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J Am Heart Assoc


Background: Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin-1β in HFpEF pathogenesis are poorly understood.

Methods and Results: C57/Bl6J and interleukin-1β(-/-) male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin-1β(-/-) mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin-1β(-/-) mice were fed a high-fat diet with N[w]-nitro-l-arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high-fat diet and N[w]-nitro-l-arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin-1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms.

Conclusions: Our data suggest that interleukin-1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.

Medical Subject Headings

Mice; Male; Animals; Heart Failure; Stroke Volume; Interleukin-1beta; Drinking Water; Cardiomyopathies; Inflammation

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