Acute limb heating improves macro- and microvascular dilator function in the leg of aged humans

We demonstrate that lower limb heating acutely improves macro- and microvascular dilator function within the atherosclerotic prone vasculature of the leg in aged adults. These findings provide evidence for a potential therapeutic use of chronic lower limb heating to improve vascular health in primary aging and various disease conditions.

Abstract

Local heating of an extremity increases blood flow and vascular shear stress throughout the arterial tree. Local heating acutely improves macrovascular dilator function in the upper limbs of young healthy adults through a shear stress-dependent mechanism but has no such effect in the lower limbs of this age group. The effect of acute limb heating on dilator function within the atherosclerotic prone vasculature of the lower limbs of aged adults is unknown. Therefore, the purpose of this study was to test the hypothesis that acute lower limb heating improves macro- and microvascular dilator function within the leg vasculature of aged adults. Nine young and nine aged adults immersed their lower limbs at a depth of ~33 cm into a heated (~42°C) circulated water bath for 45 min. Before and 30 min after heating, macro (flow-mediated dilation)- and microvascular (reactive hyperemia) dilator functions were assessed in the lower limb, following 5 min of arterial occlusion, via Doppler ultrasound. Compared with preheat, macrovascular dilator function was unchanged following heating in young adults (P = 0.6) but was improved in aged adults (P = 0.04). Similarly, microvascular dilator function, as assessed by peak reactive hyperemia, was unchanged following heating in young adults (P = 0.1) but was improved in aged adults (P < 0.01). Taken together, these data suggest that acute lower limb heating improves both macro- and microvascular dilator function in an age dependent manner.

NEW & NOTEWORTHY We demonstrate that lower limb heating acutely improves macro- and microvascular dilator function within the atherosclerotic prone vasculature of the leg in aged adults. These findings provide evidence for a potential therapeutic use of chronic lower limb heating to improve vascular health in primary aging and various disease conditions.

in humans, a number of cardiovascular responses accompany passive heat stress (13, 48). In particular, the cutaneous circulation greatly dilates to facilitate heat exchange with the environment. Given this large redistribution of blood to the periphery, cardiac output is increased, owing largely to changes in heart rate, to maintain arterial blood pressure. However, primary aging alters a number of these cardiovascular responses that accompany passive heat stress. For example, cardiac output is reduced in aged adults (38, 39), owing to an attenuated heart rate response as stroke volume is generally maintained due to an augmented Frank-Starling relationship (17). Likewise, structural and functional changes (i.e., attenuated reflex neural and local mechanisms) reduce cutaneous blood flow during passive heat stress in primary aging (21, 22, 27, 29, 36, 38). Despite these age-related differences to passive heat stress, it has been suggested that physiological responses that accompany heat stress (e.g., release of heat shock proteins) may induce beneficial cardiometabolic adaptations in a manner similar to that observed with exercise training (37).

It is well understood that dilator function is reduced in primary aging and is an independent risk factor for the development of atherosclerosis and associated cardiovascular comorbidities such as myocardial infarction and stroke (59). Importantly, this attenuated dilator function spans the arterial tree (40, 43, 52), thereby reducing bulk blood flow through large conducting vessels and reducing perfusion of tissue through the resistance vasculature. Thus prevention or attenuation of vascular dysfunction is critical to the preservation of cardiovascular health and functional capacity with primary aging. Recent investigations have highlighted that acute (58) and chronic (19, 41) limb heating improve macro- and microvascular dilator function in the upper limb of young healthy humans through shear-dependent mechanisms. Interestingly, it appears that the dilator response to acute heating is limb dependent as lower body heating does not improve macrovascular function within the leg of young adults (57). Given that the aging vasculature responds differently to interventions known to alter dilator function acutely in young humans (50), it is possible that the hemodynamic and dilator response to acute limb heating may differ across the lifespan.

Therefore, the purpose of this study was to examine thermal and hemodynamic responses during and following lower limb heating via hot water immersion in young and aged adults. Lower limb heating was chosen as the heating mode to maximize the shear stimulus in the atherosclerotic prone vasculature of the legs (1, 32, 35, 47, 54) without large changes in body core temperature that typically accompany heating of a larger body surface area. We tested the hypothesis that acute limb heating would improve macro- and microvascular dilator function in aged adults following the heating exposure, whereas dilator function would remain unchanged in young adults.

METHODS

Subjects

Subject physical characteristics are shown in Table 1. Written informed consent was obtained from all subjects subsequent to a verbal and written briefing of all experimental procedures. This study was approved by the Institutional Review Boards at the University of Texas Southwestern Medical Center and Texas Health Presbyterian Hospital Dallas and was performed in accordance with the principles outlined in the Declaration of Helsinki. Nine young (5 women) and nine aged (5 women) adults participated in this study. All subjects were free from known cardiometabolic disease. Subjects were deemed healthy following the completion of an in-depth medical history questionnaire and a resting 12-lead electrocardiogram. Subjects were required to abstain from caffeine, supplements, alcohol, and exercise for 24 h before the study. Additionally, subjects reported to the laboratory after an overnight fast. Subjects were required to abstain from over-the-counter or prescription medications at the time of the study. Young female subjects were studied during the early follicular phase of their menstrual cycle (n = 4) or during the placebo phase of oral contraceptive use (n = 1). All aged females were postmenopausal (21 ± 5 yr from cessation of menstruation) and not currently taking hormone replacement therapy.

Table 1.

Subject characteristics

	Group
	Young Adults		Aged Adults
	Men	Women	Men	Women
n	4	5	4	5
Age, yr	28 ± 4	28 ± 5	70 ± 2*	68 ± 4*
Height, cm	174 ± 9	169 ± 8†	172 ± 7	161 ± 3†
Weight, kg	72.2 ± 17.4	76.9 ± 12.9	78.0 ± 4.6	64.7 ± 8.1
Body mass index, kg/m2	23.6 ± 3.3	26.7 ± 3.7	26.1 ± 1.3	24.8 ± 3.2
Heart rate, beats/min	48.5 ± 5.4	61.0 ± 10.1†	50.5 ± 3.3	66.4 ± 8.0†
Mean arterial pressure, mmHg	87.3 ± 11.0	83.6 ± 7.4	102.5 ± 11.3*	96.2 ± 12.2*

Values are means ± SD.

^*P < 0.05 vs. young adults;

^†P < 0.05 vs. men.

Experimental Approach

Subjects reported to the laboratory at 9:00 AM following instrumentation and a ~20-min rest period, and macro- and microvascular dilator functions (described below) were assessed while the subject was supine. Subjects were then moved to the seated position and immersed their lower limbs ~33 cm into a circulating water bath (FootSmart Foot and Leg Bath Massager; FootSmart, Norcross, GA) maintained at a normothermic temperature of ~33°C. To minimize the influence of hydrostatic pressure changes, baseline hemodynamic measures were recorded after 10 min of normothermic leg immersion. Water temperature was then raised rapidly to 42°C, after which, hemodynamics were measured every 15 min during a 45-min heating period. Following heating, subjects immediately removed their legs from the water bath and returned to the supine position. Macro- and microvascular dilator functions were reassessed subsequent to a 30-min recovery period.

Measurements

Preheat and recovery measurements were performed with the subjects in the supine position. Measurements during leg immersion were performed with the subjects in the seated position. Subjects were asked to remain quiet and relaxed during all hemodynamic measurements. Room temperature was maintained at ~23°C throughout the study.

Central hemodynamics.

Arterial blood pressure was measured from the right arm using an automated sphygmomanometer (Tango+; SunTech Medical, Raleigh, NC). Beat-by-beat arterial blood pressure was measured noninvasively by finger photoplethysmography and stroke volume measured via Modelflow (Nexfin; Edwards Life Sciences, Irvine, CA). Heart rate was monitored via electrocardiogram (GE Healthcare, Milwaukee, WI) interfaced with a cardiotachometer (CWE, Ardmore, PA).

Peripheral hemodynamics.

Superficial femoral artery blood velocity and diameter were measured via duplex ultrasonography, ~2–3 cm distal to the common femoral bifurcation using a linear-array transducer (11 MHz; Phillips iE33, Andover, MA) at an insonation angle of 60°. The Doppler ultrasound was interfaced with a computer running custom software to capture blood velocity.

Intestinal, muscle, and skin temperatures.

Body core temperature was measured via a telemetric pill (HQ Palmetto, FL) ingested ~1.5 h before data collection. An implantable thermocouple (IT-18; Physitemp Instruments, Clifton, NJ) was used to measure temperature of the medial gastrocnemius muscle. Briefly, a topical anesthetic (Akorn, Lake Forest, IL) consisting of lidocaine 2.5% and prilocaine 2.5% was applied 45 min before implantation. With the use of a sterile technique, an 18-G catheter was used to implant a thermocouple ~2 cm into the gastrocnemius muscle. After implantation, the catheter was removed, leaving the thermocouple in place, and the site was covered with a transparent sterile medical dressing. Local skin temperature was measured by placing a thermocouple on the skin of the medial calf, immediately adjacent to the muscle temperature measurement site.

Macro- and microvascular dilator function.

Macrovascular dilator function was assessed via endothelial-dependent flow-mediated dilation of the superficial femoral artery in accordance with recent guidelines (56). Microvascular dilator function was assessed simultaneously via lower limb reactive hyperemia (area under the curve and peak reactive hyperemia). These measures of dilator function were performed in the right leg. Briefly, a contoured pneumatic cuff (CC17 contoured thigh cuff; Hokanson, Bellevue WA) was placed on the thigh, ~15 cm distal to the inguinal ligament. Arterial inflow to the lower limb was occluded by rapidly inflating the cuff to 220 mmHg for 5 min (E20 Rapid Cuff Inflator; Hokanson). Before cuff inflation, superficial femoral arterial diameter and blood velocity were recorded during a 1-min baseline period. Recording of these measures resumed 20 s before cuff deflation and continued for 3 min thereafter.

Data and Statistical Analyses

Central hemodynamic and thermal measures were collected at 50 Hz and analyzed offline using commercially available software (Biopac MP150). Data were averaged across 1-min bins at each indicated time point. Blood velocity measurements were determined from Doppler ultrasound audio recordings using an intensity-weighted algorithm (custom software), subsequent to demodulation of forward and reverse Doppler frequencies (9, 45, 46). Vessel diameter was determined using custom edge-detection and wall-tracking software (6, 60). Leg blood flow was calculated as cross-sectional area of the superficial femoral artery multiplied by mean blood velocity (expressed as ml/min). Superficial femoral vascular conductance was calculated by dividing blood flow by mean arterial pressure (expressed as ml·min⁻¹·mmHg⁻¹). Shear rate was calculated by multiplying 8 by the quotient of blood velocity and vessel diameter (expressed as s⁻¹).

Peak diameter measured during flow-mediated dilation was determined using an algorithm previously described by Black and colleagues (6). Reactive hyperemia area under the curve was determined by averaging blood flow (determined via simultaneously acquired diameter and velocity) across 4-s bins for the initial 20 s subsequent to release of arterial occlusion and averaged across 10-s bins thereafter. Vascular conductance was then determined for each bin to account for changes in perfusion pressure. Reactive hyperemia area under the curve was calculated by summing the product of each bin multiplied by its duration in minutes and was normalized for baseline conductance.

Our primary outcome variables were analyzed using a two-way mixed model ANOVA with repeated measures (JMP Pro 12; SAS Institute Cary, NC). Planned comparisons were used to examine specific group-time interactions. General interactions were examined using Tukey’s post hoc procedure. Flow-mediated dilation was assessed using the allometric modeling solution proposed by Atkinson et al. (3, 4), subsequent to verification of the presence of inadequate scaling by examining the slope of the relationship between logarithmically transformed baseline and peak diameter. Additionally, shear rate area under the curve summed through peak diameter was entered into the model as a covariate to account for changes in shear stimulus. Significance was set at P < 0.05. Data are reported as means ± SE unless stated otherwise (e.g., SD is used in Table 1 to demonstrate the heterogeneity in the subject pool).

RESULTS

Intestinal, Muscle, and Skin Temperatures

Thermal responses measured throughout the study are shown in Fig. 1. As expected skin, muscle, and intestinal temperatures increased during lower limb heating for both groups. Notably, when averaged across heating, gastrocnemius muscle temperature increased by 6.7 ± 0.3°C in young adults and 5.7 ± 0.3°C in aged adults (both P < 0.01 vs. 0, P = 0.03 between groups). Likewise, intestinal temperature increased by 0.4 ± 0.1°C in young adults and 0.5 ± 0.1°C in aged adults (both P < 0.01 vs. 0, P = 0.4 between groups). Calf skin (both P < 0.01 vs. preheat) and gastrocnemius muscle (both P < 0.01 vs. preheat) temperatures remained elevated in the recovery period, whereas intestinal temperature remained elevated in the recovery period for only the aged adults (P < 0.01 vs. preheat).

Fig. 1.

Skin (top), gastrocnemius muscle (middle), and intestinal (bottom) temperatures are shown before heating, every 15 min during heating, and 30 min into recovery. Open circles, young adults; black circles, aged adults. *P < 0.05 vs. thermoneutral (33°C) immersion within group; †P < 0.05 vs. young adults at the indicated time point; ‡P < 0.05 vs. preheat for young adults; #P < 0.05 vs. preheat for aged adults.

Central Hemodynamics

Central hemodynamic responses to the applied perturbations are shown in Fig. 2. Relative to normothermic limb immersion, heart rate and cardiac output increased for both groups during lower limb heating (both P < 0.01). However, these responses were lower throughout heating in the aged adults (heart rate: P = 0.04 vs. young adults; cardiac output: P < 0.01 vs. young adults). Notably, preheat mean arterial blood pressure was greater for aged adults (P = 0.04 vs. young adults) but decreased progressively during limb heating such that the age-related difference was negligible by the end of the heating regimen. The reduction in mean arterial blood pressure from preheating baseline persisted into the recovery period for the aged adults only (P = 0.03 vs. preheat).

Fig. 2.

Heart rate (top), cardiac output (middle), and mean arterial blood pressure (bottom) are shown before heating, every 15 min during heating, and 30 min into recovery. Open circles, young adults; black circles, aged adults. *P < 0.05 vs. thermoneutral (33°C) immersion within group; †P < 0.05 vs. young adults at the indicated time point; ‡P < 0.05 vs. preheat for young adults; #P < 0.05 vs. preheat for aged adults.

Peripheral Hemodynamics

Peripheral hemodynamics measured throughout the study are shown in Fig. 3 and Table 2. Superficial femoral artery blood flow and vascular conductance increased for both groups during lower limb heating (both P < 0.01); however, these measures were lower during limb heating in aged adults (both P ≤ 0.01 vs. young adults). Mean shear rate increased for both groups during lower limb heating (both P < 0.01 vs. normothermic limb immersion), but there were no differences in this response between groups (P = 0.3). When averaged across lower limb heating, the superficial femoral artery shear rate increased by 329.3 ± 20.2 s⁻¹ in young adults and 283.4 ± 25.0 s⁻¹ in aged adults (both P < 0.01 vs. 0, P = 0.1 between groups).

Fig. 3.

Superficial femoral artery blood flow (top), vascular conductance (middle), and shear rate (bottom) are shown before heating, every 15 min during heating, and 30 min into recovery. Open circles, young adults; black circles, aged adults. *P < 0.05 vs. thermoneutral (33°C) immersion within group; †P < 0.05 vs. young adults at the indicated time point; ‡P < 0.05 vs. preheat for young adults; #P < 0.05 vs. preheat for aged adults.

Table 2.

Superficial femoral artery shear rate characteristics

	Preheat		Thermoneutral Leg Immersion (33°C)		15-min Heated Leg Immersion (42°C)		30-min Heated Leg Immersion (42°C)		45-min Heated Leg Immersion (42°C)		Recovery
	Young Adults	Aged Adults	Young Adults	Aged Adults	Young Adults	Aged Adults	Young Adults	Aged Adults	Young Adults	Aged Adults	Young Adults	Aged Adults
Antegrade shear rate, s−1	118 ± 14	114 ± 21	79 ± 9	71 ± 11	368 ± 44*	285 ± 43*	387 ± 40*	342 ± 49*	394 ± 39*	355 ± 52*	142 ± 15†	153 ± 25†
Retrograde shear rate, s−1	−61 ± 11	−54 ± 15	−27 ± 2	−25 ± 4	−1 ± 1*	−1 ± 1*	0 ± 0*	−1 ± 1*	0 ± 0*	−1 ± 1*	−51 ± 8†	−35 ± 7†

Values are means ± SE.

^*P < 0.05 vs. thermoneutral (33°C) immersion within group;

^†P < 0.05 vs. preheat within group.

Macro- and Microvascular Dilator Function

Macrovascular dilator function in response to the heating protocol is shown in Fig. 4. Additional hemodynamic measures germane to the assessment of macrovascular dilator function by flow-mediated dilation are presented in Table 3. Preheat superficial femoral artery flow-mediated dilation was lower in aged adults (P < 0.01). Lower limb heating did not change flow-mediated dilation in young adults (P = 0.6 vs. preheat) but increased this variable in aged adults (P = 0.04 vs. preheat). However, despite this increase, flow-mediated dilation tended to remain lower in aged adults in the recovery period (P = 0.06).

Fig. 4.

Macrovascular dilator function, assessed via flow-mediated dilation, is shown before heating and 30 min into recovery. Open bars, young adults; black bars, aged adults. *P < 0.05 vs. preheat; †P < 0.05 vs. young adults at the indicated time point.

Table 3.

Superficial femoral artery hemodynamics during assessment of macrovascular dilator function

	Preheat		Recovery
	Young Adults	Aged Adults	Young Adults	Aged Adults
Baseline diameter, cm	0.657 ± 0.027	0.647 ± 0.045	0.645 ± 0.029*	0.641 ± 0.044*
Peak diameter, cm	0.686 ± 0.025	0.661 ± 0.043	0.674 ± 0.028	0.664 ± 0.044
ΔDiameter, cm	0.029 ± 0.003	0.014 ± 0.003†	0.029 ± 0.002	0.023 ± 0.002*†
Time to peak diameter, s	97.3 ± 13.9	73.3 ± 12.3	85.5 ± 15.3	72.5 ± 8.1
Shear rate AUC	22,739 ± 2,014	23,956 ± 3,729	29,386 ± 2,814*	35,305 ± 6,026*

Values are means ± SE. Shear rate AUC, shear rate area under the curve through peak diameter.

^*P < 0.05 vs. preheat within group;

^†P < 0.05 vs. young adults at indicated time point.

The effect of lower limb heating on microvascular dilator function is shown in Fig. 5. Preheat reactive hyperemia area under the curve did not differ between groups (P = 0.8). Lower limb heating increased reactive hyperemia area under the curve for both groups (both P < 0.01 vs. preheat). However, this increase did not differ between groups (P = 0.4). Peak reactive hyperemia tended to be lower in aged adults during the preheating period (P = 0.07). Furthermore, lower limb heating did not change peak reactive hyperemia in young adults (P = 0.1 vs. preheat) but did increase it in aged adults (P < 0.01 vs. preheat) such that the age-related difference in peak reactive hyperemia was negligible (P = 0.2).

Fig. 5.

Microvascular dilator function, assessed via reactive hyperemia area under the curve (left) and peak reactive hyperemia (right), is shown before heating and 30 min into recovery. AUC, area under the curve. Open bars, young adults; black bars, aged adults. *P < 0.05 vs. preheat; †P = 0.07 vs. young adults at the indicated time point.

DISCUSSION

The purpose of this study was to examine the effect of acute lower limb heating, via hot water immersion, on macro- and microvascular dilator function in young and aged adults. In partial agreement with our hypothesis, we found that acute lower limb heating improved both macro- and microvascular dilator function in aged adults. However, in young adults, we found that acute heating only improved microvascular dilator function, when assessed as reactive hyperemia area under the curve but not when assessed by peak reactive hyperemia. Taken together, these findings suggest that acute lower limb heating, via hot water immersion, improves dilator function in an age-dependent manner.

Age, Vascular Function, and Acute Limb Heating

It is well understood that upper limb endothelial-dependent macrovascular dilator function is reduced with advancing age (15, 51, 52), even in the absence of overt cardiovascular disease (11). In agreement with prior work (43, 50), we also observed an age-related decline in endothelial-dependent macrovascular dilator function of the lower limb. Importantly, our data also demonstrate that the attenuated macrovascular dilator function in aged adults is not exclusively quiescent but is amenable acutely by limb heating. Interestingly, we found that macrovascular dilator function was unchanged in the lower limb of young adults following acute heating, an observation supported by recent work from Thomas and colleagues using lower body hot water immersion (57). It is unclear why the dilator response to acute heating differs between young and aged adults. It is possible that lower limb heating of this magnitude and duration is not severe enough to improve macrovascular dilator in the young adults. However, although speculative, we believe this differing response may be due to a “ceiling effect,” which prevents further improvements in young adults who express a healthy endothelium. Conversely, improvements are observed in aged individuals who express endothelial dysfunction as they have room for improvement. A similar observation has been reported following acute shear rate manipulation. Specifically, Schreuder et al. (49, 50) demonstrated that acute increases in retrograde shear rate attenuated endothelial-dependent dilator function in the brachial and superficial femoral arteries of young adults but had no effect in aged adults. Thus it appears that the effectiveness of a stimulus in changing dilator function can be altered across the lifespan. These observations suggest that a functional endothelium can become dysfunctional, whereas a dysfunctional endothelium can become more functional.

Attenuated dilator function associated with aging spans the entire vascular tree, from large conducting vessels to the microvasculature perfusing tissue (40, 51, 52). When assessed by reactive hyperemia area under the curve, we found that acute limb heating increased microvascular dilator function in both groups, indicating an improved ability of the downstream resistance vasculature to dilate. However, peak reactive hyperemia, which was attenuated at baseline in the aged adults, increased only in aged adults following acute limb heating. It is unclear why such a difference exists between these two measures of microvascular dilator function. Nevertheless, it is important to recognize that peak reactive hyperemia is highly predictive of future cardiovascular events in healthy and diseased populations (2, 23). Moreover, an apparent age-related decline in microvascular dilator function emerges when assessed by peak reactive hyperemia, suggesting this technique may offer an improved sensitivity to detect microvascular dysfunction. Taken together, our results indicate that acute limb heating, via hot water immersion, improves macro- and microvascular dilator function in aged adults.

Possible Mechanisms of Improved Dilator Function

Endothelial cells express a number of mechanoreceptors that sense changes in shear stress magnitude, direction, amplitude, and frequency (5). These mechanoreceptors then transduce these physical signals into alterations in vessel function through numerous signaling pathways within the endothelium and vascular smooth muscle, some of which are related to the formation of vasodilator substances such as nitric oxide and alterations in cellular oxidative stress and inflammation (34). Moreover, vascular function can be altered directly through shear-activated ion channels such as inwardly rectifying potassium channels and Na⁺-K⁺-ATPase (26). Importantly, these mechanisms have been implicated in the regulation and/or modulation of flow-mediated dilation and reactive hyperemia in humans (14, 16, 31). Therefore, given that lower limb heating greatly increases limb blood flow and shear stress in both conduit and resistance vessels of the leg (12, 20), it is reasonable to hypothesize that elevated shear stress and associated signaling mechanisms mediate the acute improvement in lower limb dilator function following heating. In support of this, Tinken et al. (58) demonstrated that the improvement in brachial artery dilator function following acute heating in younger adults is inhibited when the rise in shear stress is minimized via unilateral cuff inflation.

As highlighted recently, the formation of heat shock proteins during periods of elevated body core temperature may improve dilator function through various signaling mechanisms (37). Averaged across both groups, intestinal temperature increased by ~0.7°C with 45 min of lower limb heating and remained elevated 30 min into the recovery period in only aged adults. It is unclear if this modest increase in body core temperature reached the temperature threshold necessary for induction of heat shock proteins. However, given that muscle temperature increased by ~7.0°C (averaged across both groups) and remained elevated in recovery, it is possible that the induction of heat shock proteins may occur locally within the leg irrespective of body core temperature. Future work is necessary to determine the magnitude of heat shock protein induction with lower limb heating and whether this occurs within the heated muscle and/or if the proteins can be detected.

Arterial Blood Pressure Responses Following Acute Limb Heating

In aged adults, acute limb heating induced a profound reduction in arterial blood pressure, whereas blood pressure was well maintained in young adults. In young adults, cardiac output was appreciably elevated by the heating stimulus, thus offsetting elevated peripheral vasodilation and thereby maintaining arterial blood pressure. However, in aged adults, peripheral vasodilation was not completely offset by increases in cardiac output, suggesting a fundamental alteration of the neural mechanisms regulating arterial blood pressure following acute lower limb heating. Further research is needed to determine the precise mechanism/s mediating reductions in arterial blood pressure following acute lower limb heating.

Experimental Considerations

Our experimental approach was designed to examine the acute thermal and hemodynamic responses to lower limb heating in young and aged adults. The extent to which these positive changes persist following the observed recovery period (30 min postheating) is unclear. Furthermore, it is uncertain if the observed responses improve long-term vascular health. That said, it is tempting to speculate that the acute improvements in dilator function provide a “window” into long-term adaptations that might occur with chronic lower limb heating. Further work is necessary to determine if chronic lower limb heating can reverse or attenuate vascular dysfunction associated with primary aging.

Microvascular dilator function, as assessed via reactive hyperemia, is thought to reflect function within both the cutaneous and skeletal muscle vasculatures. It is well understood that the cutaneous circulation is highly responsive to elevated temperatures. As such, one might presume that the change in microvascular dilator function following limb heating is driven exclusively by changes in the cutaneous circulation. However, recent work suggests that skeletal muscle blood flow is elevated during lower limb heating (12, 20, 28). Therefore, it is likely that the acute improvement in microvascular function occurs as a result of shear stress-dependent and heat-dependent alterations within both the cutaneous and skeletal muscle vascular beds. However, the contribution of each vascular bed to the overall response remains unclear.

Finally, a number of methodological considerations should be noted. First, we cannot say with certainty that endothelial-independent (i.e., smooth muscle) function is not driving the heightened macrovascular dilatory response observed following heating in aged adults. Second, while studying younger women in the early follicular phase (when sex hormones are low) likely reduces data variability, it cannot completely mitigate the effect of sex hormones within and between sexes. Thus some of the variability in the thermoregulatory and vascular findings may originate from the potential effects of differing levels of sex hormones between subjects. Third, given that Modelflow estimates of stroke volume/cardiac output and other waveform-derived indexes (e.g., arterial pressure via Peňáz) can be problematic with substantially more profound heat stress than that imposed herein (18, 53), these values in the present study should be interpreted judiciously. Fourth, the translation of the observed changes in flow-mediated dilation and reactive hyperemia into a clinically meaningful outcome is difficult, especially given the acute nature of the intervention. Clearly, a more meaningful approach would be a chronic heating paradigm designed to improve dilator function in addition to clinically relevant outcomes (e.g., functional capacity) so that the translatability of findings can be put into perspective. Finally, given the modest improvement in macrovascular function, one might presume that this change is clinically irrelevant. However, a recent meta-analysis (25) suggested that a reduction in brachial artery flow-mediated dilation of 1% is clinically meaningful as it increases the risk for future cardiovascular events by 13%. While we do not know if an improvement in flow-mediated dilation by 1% can reduce the risk for future cardiovascular events, this does suggest that even small changes in dilator function are important and clinically relevant. Furthermore, it should also be noted that the macrovascular dilatory response is critically dependent on the baseline diameter of the imaged vessel. That is, larger vessels, such as the superficial femoral artery, dilate less than other vessels with a much smaller diameter (brachial artery). Thus it is possible that any improvement in a vessel that is “more resistant” to flow-mediated dilation is, in our view, meaningful.

Perspectives

Over the last decade, “thermal therapy” has gained attention as a novel therapeutic strategy to improve cardiovascular health and functional capacity in healthy and diseased populations (7, 8, 24, 30, 33, 37, 42). In healthy individuals, chronic whole body heating improves various measures of vascular health (7, 8, 10, 41). In clinical populations, chronic whole body heating increases 6-min walk distance and improves vascular and cardiac function in patients with chronic heart failure (30, 44). Furthermore, Tei et al. (55) reported in patients with peripheral artery disease that 10 wk of whole body heating (via far infrared-ray dry sauna blanket warming) increased ankle brachial index, increased performance on a 6-min walk test, improved leg perfusion, and augmented collateral vessel growth. These findings provide convincing evidence that thermal therapy can improve cardiovascular health and functional capacity. However, whole body heating of this magnitude and duration may increase the risk for heat illness, especially in diseased populations. Moreover, the applicability of using whole body heating via sauna or hot water immersion is uncertain as equipment cost is substantial and compliance may be low if patients are required to travel if they cannot afford in-home therapy. The current study raises the possibility that targeted heating of the lower extremities may be an alternative approach that is safe and inexpensive and yet effective at improving cardiovascular health and functional capacity in healthy and diseased populations with physical limitations such as peripheral artery disease or spinal cord injury. Furthermore, because lower limb heating via hot water immersion can be performed easily in home, therapeutic compliance is likely to be much greater than what might be expected if patients had to travel to a treatment facility.

Summary

Passive heat stress induces substantial changes to the human cardiovascular system. In this study, we utilized lower limb heating, via hot water immersion, to increase peripheral blood flow and shear rate. Our findings demonstrate that acute lower limb heating improves macro- and microvascular dilator function within the aging vasculature. These findings provide evidence for the prospective therapeutic use of chronic lower limb heating to improve vascular health.

GRANTS

This research was funded by the National Institute of General Medical Science Grants GM-068865 and GM-117693.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

S.A.R., D.G., and C.G.C. conception and design of research; S.A.R., D.G., A.N.A., M.N.C., K.K., and C.G.C. performed experiments; S.A.R., D.G., A.N.A., M.N.C., K.K., and C.G.C. analyzed data; S.A.R., D.G., A.N.A., M.N.C., K.K., and C.G.C. interpreted results of experiments; S.A.R. drafted the manuscript; D.G., A.N.A., M.N.C., K.K., and C.G.C. edited and revised manuscript; D.G., A.N.A., M.N.C., K.K., and C.G.C. approved final version of manuscript.