Primer

Classic and exertional heatstroke

Abderrezak Bouchama 1 ✉, Bisher Abuyassin1, Cynthia Lehe1, Orlando Laitano2,
Ollie Jay3, Francis G. O’Connor4 and Lisa R. Leon5
Abstract | In the past two decades, record-breaking heatwaves have caused an increasing number
of heat-​related deaths, including heatstroke, globally. Heatstroke is a heat illness characterized by
the rapid rise of core body temperature above 40 °C and central nervous system dysfunction. It is
categorized as classic when it results from passive exposure to extreme environmental heat and as
exertional when it develops during strenuous exercise. Classic heatstroke occurs in epidemic form
and contributes to 9–37% of heat-​related fatalities during heatwaves. Exertional heatstroke sporad-
ically affects predominantly young and healthy individuals. Under intensive care, mortality reaches
26.5% and 63.2% in exertional and classic heatstroke, respectively. Pathological studies disclose
endothelial cell injury, inflammation, widespread thrombosis and bleeding in most organs. Survivors
of heatstroke may experience long-​term neurological and cardiovascular complications with a per-
sistent risk of death. No specific therapy other than rapid cooling is available. Physiological and
morphological factors contribute to the susceptibility to heatstroke. Future research should
identify genetic factors that further describe individual heat illness risk and form the basis of
precision-based public health response. Prioritizing research towards fundamental mechanism
and diagnostic biomarker discovery is crucial for the design of specific management approaches.

1
King Abdullah International Heatstroke is a life-​threatening illness typically associated Owing to anthropogenic climate change, the fre-
Medical Research Center, with an uncontrolled rise in core body temperature above quency of severe heatwaves has increased worldwide,
Experimental Medicine 40 °C and central nervous system (CNS) dysfunction, especially over the past two decades 10–13. Decadal
Department, King Saud bin
such as delirium, convulsions or coma1. Classic heatstroke increases in heatwave duration, frequency and cumu-
Abdulaziz University for
Health Sciences, Ministry of
(CHS) results from passive exposure to high ambient lative heat since 1950 continue to accelerate in almost
National Guard — Health temperatures often accompanied by high humidity and all global regions10. For example, in the USA, the num-
Affairs, Riyadh, Saudi Arabia. occurs in epidemic form during heatwaves, particularly ber of heatwaves tripled to six per year between 1960
2
Department of Nutrition & among older individuals who often have pre-​existing and 2010 (ref.13). Heatstroke is believed to account for
Integrative Physiology, illnesses1,2. Exertional heatstroke (EHS) typically occurs a substantial proportion of the morbidity and mortal-
College of Health and Human
in otherwise healthy younger individuals during vigorous ity that occur during heatwaves14–18. Data from the USA
Sciences, Florida State
University, Tallahassee,
exercise in hot or temperate environments. It is usually and Europe indicate that it may contribute to 9–37% of
FL, USA. observed in recreational and elite athletes, as well as in fatalities during heatwaves14–16. Furthermore, a third
3
Faculty of Medicine and military personnel and occupational workers2. A factor of the human population worldwide is exposed to possi-
Health, University of Sydney, that distinguishes EHS from CHS is the participation of bly deadly environmental heat for >20 days each year19.
Sydney, New South Wales, skeletal muscle contraction, which generates large quanti- If no mitigating measures to reduce greenhouse gases are
Australia.
ties of metabolic heat that cannot be sufficiently dissipated taken, this is anticipated to rise to 78% of the population
4
Military and Emergency to prevent critical levels of internal body heat storage3,4. within a few decades19. Hence, the health threat from
Medicine, Uniformed Services
University, Bethesda,
Regardless of aetiology, heatstroke manifests at clinical heatwaves has emerged as a global public health chal-
MD, USA. presentation as a systemic illness that includes encepha- lenge for the twenty-​first century with genuine concern
5
Thermal and Mountain lopathy, hypotension, respiratory failure, liver, muscle and at the individual, health system and societal levels19–22.
Medicine Division, United kidney injury, coagulopathy, vomiting and diarrhoea2,5–7. Hyperthermia due to exposure to exogenous or
States Army Research The first accounts of CHS were attributed to endogenous heat production is a considerable stressor for
Institute of Environmental Hippocrates who described around 400 bc how the humans23–27. Within just a few hours, heat may damage
Medicine, Natick,
Massachusetts, USA.
heat from the sun could lead to fevers and convulsions8. proteins, lipids and nucleic acids, which are central to the
✉e-​mail: bouchamaab@ Nevertheless, a contemporary link between heat stress, structure and function of cells, potentially culminating in
ngha.med.sa hyperthermia and the clinical manifestations of heat- multiple organ damage and death24,27–29. In defence against
https://doi.org/10.1038/ stroke was recognized only in the twentieth century extreme heat stress, thermoregulation and the heat stress
s41572-021-00334-6 following the advent of clinical thermometry9. response (HSR), a gene expression programme conserved

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across species, are activated to maintain core body tem- 0.52 per 100,000 population (patients >65 years of age)36.
perature and homeostatic balance, respectively24–27,30–34. In Japan, 7,502 deaths due to heat illness occurred from
According to current knowledge, heat stress develops into 1970 to 2009; however, the number of heat-​related deaths
heatstroke owing to the incapacity of thermoregulation differed substantially between years (219 deaths in 2009
to maintain core temperature within a range compati- and 1,684 in 2010), possibly owing to a varying number
ble with molecular and cellular functions1. In addition, of days with high temperature in these years37. In the
inability of the HSR to preserve homeostasis, mainly central region of France, heat-​related illnesses, including
proteostasis, has been suggested to have a role1. heatstroke, hyperthermia and dehydration, accounted for
In this Primer on CHS and EHS, we describe the epi- 0.9% of fatalities during a normal summer without heat-
demiology of heatstroke and the latest understanding waves compared with cancer (30.4%) and cardiovascular
of thermoregulation and the HSR, the two fundamen- diseases (30.2%)38. This proportion jumped markedly to
tal mechanisms for human adaptation and survival in 28.9% in the summer heatwave of 2003 (ref.38). Hence,
extreme heat stress, including likely mechanisms of their the public health effects of extreme environmental
failure and pathophysiological processes that result in heat must be appreciated during heatwaves.
heatstroke. We discuss heatstroke diagnosis and meas- The devastating health effects of heatwaves are best
ures for prevention, as well as therapeutic strategies illustrated by heat-​related morbidity and mortality
to reduce heatstroke-​related mortality and morbidity. statistics estimated retrospectively as excess hospital
Finally, we provide an overview of long-​term complica- visits to emergency departments, hospital admissions
tions in patients with heatstroke and highlight important or deaths following major heatwaves15–17,37–45 (Table 1).
areas for future research. Presentations of CHS often surpass those of other
disease categories that are the typical causes of hospi-
Epidemiology tal admission18 and, during some heatwaves, have led
Classic heatstroke to overwhelmed medical emergency transport46 and
CHS is common in hot climatic regions; for exam- severe bed shortages39. In addition to the stress on local
ple, during the mass gathering of Muslim pilgrims in health-​care systems, the number of deaths attributed to
the holy city of Makkah located in the desert of Saudi heat was extraordinarily high during heatwave periods,
Arabia, heatstroke incidence increased from 22 to 250 but the precise proportion of deaths due to heatstroke
per 100,000 pilgrims as the date of the gathering moved itself remains poorly defined14–17,41,47. Quantification of
from October to August35. In temperate or cold climates, heat-​related morbidity and deaths is challenging and
heat-​related deaths, including heatstroke, are relatively generated data must be interpreted cautiously (Box 1).
infrequent. From 1999 to 2010, 8,081 heat-​related deaths Diagnosing CHS in those patients who reach hos-
were reported in the USA, of which nearly two-​thirds pitals is reasonably straightforward. Most display the
occurred in summertime 36. During this time, the archetypical signs of high core body temperature and
crude heat-​related death rate varied with age from 0.15 neurological alterations during heatwaves. Thus, if the
per 100,000 population (patients >35 years of age) to patient subsequently dies, death can be unambiguously
attributed to heatstroke. However, difficulties arise for the
Table 1 | Classic heatstroke morbidity and mortality during major heatwaves high number of people who succumb outside health facil-
ities during heatwaves. CHS happens in epidemic form,
Heatwave Year Event Refs
location and its natural course is swift, resulting in death in <24 h
if not recognized and treated. During the French and US
Chicago, USA 1995 1,072 (11% increase) excess hospitalizations; 17,45

heatstroke leading cause of >700 excess deaths

heatwaves, 47% and 61% of the people with CHS, respec-
in 7 days tively, were admitted to hospital or died within 24 h of the
documented onset of CHS14,16,48. Half of the 1,000 patients
France 2003 2,600 excess emergency department visits in Paris; 15,38,39

1,900 excess hospitalizations and 475 excess deaths who died of CHS during the 1987 pilgrimage to Makkah
in 14 days; 14,729 excess deaths in France (1,313 failed to reach a hospital35. Attributing death to CHS in
confirmed classic heatstroke-​related deaths) these instances is difficult owing to the lack of reliable
Western Europe 2003 >70,000 excess deathsa; three heatwaves ranging 41 diagnostic criteria either before or after death, including
(16 countries) from 4 to 20 days biochemical markers, or histological and/or immunohis-
California, USA 2006 16,166 excess emergency department visits in 15 days 42 tochemistry changes49–51. Clear, standardized criteria have
been recommended to circumvent this problem49 (Box 1).
Russia 2010 55,000 excess deaths in ~36 days
a 47
However, these criteria are essentially based on the meas-
Karachi, Pakistan 2015 1,220 deaths due to heatstroke in ~30 daysb 40
ured core body temperature, which is often either not
Japan 2018 34,147 heat-​related emergency transports 46 recorded or measured when it has dropped. As a result,
(997 confirmed heatstroke) in 11 days death is not certified as due to heatstroke, underestimating
United Kingdom 2019 892 excess deathsa; three heatwaves of duration 2, 43 the incidence of heatstroke fatalities.
6 and 7 days
France 2019 ~1,435 excess deathsa in two heatwaves of duration 312 Exertional heatstroke
7 and 13 days Although EHS is already classified as the third leading
British Columbia, 2021 526 heat-​related deathsa in 6 days 44 cause of death in athletes during physical activity, its
Canada prevalence is likely underestimated52. Several factors
a
Proportion caused by classic heatstroke unknown. bOnly death certificates with complete complicate its clinical diagnosis, such as prompt treat-
information used; likely underestimation of actual mortality. ment at the site of collapse without clinical reporting,

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Box 1 | Quantifying heat-​related morbidity and mortality Thermoregulation

Normothermia. Core body temperature is critical for
Various methods are used to quantify heat-​related morbidity and mortality. Owing to molecular and cellular functions and is, therefore, main-
a lack of definitions and varying baseline criteria, generated data must be interpreted tained very tightly in a narrow range30–33. The rectal
cautiously. In general, heat-​related morbidity (derived from emergency department temperature of a healthy human is regulated between
visits and hospital admission) and mortality during heatwaves are estimated
36.7 °C and 37.5 °C. This core temperature range is
retrospectively.
considered a thermoneutral zone, in which it can fluc-
Calculating excess morbidity and mortality tuate without evoking autonomic thermoregulatory
• Excess morbidity and mortality are calculated as the difference between observed mechanisms31–33.
morbidity and deaths during a heatwave period and morbidity and deaths during the When exposed to endogenous and/or exogenous
same period in the previous years without heatwaves. heat stress, core temperature is maintained within safe
• Excess deaths are grouped and classified under the category of heat-​related deaths, limits by the transport of internally generated heat to
which includes heatstroke and chronic medical conditions aggravated by heat, the skin and subsequent dissipation from the skin
particularly cardiovascular diseases.
to the surrounding environment (Fig. 1). High ambient
• The generated data must be interpreted cautiously. First, no standard method for temperatures reverse the temperature gradient between
quantifying excess deaths exists, which precludes comparisons between studies.
skin and air, changing the dry heat transfer processes
Second, quantification methods differ owing to varying baseline time periods,
analytical models and affected populations.
of convection and radiation from heat loss to heat gain.
High ambient humidity further blunts sweat evapora-
Fundamental challenges to accurate quantification tion. Hence, in hot and humid conditions, especially
• No universal definitions of heatstroke death and non-​heatstroke heat-​related deaths when combined with physical activity, there is a high
exist, so untangling the causes of heat-​related death is difficult. risk of a sustained imbalance between internal metabolic
• Attribution of death to heatstroke is challenging because of the lack of reliable heat production and net heat dissipation from the skin,
diagnostic criteria. Post-​mortem histological changes, immunohistochemistry resulting in continuous body storage and constantly ris-
findings and biochemical markers are not specific. The diagnosis of heatstroke death ing core temperature, which can evolve into heatstroke
is primarily achieved by eliminating other causes of death and using situational if left unchecked.
indicators, such as body temperature upon collapse of ≥40.6 °C. If the body Skeletal muscle constitutes almost half of total body
temperature has been lowered through cooling, mental status alterations and
mass in humans and other mammals and is the main
increased liver and muscle enzyme levels can be evidence of heatstroke49.
contributor to endogenous heat production during phys-
• Death is designated as heat-​related when the ante-​mortem body temperature is not
ical activity3,4. Skeletal muscle contractions rely on the
available but evidence of high ambient temperature at the time of collapse exists.
energy released by the hydrolysis of ATP into ADP3,4.
• These criteria can lead to misclassification, as heatstroke death is based on core body
A large proportion of this energy is released as meta-
temperature, which is either measured belatedly when it is already low or not
recorded and because heatstroke is often missing in death certificates, resulting in
bolic heat depending on the mechanical efficiency of
misclassification and an underestimation of the incidence of heatstroke mortality. that activity. From the perspective of whole-​body heat
balance, sitting, or walking or running on a flat surface
results in zero-​sum external mechanical work because
misdiagnosis due to overlapping signs and symptoms any positive external work that is produced is counter-
with other exercise-​induced conditions (for example, balanced by equal quantities of negative work, meaning
hyponatraemia, hypotension and hypoglycaemia), body all metabolic energy ultimately becomes heat energy that
temperature recordings at peripheral sites (for example, must be dissipated to the surrounding environment62.
axilla, tympanic membrane or forehead), which are often Cycling is the most mechanically efficient activity with
inaccurate, or after cooling, which results in an under- 20–25% of energy converted into the external work
estimation of core temperature. Thus, determining the needed to overcome the forces resisting wheel motion,
incidence and prevalence of EHS with precision is chal- such as friction63. A rise in core temperature during
lenging and very few data are available52. Most epidemi- physical activity correlates with the rate of metabolic
ological studies report the incidence of exertional heat heat production per unit of total body mass, irrespec-
illnesses, including heat cramps and heat exhaustion tive of exercise intensity relative to aerobic capacity
instead of EHS specifically, owing to the small number of (%VO2max)64–66. The metabolic heat produced by skel-
cases53,54. Nonetheless, large data sets that evaluated EHS etal muscle is a substantial contributor to hyperthermia
during long-​distance road races reported an incidence during EHS but is broadly absent during CHS.
ranging between 1.6 and 2.13 per 1,000 finishers in the
civilian population without mortality55,56. A systematic Hyperthermia. An increase in skin or internal organ
review on exertional heat illnesses in the military glob- heat is sensed by thermosensors, including transient
ally reported an incidence range of 0.2–10.5 per 1,000 receptor potential (TRP) channels, expressed in their
person-​years and prevalence of 0.3–9.3%57. Mortality of cell membranes31,32,34 (Fig. 2a). TRP channels are mem-
EHS varies widely across studies and ranges between 2% bers of a superfamily of cation channel thermore-
and 26.5%; however, differences in study design preclude ceptors, evolutionarily conserved across species31,32,34.
comparison58–61. The TRP channels discriminate cold, warm and noxious
hot and cold, covering the entire range of temperatures
Mechanisms sensed by mammals31,32,34. Thermosensory information
Full understanding of the pathogenesis of heatstroke propagates as action potentials to composite set-​points
requires knowledge of the host thermoregulatory and located within a complex neuroanatomical circuitry
heat stress responses to extreme heat stress24–27,30–32. in the CNS to elicit thermoregulatory responses31,32,34.

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The circuitry includes the spinal cord, the cortical must be supported by a greater than twofold increase in
somatosensory system, the thalamus and the hypo- cardiac output and a concurrent reduction in splanch-
thalamus preoptic area. The primary somatosensory nic and kidney blood flow to maintain arterial blood
cortex perceives the skin or internal temperature and pressure67,68. Simultaneously, central blood volume
elicits behavioural responses 31,34. The preoptic area and preload are decreased. Thus, the rise in cardiac
responds better to changes in core body temperature output must be achieved by tachycardia and increased
and mediates the autonomic responses31,34. Efferent vol- myocardial contractility, which require elevated levels
untary responses include escaping the heat by seeking of myocardial oxygen consumption67,68. Furthermore,
a cold environment or shedding clothing. Involuntary sweating rates can typically reach 1–2 l/h and, if lost
responses consist of increasing cutaneous blood flow body water stores are not replenished, hypovolaemia
and cardiac output to hasten the transport of heat from occurs, thereby further elevating cardiovascular strain33.
the core to the skin surface for heat dissipation to the Exercise in the heat increases cardiovascular strain fur-
surrounding environment and initiating sweating via ther, as the available cardiac output is divided between
cholinergic pathways31,33,34. the skin for thermoregulation and actively contracting
The need to rapidly transport heat via the blood- muscles that require high oxygen delivery70.
stream from the body core and contracting skeletal
muscles to the cutaneous circulation generates con- Overload of thermoregulation. Human thermoreg-
siderable cardiovascular strain, which can be fatal in ulation obeys the laws of thermodynamics on heat
individuals with existing cardiovascular disease67–69. transfer33,71 (Fig. 1). Accordingly, theoretical environ-
Heat increases the sympathetic nerve activity, leading mental thresholds can exceed human thermoregulatory
to cutaneous vasodilation and massive elevations in capacity to maintain core body temperature compati-
cutaneous blood flow, up to around two-​thirds of the ble with life even in the healthiest individuals71,72. This
cardiac output67,68. This redistribution of blood flow threshold of heat tolerability has been estimated as a

Pair

Evaporation
Pskin – Pair
Modified by v

Convection
Tskin – Tair
Modified by v
Radiation
Tskin – Trad
Tcore
41 °C
40 °C Tskin
39 °C 39 °C
38 °C 38 °C
37 °C 37 °C
36 °C 36 °C
35 °C
34 °C
33 °C

Internal Net heat Internal 32 °C

heat – loss to = body heat Tcore
production environment storage ↓(Tcore – Tskin) = ↑ Blood flow requirement = ↑ Tachycardia = ↑ CV strain

Fig. 1 | Fundamental principles of thermoregulation. To prevent heatstroke, dissipation. Internal heat production is determined by metabolic energy
metabolic heat must first be transferred via the circulatory system to the skin expenditure, which is dependent on the rate of oxygen consumption (VO2)
and then transferred from the skin surface to the surrounding environment via and the utilized fuel (carbohydrate and fat) mixture, minus energy expended
convection, radiation and/or evaporation. Heat loss or gain via conduction is as external work. Convection and radiation are dependent on the temperature
considered negligible. Heat transfer to the skin depends on the core-​to-​skin difference between the skin and ambient air (Tair) and mean radiant
temperature gradient (Tcore − Tskin) and blood flow rate (indicated by the temperature (Trad), respectively. When Tair or Trad exceeds Tskin, convection or
thickness of red lines). For the same amount of internal heat transfer, a smaller radiation becomes a pathway for additional heat gain. Evaporation is driven
Tcore − Tskin must be compensated by higher blood flow, which induces more by the difference between the absolute humidity of the skin (Pskin) and air (Pair),
tachycardia and cardiovascular (CV) strain. Increases in Tcore ultimately arise with the former regulated by eccrine sweating. Both convection and
from a mismatch between internal heat production and net external heat evaporation are further modified by air velocity (v) across the skin.

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wet-​bulb temperature (Tw; representing combinations configuration or tag irreparable proteins for proteas-
of humidity and temperature) of 35 °C for >6 h (ref.72). omal degradation, preserving cellular structures and
Tw has already exceeded 35 °C on Earth, albeit in limited functions27,83,86. Furthermore, the burden of unfolded or
areas and for very brief periods72; however, most global misfolded proteins in the endoplasmic reticulum and
climate change projections predict that this thresh- mitochondria engages the unfolded protein response
old will be reached at regional scales in the coming (UPR) to maintain proteostasis87,88. The UPR activates
decades71–73. The real environmental limit for survival complex intracellular signalling pathways to increase the
is almost certainly below a Tw threshold of 35 °C, as this protein-​folding capacity and decrease the load of pro-
approach assumes no clothing is worn, a basal metabolic teins in these stressed organelles to maintain cell viability
rate of complete rest and no solar radiation exposure74. and function or induce apoptosis88. Thus, together, the
In fact, body core temperatures between 40 °C and near HSR and UPR prevent cellular damage caused by protein
44 °C have been documented in patients with heatstroke, toxicity.
at much lower environmental Tw (refs1,2). For instance, Genome-​wide transcriptional studies show that the
the unprecedented high numbers of heat-​related mor- HSR in mammals goes beyond activation of HSP genes
tality and morbidity observed during the 2003 European and simultaneously induces expression of several hun-
and 2010 Russian heatwaves occurred at Tw values ≤28 °C dred genes related to crucial stress pathways that are
(ref.72). The inability of the thermoregulatory system to independent of HSF1 (refs23,26,89). These include mainte-
prevent hyperthermia, resulting in heatstroke, has been nance and repair of the cytoskeleton, DNA and chroma-
attributed to several environmental, morphological and tin, and inhibition of nuclear factor-​κB (NF-​κB), which
clinical risk factors that increase vulnerability to heat influences inflammation and adaptive immunity23,26,89.
stress at lower Tw (Box 2). In addition, energy sourcing shifts from oxidative phos-
phorylation to aerobic glycolysis, perhaps to minimize
Heat stress response oxidative stress23,90. A genome-​wide expression study in
Proteotoxic stress. Environmental heat is considered healthy individuals exposed to extreme heat in a sauna
extreme when ambient temperatures are higher than the with full phenotype recovery revealed an HSR that
historical average of an area75,76. In the USA, extreme heat has similarities to that of other mammals and model
is defined as heatwave if it lasts two or more consecutive organisms, such as flies, worms and yeasts, indicating
days in which the daily minimum apparent temperature evolutionary conservation23. Furthermore, young and
(the actual temperature adjusted for humidity) in a par- healthy soldiers who experienced exertional heat injury
ticular city exceeds the 85th percentile of historical tem- showed high HSP gene expression levels and simultane-
peratures for that city75. However, no standard method ous induction of many other genes, further indicating
to define heatwave exists; accordingly it varies across the broad and essential role of the HSR in severe heat
countries. In Europe, the WHO considers heatwave as a stress91.
period in which the maximum and minimum apparent Studies in the nematode Caenorhabditis elegans
temperatures exceed the 90th percentile of the monthly show that the HSR is not cell-​autonomous but is a
distribution for at least 2 days76. Extreme heat can highly coordinated and hierarchical process controlled
overwhelm the thermoregulatory mechanisms, result- by a thermosensory neuron92–95. When the HSR occurs
ing in hyperthermia, as in heatstroke. Hyperthermia in particular cells, the information is propagated to
can provoke damage to proteins, membrane lipids unstressed neighbouring cells through intercellular
and DNA and alter the redox state of cells, resulting communication and systemically to distant tissues and
in cellular dysfunction, tissue damage and death24,27 organs through paracrine and endocrine signalling96.
(Fig. 2b) . Proteins maintain a native structure and Thus, a thermosensory neuron regulates the HSR
function optimally in a narrow temperature window, in the nematode, suggesting coordination between
and a slight increase in temperature can cause proteins to thermoregulation and HSR. There is no evidence of
unfold or misfold, forming aggregates that can result in coordination between these two fundamental defence
cell-​cycle arrest, growth or proliferation24,27. The influx of mechanisms in humans. Thermosensitive neurons
misfolded proteins was found to be a signal for activating activated by ambient warmth elicit behavioural and
the HSR in bacteria, human cultured cells and model autonomic responses to control body temperature
organisms, such as flies, worms and yeasts77–79. The role independently of the HSR93.
of the HSR is to avert protein misfolding and aggrega-
tion, thereby ensuring the integrity and functionality of Failure of the HSR. Induced HSPs have been observed
the proteome77–83. to be highly protective in human cell culture,
Saccharomyces cerevisiae, C. elegans, Drosophila melano-
Regulation of the heat stress response. Upon heat stress, gaster and rodent models, and humans with heat stress
heat shock protein (HSP) expression is rapidly induced injury, supporting the notion that the HSR is a central
by heat shock transcription factors (HSFs; evolutionar- component of the defence mechanisms against danger-
ily conserved from yeast to human), particularly HSF1 ous environmental heat28,97–100. Accordingly, conditions
and HSF2 (refs84,85). The HSR involves a rapid (within that weaken the HSR, including ageing, lack of acclima-
minutes) and transient reprioritization of the tran- tization to heat and possibly epigenetic and genetic fac-
scriptome programme to stress-​related genes instead tors, may predispose an individual to heatstroke (Box 3).
of growth-​related genes25,26,85,86. Induced HSPs identify It is well established that ageing decreases HSF1 binding
misfolded proteins, assist in the refolding to their usual activity through chromatin and histone modifications,

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a Thermoregulatory response

Environment Skin Body

Somatosensory
cortex

Peripheral Behavioural
Dorsal root temperature adjustment
ganglion

High Cutaneous
temperature Thalamus circulation
and humidity
Preoptic area Sympathetic
nerve activation
Sensory
TRP channel nerve
Autonomic Vasodilation
response
Sweat glands
Core
temperature
Cholinergic
Heat pathway
activation Increased
Muscle
sweating
Pathogenic factors
• Extreme heat and humidity
• Coexisting illnesses
• Medications
• Old age Muscle Heat
• Strenuous exercise contraction generation

b Heat stress response

Environment Cytoplasm
HSF1 monomer
High Misfolded Aggregated
temperature protein proteins Nucleus
and humidity

Constitutively
expressed
HSPs HSF1
trimer
Prevention of
aggregation

Muscle Heat Inducible

contraction generation Unfolded protein response HSPs
Refolding Proteasome
• Increased folding capacity
• Reduced protein synthesis
Pathogenic factors • Apoptosis
• HSR duration and magnitude
• Lack of acclimatization
• Old age
• Genetic variants

Degradation

ER
Mitochondrion

preventing HSF1 from accessing DNA heat shock ele- characterized by reduced proteostasis capacities, might
ments and inducing HSP gene expresssion82,101. This may increase susceptibility to heatstroke82,101.
lead to an inability to maintain protein function and to
clear misfolded and aggregated proteins induced by Pathophysiology
extreme environmental heat during heatwaves. Hence, Heat toxicity. When thermoregulation is overwhelmed
neurodegenerative diseases, such as Alzheimer disease, by environmental or endogenous heat, core body tem-
Parkinson disease and Huntington disease, which are perature increases, exceeding 40 °C in patients with

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◀ Fig. 2 | The potential pathogenic mechanisms that can result in heatstroke. The Innate immunity. Heatstroke elicits activation of the
human response to extreme environmental heat or endogenous heat produced by mus- innate immune response, characterized by leukocy-
cle during strenuous exercise is characterized by both thermoregulatory and heat stress tosis and the release of pro-​inflammatory cytokines,
responses. a | An increase in skin, muscle or core temperature is sensed by thermosen- adhesion molecules and acute-​phase proteins, such as
sors, including transient receptor potential (TRP) channels, members of a superfamily of
C-​reactive protein1,2 (Fig. 3). Increased levels of circulat-
cation channel thermoreceptors, on the skin and/or internal organs. The information is
conveyed as action potentials to the somatosensory cortex via the dorsal root ganglia ing pro-​inflammatory and anti-​inflammatory cytokines
and the thalamus, and directly to the preoptic area of the hypothalamus. The somatosen- and chemokines have been documented in patients
sory cortex perceives the peripheral temperature and elicits a behavioural adaptation. with EHS and CHS and in animal models 106,112–117.
The preoptic area better perceives the core temperature and triggers autonomic Pathological findings in experimental models confirm
responses, namely, cutaneous vasodilation through withdrawal of sympathetic vaso­ widespread inflammation that manifests in vascular
constrictive tone and activation of the sympathetic nerve system, and the stimulation of congestion and homing of leukocytes and their migra-
sweating through activation of the cholinergic pathway. The cutaneous vasodilation, in tion from vascular beds to interstitial tissues in many
turn, results in a more than twofold increase in cardiac output, of which ~70% is redistri­ organs of the body104,106,118.
buted to the skin circulation at the expense of splanchnic and renal blood flow. Extreme The role of innate immunity is to protect the host
environmental heat, old age, coexisting illness, medications and strenuous exercise are
against infection by recognizing pathogen-​associated
potential pathogenic factors that determine whether the patient’s condition will progress
to heatstroke. b | During heat stress, an increase in misfolded or aggregated proteins molecular patterns (PAMPs) through pattern recogni-
elicits stress in the cell, including the cytosol, nucleus, endoplasmic reticulum (ER) and tion receptors (PRRs) and activating the appropriate
mitochondria. Constitutively expressed heat shock proteins (HSPs) release inactive immune response119. It is also established that innate
monomeric heat shock factor 1 (HSF1), which moves to the nucleus, where it forms immunity can be activated during sterile conditions,
a trimer. Trimeric HSF1 binds to heat shock element sequences of the DNA and activates such as trauma, burns or haemorrhage. In this case,
genes that encode inducible HSPs. ER and mitochondrial stress activate the unfolded only intracellular molecules that are released into the
protein response (UPR), an autonomous signalling pathway, which alleviates the stress circulation because of cell necrosis are recognized as a
by reducing protein synthesis and increasing folding capacity, or inducing apoptosis if molecular pattern (termed damage-​associated molecu-
the stress remains unresolved. Induced HSPs help misfolded proteins to regain their lar patterns (DAMPs)) by the same PRRs. The DAMPs
native structure, prevent aggregation or direct irreversibly damaged proteins towards
serve as alarmins or danger signals that cells are dying
proteasomal degradation. The duration and magnitude of the heat shock response
(HSR) are determined by the individual’s age, genetic and epigenetic regulation, and by necrosis, so that defence and repair systems are
acclimatization to heat. Part a adapted from ref.34, Springer Nature Limited. directed to injury sites. In human and animal models,
heatstroke, PAMPs and DAMPs have been implicated
in activating innate immunity112,120–122. This includes
heatstroke (Fig. 3). Studies in cell lines and large animal endotoxins leaking into the circulation from the dam-
models have demonstrated that extreme heat directly aged gut, or alarmins, such as IL-1α, high mobility
induces macromolecular injury, including of proteins, group protein B1 (HMGB1) and HSP72, from dying
DNA and lipid membranes, and structural damage to cells and signalling through Toll-​like receptor 4 (TLR4)
the cells24,27. Structural damage affects the cytoskeleton and other PRRs112,120–122. The binding of these ligands to
and most organelles, such as mitochondria, lysosomes, their receptors activates downstream signalling towards
Golgi apparatus and the endoplasmic reticulum, alter- NF-​κB activation, promoting inflammatory responses
ing their functions and resulting in cell death24,27,102. Heat and cytokine release123.
toxicity can culminate in both necrotic and apoptotic Studies on modulation of the inflammatory response
cell death29,102–104. The severity of cell injury depends on in animal models of heatstroke found that neutralizing
both the level and duration of hyperthermia, leading to the inflammatory response with an IL-1 receptor antag-
the concept of critical thermal maximum, a threshold onist, corticosteroids or recombinant activated protein
beyond which near-​lethal or lethal cell injury occurs105. C reduced organ damage and improved survival124–126.
A clinically relevant nonhuman primate model of CHS Conversely, studies in mice in which IL-6 and tumour
that reproduces the cellular injury, neurological mor- necrosis factor (TNF) receptor expression was lacking
bidity and mortality of human disease showed that and in nonhuman primates that received corticoster-
heat injury is gradual and reversible until a threshold oids observed increased mortality127–129. These findings
temperature of 43 °C is attained106. These experimen- suggest that the inflammatory response exists along a
tal data suggest that early intervention can prevent the continuum that may elicit beneficial or detrimental
progression to lethality. effects depending on the timing and magnitude of the
A critical thermal maximum was determined in var- elicited response. As a result, whether the activation of
ious mammalian species but not in humans2. However, the host inflammatory response contributes to the multi-
indirect evidence suggests that it may range between ple organ system dysfunctions and death of patients with
41.6 °C and 42 °C for 1 h in sedated, unacclimatized, heatstroke remains to be fully elucidated.
well-​hydrated men105. By contrast, well-​trained ath-
letes have been reported to tolerate core temperatures Coagulation. Heatstroke is associated with early activa-
as high as 41.7 °C with no adverse events 107, which tion of coagulation and fibrinolytic systems130,131 (Fig. 3).
was attributed to acclimatization to high muscle and Fibrinolysis is rapidly repressed by an early rise in plas-
body temperatures during routine exercise training108. minogen activator inhibitor 1 activity, resulting in a
A growing number of studies suggest that genetic traits two-​phase response pattern of fibrinolysis activation
and epigenetic regulation to exercise training may also followed by inhibition127,130,131. In a nonhuman primate
contribute to thermotolerance to extreme heat109–111 model of heatstroke, the inhibition of tissue factor, which
(Box 3). has an activating role in the clotting cascade, attenuates

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Box 2 | Risk factors for heatstroke supported by the finding of increased plasma levels of
biomarkers of endothelial cell activation, such as solu-
• Environmental factors ble thrombomodulin, VWF antigen, endothelin, soluble
-- High humidity, high thermal radiation, low wind speed313. endothelial cell leukocyte adhesion molecule 1 (ELAM1)
-- Consecutive days with high overnight temperature314.
and intercellular adhesion molecule 1 (ICAM1) in
-- Air pollution315.
humans and baboon models of heatstroke106,134,135.
• Individual variation in core temperature
-- Adiposity: increased rise in core temperature at a >3-​fold difference in percentage
Skeletal muscle. Skeletal muscles have a high tolerance
of body fat316.
-- Metabolic heat production: during physical exertion, heat production per unit of to heat-​induced damage compared with other tissues,
body mass determines the rise in the core temperature of an individual irrespective perhaps owing to repeated heat exposure during nor-
of %VO2max or body size64. For a fixed absolute heat production, rise in core mal physical work136. Resting skeletal muscle temper-
temperature is inversely correlated to total body mass317. ature is ~35 °C and remains 0.65–0.95 °C higher than
-- Movement economy: economical runners can produce ~30% less heat with a ~0.5 °C core temperature during exercise to facilitate heat
smaller increase in core temperature than uneconomical runners of the same mass transfer137. Theoretically, if a patient with EHS typically
at the same treadmill speed316. has a core temperature >40.5 °C, the skeletal muscle
-- Aerobic fitness and heat acclimatization: 7–10 consecutive days of 1–2 h of extreme temperature will be ~41.5 °C at the time of collapse,
heat exposure with exercise induces physiological adjustments (heat acclimatization) with some regional differences based on activity level137.
that enable complete skin surface sweat coverage to lift heat loss to the biophysical
In vitro, this temperature level has been shown to induce
limit318. Regular physical training, even in temperate environments, induces partial
heat acclimatization319. Concurrent increases in VO2max do not independently increased resting muscle tension, which is attributed to
alter heat loss capacity. an elevation in Ca2+ and reactive oxygen species lev-
-- Age: impairments of heat loss mechanisms can yield differences in core temperature els within the contractile apparatus138–140. The elevated
in individuals >60 years of age. muscle tension presumably increases the chance of tissue
-- Sex: submaximal rates of heat loss are comparable between men and women, damage, which may be associated with a high incidence
but lower maximal rates of heat loss during heat stress are observed in women of rhabdomyolysis in patients with EHS138–140.
than in men320. Rhabdomyolysis results in the leakage of intramuscu-
• Clinical factors lar content into the circulation, which ultimately leads
-- Disruption of sweat gland function can occur in those with skin injury (burns)321. to kidney overload and failure141,142. Although rhabdo-
-- Heart failure, peripheral vascular diseases, and medications (sympathomimetic myolysis can be induced by the effects of heat them-
or anticholinergic) can impair behavioural or autonomic thermoregulatory selves, genetic mutations associated with Ca2+-​handling
responses107–109.
channels within the contractile apparatus have been
• Risk factors unique to exertional heatstroke: over-​motivation of the individual associated with the occurrence of EHS, rhabdomyolysis
performing beyond their level of acclimatization or fitness136,322.
and other myopathies143–147. Calcium has a crucial role
in muscle contraction. It is stored in the sarcoplasmic
the coagulation activation, suggesting that tissue factor reticulum or enters the muscle from outside the myofi-
is the main trigger of coagulopathy in this condition132. bre. Owing to its high affinity for troponin C, Ca2+ binds
However, tissue factor neutralization did not decrease to the tropomyosin complex and uncovers the active
cell injury and multiple organ tissue damage, indicating sites, enabling crossbridge interaction and contraction.
that coagulopathy is not a requirement for the patho- The ryanodine and dihydropyridine voltage-​dependent
genesis of heatstroke. Furthermore, inhibition of tissue receptors regulate Ca2+ homeostasis. Mutations in the
factor was not associated with modulation of the con- genes encoding ryanodine receptor 1 (RYR1), calse-
comitant systemic inflammatory response syndrome of questrin 1 (CASQ1) and calcium voltage-​gated chan-
heatstroke, suggesting no apparent crosstalk between nel subunit α1 S (CACNA1S), which are associated
the two systems132. Further studies are needed to clarify with malignant hyperthermia and anaesthesia-​induced
whether modulating the coagulation alterations would rhabdomyolysis, have been implicated in the patho-
be beneficial in the treatment of heatstroke. genesis of EHS143–147. To date, it is still unclear how
dysregulated muscle Ca2+ homeostasis induces EHS,
Endothelium. In heatstroke, the normal barrier func- as collapsed patients with EHS show muscle flaccidity
tion of the endothelium is disrupted. There is evidence rather than rigidity, suggesting that excess amounts
of endothelial cell damage in the heart, lungs, liver, of Ca2+ in the contractile apparatus may be absent.
jejunum and spleen in nonhuman primate models and Nevertheless, experimental data in RYR1-​mutant mice
humans with heatstroke104,133 (Fig. 4). In this setting, the suggest that heat-​induced sudden death may be partly
vascular endothelium is discontinuous, revealing wid- due to Ca2+-​dependent increases in reactive oxygen and
ening gaps between neighbouring endothelial cells and nitrogen levels, which further amplify muscle mem-
enhanced endothelial cell apoptosis, resulting in struc- brane excitability, injury and death following strenuous
tural barrier impairment. In addition, immunostaining exercise148. As clinical studies continue to describe cases
and electron microscopy demonstrate functional altera- of EHS associated with RYR1 mutation, this hypothesis
tion of the endothelium, including increased expression still warrants further investigation144,149–151.
of von Willebrand factor (VWF) antigen, exposure of A potential alternative mechanism involved in exer-
collagen fibres, activated platelets, fibrin and leucocytes tional rhabdomyolysis and EHS is that severe hyper-
at the sites of vascular endothelial injury. Taken together, thermia in combination with other factors, such as
the endothelium may contribute to the coagulopathy dehydration, may decrease muscle blood flow owing
and inflammation of heatstroke. This interpretation is to competition for the available cardiac output between

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the skin and active muscles. These adjustments make signs. Other neurological findings include seizures,
skeletal muscles ischaemic during exercise in heat severe alteration of the level of consciousness, including
stress152. Reductions in O2 delivery decrease ATP turn- deep coma, areflexia, miosis and absence of brainstem
over in muscle — despite a reported compensatory reflexes158,159. The neurological manifestations subside
increase in O2 extraction in hyperthermia152 — which completely following cooling and supportive therapy
can increase intramuscular Ca2+ content owing to an in most patients. Of the patients who survive CHS or
inability to actively transport Ca2+ back to the endo- EHS, 10–28% sustain cognitive and motor dysfunction,
plasmic reticulum153. Increased intramuscular Ca2+ in which cerebellar syndromes predominate60,161–169.
leads to the activation of proteolytic enzymes (for Follow-​up brain imaging discloses more frequent dam-
example, caspases) that contribute to the skeletal muscle age to the cerebellum, followed by the hippocampus,
breakdown seen in exertional rhabdomyolysis154. This midbrain and thalamus161–169.
potential mechanism requires further elucidation in the
context of EHS. Haematological. Coagulation disturbances are common
features of heatstroke130,131,170–174. The manifestations
Diagnosis, screening and prevention range from mild activation of coagulation and fibrinol-
Presentation ysis to severe disseminated intravascular coagulation
Clinical and experimental studies show that heatstroke is (DIC). Diffuse bleeding from various sites secondary to
a systemic illness that can alter most organs, even though clotting factor and platelet depletion is often associated
CNS manifestations dominate6,57,104,155–157. The signs and with fatal heatstroke. In addition, the levels of antico-
symptoms at presentation, the number and the time agulants protein C and antithrombin III are decreased
course of organ dysfunction and failure vary and depend in patients with severe heatstroke130,131. Autopsy studies
on the severity of heatstroke5,6,57,104,155,156,158. invariably show diffuse haemorrhage and the presence
of widespread microvascular and macrovascular throm-
Central nervous system. Neurological alterations are bosis in various organs159,175. Severe DIC may be a pre-
striking manifestations of CHS and EHS. They often dictor of acute respiratory distress syndrome (ARDS)
appear suddenly without obvious warning signs in and death130,170.
around two-​thirds of patients and may manifest as a
disturbed mental state, including confusion, delirium Cardiovascular. Tachycardia is common and may be
or lethargy5,57,158–160. Heatstroke may also start progres- associated with circulatory failure6,158,176. Shock may
sively with nonspecific signs and symptoms lasting min- be present in 18–65% of patients and is associated with
utes, hours or even days, including fainting, dizziness, morbidity and mortality5,58,156,177–179. The pathogen-
headache, restlessness or confusion, difficulty in swal- esis of shock in this setting is not fully understood176.
lowing or speaking158,159. On examination, patients may Haemodynamic measurements in small series of
be agitated and combative, with typically no localizing patients with CHS using right heart catheterization
predominantly show a distributive shock resembling
sepsis, namely elevated cardiac output, low systemic vas-
Box 3 | Acclimatization cular resistance and normal or decreased cardiac filling
Acclimatization describes the physiological changes that occur during exposure to pressure178,180,181. Hypodynamic shock with decreased
a gradual increase in ambient heat or incremental rise in levels of physical exercise, cardiac output and elevated systemic vascular resistance
which lead to a decrease of the strain caused by stressful changes in environmental has also been observed, particularly in elderly patients178.
heat323,324. The adaptation results in improved thermoregulatory and heat stress
responses, reducing the risk of heatstroke. Pulmonary. Tachypnea is consistently present in patients
• Higher stroke volume and maximal aerobic capacity, lower heart rate and increased with heatstroke and is ascribed to heat-​induced hyper-
cutaneous blood flow at a given core temperature1,324 ventilation and primary respiratory alkalosis177,182,183.
• Earlier initiation and higher rate of sweating with reduced sodium and chloride Hypoxaemia can also occur without overt respiratory
concentrations to minimize the risk of dehydration and hypotension1,324 failure. The frequency of severe hypoxaemia with acute
• Faster induction of heat shock protein expression to preserve proteins and cellular respiratory distress requiring endotracheal intubation
homeostasis and ventilatory support ranges from 10% to 23%6.
These phenotypic changes occur in the course of days to weeks, are reversible Pulmonary oedema is found at autopsy in 60% of
and have been attributed to both genomic and epigenetic mechanisms in exertional patients159. Lung injury can be reproduced in the non­
heatstroke109,110,303. human primate model, and is associated with syste­
In classic heatstroke, no genetic variants or epigenetic factors that could influence
mic and lung inflammation, diffuse thrombosis and
pathophysiology have been discovered so far. In exertional heatstroke (EHS), four
candidate genes have been postulated to influence pathophysiology: RYR1 (encoding
endothelial damage, which might contribute to alveolar-
ryanodine receptor 1), CASQ1 (encoding calsequestrin 1), CACNA1S (encoding calcium capillary membrane damage104. Other potential aetiolo-
voltage-​gated channel subunit α1 S) and TRPV1 (encoding transient receptor potential gies of respiratory failure include aspiration pneumonitis
cation channel subfamily V member 1)147,306–308. Variants of these genes were documented in patients in coma unable to protect their airway.
in a small cohort of patients with EHS, and validated in genetically modified mice147,306–308.
Further linkage and genome-​wide association studies are needed to confirm their role. Renal. Renal dysfunction varies from mild proteinuria
Epigenetic modifications associated with gene expression and phenotypic changes and abnormalities in urine sediment to acute kidney
were demonstrated in human skeletal muscle after long endurance training111. injury (AKI)5,159,184,185. AKI is more common in EHS
Epigenetic reprogramming associated with immunosuppression and an altered heat than in CHS, and can progress to renal failure requiring
shock response was demonstrated in mice who experienced EHS325.
dialysis186,187. The cause of renal failure is multifactorial

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and may include shock, rhabdomyolysis and direct transplantation have been reported in patients with
thermal injury188. EHS189,190.
Diarrhoea is consistently present in heatstroke at
Gastrointestinal. Liver dysfunction is frequent in heat- presentation and subsides after cooling without specific
stroke, and can sporadically progress to liver failure, therapy. Pathological findings in experimental animal
particularly in patients with EHS189–191. Liver injury is models show severe jejunal damage with disorganization
characterized by an early increase in serum alanine of jejunal microvilli and enhanced apoptotic cell death
transaminase and lactic dehydrogenase, reaching a in the lamina propria104. However, whether similar pat-
zenith after a few days, followed by a rise in bilirubin terns of injury are present in humans with heatstroke is
on the second or third day159,179. Histological find- not known192. Nevertheless, heat-​induced gut and liver
ings consist of congestion, centrilobular necrosis and injury were proposed as the possible mechanism under-
cholestasis159,191. Anecdotal cases of liver failure asso- lying the presence of endotoxins in the circulation in
ciated with massive hepatocyte necrosis requiring liver humans and experimental models112,193,194.

Endothelium
Tissue of organs Cell injury Apoptosis Necrosis Endothelial cell

Circulation
Pattern recognition
receptor
• Alarmins
(IL-1α, HMGB1, HSP72)
• Tissue-factor-containing microparticles
• Endotoxins

Neutrophil Monocyte

Tissue factor

Thrombus formation
Release of Activation of
pro-inflammatory and coagulation and
anti-inflammatory inhibition of
cytokines fibrinolysis

Activated
platelet
Red
blood cell

Neutrophil Damage
infiltration and leakage Bleeding

Fig. 3 | Putative mechanisms of tissue injury and organ dysfunction in heatstroke. Excessive heat can lead to cell
injury, or apoptotic and necrotic cellular death. Dying cells release alarmins, such as IL-1α, high mobility group protein B1
(HMGB1) and heat shock protein 72 (HSP72), into the systemic circulation. In addition, microparticles containing tissue
factor, which has an activating role in the clotting cascade, are released by dying cells into the circulation, and endotoxins
can leak from the damaged gut. These factors activate neutrophils and mononuclear cells through pattern recognition
receptors, including Toll-​like receptor 4, which then release pro-​inflammatory and anti-​inflammatory cytokines, activating
the vascular endothelium and coagulation as well as inhibiting fibrinolysis. Ischaemia–reperfusion injury, excessive
secondary inflammatory activation and disseminated intravascular coagulation may contribute to further cellular injury
and organ tissue damage and dysfunction. Solid arrows indicate pathways supported by clinical or experimental data, and
the dashed arrow designates a putative pathway.

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Liver Fig. 4 | Structural and ultrastructural alterations in mod-

a b c els of heatstroke. Structural and ultrastructural tissue and
cellular changes in various organs occur during heatstroke,
as exemplified in animal models of the condition104,106.
Liver: marked pan-​lobular sinusoidal congestion in the liver
CV CV CV in severe heatstroke (panel a), extending from portal triads
to central veins (CVs) with an accumulation of leukocytes in
sinusoids (arrows). No substantial abnormalities in moder-
ate heatstroke (panel b) apart from platelets adhering to
sinusoidal endothelium (arrows). Unremarkable liver in
Jejunum
control animals (panel c). Jejunum: marked capillary dila-
d e f tion, red blood cell (RBC) engorgement (solid arrows) and
increase in surrounding inflammatory cell content (dashed
arrow) with the loss of surface epithelial cells in severe
heatstroke (panel d). Only minimal villous capillary dilation
(arrow) in moderate heatstroke (panel e). Normal villi in
control animals (panel f). Kidney: tubular granular cell (solid
arrow), epithelial cell (arrowhead) and RBC (dashed arrow)
casts in severe heatstroke (panel g). Minimal tubular
Kidney changes in moderate heatstroke (panel h). Normal tubules
g h i in control animals (panel i). Glomerular changes include
increased mesangial cellularity (solid arrows) in both severe
heatstroke (panel j) and moderate heatstroke (panel k),
narrowing of the glomerular capillaries in moderate heat-
stroke (panel k) and dilation of glomerular capillaries, with
increased intra-​glomerular platelets (dashed arrows) and
spillage of RBCs into Bowman’s space (arrowhead) in
severe heatstroke (panel j). Normal glomeruli in control ani-
mals (panel l). Ultrastructural changes in liver, kidneys and
j k l
jejunum: liver (panels m–o); obliterated space of Disse in
both severe (panel m) and moderate (panel n) heatstroke,
with reduction of hepatic microvilli to irregular stubs
(arrows). In moderate heatstroke, loss of internal lysosome
structure (solid arrow) and ring profile of mitochondrial
cristae (dashed arrow). Normal hepatic microvilli in control
animals (solid arrows, panel o), projecting into the space of
Disse. Kidney (panel p): activated platelets interacting with
Liver, kidneys and jejunum ultrastructural changes RBC (solid arrow), neutrophil (dashed arrow) and endothe-
lium (arrowhead) in the glomerular capillary. Jejunum
m n o
(panels q and r): thrombus comprising RBCs, platelets and
fibrin (RPF) obstructing the jejunal microcirculation and
breach in the endothelium with platelets leaking into the
interstitial space (arrows). Platelets (dashed arrow) and
leukocyte (arrowhead) interacting with subendothelial
elements, including collagen fibres (asterisk) (panel r).
Haematoxylin and eosin stain; magnification ×200
(panels a–i) or ×400 (panels j–l). Electron photomicrographs;
p q r original magnification ×12,000 (panels m and o), ×15,000
(panel n) or ×2,950 (panels p–r).

cardiac and renal cells, in line with observations made

RBC RPF in rodents103,104. No apoptotic cell death was observed in
humans, probably owing to the delay in performing a
* post-​mortem examination. Ultrastructural changes
were found in several organs, including the gut, kid-
neys, lungs, liver, muscle and spleen, confirming obser-
Pathology. Post-​mortem studies in patients with heat- vations in humans (Fig. 4). The changes consisted of
stroke show that death is associated with oedema, vas- substantial gaps between endothelial cells, ballooning
cular congestion, inflammation and endothelial damage of the cytoplasm and alteration of most organelles,
together with thrombosis and haemorrhagic necrosis in includ­ing Weibel–Palade bodies, mitochondria and lys-
most organs104,133,159,175. These findings were recapitu- osomes. Weibel–Palade bodies are specific to endothe-
lated and expanded on in a nonhuman primate model lial cells and store VWF and various other proteins that
of heatstroke104 (Figs 4,5). In addition to necrotic cell mediate haemostasis, inflammation and tissue repair195.
death, apoptotic death was demonstrated and seemed Collectively, these findings suggest that necrotic and
to be organ specific, as cells of the jejunum, lung, spleen apoptotic cell death attributed to heat and secondary
and thymus showed more apoptosis than hepatic, vascular endothelium activation, excessive inflammation

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a b conditions can result in the core body temperature levels

seen in heatstroke, so it should not pose any diagnostic
dilemma. These conditions include malignant hyper-
thermia, neuroleptic malignant syndrome, cerebrovas-
cular accidents, toxic effects of drug (recreational drugs
and serotonergic medications) and thyrotoxicosis. Most
of these conditions occur in a specific setting, such as
anaesthesia during surgery, the use of neuroleptic or rec-
reational drugs, and thyroid diseases, which facilitates
their recognition6,158,159.
No specific biomarkers for confirming the diagno-
sis of heatstroke exist. Biochemical tests are performed
to guide supportive therapy. In CHS, the predominant
acid–base alteration is combined respiratory alkalosis and
Fig. 5 | Brain damage in nonhuman primate models of heatstroke. a | In control
metabolic acidosis, which are attributed to heat-​induced
animals, normal cerebellum and Purkinje cells (arrows). b | In animals with moderate
heatstroke, early Purkinje cell necrosis (dashed arrows) and normal Purkinje cell (solid hyperventilation and a mild increase in lactic acid levels,
arrow). Haematoxylin and eosin staining; original magnification ×200 (panel a) or ×400 respectively7,183. In EHS, severe metabolic acidosis is com-
(panel b). Reprinted with permission from ref.106, American Physiological Society. mon, ascribed to increased lactic acid levels from skeletal
muscle7. Sodium, potassium, calcium and magnesium
levels are unremarkable in CHS, but phosphate levels are
and disseminated intravascular coagulation are the very low owing to renal loss5,6,200. Patients with EHS may
processes that underlie tissue damage, multiple organ show hyponatraemia, hypokalaemia, hypophosphataemia,
dysfunction and death in patients with heatstroke67,196. hypomagnesaemia and hypocalcaemia57,186. Owing to mus-
cle damage, creatine kinase activity is elevated in CHS but
Diagnosis rarely progresses to severe rhabdomyolysis as observed in
The diagnosis of heatstroke is clinically based on a triad EHS6. Massive muscle necrosis can occur in EHS and lead
of CNS alteration, hyperthermia and history of expo- to AKI and renal failure with life-​threatening hyperkalae-
sure to extreme environmental heat or vigorous muscle mia; other associated electrolyte imbalances include hyper-
exertion1,2. Hyperthermia and CNS alteration are the phosphataemia, hyperuricaemia, hypermagnesaemia and
two defining features of heatstroke158,159. Hyperthermia high-​anion gap metabolic acidosis201. Hyperglycaemia can
commonly ranges between 40 °C and 43.6 °C in most be observed in patients with CHS upon arrival at the hos-
patients6,158,159. However, core body temperature can be pital and subsides without specific therapy after cooling,
<40 °C upon arrival at the hospital. Importantly, this whereas hypoglycaemia can be observed in patients with
should never lead to the exclusion of a diagnosis of heat- EHS200. Liver function abnormalities are mild-​to-​moderate
stroke. For example, it is not uncommon that temperature on admission and can worsen despite cooling, but rarely to
drops in the ambulance during transport or by withdraw- the point of overt failure in CHS, as observed in EHS202,203.
ing the patient from a hot environment before measuring Haematological alterations include leukocytosis caused
their temperature. Core temperature can be determined by neutrophilia, and haematocrit values usually remain
from many body sites including the gastrointestinal tract normal unless there is haemorrhage due to coagulopa-
(oral, oesophageal or rectal), the vascular system (pul- thy that may worsen rapidly to severe DIC, particularly
monary artery) and the head (tympanic membrane or in EHS130,131,204. Electrocardiographic (ECG) changes in
forehead)197,198. Although labour-​intensive and not always CHS and EHS are nonspecific and can include sinus tach-
convenient, rectal temperature is the most accurate site in ycardia, conduction defects, atrial fibrillation, prolonged
the clinical setting, and should be used for the diagnosis of QT interval, nonspecific ST–T wave changes and elevated
heatstroke197,198. Temperature measurements at peripheral troponin levels205–207. Patients with CHS are generally older
sites, including tympanic membrane, forehead and mouth, than those with EHS; specific ECG changes (for example,
are not reliable in humans experiencing heat stress197–199. ST elevations localized to a specific area of coronary cir-
Besides hyperthermia, it is crucial to be aware that culation) may reflect occult coronary artery disease rather
patients with neurological disturbances due to heat- than heatstroke208.
stroke show no focal signs. However, the presence of Immediate and aggressive cooling has been demon-
focal neurological signs should immediately rule out strated to have a profound effect on heatstroke mor-
heatstroke and trigger a work-​up to identify other aeti- bidity and survival; around one-​third of patients may
ologies. Lumbar puncture and brain imaging using CT progress from dysfunction to failure of one or more
or MRI are not indicated to diagnose heatstroke. If these organs, resulting in deep coma, ARDS, profound DIC
tests are performed to rule out other causes of neurolog- with severe haemorrhagic diathesis, liver failure and
ical alteration associated with hyperthermia, the cere- acute kidney failure6,61,155,156,209.
brospinal fluid is usually normal, except for occasional
pleocytosis, and brain imaging shows no structural Screening
damage at presentation2,5,160. CHS and EHS, and their associated morbidity and
The clinical presentation of CHS or EHS is archetypal mortality, are preventable. Many studies have been per-
within a specific context, that is, extreme environmen- formed to identify risk factors that might contribute to
tal heat or strenuous exercise. Furthermore, few other susceptibility to heat-​related deaths including CHS.

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In a meta-​analysis of six case–control studies com- heat illness and exercising during heatwaves or unex-
prising >1,000 heat-​related deaths and controls matched pectedly hot weather57,214,215. Risk factors additionally
for age and neighbourhood during heatwaves in Europe unique to exertional heat illness include over-​motivation
and the USA210, the factors associated with the maxi- of the individual from either intrinsic or extrinsic pres-
mum risk of dying from environmental heat including sure to perform beyond the level of acclimatization
from CHS were poor general health (being confined to or fitness57,214–216. Knowledge of these and other afore-
bed, unable to care for oneself or to leave home daily) mentioned risk factors can serve to guide primary pre-
and pre-​existing cardiovascular, pulmonary or psychi- vention through education, screening and mitigation
atric conditions210. Furthermore, psychotropic medica- strategies217–219. Physical fitness assessments in athletic
tions increased the risk of death during heatwaves, as and military populations may be useful predictive
they can impede heat dissipation mechanisms, including tools to prevent EHS, whereas motivational factors
appropriate behaviour (seeking cooling places, avoiding are more difficult to recognize and mitigate during an
exercise and staying hydrated) and autonomic responses, intense physical event. Studies are underway to iden-
such as sweating and cardiovascular adjustment during tify screening methodologies of heat acclimatization
thermoregulation211–213. status in military populations (for example, epigenetic
Several studies described potential risk factors for screening), but these are in their infancy at this time.
EHS2,57,214–216. The most common include low physical
fitness, lack of heat acclimatization, obesity, a history of Prevention
The framework for most public health responses to
Box 4 | Chain of survival for patients with exertional heatstroke extreme environmental heat includes an early heat
warning system, specific care for vulnerable population
The chain of survival for exertional heatstroke, comparable to classic heatstroke,
starts with primary prevention, leveraging known risk factors and mitigation strategies. groups, reducing heat exposure and facilitating access to
Survival depends on rapid recognition and assessment with the provision of prompt a cool environment210,220,221 (Boxes 4,5).
and emergent on-​site cooling. Cooling and supportive therapy should be continued In CHS, withdrawing from heat, even for a short
throughout transport and hospitalization, with the final link being the graduated time, is the principal protective measure during peri-
provision of return to activity. ods of extreme environmental heat210. Other factors
I. Prevention such as using a fan or taking extra showers have been
a. Education linked to a reduced risk of death, but the associations
i. Heat stress education to participants, supervisors, coaches and leaders should did not reach statistical significance210. Accordingly,
include risk factors, mitigation strategies and the recognition of heat strain home air-​conditioning or visiting and staying in cool
ii. Emergency action planning should include provision of on-​site cooling places for a short period is protective. However, the reli-
b. Risk assessment and enhancement ance on air-​conditioning often excludes many of those
i. Acclimatization status who are most vulnerable to CHS and may not be able
ii. Physical fitness, obesity to afford access to mechanical cooling owing to low
c. Event mitigation strategies
income220. Sustainable and accessible cooling strategies
i. Modification of event workload based on local wet-​bulb globe temperature
(Tw) assessment
focus on cooling the individual as opposed to the sur-
ii. Provision of intra-​event hydration and on-​site cooling modalities rounding environment by exploiting heat transfer path-
ways of evaporation and convection at the skin surface.
II. Prehospital care: rapid recognition, assessment and initial management
Physiological and modelling studies have demonstrated
a. Rapid assessment and recognition
i. Core temperature assessment with rectal thermometer, performed
the efficacy of electric fans for cooling the body with-
by a qualified health-​care provider, is recommended when possible out changing environmental temperature, and these are
b. On-​site cooling ~50 times cheaper to operate than air-​conditioning, but
i. Cold-​water immersion provides superior cooling rates and is recommended as their clinical efficacy requires testing in well-​designed
a first-​line intervention326 clinical trial222,223. In the case of disruptions to electrical
ii. When cold-​water immersion of the body is not practical or readily available, power, preliminary physiological studies indicate that
the fastest existing cooling technique should be used water dousing (application of water to the skin) is the most
iii. When cooling on-​site is available and initiated, it is recommended that effective use of this resource for minimizing the devel-
cooling be completed (patient cooled to 38.9 °C) before transport to opment of physiological heat strain in both humid and
advanced clinical care
arid heatwaves224.
III. Emergency medical transport As EHS is generally the result of planned occupa-
a. Activate emergency medical services with immediate transfer to a facility tional, recreational and sport activity in heat, unique
appropriate for advanced clinical care opportunities for prevention and mitigation exist215,225,226.
b. Supportive care to include continued cooling facilitation en-​route
Proven primary prevention interventions include
IV. Advanced clinical care improving physical fitness, ensuring adequate hydration,
a. Communication between care teams from prehospital care to advanced clinical leveraging activity, specific acclimatization and modifi-
care is recommended to enhance opportunities to optimize patient outcomes322 cation of workload dependent on the risk assessment of
b. Monitor and provide supportive therapy for multi-​organ failure and dysfunction
an event (for example, wet-​bulb globe temperature)227–231.
V. Recovery and return to activity Administrative policies and leadership have essential
a. Patients should be deemed clinically recovered by the medical team before roles in enhancing compliance with strategies that have
resuming physical activity been demonstrated to be effective232,233. Appropriate event
b. Return to activity should be individualized, and physical activity and heat risk assessment is crucially important in the prevention
exposure should be progressively re-​introduced over several weeks to months
and management of EHS, with preparation including

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Box 5 | Chain of survival for patients with classic heatstroke adjuvant pharmacological agent that can hasten cool-
ing, including dantrolene sodium or antipyretics, such
The chain of survival for classic heatstroke (CHS) starts with primary prevention, as acetaminophen or NSAIDs2,6. Dantrolene sodium is a
awareness of the dangers of heat and appropriate out-​of-​hospital intervention. postsynaptic muscle relaxant indicated in the treatment
Survival depends on prompt diagnosis, rapid activation of emergency medical services of malignant hyperthermia to reduce excessive muscle
and initiation of cooling outside the hospital. Cooling and supportive therapy should
excitation–contraction241. Dantrolene antagonizes the
be continued throughout transport and hospitalization.
ryanodine receptors within the sarcoplasmic reticulum,
I. Early warning system eliciting inhibition of calcium release into the cytosol,
a. Education reversing muscle rigidity and body heat production241.
i. Inform the public about heat illnesses and first aid measures
In a double-​blind randomized study in patients with
ii. Conduct professional CHS management sessions for paramedics
b. Population risk assessment and enhancement
CHS, dantrolene sodium did not reduce the cooling
i. Identify isolated vulnerable populations, establish contact and ensure time, multiple organ injury or length of hospital stay6.
adequate ventilation of their spaces In preclinical rodent models of EHS242 and CHS243,
ii. Prepare air-​conditioned public transport and increase shaded waiting areas administration of NSAIDs showed no benefit and
iii. Assure hospital preparedness to receive high number of patients with increased morbidity from gut injury, respectively. There
heat-​related illnesses, including heatstroke is no evidence to support the use of antibiotics in the
c. Mitigation strategies prevention or therapy of heatstroke244.
i. Avoid scheduled or habitual sport activities
ii. Prohibit non-​essential laborious work Physical cooling
iii. Encourage spending a few hours in a cold environment
Cooling should be started at the site of patient collapse
iv. Take additional showers or baths
v. Avoid direct sun exposure
and pursued nonstop during transport and at the hos-
vi. Keep hydrated pital. There is no proven specific threshold temperature
at which cooling should be discontinued176. Rapid cool-
II. Rapid recognition, assessment and initial management
ing with cold-​water immersion to a rectal temperature
a. Rapid assessment and recognition
i. Measure core temperature with rectal thermometer when possible, specifically
of 38.8 °C resulted in 100% survival in a large series of
in patients with altered mental status (delirium, convulsions or coma) patients with EHS56. Overall, body core temperatures
ii. If patient’s core temperature is >40 °Ca, immediately contact emergency between 37 °C and 40 °C have been used as end points for
medical services (diagnosis of heatstroke is likely) terminating cooling without any immediately apparent
b. On-​site cooling difference in survival, but the associated long-​term neuro­
i. Move the patient to a cooler space logical morbidity remains unknown176. Nevertheless,
ii. Begin external cooling with on-​site available methodsb on the basis of the known susceptibility of the brain to
iii. Check airways, breathing and circulation extreme heat, it might be prudent to stop cooling at 37 °C
iv. Apply basic life support if indicated until robust data are generated that indicate otherwise.
III. Emergency medical transport Furthermore, mice allowed to cool passively progress to
a. Immediately transfer to the nearest hospital hypothermia during recovery from heatstroke, suggesting
b. Keep cooling throughout transport and at the hospital until core body that low core body temperature may be protective, parti­
temperature reaches 37 °C cularly for brain tissue245,246. Owing to the large surface to
IV. Advanced clinical care body mass ratio of mice, hypothermia is a known pro-
a. Monitor and provide supportive therapy for multi-​organ failure and dysfunction tective response used by these species to survive severe
a
Rectal temperature <40 °C should not rule out the diagnosis of heatstroke during heat stress. environmental stressors, such as dehydration, food dep-
b
Immersion in iced water or, alternatively, place ice packs or cool wet towels on the neck, rivation and heatstroke. This regulated, adaptive and
axillae and groin; spray the skin with cool to tepid water (20–30 °C)1,253,254 combined with protective response may be responsible for the lack of
continuous fanning.
brain injury in mice with heatstroke that were allowed to
display this response naturally in a laboratory setting246.
ensuring adequate hydration, the provision of intra-​event However, extrapolating data from animals to humans is
and/or activity cooling, and an emergency action plan not predictive; differences in thermal dynamics alone pre-
in the event of an exertional heat illness234–236. Multiple clude cooling in humans until induction of hypothermia
resources are available to assist leaders in both improv- as a brain preservation modality, and carefully designed
ing acclimatization and appropriately scheduling and clinical trials are required to investigate this approach.
modifying events in conditions of extreme heat227,237,238. Cooling techniques for patients with heatstroke are
categorized into conductive1,11,247–249 and evaporative
Management methods176,247 (Fig. 6). In the management of CHS, no
Optimal management of a patient with heatstroke robust evidence indicates superiority of any specific
requires an effective chain of survival comparable to cooling method176. In EHS, immersion in iced water
that described for emergency cardiac care (Boxes 4,5). on-​site within minutes of the onset of EHS was effec-
Cornerstones in this chain of survival include rapid tive and safe176,250–252. Cooling rates >0.15 °C per minute
recognition of heatstroke, prehospital management were associated with improved outcomes in survival and
with initiation of on-​site cooling and contact with the morbidity61. Thus, cooling should be available on-​site, par-
emergency medical system1,176,239. Cell injury and tis- ticularly for EHS, to prevent treatment delays and cooling
sue damage are functions of both the level and dura- interruptions during transport to medical facilities251,252.
tion of hyperthermia; thus, rapid cooling is paramount The choice of cooling technique for CHS is difficult
to improve patient outcome29,103,106,239,240. There is no because, during heatwaves, emergency departments might

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need to care for many frail elderly patients at the same Moreover, their benefits (that is, fast and well-​tolerated
time. Thus, the approach should be pragmatic, selecting cooling, which is an important determinant of heatstroke
cooling modalities on the basis of their availability and outcome) may be offset by the time needed to start these
the familiarity of health-​care providers with them176. In devices. The next developments in management may
practice, combining conductive cooling with ice packs rely on progress in biosensors and artificial intelligence
and spraying the body with cold to tepid water (20–30 °C) to create a hypothalamus-​like intelligent system to
while continuously fanning, are methods that are easy to achieve predictable and fast cooling, eliminate shiver-
apply, non-​invasive and well tolerated1,176,253,254 (Box 5). ing, maintain skin blood flow and reduce the need for
A new generation of cooling devices including endo- sedation, which is often required to control the adverse
vascular and intranasal cooling, vests, helmets, pads and effects of current cooling techniques261.
blankets engineered from high heat-​conductive bioma-
terials (Fig. 6) has been developed based on the findings Supportive therapy
that induced hypothermia may protect the brain after Similar to other emergency conditions, basic and
cardiac arrest255–260. These devices can be used to treat advanced cardiac life support may be required in heat-
patients with CHS or EHS without cardiac arrest; how- stroke, but its use should not hinder cooling. Airway
ever, their efficacy should be assessed to determine where intubation and mechanical ventilation should be indi-
they fit in the current cooling armamentarium. Most of cated clinically, as arterial blood gas levels are difficult
these devices can only be used in hospitals, and specif- to interpret in hyperthermic conditions7. Hypotension
ically in specialized units, such as emergency depart- usually responds to volume replacement and cooling176.
ments, recovery rooms and intensive care units. For The management of heatstroke complications, such
example, endovascular cooling catheters require trained as ARDS, AKI, DIC, liver dysfunction, seizures and
physicians and radiological aid for insertion and sophis- coma, is similar to the organ support provided for other
ticated equipment (monitors and management units). conditions, such as trauma or sepsis1,156,157,176.

a Conventional b Modern
Cooling helmet

Ice pack Transnasal cooling

Endovascular cooling

4 ºC i.v. fluid Cooling vest

Sensor

Thermal
Evaporation Cooling pad management
Wet unit
gauze

Cool air

Whole body Cooling blanket

cold water
immersion

Fig. 6 | Conventional and novel cooling techniques. a | Conventional results in a heat loss of 1 kcal (refs176,247). Its effectiveness depends on a high
cooling is based on conductive and/or evaporative physical principles. gradient of water vapour pressure, which is achieved via water wetting of
Conductive cooling is based on establishing the largest possible gradient the body surface or covering the skin with wet gauze and providing
of temperature between the body core and the skin to accelerate passive continuous fanning. b | Modern cooling devices are based on conductive
heat transfer from the core to the surrounding ice, cold water or cooling cooling principles and include endovascular and intranasal cooling, vests,
fabric in contact with the skin1,11,247, or via infusion of cold saline at 4 °C helmets, pads and blankets engineered from highly heat-​conductive
(refs248,249). Ice packs are applied to the skin overlying the large vessels of biomaterials. These can be controlled via thermal management units that
the neck, groin and axillae, which are more effective in reducing core use real-​time skin and core temperature sensor data and sophisticated
temperature. Cooling by evaporation is based on the thermodynamic algorithms to adjust the cold output to a preset target core body
principle that the conversion of 1.7 ml of water from the skin into vapour temperature255–259. i.v., intravenous.

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Quality of life cardiovascular events and 5.5 times greater incidence

Research on heatstroke has mainly focused on imme- of ischaemic stroke268. The mechanisms that underlie
diate outcomes, such as mortality, without con- the cardiovascular complications of EHS are not clearly
sidering the quality of life as an essential outcome. apparent in humans. A study using a preclinical mouse
However, this may change as the few studies investi- model tested whether a single episode of EHS would
gating the long-​term quality of life and outcome fol- result in myocardial abnormalities several weeks after
lowing heatstroke suggest that heatstroke profoundly the episode when mice were clinically and behaviour-
affects neurological60,161–169,262–266 and cardiovascular ally recovered from the heatstroke insult269. The myo-
functions267,268, and survival60,155,209,267. However, these cardium of female mice developed marked elevations
findings should be interpreted cautiously, as they neither of free fatty acids, ceramides and diacylglycerols269.
controlled nor accounted for the treatment provided Substrate flow in glycolytic and tricarboxylic acid cycles
immediately after the onset of heatstroke or the patients’ was limited, with a build-​up of markers consistent with
lifestyle and activities during follow-​up. Nevertheless, oxidative stress and damage. These results indicate that
these studies suggest that investigation of the long-​term the myocardium may be vulnerable to a slowly emerg-
outcomes of heatstroke is important, particularly as a ing metabolic disorder after EHS, resulting in long-​term
high number of heatstroke cases are expected owing to cardiovascular complications269. Taken together, retro-
increasing frequency and intensity of heatwaves on a spective and preclinical evidence indicate that a single
rapidly warming planet10,12,13. EHS episode may induce cardiovascular complications
later in life.
Neurological complications It is also known that EHS increases the risk of a sec-
Early studies on the long-​term consequences of CHS ond episode of EHS. Clinical data suggest that 4.1–15.4%
and EHS were essentially anecdotal case reports based of patients who experience EHS reported an EHS epi-
on brain imaging studies; however, most describe cere- sode up to 2 years before216,270,271. Whether previously
bellar damage characterized by vanishing Purkinje cells sustained cardiovascular injury and damage might have
and ensuing shrinkage of the cerebellum resulting in a role in the risk of recurrent EHS remains unclear.
severe infirmity161–169,262–266. The loss of Purkinje cells was
observed post mortem159,161 and replicated in a baboon Outlook
model of CHS106 (Fig. 5). Why these particular cells are The frequency of severe heatwaves is increasing, as has
more vulnerable to the damaging effect of hyperther- been predicted by sophisticated climate models11,13.
mia warrants further study. In addition to the cerebel- Importantly, the duration of heatwaves has increased,
lum, imaging studies months and years after heatstroke with higher night-​time temperatures precluding the
showed damage to other brain regions, including the relief of heat stress provided by cool night temperatures13.
hippocampus, midbrain and thalamus161–169,262,263. Accordingly, the population at risk of dying from
Systematic examination of the long-​term conse- extreme environmental heat, including heatstroke, may
quences of CHS commenced only in the past two dec- continue to increase unless strict public health measures
ades, with the emergence of severe heatwaves that have to protect vulnerable populations are implemented and
taken thousands of lives. The preliminary data show access to cool places is facilitated. Furthermore, there is
that 10–28% of patients who survive either CHS or a need to develop specific diagnostic tests, therapies and
EHS may sustain cognitive and functional neurological biomarkers for early recognition for heatstroke and to
damage2,60,155,209. Furthermore, the neurological disabil- identify those at risk of death or developing debilitating
ities remained unchanged after 1 and 2 years in EHS60 neurological complications.
and CHS155,209, respectively. Moreover, the neurological
sequelae were independently associated with mortality Developing specific therapy
in the months and years after CHS24,27. The mechanisms Care of patients with heatstroke remains essentially
that underlie the severe functional impairment and con- supportive. Many specific therapeutic targets have been
tinued increased mortality after heatstroke have yet to be evaluated in animal models of heatstroke, but none has
elucidated. Understanding the pathways that result in reached clinical testing to date. Accordingly, no specific
neurological injury at the physiological and molecular therapy is available that is approved for use in heatstroke.
levels is crucial for identifying targeted brain protection The exuberant inflammatory response and coagulation
strategies during heatstroke. activation resulting in DIC have been the main targets
of experimental interventions using biological response
Cardiovascular complications modifier agents122,272–281 (Table 2).
Retrospective studies suggest that an episode of EHS Studies on the role of corticosteroids to modulate
can induce long-​term cardiovascular consequences and inflammation heatstroke yielded conflicting results
continued risk of death. No comparable observations depending on the models used. In rats, steroids reduced
on long-​term cardiovascular complications have been the inflammatory response, minimized brain damage
reported in CHS to date. In a military cohort study, and improved the outcome126. However, these favoura-
patients with severe heat illness had a 40% increased ble findings were not reproduced in nonhuman primate
risk of all-​cause mortality, particularly from cardio- models272. Other anti-​inflammatory approaches, includ-
vascular diseases, compared with reference cases267. ing blocking early cytokines or mediators of inflam-
Furthermore, a 14-​year follow-​up study in patients with mation, DAMPs or removing all pro-​inflammatory
EHS reported a four times higher incidence of major mediators from the circulation with extracorporeal

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techniques, are being tested in experimental mod- tissue factors and factor VII inhibitors, are being eval-
els as means to reduce an overly excessive immune uated in animal models of heatstroke as a therapy to
response120,122,273,277,278,282,283. neutralize the excessive activation of coagulation and
Various anticoagulants, including recombinants acti- prevent its progression to thrombotic and haemorrhagic
vated protein C, antithrombin III, thrombomodulin, complications122,127,132,274,276. These studies had variable

Table 2 | Experimental therapies for heatstroke

Agent Target Function Species Findings Ref.
Anticoagulants
Recombinant human Endothelial protein Anticoagulant, Baboons Cytoprotective; no effect on 127

activated protein C C receptor and cytoprotective, coagulation activation

protease-​activated anti-​inflammatory
receptor 1 Rats Improved survival; attenuated 276

coagulopathy; attenuated multiple

organ injury including brain;
attenuated systemic inflammation
Thrombomodulin Thrombin receptor Anticoagulant (inhibiting Mice Increased survival; attenuated 275

procoagulant functions systemic and tissue inflammation and

of thrombin) coagulation activation
Rats Improved survival; attenuated multiple 122

organ injury; attenuated systemic

inflammation and coagulation activation
Danaparoid Factor Xa and factor IX Anticoagulant Rats Increased survival; attenuated 273

multiple organ injury; attenuated

systemic inflammation; attenuated
coagulopathy
Antithrombin III Factor IIa (thrombin), Anticoagulant, thrombin Rats Reduced mortality; attenuated 274

factor Xa and factor IXa neutralization multiple organ injury; attenuated

systemic inflammation and coagulation
activation
Recombinant nematode Tissue factor and Anticoagulant, thrombin Baboons Inhibition of coagulation activation; 132

anticoagulant protein c factor VII inhibition antithrombotic; no survival benefit

Immunomodulators
Glucocorticoids Glucocorticoid Immunomodulation, Baboons No survival benefit; aggravation of 272

receptor anti-​inflammatory tissue injury

Rats Survival benefits; attenuated 126

inflammation; reduced brain injury

TRPV4 antagonist TRPV4 ion channels Anti-​inflammatory Mice Increased survival; attenuated heat loss 281

during recovery; attenuated multiple

organ injury; decreased inflammation
and coagulation activation
Human recombinant IL-1R Anti-​inflammatory Rabbits Increased survival; haemodynamic 278

IL-1Ra (blockade of IL-1 function) stabilization; attenuated brain injury;

attenuated systemic oxidative stress
Electrical vagus nerve Cholinergic Immunomodulation Rats Improved survival; attenuated tissue 280

stimulation anti-​inflammatory (suppression of and systemic inflammation; attenuated

pathway pro-​inflammatory endothelial injury
cytokine release)
IL-6 IL-6R Immunomodulation Mice Increased heat tolerance; maintained 277

intestinal integrity; attenuated systemic

inflammation
Janus kinase inhibitor Signal-​transducing Anti-​inflammatory Rats Increased survival; alleviated brain 279

gp130 receptor and injury; alleviated systemic inflammation

epidermal growth and oxidative stress
factor receptor
Calcium homeostasis modulators
Selective RYR1 inhibitor RYR1 Reduction of intracellular Mice (RYR1 Dose-​dependently improved survival; 284

Ca2+ release p.R2509C) reduced maximum temperature

RYR1 inhibitor AMPK and RYR1 Inhibition of RYR1-​ Mice (RYR1Y524S) Increased survival; alleviated rectal 148

mediated Ca2+ leak, temperature; alleviated hyperkalaemia;

reduction of oxidative alleviated oxidative and nitrosative
and nitrosative stress stress in myofibres
AMPK, 5′-​AMP-​activated protein kinase; RYR1, type 1 ryanodine receptor; TRPV4, transient receptor potential cation channel subfamily V member 4.

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results and further research is needed before clinical that DNA methylation occurs in a tissue-​specific and
evaluation can be considered. gene-​specific manner following chronic and acute
Studies in mice with mutant RYR1 demonstrate that exercise303. This suggests that epigenetics might be a cru-
drugs that reduce calcium leakage and oxidative stress cial mechanism that enables humans to adapt to the fre-
in muscles to restore skeletal calcium homeostasis can quent and intense heatwaves induced by climate change,
prevent and reverse lethal EHS148,284. However, before which warrants further study301,303,304. The distinction
considering further steps towards clinical testing, the between the traditional heat acclimatization phenotypes,
precise role of calcium metabolism in the pathogenesis such as lower core temperature and improved setting,
of EHS in humans requires further investigation. and epigenetics is subtle in that epigenetics involves
Finally, several studies suggest that infusion of stem gene expression modifications that may not be readily
cells can modulate the biology of heatstroke, including apparent phenotypically109. However, thermotolerance
reducing inflammation, coagulation and apoptotic cell is the primary outcome of heat acclimatization owing to
death, resulting in improved outcomes285–290. However, innate cytoprotective pathways that are enhanced and
understanding the biology of heatstroke, particularly the can, therefore, combat additional stressors to which the
articulation between the immune and stress response, body has not previously been exposed305. This type of
will be crucial to the success of any of these biological ‘cross-​tolerance’ suggests a commonality of signalling
modifier agents. pathways that are activated by non-​similar stressors and
is a unique aspect of epigenetic changes to heatstroke (or
Discovering biomarkers heat stress) that are critical for survival, beyond just the
In contrast to the development of therapy, research on immediate reduction in core temperature.
discovering biomarkers to aid the diagnosis of heatstroke Elucidating the genetic determinants of heatstroke
or identification of patients at risk of neurological dam- should be one of the priorities in biomedical research
age or death has been lagging. The advent of omics, as climate change seems to accelerate with its corollary,
including genomics, epigenomics, transcriptomics, pro- more intense heatwaves. To date, no genetic variants that
teomics and metabolomics, may fill this gap and increase could influence heatstroke biology have been uncovered
the likelihood of discovering specific signatures for the in CHS. For EHS, four candidate genes have been pos-
diagnosis or prognosis of heatstroke23,89,291–293. tulated, including RYR1, CASQ1, CACNA1S and TRPV1
(refs147,306–308). Variants of these genes were documented
Precision public health approach in a small cohort of patients with EHS147,306–308. Mice with
More than two-​thirds of the human population are Ryr1 and Casq1 variants exhibit muscle contractures, rhab-
predicted to be subjected to harmful heat in the near domyolysis and death following exposure to high envi-
future19. In most regions globally, excessive environ- ronmental temperatures that can be reversed by therapy,
mental heat may mean that life will not be sustainable73. validating their pathogenic role in EHS284,309,310. However,
A precision public health approach is needed to face the experimental models did not express the complete phe-
this emerging threat294. Determinants of death during notype, including CNS dysfunction, suggesting that addi-
heatwaves, including health and socioeconomic factors, tional genetic variants might be implicated. Nevertheless,
such as ageing, comorbidities, medications, housing, these gene candidates merit linkage and large-​scale associ-
level of education and access to air-​conditioning, have ation studies to help establish their role in the pathogenesis
been extensively studied. However, research on epige- of heatstroke, particularly those amenable to therapy284.
netics and gene–environmental heat interactions that The integration of genetic and non-​genetic factors and
would enhance individual risk prediction to heat stress their interactions with environmental heat may provide
is lacking. These investigations would provide more pre- more precise data to help improve risk prediction models
cise data for targeted prevention and better protection of for heatstroke and devise improved precision public health
population health during heatwaves. interventions and personalized care during heatwaves.
Most living species respond rapidly to environmental Many questions concerning the HSR in the popul­
stress, including cold and hot temperatures, and acclima- ation during heatwaves remain unanswered. For example,
tize to long-​term temperature changes through epige- it is unclear what level of environmental heat triggers the
netic mechanisms. The epigenetic changes include DNA HSR, the magnitude of inter-​individual variability,
and histone methylation and acetylation, and noncod- the duration of the HSR and the determinants leading to
ing RNA modifications295,296. The binding of methyl or failure to maintain homeostasis. Of note, the HSR decreases
acetyl radicals to CpG dinucleotides and histone, respec- metabolism, protein synthesis and cellular growth and
tively, can repress or activate gene expression and RNA proliferation, which is not sustainable over time311. The
splicing, altering phenotypes without changing DNA answers to these questions would provide insights into
sequences295,296. These reversible regulatory mechanisms the mechanisms that underlie the progression from heat
have been demonstrated to confer high phenotype plas- stress to heatstroke. In addition, they may improve under-
ticity during heat stress in plants to mammals296. These standing of the HSR to help develop a precise large-​scale
include thermotolerance via the acceleration of the HSR, acclimatization protocol of the population. Furthermore,
induction of HSPs, stabilization of the proteome and it would create the possibility of modulating the HSR for
increased survival297–301. Notably, epigenetic regulation has long-​term human protection in the face of substantially
been shown to be transmissible to future generations302. increased environmental temperatures in the near future.
Data on epigenetic regulation in humans during
heat stress are scarce; however, several studies revealed Published online xx xx xxxx

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1. Bouchama, A. & Knochel, J. P. Heat stroke. N. Engl. J. 25. Lopez-​Maury, L., Marguerat, S. & Bahler, J. Tuning 49. Donoghue, E. R. et al. Criteria for the diagnosis of
Med. 346, 1978–1988 (2002). gene expression to changing environments: from rapid heat-​related deaths: National Association of Medical
2. Leon, L. R. & Bouchama, A. Heat stroke. Compr. Physiol. responses to evolutionary adaptation. Nat. Rev. Examiners. Position paper. National Association of
5, 611–647 (2015). Genet. 9, 583–593 (2008). Medical Examiners Ad Hoc Committee on the
3. González-​Alonso, J., Quistorff, B., Krustrup, P., 26. Mahat, D. B., Salamanca, H. H., Duarte, F. M., Definition of Heat-​Related Fatalities. Am. J. Forensic
Bangsbo, J. & Saltin, B. Heat production in human Danko, C. G. & Lis, J. T. Mammalian heat shock Med. Pathol. 18, 11–14 (1997).
skeletal muscle at the onset of intense dynamic response and mechanisms underlying its genome-​wide 50. Nixdorf-​Miller, A., Hunsaker, D. M. & Hunsaker, J. C.
exercise. J. Physiol. 524, 603–615 (2000). transcriptional regulation. Mol. Cell 62, 63–78 3rd Hypothermia and hyperthermia medicolegal
4. Griffin, G. E. & Goldspink, G. The increase in skeletal (2016). investigation of morbidity and mortality from
muscle mass in male and female mice. Anat. Rec. This study demonstrates that the mammalian heat exposure to environmental temperature extremes.
177, 465–469 (1973). shock response is fast and extensive, leading to Arch. Pathol. Lab. Med. 130, 1297–1304 (2006).
5. Austin, M. & Berry, J. Observations on one hundred the expression of several hundreds of genes not 51. Palmiere, C. & Mangin, P. Hyperthermia and
cases of heatstroke. J. Am. Med. Assoc. 161, limited to HSF1-induced genes. postmortem biochemical investigations. Int. J. Leg.
1525–1529 (1956). 27. Richter, K., Haslbeck, M. & Buchner, J. The heat shock Med. 127, 93–102 (2013).
6. Bouchama, A. et al. Ineffectiveness of dantrolene response: life on the verge of death. Mol. Cell 40, 52. Howe, A. S. & Boden, B. P. Heat-​related illness in
sodium in the treatment of heatstroke. Crit. Care Med. 253–266 (2010). athletes. Am. J. Sports Med. 35, 1384–1395 (2007).
19, 176–180 (1991). 28. Kourtis, N., Nikoletopoulou, V. & Tavernarakis, N. 53. Yankelson, L. et al. Life-​threatening events during
7. Bouchama, A. & De Vol, E. B. Acid-​base alterations in Small heat-​shock proteins protect from heat-​stroke- endurance sports: is heat stroke more prevalent than
heatstroke. Intensive Care Med. 27, 680–685 (2001). associated neurodegeneration. Nature 490, 213–218 arrhythmic death? J. Am. Coll. Cardiol. 64, 463–469
8. Casa, D. et al. Historical perspectives on medical (2012). (2014).
care for heat stroke, part 1: ancient times through 29. Roti Roti, J. L. Cellular responses to hyperthermia 54. Gamage, P. J., Fortington, L. V. & Finch, C. F.
the nineteenth century: a review of the literature. (40–46 °C): cell killing and molecular events. Epidemiology of exertional heat illnesses in organised
Athl. Train. Sports Health Care 2, 132–138 (2010). Int. J. Hyperth. 24, 3–15 (2008). sports: A systematic review. J. Sci. Med. Sport. 23,
9. Casa, D. et al. Historical perspectives on medical care 30. Mackowiak, P. A. Concepts of fever. Arch. Intern. Med. 701–709 (2020).
for heat stroke, part 2: 1850 through the present: 158, 1870–1881 (1998). 55. Breslow, R. G. et al. Medical Tent Utilization at
a review of the literature. Athl. Train. Sports Health Care 31. Nakamura, K. Central circuitries for body temperature 10-km road races: injury, illness, and influencing
2, 178–190 (2010). regulation and fever. Am. J. Physiol. Regul. Integr. factors. Med. Sci. Sports Exerc. 51, 2451–2457
10. Perkins-​Kirkpatrick, S. E. & Lewis, S. C. Increasing Comp. Physiol. 301, R1207–R1228 (2011). (2019).
trends in regional heatwaves. Nat. Commun. 11, 3357 32. Nakamura, K. & Morrison, S. F. A thermosensory 56. Demartini, J. K. et al. Effectiveness of cold water
(2020). pathway that controls body temperature. immersion in the treatment of exertional heat stroke
11. Watts, N. et al. The 2020 report of The Lancet Nat. Neurosci. 11, 62–71 (2008). at the Falmouth Road Race. Med. Sci. Sports Exerc.
Countdown on health and climate change: responding 33. Guyton, A. & Hall, J. E. Body Temperature, Temperature 47, 240–245 (2015).
to converging crises. Lancet 397, 129–170 (2021). Regulation and Fever (W. B. Saunders, 2000). 57. Alele, F. O., Malau-​Aduli, B. S., Malau-​Aduli, A. E. O.
12. Vicedo-​Cabrera, A. M. et al. The burden of heat-​ 34. Vriens, J., Nilius, B. & Voets, T. Peripheral & Crowe, M. J. Epidemiology of exertional heat illness
related mortality attributable to recent human-​ thermosensation in mammals. Nat. Rev. Neurosci. 15, in the military: a systematic review of observational
induced climate change. Nat. Clim. Chang. 11, 573–589 (2014). studies. Int. J. Environ. Res. Public Health 17, 7037
492–500 (2021). 35. Ghaznawi, H. I. & Ibrahim, M. A. Heatstroke and heat (2020).
13. USGCRP. 2017: Climate Science Special Report: exhaustion in pilgrims performing the Haj (annual 58. Donham, B. P., Frankfurt, S. B., Cartier, R. A.,
Fourth National Climate Assessment, Volume I pilgrimage) in Saudi Arabia. Ann. Saudi Med. 7, O’Hara, S. M. & Sieg, V. C. Low Incidence of death
(eds Wuebbles, D. J. et al.) 470 (U.S. Global Change 323–326 (1987). and renal failure in United States military service
Research Program, 2017). 36. Centers for Disease Control and Prevention. members hospitalized with exertional heat stroke:
14. Carré, N., Ermanel, C., Isnard, H. & Ledrans, M. Décès Heat-​related Illness. CDC https://www.cdc.gov/ a retrospective cohort study. Mil. Med. 185,
par coup de chaleur dans les établissements de santé pictureofamerica/pdfs/picture_of_america_heat-​ 362–367 (2020).
en France: 8 aout-19 aout 2003. Bull. Epidemiol. related_illness.pdf (2021). 59. Sithinamsuwan, P. et al. Exertional heatstroke: early
Hebd. 45, 226–227 (2003). 37. Nakamura, S. & Aruga, T. Epidemiology of heat illness. recognition and outcome with aggressive combined
This study reveals that the time between onset Japan Med. Assoc. J. 56, 162–166 (2013). cooling — a 12-year experience. Mil. Med. 174,
of heatstroke signs and symptoms and death 38. Hemon, D. et al. Surmortalité liée à la canicule 496–502 (2009).
was <24 h in 47% of 2,417 patients, independent d’août 2003 en France. Bull. Epidemiol. Hebd. 60. Yang, M. et al. Outcome and risk factors associated
of age, sex and type of housing. 45–46, 221–225 (2004). with extent of central nervous system injury due to
15. Fouillet, A. et al. Excess mortality related to the 39. Dhainaut, J. F., Claessens, Y. E., Ginsburg, C. & exertional heat stroke. Medicine 96, e8417 (2017).
August 2003 heat wave in France. Int. Arch. Occup. Riou, B. Unprecedented heat-​related deaths during 61. Filep, E. M. et al. Exertional heat stroke, modality
Environ. Health 80, 16–24 (2006). the 2003 heat wave in Paris: consequences on cooling rate, and survival outcomes: a systematic
16. Jones, T. S. et al. Morbidity and mortality associated emergency departments. Crit. Care 8, 1–2 (2004). review. Medicina 56, 589 (2020).
with the July 1980 heat wave in St Louis and Kansas 40. Ghumman, U. & Horney, J. Characterizing the impact 62. Bobbert, A. C. Energy expenditure in level and
City, Mo. JAMA 247, 3327–3331 (1982). of extreme heat on mortality, Karachi, Pakistan, June grade walking. J. Appl. Physiol. 15, 1015–1021
This study shows that 61% of patients with 2015. Prehosp. Disaster Med. 31, 263–266 (2016). (1960).
heatstroke were hospitalized or died in <24 h from 41. Robine, J. M. et al. Death toll exceeded 70,000 in 63. Luhtanen, P., Rahkila, P., Rusko, H. & Viitasalo, J. T.
the onset of the heat illness. Europe during the summer of 2003. C. R. Biol. 331, Mechanical work and efficiency in ergometer bicycling
17. Semenza, J. C. et al. Heat-​related deaths during the 171–178 (2008). at aerobic and anaerobic thresholds. Acta Physiol.
July 1995 heat wave in Chicago. N. Engl. J. Med. This population-​level epidemiological study Scand. 131, 331–337 (1987).
335, 84–90 (1996). demonstrates the unprecedented incidence of 64. Ravanelli, N., Cramer, M., Imbeault, P. & Jay, O.
This study demonstrates that the mortality heat-​related deaths during the European heatwave The optimal exercise intensity for the unbiased
in heatwaves is due to heatstroke and heat-​ of 2003, underlining the emerging danger of comparison of thermoregulatory responses
aggravating chronic medical conditions, particularly climate changes to human health. between groups unmatched for body size during
cardiovascular diseases. 42. Knowlton, K. et al. The 2006 California heat wave: uncompensable heat stress. Physiol. Rep. 5, e13099
18. Bobb, J. F., Obermeyer, Z., Wang, Y. & Dominici, F. impacts on hospitalizations and emergency (2017).
Cause-​specific risk of hospital admission related to department visits. Environ. Health Perspect. 117, 65. Cramer, M. N. & Jay, O. Selecting the correct
extreme heat in older adults. JAMA 312, 2659–2667 61–67 (2009). exercise intensity for unbiased comparisons
(2014). 43. Public Health England. PHE Heatwave Mortality of thermoregulatory responses between groups of
19. Mora, C. et al. Global risk of deadly heat. Nat. Clim. Monitoring, Summer 2019. Public Health England different mass and surface area. J. Appl. Physiol. 116,
Change 7, 501 (2017). https://assets.publishing.service.gov.uk/government/ 1123–1132 (2014).
This study identifies a global threshold beyond uploads/system/uploads/attachment_data/file/ 66. Jay, O., Bain, A. R., Deren, T. M., Sacheli, M. &
which daily mean surface air temperature and 942646/PHE_heatwave_report_2019.pdf (2019). Cramer, M. N. Large differences in peak oxygen
relative humidity become deadly and predicts a 44. Government of British Columbia. Coroner Responded uptake do not independently alter changes in
48–74% increase in exposure of the world’s Deaths in B.C., June 25-July 1, 2016-2021. core temperature and sweating during exercise.
population to this deadly threshold depending on Government of British Columbia https://www2.gov.bc. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301,
the level of reduction in greenhouse gas emissions. ca/gov/content/life-​events/death/coroners-​service/ R832–R841 (2011).
20. Coombs, A. Climate change concerns prompt improved news-​and-updates/coroner-​responded-deaths 67. Crandall, C. G. & Wilson, T. E. Human cardiovascular
disease forecasting. Nat. Med. 14, 3 (2008). (2021). responses to passive heat stress. Compr. Physiol. 5,
21. Meehl, G. A. & Tebaldi, C. More intense, more 45. Semenza, J. C., McCullough, J. E., Flanders, W. D., 17–43 (2015).
frequent, and longer lasting heat waves in the McGeehin, M. A. & Lumpkin, J. R. Excess hospital 68. Rowell, L. B. Cardiovascular aspects of human
21st century. Science 305, 994–997 (2004). admissions during the July 1995 heat wave in thermoregulation. Circ. Res. 52, 367–379 (1983).
22. World Health Organization. Protecting Health from Chicago. Am. J. Prev. Med. 16, 269–277 (1999). This important review recapitulates the global
Climate Changes: Global Research Priorities. WHO 46. Hayashida, K., Shimizu, K. & Yokota, H. Severe and regional haemodynamic changes during
http://apps.who.int/iris/bitstream/handle/10665/44133/ heatwave in Japan. Acute Med. Surg. 6, 206–207 thermoregulation in humans experiencing heat
9789241598187_eng.pdf (2009). (2019). stress.
23. Bouchama, A. et al. A model of exposure to extreme 47. Barriopedro, D., Fischer, E. M., Luterbacher, J., 69. Ebi, K. L. et al. Hot weather and heat extremes: health
environmental heat uncovers the human transcriptome Trigo, R. M. & Garcia-​Herrera, R. The hot summer of risks. Lancet 398, 698–708 (2021).
to heat stress. Sci. Rep. 7, 9429 (2017). 2010: redrawing the temperature record map This paper provides a detailed description of the
24. Kultz, D. Molecular and evolutionary basis of the of Europe. Science 332, 220–224 (2011). different physiological mechanistic pathways for
cellular stress response. Annu. Rev. Physiol. 67, 48. Lee, D. H. Epidemic heat effects. JAMA 247, morbidity and mortality during extreme heatwave
225–257 (2005). 3354–3355 (1982). exposure.

Nature Reviews | Disease Primers | Article citation ID: (2022) 8:8 19

0123456789();:
Primer

70. González-​Alonso, J., Crandall, C. G. & Johnson, J. M. homeostasis at the organismal level. Proc. Natl Acad. 120. Dehbi, M. et al. Hsp-72, a candidate prognostic
The cardiovascular challenge of exercising in the heat. Sci. USA 112, E2497–E2506 (2015). indicator of heatstroke. Cell Stress Chaperones 15,
J. Physiol. 586, 45–53 (2008). 95. Tatum, M. C. et al. Neuronal serotonin release triggers 593–603 (2010).
71. Sherwood, S. C. & Huber, M. An adaptability limit the heat shock response in C. elegans in the absence 121. Dehbi, M. et al. Toll-​like receptor 4 and high-​mobility
to climate change due to heat stress. Proc. Natl Acad. of temperature increase. Curr. Biol. 25, 163–174 group Box 1 are critical mediators of tissue injury and
Sci. USA 107, 9552–9555 (2010). (2015). survival in a mouse model for heatstroke. PLoS ONE
72. Raymond, C., Matthews, T. & Horton, R. M. The 96. Tan, C. L. et al. Warm-​sensitive neurons that control 7, e44100 (2012).
emergence of heat and humidity too severe for human body temperature. Cell 167, 47–59.e15 (2016). 122. Hagiwara, S. et al. Recombinant thrombomodulin
tolerance. Sci. Adv. 6, eaaw1838 (2020). 97. Riabowol, K. T., Mizzen, L. A. & Welch, W. J. Heat shock prevents heatstroke by inhibition of high-​mobility
73. Pal, J. S. & Eltahir, E. A. B. Future temperature is lethal to fibroblasts microinjected with antibodies group box 1 protein in sera of rats. Shock 34,
in southwest Asia projected to exceed a threshold against hsp70. Science 242, 433–436 (1988). 402–406 (2010).
for human adaptability. Nat. Clim. Change 6, 197 98. Moseley, P. L. Heat shock proteins and heat 123. Kawai, T. & Akira, S. The role of pattern-​
(2015). adaptation of the whole organism. J. Appl. Physiol. recognition receptors in innate immunity: update
74. Vanos, J. K., Baldwin, J. W., Jay, O. & Ebi, K. L. 83, 1413–1417 (1997). on Toll-​like receptors. Nat. Immunol. 11, 373–384
Simplicity lacks robustness when projecting 99. Yang, Y. L. & Lin, M. T. Heat shock protein expression (2010).
heat-health outcomes in a changing climate. protects against cerebral ischemia and monoamine 124. Chen, C. M. et al. Activated protein C therapy in a rat
Nat. Commun. 11, 6079 (2020). overload in rat heatstroke. Am. J. Physiol. 276, heat stroke model. Crit. Care Med. 34, 1960–1966
75. United States Environmental Protection Agency. H1961–H1967 (1999). (2006).
Climate Change Indicators: Heat Waves. EPA 100. Lee, W. C., Wen, H. C., Chang, C. P., Chen, M. Y. & 125. Lin, M. T., Liu, H. H. & Yang, Y. L. Involvement of
https://www.epa.gov/climate-​indicators/climate-​ Lin, M. T. Heat shock protein 72 overexpression interleukin-1 receptor mechanisms in development of
change-indicators-​heat-waves (2021). protects against hyperthermia, circulatory shock, and arterial hypotension in rat heatstroke. Am. J. Physiol.
76. WHO, Regional Office for Europe. Heat Threatens cerebral ischemia during heatstroke. J. Appl. Physiol. 273, H2072–H2077 (1997).
Health: Key figures for Europe. WHO https://www. 100, 2073–2082 (2006). 126. Liu, C. C., Chien, C. H. & Lin, M. T. Glucocorticoids
euro.who.int/en/health-​topics/environment-​and- 101. Zelin, E. & Freeman, B. C. Lysine deacetylases regulate reduce interleukin-1 concentration and result in
health/Climate-​change/archive/heat-​threatens-health-​ the heat shock response including the age-​associated neuroprotective effects in rat heatstroke. J. Physiol.
key-figures-​for-europe (2021). impairment of HSF1. J. Mol. Biol. 427, 1644–1654 527, 333–343 (2000).
77. Hiromi, Y., Okamoto, H., Gehring, W. J. & Hotta, Y. (2015). 127. Bouchama, A. et al. Recombinant activated
Germline transformation with Drosophila mutant actin 102. Buckley, I. K. A light and electron microscopic study protein C attenuates endothelial injury and inhibits
genes induces constitutive expression of heat shock of thermally injured cultured cells. Lab. Invest. 26, procoagulant microparticles release in baboon
genes. Cell 44, 293–301 (1986). 201–209 (1972). heatstroke. Arterioscler Thromb. Vasc. Biol. 28,
78. Parsell, D. A. & Sauer, R. T. Induction of a heat 103. Sakaguchi, Y. et al. Apoptosis in tumors and normal 1318–1325 (2008).
shock-like response by unfolded protein in Escherichia tissues induced by whole body hyperthermia in rats. 128. Leon, L. R. The thermoregulatory consequences of
coli: dependence on protein level not protein Cancer Res. 55, 5459–5464 (1995). heat stroke: are cytokines involved? J. Therm. Biol.
degradation. Genes Dev. 3, 1226–1232 (1989). 104. Roberts, G. T. et al. Microvascular injury, thrombosis, 31, 67–81 (2006).
79. Satyal, S. H. et al. Polyglutamine aggregates alter inflammation, and apoptosis in the pathogenesis of 129. Leon, L. R., Dineen, S., Blaha, M. D.,
protein folding homeostasis in Caenorhabditis heatstroke: a study in baboon model. Arterioscler Rodriguez-​Fernandez, M. & Clarke, D. C. Attenuated
elegans. Proc. Natl Acad. Sci. USA 97, 5750–5755 Thromb. Vasc. Biol. 28, 1130–1136 (2008). thermoregulatory, metabolic, and liver acute phase
(2000). This study describes the structural and protein response to heat stroke in TNF receptor
80. Ashburner, M. & Bonner, J. J. The induction of ultrastructural damage caused by heatstroke knockout mice. Am. J. Physiol. Regul. Integr. Comp.
gene activity in Drosophila by heat shock. Cell 17, in a nonhuman primate model that replicates Physiol. 305, R1421–R1432 (2013).
241–254 (1979). human heatstroke pathology. 130. al-​Mashhadani, S. A. et al. The coagulopathy of heat
81. Feder, M. E. & Hofmann, G. E. Heat-​shock proteins, 105. Bynum, G. D. et al. Induced hyperthermia in sedated stroke: alterations in coagulation and fibrinolysis in
molecular chaperones, and the stress response: humans and the concept of critical thermal maximum. heat stroke patients during the pilgrimage (Haj) to
evolutionary and ecological physiology. Annu. Rev. Am. J. Physiol. 235, R228–R236 (1978). Makkah. Blood Coagul. Fibrinolysis 5, 731–736
Physiol. 61, 243–282 (1999). 106. Bouchama, A. et al. Inflammatory, hemostatic, and (1994).
82. Morimoto, R. I. The heat shock response: systems clinical changes in a baboon experimental model for 131. Bouchama, A. et al. Activation of coagulation and
biology of proteotoxic stress in aging and disease. heatstroke. J. Appl. Physiol. 98, 697–705 (2005). fibrinolysis in heatstroke. Thromb. Haemost. 76,
Cold Spring Harb. Symp. Quant. Biol. 76, 91–99 107. Byrne, C., Lee, J. K., Chew, S. A., Lim, C. L. & Tan, E. Y. 909–915 (1996).
(2011). Continuous thermoregulatory responses to mass-​ 132. Bouchama, A. et al. Tissue factor/factor VIIa pathway
83. Gidalevitz, T., Prahlad, V. & Morimoto, R. I. The stress participation distance running in heat. Med. Sci. mediates coagulation activation in induced-​heat stroke
of protein misfolding: from single cells to multicellular Sports Exerc. 38, 803–810 (2006). in the baboon. Crit. Care Med. 40, 1229–1236 (2012).
organisms. Cold Spring Harb. Perspect. Biol. 3, 108. Kuennen, M. et al. Thermotolerance and heat Using a human primate model of heatstroke, this
a009704 (2011). acclimation may share a common mechanism in study demonstrates that tissue factor initiates
84. Gomez-​Pastor, R., Burchfiel, E. T. & Thiele, D. J. humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. the coagulation activation in heatstroke.
Regulation of heat shock transcription factors and 301, R524–R533 (2011). 133. Sohal, R. S., Sun, S. C., Colcolough, H. L. &
their roles in physiology and disease. Nat. Rev. Mol. 109. Horowitz, M. Epigenetics and cytoprotection with heat Burch, G. E. Heat stroke. An electron microscopic
Cell Biol. 19, 4–19 (2018). acclimation. J. Appl. Physiol. 120, 702–710 (2016). study of endothelial cell damage and disseminated
85. Vihervaara, A., Duarte, F. M. & Lis, J. T. Molecular 110. Bouchard, C. Genomic predictors of trainability. intravascular coagulation. Arch. Intern. Med. 122,
mechanisms driving transcriptional stress responses. Exp. Physiol. 97, 347–352 (2012). 43–47 (1968).
Nat. Rev. Genet. 19, 385–397 (2018). 111. Lindholm, M. E. et al. An integrative analysis reveals 134. Bouchama, A., Hammami, M. M., Haq, A., Jackson, J.
86. van Oosten-​Hawle, P. & Morimoto, R. I. Transcellular coordinated reprogramming of the epigenome and the & al-​Sedairy, S. Evidence for endothelial cell
chaperone signaling: an organismal strategy for transcriptome in human skeletal muscle after training. activation/injury in heatstroke. Crit. Care Med. 24,
integrated cell stress responses. J. Exp. Biol. 217, Epigenetics 9, 1557–1569 (2014). 1173–1178 (1996).
129–136 (2014). 112. Bouchama, A., Parhar, R. S., el-​Yazigi, A., Sheth, K. & 135. Shieh, S. D., Shiang, J. C., Lin, Y. F., Shiao, W. Y. &
87. Haynes, C. M. & Ron, D. The mitochondrial UPR — al-​Sedairy, S. Endotoxemia and release of tumor Wang, J. Y. Circulating angiotensin-​converting enzyme,
protecting organelle protein homeostasis. J. Cell Sci. necrosis factor and interleukin 1 alpha in acute von Willebrand factor antigen and thrombomodulin in
123, 3849–3855 (2010). heatstroke. J. Appl. l Physiol. 70, 2640–2644 (1991). exertional heat stroke. Clin. Sci. 89, 261–265 (1995).
88. Walter, P. & Ron, D. The unfolded protein response: 113. Bouchama, A., al-​Sedairy, S., Siddiqui, S., Shail, E. & 136. O’Connor, F. G., Grunberg, N. E., Harp, J. B. &
from stress pathway to homeostatic regulation. Rezeig, M. Elevated pyrogenic cytokines in heatstroke. Duster, P. A. Exertion-​related illness: the critical roles
Science 334, 1081–1086 (2011). Chest 104, 1498–1502 (1993). of leadership and followership. Curr. Sports Med. Rep.
89. Sonna, L. A., Fujita, J., Gaffin, S. L. & Lilly, C. M. 114. Huisse, M. G. et al. Leukocyte activation: the link 19, 35–39 (2020).
Invited review: effects of heat and cold stress on between inflammation and coagulation during 137. Racinais, S., Cocking, S. & Périard, J. D. Sports and
mammalian gene expression. J. Appl. Physiol. 92, heatstroke. A study of patients during the 2003 heat environmental temperature: from warming-​up to
1725–1742 (2002). wave in Paris. Crit. Care Med. 36, 2288–2295 (2008). heating-​up. Temperature 4, 227–257 (2017).
90. Lee, J. E., Oney, M., Frizzell, K., Phadnis, N. & 115. Lu, K. C., Wang, J. Y., Lin, S. H., Chu, P. & Lin, Y. F. 138. Laitano, O. et al. Osmolality selectively offsets the
Hollien, J. Drosophila melanogaster activating Role of circulating cytokines and chemokines in impact of hyperthermia on mouse skeletal muscle
transcription factor 4 regulates glycolysis during exertional heatstroke. Crit. Care Med. 32, 399–403 in vitro. Front. Physiol. 9, 1496 (2018).
endoplasmic reticulum stress. G3 5, 667–675 (2004). 139. van der Poel, C. & Stephenson, D. G. Effects of
(2015). 116. King, M. A., Leon, L. R., Morse, D. A. & Clanton, T. L. elevated physiological temperatures on sarcoplasmic
91. Sonna, L. A. et al. Exertional heat injury and gene Unique cytokine and chemokine responses to reticulum function in mechanically skinned muscle
expression changes: a DNA microarray analysis study. exertional heat stroke in mice. J. Appl. Physiol. 122, fibers of the rat. Am. J. Physiol. Cell Physiol. 293,
J. Appl. Physiol. 96, 1943–1953 (2004). 296–306 (2017). C133–C141 (2007).
92. Guisbert, E., Czyz, D. M., Richter, K., McMullen, P. D. 117. Iwaniec, J. et al. Acute phase response to exertional 140. van der Poel, C., Edwards, J. N., Macdonald, W. A. &
& Morimoto, R. I. Identification of a tissue-​selective heat stroke in mice. Exp. Physiol. 106, 222–232 Stephenson, D. G. Effect of temperature-​induced
heat shock response regulatory network. PLoS Genet (2021). reactive oxygen species production on excitation-​
9, e1003466 (2013). 118. Biedenkapp, J. C. & Leon, L. R. Increased cytokine contraction coupling in mammalian skeletal muscle.
93. Prahlad, V., Cornelius, T. & Morimoto, R. I. Regulation and chemokine gene expression in the CNS of mice Clin. Exp. Pharmacol. Physiol. 35, 1482–1487
of the cellular heat shock response in Caenorhabditis during heat stroke recovery. Am. J. Physiol. Regul. (2008).
elegans by thermosensory neurons. Science 320, Integr. Comp. Physiol. 305, R978–R986 (2013). 141. Thongprayoon, C. et al. Impact of rhabdomyolysis
811–814 (2008). 119. Rock, K. L., Lai, J. J. & Kono, H. Innate and adaptive on outcomes of hospitalizations for heat stroke
94. Takeuchi, T. et al. Intercellular chaperone transmission immune responses to cell death. Immunol. Rev. 243, in the United States. Hosp. Pract. 48, 276–281
via exosomes contributes to maintenance of protein 191–205 (2011). (2020).

20 | Article citation ID: (2022) 8:8 www.nature.com/nrdp

0123456789();:
 Primer

142. Clarkson, P. M., Kearns, A. K., Rouzier, P., Rubin, R. & 167. McLaughlin, C. T., Kane, A. G. & Auber, A. E. 193. Gathiram, P., Gaffin, S. L., Brock-​Utne, J. G. &
Thompson, P. D. Serum creatine kinase levels and MR imaging of heat stroke: external capsule and Wells, M. T. Time course of endotoxemia and
renal function measures in exertional muscle damage. thalamic T1 shortening and cerebellar injury. cardiovascular changes in heat-​stressed primates.
Med. Sci. Sports Exerc. 38, 623–627 (2006). Am. J. Neuroradiol. 24, 1372–1375 (2003). Aviat. Space Environ. Med. 58, 1071–1074 (1987).
143. Gardner, L. et al. Investigating the genetic 168. Ookura, R., Shiro, Y., Takai, T., Okamoto, M. & 194. Shapiro, Y., Alkan, M., Epstein, Y., Newman, F. &
susceptibility to exertional heat illness. J. Med. Gene. Ogata, M. Diffusion-​weighted magnetic resonance Magazanik, A. Increase in rat intestinal permeability
57, 531–541 (2020). imaging of a severe heat stroke patient complicated to endotoxin during hyperthermia. Eur. J. Appl.
144. Dlamini, N. et al. Mutations in RYR1 are a common with severe cerebellar ataxia. Inter. Med. 48, Physiol. Occup. Physiol. 55, 410–412 (1986).
cause of exertional myalgia and rhabdomyolysis. 1105–1108 (2009). 195. Valentijn, K. M., Sadler, J. E., Valentijn, J. A.,
Neuromuscul. Disord. 23, 540–548 (2013). 169. Sudhakar, P. J. & Al-​Hashimi, H. Bilateral hippocampal Voorberg, J. & Eikenboom, J. Functional architecture
145. Protasi, F., Paolini, C. & Dainese, M. Calsequestrin-1: hyperintensities: a new finding in MR imaging of Weibel-​Palade bodies. Blood 117, 5033–5043
a new candidate gene for malignant hyperthermia and of heat stroke. Pediatr. Radiol. 37, 1289–1291 (2011).
exertional/environmental heat stroke. J. Physiol. 587, (2007). 196. Hall, D. M. et al. Mechanisms of circulatory and
3095–3100 (2009). 170. el-​Kassimi, F. A., Al-​Mashhadani, S., Abdullah, A. K. intestinal barrier dysfunction during whole body
146. Michelucci, A. et al. Strenuous exercise triggers a life-​ & Akhtar, J. Adult respiratory distress syndrome and hyperthermia. Am. J. Physiol. Heart Circ. Physiol.
threatening response in mice susceptible to malignant disseminated intravascular coagulation complicating 280, H509–H521 (2001).
hyperthermia. FASEB. J. 31, 3649–3662 (2017). heat stroke. Chest 90, 571–574 (1986). This landmark study shows the effects of
147. Roux-​Buisson, N. et al. Identification of variants of the 171. Meikle, A. W. & Graybill, J. R. Fibrinolysis and hyperthermia on the generation of reactive oxygen
ryanodine receptor type 1 in patients with exertional hemorrhage in a fatal case of heat stroke. N. Engl. J. species generation, which limits heat tolerance
heat stroke and positive response to the malignant Med. 276, 911–913 (1967). by promoting circulatory and intestinal barrier
hyperthermia in vitro contracture test. Br. J. Anaesth. 172. Perchick, J. S., Winkelstein, A. & Shadduck, R. K. dysfunction.
116, 566–568 (2016). Disseminated intravascular coagulation in heat stroke. 197. Taylor, N. A., Tipton, M. J. & Kenny, G. P.
148. Lanner, J. T. et al. AICAR prevents heat-​induced Response to heparin therapy. JAMA 231, 480–483 Considerations for the measurement of core, skin and
sudden death in RyR1 mutant mice independent (1975). mean body temperatures. J. Therm. Biol. 46, 72–101
of AMPK activation. Nat. Med. 18, 244–251 (2012). 173. Shibolet, S., Fisher, S., Gilat, T., Bank, H. & Heller, H. (2014).
149. Snoeck, M. et al. RYR1-related myopathies: Fibrinolysis and hemorrhages in fatal heatstroke. 198. Huggins, R., Glaviano, N., Negishi, N., Casa, D. J. &
a wide spectrum of phenotypes throughout life. N. Engl. J. Med. 266, 169–173 (1962). Hertel, J. Comparison of rectal and aural core body
Eur. J. Neurol. 22, 1094–1112 (2015). 174. Weber, M. B. & Blakely, J. A. The haemorrhagic temperature thermometry in hyperthermic, exercising
150. Sagui, E. Malignant hyperthermia, exertional heat diathesis of heatstroke. A consumption coagulopathy individuals: a meta-​analysis. J. Athl. Train. 47,
illness, and ryr1 variants: the muscle may not be the successfully treated with heparin. Lancet 1, 329–338 (2012).
brain. Anesthesiology 124, 510 (2016). 1190–1192 (1969). 199. Briner, W. W. Jr Tympanic membrane vs rectal
151. Sagui, E. et al. Is there a link between exertional heat 175. Chao, T. C., Sinniah, R. & Pakiam, J. E. Acute heat temperature measurement in marathon runners.
stroke and susceptibility to malignant hyperthermia? stroke deaths. Pathology 13, 145–156 (1981). JAMA 276, 194 (1996).
PloS ONE 10, e0135496 (2015). 176. Bouchama, A., Dehbi, M. & Chaves-​Carballo, E. 200. Bouchama, A., Cafege, A., Robertson, W., al-​Dossary, S.
152. González-​Alonso, J., Calbet, J. A. & Nielsen, B. Cooling and hemodynamic management in & el-​Yazigi, A. Mechanisms of hypophosphatemia
Muscle blood flow is reduced with dehydration heatstroke: practical recommendations. Crit. Care 11, in humans with heatstroke. J. Appl. Physiol. 71,
during prolonged exercise in humans. J. Physiol. 513, R54 (2007). 328–332 (1991).
895–905 (1998). 177. Hart, G. R. et al. Epidemic classical heat stroke: 201. Knochel, J. P. Exertional rhabdomyolysis. N. Eng. J.
153. Laitano, O., Oki, K. & Leon, L. R. The role of skeletal clinical characteristics and course of 28 patients. Med. 287, 927–929 (1972).
muscles in exertional heat stroke pathophysiology. Medicine 61, 189–197 (1982). 202. Hassanein, T., Razack, A., Gavaler, J. S. &
Int. J. Sports Med. 42, 673–681 (2021). 178. Sprung, C. L. Hemodynamic alterations of heat stroke Van Thiel, D. H. Heatstroke: its clinical and
154. Hyatt, H. W. & Powers, S. K. The role of calpains in the elderly. Chest 75, 362–366 (1979). pathological presentation, with particular attention
in skeletal muscle remodeling with exercise and 179. O’Donnell, T. F. Jr Acute heat stroke: epidemiologic, to the liver. Am. J. Gastroenterol. 87, 1382–1389
inactivity-​induced atrophy. Int. J. Sports Med. 41, biochemical, renal, and coagulation studies. JAMA (1992).
994–1008 (2020). 234, 824–828 (1975). 203. Kew, M. C., Minick, O. T., Bahu, R. M., Stein, R. J. &
155. Argaud, L. et al. Short- and long-​term outcomes 180. Al-​Harthi, S. S., El-​Deane, M. S., Akhtar, J. & Kent, G. Ultrastructural changes in the liver in
of heatstroke following the 2003 heat wave in Al-​Nozha, M. M. Hemodynamic changes and heatstroke. Am. J. Pathol. 90, 609–618 (1978).
Lyon, France. Arch. Intern. Med. 167, 2177–2183 intravascular hydration state in heat stroke. 204. Bouchama, A. et al. Distribution of peripheral blood
(2007). Ann. Saudi Med. 9, 378–383 (1989). leukocytes in acute heatstroke. J. Appl. Physiol. 73,
156. Misset, B. et al. Mortality of patients with heatstroke 181. Dahmash, N. S., al Harthi, S. S. & Akhtar, J. Invasive 405–409 (1992).
admitted to intensive care units during the 2003 heat evaluation of patients with heat stroke. Chest 103, 205. Costrini, A. M., Pitt, H. A., Gustafson, A. B. &
wave in France: a national multiple-​center risk-​factor 1210–1214 (1993). Uddin, D. E. Cardiovascular and metabolic
study. Crit. Care Med. 34, 1087–1092 (2006). 182. Gaudio, J., R. & Abramson, N. Heat-​induced manifestations of heat stroke and severe heat
157. Shapiro, Y. & Seidman, D. S. Field and clinical hyperventilation. J. Appl. Physiol. 25, 742–746 exhaustion. Am. J. Med. 66, 296–302 (1979).
observations of exertional heat stroke patients. (1968). 206. Paul, A., Alex, R., Jacob, J. R. & Yadav, B. Effects
Med. Sci. Sports Exerc. 22, 6–14 (1990). 183. Sprung, C. L., Portocarrero, C. J., Fernaine, A. V. & of heat stroke on surface ECG: a study on clinical
158. Ferris, E. B., Blankenhorn, M. A., Robinson, H. W. & Weinberg, P. F. The metabolic and respiratory outcomes. Heart Asia 11, e011221–e011221 (2019).
Cullen, G. E. Heat stroke: clinical and chemical alterations of heat stroke. Arch. Intern. Med. 140, 207. Hausfater, P. et al. Elevation of cardiac troponin I
observations on 44 cases. J. Clin. Invest. 17, 665–669 (1980). during non-​exertional heat-​related illnesses in the
249–261 (1938). 184. Schrier, R. W. et al. Renal, metabolic, and circulatory context of a heatwave. Crit. Care 14, R99–R99
159. Malamud, N., Haymaker, W. & Custer, R. Heatstroke: responses to heat and exercise. Studies in military (2010).
a clinico-​pathologic study of 125 fatal cases. Mil. Surg. recruits during summer training, with implications for 208. Akhtar, M. J., al-​Nozha, M., al-​Harthi, S. & Nouh, M. S.
99, 397–449 (1946). acute renal failure. Ann. Intern. Med. 73, 213–223 Electrocardiographic abnormalities in patients with
This landmark post-​mortem study reveals that (1970). heat stroke. Chest 104, 411–414 (1993).
heatstroke is a systemic illness that causes 185. Kew, M. C. et al. The effects of heatstroke on the 209. Dematte, J. E. et al. Near-​fatal heat stroke during the
extensive damage to most organs in the body. function and structure of the kidney. Q. J. Med. 36, 1995 heat wave in Chicago. Ann. Intern. Med. 129,
160. Yaqub, B. A. Neurologic manifestations of heatstroke 277–300 (1967). 173–181 (1998).
at the Mecca pilgrimage. Neurology 37, 1004–1006 186. Satirapoj, B., Kongthaworn, S., Choovichian, P. & This is the first study to show systematically that
(1987). Supasyndh, O. Electrolyte disturbances and risk heatstroke leads to long-​term severe neurological
161. Bazille, C. et al. Brain damage after heat stroke. factors of acute kidney injury patients receiving disability with a continuous risk of death after
J. Neuropathol. Exp. Neurol. 64, 970–975 (2005). dialysis in exertional heat stroke. BMC Nephrol. 17, 1 year.
162. Fuse, A. et al. Reversible focal cerebral cortical 55 (2016). 210. Bouchama, A. et al. Prognostic factors in heat wave
lesions in a patient with heat stroke. Intern. Med. 52, 187. Thongprayoon, C. et al. Impact of acute kidney injury related deaths: a meta-​analysis. Arch. Intern. Med.
377–380 (2013). on outcomes of hospitalizations for heat stroke in the 167, 2170–2176 (2007).
163. Fushimi, Y., Taki, H., Kawai, H. & Togashi, K. Abnormal United States. Diseases 8, 28 (2020). This meta-​analysis of case-​controlled studies
hyperintensity in cerebellar efferent pathways on 188. Knochel, J. P. Heat stroke and related heat stress establishes the risks associated with death during
diffusion-​weighted imaging in a patient with heat disorders. Dis. Mon. 35, 301–377 (1989). heatwaves, and shows that withdrawing from
stroke. Clin. Radiol. 67, 389–392 (2012). 189. Bi, X., Deising, A. & Frenette, C. Acute liver failure environmental heat for a few hours is the only
164. Guivarch, E., Fichet, J., Silvera, S., Zuber, B. & from exertional heatstroke can result in excellent long-​ protective factor.
Cariou, A. Prolonged but reversible coma: an unusual term survival with liver transplantation. Hepatology 211. Ellis, F. Heat wave deaths and drugs affecting
complication of severe heatstroke. Intensive Care 71, 1122–1123 (2020). temperature regulation. Br. Med. J. 2, 474 (1976).
Med. 38, 1571–1572 (2012). 190. Figiel, W. et al. Fulminant liver failure following a 212. Martinez, M., Devenport, L., Saussy, J. & Martinez, J.
165. Lee, J., Choi, J., Kang, S.-Y., Kang, J.-H. & Park, J.-K. marathon: five case reports and review of literature. Drug-​associated heat stroke. South Med. J. 95,
Heat stroke: increased signal intensity in the bilateral World J. Clin. Cases 7, 1467–1474 (2019). 799–802 (2002).
cerebellar dentate nuclei and splenium on diffusion-​ 191. Kew, M., Bersohn, I., Seftel, H. & Kent, G. Liver 213. Vassallo, S. U. & Delaney, K. A. Pharmacologic effects
weighted MR imaging. Am. J. Neuroradiol. 30, e58 damage in heatstroke. Am. J. Med. 49, 192–202 on thermoregulation: mechanisms of drug-​related
(2009). (1970). heatstroke. J. Toxicol. Clin. Toxicol. 27, 199–224
166. Mahajan, S. & Schucany, W. G. Symmetric bilateral 192. Novosad, V. L., Richards, J. L., Phillips, N. A., (1989).
caudate, hippocampal, cerebellar, and subcortical King, M. A. & Clanton, T. L. Regional susceptibility 214. Rav-​Acha, M., Hadad, E., Epstein, Y., Heled, Y. &
white matter MRI abnormalities in an adult patient to stress-​induced intestinal injury in the mouse. Moran, D. S. Fatal exertional heat stroke:
with heat stroke. Proc. (Bayl. Univ. Med. Cent.) 21, Am. J. Physiol. Gastrointest. Liver Physiol. 305, a case series. Am. J. Med. Sci. 328, 84–87
433–436 (2008). G418–G426 (2013). (2004).

Nature Reviews | Disease Primers | Article citation ID: (2022) 8:8 21

0123456789();:
Primer

215. Grundstein, A. J., Hosokawa, Y. & Casa, D. J. Fatal 238. Adams, W. M. et al. Roundtable on preseason 261. Bouchama, A. & Almuntashri, A. Patent title: Artificial
exertional heat stroke and American football players: heat safety in secondary school athletics: heat hypothalamus for body temperature regulation
the need for regional heat-​safety guidelines. J. Athl. acclimatization. J. Athl. Train. 56, 352–361 (2021). USPTO (2016).
Train. 53, 43–50 (2018). 239. Vicario, S. J., Okabajue, R. & Haltom, T. Rapid 262. Guerrero, W. R., Varghese, S., Savitz, S. & Wu, T. C.
216. Abriat, A., Brosset, C., Brégigeon, M. & Sagui, E. cooling in classic heatstroke: effect on mortality rates. Heat stress presenting with encephalopathy and MRI
Report of 182 cases of exertional heatstroke in Am. J. Emerg. Med. 4, 394–398 (1986). findings of diffuse cerebral injury and hemorrhage.
the French armed forces. Mil. Med. 179, 309–314 240. Dewey, W. C., Hopwood, L. E., Sapareto, S. A. & BMC Neurol. 13, 1 (2013).
(2014). Gerweck, L. E. Cellular responses to combinations 263. Kim, K. K. et al. Neurological manifestations and
217. Casa, D. J. et al. The inter-​association task force for of hyperthermia and radiation. Radiology 123, image findings in patients with exercise-​induced
preventing sudden death in secondary school athletics 463–474 (1977). heat stroke. J. Korean Neurol. Assoc. 22, 115–121
programs: best-​practices recommendations. J. Athl. 241. Glahn, K. P. E. et al. Availability of dantrolene for (2004).
Train. 48, 546–553 (2013). the management of malignant hyperthermia crises: 264. Albukrek, D., Bakon, M., Moran, D. S., Faibel, M. &
218. Wu, Y. et al. Context-​aware heatstroke relief station European Malignant Hyperthermia Group guidelines. Epstein, Y. Heat-​stroke-induced cerebellar atrophy:
placement and route optimization for large outdoor Br. J. Anaesth. 125, 133–140 (2020). clinical course, CT and MRI findings. Neuroradiology
events. Int. J. Health Geogr. 20, 23 (2021). 242. Garcia, C. K. et al. Effects of ibuprofen during 39, 195–197 (1997).
219. Morris, N. B. et al. Sustainable solutions to mitigate exertional heat stroke in mice. Med. Sci. Sports Exerc. 265. Rav-​Acha, M., Shuvy, M., Hagag, S., Gomori, M.
occupational heat strain - an umbrella review of 52, 1870–1878 (2020). & Biran, I. Unique persistent neurological sequelae
physiological effects and global health perspectives. 243. Audet, G. N. et al. Pretreatment with indomethacin of heat stroke. Mil. Med. 172, 603–606 (2007).
Environ. Health 19, 95 (2020). results in increased heat stroke severity during 266. Schermann, H., Sherman, M. & Rutenberg, R. Case
220. Jay, O. et al. Reducing the health effects of hot recovery in a rodent model of heat stroke. J. Appl. report of a new headache developed by a combat
weather and heat extremes: from personal cooling Physiol. 123, 544–557 (2017). soldier after an episode of exertional heat illness.
strategies to green cities. Lancet 398, 709–724 244. Walter, E. & Gibson, O. The efficacy of antibiotics in Front. Neurol. 8, 383–383 (2017).
(2021). reducing morbidity and mortality from heatstroke — a 267. Wallace, R. F., Kriebel, D., Punnett, L., Wegman, D. H.
221. Lowe, D., Ebi, K. L. & Forsberg, B. Heatwave early systematic review. J. Therm. Biol. 88, 102509 (2020). & Amoroso, P. J. Prior heat illness hospitalization
warning systems and adaptation advice to reduce 245. Leon, L. R., DuBose, D. A. & Mason, C. W. Heat stress and risk of early death. Environ. Res. 104, 290–295
human health consequences of heatwaves. Int. J. induces a biphasic thermoregulatory response in mice. (2007).
Environ. Res. Public Health 8, 4623–4648 (2011). Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, 268. Wang, J. C. et al. The association between heat stroke
222. Morris, N. B. et al. Electric fan use for cooling during R197–R204 (2005). and subsequent cardiovascular diseases. PLoS ONE
hot weather: a biophysical modelling study. Lancet 246. Leon, L. R., Gordon, C. J., Helwig, B. G., Rufolo, D. M. 14, e0211386 (2019).
Planet Health 5, e368–e377 (2021). & Blaha, M. D. Thermoregulatory, behavioral, and This 14-year follow-​up study shows that patients
223. Morris, N. B., English, T., Hospers, L., Capon, A. metabolic responses to heatstroke in a conscious who have heatstroke have an increased incidence
& Jay, O. The effects of electric fan use under mouse model. Am. J. Physiol. Regul. Integr. Comp. of acute myocardial infarction and an increased
differing resting heat index conditions: a clinical trial. Physiol. 299, R241–R248 (2010). incidence of acute ischaemic stroke.
Ann. Intern. Med. 171, 675–677 (2019). 247. Wyndham, C. H. et al. Methods of cooling subjects 269. Laitano, O. et al. Delayed metabolic dysfunction in
224. Morris, N. B. et al. A preliminary study of the effect with hyperpyrexia. J. Appl. Physiol. 14, 771–776 myocardium following exertional heat stroke in mice.
of dousing and foot immersion on cardiovascular and (1959). J. Physiol. 598, 967–985 (2020).
thermal responses to extreme heat. JAMA 322, 248. Morrison, K. E., Desai, N., McGuigan, C., Lennon, M. This study shows that exertional heat stroke
1411–1413 (2019). & Godek, S. F. Effects of intravenous cold saline on promotes negative changes in the metabolome of
225. Nelson, D. A., Deuster, P. A., O’Connor, F. G. & hyperthermic athletes representative of large football the myocardium that emerge only 9–14 days after
Kurina, L. M. Timing and predictors of mild and severe players and small endurance runners. Clin. J. Sport the episode.
heat illness among new military enlistees. Med. Sci. Med. 28, 493–499 (2018). 270. Schermann, H. et al. Probability of heat intolerance:
Sports Exerc. 50, 1603–1612 (2018). 249. Mok, G., DeGroot, D., Hathaway, N. E., Bigley, D. P. & standardized interpretation of heat-​tolerance testing
226. Morrissey, M. C. et al. Heat safety in the workplace: McGuire, C. S. Exertional heat injury: effects of adding results versus specialist judgment. J. Athl. Train. 53,
modified delphi consensus to establish strategies cold (4 °C) intravenous saline to prehospital protocol. 423–430 (2018).
and resources to protect the US worker. Geohealth 5, Curr. Sports Med. Rep. 16, 103–108 (2017). 271. Stearns, R. L. et al. Incidence of recurrent exertional
e2021GH000443 (2021). 250. Smith, J. E. Cooling methods used in the treatment heat stroke in a warm-​weather road race. Medicina
227. Roberts, W. O. Determining a “do not start” of exertional heat illness. Br. J. Sports Med. 39, 56, 720 (2020).
temperature for a marathon on the basis of adverse 503–507 (2005). 272. Bouchama, A. et al. Glucocorticoids do not protect
outcomes. Med. Sci. Sports Exerc. 42, 226–232 251. Douma, M. J. et al. First aid cooling techniques for against the lethal effects of experimental heatstroke
(2010). heat stroke and exertional hyperthermia: a systematic in baboons. Shock 27, 578–583 (2007).
228. Racinais, S. et al. Consensus recommendations on review and meta-​analysis. Resuscitation 148, 273. Hagiwara, S. et al. Danaparoid sodium attenuates the
training and competing in the heat. Br. J. Sports Med. 173–190 (2020). effects of heat stress. J. Surg. Res. 171, 762–768
49, 1164–1173 (2015). This meta-​analysis shows that water immersion (2011).
229. Hosokawa, Y. et al. Activity modification in heat: techniques (using 1–17 °C water) more effectively 274. Hagiwara, S. et al. High-​dose antithrombin III prevents
critical assessment of guidelines across athletic, lowers core body temperatures than passive heat stroke by attenuating systemic inflammation in
occupational, and military settings in the USA. cooling in adults with hyperthermia. rats. Inflamm. Res. 59, 511–518 (2010).
Int. J. Biometeorol. 63, 405–427 (2019). 252. McDermott, B. P. et al. Acute whole-​body cooling for 275. Kawasaki, T., Okamoto, K., Kawasaki, C. &
230. Kerr, Z. Y. et al. The association between mandated exercise-​induced hyperthermia: a systematic review. Sata, T. Thrombomodulin improved liver injury,
preseason heat acclimatization guidelines and J. Athl. Train. 44, 84–93 (2009). coagulopathy, and mortality in an experimental
exertional heat illness during preseason high school 253. Al-​Aska, A. K., Abu-​Aisha, H., Yaqub, B., Al-​Harthi, S. S. heatstroke model in mice. Anesth. Analg. 118,
American football practices. Environ. Health Perspect. & Sallam, A. Simplified cooling bed for heatstroke. 956–963 (2014).
127, 47003 (2019). Lancet 1, 381 (1987). 276. Lin, X. J. et al. Activated protein C can be used as a
231. Sawka, M. N. et al. American College of Sports 254. Graham, B. S., Lichtenstein, M. J., Hinson, J. M. & prophylactic as well as a therapeutic agent for heat
Medicine position stand. Exercise and fluid Theil, G. B. Nonexertional heatstroke. Physiologic stroke in rodents. Shock 32, 524–529 (2009).
replacement. Med. Sci. Sports Exerc. 39, 377–390 management and cooling in 14 patients. Arch. Intern. 277. Phillips, N. A., Welc, S. S., Wallet, S. M., King, M. A. &
(2007). Med. 146, 87–90 (1986). Clanton, T. L. Protection of intestinal injury during
232. Kerr, Z. Y. et al. Exertional heat-​stroke preparedness 255. Bursey, M. M., Galer, M., Oh, R. C. & Weathers, B. K. heat stroke in mice by interleukin-6 pretreatment.
in high school football by region and state mandate Successful management of severe exertional heat J. Physiol. 593, 739–753 (2015).
presence. J. Athl. Train. 54, 921–928 (2019). stroke with endovascular cooling after failure of 278. Shen, K. H., Chang, C. K., Lin, M. T. & Chang, C. P.
233. Scarneo-​Miller, S. E., Saltzman, B., Adams, W. M. & standard cooling measures. J. Emerg. Med. 57, Interleukin-1 receptor antagonist restores
Casa, D. J. Regional requirements influence adoption e53–e56 (2019). homeostatic function and limits multiorgan damage
of exertional heat illness preparedness strategies in 256. Manegold, R., Fistera, D., Holzner, C. & Risse, J. in heatstroke. Eur. J. Appl. Physiol. 103, 561–568
United States high schools. Medicina 56, 488 (2020). Effective intranasal cooling in an 80 year old (2008).
234. Parsons, J. T., Anderson, S. A., Casa, D. J. & patient with heatstroke. Am. J. Emerg. Med. 38, 279. Tao, Z. et al. JAK2/STAT3 pathway mediating
Hainline, B. Preventing catastrophic injury and 2488.e1–2488.e2 (2020). inflammatory responses in heatstroke-​induced rats.
death in collegiate athletes: interassociation 257. Hosokawa, Y., Belval, L. N., Adams, W. M., Int. J. Clin. Exp. Pathol. 8, 6732–6739 (2015).
recommendations endorsed by 13 medical and sports Vandermark, L. W. & Casa, D. J. Chemically 280. Yamakawa, K. et al. Electrical vagus nerve stimulation
medicine organisations. Br. J. Sports Med. 54, 208 activated cooling vest’s effect on cooling rate attenuates systemic inflammation and improves
(2020). following exercise-​induced hyperthermia: a survival in a rat heatstroke model. PLoS ONE 8,
235. Benjamin, C. L. et al. The effects of hydration randomized counter-​balanced crossover study. e56728 (2013).
status and ice-​water dousing on physiological and Medicina 56, 539 (2020). 281. Zhu, Y. H. & Pei, Z. M. GSK2193874 treatment at
performance indices during a simulated soccer match 258. Yeargin, S. et al. Physiological and perceived effects of heatstroke onset reduced cell apoptosis in heatstroke
in the heat. J. Sci. Med. Sport 24, 723–728 (2021). forearm or head cooling during simulated firefighting mice. Cell. Mol. Biol. 64, 36–42 (2018).
236. Hosokawa, Y. et al. Prehospital management of activity and rehabilitation. J. Athl. Train. 51, 927–935 282. Chen, G. M. et al. Clearance of serum solutes
exertional heat stroke at sports competitions: (2016). by hemofiltration in dogs with severe heat stroke.
International Olympic Committee Adverse Weather 259. Tan, P. M. et al. Evaluation of various cooling systems Scand. J. Trauma. Resusc. Emerg. Med. 22, 49
Impact Expert Working Group for the Olympic Games after exercise-​induced hyperthermia. J. Athl. Train. 52, (2014).
Tokyo 2020. Br. J. Sports Med. 55, 1405–1410 108–116 (2017). 283. Chen, G. M. et al. Effects of continuous
(2021). 260. Bernard, S. A. et al. Treatment of comatose survivors haemofiltration on serum enzyme concentrations,
237. Racinais S., Sawka, M. N., Daanen, H. & Périard, J. D. of out-​of-hospital cardiac arrest with induced endotoxemia, homeostasis and survival in dogs with
in Heat Stress in Sport and Exercise (eds Périard, J. D. hypothermia. N. Engl. J. Med. 346, 557–563 severe heat stroke. Resuscitation 83, 657–662
& Racinais, S.) 159–178 (Springer, 2019). (2002). (2012).

22 | Article citation ID: (2022) 8:8 www.nature.com/nrdp

0123456789();:
 Primer

284. Yamazawa, T. et al. A novel RyR1-selective inhibitor mediated cytoprotective memory. J. Appl. Physiol. 320. Gagnon, D. & Kenny, G. P. Does sex have an
prevents and rescues sudden death in mouse models 109, 1552–1561 (2010). independent effect on thermoeffector responses
of malignant hyperthermia and heat stroke. 302. Skinner, M. K. Environmental stress and epigenetic during exercise in the heat? J. Physiol. 590,
Nat. Commun. 12, 4293 (2021). transgenerational inheritance. BMC Med. 12, 153 5963–5973 (2012).
285. Hwang, W. S. et al. Human umbilical cord blood-​ (2014). 321. Belval, L. N. et al. Interaction of exercise intensity
derived CD34+ cells can be used as a prophylactic 303. Voisin, S., Eynon, N., Yan, X. & Bishop, D. J. and simulated burn injury size on thermoregulation.
agent for experimental heatstroke. J. Pharmacol. Sci. Exercise training and DNA methylation in humans. Med. Sci. Sports Exerc. 53, 367–374 (2021).
106, 46–55 (2008). Acta Physiol. 213, 39–59 (2015). 322. Belval, L. N. et al. Consensus statement - prehospital
286. Liu, W. S. et al. Human umbilical cord blood cells 304. Burggren, W. Epigenetic inheritance and its role care of exertional heat stroke. Prehosp. Emerg. Care
protect against hypothalamic apoptosis and systemic in evolutionary biology: re-​evaluation and new 22, 392–397 (2018).
inflammation response during heatstroke in rats. perspectives. Biology 5, 24 (2016). 323. Bligh, J. & Johnson, K. G. Glossary of terms for
Pediatr. Neonatol. 50, 208–216 (2009). 305. Horowitz, M. Heat acclimation and cross-​tolerance thermal physiology. J. Appl. Physiol. 35, 941–961
287. Tseng, L. S., Chen, S. H., Lin, M. T. & Lin, Y. C. against novel stressors: genomic-​physiological linkage. (1973).
Umbilical cord blood-​derived stem cells improve heat Prog. Brain Res. 162, 373–392 (2007). 324. Périard, J. D., Racinais, S. & Sawka, M. N.
tolerance and hypothalamic damage in heat stressed 306. Fiszer, D. et al. Next-​generation sequencing of Adaptations and mechanisms of human heat
mice. Biomed. Res. Int. 2014, 685683 (2014). RYR1 and CACNA1S in malignant hyperthermia acclimation: applications for competitive athletes
288. Tseng, L. S., Chen, S. H., Lin, M. T. & Lin, Y. C. and exertional heat illness. Anesthesiology 122, and sports. Scand. J. Med. Sci. Sports 25 (Suppl. 1),
Transplantation of human dental pulp-​derived 1033–1046 (2015). 20–38 (2015).
stem cells protects against heatstroke in mice. 307. Li, Y., Wang, Y. & Ma, L. An association study 325. Murray, K. O. et al. Exertional heat stroke leads
Cell Transplant. 24, 921–937 (2015). of CASQ1 gene polymorphisms and heat stroke. to concurrent long-​term epigenetic memory,
289. Umemura, Y. et al. Bone marrow-​derived mononuclear Genomics Proteom. Bioinforma. 12, 127–132 immunosuppression and altered heat shock response
cell therapy can attenuate systemic inflammation (2014). in female mice. J. Physiol. 599, 119–141 (2021).
in rat heatstroke. Scand. J. Trauma. Resusc. Emerg. 308. Bosson, C. et al. Variations in the TRPV1 gene are This study demonstrates in a mouse exertional
Med. 26, 97 (2018). associated to exertional heat stroke. J. Sci. Med. heat stress model that heatstroke induces long-​
290. Zhang, Y. et al. Mesenchymal stem cells provide Sport 23, 1021–1027 (2020). term immune and heat shock responses that may
neuroprotection by regulating heat stroke-​induced 309. Durham, W. J. et al. RyR1 S-​nitrosylation underlies be linked to specific epigenetic profiles in bone
brain inflammation. Front. Neurol. 11, 372 (2020). environmental heat stroke and sudden death in marrow-​derived monocytes.
291. Sonna, L. A. et al. Effect of acute heat shock on gene Y522S RyR1 knockin mice. Cell 133, 53–65 (2008). 326. Casa, D. J. et al. Cold water immersion: the gold
expression by human peripheral blood mononuclear 310. Dainese, M. et al. Anesthetic- and heat-​induced standard for exertional heatstroke treatment.
cells. J. Appl. Physiol. 92, 2208–2220 (2002). sudden death in calsequestrin-1-knockout mice. Exerc. Sport Sci. Rev. 35, 141–149 (2007).
292. Stallings, J. D. et al. Patterns of gene expression FASEB J. 23, 1710–1720 (2009).
associated with recovery and injury in heat-​stressed 311. Lamech, L. T. & Haynes, C. M. The unpredictability Author contributions
rats. BMC Genomics 15, 1058 (2014). of prolonged activation of stress response pathways. Introduction (A.B., C.L., O.L., O.J., F.G.O. and L.R.L.);
293. Zhang, H. J., Drake, V. J., Morrison, J. P., Oberley, L. W. J. Cell Biol. 209, 781–787 (2015). Epidemiology (A.B., O.J., F.G.O. and L.R.L.); Mechanisms/
& Kregel, K. C. Selected contribution: differential 312. Santé publique France. Bilan de mortalité des pathophysiology (A.B., B.A., C.L., O.L., O.J. and L.R.L.);
expression of stress-​related genes with aging and épisodes de chaleur de juin et juillet 2019. Santé Diagnosis, screening and prevention (A.B., F.G.O. and L.R.L.);
hyperthermia. J. Appl. Physiol. 92, 1762 (2002). publique France https://www.santepubliquefrance.fr/ Management (A.B., B.A., C.L., O.L., O.J., F.G.O. and L.R.L.);
294. Khoury, M. J. et al. From public health genomics to determinants-​de-sante/climat/fortes-​chaleurs-canicule/ Quality of life (A.B., B.A., C.L., O.L., F.G.O. and L.R.L.);
precision public health: a 20-year journey. Genet. documents/bulletin-​national/systeme-​d-alerte-​ Outlook (A.B., B.A., C.L., O.L., O.J., F.G.O. and L.R.L.);
Med. 20, 574–582 (2018). canicule-et-​sante.-bilan-​de-mortalite-​des-episodes-​ Overview of the Primer (A.B.).
295. Rakyan, V. K., Down, T. A., Balding, D. J. & Beck, S. de-chaleur-​de-juin-​et-juillet-2019 (2019).
Epigenome-​wide association studies for common 313. Parsons, K. Human Thermal Environments: The Effects Competing interests
human diseases. Nat. Rev. Genet. 12, 529–541 of Hot, Moderate, and Cold Environments on A.B. is patent holder for ‘Artificial hypothalamus for body
(2011). Human Health, Comfort, and Performance 3rd edn temperature regulation’ (US20170216086A1; co-​inventor:
296. McCaw, B. A., Stevenson, T. J. & Lancaster, L. T. (CRC Press, 2002). A. Almuntashri) but has not received any royalties. The pat-
Epigenetic responses to temperature and climate. 314. Clarke, J. F. Some effects of the urban structure ent describes the next generation of cooling systems; cur-
Integ. Comp. Biol. 60, 1469–1480 (2020). on heat mortality. Environ. Res. 5, 93–104 (1972). rently at proof-​of-​concept stage. F.G.O. is a medical and
This review identifies areas of future research 315. Piver, W. T., Ando, M., Ye, F. & Portier, C. J. science advisory board member of Korey Stringer Institute.
in epigenetic responses to environmental Temperature and air pollution as risk factors for heat The other authors declare no competing interests.
temperature change. stroke in Tokyo, July and August 1980-1995. Environ.
297. Hu, Z. et al. Histone acetyltransferase GCN5 is Health Perspect. 107, 911–916 (1999). Disclaimer
essential for heat stress-​responsive gene activation 316. Dervis, S. et al. A comparison of thermoregulatory The opinions or assertions contained herein are the private
and thermotolerance in Arabidopsis. Plant J. 84, responses to exercise between mass-​matched groups views of the author(s) and are not to be construed as official
1178–1191 (2015). with large differences in body fat. J. Appl. Physiol. or as reflecting the views of the Army, Uniformed Services
298. Petesch, S. J. & Lis, J. T. Rapid, transcription-​ 120, 615–623 (2016). University of the Health Sciences, or the Department of
independent loss of nucleosomes over a large 317. Cramer, M. N. & Jay, O. Explained variance in Defense.
chromatin domain at Hsp70 loci. Cell 134, 74–84 the thermoregulatory responses to exercise: the
(2008). independent roles of biophysical and fitness/fatness-​ Peer review information
299. Dai, T. M. et al. Molecular characterizations of DNA related factors. J. Appl. Physiol. 119, 982–989 (2015). Nature Reviews Disease Primers thanks Oliver Gibson,
methyltransferase 3 and its roles in temperature 318. Gagge, A. P. & Gonzalez, R. R. in Comprehensive Zachary Schlader, Rebecca Stearns and the other, anony-
tolerance in the whitefly, Bemisia tabaci Mediterranean. Physiology 45–84 (Wiley, 1996). mous, reviewer(s) for their contribution to the peer review of
Insect Mol. Biol. 27, 123–132 (2018). A comprehensive overview of the fundamental this work.
300. Vabulas, R. M., Raychaudhuri, S., Hayer-​Hartl, M. & factors altering human heat balance during passive
Hartl, F. U. Protein folding in the cytoplasm and the and active heat stress. Publisher’s note
heat shock response. Cold Spring Harb. Perspect. Biol. 319. Ravanelli, N., Coombs, G. B., Imbeault, P. & Jay, O. Springer Nature remains neutral with regard to jurisdictional
2, a004390 (2010). Maximum skin wettedness after aerobic training with claims in published maps and institutional affiliations.
301. Tetievsky, A. & Horowitz, M. Posttranslational and without heat acclimation. Med. Sci. Sports Exerc.
modifications in histones underlie heat acclimation-​ 50, 299–307 (2018). © Springer Nature Limited 2022

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