Passive heat therapy for cerebral protection: new ideas of age‐old concepts

The roots of heat therapy extend far into history, with the earliest known use of heating as a therapy dating back to Egyptian physicians during the fifth century BC who harnessed the heat provided by the sun and natural volcanic hot air caverns. Passive heating is a tradition present today in a diverse range of cultures to promote health and well-being. Across the globe, these traditions differ in details and names – sauna or sweat lodge, onsen or hammam, banya or bath, jimjilbang or hot springs – yet share a unified approach: relaxation in a hot environment. Despite its ancient origins and applications, the association of passive heat therapy and health outcomes are only just emerging, with little understanding of the mechanistic underpinnings of the protective effects of regular heat therapy. In a recent article in The Journal of Physiology, Brunt et al. (2018) sought to identify the potential mechanisms underlying the physiological benefits of passive heat therapy, specifically for protection against cellular stress. By developing an in vitro model of hypoxia–reoxygenation, Brunt and colleagues isolated the effects of heat stress and the influence of circulating factors on endothelial cell protection. Simply heating endothelial cells mitigated the inflammatory and oxidative stress response to hypoxia–reoxygenation. Similar findings were observed after treating cells with serum from participants who completed either one 60 min session or 8 weeks of passive heat therapy (90 min sessions, 4–5 times per week). These results suggest that both local cell temperature and circulating factors confer cellular protection against hypoxia–reoxygenation stress. In vitro hypoxia–reoxygenation models are often used to reflect ischaemia–reperfusion (I/R) in vivo, which is particularly relevant for simulating intra-arterial occlusion models of ischaemic stroke. Stroke is the second leading cause of death worldwide and ischaemic strokes are the most common form (∼85%). Given the high metabolic rate relative to its mass and low substrate storage capacity, the brain is extremely vulnerable to disruptions in oxygen supply. The brain is particularly susceptible to ischaemia; yet, in stroke or following cardiac arrest, the brain can often endure long periods of ischaemia (e.g. only 20% of stroke events arrive at the hospital in <2 h), which quickly lead to cellular hypoxia and neurological damage due to reactive oxygen species (ROS) production during the ischaemic cascade and subsequent reperfusion injury. The I/R injury damage can lead to endothelial dysfunction, paralysis and disrupted abilities to perform activities of daily living if not reversed in a timely manner; thus, strategies are needed to help to protect neurons from I/R damage and the associated risk of dementia. This raises the question of whether the cellular protection observed by Brunt et al. 2018 manifests in neurons or cerebral microvascular endothelial cells. An intriguing avenue of research may be emerging from perennial cultural practices. In >2000 men followed for ∼20 years as part of the Kuopio Ischaemic Heart Disease Risk Factor Study, the risk of dementia and Alzheimer's disease was three times lower in those who more regularly participated in Finnish sauna bathing (Laukkanen et al. 2017). This finding suggests a neuroprotective effect of chronic heat therapy. Of course, the epidemiological nature of this study does not provide a physiological explanation but, importantly, the observations were adjusted for health risk factors, lifestyle and socioeconomic status. Whether heat therapy promotes a resilient brain in humans merits investigation, and the recent data reported by Brunt et al. provide an intriguing hypothesis regarding a potential mechanism to explain the association between sauna bathing and the risk of Alzheimer's disease and cognitive decline (Laukkanen et al. 2017). Given the difficult nature of performing mechanistic studies in the human brain, important information must be gleaned from animal models regarding heat-related mechanisms of cerebral protection following I/R. For example, data indicates that heat preconditioning (e.g. a single exposure to 42°C core temperature for 15 min) provides neuroprotection against cerebral ischaemia in rats via the attenuation of ROS accumulation (Wang et al. 2005). Such benefits appear to occur when heat shock protein (HSP) expression (e.g. HSP72) is increased but not after returning to basal levels, therefore suggesting that heat preconditioning might need to be recent (e.g. <1 week) or of sufficient exposure (e.g. several weeks) to induce chronic HSP elevation. A recent study demonstrated that increased levels of microvascular endothelial HSP27 (achieved using transgenic mice with overexpression of HSP27) preserves the integrity of the blood–brain barrier during I/R and prevents the infiltration of macrophages and neutrophils into the brain parenchyma (Shi et al. 2017). Yacobi et al. (2014) also demonstrated the importance of glutamate receptors during hypoxic insults, which facilitate neuronal death via calcium penetration following a large glutamate surge. In this study, long term (30 days), but not short term (2 days), heat-acclimated rats exhibited lower presence of NMDA GluN1 proteins (i.e. lower receptor density) and reduced calcium permeability, highlighting different mechanisms by which heat acclimation-induced hypoxia cross-tolerance confers neuroprotection (Yacobi et al. 2014). Importantly, these results translated into improved functional outcomes of behaviour assessment in the 30-day heat-acclimated rats following hypoxia, indicating preserved cognitive function (Yacobi et al. 2014). These studies provide evidence to support the hypothesis that, broadly similarly to Brunt et al. (2018), both acute and chronic heat treatment induce beneficial cellular responses and afford at least some level of protection against cellular stress. However, the effects of heat therapy for cerebral protection in humans and its potential mechanisms (e.g. heat vs. circulating factors) remain unknown. Most importantly, whether heat has the capacity to produce clinically relevant outcomes in humans has yet to be tested. The potentially beneficial effects of passive heating on the cerebrovasculature might be counterintuitive. For example, high brain temperatures can increase permeability of the blood–brain barrier and cause hyperthermia-induced hyperventilation leading to cerebral hypoperfusion. Therefore, restricting acute bouts of heating to moderate levels might be necessary to observe cerebrovascular benefits. However, the physiological effects of repeated exposures to heat stress (e.g. reduced blood pressure and artery stiffness, Q10 effect, etc.) could have important implications for preventing cerebral vascular decline. Moreover, physiological acclimation occurs with chronic heating such that basal levels of HSPs are upregulated. Indeed, it has also been suggested that benefits accrued from heat acclimation have a memory-like feature, permitting rapid restoration of previously acquired protection even after the loss of acclimation (Horowitz, 2016). This fascinating feature of retention of some acclimation responses could prove very useful in the consideration of health across the lifespan. Could heat acclimation performed in young adulthood or middle age allow older individuals to more easily re-acclimate and reap the protective health benefits of heating against cognitive decline and dementia? Although it would not be possible to delineate the influences of exercise and heat in isolation, post-exercise heat acclimation protocols might be a potential method of eliciting both shear-mediated and temperature-induced mechanisms of vascular protection. The impact of exercise on overall brain health and cognitive function is well known, but the effects of heat therapy for cerebral protection have not been fully clarified. Exercise offers many additional advantages (endocrine, metabolic, etc.) from heat therapy; therefore, physical activity is an important component of a healthy lifestyle that should not be overlooked. However, as more knowledge of the benefits of heat therapy emerge, its utility as an adjunct therapy may be important in an era of declining physical activity. Moreover, passive heating may be a promising alternative to exercise in populations with larger barriers to exercise (e.g. spinal cord injury, peripheral artery disease, heart failure). Nevertheless, it is now appreciated that heat therapy can reduce cardiovascular risk factors (e.g. blood pressure, central artery stiffness), which are primary risk factors for stroke and cerebrovascular disease. With the application of heat therapy as a traditional health practice spanning diverse cultures and thousands of years, the mounting evidence for its benefits is not surprising. However, it is important to recognize that the majority of the mechanistic data discussed above stem from animal or ex vivo studies, which may not be fully representative of human physiology. Indeed, different experimental conditions, suitability of the animal model and disparity of experimental outcomes all contribute to the lack of translation from animal models to human research. Collectively, these data warrant further investigation of heat acclimation, HSP expression, and their effects on the human cerebral circulation. Regardless, isolating temperature from circulating factors and shear-mediated mechanisms in humans is difficult, if not impossible, and Brunt et al. are therefore commended for their study combining in vitro models with human serum to provide insight on the mechanisms involved in heat therapy. None declared. Both 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. G.B.C. was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Postgraduate Doctoral and Killam Doctoral Scholarships. J.C.T. was supported by an Alexander Graham Bell Doctoral Canada Graduate Scholarship (NSERC). We thank Dr Philip Ainslie for his insightful feedback.

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