Carotid Body Chemosensory Drive Shapes the Heart Proteome in HFpEF: Implications for Disease Susceptibility

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent cardiovascular disorder, yet the mechanisms initiating cardiac vulnerability remain poorly defined. Enhanced carotid body (CB) chemoreflex sensitivity has been reported in HFpEF patients, raising the possibility that chemosensory drive itself may predispose the heart to pathological remodeling. Here, we tested whether differences in resting chemoreflex drive, classified as low versus high, modulate susceptibility to HFpEF and shape myocardial proteomic signatures that prime the heart toward dysfunction. Adult C57BL/6J mice were exposed to a 16-week high-fat diet (60% kcal fat) combined with L-NAME (0.6 g/L) to induce HFpEF. At the end of treatment, cardiac diastolic function (E/A ratio and tissue Doppler indices) and ventilatory chemoreflex sensitivity (hypoxic ventilatory response to FiO 2 ≈10%) were assessed using echocardiography and whole-body plethysmography, respectively. Hearts were then collected, rapidly frozen, and processed for proteomic analysis. Left ventricular samples underwent urea-based lysis, trypsin digestion, C18 desalting, and high-resolution LC-MS/MS profiling on Orbitrap instrumentation. Protein identification and quantification were performed using MaxQuant with a 1% false-discovery rate. High chemoreflex drive was strongly associated with HFpEF incidence: 80% of mice with a chemoreflex gain ≥0.15 ΔVE/FiO 2 % developed clear diastolic dysfunction. Moreover, chemoreflex magnitude positively correlated with the severity of HFpEF. Proteomic profiling revealed 447 (p< 0.05) differentially expressed proteins in HFpEF hearts relative to controls. Remarkably, control animals with high chemoreflex drive exhibited a myocardial protein-protein interaction network strikingly similar to that of HFpEF mice, suggesting that elevated chemosensory drive establishes a pre-disease molecular phenotype. Both high-chemoreflex controls and HFpEF mice displayed coordinated disruption of mitochondrial bioenergetics, including downregulation of ISCU and NDUFAF3, along with altered ATP5IF1, consistent with impaired complex-I function, reduced oxidative phosphorylation, and heightened oxidative stress. Additional signatures included activation of ER-stress and proteostasis-failure pathways, ferroptosis-related iron dysregulation, and diminished structural and mechanotransduction regulators (CHD4, LPP, PRUNE2). Upregulation of inflammatory mediators (NGP) and hypoxia-linked apoptotic markers (FAM162A) further indicated a myocardium under sustained metabolic and inflammatory strain. Together, these findings support a model in which elevated CB chemoreflex drive reshapes the myocardial proteome toward a vulnerable state characterized by mitochondrial dysfunction, ER stress, iron-handling imbalance, inflammation, and structural remodeling. This chemoreflex-driven molecular profile aligns closely with core biological processes implicated in HFpEF development and may represent an early, targetable determinant of disease susceptibility. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.