Local Passive Heat for the Treatment of Hypertension in Autonomic Failure

Abstract

Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Keywords: autonomic failure; heat; orthostatic hypotension; supine hypertension; thermoregulation.

Conflict of interest statement

Biaggioni received 2 donated units of the Norm‐O‐Temp system and Gelli‐roll pads from Cincinnati Sub‐Zero for the conduct of the overnight studies. The remaining authors have no disclosures to report.

Figures

Figure 1. Acute effects of local passive heat (Protocol 1).

Changes from baseline in abdominal skin and core body temperatures (A), supine systolic blood pressure (ΔSBP, B) and diastolic blood pressure (ΔDBP, C) during 2 hours of local heat (40–42°C applied over the abdomen and pelvis with an electric heating pad) or sham control. Local passive heat decreased supine SBP and DBP and produced a small, but significant, increase in core body temperature compared with sham control. Values are expressed as mean±SEM. Overall differences were analyzed by 2‐way repeated‐measures ANOVA (P≤0.01 for treatment effect and P<0.001 for treatment×time interaction in all comparisons). *P<0.001 and †P<0.05 vs sham, adjusted for multiple comparisons using Bonferroni correction.

Figure 2. Acute effects of local controlled passive heat on systemic and skin hemodynamics (Protocol 1).

A, Percent changes from baseline in systemic hemodynamic parameters at 2 hours of controlled passive heating (40–42°C applied over the abdomen and pelvis with an electric heating pad) or sham control. Local passive heat significantly decreased cardiac output (CO) and stroke volume (SV) compared with sham control, whereas systemic vascular resistance (SVR) and heart rate (HR) were similar between groups. B, Percent changes from baseline in abdominal and calf skin blood flow (skin BF) and cutaneous vascular conductance (CVC) at 2 hours post‐intervention. Compared with sham control, passive heat significantly increased local skin BF and CVC in the abdomen (directly under the heating pad) but had no significant effect in the calf, a distal site not exposed to the heating source. Values are expressed as mean±SEM. *P<0.05 vs sham.

Figure 3. Effect of overnight heat therapy on nighttime BP (Protocol 2).

A, The time course of the change in systolic blood pressure (ΔSBP) in patients with autonomic failure and nocturnal supine hypertension. Passive heat (38°C) was applied with a water‐perfused heating pad placed under the patient's torso and proximal thighs from 10 pm to 6 am (bold line). Changes from baseline (8 pm) in supine SBP (∆SBP) are expressed as mean±SEM. Overnight heat therapy decreased SBP compared with placebo (P<0.01 for treatment effect and treatment×time interaction, 2‐way repeated measures ANOVA). *P<0.01 vs placebo, adjusted for multiple comparisons using Bonferroni correction. B, The relation between the depressor response to overnight heat therapy (calculated as the difference in the supine SBP at 4 am between heat and placebo nights, ∆SBP4AM) and the change in orthostatic tolerance the morning after heat treatment (estimated as the difference in the area under the curve of standing SBP between overnight heat therapy and placebo groups, ∆AUCSBP). Patients with greater reductions in supine SBP with overnight heat had greater improvements in morning orthostatic tolerance.

Figure 4. Maximal BP‐lowering effects of pharmacologic treatment for nocturnal supine hypertension and overnight heat therapy.

Maximal reductions from baseline in nocturnal supine systolic BP (ΔSBP) were measured after a single dose of placebo pill, 0.1 mg/hour nitroglycerin patch, 11 0.1 mg clonidine PO, 11 50 mg losartan PO, 7 5 mg nebivolol PO, 10 25 mg sildenafil PO, 10 30 mg nifedipine PO, 5 and 50 mg eplerenone PO 8 given at 8 pm. Local heat therapy (38°C) was applied from 10 pm to 6 am. The maximal reduction in nocturnal supine SBP during local heat was similar to that of pharmacological therapy. Values are expressed as mean±SEM.