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Abstract
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to the editor: We would like to compliment Caldwell et al. (1) on their extremely interesting investigation of successive exertional heat injuries (EHIs) in mice. Hyperthermia can cause devastating consequences, the most severe being exertional heat stroke (EHS), characterized by core temperature (Tcore) > 40.5°C and central nervous system (CNS)-dysfunction. Left untreated, EHS can cause organ failure and death. The authors define EHI as a less severe condition with the absence of CNS abnormalities and fatality (1).
EHS in mice purportedly leads to pathophysiological consequences protracted from the initial injury. Dysfunctional myocardial metabolism emerges after ∼14 days in females only (2). In addition, epigenetic signatures emerge 30 days post-EHS in females consistent with an altered heat shock response and immune suppression in vitro (3). Coupled with epidemiological data suggesting EHS survivors may be more susceptible to disease (4-6) and recurrent EHS later in life (7), these findings provide potential underlying mechanisms.
Caldwell (1) elucidated unexpected findings contrary to previous studies. Male mice ran until loss of consciousness (LOC) or a Tcore > 42.7°C (EHI0), repeating the protocol 1 (EHI1), 3 (EHI3), or 7 (EHI7) days later (1). Surprisingly, mice performed better along with a blunted hypothermic depth during recovery in all subsequent sessions, with the greatest effect in EHI1. Plasma and liver Hsp70 acutely rose the most in EHI1, which is suggested to contribute to this group's transient heat resilience. However, Islam et al. (8) showed higher Hsp72 in liver, muscle, heart, and kidney in heat intolerant compared with tolerant mice. MIP-1β showed a delayed (∼7 days; nonsignificant) rise in EHI1, and it is tempting to speculate a link between the upregulated inflammatory pathways 30 days post-EHS (3). Lastly, corticosterone was suppressed in EHI1 3 h post-EHI and thought to be linked to blunted hypothermic depth (1). If a link exists between the two, one would expect the corticosterone at the 30-min time point to also be suppressed since the hypothermic duration in EHI1 was ∼16 min.
There are a few points to consider. First, the authors state that they induced EHI, however LOC is indeed CNS dysfunction, was a criterion for exercise termination, and CNS-dysfunction without LOC (e.g., disorientation) is observed in human EHS victims. Therefore, how was it determined that CNS-dysfunction without LOC did not occur? Maximal Tcore was identical to Laitano et al.'s work (2), where all mice suffered LOC and allegedly EHS. A consensus should be established delineating EHI versus EHS. Second, sex differences post-EHS (9) (corticosterone, heat tolerance) suggest comparing males and females is warranted. Third, the performance in EHI1 contrasts with heat intolerance after EHS in humans. Although we are not aware of human data suggesting performance benefit after heat illness, testing in our laboratory shows initial heat intolerance with EHS survivors. We acknowledge the authors may disagree given their definition of EHI, but hyperthermia (>40.5°C) + LOC in humans typically constitutes EHS. It would be interesting if mice in previous work would have benefited similarly during successive exposures even considering the observed long-term pathophysiology...
Language: en |