Acute heat exposure protects against endothelial ischemia-reperfusion injury in aged humans

Abstract

Nonpharmacological therapies that protect against endothelial ischemia-reperfusion injury (I/R) remain limited in aged adults. Acute heat exposure protects against endothelial I/R injury in young adults, but its efficacy has never been explored in aged adults. Therefore, we tested the hypothesis that acute heat exposure would prevent the attenuation of endothelium-dependent vasodilation after I/R injury in aged adults. Nine (2 men, 69 ± 8 yr) aged adults were exposed to a thermoneutral control condition or whole body passive heating (water-perfused suit) sufficient to increase body core temperature by 1.2°C. Experiments were separated by at least 7 days. Heat exposure was always performed first to time match the thermoneutral control condition. Endothelium-dependent vasodilation was assessed via flow-mediated dilation of the brachial artery before (pre-I/R) and after I/R injury (post-I/R), which was induced by 20 min of arm ischemia followed by 20 min of reperfusion. Flow-mediated dilation was reduced following I/R injury for the thermoneutral control condition (pre-I/R, 4.5 ± 2.9% vs. post-I/R, 0.9 ± 2.8%, P < 0.01), but was well maintained with prior heat exposure (pre-I/R, 4.4 ± 2.8% vs. post-I/R, 3.5 ± 2.8%, P = 0.5). Taken together, acute heat exposure protects against endothelial I/R injury in aged adults. These results highlight the therapeutic potential of heat therapy to prevent endothelial dysfunction associated with I/R injury in aged adults who are most at risk for an ischemic event.

INTRODUCTION

Ischemic heart disease is the leading cause of death globally (1). Interventions that restore vessel patency (e.g., percutaneous coronary intervention) rapidly reestablish blood flow during an ischemic event but can simultaneously augment tissue and organ damage, a condition known as ischemia-reperfusion (I/R) injury (2). Although several mechanisms are thought to contribute to I/R injury, endothelial dysfunction has emerged as a strong contributor to the overall condition. Importantly, in severe cases, endothelial dysfunction can lead to a sustained tissue malperfusion despite the restoration of vessel patency (3, 4). This “no-reflow” phenomenon can induce systemic inflammation, remote organ damage, multiple organ failure, and ultimately lead to death (5).

The prevalence of vascular dysfunction increases significantly after the age of ∼55 (6–9) and is a major risk factor for severe I/R injury (10). Unfortunately, nonpharmacological therapies that protect endothelial function and attenuate the magnitude of I/R injury remain limited in this population. Life-long endurance exercise training exerts a robust protection against endothelial I/R injury in aged adults (11). However, the implementation of an endurance exercise training program may be challenging in aged adults, particularly in those individuals who are unwilling or unable to exercise. In addition, other nonpharmacological interventions such as ischemic preconditioning protect endothelial function following I/R injury in young healthy adults but have failed to provide equal protection in sedentary aged adults (11, 12). We (13, 14) and others (15) have demonstrated that acute heat exposure protects endothelial function in young healthy adults exposed to an experimental model of acute I/R injury. However, this efficacy has never been explored in aged adults who are most at risk for an ischemic event.

The purpose of this study was to determine determine if acute heat exposure protects against endothelial I/R injury in aged adults. We tested the hypothesis that acute heat exposure would prevent the attenuation of endothelium-dependent vasodilation following acute I/R injury in aged adults. In addition, we recently demonstrated that acute heat exposure protects against endothelial I/R injury young adults while concomitantly maintaining serum heat shock protein 90α concentrations (14). Therefore, we tested a secondary hypothesis that acute heat exposure would prevent the attenuation of serum heat shock protein 90α following I/R injury in aged adults.

METHODS

Participants

Written informed consent was obtained from all participants following a verbal and written explanation of all experimental procedures. This study was approved by the North Texas Regional Institutional Review Board (Project No. 1660335) and was performed in accordance with the principles outlined in the Declaration of Helsinki, except for registration in a database. Men and women were included in the study if they were deemed free from cardiometabolic disease following the completion of an in-depth medical history questionnaire and a resting 12-lead electrocardiogram. A complete list of participant inclusion/exclusion criteria can be found in an accompanying supplement (Supplemental Table S1; see https://doi.org/10.6084/m9.figshare.19122635.v1). Seven participants identified as non-Hispanic white, whereas the other two participants identified as Asian. Participants were required to abstain from caffeine, supplements, alcohol, and exercise for 24 h before the study. Participants were also required to abstain from over-the-counter or prescription medications at the time of the study. Women were postmenopausal (18 ± 11 yr from cessation of menstruation) and were not undergoing hormone replacement therapy. Participant physical characteristics including sex, age, height, weight, body mass index, and blood chemistry indices are shown in Table 1.

Table 1.

Participant characteristics

Men/Women	2/7
Age, yr	69 ± 8
Height, cm	162 ± 6
Weight, kg	68 ± 13
BMI, kg·m−2	25.6 ± 5.1
Total cholesterol, mg·dL−1	177 ± 27
High-density lipoprotein, mg·dL−1	64 ± 19
Low-density lipoprotein, mg·dL−1	93 ± 23
Triglycerides, mg·dL−1	100 ± 44
Glucose, mg·dL−1	93 ± 8

Data are presented as means ± SD.

Experimental Approach

Participants were exposed to a thermoneutral control condition or whole body passive heat exposure sufficient to increase body core temperature by 1.2°C. This target body core temperature was based on a previous study from our group in which acute heat exposure (via a water perfused suit) was used to prevent endothelial I/R injury in young adults (14). Because we were unable to predict the duration required to reach target body core temperature for each participant, heat exposure was always performed first to time match the thermoneutral control condition and to reduce intraindividual variability. In addition, using this approach allowed us to retrospectively compare data from this investigation to historical data from our laboratory that was collected using an identical approach (i.e., time-matching the thermoneutral condition to the duration of heat exposure) in young healthy adults (14). Given the nature of the thermal exposures used in this investigation, participants nor research personnel were blinded.

For each thermal condition, participants reported to the laboratory at ∼8:30 AM after an overnight fast and were provided a standardized breakfast before each experiment. Participants donned a specialized tube-lined suit (Med-Eng, Ottawa, ON, Canada) that circulates water of varying temperatures to manipulate skin temperature, except at the head, feet, hands, and right arm where ultrasound measurements were made. After instrumentation and a ∼20-min thermoneutral rest period, endothelium-dependent vasodilation was assessed in the right arm (pre-I/R). Hot water (∼48°C) was then circulated through the tube-lined suit to clamp mean skin temperature at ∼40°C and increase body core temperature by 1.2°C. Heating was then immediately terminated and thermoneutral water was circulated through the suit during a 60-min recovery period. Immediately thereafter, I/R injury was induced in the right arm by placing a pneumatic cuff (SC5, Hokanson, Bellevue, WA) immediately distal to the axilla and rapidly inflating it to 250 mmHg (E20 Rapid Cuff Inflator, Hokanson, Bellevue, WA). The cuff was always placed proximal to the ultrasonography site and complete circulatory arrest was confirmed by absence of a palpable radial pulse. After 20 min of ischemia, the cuff was rapidly deflated, and reperfusion was allowed for 20 min. This model of forearm I/R injury attenuates endothelium-dependent vasodilation with no effect on endothelium-independent vasodilation (3, 16–19). Endothelium-dependent vasodilation was reassessed immediately upon completion of reperfusion (post-I/R). For the thermoneutral control condition, skin temperature was clamped at 33°C throughout. Participants were allowed to drink water ad libitum throughout their first experiment and consumption was matched in the subsequent experiment. An experimental schematic is shown in Fig. 1.

Figure 1.

Experimental schematic. Vertical arrow denotes thermal and hemodynamic measurements. *Assessment of endothelial function via flow-mediated dilation. Blood collection tube denotes sampling of venous blood for quantification of serum heat shock protein 90α.

Measurements

Participants remained supine throughout the experiment and were asked to stay quiet and relaxed during all hemodynamic measurements. Laboratory temperature was maintained at ∼21°C during experimentation.

Thermal measures.

Body core temperature was measured via a telemetric pill (HQ, Inc., Palmetto, FL) that was ingested the evening prior experimentation. Mean (nonweighted) skin temperature was measured from four thermocouples (Omega Engineering, Inc., Norwalk, CT) placed at the following anatomical locations: 1) anterior torso ∼6–8 cm inferior to the left clavicle; 2) posterior torso at the left scapular angle; 3) anterior thigh ∼28–32 cm inferior to the left inguinal ligament; and 4) posterior thigh ∼10–20 cm inferior to the left gluteal sulcus.

Hemodynamics.

Heart rate was monitored continuously via electrocardiogram (Solar 8000 M, GE Healthcare, Chicago, IL). Arterial blood pressure was measured using an automated sphygmomanometer (Tango M2, SunTech Medical, Morrisville, NC) placed on the left arm. Brachial artery diameter and blood velocity were measured in the right arm via duplex ultrasonography (11 MHz, Phillips iE33, Andover, MA) using a linear array transducer and an insonation angle of 60°. The ultrasound was interfaced with a computer running custom software to capture blood velocity (DUC²). The location of the ultrasound transducer was marked on the skin to ensure consistent placement throughout each experiment. In addition, care was taken to match ultrasound settings (e.g., sample volume size and depth) to ensure consistent probe placement between experiments. Brachial artery diameter and blood velocity were recorded at each 0.3°C increase in body core temperature. For the thermoneutral condition, time-matched measurements were made at 25%, 50%, 75%, and 100% of the duration of each participant’s heat exposure.

Endothelial function.

Endothelium-dependent vasodilation was assessed via flow-mediated dilation of the brachial artery in accordance with recent guidelines (20, 21). Briefly, a pneumatic cuff (SC5D, Hokanson, Bellevue, WA) was placed on the forearm, immediately distal to the olecranon process. Arterial inflow to the forearm was occluded by rapidly inflating the cuff to 220 mmHg for 5 min (E20 Rapid Cuff Inflator, Hokanson, Bellevue, WA). Before cuff inflation, brachial artery diameter and blood velocity were recorded during a 1-min baseline period and resumed 20 s before cuff deflation and continued for 3 min thereafter.

Blood sampling and analysis.

A 22-gauge intravenous catheter was placed in an antecubital vein of each participant’s arm that was exposed to I/R injury. Before each assessment of endothelial function, venous blood was collected into a Vacutainer and allowed to sit for 30 min before centrifugation at 1,300 g for 15 min at 4°C. Concentrations of serum heat shock protein 90α were measured using a commercially available enzyme-linked immunosorbent assay (Enzo Life Sciences, Farmingdale, NY).

Retrospective analysis.

Using data previously published by our laboratory (14), we retrospectively analyzed the heat-induced protection of endothelial function between young and aged adults and across thermal conditions by comparing the change in flow-mediated dilation from pre- to post-I/R. Notably, data from our prior study in young adults and those in the current study were collected using an identical experimental approach. Data were calculated as the change in ANCOVA-adjusted flow-mediated dilation from pre- to post-I/R time points.

Data and Statistical Analyses

Blood velocity was determined from Doppler ultrasound audio recordings using an intensity-weighted algorithm (custom software), subsequent to demodulation of forward and reverse Doppler frequencies (22–25). Blood velocities were then thin-beam corrected using an average correction factor of 0.971 ± 0.040 (22). Correction factors were based on a measured ultrasound probe beam-width of 3.67 mm and a vessel depth of 1.8 ± 0.4 cm. Vessel diameter was determined using custom edge-detection and wall-tracking software (26, 27). Peak diameter measured during flow-mediated dilation was determined using an algorithm previously described by Black et al. (26). Blood flow was calculated by multiplying the cross-sectional area of the brachial artery by mean blood velocity (reported in mL·min⁻¹). Vascular conductance was calculated by dividing blood flow by mean arterial pressure (expressed as mL·min⁻¹·mmHg⁻¹). Shear stress was estimated using shear rate, which was calculated by multiplying 8 by the quotient of mean blood velocity and vessel diameter (expressed as s⁻¹).

One participant chose not to return for the thermoneutral experiment due to the discomfort associated with I/R injury. As such all hemodynamic and thermal outcome measures were analyzed using a two-way (condition × time) mixed model analysis of variance (ANOVA) with repeated measures (JMP 14; SAS Institute, Inc., Cary, NC). Interactions were further examined using Tukey’s post hoc procedure. Flow-mediated dilation was assessed using the allometric modeling solution proposed by Atkinson et al. (28, 29) subsequent to verification of the presence of inadequate scaling by examining the slope of the relation between logarithmically transformed baseline and peak diameter. Shear rate area under the curve summed through peak diameter was also entered into the model as a covariate to account for changes in shear stimulus. Serum concentrations of serum heat shock protein 90α were measured with a two-way (condition × time) mixed model ANOVA. A two-way (condition × age group) mixed model ANOVA with repeated measures was used for the retrospective analysis. Using preliminary studies and data from our prior work (13, 30), we performed a power analysis using an α = 0.05, a β = 0.8, and a partial η² = 0.14 and determined that a sample size of n = 9 provided sufficient power (G*Power; a priori F-test: within-between interaction for repeated measures ANOVA).

RESULTS

Thermal Exposure

Compared with the thermoneutral condition (33.1 ± 0.3°C), skin temperature was greater during heat exposure (40.0 ± 0.5°C; P < 0.01). Accordingly, body core temperature increased by 1.2 ± 0.0°C during heat exposure but remained within 0.2 ± 0.3°C of baseline for the thermoneutral condition. The time to reach a 1.2°C increase in body core temperature during heat exposure was 67 ± 9 min (range: 58–80 min).

Hemodynamics

Select brachial artery hemodynamics are shown in Fig. 2. Other hemodynamics measured at baseline and during each thermal exposure are shown in Table 2. Heart rate (P = 0.9) and mean arterial blood pressure (P = 0.9) did not differ between thermal conditions at baseline. Heart rate increased during heat exposure (P < 0.01 vs. baseline), whereas mean arterial pressure decreased (all time points except Δ 0.3°C; P ≤ 0.04 vs. baseline). Forearm blood flow and vascular conductance did not differ between conditions at baseline (both P = 0.9). Forearm blood flow and vascular conductance increased during heat exposure (both P < 0.01) but were relatively unchanged during the thermoneutral condition (both P = 0.9).

Figure 2.

Brachial artery blood velocity (top), diameter (middle), and shear rate (bottom) are shown across time for both thermal conditions. Data were analyzed using a two-way (condition × time) mixed-model analysis of variance with repeated measures. Thermoneutral, n = 8; heat exposure, n = 9. *P < 0.05 vs. baseline within thermal condition; †P < 0.05 vs. thermoneutral condition at the indicated time point.

Table 2.

Central and peripheral hemodynamics measured during thermoneutral control or heat exposure

	Baseline	Time Match or Δ 0.3°C	Time Match or Δ 0.6°C	Time Match or Δ 0.9°C	Time Match or Δ 1.2°C
	Thermoneutral
Heart rate, beats·min−1	66 ± 5	64 ± 4	63 ± 3	61 ± 4	61 ± 5
Mean arterial pressure, mmHg	92 ± 11	96 ± 10	97 ± 11	98 ± 11	100 ± 13
Brachial artery blood flow, mL·min−1	27 ± 8	24 ± 6	23 ± 9	21 ± 7	23 ± 8
Brachial artery vascular conductance, mL·min−1·mmHg−1	0.30 ± 0.09	0.26 ± 0.08	0.24 ± 0.09	0.22 ± 0.07	0.23 ± 0.07
	Heat exposure
Heart rate, beats·min−1	70 ± 6	79 ± 9*#	81 ± 10*#	87 ± 11*#	93 ± 9*#
Mean arterial pressure, mmHg	94 ± 8	86 ± 9#	83 ± 8*#	84 ± 8*#	85 ± 6*#
Brachial artery blood flow, mL·min−1	27 ± 5	148 ± 45*#	172 ± 49*#	199 ± 42*#	234 ± 41*#
Brachial artery vascular conductance, mL·min−1·mmHg−1	0.29 ± 0.09	1.72 ± 0.49*#	2.09 ± 0.59*#	2.36 ± 0.47*#	2.75 ± 0.52*#

Values are means ± SD. Δ°C denotes measurement at the respective increase in body core temperature during heat exposure or the time match during the thermoneutral condition. *P < 0.01 vs. baseline within thermal condition. #P < 0.01 vs. thermoneutral at the indicated time point.

Endothelial Function

Indices relevant to the assessment of endothelial function via flow-mediated dilation are shown in Table 3. ANCOVA-adjusted flow-mediated dilatory responses are shown for both conditions at pre- and post-I/R time points in Fig. 3. A condition by time interaction was observed for flow-mediated dilation (P = 0.01). Post hoc tests indicated that flow-mediated dilation did not differ between conditions at the pre-I/R time point (thermoneutral, 4.5 ± 2.9% vs. heat exposure, 4.4 ± 2.8%, P = 0.9). Flow-mediated dilation was attenuated following I/R injury for the thermoneutral condition (0.9 ± 2.8%, P < 0.01 vs. pre-I/R) but was well maintained following heat exposure (3.5 ± 2.8%, P = 0.5 vs. pre-I/R). In addition, flow-mediated dilation measured at the post-I/R time point was attenuated following the thermoneutral condition when compared with heat exposure (P < 0.01).

Table 3.

Brachial artery hemodynamics during flow-mediated dilation

	Thermoneutral		Heat Exposure
	Pre-I/R	Post-I/R	Pre-I/R	Post-I/R
Baseline diameter, cm	0.325 ± 0.056	0.341 ± 0074*	0.329 ± 0.058	0.357 ± 0.069*
ΔDiameter, cm	0.016 ± 0.009	0.003 ± 0.008*†	0.015 ± 0.009	0.010 ± 0.007
Time to peak diameter, s	44 ± 24	51 ± 19	44 ± 27	50 ± 27
Shear rate AUC	33,640 ± 16,669	35,992 ± 19,678	42,576 ± 34,164	40,011 ± 24,327

Values are means ± SD. Shear rate AUC, shear rate area under the curve through peak diameter. *P = 0.01 vs. pre-I/R within thermal condition; †P = 0.04 vs. heat exposure at the indicated time point.

Figure 3.

ANCOVA-adjusted flow-mediated dilatory responses are shown for both thermal conditions at the pre- and post-ischemia-reperfusion (I/R) time points. Data were analyzed using a two-way (condition × time) mixed model analysis of variance with repeated measures. Logarithmically transformed baseline diameter and shear rate area under the curve summed through peak diameter were entered into the model as covariates. Thermoneutral n = 8, heat exposure n = 9. *P < 0.05 vs. baseline within thermal condition; †P < 0.05 vs. thermoneutral condition at the indicated time point.

Heat Shock Protein 90α

Blood was successfully drawn in n = 7 for the thermoneutral condition and n = 5 for heat exposure. Baseline serum heat shock protein 90α concentrations did not differ between thermal conditions (thermoneutral, 10.1 ± 2.2 ng·mL⁻¹ vs. heat exposure, 12.8 ± 4.4 ng·mL⁻¹; P = 0.5), nor did they differ at the post-I/R time point (thermoneutral, 12.1 ± 4.3 ng·mL⁻¹ vs. heat exposure, 12.7 ± 6.3 ng·mL⁻¹; P = 0.5).

Retrospective Analysis

ANCOVA-adjusted flow-mediated dilatory responses are shown across conditions and age groups in Fig. 4. The change in flow-mediated from pre- to post-I/R injury did not differ between age groups (P = 0.2 for main effect of age). Ischemia-reperfusion injury reduced flow-mediated dilation for both age groups following the thermoneutral condition but was well protected following heat exposure (P < 0.01 for main effect of condition).

Figure 4.

Reduction in flow-mediated dilation induced by ischemia-reperfusion (I/R) injury is shown for young and aged adults following a thermoneutral condition or heat exposure. Data were calculated as the change in ANCOVA-adjusted flow-mediated dilation from pre- to post-I/R time points. Data were analyzed using a two-way (condition × age group) mixed model analysis of variance with repeated measures. Young, n = 8. Aged, n = 9. †P < 0.01 vs. thermoneutral within age group. Each box represents the median, and the 25th and 75th percentiles. Whiskers denote the 10th and 90th percentiles. Dotted line within a given box denotes the mean. Data for young adults taken from Hemingway et al. (14).

DISCUSSION

The purpose of this study was to determine if acute heat exposure protects against endothelial I/R injury in aged adults. In support of our hypothesis, we found that I/R injury attenuated endothelial function for the thermoneutral control condition but was protected when preceded by whole body heat exposure. In addition, in contrast to our prior findings in young adults (14), serum heat shock protein 90α did not differ between thermal conditions following I/R injury.

Heat Exposure and Protection against Endothelial I/R Injury: Influence of Age

We and others have demonstrated previously that acute heat exposure protects against endothelial I/R injury in young healthy humans (13, 15). We extend these observations in the current study by demonstrating that acute heat exposure has a similar protective effect in aged adults. However, it was unclear if the magnitude of protection induced by acute heat exposure in aged adults differs from their younger counterparts. Therefore, using data previously published by our laboratory (14), we retrospectively analyzed the heat-induced protection of endothelial function between age groups and across thermal conditions by comparing the change in flow-mediated dilation from pre- to post-I/R. We found that I/R injury impairs endothelial function to the same extent in both age groups following the thermoneutral condition, but was protected with prior heat exposure, the magnitude of which was nearly identical between age groups (Fig. 4). These findings suggest that acute heat exposure similarly protects endothelial function following I/R injury across the human life span.

Mechanisms Mediating Protection against Endothelial I/R Injury

The mechanism/s mediating protection against endothelial I/R injury following heat exposure remain unclear. Using an ex vivo preparation, Brunt et al. (31) provided evidence suggesting that the direct effect of heat on endothelial cells and/or humoral factors released in response to elevated body core temperature contribute to the protection against I/R injury. In further support of these data, we recently demonstrated that the increase in shear stress induced by acute heat exposure does not contribute to the protection of endothelial function following I/R injury in vivo (14). Thus, it appears that pathways responsive to changes in local and/or body core temperature and the release of autocrine, paracrine, or endocrine factors are the primary mechanisms mediating protection against I/R injury. Along these lines, we demonstrated that I/R injury reduced serum heat shock protein 90α concentrations, whereas acute heat exposure prevented such a reduction and concomitantly protected endothelial function in young adults (14). Heat shock protein 90α is a stress-inducible molecular chaperone that stabilizes and activates hundreds of proteins that modulate intracellular processes ranging from proteostasis to DNA repair and transcription (32). Importantly, heat shock protein 90α has been shown to attenuate myocardial I/R injury via nitric-oxide dependent mechanisms (33) and can function as a circulating proimmune signal that can augment pathophysiological stress resistance within endothelial cells (34). However, in the current study, we found that heat exposure protected endothelial function following I/R injury despite having no impact on serum heat shock protein 90α in aged adults. Thus, the underlying mechanisms mediating protection against endothelial I/R injury may differ between young and aged adults. This remains an exciting area for future investigation.

Experimental Considerations

Several experimental considerations warrant discussion. First, participants included in this study were healthy and free from cardiometabolic disease. Thus, the protective effect of heat exposure may differ in aged adults with overt disease or other clinical populations with exaggerated endothelial dysfunction (e.g., type 2 diabetes). Second, the extent to which acute heat exposure affords protection against endothelial I/R beyond the initial recovery period or how this response relates to chronic exposure (i.e., heat therapy) is unclear. Third, extracellular heat shock protein 90α was not likewise measured intracellularly. Thus, our findings may not reflect changes occurring within endothelial cells. In addition, serum heat shock protein 90α was assessed in a limited sample size. As such, these findings should be interpreted judiciously. Fourth, we did not assess endothelium-independent vasodilation. Thus, we cannot say with certainty that the protective effect of heat exposure is due primarily to improved endothelial function. However, several studies have demonstrated that the model of arm I/R injury used in this study has no effect on endothelium-independent vasodilation (3, 16–19). Thus, the protection of endothelial function in aged adults induced by acute heat exposure is likely mediated by changes within the endothelium, with no change in the vascular smooth muscle function. Fifth, we used an experimental model of I/R injury which may not fully reproduce clinical I/R injury nor fully capture the protective effect that heat exposure may have on vascular beds susceptible to endothelial I/R injury (e.g., coronary circulation). However, the forearm model used in this study remains the only method available to ethically induce endothelial I/R injury in humans.

Perspectives and Summary

Although various nonpharmacological interventions have proven efficacy to protect against endothelial I/R injury in young adults, they remain limited in aged adults. Acute high-intensity interval exercise (35), ischemic preconditioning (12), and hypoxic preconditioning (36) all protect against endothelial I/R injury in young adults. However, these benefits do not always translate to aged adults. For example, van den Munckhof et al. (12) demonstrated that ischemic precondition induces a robust protection against endothelial I/R injury in young adults but has limited efficacy in aged adults. Interestingly, lifelong endurance (11) or resistance (37) exercise training exerts a robust protection against endothelial I/R injury in aged adults. However, the implementation of exercise training programs may be challenging, particularly in those aged individuals who are unwilling or unable to exercise. Furthermore, it is unknown if lifelong exercise is a requisite to confer protection or if exercise training undertaken by sedentary individuals at midlife would be equally efficacious. Our results and those of others demonstrate a clear efficacy of heat exposure to protect against endothelial I/R injury across the life span. Thus, heat therapy could fill the current therapeutic gap in aged adults or in many other populations with limitations that prevent participation in exercise training.

Acute heat exposure protects against endothelial I/R injury in young adults, but its efficacy in aged adults who are more at risk for an ischemic event was previously unknown. Our data suggest that acute whole body heat exposure protects against endothelial I/R injury in aged adults, the magnitude of which is similar to that observed in young adults. Our findings highlight the therapeutic potential of heat therapy to improve vascular health in aged adults, and ultimately reduce cardiovascular morbidity and mortality.

SUPPLEMENTAL DATA

Supplemental Table S1: https://doi.org/10.6084/m9.figshare.19122635.v1.

GRANTS

Funding was provided by the National Institutes of Health Grants R01AG059314 and T32AG020494.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

H.W.H. and S.A.R. conceived and designed research; H.W.H., R.E.R., A.M.M., A.H.O-Y., G.P.K., and S.A.R. performed experiments; H.W.H. analyzed data; H.W.H. and S.A.R. interpreted results of experiments; H.W.H. and S.A.R. prepared figures; H.W.H. drafted manuscript; H.W.H., R.E.R., A.M.M., A.H.O-Y., G.P.K., and S.A.R. edited and revised manuscript; H.W.H., R.E.R., A.M.M., A.H.O-Y., G.P.K., and S.A.R. approved final version of manuscript.