Investigation of pulmonary vascular function in the setting of heart failure with preserved ejection fraction

Background: Heart failure is the commonest cardiovascular cause for hospital admission in people aged >65years. It has become increasingly evident that HF with preserved ejection fraction (HFpEF) is the commonest form of HF, accounting for more than 50% of all cases. Concerningly, to date, no therapy has been shown to improve survival or to consistently reduce hospitalization and quality of life. As such, HFpEF remains an area of major unmet clinical need. The pathophysiology of HFpEF is complex, with major cardiovascular elements related to increased myocardial and arterial stiffness. These features are related to ageing and concomitant hypertension. Recent theories have also focused on the potential role of the venous circulation and its stiffness, given that venous compliance is an important contributor to the mean circulatory filling pressure. This study will investigate pulmonary vascular compliance in animal models HFpEF. Project aim: Our laboratory has established models in mice designed to recapitulate features of HFpEF. These studies are performed in aging hypertensive mice and in obese mice. In this study we plan to collect the pulmonary vein and study the mechanical properties (stiffness) and to study the histological, cellular and molecular properties compared to healthy mice. By understanding the way in which veins remodel, and the stimuli that drive the process we hope to develop better treatments for HFpEF. Techniques: It is anticipated that this project will involve developing and monitoring an animal model of hypertension- or diet-induced CVD, histological and biochemical analysis of fibrosis and inflammation, behavioral and functional assessments (echocardiography, metabolic cages, echoMRI), and vascular function assessment with myography as well as gene expression (RNA extractions and qPCR).