Biomarkers of multiorgan injury in a preclinical model of exertional heat stroke

Key points Exposure to exertional heat stroke (EHS) is associated with increased risk of long‐term cardiovascular disorders in humans. We demonstrate that in female mice, severe EHS results in metabolic changes in the myocardium, emerging only after 9–14 days. This was not observed in males that were symptom‐limited at much lower exercise levels and heat loads compared to females. At 14 days of recovery in females, there were marked elevations in myocardial free fatty acids, ceramides and diacylglycerols, consistent with development of underlying cardiac abnormalities. Glycolysis shifted towards the pentose phosphate and glycerol‐3‐phosphate dehydrogenase pathways. There was evidence for oxidative stress, tissue injury and microscopic interstitial inflammation. The tricarboxylic acid cycle and nucleic acid metabolism pathways were also negatively affected. We conclude that exposure to EHS in female mice has the capacity to cause delayed metabolic disorders in the heart that could influence long‐term health. Abstract Exposure to exertional heat stroke (EHS) is associated with a higher risk of long‐term cardiovascular disease in humans. Whether this is a cause‐and‐effect relationship remains unknown. We studied the potential of EHS to contribute to the development of a ‘silent’ form of cardiovascular disease using a preclinical mouse model of EHS. Plasma and ventricular myocardial samples were collected over 14 days of recovery. Male and female C57bl/6J mice underwent forced wheel running for 1.5–3 h in a 37.5°C/40% relative humidity until symptom limitation, characterized by CNS dysfunction. They reached peak core temperatures of 42.2 ± 0.3°C. Females ran ∼40% longer, reaching ∼51% greater heat load. Myocardial and plasma samples (n = 8 per group) were obtained between 30 min and 14 days of recovery, analysed using metabolomics/lipidomics platforms and compared to exercise controls. The immediate recovery period revealed an acute energy substrate crisis from which both sexes recovered within 24 h. However, at 9–14 days, the myocardium of female mice developed marked elevations in free fatty acids, ceramides and diacylglycerols. Glycolytic and tricarboxylic acid cycle metabolites revealed bottlenecks in substrate flow, with build‐up of intermediate metabolites consistent with oxidative stress and damage. Males exhibited only late stage reductions in acylcarnitines and elevations in acetylcarnitine. Histopathology at 14 days showed interstitial inflammation in the female hearts only. The results demonstrate that the myocardium of female mice is vulnerable to a slowly emerging metabolic disorder following EHS that may harbinger long‐term cardiovascular complications. Lack of similar findings in males may reflect their lower heat exposure.

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“…The pre‐clinical model of EHS employed in the current study was previously described in detail (King et al . 2015, 2017; Garcia et al . 2018).…”

Section: Methodsmentioning

confidence: 99%

“…The pre-clinical model of EHS employed in the current study was previously described in detail (King et al 2015(King et al , 2017Garcia et al 2018). Briefly, mice were taken to the lab from the animal facility 24 h prior to the experiment but kept on the same light cycle and in their home cage.…”

Section: Exertional Heat Strokementioning

confidence: 99%

Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

Laitano

Garcia

Mattingly

et al. 2020

The Journal of Physiology

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“…Currently, considerations for recovery and return to activity decisions after exertional heat stroke (EHS) are highly subjective and circumstantial (based on 'best guess' [1]), despite extensive injury characterization in day laborers [2][3][4], religious pilgrims (Hajjis) [5][6][7], athletes [8][9][10], military personnel [11][12][13][14][15][16], and experimental animal models [17][18][19]. Previous studies have failed to build a consensus or generalizable guideline for normalization of clinical laboratory markers following EHS, even though these markers are currently used as the primary indicator of EHS recovery by the American College of Sport Medicine (ACSM), the National Athletic Trainers' Association (NATA), and the United States Army [1,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

“…End-organ injuries are among the defining features of EHS, although initial presentation and diagnosis is established by central nervous system dysfunction with severe hyperthermia [23]. Experimental models of EHS, and autopsies from fatal EHS cases have shown that nearly every organ is impacted [11,19]. This organ and tissue injury is a consequence of the cytotoxic effects of heat, and hypoperfusion of splanchnic tissues due to increased peripheral blood flow [24].…”

Section: Introductionmentioning

confidence: 99%

Biochemical recovery from exertional heat stroke follows a 16-day time course

et al. 2020

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BackgroundThe aim of this study was to characterize the time-resolved progression of clinical laboratory disturbances days-following an exertional heat stroke (EHS). Currently, normalization of organ injury clinical biomarker values is the primary indicator of EHS recovery. However, an archetypical biochemical recovery profile following EHS has not been established. MethodsWe performed a retrospective analysis of EHS patient records in US military personnel from 2008-2014 using the Military Health System Data Repository (MDR). We focused on commonly reported clinical laboratory analytes measured on the day of injury and all proceeding follow-up visits. ResultsOver the prescribed period, there were 2,529 EHS episodes treated at 250 unique treatment locations. Laboratory results, including a standardized set of blood, serum and urine assays, were analyzed from 0-340 days following the initial injury. Indicators of acute kidney injury, including serum electrolyte disturbances and abnormal urinalysis findings, were most prevalent on the day of the injury but normalized within 24-48hours (creatinine, blood urea nitrogen, and blood and protein in urine). Muscle damage and liver function-associated markers peaked 0-4 days after injury and persisted outside their respective reference ranges for 2-16 days (alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, myoglobin, prothrombin time). ConclusionBiochemical recovery from EHS spans a 16-day time course, and markers of end-organ damage exhibit distinct patterns over this period. This analysis underscores the prognostic value of each clinical laboratory analyte and will assist in evaluating EHS patient presentation, injury severity and physiological recovery.

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“…An interesting preclinical detailed model of HS exposed mice to high temperature [14]. It was created to clarify the pathophysiology of HS and it is the first model of HS in mice that resembles human HS.…”

Section: Discussionmentioning

confidence: 99%

Non-Exertional Heatstroke: A Case Report and Review of the Literature

et al. 2017

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Patient: Female, 41Final Diagnosis: HeatstrokeSymptoms: ComaMedication: —Clinical Procedure: Intensive Care Unit-Internal MedicineSpecialty: Critical Care MedicineObjective:Rare co-existance of disease or pathologyBackground:Heatstroke (HS) is a life-threatening condition characterized by an elevation of the core body temperature above 40°C, central nervous system dysfunction, and possible multi-organ failure. HS can trigger systemic inflammation, disseminated intravascular coagulation (DIC), rhabdomyolysis, cerebral edema and seizures, pulmonary edema, heart dysfunctions, and renal and hepatic failure.Case Report:We report the case of a 41-year-old Romanian woman with a history of alcoholism who developed HS after arriving by bus in Verona, Italy in June 2016. The patient developed consecutive multi-organ dysfunction, including liver and renal failure, rhabdomyolysis, DIC, and arrhythmia. The patient was successfully treated with conservative measures. After 17 days, she recovered completely.Conclusions:The exact mechanism of HS-related multiple organ dysfunction is not completely understood and its pathogenesis is complex. It involves inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Development of a model in which chronic alcohol abuse alters oxidative, inflammatory, and ER stress response could also be a conceivable solution to the positive prognosis of severe HS patients, in which liver failure has a prominent role.

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Biomarkers of multiorgan injury in a preclinical model of exertional heat stroke

Cited by 47 publications

References 60 publications

Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

Biochemical recovery from exertional heat stroke follows a 16-day time course

Non-Exertional Heatstroke: A Case Report and Review of the Literature

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