Repeated exposure to passive heat stress ('heat therapy') has widespread physiological benefits, including cellular protection against novel stressors. Increased heat shock protein (HSP) expression and upregulation of circulating factors may impart this protection. We tested the isolated abilities of mild heat pretreatment and serum from human subjects (n = 10) who had undergone 8 weeks of heat therapy to protect against cellular stress following hypoxia-reoxygenation (H/R), a model of ischaemic cardiovascular events. Cultured human umbilical vein endothelial cells were incubated for 24 h at 37°C (control), 39°C (heat pretreatment) or 37°C with 10% serum collected before and after 8 weeks of passive heat therapy (four to five times per week to increase rectal temperature to ≥ 38.5°C for 60 min). Cells were then collected before and after incubation at 1% O for 16 h (hypoxia; 37°C), followed by 20% O for 4 h (reoxygenation; 37°C) and assessed for markers of cell stress. In control cells, H/R increased nuclear NF-κB p65 protein (i.e. activation) by 106 ± 38%, increased IL-6 release by 37 ± 8% and increased superoxide production by 272 ± 45%. Both heat pretreatment and exposure to heat therapy serum prevented H/R-induced NF-κB activation and attenuated superoxide production; by contrast, only exposure to serum attenuated IL-6 release. H/R also decreased cytoplasmic haemeoxygenase-1 (HO-1) protein (known to suppress NF-κB), in control cells (-25 ± 8%), whereas HO-1 protein increased following H/R in cells pretreated with heat or serum-exposed, providing a possible mechanism of protection against H/R. These data indicate heat therapy is capable of imparting resistance against inflammatory and oxidative stress via direct heat and humoral factors.

Polycystic ovary syndrome (PCOS) affects up to 15% of women and is associated with increased risk of obesity and cardiovascular disease. Repeated passive heat exposure [termed “heat therapy” (HT)] is a lifestyle intervention with the potential to reduce cardiovascular risk in obesity and PCOS. Women with obesity ( n = 18) with PCOS [age 27 ± 4 yr, body mass index (BMI) 41.3 ± 4.7 kg/m2] were matched for age and BMI, then assigned to HT ( n = 9) or time control (CON; n = 9). HT subjects underwent 30 one-hour hot tub sessions over 8–10 wk, whereas CON subjects did not undergo HT. Muscle sympathetic nerve activity (MSNA), blood pressure, cholesterol, C-reactive protein, and markers of vascular function were assessed at the start (Pre) and end (Post) of 8–10 wk. These measures included carotid and femoral artery wall thickness and flow-mediated dilation (FMD), measured both before and after 20 min of ischemia-20 min of reperfusion (I/R) stress. HT subjects exhibited reduced MSNA burst frequency (Pre: 20 ± 8 bursts/min, Post: 13 ± 5 bursts/min, P = 0.012), systolic (Pre: 124 ± 5 mmHg, Post: 114 ± 6 mmHg; P < 0.001) and diastolic blood pressure (Pre: 77 ± 6 mmHg, Post: 68 ± 3 mmHg; P < 0.001), C-reactive protein (Pre: 19.4 ± 13.7 nmol/L, Post: 15.2 ± 12.3 nmol/L; P = 0.018), total cholesterol (Pre: 5.4 ± 1.1 mmol/L, Post: 5.0 ± 0.8 mmol/L; P = 0.028), carotid wall thickness (Pre: 0.054 ± 0.005 cm, Post: 0.044 ± 0.005 cm; P = 0.010), and femoral wall thickness (Pre: 0.056 ± 0.009 cm, Post: 0.042 ± 0.005 cm; P = 0.003). FMD significantly improved in HT subjects over time following I/R (Pre: 5.6 ± 2.5%, Post: 9.5 ± 1.7%; P < 0.001). No parameters changed over time in CON, and BMI did not change in either group. These findings indicate that HT reduces sympathetic nerve activity, provides protection from I/R stress, and substantially improves cardiovascular risk profiles in women who are obese with PCOS.

Rationale: Passive heat therapy improves vascular endothelial function, likely via enhanced nitric oxide (NO) bioavailability, although the mechanistic stimuli driving these changes are unknown. Objective: To determine the isolated effects of circulating (serum) factors on endothelial cell function, particularly angiogenesis, and NO bioavailability. Methods and Results: Cultured human umbilical vein endothelial cells (HUVECs) were exposed to serum collected from 20 healthy young (22 ± 1 years) adults before (0 wk), after one session of water immersion (Acute HT), and after 8 wk of either heat therapy (N = 10; 36 sessions of hot water immersion; session 1 peak rectal temperature: 39.0 ± 0.03°C) or sham (N = 10; 36 sessions of thermoneutral water immersion). Serum collected following acute heat exposure and heat therapy improved endothelial cell angiogenesis (Matrigel bioassay total tubule length per frame, 0 wk: 69.3 ± 1.9 mm vs. Acute HT: 72.8 ± 1.4 mm, p = 0.04; vs. 8 wk: 73.0 ± 1.4 mm, p = 0.03), with no effects of sham serum. Enhanced angiogenesis was NO-mediated, as addition of the NO synthase (NOS) inhibitor L-NNA to the culture media abolished differences in tubule formation across conditions (0 wk: 71.3 ± 1.8 mm, Acute HT: 71.6 ± 1.9 mm, 8 wk: 70.5 ± 1.6 mm, p = 0.69). In separate experiments, we found that abundance of endothelial NOS (eNOS) was unaffected by Acute HT serum (p = 0.71), but increased by 8 wk heat therapy serum (1.4 ± 0.1-fold from 0 wk, p < 0.01). Furthermore, increases in eNOS were related to improvements in endothelial tubule formation (r 2 = 0.61, p < 0.01). Conclusions: Passive heat therapy beneficially alters circulating factors that promote NOmediated angiogenesis in endothelial cells and increase eNOS abundance. These changes may contribute to improvements in vascular function with heat therapy observed in vivo.

Passive hot water immersion promotes improvements in glucose control in humans, potentially by enhancing insulin sensitivity. In animal models, this improvement is mediated by increased heat shock protein (HSP) abundance, which inhibits production of inflammatory compounds that interfere with intracellular insulin signaling. The impact of repeated passive hot water immersion (termed ‘heat therapy’) on inflammation, HSP abundance, and insulin signaling in human adipose tissue have not been explored in an insulin‐resistant population such as obese women with Polycystic Ovary Syndrome (PCOS). While exercise training can improve insulin sensitivity in PCOS, novel treatments such as heat therapy are warranted as many individuals are unable to fully benefit from a traditional exercise program due to poor exercise tolerance or capacity. Therefore, the objective of this study was to examine changes in insulin signaling, inflammatory proteins, and HSPs in subcutaneous adipose tissue of obese women with PCOS undergoing an 8–10 week heat therapy intervention. Six obese women with PCOS (Age: 26±3y, BMI 42±2 kg·m2) underwent heat therapy, consisting of 30 × 1‐hr hot tub sessions over 8–10 weeks (3–4 per week) in 40.5°C water. Subcutaneous adipose tissue biopsies were collected from the periumbilical region at the start (Pre) and end (Post) of the chronic heat intervention. Tissue samples were analyzed using immunoblotting for HSP27, HSP70, and inflammatory proteins known to be impacted by HSPs and interfere with insulin signaling, including c‐Jun‐NH2‐terminal Kinase (JNK; inhibited by HSP70) and Inhibitor of Kappa B Kinase β (IKKβ; inhibited by HSP27). Additionally, a sub‐set of primary adipocytes in n=4 subjects were serum starved for 2 hours, then exposed to 1.2 nM insulin for 5 minutes for insulin signaling (p‐AKT) analysis using immunoblotting. All targets were quantified relative to loading control and expressed as a fold change from Pre to Post. Following heat therapy, insulin signaling (p‐AKT) increased in all subjects (4.1±2.0‐fold increase, p=0.19) despite no change in BMI (p=0.42). IKKβ significantly decreased (0.50 ± 0.06‐fold decrease, p=0.02) and JNK tended to decrease (0.48 ± 0.17‐fold decrease, p=0.09) after heat therapy. Abundance of HSP27 increased in all subjects (1.27 ± 0.14‐fold increase, p=0.18), while, conversely, HSP70 abundance significantly decreased (0.42±0.12‐fold decrease; p=0.03). In these preliminary data, heat therapy appears to promote improved insulin signaling in obese women with PCOS. This improvement is likely due to observed decreases in adipose tissue inflammation, potentially mediated in part by increased HSP27 abundance. Regular heat exposure has promise as a novel treatment in insulin‐resistant individuals to improve metabolic function. Heat can potentially be implemented as a complement or as a transition to exercise training to improve metabolic health, particularly in patient populations with severe metabolic dysfunction, mobility limitations, or low exercise tolerance. Support or F...

METHODS: Data was collected on 41 active adults who completed a 11km road race. Age (mean±standard deviation [SD]): 44.7±15.7 years; VO 2 max: 42.7±9.2 ml/kg/min; percent body fat: 22.4±9.6%. CRI was assessed at baseline for 10 minutes in a supine position in a thermoneutral environment. At the road race, CRI was assessed for 2 minutes pre-race and post-race in the supine position. Heart rate and oxygen saturation were assessed alongside CRI. Environmental conditions were captured surrounding the race. Core temperature was assessed post-race. Descriptive statistics (mean±SD) were calculated and paired-samples t-tests were utilized to compare baseline to pre-race, baseline to post-race, and pre-race to post-race. RESULTS: Post-race CRI (mean ± SD: 0.70±0.32) significantly diminished compared to baseline values (0.91±0.07; p<0.001). Post-race CRI was significantly diminished (p<0.001) compared to pre-race CRI measures (mean±SD: 0.88±0.09). Resting heart rate increased from baseline (mean±SD: 59.6±10.4 bpm) to pre-race (65.4±11.2 bpm) and to post-race (85.1±16.9 bpm). Runners were characterized as hyperthermic following the race (core temperature: 38.90±1.20 ºC). Environmental conditions upon finishing the race were 22.78 ºC, 53% RH, and 21.67 ºC WBGT. CONCLUSIONS: Following physically demanding exercise in the heat, CRI monitoring may be able to detect changes resulting from increased physiological stress and may be utilized to prevent collapse. Future studies should assess the extent to which thermal stress is correlated to changes in CRI.