel treatment options for this HF sub-population. Further, population studies have repeatedly found HFpEF to disproportionally effect women 2:1 over the age of sixty-five compared to men. Therefore the purpose of my dissertation was two-fold: (1) To examine novel treatment perspectives testing pharmacological interventions for treatment of heart failure with preserved ejection fraction; and (2) A clinical perspective examining mechanisms responsible for the increased prevalence of HFpEF in women. A novel miniature swine model displaying key characteristics of HFpEF was used to assess both of these aims. Aim one evaluated the efficacy of three different pharmacological treatments. The first drug cyclospsorine, aimed at inhibiting cylophilin D and preventing mitochondria permeability transition and the second drug tadalafil, aimed at inhibiting phosphodiesterase 5 and preserving cyclic guanine monophosphate (cGMP) both were ineffective in treating HFpEF. However, the third drug tested, saxagliptin; a dipeptidyl-peptidase 4 inhibitor, aimed at preserving cGMP, improved both cellular and functional cardiovascular outcomes in our mini-swine HFpEF model. This study highlighted the potential benefit of saxagliptin's for treatment of HFpEF, which currently lacks any viable therapeutic options. The purpose of the second aim was to evaluate HFpEF from a clinical prospective, in effort to uncover what mechanisms actually lead to the development of HFpEF. We hypothesized female sex hormones would protect against pressure overload-induced cardiomyocyte calcium handling and contractile abnormalities, thus preserving overall cardiomyocyte function. In contrast to our hypothesis, our results found regardless of hormone status, compromised cardiomyocyte excitation-contraction coupling (ECC) was evident by impaired calcium release and reuptake in parallel with diminished contractile function. Cardiomyocyte dysfunction was associated with distinct alterations to the protein levels and phosphorylation state of important calcium handling and contractile proteins. Our results show impaired cardiomyocyte function contributes to pressure-overload HF regardless of hormone status in a translational model with potential relevance to human HFpEF. While important advances have been made in our understanding of the haemodynamic and cellular pathophysiology HFpEF as well as contributing mechanisms associated with the disease, further research is urgently required to determine how to better target these abnormalities to reduce the substantial burden of morbidity and mortality in this form of HF, which is reaching epidemic proportions.
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