Passive Heat Therapy for Lowering Systolic Blood Pressure and Improving Vascular Function in Mid-life and Older Adults

Inclusion Criteria:

• Able to provide informed consent (no clinical diagnosis of dementia or relateddiseases AND mini mental state exam score >20).

• Willing to accept random assignment to intervention.

• Aged 40+ years.

• Premenopausal women must not be pregnant (confirmed by urine pregnancy test).

• Casual systolic blood pressure 115-159 mmHg.

• Sufficiently healthy to undergo heat stress, as determined by the CTRC physician Dr.Wolfe and physician of record Dr. Chonchol based on medical history, physical exam,blood chemistries, and 12-lead ECG at rest and during the graded exercise test.Subjects with established clinical diseases may participate so long it is notdetermined that heat therapy could be detrimental to their health (determinedcase-by-case, but examples of subjects who may be excluded include those currentlyundergoing chemotherapy treatment or chronic kidney disease patients requiringdialysis).

• Ability to refrain from the use of dietary supplements, anti-inflammatorymedications, and prescription medications prior to experimental testing and/or waterimmersion visits in some cases (occasionally used PDE5 inhibitors and nitrites) (forthe durations described above), as determined by the CTRC physician and approved bythe subject's primary care provider if deemed necessary (see Procedures below formore detail). (rationale: many of these agents can acutely modulate vascularfunction).

• Weight stable in the prior 3 months (≤ 2 kg weight change) and willing to remainweight stable over the course of the study.

• Willing to maintain physical activity, diet, and other lifestyle factors for theentire 6-month duration of the study.

• Free from alcohol dependence or abuse, as defined by the American PsychiatryAssociation, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).

Exclusion Criteria:

• Individuals taking 3+ anti-hypertensive medications (rationale: these individualstypically have resistant or secondary hypertension. Individuals taking 1-2anti-hypertensive medications will still be included, with the exception ofbeta-blockers.)

• SBP 140-159 mmHg but not on anti-hypertensive medications. (rationale: ACC/AHAguidelines indicate that immediate pharmacotherapy is advised for these individuals.Potential subjects with SBP in this range will discuss options/receiverecommendations from a CTRC physician and be referred to their primary careprovider. If they begin anti-hypertensive medication, they will be eligible toparticipate in the study after they have been on them for at least 3 months,assuming they still qualify. If they decide not to begin anti-hypertensivemedications, they must receive approval for their primary care provider that it isok for them to participate in the study.)

• Regular vigorous aerobic/endurance exercise: >4 bouts per week for >30 min per boutat a workload of >10 METS, determined based on screening surveys and workloadconfirmed by MAQ during Visit 1. (rationale: aerobic exercise training independentlylowers blood pressure and improves arterial function33,74,75).

• Body mass index (BMI) >40 kg/m2 (rationale: BP and vascular measurements can beinaccurate in severely obese subjects and these subjects may differ in many waysfrom normal weight, overweight, or less obese subjects).

• Current use of anticholinergics (e.g. amitriptyline), alpha-blockers (e.g. Flomax),and beta-blockers (e.g., propranolol) (rationale: these medications can interferewith thermoregulation and/or control of blood pressure during heat stress). *Note:anti-hypertensive medications besides beta-blockers will be allowed-see "Additionalconsiderations for subjects taking anti-hypertensive medications" below under theintervention procedures for Section XI.).

• Current use of certain prescription medications taken at a dose or frequency highenough to potentially interfere with thermoregulation and/or blood pressure controlduring heat stress. These include nitrates and nitrites (e.g. nitroglycerin), PDE5inhibitors (e.g. Viagra), amphetamines (e.g., ADD/ADHD drugs), insulin, and thyroidmedications. Risk of each of these classes of medications depends on dose and othermedications also being taken. Thus, Drs. Wolfe and Chonchol will make decisionswhether subjects taking these medications should be excluded. (Note: occasional useof PDE5 inhibitors and nitrates ok so long as they are not taken for the followingdurations around water immersion sessions, PDE5 inhibitors: 24 hours before throughthe 8 hours after; nitrates: 8 hours before through 8 hours after, and (for bothclasses of medications) in the 48 hours before through the 48 hours after visits inwhich nitroglycerin is administered [visits 3, 10, & 13] - Drs. Wolfe and Choncholcan extend these durations as they deem necessary and will have the opportunity todo so during the medication review process at screening).

• Orthostatic hypotension, as determined by medical history or during screening as areduction of >20 mmHg on SBP and/or >10 mmHg in diastolic BP within 3 min of goingfrom seated to standing (rationale: passive heat therapy is contraindicated forindividuals with orthostatic hypotension).

• Active, untreated atrial fibrillation or flutter (rationale: it is possibleindividuals with atrial fibrillation/flutter may have a higher risk of arrhythmiasduring hot water immersion).

• Unstable cardiovascular diseases (e.g., unstable angina or recent myocardialinfarction or stroke) (rationale: heat therapy is contraindicated for individualswith unstable CVDs).

• Recent major change in health status within previous 3 months (e.g., surgery,significant infection or illness, including COVID-19). What is considered "major" or "significant" may be evaluated by the physician of record on a case-by-case basis.An example of a surgery that would likely not be considered "major" is out-patientremoval of a basal cell carcinoma. "Significant" infections include those requiringhospitalization or long durations (i.e., months) of recovery. Additionally, subjectswith acute fever/illness (Tre ≥ 38.0°C) will not be able to undergo screening orparticipate in water immersion sessions until fever/illness has resolved. Subjectswith a confirmed positive case of COVID-19 will not be able to participate untilCOVID-19 symptoms have resolved and 2 weeks after diagnosis. Subjects will be askedto let us know if they are sick so that sessions/testing can be rescheduled.

• Open wounds or skin lesions. History of skin-related conditions or sensitivities toprolonged water immersion or exposure to pool chemicals.

• Blood donation within the past 2 months (if subjects have donated blood within thelast 2 months, we will ask if they are willing to delay the start of the study untilit has been 2 months since their last blood donation)

• Inability to tolerate blood draws, intravenous catheters, including past fainting inresponse to blood sampling. (rationale: at the least, we must be able to obtainenough blood for clinical chemistries to ensure safety).