By Andrea Albieri, PhD – Senior Advisor Scientist at Life Health Centers
The heat shock response is a highly conserved primitive and essential response for survival against a wide range of stresses, including Hyperthermia (extremes of temperature). Fever is a more recently evolved response. During fever, organisms raise their core body temperature and temporarily subject themselves to thermal stress when facing infections. The usual 2–3 °C increase in core body temperature during fever activates and utilizes elements of the heat shock (HS) response pathway to modify cytokine and chemokine gene expression. Besides, cellular signaling and immune cell mobilization are triggered to target sites of inflammation, infection and injury (1).
Interestingly, typical proinflammatory agonists modify the heat shock-induced expression of heat shock proteins (HSP) genes, suggesting a complex reciprocal regulation between the inflammatory pathway and the heat shock response pathway (1).
Although fever is recognized as a component of the acute-phase response to infection and perceived to be a response limited to mammals and birds, other animals, including lower vertebrates, arthropods, and annelids also increase their core temperature in response to infection or injury (2).
Febrile temperatures are so closely linked to the inflammatory response where heat is one of the four cardinal signs of inflammation, along with pain, redness, and swelling, as described by Celsius in ~30 BC. The induction and maintenance of a physiological core temperature at febrile levels in warm-blooded animals, including humans, occurs at a high metabolic cost such that a 1°C rise in body temperature requires a 10–12.5% increase in metabolic rate. Specifically, in humans, generating fever through thermogenic shivering requires up to a 6-fold increase in metabolic rate (3, 4, 5, 6).
The evolutionary conservation of the fever response over millions of years is in line with its protective role. The survival benefit conferred on the host outweighs the metabolic cost of elevating core body temperatures during infection (3).
Fever must confer benefit that generally outweighs these costs in the infected or injured host. Furthermore, given the phylogenetic age of fever, the immunological processes that are active during febrile illnesses have had ample opportunity to evolve for optimal function at febrile temperatures (1).
While fever is a systemic response to infection and injury, the HS response acts as a defense mechanism against cellular stress. The HS response, which is also a highly conserved ancient biological process, is essential for survival against different environmental stresses, including extremes of temperature, chemicals and radiations which can cause denaturation of essential cellular proteins. Also referred to as the ‘cellular stress response’ the HS response is accompanied with reprogramming the cell to preferentially express a set of stress-inducible proteins namely the heat shock proteins (HSPs) (1).
HSPs are a group of protective proteins that are upregulated in response to many types of stress, including heat, stress and injury (7, 8). Other stressors may also include nutrient deficiency, oxidative stress, acute or chronic inflammatory diseases, viral infections, ischemia, heavy metals, exercise, gravity, and bacterial infections (9). They induce expression of a family of genes known as the heat shock protein genes. The DNA sequence that makes up this family of genes is highly conserved across species (10).
Molecular chaperones, also a functional name for HSPs, are found in all living cells and form part of the defense system against internal and external stressors. They are primarily grouped into two major groups according to their characteristics as the high molecular weight and the small molecular weight HSPs. The high molecular weight HSPs, ranging from 60 to 110 kDa, are energy-dependent and their primary cellular function is binding and folding of nascent proteins, even though assembling, transportation, and vaccination against cancer metastasis. Degradation of improperly-folded peptides have also been reported. Small molecular weight HSPs or heat shock protein β (HspBs), which range from 15 to 43 kDa, are ATP-independent molecular chaperones, and functions have been documented in embryo developmental processes, formation of respiratory organs, like cardiac muscles, as biomarkers for tumor formation, in exercise-induced stress, as well as in protein folding (9).
The HSPs are named according to their molecular size. The 70-kd protein is referred to as HSP70, and the gene coding for that protein would be hsp70. Members of the HSP70 family are the most extensively studied group of stress proteins to date. Some members of the HSP70 family are expressed constitutively, and others are strictly stress inducible (8). The 70-kDa heat shock protein (HSP70) family of molecular chaperones is a ubiquitous class of molecular chaperones and conserved protein families throughout evolution. Upregulation of the HSP70 family promotes cell survival in the face of endogenous or exogenous challenges. In the heart, HSP70 and its protein homologue, are integral for disease prevention and protecting cardiomyocytes from stress (11).
HSP72, a member of the HSP70 family, is not increased in heart failure because HSF activity is not changed; however, increased expression of HSP60 may be driven by NFκB activation (12). Considering temperature increase, detectable HSP70 protein expression requires 24 h exposure at 38.5 C, 6 h exposure at 39.5 C, and only 1 h exposure at 41 C. (Life Health Centers use temperatures as high as 103F = 39.44C; 104F = 40C, and 105F = 40.55C)
It is evident that the three components of the HS response pathway, namely the stressor, the central activator, and the final product, which is a HSP, have all evolved to perform additional functions beyond the typical cellular stress response. All three components have strong immunomodulatory effects that include mobilization of immune cells, regulation of proinflammatory cytokine/chemokine gene expression and activation of both pro- and anti-inflammatory pathways (1).
Temperature like 41–42o C may represent a key temperature threshold in human cells above which the relationship between hsp70 gene activation and temperature shifts. That 41o C is the upper limit of the normal human febrile range underscores the biological significance of this relationship (13).
Nowadays, high body temperatures can also be achieved using external methods to target different treatments. Under circumstances like these, increasing in total body temperature is not related to an infection, stress, exercise, or any pathology. Passive hyperthermia therapy, like sauna therapy, increases body temperature and acts mainly in the cardiovascular system, inducing cutaneous vasodilation and increasing skin blood flow, heart rate (14), cardiac output, and sweating (15) while reducing total peripheral resistance, diastolic pressure, and mean arterial pressure (16).
Furthermore, saunas have been used to relieve pain while treating various disorders have been shown to benefit patients with depression and fatigue. Furthermore, they may provide a promising therapy for patients with lifestyle-related diseases, such as, obesity. By contrast, some studies have revealed the adverse effects of sauna therapy. The most serious adverse effect during sauna therapy (passive hyperthermia) or within the first 12 h thereafter is sudden death, which is usually due to an underlying, although not necessarily previously diagnosed, cardiovascular disease (17).
Simon Fraser University professor Peter Ruben found when studying the proteins that underlie electrical signaling in the heart and subjecting those proteins to conditions that are similar to the stress of exercise (which may be considered active hyperthermia), in some cases, that temperature can cause changes that trigger arrhythmia.
When muscle cells in our hearts contract rhythmically and in a well-coordinated way, the heart efficiently pumps blood throughout our bodies. When the rhythmic pumping action is disrupted by an arrhythmia, our hearts can no longer distribute blood. In extreme cases, this leads to sudden cardiac death. He adds: “The electrical signal behind muscle contraction is produced by tiny protein molecules in the membrane of our heart cells. Temperature fluctuations modify the way all proteins behave, but some DNA mutations can make proteins especially sensitive to changes in temperature.” (18)
An example may be the E1784K mixed syndrome mutant of the cardiac voltage-gated sodium channel that responds differently to temperature changes compared to the R1193Q mutant and wild-type. Hyperthermia exacerbates the Brugada syndrome 1 phenotype, which may be arrhythmogenic in E1784K mutants (18).
However, experiments in rat demonstrated that the ability to induce cardiac HSP72 is reduced after exposure to hyperthermia. It is supposed that an increase in the level of HSP72 in the failing heart would be beneficial for reducing the myocardial damage. However, the induction of HSP72 after an exposure to heat shock is blunted in the failing rat heart following myocardial infarction (19).
On the other hand, a study conducted by Basford et al observed that sauna bathing under the moderate and supervised conditions appears to be well tolerated and may be safe for people with chronic heart failure (20).
Interestingly, Brunt and colleagues investigated the effects of 8 weeks of repeated hot water immersion (‘heat therapy’) on various biomarkers of cardiovascular health in young, sedentary humans. Their results showed for the first time that heat therapy has widespread and robust effects on vascular function, and as such, could be a viable treatment option for improving cardiovascular health in a variety of patient populations, particularly those with limited exercise tolerance and/or capabilities. Heat therapy improved endothelium-dependent dilatation, arterial stiffness, intima media thickness and blood pressure, indicating improved cardiovascular health. These data suggested that heat therapy may provide a simple and effective tool for improving cardiovascular health in various populations (21).
It is known that heat is a natural vasodilator. The right use of heat in the form of thermal baths, saunas, and/or heating pads is slowly gaining recognition as a potential supplement to pharmaceuticals to improve endothelial function and cardiorenal hemodynamics in select patients with chronic heart failure.
Salutary responses were thought to persist long after the course of treatment had been completed. These responses included slowing of the pulse, increase in pulse volume, more distinct heart sounds, reduction in heart size, slowing and increased depth of respirations, and enhanced urinary output (22).
An important highlight considering hyperthermia was observed in an experiment which demonstrated that exposure of human subjects to a warm or cool environment via a water-perfused garment (fitted suit that covers the body except the hands, feet, neck and head) rather than a stress also induced a significant change in metabolism (e.g., occupational tasks, exercise, or shivering). This important distinction of passive-thermal stress versus exercise-thermal stress allows for the determination of direct thermal effects or physiological responses to the thermal stress independent of increases in cardiac output needed to perfuse working muscles or other changes associated with exercise-heat or exercise-cold stress. These passive-thermal stresses cause large redistributions of blood flow, especially in the skin, but these blood flow redistributions are different than those seen during exercise and some other passive-thermal stress models such as water immersion (23).
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- Hilfiker-Kleiner D, Landmesser U, Drexler H. Molecular mechanisms in heart failure: focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. J Am Coll Cardiol Oct 27;2006 48(9SupplA):A56–66.
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- Ranek MJ, Stachowski MJ, Kirk JA, Willis MS. The role of heat shock proteins and co-chaperones in heart failure. Philos Trans R Soc Lond B Biol Sci. Jan 19;373(1738), 2018.
- Wanga Y, Chena L, Hagiwaraa N, and Knowlton AA. Regulation of heat shock protein 60 and 72 expression in the failing heart. J Mol Cell Cardiol. 2010 February ; 48(2): 360
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- Radtke T, Poerschke D, Wilhelm M, Trachsel LD, Tschanz H, Matter F, Jauslin D, Saner H, Schmid JP. Acute effects of Finnish sauna and cold-water F.-L. Yang et al. Journal of Thermal Biology 69 (2017) 95–103 102 immersion on haemodynamic variables and autonomic nervous system activity in patients with heart failure. Eur. J. Prev. Cardiol. 23, 593–601, 2016.
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- Brunt VE, Howard MJ, Francisco MA, Ely BR, Minson CT. Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans. J. Physiol. 594, 5329–5342, 2016.
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- Marunouchi T, Murata M,Takagi N, Tanonaka K. Possible Involvement of Phosphorylated Heat-Shock Factor-1 in Changes in Heat Shock Protein 72 Induction in the Failing Rat Heart Following Myocardial Infarction. Pharm. Bull. 36(8):1332–1340, 2013.
- Basford JR, Oh JK, Allison TG, Sheffield CG, Manahan BG, Hodge DO, Jamil Tajik AJ, Rodeheffer RJ, Tei C. Safety, Acceptance, and Physiologic Effects of Sauna Bathing in People With Chronic Heart Failure: A Pilot Report. Arch Phys Med Rehabil 90:173-177, 2009.
- Vienna E. Brunt, Matthew J. Howard, Michael A. Francisco, Brett R. Ely and Christopher T. Minson. Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans. J Physiol 594(18):5329–5342, 2016.
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