Attenuation of exaggerated blood pressure responses to exercise: a byproduct of improved vascular function with passive heat therapy?

Cardiovascular diseases (CVDs) are the leading cause of mortality in developed societies. An exaggerated blood pressure response to exercise (i.e. one that is in excess of that needed to supply adequate blood flow to working skeletal muscle) is an underappreciated, yet important, indicator of CVD risk. Not only does an exaggerated blood pressure response reduce exercise tolerance, thereby limiting individuals’ abilities to participate in a healthy lifestyle intervention, but it is associated with an as much as 4-fold higher risk of future CVD, even when accounting for traditional CVD risk factors (Miyai et al. 2002). Certain populations, such as those with hypertension or peripheral artery disease (PAD), are predisposed to exaggerated blood pressure responses to exercise, consistent with a greater CVD risk profile. However, this phenomenon is not exclusive to these patient populations – it can also occur in healthy individuals who are normotensive at rest. Furthermore, otherwise healthy individuals who have exaggerated blood pressure responses to exercise also have worse vascular endothelial function and stiffer arteries (two other independent predictors of CVD risk) compared to individuals with normal exercise blood pressure (Sarma et al. 2020). Therefore, identifying interventions that attenuate exaggerated exercise blood pressure may help to reduce the overall risk of CVD and could have significant implications in public health. Although other mechanisms exist, a major contributor to exaggerated blood pressure responses to exercise is a hypersensitive exercise pressor reflex. The exercise pressor reflex is composed of the skeletal muscle mechano- and metabo-reflexes, which respond to mechanical (i.e. muscle contraction) and metabolic (i.e. byproducts of muscle metabolism) stimuli within the working muscle, respectively. One specific receptor that is associated with the metabo-reflex is the purinergic P2X3 receptor, located on the sensory nerves that travel from the skeletal muscle to the spinal cord. Upon activation of P2X3 receptors by elevations in extracellular ATP, which indicates ischaemia in the muscle, the sensory nerves transduce signals to the rostral ventrolateral medulla to increase sympathetic outflow, thereby increasing blood pressure and subsequently blood flow to the exercising muscle. In muscle that experiences recurrent ischaemia during exercise, such as occurs downstream of the atherosclerotic lesions in PAD, abundance and/or sensitivity of P2X3 receptors may increase as a compensatory response to the ischaemia and accumulation of metabolites (Liu et al. 2011). In turn, this contributes to the exaggerated blood pressure responses during exercise that are common in these patients. One healthy lifestyle intervention that has recently gained attention for its widespread beneficial effects on the cardiovascular system is passive heat therapy, i.e. the repeated, chronic use of hot baths or saunas. In epidemiological studies, lifelong passive heat therapy (habitual sauna use) lowers the risk of CVD-related mortality and incident hypertension (Laukkanen et al. 2015). Furthermore, we have shown that a heat therapy intervention (repeated hot water immersion) reduces resting blood pressure (Brunt et al. 2016). As such, heat therapy may be an effective lifestyle intervention for attenuating exaggerated blood pressure responses to exercise. In a recent study published in the Journal of Physiology, Qin et al. (2020) sought to determine if 3 days of lower limb heat treatment could attenuate exaggerated blood pressure responses to exercise via effects on the exercise pressor reflex and P2X3 receptors in a rat model of PAD. Rats underwent either sham surgery (control) or femoral artery ligation of their right hindlimb to create an ischaemic condition via arterial stenosis, comparable to that caused by atherosclerosis in PAD. For heat treatment, two heating pads were placed on the examined limb to raise and maintain gastrocnemius muscle temperature ∼1.5°C above baseline. This procedure lasted 30 min and was performed twice a day for three consecutive days. Rats were then decerebrated to eliminate confounding effects of anaesthesia, and the effects of simulated PAD and heat treatment on the exercise pressor reflex were assessed by static muscle contraction (i.e. mechanical stimulation of the reflex) and α,β-methylene ATP infusion into the femoral artery (i.e. metabolic stimulation). Increases in blood pressure in response to both mechanical and metabolic stimuli were greater in PAD rats compared to controls, but were attenuated to control levels in PAD rats who underwent heat treatment. Interestingly, attenuation of this exaggerated blood pressure response was accompanied by alterations in P2X3 receptor protein levels and sensory nerve firing. PAD rats had a higher abundance of P2X3 receptor protein in the muscle sensory nerves compared to control rats and subsequently greater firing of the sensory nerves, on average, in response to the mechanical and metabolic stimuli; both were suppressed in PAD rats that underwent heat treatment back to control levels. Together, these data indicate that heat treatment attenuates the exaggerated exercise pressor reflex in PAD rats by preventing upregulation of P2X3 receptors. Although addressing other upstream mechanisms was outside the scope of the authors’ investigation, Qin et al. speculated that improved perfusion of the examined limb following heat treatment in PAD rats may have contributed to the observed benefits. We found this notion to be particularly intriguing, as based on our work in this field (e.g. Brunt et al. 2016) and work from other groups, we suggest that much of the cardiovascular benefits of heat treatment/therapy stem from effects on the vasculature. In the context of PAD, greater perfusion following heat treatment may have attenuated ischaemia during exercise, thereby lessening metabolite accumulation in the working muscle, resulting in reduced stimulation of the muscle afferent nerves and subsequently tempering blood pressure responses to exercise. In support of this notion, Pellinger et al. (2019) demonstrated that lower leg heating, for as little as 15 min, increased lower leg perfusion and walking capacity in patients with PAD. Importantly, both of these observations were made 30+ min after heating, i.e. blood flow remained elevated even though the need to direct blood flow to the skin for heat dissipation had subsided, indicating an adaptive response. These improvements in walking capacity, which is commonly limited in PAD patients due to pain associated with metabolite buildup, suggest that passive heating promoted clearance of accumulated metabolites from the exercising muscle. Two mechanisms by which heat treatment may have improved perfusion to the exercising muscle are angiogenesis and improved vascular endothelial function. Angiogenesis, the process by which new blood vessels are formed, may have provided alternative routes for blood to bypass the arterial stenoses. In mice with unilateral femoral artery ligation (i.e. the same model of PAD used by Qin et al.), 3 weeks of infrared sauna therapy increased capillary density and restored resting perfusion to the experimental hindlimbs to levels comparable to the unaffected limb (Akasaki et al. 2006). Given the short duration of heat treatment utilized by Qin et al., it is unclear whether angiogenesis could have contributed substantially enough to account for the attenuation in the exercise pressor reflex that they observed. However, Kuhlenhoelter et al. (2016) demonstrated that, in healthy young individuals, just one session of leg heat treatment increased various pro-angiogenic factors in skeletal muscle. Thus, even short-term heat treatments may be capable of promoting increased tissue perfusion. Additionally, we and others have shown that heat therapy improves vascular endothelial function (Brunt et al. 2016), even following just one session. Romero et al. (2017) observed that 45 min of acute limb heating improved macro- and microvascular endothelium-dependent dilatation in the lower limb of older adults. Improved endothelium-dependent dilatation in smaller arteries and microvasculature at or near the exercising muscle following heat treatment could help to offset PAD-related ischaemia. Both angiogenesis and improved vascular endothelial function with heat therapy are mediated by increased bioavailability of the vasoprotective and vasodilatory molecule nitric oxide (Akasaki et al. 2006). A number of molecular mechanisms have been proposed as upstream modulators of these processes, including upregulation of heat shock proteins, alterations in the profiles of circulating factors and/or reductions in oxidative stress. Due to the overlap of these mechanistic pathways, these factors may promote both angiogenesis and endothelial function simultaneously. Specifically, one session of lower body heating increased expression of heat shock proteins and various circulating factors, and this was associated with upregulation of angiogenic factors (Kuhlenhoelter et al. 2016). In addition to driving improvements in perfusion to facilitate clearance of metabolites, these pathways may also directly interact with the exercise pressor reflex signalling, possibly through altering afferent or sympathetic nerve signal transduction (e.g. via changes in receptor expression/sensitivity or downstream signalling). In conclusion, the study by Qin et al. (2020) adds to the growing body of literature indicating widespread beneficial effects of heat treatment/therapy on the cardiovascular system. Specifically, the authors elucidated a novel mechanistic pathway that may explain, at least in part, the improvements in exercise capacity that have been previously observed in PAD patients following heat treatment (e.g. Pellinger et al. 2019). Here, we suggest that heat treatment-mediated improvements in vascular function and angiogenesis occur upstream of the attenuation of P2X3 receptor expression and exercise pressor reflex activation observed by Qin et al. If true, these findings may also have implications for reducing the risk and/or severity of CVD in other populations besides PAD patients. Attenuating exaggerated blood pressure responses to exercise through heat treatment, and thereby improving exercise tolerance, could allow individuals with otherwise limited exercise capabilities to initiate exercise training programmes and achieve robust improvements in overall cardiovascular health. Thus, the collective literature is providing increasingly convincing evidence that heat therapy, even in small doses, may be a promising alternative and/or adjunctive strategy for reducing CVD-associated morbidity and mortality. None. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The authors are supported by NIH R01 HL134887. The authors would like to thank their mentor, Dr Douglas Seals, for his guidance and support.