Hypertension (HTN) is a major risk factor for cardiovascular, cerebrovascular, and renal disease, and its prevalence is increasing, particularly among the elderly. While the pathophysiology of HTN is multi-factorial, two major contributors appear to be salt-sensitivity and activation of the immune system. The prevailing paradigm regarding salt-sensitive HTN is based upon increased plasma volume and hydrostatic forces induced by intravascular sodium retention. Until recently, there was little consideration of the possibility that extravascular sodium stores may play a role in HTN. Through use of a novel non-invasive 23Na-magnetic resonance imaging (MRI) technique, we have demonstrated the presence of significant sodium accumulation in skin and skeletal muscle. Experimental evidence indicates that these tissue sodium stores can trigger the immune system, particularly the helper T cells (Th17) that produce interleukin-17 (IL17). Activation of these T cells and the cytokine they produce, IL17, induces HTN in animal models. In preliminary studies, we have shown that skin sodium content is associated with systolic blood pressure. We also found that circulating IL17 levels are higher in hypertensive compared with normotensive individuals. However, definitive data from larger, community cohorts are needed. The Multi-Ethnic Study of Atherosclerosis (MESA) is the ideal cohort in which to translate our preliminary findings. Our underlying hypothesis is that tissue sodium-induced inflammation contributes to the development and progression of HTN, particularly salt-sensitive HTN. We propose an ancillary study with the following specific aims: 1) to define the distribution of tissue Na+ content in middle-aged to elderly individuals in the community, 2) to investigate the association of tissue sodium levels with blood pressure, and 3) to examine the association of tissue sodium with Th17 and other cellular markers of inflammation. We will non-invasively quantify skin sodium concentration using 23Na-MRI and measure blood pressure in all eligible MESA participants at the Chicago, IL field center during exam 6 (2016-2018). We will also quantify the number and types of circulating immune cells, such as Th17 cells, among MESA participants who undergo MRI measurement of tissue sodium concentration. The proposed research represents a unique opportunity to leverage a large, well-phenotyped, community population in which to translate novel findings from preclinical and early human studies to gain a deeper understanding of pathophysiologic contributors to HTN. The proposed research represents a systematic effort to build upon the investigators' prior studies on the mechanisms underlying HTN and the novel interactions between tissue sodium, inflammation, and blood pressure. These studies have the potential to provide important insight into the determinants of HTN. Furthermore, because visualizing tissue sodium by MRI is a novel non-invasive technology, establishing that tissue sodium is associated with inflammation and HTN could suggest novel approaches to the prevention and treatment of HTN and related disorders.

Public Health Relevance

High blood pressure, or hypertension, is a major cause of heart disease, stroke, and kidney disease and is more common in middle-aged to elderly individuals. Salt (sodium) retention and inflammation are thought be important reasons why people develop hypertension, but the actual mechanisms are not completely understood. New data suggest that accumulation of sodium in tissues such as skin may be an important cause, by inducing inflammation; therefore, we propose to investigate this novel hypothesis by studying participants in the Multi-Ethnic Study of Atherosclerosis, which could lead to new approaches for treating hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Srinivas, Pothur R
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Vanderbilt University Medical Center
United States
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