| Summary: |
Heart failure (HF) is a highly prevalent syndrome of impaired cardiac function that constitutes the main cause of hospitalization and disability amongst the elderly, a leading cause of mortality, morbidity and resource consumption. HF with preserved ejection fraction (HFpEF) which is characterized by preserved ejection, impaired cardiac filling, lung congestion and effort intolerance accounts for a rising proportion of over 50% of cases due to ageing and increasing incidences of systemic arterial hypertension (SAH), obesity and diabetes mellitus (DM). Although initially believed to be of better prognosis we now realize HFpEF's prognosis is grim, (65% 5-year mortality) and has remained unchanged. Indeed, current therapy aims only at symptom relief. HFpEF patients may constitute an heterogeneous group with extensive comorbidities that lead to systemic inflammation, microvascular dysfunction, enhanced reactive oxygen species (ROS) production, reduced bioavailability of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) and thus reduced protein kinase G (PKG) activity in cardiomyocytes (CM) which in turn leads to titin hypophosphorylation and extracellular matrix (ECM) remodelling, the key downstream determinants of myocardial stiffness. Therapeutic trials targeting downstream elements such as cGMP availability were unsuccessful, highlighting the need for a thorough understanding of upstream mechanisms, namely the role of comorbidities, microvascular dysfunction and disturbances of cell-communication. The current proposal sets forth to address this issue by a mixed strategy of discovery science approach through comprehensive multi-omics studies in plasma and tissues from HFpEF patients and animal models with and without comorbidities (DM, SAH and obesity), and an hypothesis-driven approach focusing on disturbances of cell function and communication in endothelial cells (EC), cardiac fibroblasts (CF), adipocytes and CM. A holistic view of HFpEF and of t  |
Summary
Heart failure (HF) is a highly prevalent syndrome of impaired cardiac function that constitutes the main cause of hospitalization and disability amongst the elderly, a leading cause of mortality, morbidity and resource consumption. HF with preserved ejection fraction (HFpEF) which is characterized by preserved ejection, impaired cardiac filling, lung congestion and effort intolerance accounts for a rising proportion of over 50% of cases due to ageing and increasing incidences of systemic arterial hypertension (SAH), obesity and diabetes mellitus (DM). Although initially believed to be of better prognosis we now realize HFpEF's prognosis is grim, (65% 5-year mortality) and has remained unchanged. Indeed, current therapy aims only at symptom relief. HFpEF patients may constitute an heterogeneous group with extensive comorbidities that lead to systemic inflammation, microvascular dysfunction, enhanced reactive oxygen species (ROS) production, reduced bioavailability of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) and thus reduced protein kinase G (PKG) activity in cardiomyocytes (CM) which in turn leads to titin hypophosphorylation and extracellular matrix (ECM) remodelling, the key downstream determinants of myocardial stiffness. Therapeutic trials targeting downstream elements such as cGMP availability were unsuccessful, highlighting the need for a thorough understanding of upstream mechanisms, namely the role of comorbidities, microvascular dysfunction and disturbances of cell-communication. The current proposal sets forth to address this issue by a mixed strategy of discovery science approach through comprehensive multi-omics studies in plasma and tissues from HFpEF patients and animal models with and without comorbidities (DM, SAH and obesity), and an hypothesis-driven approach focusing on disturbances of cell function and communication in endothelial cells (EC), cardiac fibroblasts (CF), adipocytes and CM. A holistic view of HFpEF and of the role of comorbidities will be achieved by correlating and integrating transcriptomics, proteomics and lipidomics studies with clinical data. Gene variants that may predispose to HFpEF will be gauged by genomics. Variants will be explored in cell and animal models of disease achieved by induced pluripotent (iPS) and mutated human embryonic stem cell (hES) methodologies. Different aspects of EC, CF and adipocyte activation and dysfunction will be assessed focusing on previously unexplored issues such as autophagy and mitochondrial dysfunction. Cell communication by way of gap junctions and exosomes will also be investigated. The impact on CM and myocardium will be comprehensively assessed in vitro and in vivo. Finally, preclinical testing of functional foods, synthetic antioxidants, enhanced bioavailability putative therapeutic molecules as well as other potentially effective gene targets identified along the project´s course will be assayed.
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