Defining the roles and therapeutic potential of C-type natriuretic peptide in the cardiac and vascular dysfunction underpinning heart failure with preserved ejection fraction

Left ventricular (LV) remodelling occurs in response to pressure-overload or injury as an adaptive, compensatory mechanism to normalise wall stress and preserve cardiac output. However, sustained biomechanical and neurohormonal activation results in a maladaptive, pathological transformation encompassing changes in myocardial architecture and function leading to heart failure (HF). Whether associated with reduced (50%; HFpEF) ejection fraction, the prognosis is poor (~50% 5-year mortality). We have played a prominent role in establishing critical (patho)physiological protective roles for C-type natriuretic peptide (CNP) in maintaining cardiac structure and function in the setting of HFrEF, slowing atherogenesis, coordinating angiogenesis, and dampening leukocyte/platelet reactivity; seminal observations enabled through in-house development of unique transgenic mouse strains with cell-restricted CNP deletion, and novel pharmacological tools. Herein we propose to extend this body of work to delineate the role(s) of CNP in the pathogenesis of HFpEF by implementing a multi-disciplinary research programme in vitro and in vivo, including pre-clinical models of disease and proof-of-concept studies in heart tissue and blood vessels from patients with HFpEF/diastolic dysfunction. This work should therefore radically advance understanding of the role(s) of CNP in offsetting the pathogenesis of HFpEF and offer potential to overtly improve treatment.