Key result
ANGPTL2 inhibition prevents HFpEF development by preserving macrophage communication in hypertensive mice.
Why the study?
Hypertensive stress and sympathetic overactivation, rather than obesity, are dominant features in some HFpEF cohorts, but the underlying macrophage signaling mechanisms remain unclear.
Does hypertensive stress combined with endothelial dysfunction drive HFpEF development via macrophage signaling rewiring independently of obesity?
Does hypertensive stress combined with endothelial dysfunction drive HFpEF development via macrophage signaling rewiring independently of obesity?
HFpEF in Japanese patients is predominantly driven by sympathetic overactivation and hypertension rather than obesity, mediated through hypertensive stress and endothelial dysfunction rewiring cardiac macrophage intercellular signaling.
Supports ANGPTL2 inhibition in hypertensive HFpEF models; leaves open translation to human non-obese disease.
Heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical challenge. Although obesity is common in many HFpEF cohorts from Europe and North America, three Japanese HFpEF cohorts identified hypertension and sympathetic overactivation, rather than obesity, as dominant features. To model these features, we established an HFpEF mouse model in which sympathetic activation induces hypertensive heart disease, while endothelial dysfunction acts as a second hit driving progression to HFpEF. Hypertensive stress rewires cardiac macrophage-derived intercellular signaling, impairing macrophage-to-cardiomyocyte BMP signaling and fatty acid oxidation while enhancing macrophage-to-fibroblast PDGF signaling, thereby promoting metabolic remodeling, inflammation, and fibrosis. ANGPTL2 inhibition preserves macrophage intercellular communication and prevents HFpEF development. These findings identify cardiac macrophage signaling rewiring as a central mechanism linking hypertensive stress to metabolic remodeling and inflammation, revealing a pathogenic pathway for HFpEF in the absence of obesity that is distinct from HFpEF associated with obesity.
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Kinoshita et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF) (n=572). Anti-ANGPTL2 monoclonal antibody vs. Isotype-matched control IgG was evaluated on Development of HFpEF phenotypes (diastolic dysfunction, cardiac hypertrophy, and fibrosis) in an in vivo mouse model. ANGPTL2 inhibition preserved macrophage intercellular communication and prevented the development of HFpEF in a non-obese mouse model driven by hypertensive stress and endothelial dysfunction.
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