Abstract
AIMS: Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure with no effective treatment. While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence. METHODS AND RESULTS: ZSF1-Obese rats, a cardiometabolic model of HFpEF, were used to investigate systemic and cardiac inflammation, and to characterise the senescent program in immune, circulating endothelial and cardiac cells, before disease onset and onward. Using patient samples, we further evaluated the association between cellular senescence and diagnostic and prognostic markers of HFpEF. Finally, we administered a senolytic - Navitoclax - at two time-points, before and after the appearance of HFpEF. CONCLUSION: ZSF1-Obese rats had increased immune and endothelial senescent cells in their peripheral blood and myocardium, together with exacerbated systemic inflammation and endothelial damage, compared to control ZSF1-Lean rats. Moreover, increased circulating senescent leucocytes were associated with markers of disease severity in patients with HFpEF. Senescent cell clearance decreased circulating B-type natriuretic peptide levels and attenuated inflammation, vascular remodelling, and cardiac fibrosis. Additionally, it improved renal function and reduced pulmonary oedema. Our findings suggest that senotherapeutics may improve the treatment for HFpEF by attenuating systemic effects of the disease whilst reducing cardiac fibrosis and endothelial rarefaction.