Neutrophil arrest in myocardial capillaries drives hypoxia and impairs diastolic function in a mouse model of heart failure with preserved ejection fraction

Abstract

Impairments in myocardial blood flow have been recognized for decades in human patients with and animal models of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms and roles in pathogenesis remain poorly understood. Using intravital cardiac microcopy in a two-hit mouse model of HFpEF that combines high fat diet and inhibition of nitric oxide synthase, we identified an increase in slow or non-flowing neutrophils in capillaries compared to Control mice. In other mouse models of disease (e.g., in the brain of Alzheimers Disease mice), the presence of such stalled neutrophils leads to organ-wide decreases in perfusion and oxygenation. Administration of antibodies against the neutrophil surface protein Ly6G to deplete neutrophils reduced the number of arrested neutrophils in myocardial capillaries, leading to improvements in myocardial hypoxia, diastolic function, and exercise capacity. This study identifies a previously uncharacterized cellular mechanism that explains myocardial blood flow deficits in mouse models of HFpEF, and demonstrates that improving myocardial blood flow improves cardiac function, without necessitating reversal of pathologic remodeling. Restoring myocardial perfusion by decreasing neutrophil arrest in myocardial capillaries may provide a strategy for improving heart function in HFpEF patients in the future.