Hypertension, Salt Sensitivity of Blood Pressure
Conditions
Brief summary
Salt sensitivity of blood pressure (SSBP) is defined as the change in blood pressure (BP) in relation to change in salt intake. An increase in BP from low- to high-salt diet is common and associated with an increased risk of cardiovascular morbidity and mortality, even among normotensive individuals. Yet, the pathophysiology of SSBP is not well understood. The prevailing paradigm is that abnormalities of neurohormones that regulate sodium (Na+) retention and excretion and/or Na+ transporting pathways create Na+ imbalances that underlie susceptibility to SSBP. As a homeostatic mechanism, BP fluctuates to maintain Na+ balance, i.e. higher BP is needed for pressure natriuresis to excrete excess Na+. An alternate framework emphasizes vascular dysregulation as the inciting mechanism. In both constructs, how Na+ itself influences BP remains incompletely understood. Our preliminary work suggests that excess Na+ induces a pro-inflammatory state that sustains higher BP. Interleukin-6 (IL-6) drives the induction of interleukin-17 (IL-17) secreting T helper 17 cells that were recently demonstrated to be pathogenic in response to Na+ exposure. IL-6, IL-17 and related cytokines regulate renal Na+ transporters and raise BP through vascular inflammation, fibrosis, and impaired vasodilation. The immune response to high- and low-salt diet in humans, however, is not completely understood, emphasizing the need for more detailed human studies, with deeper immune profiling under controlled salt conditions and with neurohormonal assessment. Our overarching postulate is that the inflammatory response to excess dietary salt intake is associated with SSBP. The Coronary Artery Risk Development in Young Adults (CARDIA) study is the ideal cohort in which to translate our preliminary findings. Investigators propose to investigate SSBP in CARDIA using standardized low- and high-salt diets and 24-hour ambulatory BP monitoring. Investigators will quantify SSBP in a total of 500 participants from the Chicago and Birmingham field centers during the upcoming year 35 exam (beginning in 2020). Our specific aims are: 1) to define the distribution of SSBP and its clinical correlates in a contemporary community-based US cohort of middle-aged individuals; 2) to investigate the immune response to dietary salt loading, and 3) to investigate the association between the immune and BP responses to dietary salt loading. The proposed study represents a unique opportunity to leverage a large, well-phenotyped cohort to test novel hypotheses regarding SSBP. Phenotyping SSBP using standardized high- and low-salt diets in CARDIA will be novel as this has never been performed in any of the existing US based NHLBI sponsored cardiovascular epidemiologic cohorts. The proposed work has the potential to yield a more readily available approach for differentiating an individual as salt-sensitive or resistant. New insights into the pathophysiology of SSBP should also provide a foundation for investigating high-impact clinical applications, by informing future studies of therapies directed at SSBP. The scientific rigor is further enhanced by the rich clinical, genetic, and biochemical data available in CARDIA.
Interventions
DIETARY_SUPPLEMENTHigh Salt Diet
Patients will be randomized to be on a high salt diet for 7 days.
DIETARY_SUPPLEMENTLow Salt Diet
Patients will be randomized to be on a low salt for 7 days.
Sponsors
Vanderbilt University Medical Center
Northwestern University
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Potentially eligible individuals must consent to and be willing to adhere to the study protocol. We will include individuals not taking anti-HTN medications, i.e. normotensives and untreated hypertensives, and individuals with controlled HTN by use of ≤ 3 anti-HTN medications.
Exclusion criteria
* Unwilling to adhere to the study protocol * Resistant HTN, defined as taking ≥ 4 anti-HTN medications to control BP or uncontrolled BP despite ≥ 3 anti-HTN medications that includes a diuretic * Contraindications to high- or low-salt diet (e.g. heart, renal, or liver failure, postural orthostatic tachycardia syndrome) * Use of salt tabs, fludricortisone, midodrine * Contraindications to 24hr ABPM: bilateral upper extremity lymphedema, cuff will not fit * Medical contraindications to foods, e.g. celiac disease, nut allergy, egg allergy, etc. * Year 35 core exam systolic BP \< 90 or \> 160 mm Hg or diastolic BP \< 50 or \> 100 mm Hg * Current use of steroids, NSAIDS, anti-inflammatories * Rheumatologic condition (e.g. Lupus, Rheumatoid Arthritis, Psoriatic arthritis, Inflammatory Bowel Disease, Multiple Sclerosis * Immune deficiency or immunosuppressed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Salt Sensitivity of Blood Pressure | 14 days total which is 7 days each of high- and low-salt diet | The change in 24-hour ambulatory mean arterial pressure (MAP) following one week of high-salt and following one week of low-salt diet. This is calculated as the 24 hour ambulatory MAP on the high-salt diet minus the 24 hour ambulatory MAP on the low-salt diet. |
| Immune Response to Dietary Salt Loading, Change in Circulating Levels of IL-6 | 14 days total which is 7 days each of high- and low-salt diet | The change in circulating levels of interleukin-6 (IL-6) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-6 level on the high-salt diet minus the IL-6 level on the low-salt diet. |
| Immune Response to Dietary Salt Loading, Change in Circulating Levels of IL-17 | 14 days total which is 7 days each of high- and low-salt diet | The change in circulating levels of interleukin-17 (IL-17) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-17 level on the high-salt diet minus the IL-17 level on the low-salt diet. |
| Immune Response to Dietary Salt Loading, IL-10, Change in Circulating Levels of IL-10 | 14 days total which is 7 days each of high- and low-salt diet | The change in circulating levels of interleukin-10 (IL-10) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-10 level on the high-salt diet minus the IL-10 level on the low-salt diet. |
Countries
United States
Participant flow
Pre-assignment details
A total of 281 individuals consented (were enrolled). Of these 228 actually started the study, i.e., were assigned to a study group. The 53 that were consented/enrolled but did not start the study, either did not schedule study start dates, or no longer wanted to participate prior to assignment of study diet order. This study investigates salt-sensitivity of BP (SSBP), measured as change in BP between one-week of high-salt minus one-week of low-salt diet. SSBP was determined in 213.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 75 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 70 Participants |
| Region of Enrollment United States | 95 participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 217 | 0 / 215 |
| other Total, other adverse events | 21 / 217 | 17 / 215 |
| serious Total, serious adverse events | 0 / 217 | 0 / 215 |
Outcome results
None listed