Plasma Histone H1 Stratifies Salt-Sensitive Versus Salt-Resistant Immune and Blood Pressure Responses in Humans

Background: Salt-sensitivity of blood pressure (SSBP) is characterized by exaggerated blood pressure responses to sodium intake. SSBP is associated with oxidative stress and driven by immune activation. Circulating histones, including histone H1, are associated with inflammation and may reflect underlying immune priming. We hypothesized that baseline plasma histone H1 would relate to salt-induced hemodynamic and oxidative responses in salt-sensitive (SS) individuals and may indicate underlying inflammatory priming. Methods: Participants completed a controlled inpatient dietary salt-loading and -depletion protocol. Salt sensitivity was defined using the Salt-Sensitivity Index (SSI; |ΔSBP| from salt-loading to salt-depletion). Plasma collected at baseline was analyzed for histone H1 (ELISA; SS n=6, SR n=5; age 55 ± 9 yr; 55% female; 45% Black; baseline SBP 147 ± 15 mmHg) and IL-1β (13-plex Luminex; SS n=6, SR n=8; age 52 ± 7 yr; 57% female; 43% Black; baseline SBP 143 ± 13 mmHg). PBMCs were used to quantify isolevuglandins (IsoLGs) in CD14 + classical monocytes at baseline, salt loading, and salt depletion. Linear regression tested associations within SS and SR groups and interaction effects. Results: Baseline IL-1β tended to be higher in SS versus SR participants (p = 0.093). Baseline histone H1 did not differ between phenotypes. However, H1 showed strong phenotype-specific relationships with salt-evoked responses. In SS individuals, baseline H1 was positively associated with SSI (β = 2.38, p = 0.049), whereas no association was observed in SR (β = –0.24, p = 0.75). A similar pattern emerged for monocyte oxidative responses. In SS participants, H1 was significantly associated with the salt-induced change in %IsoLG + CD14 + monocytes (β = 18.55, p = 0.022). No association occurred in SR (β = –1.47, p = 0.745), and the interaction was significant (Δβ = –20.02, p = 0.036). Baseline H1 was not associated with baseline SBP or baseline monocyte IsoLGs. Conclusions: SS participants exhibited higher baseline plasma IL-1β levels than SR individuals, consistent with a more pro-inflammatory circulating milieu. Baseline plasma histone H1 showed phenotype-specific associations with salt-evoked responses in SBP and IsoLG + classical monocytes. This pattern aligns with prior work linking salt-induced IsoLG + monocyte responses to SSI, further supporting a role for inflammatory priming. These preliminary findings suggest that, in addition to IsoLGs, circulating histone H1 may reflect heightened inflammatory and hemodynamic responsiveness in SSBP. 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.