Impact of microvascular endothelial signalling on remodelling progression in experimental and clinical heart failure with preserved ejection fraction

Whilst incidence of heart failure with preserved ejection fraction (HFpEF) continues to increase, key disease drivers remain poorly defined with limited available clinical strategies. Coronary microvascular dysfunction (CMD) is evident in a significant proportion of HFpEF patients, which is linked with distinct pathophysiology and increased susceptibility to stress, and holds clear potential as an innovative diagnostic, prognostic, and therapeutic target. We hypothesise that coronary microvascular endothelial cell (CMEC) dysfunction is central to experimental and clinical HFpEF and linked with adverse cardiovascular remodelling, disease progression and common signalling pathways. As these aspects are currently poorly defined and experimental HFpEF is incompletely characterised with respect to clinical disease, the principle aim of this focused project is to provide proof-of-concept and feasibility as important foundation for comprehensive analysis. Specifically, we will (1) characterise CMEC dysfunction and adverse cardiovascular remodelling in experimental HFpEF, and (2) define cardiac signalling alterations during HFpEF progression with comparison to patient samples and data. We expect to identify common CMEC pathways in experimental and clinical HFpEF as a key determinant of progressive adverse tissue remodelling and basis for programmatic translational investigation.