Abstract Body (Do not enter title and authors here): Introduction
C-type natriuretic peptide (CNP) is an endogenous paracrine mediator released by endothelial cells and cardiomyocytes during inflammation and cardiac stress. CNP is known to regulate various aspects of myocardial structure and function including myocyte contractility, coronary vascular reactivity and fibrosis. However, an intrinsic role for the peptide in offsetting the pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unsubstantiated.

Aim
To investigate whether endogenous CNP preserves diastolic function in the setting of HFpEF by maintaining cardiac structure, reducing myocardial fibrosis, and dampening inflammation.

Methods
Endothelial (ecCNP^-/-) and cardiomyocyte (cmCNP^-/-) -restricted CNP knockout and natriuretic peptide receptor-C (NPR-C^-/-) knockout mice were subjected to a high fat diet (HFD) plus N^G-nitro-L-arginine methyl-ester (L-NAME; 100mg/kg/day; p.o.) ‘two-hit’ model of HFpEF. Echocardiography was performed at baseline and endpoint to assess cardiac structure and function. Blood pressure, heart weight and lung wet weight were determined, and cardiac sections processed to establish fibrotic burden and immune cell infiltration.

Results
ecCNP^-/- animals developed a more severe HFpEF phenotype in comparison to WT littermates, as illustrated by greater diastolic dysfunction (e.g. isovolumetric relaxation time, IVRT; myocardial performance index, MPI) and greater myocardial immune cell infiltration. In contrast, whilst cmCNP^-/- animals did not exhibit any overt deficiency in diastolic function in experimental HFpEF, myocardial fibrosis was exacerbated in these mice. Interestingly, diastolic dysfunction (e.g. IVRT, MPI, E/e’) and fibrotic burden were also significantly greater in mice lacking the cognate receptor NPR-C suggesting it is this NPR subtype that underpins the combined beneficial actions of endothelial and cardiomyocyte -derived CNP.

Conclusions
Endogenous CNP, of endothelial and cardiomyocyte origin, plays an important role in mitigating the development of diastolic dysfunction, inflammation and ventricular stiffening in HFpEF; this salutary action is underpinned by activation of NPR-C. Targeting CNP/NPR-C signalling may therefore be of therapeutic benefit in this disorder.

Funding
British Heart Foundation Programme Grant (RG/F/23/110123) and Biotechnology and Biological Sciences Research Council CASE PhD studentship (BB/W509991/1).