Diabetes predisposes to a wide array of cardiovascular-complications. Heart-failure (HF) is one of the most debilitating in terms of patient outcomes and survival. We are facing an epidemic of diabetes-induced HF, as a result of increased global-prevalence of diabetes together with an ageing population. Diabetic patients account for up to one third of patients in HF clinical trials, with diabetes an independent predictor of poor outcome. The full spectrum of potential-mechanisms contributing to this HF phenotype in the context of diabetes is not fully resolved.
Prof Rebecca Ritchie has built a strong international reputation with regard to diabetes-induced HF (recognised by recent lead authorships in Circ-Res, JACC etc). She has driven interrogation of the causes of this major healthcare-burden, as well as pursuit of new therapeutic-strategies to target this unmet clinical-need.
The current application builds on 2 recent discoveries from her team. Firstly, that glucose-driven enzymatic-modification of myocardial-proteins by the sugar, β-N-acetylglucosamine (O-GlcNAc), is increased in diabetic human-myocardium, and positively correlated with myocardial-dysfunction. Secondly, that fine-tuning the regulatory enzymes controlling O-GlcNAc-modification governs the functional and structural phenotype of diabetic-myocardium. Increased metabolic flux towards O-GlcNAc-modification directly increases stiffness of the heart and impairs its function.
Through an innovative collaboration encompassing cardiac-pathophysiology (CIA-Ritchie, CIC-de-Blasio, AI-Erickson), cutting-edge mass-spectroscopy-based proteomics (CIB-Greening) and cardiothoracic surgical-expertise (AI-Zimmet), we will undertake comprehensive analysis in human cardiac-biopsies to identify (and quantitate), for the first time, specific individual sites of proteins modified by diabetes in human-heart as a result of these glucose-driven changes, and dissect their contribution to diabetes-induced HF.
Last updated12 July 2021