Sex differences in long‐term effects of exertional heat stroke on myocardial metabolism

Prolonged exposure to heat, particularly when combined with exercise and high humidity, can put significant strain on the cardiovascular system. Indeed, the combination of exercise and heat stress can greatly challenge the stability of the cardiovascular system, which must perfuse active skeletal muscles and simultaneously perfuse the skin to meet both metabolic and thermoregulatory demands. This competing demand for blood flow to the skin and exercising muscles can alter cardiac function and induce severe circulatory strain – characterized by reductions in cardiac output, stroke volume, arterial pressure, and blood flow to the brain, skin and skeletal muscles – prior to exhaustion (Crandall & Gonzalez-Alonso, 2010). Although the mechanisms underpinning these responses are not well understood, studies contend that several factors interact to transiently depress diastolic and/or systolic function during exercise in hyperthermic conditions. Studies in humans and other animals have reported the occurrence of microscopic abnormalities in the heart following heat stroke – with notable post-mortem findings including myofibrillar degeneration, interstitial oedema, myocardial inflammation and transmural myocardial infarction. However, very few studies have investigated the long-term effects of exertional heat stroke on myocardial function in surviving individuals. Thus far, investigations have been confined to retrospective cohort studies of individuals with a prior history of heat stroke. Although these studies have reported a strong association between heat stroke and subsequent cardiovascular disease, the extent to which the magnitude of heat stress, intensity/duration of exercise (in relevant cases) and sex contribute to increasing the risk of cardiovascular disease later in life, is not completely understood and warrants investigation. In a recent issue of The Journal of Physiology, Laitano et al. (2020) investigated the long-term impact of exertional heat stroke on myocardial metabolism in male and female mice exercised, via forced running wheels, in an environmental chamber at 37.5°C with 40% relative humidity. Animals were exercised until symptom-limited (loss of consciousness) and recovered over a 14-day period. Plasma and myocardial ventricular tissue samples were analysed using metabolomic and lipidomic platforms over the course of the recovery period and histological analysis of ventricular tissue was performed to assess for myocardial lesions. The major findings of the study are: (1) Myocardial glycolytic flux was altered in female mice, post-exertional heat stroke, with a shift towards the pentose phosphate pathway and the glycerol-3-phosphate dehydrogenase pathway late in the recovery period; (2) Flux through the tricarboxylic acid cycle in the female myocardium was suppressed, particularly at the level of isocitrate dehydrogenase; (3) Female mice showed a build-up, albeit gradual, of free fatty acids, ceramides, and diacylglycerols over the course of the 14-day recovery period; (4) Evidence of oxidative stress, myocardial injury, and inflammation were also noted in the female heart; (5) Pronounced changes in the myocardium of male mice were largely absent – except for a late-stage reduction and elevation in myocardial acylcarnitine and acetylcarnitine, respectively. Collectively, the study provides evidence of a gradual emergence of metabolic dysfunction in the female heart following exertional heat stroke, akin to that seen in the failing diabetic heart, that is largely absent in males. The distinct sex-related difference in the long-term effects of exertional heat stroke on cardiovascular health warrants further discussion, particularly in regards to thermoregulation in females. Generally, the thermoregulatory set point – the temperature at which sweating and cutaneous blood flow increase – is lower in females than males. Thus, when performing a comparable degree of work as males or when exposed to hot and humid exercise conditions similar to males, females are likely to store less heat than their male counterparts. In fact, Stephenson and Kolka (1988) noted this difference in thermoregulatory set point between males and females as a likely reason why women must exercise at a higher level of oxygen consumption than men to elevate their core temperature to the same level as men. Interestingly, Laitano et al. (2020) addressed this difference with their preclinical model of exertional heat stroke, acknowledging that while female mice reached a nearly identical peak core temperature to that of males, females were exposed to greater heat and exercise load during the course of the exercise protocol. This observation lends weight to the notion that greater cardiovascular strain and subsequent cardiac dysfunction in the long term would conceivably occur in animals that undergo prolonged exercise in a hot and humid environment – precisely, female mice. An alternate contributory factor that warrants consideration, although not addressed in the study, is the role of the female menstrual cycle and its effect on core temperature and cutaneous blood flow. In menstruating women, core temperature is approximately 0.5°C higher in the luteal phase than in the follicular phase; thus, inducing a higher thermoregulatory set point for the initiation of sweating and cutaneous vasodilation. In hyperthermic conditions, this change can delay the onset of thermoregulatory mechanisms in females, leading to an increased accumulation of heat and potentially placing females at a higher risk for heat-related illnesses. In this study, since female mice showed a greater resistance to hyperthermia than males, it is possible that the oestrus phase of female mice did not play a significant role in the core temperature profiles noted during the exertional heat stroke protocol. Nonetheless, consideration of the oestrus phase of female mice in future studies should be made as it may be useful in determining the contributions of sex differences in temperature regulation during exercise and heat stress and its impact on long-term cardiovascular health. Sex-related differences in morbidity and mortality rates associated with cardiovascular diseases, and the direct link between cardiac function and metabolism, lends credence to the observation that exertional heat stroke impacts long-term cardiovascular health by inducing alterations in myocardial metabolism. In the normal adult heart, fatty acids provide most of the energy – with females relying on fatty acids to a greater extent than males. However, under conditions of stress, the heart adjusts its substrate preference by reducing its reliance on fatty acid oxidation, and increasing glucose metabolism to meet energy demands (Wittnich et al. 2013). Studies have shown that although shifts in substrate preference can be beneficial in maintaining energy supply in the short term, it can become detrimental in the long term. The study by Laitano et al. supports this notion by providing important information to the current pool of evidence. In the first few hours of recovery, post-exertional heat stroke, the authors report an acute energy substrate crisis in both male and female mice, from which both sexes recover within 24 h. However, in the later stages of the recovery period (9 to14 days), the authors note stark differences between the animals, with the myocardium of female mice showing reductions in glucose and other metabolites in the glycolytic pathway, and an accumulation of free fatty acids, ceramides, and diacylglycerols in the myocardium – consistent with conditions of metabolic stress such as that noted in the diabetic heart and the ischaemic heart. From this observation, one can infer that the underlying cause for the distinct sex-related differences in myocardial metabolism post-exertional heat stroke may be attributed to the substrate selection preferences of the female heart. Overall, the importance of the findings of Laitano et al. cannot be understated given the demonstration of large epidemiological studies that exertional heat stroke can induce long-term detrimental effects on cardiovascular health. The authors succeed in highlighting a potential link between exertional heat stroke and long-term alterations in myocardial metabolism, and acknowledge – to some extent – the role sex may play. A potential drawback of the study, however, lies with the experimental design. The rationale provided by the authors in using a 4-day time point – considered a midway point for the 14-day recovery period by the authors – as control for all experimental time points is unsatisfactory. While the authors contend that the animals should have completely recovered from their bout of exercise by day 4, it has not escaped attention that the premise of the study rests on the assumption that an apparent return to homeostasis – as noted in exertional heat stroke patients – is not indicative of health in the long term. Sole author None declared. Antoinette Bugyei-Twum was funded by a CIHR Strategic Training Fellowship (TGF-53877) and a Queen Elizabeth II Heart & Stroke Foundation of Ontario Graduate Scholarships in Science and Technology.

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