Macrophage Reprogramming Induced by Hypertensive Stress Underlies Pathogenesis of Non-Obese Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality worldwide; nonetheless, effective therapies remain elusive. In Western populations, HFpEF is typically obesity-related, whereas in Asia it frequently develops in non-obese patients with hypertension and underlying mechanisms are poorly defined. Here, analysis of two Japanese hospital cohorts revealed that obesity and metabolic comorbidities are uncommon in HFpEF, while sympathetic overactivation and hypertension predominated. To model this condition, we combined isoproterenol (ISO)–induced sympathetic activation with L-arginine methyl ester (L-NAME)-induced endothelial dysfunction, establishing the first non-obese HFpEF mouse model. These mice exhibited hallmark HFpEF features, whereas ISO alone caused hypertensive heart disease (HHD) without HFpEF, indicating that a "second hit" is essential for HFpEF progression. HFpEF mice showed expansion and reprogramming of cardiac macrophages to Pla2g7⁺ phenotypes and fibroblast activation via PDGF signaling, as loss of Timd4⁺ resident macrophages impaired cardiomyocyte energetics due to diminished BMP signaling. These outcomes drove maladaptive remodeling and inflammation, which precedes HFpEF onset. Notably, inhibition of the inflammatory mediator ANGPTL2 attenuated cardiac inflammation and prevented HFpEF progression. Our findings identify hypertensive stress-induced macrophage reprogramming as a central mechanism of non-obese HFpEF and highlight cardiac inflammation as a promising therapeutic target.