Project Summary Age-related increases in systolic blood pressure (SBP) and vascular dysfunction are major factors driving cardiovascular diseases (CVD) in “mid-life” (50-64 years) and older (65+) (ML/O) adults. Much of the elevated CVD risk occurs in ML/O adults with casual (resting) SBP in the “elevated” (120-129 mmHg) and stage 1 hypertension (130-139 mmHg) ranges and is associated with: a) impaired endothelial function (decreased brachial artery flow-mediated dilation [FMDBA]); and b) stiffening of the large elastic arteries (increased carotid- femoral pulse wave velocity [CFPWV], i.e., aortic stiffness, and carotid artery β-stiffness index), all mediated by excess reactive oxygen species (ROS)-related oxidative stress, which reduces nitric oxide (NO) bioavailability. Current guidelines recommend that SBP in these ranges be treated with lifestyle strategies for ~3 months prior to considering drug therapy. We have shown in healthy young adults that passive heat therapy (hot water immersion to raise core temperature from ~37.0 to 38.5-39.0°C) is safe and may improve SBP and vascular function. We recently completed a small pilot trial (n=23) in ML/O adults and found that 30 sessions of heat therapy over ~10 weeks was safe/well-tolerated, reduced casual SBP (~10 mmHg) and ambulatory 24- h SBP (~6 mmHg), increased FMDBA and NO bioavailability, and reduced CFPWV, carotid β-stiffness and vascular oxidative stress. Exposing endothelial cells in culture to serum obtained from subjects after (vs. before) heat therapy suppressed basal ROS production and increased acetylcholine-stimulated NO production, indicating that changes in “circulating factors” may, at least in part, transduce the CV benefits of heat therapy. As the required next step in translation of passive heat therapy to eventual clinical practice, we propose a larger, properly powered, randomized, sham-controlled, parallel group design, single-site clinical trial to assess the efficacy, safety, underlying mechanisms, and potential lasting effects of passive heat therapy (36 x 60-min sessions over ~12 weeks) vs. sham (thermoneutral water immersion) for decreasing casual and 24-h SBP and improving vascular function in ML/O men and women with elevated SBP/stage 1 hypertension. To determine before, after passive heat therapy vs. sham (control), and after 4 and 12 weeks of follow-up: Aim 1: Casual (resting) and 24-h BP. Safety, tolerability, and implementation feasibility will also be assessed. Aim 2: Vascular endothelial function (FMDBA) and aortic (CFPWV) and carotid (β-stiffness index) stiffness. Aim 3: a) Oxidative stress-related suppression of FMDBA (acute increase in FMDBA in response to a supra- therapeutic infusion of the ROS scavenger, vitamin C); b) markers of oxidative stress, pro-oxidant signaling, and antioxidant defenses in endothelial cells obtained from clinical endovascular biopsy; c) abundance and content of circulating microvesicles (MVs); and d) NO bioavailability, ROS production, and NO-mediated angiogenesis (functional assay of NO bioavailability) in cultured endothelial cells exposed to 1) intact plasma, 2) MV-depleted plasma, or 3) isolated MVs collected from subjects before vs. after heat therapy or sham.

Project Narrative Age-related increases in systolic blood pressure (SBP) and impaired artery function are major risk factors for cardiovascular diseases (CVD), stroke, cognitive impairments and dementia in “mid-life” (50-64 years) and older (65+ years) (ML/O) men and women, especially in those ML/O adults with SBP in the ranges of “elevated” SBP (120-129 mmHg) and stage 1 hypertension (SBP 130-139 mmHg). We propose to conduct a clinical trial to assess the effectiveness and safety of “passive heat therapy” (repeated hot tub use) vs. “sham” (repeated sitting in water set to normal body temperature) for decreasing SBP and improving artery function in ML/O men and women with elevated SBP or stage 1 hypertension. We will also gain insight into the molecular mechanisms underlying these potential effects of passive heat therapy, and whether the effects of heat therapy can last for up to 12 weeks after stopping hot tub sessions.