Hypertensive Stress Rewires Immune Cell Signals in a Common Heart Failure Syndrome Independent of Obesity

Heart failure with preserved ejection fraction, known as HFpEF, has long been one of cardiology’s most stubborn puzzles. The heart’s pumping muscle still squeezes with apparently normal force, yet the organ cannot relax and fill properly, leaving patients breathless, swollen, and progressively disabled. Roughly half of all heart failure cases fall into this category, and unlike heart failure with reduced ejection fraction, it has almost no proven disease-modifying therapies. Now a large Japanese research collaboration has uncovered a mechanism that may explain why the syndrome looks so different across populations, and in doing so has identified a molecular target that could reshape how the disease is treated.

The new study, published in Nature Communications by a team led by Yuichi Oike and Michio Sato of Kumamoto University together with colleagues across Japan and at Bristol Myers Squibb, began with an epidemiological observation that has often been overlooked. In three separate Japanese HFpEF cohorts, the dominant clinical features were not obesity, which is common in European and North American HFpEF populations, but hypertension and overactivation of the sympathetic nervous system, the branch of the autonomic nervous system that drives the fight-or-flight response. This distinction matters because most experimental models of HFpEF have been built around obesity and metabolic syndrome, potentially missing the biology that drives the disease in a large share of patients worldwide.

To capture that non-obese phenotype, the researchers engineered a mouse model in which two insults converge. First, sympathetic activation induces hypertensive heart disease, subjecting the heart to chronic pressure overload. Second, endothelial dysfunction, a impairment of the blood vessel lining that normally helps regulate vascular tone and tissue perfusion, acts as a second hit that pushes the stressed heart across the threshold into full HFpEF. Only when both factors were present did the animals develop the characteristic signature of the human syndrome: the heart stiffens, filling pressures rise, and exercise capacity collapses, all while the pumping fraction remains preserved.

With a faithful model in hand, the team turned to the heart’s resident immune cells. Macrophages, the versatile white blood cells that patrol tissues and coordinate inflammation, have increasingly been recognized as active participants in cardiac remodeling rather than passive bystanders. Using single-cell transcriptomics and intercellular signaling analysis, the investigators found that hypertensive stress fundamentally rewires the communication network that cardiac macrophages maintain with their neighbors. The rewiring was not subtle. It reoriented the entire signaling economy of the heart toward two opposing but equally damaging outcomes.

On one side of the ledger, macrophage-to-cardiomyocyte signaling through the bone morphogenetic protein, or BMP, pathway was markedly impaired. BMP signaling in heart muscle cells supports fatty acid oxidation, the metabolic process by which cardiomyocytes burn fat as their preferred fuel. When macrophages stop delivering this signal, the heart muscle cells shift away from efficient fat metabolism, a metabolic remodeling that starves the working myocardium of energy and promotes dysfunction. On the other side, macrophage-to-fibroblast signaling through platelet-derived growth factor, or PDGF, was enhanced. Fibroblasts are the scar-forming cells of the heart, and amplified PDGF signaling drove them into a proliferative, fibrosis-producing state, stiffening the cardiac tissue further and worsening diastolic function.

The linchpin connecting these two arms of the rewired network turned out to be a secreted protein called angiopoietin-like protein 2, or ANGPTL2. This molecule, which the group had previously studied in the context of chronic inflammation and vascular biology, was upregulated in cardiac macrophages under hypertensive stress and appeared to orchestrate the pathological shift in intercellular communication. When the researchers inhibited ANGPTL2, using a neutralizing antibody developed in collaboration with Bristol Myers Squibb, the macrophage signaling network was largely preserved. The metabolic collapse in cardiomyocytes was blunted, fibroblast activation was restrained, inflammation and fibrosis were reduced, and, critically, the animals were protected from developing HFpEF.

These findings carry several layers of significance. Scientifically, they elevate cardiac macrophage signaling from a correlate of heart failure to a central causal mechanism, positioning a single immune-derived node as the link between mechanical stress, metabolic remodeling, inflammation, and fibrosis. Clinically, they suggest that HFpEF is not one disease but at least two, with an obesity-driven form on one side and a hypertension-and-sympathetic-activation-driven form on the other. If the macrophage rewiring described here proves to operate specifically in the non-obese variant, therapies targeting ANGPTL2 could offer a precision approach that current broad-spectrum HFpEF trials have lacked.

The translational path is plausible but not guaranteed. The work was performed in mice, and human HFpEF is notoriously heterogeneous, shaped by age, sex, comorbidities, and environment in ways that animal models only approximate. The researchers themselves note that their model was designed to reproduce the Japanese clinical picture, and whether the same macrophage signaling rewiring operates in obese HFpEF patients in Western cohorts remains an open question. Still, the existence of a validated neutralizing antibody against ANGPTL2, developed with an industry partner, means that the pharmacological tools needed to test the hypothesis in patients already exist, which is far from typical for early mechanistic discoveries.

For the millions of people living with HFpEF, many of them older adults with long-standing hypertension and no obesity at all, the study offers something the field has lacked for decades: a molecular explanation rooted in the immune system for why their hearts stiffen and fail despite a preserved pumping fraction. It also reframes the macrophage not merely as a source of inflammation but as a metabolic regulator of the heart, one whose signals can either sustain or sabotage the energy metabolism of the muscle it surrounds. If subsequent studies confirm that blocking ANGPTL2 preserves macrophage communication in humans as it does in mice, the discovery could mark the beginning of the first mechanism-targeted therapy for a form of heart failure that has resisted every treatment attempt so far.

Subject of Research: How hypertensive stress rewires cardiac macrophage signaling to drive heart failure with preserved ejection fraction independent of obesity

Article Title: Hypertensive stress rewires macrophage signaling in heart failure with preserved ejection fraction independent of obesity

Article References: Kinoshita, Y., Sato, M., Kadomatsu, T., Katoh, M., Ikeda, K., Yoshioka, G., Matsue, Y., Fujimoto, W., Kurabayashi, A., Okadome, Y., Torigoe, D., Wakayama, T., Horiguchi, H., Kusaba, R., Peiwen, X., Gurbuzbalaban, B. E., Rakestraw, G., Yamniuk, A., Pipes, G. T., … Oike, Y. (2026). Hypertensive stress rewires macrophage signaling in heart failure with preserved ejection fraction independent of obesity. Nature Communications. https://doi.org/10.1038/s41467-026-78375-2

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78375-2

Keywords: heart failure, HFpEF, macrophages, hypertension, ANGPTL2, fibrosis, metabolic remodeling, cardiomyocytes, fibroblasts, endothelial dysfunction, sympathetic activation, Nature Communications