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Objective: Heart failure with preserved ejection fraction is a major health care issue which has been difficult to manage to date, due to its complex and not well understood pathophysiology. Specifically, if a wealth of literature focuses on heart failure with preserved ejection fraction cardiac component, very little information can be found on its vascular component. Our goal is to unravel the critical role of cardiac small vessel disease in the pathophysiology of diastolic dysfunction. Approach and Results: To do so, we used leptin receptor deficient (Leprdb/db ) female mice, a recognized model of diastolic dysfunction. In these mice, the increased end-diastolic pressure signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation, and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Leprdb/db and control mice confirmed endothelial dysfunction and systemic inflammation, but above all, revealed a strong increase in several mast cell markers (notably FceR1a [high affinity immunoglobulin epsilon receptor subunit α], tryptase, and chymase). We then confirmed this accumulation of activated mast cells in the heart of Leprdb/db mice via histology. Importantly, we found that both mast cell degranulation inhibition and specific histamine blockade reduced vascular leakage, leucocyte infiltration, and subsequently end-diastolic pressure in Leprdb/db mice. This demonstrated, for the first time, that mast cells, via histamine release, participate in the development of cardiac small vessel disease leading to diastolic dysfunction.Conclusions: Cardiac small vessel disease is a key mechanism of heart failure with preserved ejection fraction pathophysiology that can be targeted to prevent the occurrence of diastolic dysfunction, by using both mast cell stabilizers and antihistaminic drugs.

Mast Cells Are the Trigger of Small Vessel Disease and Diastolic Dysfunction in Diabetic Obese Mice