Myocardial Inflammatory Remodeling in HFpEF: Potential Role of Chemoreflex-Induced Low-Grade Inflammation

Heart failure (HF) is a complex syndrome resulting from the heart’s inability to efficiently pump blood, and it imposes a huge public health burden worldwide. Importantly, at least half of patients diagnosed with HF have preserved ejection fraction (HFpEF). Despite its prevalence, the mechanism underpinning the development of HFpEF remains poorly defined. Recently, we found evidence showing that enhanced peripheral chemoreflex sensitivity is present in experimental HFpEF and that this was closely linked to the incidence of HFpEF. Since exaggerated chemoreflex sensitivity has been proposed as a key pathophysiological component of low-grade inflammation in several conditions, we hypothesized that mice with HFpEF will display increases in chemoreflex drive and systemic inflammation. Furthermore, we hypothesize that alterations in the inflammatory milieu during HFpEF reshape the immune cell repertoire within the failing heart. Accordingly, we measure chemoreflex function in HFpEF and characterize the cytokine proteome in the blood. Then, we develop a comprehensive method to study the immune cell population composition in the myocardium of HFpEF mice. HFpEF was induced in mice (16 weeks of high fat diet + nitric oxide synthase inhibitor in water). HFpEF was confirmed via transthoracic echocardiography with trans mitral flow doppler imaging to determine early to late LV filling velocities (E/A ratio). Chemoreflex drive was studied using whole-body plethysmography by allowing the mice to breathe a hypoxic and/or hypercapnic gas mixture while recording the ventilatory response. Systemic inflammation was assessed using cytokine proteome profiler array, followed by pathway enrichment analysis. Lastly, myocardial immune cell population was quantified using flow cytometry. Compared to age-matched control mice, HFpEF mice exhibited increases in chemoreflex drive and overt signs of systemic inflammation evidenced by significant increases in several pro-inflammatory cytokines. Notably, pathway analysis revealed enrichment of cytokine-mediated signaling, leukocyte migration, and chemotaxis in HFpEF. Myocardial immune cell profiling demonstrated a significant ~2-fold increase in CD45 + cells in the left ventricle of HFpEF mice compared to Control (5.4±2.6 vs 2.2±0.1% of live cells, HFpEF vs. Control). Importantly, the larger number of CD45+ cells found in HFpEF was associated with significant increases in infiltrating and cardiac resident macrophages, T and B cells, and Natural Killer T cells. Conversely, neutrophils, eosinophils, and NK cells were more abundant in age-matched healthy control mice. No changes in the number of monocytes were found between conditions. Our results showed that HFpEF mice displayed enhanced chemoreflex drive and sterile inflammation. Importantly, we also found that HFpEF animals showed profound remodeling of myocardial immune cell composition, characterized by increased adaptive and innate immune subsets and systemic inflammatory activation. Together these findings highlight the potential role of chemoreflex-induced inflammation on cardiac immune dysregulation during HFpEF. Funding: NIH R01HL176779 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.