Stress‐Induced Cardiomyopathy Following Exertional Heat Stroke in Mice

INTRODUCTION Apparent return to homeostasis may not be the end of concerns for exertional heat stroke (EHS) victims. It is well known that patients with cardiovascular diseases are more prone to develop heat related illnesses due to impaired thermoregulation. Epidemiological data suggest EHS exposure is associated with a ~2.5 times higher risk of long‐sterm cardiovascular disease in humans. However, whether EHS results in cardiovascular disorders remains unknown. OBJECTIVE To determine the potential of EHS to contribute to development of a stress‐induced cardiomyopathy using a preclinical mouse model of EHS. METHODS Male and female C57bl/6J mice underwent forced wheel running for 1.5–3 h in a 37.5°C/40% relative humidity environmental chamber until symptom limitation, characterized by central nervous system dysfunction at peak core temperatures of 42.2 ± 0.3 °C. Sham exercise control mice ran for the same duration as EHS mice at 22.5°C. Myocardial and plasma samples (n = 8/group) were obtained between 30 min −14 d recovery, analyzed using metabolomics/lipidomics platforms and compared to sham exercise controls. Data are presented as fold‐change from control. RESULTS Females ran ~40% longer than males (121.16 ± 22 vs. 189.25 ± 35 min; P < 0.05), with a ~51% greater heat load (240 vs.160°C·min; P < 0.05). The immediate recovery period revealed an acute energy substrate crisis characterized by a ~0.5‐fold decrease in plasma lactate, pyruvate, glucose and fructose at 3 h post EHS ( P < 0.05) from which both sexes recovered within 24 h. At 9–14 d post EHS, the myocardium of female mice developed ~0.5‐fold elevations ( P < 0.05) in free fatty acids, ceramides, and diacylglycerols. Moreover, glycolysis shifted towards the pentose phosphate and glycerol‐3P dehydrogenase pathways. Tricarboxylic acid cycle metabolites revealed bottlenecks in substrate flow and build‐up of intermediate metabolites. These changes are consistent with cardiac metabolic dysfunction observed in chronic heart failure patients. Males exhibited only late stage reductions in acylcarnitines and elevations in acetylcarnitine. CONCLUSIONS We demonstrate that the myocardium of female mice is vulnerable to a slowly emerging metabolic disorder following EHS that may lead to long‐term cardiovascular complications. If these abnormalities persist over time, it raises the possibility that untoward outcomes of severe EHS exposure could emerge later in life. Lack of similar findings in males may reflect their reduced time of heat exposure. Support or Funding Information DOD Grant BA180078. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views of the Army or the DoD.