Visualizing Vascular Mechanisms of Salt Sensitivity

This study aims to assess the salt sensitive blood pressure response to dietary salt load compared with radiological markers of salt handling.

Hypertension is a major cause of heart disease, heart failure, and stroke. Hypertension, or high blood pressure, affects people differently and is related to the body's ability to maintain healthy circulation of salt. Some individuals may be affected by salt sensitive blood pressure (SSBP), when their blood pressure changes in response to dietary salt load. SSBP is a prevalent, independent risk factor for developing cardiovascular disease that preferentially affects black individuals. Current methods to assess SSBP require dietary salt loading over the course of days to weeks, and measurement of blood pressure following high salt diet and low salt diet. Such lengthy protocols are not feasible in a clinical setting to evaluate this risk factor for cardiovascular disease, and more importantly, these procedures provide incomplete information about mechanisms of salt sensitivity. Our knowledge regarding salt handling in the body is limited. While renal dysfunction is partly responsible for SSBP, recent research points to the role of lymphatic vascular clearance in regulating tissue salt storage and blood pressure control. To better understand these mechanisms in vivo, we have recently developed a noninvasive magnetic resonance (MR) lymphangiography method sensitive to lymphatic vasculature, and applied standardized MR protocols for measuring tissue sodium and fat storage in adults with impaired lymphatic clearance. We found evidence of lymph stasis and tissue salt deposition that correlated with local subcutaneous fat volume. Here, we will test whether similar lymphatic pathways are impaired in persons with SSBP, leading to tissue salt and fat storage, in comparison to the involvement of renal dysfunction in SSBP tissue profiles. The aims of this study are to improve our understanding of vascular mechanisms of human salt storage, and to provide standardized radiologic biomarkers sensitive to the SSBP phenotype. This study will test the primary hypothesis that the SSBP response is correlated with baseline tissue sodium storage, and elevated in persons with salt sensitivity. Secondary hypotheses will address whether the SSBP response is related to fat storage, lymphatic vascular function, renal vascular function, and impaired target organ responses to salt loading, including decreased urinary sodium excretion, and less suppression of plasma renin and serum aldosterone.

10 subjects will be enrolled and each will undergo study procedures at 4 separate visits. Subjects will be randomly assigned to this study arm, differing in the order of low and high salt diets. After a baseline visit to include a noninvasive MRI scan, the subject will begin this study diet: low-salt diet, then washout consisting of the subject's typical diet, then high-salt diet. Each dietary or washout period lasts for 7 days, and study visits will occur after each period.

10 subjects will be enrolled and each will undergo study procedures at 4 separate visits. Subjects will be randomly assigned to this study arm, differing in the order of low and high salt diets. After a baseline visit to include a noninvasive MRI scan, the subject will begin this study diet: high-salt diet, then washout consisting of the subject's typical diet, then low-salt diet. Each dietary or washout period lasts for 7 days, and study visits will occur after each period.

The low-salt diet (7 days) will consist of meals, snacks and water provided by Vanderbilt's metabolic kitchen.

The high-salt diet (7 days) consists of each subject's typical diet, supplemented each day with 2 bullion broth packets, which will be provided to the subject by the study staff.

Measured as the difference in mean arterial pressure following high-salt diet compared to low-salt diet

At baseline and each of 3 study visits occurring about every 7 days, to be completed in no less than 21 days.

At baseline and each of 3 study visits occurring about every 7 days, to be completed in no less than 21 days.

At baseline and each of 3 study visits occurring about every 7 days, to be completed in no less than 21 days.

Inclusion Criteria: Identification as black race Age between 18 and 55 years Body mass index between 25 and <35 kg/m2 Normotensive or pre-hypertensive Willing to adhere to study diets Able to provide informed consent and communicate with study personnel Exclusion Criteria: Prevalent cardiovascular disease or use of medications for cardiovascular disease Current or prior history of hypertension or use of blood pressure lowering medications Current or prior history of diabetes mellitus or use of anti-diabetic medications Prevalent renal disease (eGFR < 60 ml/min/1.73m2), abnormal serum sodium or potassium Current or prior smoker Current pregnancy, or use of hormone replacement therapy or oral contraceptive Current steroid use Contraindications to MRI Active infection or open wounds on the top of the feet or hands

Crescenzi R, Marton A, Donahue PMC, Mahany HB, Lants SK, Wang P, Beckman JA, Donahue MJ, Titze J. Tissue Sodium Content is Elevated in the Skin and Subcutaneous Adipose Tissue in Women with Lipedema. Obesity (Silver Spring). 2018 Feb;26(2):310-317. doi: 10.1002/oby.22090. Epub 2017 Dec 27.

Crescenzi R, Donahue PMC, Hartley KG, Desai AA, Scott AO, Braxton V, Mahany H, Lants SK, Donahue MJ. Lymphedema evaluation using noninvasive 3T MR lymphangiography. J Magn Reson Imaging. 2017 Nov;46(5):1349-1360. doi: 10.1002/jmri.25670. Epub 2017 Feb 28.