A high salt diet is an established cause of hypertension and cardiovascular morbidity. However, recent work has shown that Na+ is stored, predominantly in tissues such as the skin, and that this storage both drives and is driven by inflammation. This discovery has exposed a fundamental gap in our understanding: we do not understand the relationship between salt, inflammation, and blood pressure in humans. It is important to fill this gap because many inflammatory diseases remain poorly controlled and are associated with hypertension and increased cardiovascular risk. The rationale for the research proposed is: 1) Na+ is stored in the skin; 2) skin Na+ concentrations can be measured by 23Na magnetic resonance imaging (MRI) and are induced by excess salt intake and associated with elevated blood pressure; 3) skin Na+ concentrations boost pro-inflammatory immune cell responses that have beneficial effects protecting against skin infection but also have potentially detrimental pro-inflammatory systemic effects; 4) a high dietary salt intake is pro-inflammatory and exacerbates autoimmune disease and arthritis in animal models. A critical knowledge gap is that the effects of dietary salt intake and tissue Na+ on inflammation and blood pressure in humans in the setting of inflammation is not known. Our overarching hypothesis is that, in the setting of inflammation, high dietary salt intake affects regulation of both blood pressure and inflammation adversely and does so through accumulation of skin Na+. Accordingly, we propose to study patients with rheumatoid arthritis (RA) as a model of chronic inflammation. RA is a prototypical, common autoimmune inflammatory disease that is associated not only with musculoskeletal consequences but also with increased hypertension and cardiovascular mortality. We will determine:
Aim 1) if skin Na+ measured by 23Na MRI is higher in patients with active RA than in patients with well-controlled RA and controls;
and Aim 2) if a low Na+ diet in patients with RA decreases skin Na+ concentrations and improves inflammation and blood pressure. These studies will define the relationship between dietary Na+ intake, tissue Na+ concentrations, inflammation, and blood pressure and will use a clinical intervention (reduced salt diet) in patients to break the self-sustaining cycle between inflammation?tissue Na+ and vascular dysfunction. The studies are innovative by moving from basic to clinical research to for the first time: 1) use 23Na MRI to determine the vascular effects of tissue Na+ in humans in the setting of inflammation; 2) define the effect of modified salt intake on autoimmune inflammatory disease in humans. The studies proposed have high potential impact since manipulation of dietary salt intake or tissue Na+ concentrations have the potential to improve inflammatory autoimmune diseases as well as their cardiovascular complications in millions of people.

Public Health Relevance

A diet high in salt is the norm in the United States even though high salt intake is associated with hypertension and cardiovascular disease. Recent studies show that salt, particularly salt stored in the tissues, also regulates inflammation. The proposed research, which defines the relationship between stored salt, inflammation and blood pressure, is of great public health importance because identifying mechanisms by which salt regulates blood pressure and inflammation could lead to interventions that improve the outcomes of both cardiovascular and inflammatory diseases ? conditions that affect millions of people.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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OH, Youngsuk
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Vanderbilt University Medical Center
United States
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