Repurposing tamibarotene to reprogram cardiac fibroblasts improves diastolic function and exercise capacity in chronic HFpEF

Introduction HFpEF is driven by progressive ventricular stiffening, where cardiac fibroblast activation and immune-cell recruitment promote fibrosis, inflammation, and reduced exercise capacity. Meflin (mesenchymal stromal cell and fibroblast-expressing Linx paralogue) marks an antifibrotic fibroblast program, but its therapeutic leverage in chronic HFpEF remains unclear. Purpose To test whether enhancing a Meflin-associated antifibrotic fibroblast program improves HFpEF phenotypes and to develop a translatable pharmacological strategy. Methods HFpEF was induced in mice using high-fat diet plus L-NAME. A chronic pressure-overload TAC model was evaluated in parallel. Loss- and gain-of-function studies used Meflin-deficient mice and cardiac AAV-mediated Meflin overexpression. A compound screen identified inducers of fibroblast Meflin, leading to evaluation of tamibarotene (AM80), an approved synthetic retinoid in Japan, administered orally. Cardiac function (including E/e’), exercise tolerance, myocardial fibrosis, and inflammation (CD68 immunostaining) were assessed by echocardiography, exercise testing, and histology. Results Meflin deficiency aggravated fibrotic remodeling and diastolic impairment across models, consistent with a protective role in limiting ventricular stiffening. Conversely, cardiac Meflin augmentation improved diastolic indices and exercise capacity while attenuating fibrosis and inflammatory remodeling. Screening identified AM80 as a potent inducer of fibroblast Meflin. Oral AM80 treatment improved key HFpEF phenotypes, including a 20% improvement in E/e’ and a 35% improvement in exercise tolerance, accompanied by a 24% reduction in myocardial interstitial fibrosis and a 45% decrease in CD68-positive macrophage infiltration, together with increased Meflin expression in cardiac fibroblasts. Conclusions Enhancing a Meflin-associated antifibrotic fibroblast program—genetically or via repurposed retinoid therapy—reduces fibrosis and inflammation and improves diastolic dysfunction and exercise capacity. Targeting fibroblast-state regulation may provide a translatable therapeutic strategy for chronic HFpEF.