Salt Sensitivity of Blood Pressure

Study Title: Determining the Presence of Salt Sensitivity in Individuals With Elevated Blood Pressure Through Dietary Salt Interventions: A Series of N-of-1 Trials Objective: To evaluate whether there are differences in blood pressure responses to dietary sodium intake between salt-sensitive and salt-resistant individuals, as identified through a salt sensitivity test. The study will use repeated dietary interventions with varying sodium content (high-sodium, low-sodium) to assess blood pressure responses in each individual, aiming to determine whether salt sensitivity is a present characteristic. Study Design: This study will utilize an N-of-1 randomized controlled trial design. It consists of two phases: Salt Sensitivity Screening: A 2-week chronic salt-loading test will be used to identify salt-sensitive and salt-resistant individuals. N-of-1 Trial: The identified salt-sensitive and salt-resistant individuals will undergo a 6-week N-of-1 trial, consisting of three cycles, with each cycle including one week of low-sodium diet and one week of high-sodium diet. This design aims to assess individual blood pressure responses to changes in sodium intake. Sample Size: A total of 72 participants will be recruited for the salt sensitivity screening, with an expected 24 participants proceeding to the N-of-1 trial. Study Population: Healthy individuals aged 20-65 years, not on antihypertensive medication or with a stable regimen for at least 3 months, with systolic blood pressure between 110-159 mmHg and diastolic blood pressure between 70-99 mmHg, who are able to eat at the research center. Primary Outcome: Reproducibility of salt sensitivity response classification. Secondary Outcomes: Changes in mean arterial pressure, systolic and diastolic blood pressure; exploratory outcomes such as sleep, mood, gut microbiome, metabolomics; safety outcomes including hypotension and hyponatremia.

Hypertension is the leading cause of preventable deaths globally, driven by complications such as myocardial infarction, stroke, heart failure, and kidney disease. Recent updates in hypertension classification by the American Heart Association (AHA) place nearly half of the U.S. population in the hypertensive category. Excess dietary salt is a major risk factor for hypertension, with 50% of hypertensive individuals exhibiting salt-sensitivity of blood pressure (SSBP). SSBP is an independent predictor of cardiovascular events and death. While kidney mechanisms in salt-sensing have been extensively studied, emerging evidence suggests that immune cells can also sense sodium (Na+). This trial hypothesizes that myeloid cell-derived isolevuglandins (IsoLGs) drive endothelial dysfunction, perpetuating the salt-sensitive phenotype. Preliminary data indicate that targeting IsoLGs with the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) may interrupt this immune-vascular axis, reducing salt sensitivity and associated cardiovascular risks. This phase 2 clinical trial aims to investigate the role of 2-HOBA in modulating immune cell function within blood vessels in hypertensive patients. The study will explore the impact of immunity on salt sensitivity and assess 2-HOBA's potential to reduce endothelial dysfunction, improve immune cell activation, and alleviate SSBP.

The overall objective of this project is to identify the key salt-sensing regions of the brain and determine the underlying mechanism of sodium sensing. The investigators will assess how the brain responds to an acute increase of salt in the blood using MRI. This will be done during a 30-minute infusion of a saline solution containing 3% salt. One trial will be conducted with a salt sensing channel blocker and one trial without the salt sensing channel blocker. This will help to assess the role of a specific salt sensing channel in the brain. Salt sensitivity of BP will be assessed using 7-day dietary feeding where participants will be given food to consume for 7-days. Comparisons will be made between salt resistant (no change in blood pressure going from low to high salt diets) and salt sensitive adults (a change in blood pressure going from low to high salt diets). The investigators think the changes in MRI will be greater in salt sensitive compared to salt resistant subjects.