News Physiol Sci 18: 215-221, 2003;
doi:10.1152/nips.01453.2003
1548-9213/03 $5.00
News in Physiological Sciences, Vol. 18, No. 6, 215-221,
December 2003
© 2003 Int. Union Physiol. Sci./Am. Physiol. Soc.
Matching the Heart to Heat-Induced Circulatory Load: Heat-Acclimatory Responses
Michal Horowitz
Division of Physiology, Hadassah School of Dental Medicine, The Hebrew University, Jerusalem 91120, Israel
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Abstract
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Heat acclimation enhances cardiac efficiency by increasing stroke volume and decreasing heart rate. These adaptations involve biochemical changes in the contractile apparatus, switched on by altered expression of genes coding contractile and calcium-regulatory proteins and partially mediated by persistent low thyroxine. Heat acclimation also produces cross-tolerance to oxygen deprivation, thus reinforcing cardiac adaptation to oxygen demand/supply mismatching via energy-sparing pathways.
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Introduction
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Upon transition from one environmental temperature to another, most animals are able to adapt physiologically and biochemically to the new environmental conditions. This process is defined as heat acclimation and, if successful, enhances heat tolerance in terms of the upper extreme of tolerable temperature and the duration of endurance in a hot environment (5). It requires concerted adaptations at all levels of body organization to produce enhanced energy-efficient acclimatory homeostasis. Physiologically, this is "translated" into an expanded dynamic thermoregulatory range. In the cardiovascular system, which serves to deliver heat to the skin, from where it is dissipated, acclimation leads to a greater volume of circulating blood together with a decreased temperature threshold for skin vasodilatation/splanchnic vasoconstriction when subjected to heat stress. Likewise, the temperature threshold for the reversal of this reflex upon thermoregulatory failure is delayed (5).
In the heart, heat acclimation produces favorable adaptations in mechanical and metabolic aspects of performance. At the systemic level, irrespective of the mode of acclimation (whether under sedentary or exercising conditions), this is manifested by a lowered heart rate and greater stroke volume (SV), together leading to an increase in cardiac work efficiency. In the past, a large body of studies on human subjects has ascribed the greater SV observed upon heat acclimation to increased venous return resulting from the heat acclimation-induced plasma volume expansion (PVE; Ref. 16). It was debatable, however, whether intrinsic changes take place in the cardiac muscle to increase its contractile force. On the basis of experiments with isolated perfused hearts, we have shown that intrinsic changes to match peripheral demands occur in the acclimated heart as a result of alterations in the expression of genes coding for contractile and calcium-regulatory proteins.
Adaptation to one environmental stressor sometimes provides protection against an additional type of stress. This phenomenon is called cross-tolerance. We have substantiated the development of cross-tolerance between heat acclimation and oxygen deprivation/reoxygenation in the heart, lending support to the hypothesis that the primary adaptation (to heat) involves protective signaling pathways used by both of these stressors.
This mini-review outlines the mechanisms leading to a matching of heart function to the peripheral vascular load during heat acclimation. Adaptations pertaining to heat acclimation-induced cardioprotection will also be discussed.
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Systemic acclimatory changes: cardiovascular performance-plasma volume interactions
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At the level of the organism, heat acclimation in the cardiovascular system is expressed as an increased ability for the occurrence of skin vasodilatation together with decreased heart rate and increased SV, suggesting increased cardiac efficiency. These changes are clearly seen after ~2 wk of acclimation in both humans and other mammals acclimated under either exercising or sedentary conditions. Senay et al. (16) as well as other investigators have provided evidence that in humans, heat acclimation-mediated PVE, which parallels the changes in cardiac hemodynamics, is the primary cause of enhanced cardiac efficiency. Furthermore, at the early stressful phase of acclimation, PVE provides compensation for the increased heart rate and the decreased SV observed during exercise in hot conditions, thus maintaining adequate cardiac output. Clearly, changes in plasma volume appear to influence both heart rate and SV by their effect on venous return and by allowing cardiac filling pressure to reach values that can lead to elevations in SV. Senay et al. (16) suggested that the magnitude of the cardiac filling pressure and the early increase in cardiovascular efficiency are fundamental events in the pathway leading to heat acclimation and enhanced thermal tolerance. In contrast, Rowell et al. (15) attributed increased cardiac efficiency primarily to a fall in core and skin temperatures, allowing heart rate to decrease and in turn allowing SV to increase through summed physical and reflex changes, whereas the cardiovascular system "simply operates in a cooler microenvironment and temporary compensatory role of PVE is inevitable" (15).
Surprisingly, understanding of the mechanisms leading to heat acclimation-mediated PVE, a key regulator of cardiac hemodynamics and heart rate, has remained inadequate. PVE has been mainly attributed to the buildup of greater plasma protein mass. Plasma volume, however, can also be rapidly affected by changes in the arterial-venous resistance to flow ratio, leading to alterations in the balance between capillary hydrostatic pressure and protein extravasation. It is therefore likely that alteration in sympathetic stimulation of the vasoconstrictor 
-adrenoreceptor (AR) and vasodilator ß-AR signaling also mediates this important feature, particularly when plasma volume is measured during bouts of exercise. Using an animal model, we have shown that ß2-AR blockade induces PVE, whereas ß-AR agonists abolish heat stress-induced PVE. In the vascular bed, heat acclimation leads to decreased density/affinity of the ß-AR, G protein sensitivity, and increased force generation by the vascular smooth muscle. Enhanced nitric oxide activity has also been observed. These changes, occurring shortly after the onset of the acclimation regimen, lead to alterations in vascular tone under adverse physiological conditions. Hence, by inference, sympathetic excitability and constitutive peripheral cellular modifications contribute an important regulatory facet to the heat acclimation-induced PVE and modulate its magnitude during both heat stress and exercise. This led to reevaluation of our understanding of the control of plasma protein flux via changes in capillary surface area as well (Fig. 1
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FIGURE 1. Heat acclimation-mediated plasma volume expansion (PVE) is mainly attributed to the buildup of a greater plasma protein mass. The documented mechanisms described over the years for acclimation under sedentary or exercising conditions by various groups are summarized. For further details, see text.
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Intrinsic adaptations in the heart
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Experiments both in intact animals and in isolated atria have shown that changes in the intrinsic properties of the pacing cells and in autonomic excitation both play a role in the control of heart rate. These experiments provided a first clue to the concept that heat acclimation leads to intrinsic cardiac modifications to match the peripheral circulatory load and were followed by extensive studies on the intrinsic adaptations of the heat-acclimated heart.
Why invoke intrinsic adaptations in the ventricles? Acclimatory changes in cardiac hemodynamics were, and still are, mainly explained by autonomic mechanisms. However, the heart is a highly regulated tissue and adapts to chronic physiological requirements. Two important changes that occur during heat acclimation, namely chronic plasma volume overload and persistent decrease in plasma thyroxine level, are known to induce biochemical adaptations in the heart by means of their effect on gene expression (e.g., Ref. 12). We therefore hypothesized that favorable acclimatory responses are induced in the ventricles to match the greater peripheral blood flow and venous return. Most of the work on this subject has been conducted on rats and mice, which, similar to humans, demonstrate lower heart rate, greater SV as well as PVE, and decreased thyroxine level upon heat acclimation. There is much evidence to corroborate this hypothesis.
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The heart as a pump: acclimatory responses
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A fundamental mechanical difference between acclimated and nonacclimated hearts is clearly seen when observing diastolic pressure-volume relationships before and after heat acclimation. The diastolic pressure-volume curve of the acclimated heart is markedly shifted to the right, allowing significantly greater chamber filling volume with no change in the filling pressure (Fig. 2A). Hence, an important change in overall ventricular function of the heat-acclimated heart is manifested by increased compliance and reduced stiffness (7). This allows the ventricle to accept an elevated venous return and then to deliver an increased SV without a great increase in end-diastolic pressure. This increase in compliance is advantageous, since it can provide an increase in cardiac output without a significant increase in heart rate. Thus the energetic cost of pumping would be lower. This mode of adaptation of the acclimated heart differs from the adaptation of the heart to exercise, an additional physiological condition that involves increased cardiac output, increased blood transfer to selective vascular beds, and elevation of body temperature. An increase in ventricular compliance is classically encountered during adaptation of the heart to volume overload, but this is accompanied by cardiac hypertrophy. This is not the case in heat acclimation, implying that the heat-acclimated heart shows a true change in its elastic properties. Pressure generation in the heat-acclimated heart is markedly increased, and so is noradrenaline-induced positive inotropy (5). Concomitantly, at high beating rates the heart fails to restitute pressure as well as it does in nonacclimated hearts, apparently due to the fact that the velocities of pressure generation and relaxation are slower (Fig. 3, 1; Refs. 3 and 7). Slower relaxation is not necessarily a maladaptation since it allows more time for cardiac filling. This integrates well with the elastic profile of the acclimated heart. Altogether, the acclimatory response is a tapestry of adaptive responses with several tradeoffs, shifting the heart to a more economical mode of operation. Direct measurements of oxygen consumption indeed show that although basal oxygen consumption upon cardiac arrest is similar before and after acclimation, in the beating heart there is a rightward shift in the cardiac work-oxygen consumption relationship (Fig. 2B); however, this is at the expense of contractile velocity (3, 7, 10).
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FIGURE 2. A: end-diastolic pressure-volume relationships, demonstrating left ventricle compliance in hearts of rats before (C) and after (AC) heat acclimation. Chamber compliance of the heat-acclimated hearts is markedly greater than that of the nonacclimated hearts. Figure is reproduced from Horowitz et al. (7). B: oxygen consumption-cardiac work (expressed as the rate-pressure product) relationship in hearts of sedentary nonacclimated (C) and 1 mo heat-acclimated (AC) rats. The marked shift to the right of the regression line of heat-acclimated hearts implies significantly increased work efficiency of the heat-acclimated heart. Figure reproduced with permission from the American Physiological Society (10).
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FIGURE 3. Top: suggested model of the heat-acclimated myocyte. Heat acclimation leads to greater pressure generation but slower velocities of contraction and relaxation. This stems from a transition from fast (V1) to slow (V3) myosin with low ATPase activity and increased phospholamban (PLB)/sarcoplasmic calcium pump (SERCA) ratio. Larger nonphosphorylated PLB mass is available for phosphorylation and thus improves positive inotropic response. Concomitantly, in the sarcolemma, ß-adrenoreceptor (AR) affinity decreases. Unpublished observations indicate that there are also alterations in the ryanodine receptors and L-type calcium channels. Circle represents subcellular area under study. For further details, see text. Bottom: 1, pressure (top) and velocities of contraction and relaxation (+dp/dt, -dp/dt; bottom) before (C) and after 1 mo acclimation (AC). 2, PLB/SERCA ratio before and after 1 mo acclimation. 3, myosin isoenzyme distribution before and after 1 mo acclimation (Data are from Refs. 3, 5, and 6).
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Contractile properties of the heat-acclimated heart: cellular aspects
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Given the mechanical adaptations observed in the heat-acclimated heart, long-term biochemical adaptive modalities identified in the heat-acclimated heart have opened a window for our understanding of their development and operation. A salient feature in cardiac contractility is calcium handling by the myocytes. Pressure generation requires an elaborate signaling system to amplify the contractile signal generated in the sarcolemma to deliver a large amount of calcium [primarily from the internal sarcoplasmic reticulum (SR) stores] needed to bind to troponin C, the calcium receptor that mobilizes the contractile proteins. The subsequent relaxation depends on reuptake of the calcium to its SR pools. Hence, the magnitude of pressure generation, as well as the velocities of contraction and relaxation, depend on the calcium signal amplitude (calcium transient) and its rate of return to the internal pool, respectively (8). Greater pressure production in the heat-acclimated myocyte, as hypothesized, was correlated with a constitutively greater calcium signal. In contrast to the rapidly developed functional responses (e.g., greater calcium transient and protein phosphorylation characterizing the sympathetically induced positive inotropic response), adaptation to chronic situations is achieved by "proliferative" mechanisms (8). Therefore, to understand the origin of the "constitutively" greater calcium transient, the primary targets of our studies were proteins associated with the contractile response. Among the sarcoplasmic proteins, phospholamban (PLB), which upon phosphorylation regulates the sarcoplasmic calcium pump (SERCA), is already known as a player in a variety of adaptive situations, as are the contractile proteins (e.g., Refs. 3, 8, and 9). Hence, these have been studied more extensively in the heat-acclimated heart.
Our current knowledge of the contractile machinery of the heat-acclimated myocyte is depicted in Fig. 3
. Heat acclimation leads to a redistribution of cardiac myosin isoenzymes from the fast V1 isoform with high ATPase activity to the predominance of the slow V3 form with low ATPase activity (6). This transition underlies the increased contractile efficiency and decreased velocity of pressure generation characterizing the heat-acclimated heart. Among the SR proteins, PLB mass was elevated by almost 50%, whereas SERCA decreased by 25%, thus leading to an elevated PLB/SERCA ratio compared with the nonacclimated phenotype (3). An elevated PLB/SERCA ratio is indicative of decreased SERCA pump activity and affinity for calcium (9). Hence, the augmented PLB/SERCA ratio measured in heat-acclimated hearts may favor a reduced rate of calcium reuptake into the SR and a slower rate of relaxation. One may argue that the augmented PLB mass makes it available for phosphorylation and thus able to produce the greater inotropic response observed in the heat-acclimated hearts. Preliminary data on excitation-contraction coupling proteins, such as the L-type calcium channels and the ryanodine receptors, imply changes in this pathway as well. Collectively, the combination of transition to the efficient V3 myosin and increased PLB expression provides a molecular adaptive aspect to increase work efficiency, which is a fundamental heat-acclimatory response.
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Metabolic changes in the heat-acclimated heart
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Oxygen consumption in the beating heat-acclimated heart, similar to that of the entire body, is lower. Concurrently, to guarantee long-term performance in the face of lowered oxygen supply, metabolic adjustments designed to enhance energy reserves take place. The glycogen level is twofold greater. Furthermore, experiments in which glycogen stores were initially depleted and then repleted by using 13C-labeled glucose provided substantiated evidence for enhanced glucose uptake followed by elevated glucose metabolites, e.g., glutamate C1 and glutamate C4 (2). This suggests structured enhancement of the metabolic machinery to elevate the energy potential of the heat-acclimated heart. In support of this concept are our results showing an increased number of GLUT4 glucose transporters (Levi E and Horowitz M, unpublished data) and increased glycolytic potential (2). Challenging anaerobic glycolysis implied increased expression together with (although indirectly, via inhibition) an altered rate of activity of GAPDH. This fits in well with the work of Podarabsky et al. (14) who, by means of evolutionary analysis of the glycolytic enzymes, identified GAPDH as one of three glycolytic enzymes important for temperature adaptation. Therefore, we can conclude that a multitude of changes are working in concert to improve the metabolic potential of the heat-acclimated heart to cope with increased peripheral load.
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The kinetics of adaptation: transition from inefficient to efficient pressure generation
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The concept of transition from "inefficient" to "efficient" as a fundamental adaptive feature during heat acclimation is better understood by looking at acclimation dynamics. An apparent acclimated state (i.e., decreased heart rate, increased contractile force) emerges shortly after the onset of heat acclimation (5). Greater pressure generation at the early phases of acclimation, similar to that in long-term acclimation, depends on the generation of a greater calcium signal (calcium transient). However, the generation of the larger calcium transient in short- and long-term acclimation is resolved by two different mechanisms. During short-term acclimation, an enhanced calcium transient is achieved by accelerated sympathetic excitability to compensate for desensitization of the adrenergic receptors and the diminished noradrenaline-induced positive inotropic response occurring at that acclimation phase (3, 5). This induces inefficient ATP utilization to produce adequate contractile force for the enhanced cardiac output required for heat dissipation. This demand is even further aggravated if exercising in the heat, as shown by Senay et al. (16). Following long-term acclimation, the heart has acquired intrinsic biochemical adaptive modalities to enhance work efficiency, comprising, as stated above: 1) a transition from the fast V1 to the slow V3 myosin isoenzyme, which has low ATPase activity predominance, and 2) an increase in the mass of the nonphosphorylated form of PLB. The presence of the V3 myosin isoenzyme, together with the larger PLB mass, provides greater pressure in the presence of lowered ATP utilization. This molecularly controlled adaptation decreases cardiac energy demands. Interestingly, the two acclimatory phases seen in the intrinsic adaptation of the heart parallel the nonstable and homeostatic phases recorded in the acclamatory systemic responses. The kinetics of cardiac adaptation with respect to integrative and humoral (see below) changes are presented in Fig. 4.
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FIGURE 4. Adaptation kinetics of the mechanical performance of the heart with respect to integrative and humoral changes. Cardiac pressure is elevated during both the early-transient and the homeostatic phases of heat acclimation. During the short-term phase, greater pressure is achieved due to accelerated autonomic excitation. It is characterized by decreased cardiac work efficiency. Effector organ output/autonomic signal (EO/S) ratio is <1. This phase is the time window during which many acclimatory long-term responses are switched on. Following long-term heat acclimation, cardiac work efficiency is enhanced (EO/S > 1). Persistent low plasma thyroxine level and elevated venous return, leading to redistribution of myosin isoforms, altered level of calcium-regulatory proteins, and decreased adrenergic receptor (AR) responsiveness are responsible for many of the changes observed. (Data are from Refs. 3, 5, 6, 10, and 16.)
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Possible mediator: persistent low plasma thyroid hormone
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Heat acclimation is a phenotypic adaptation, meaning that it is a within-lifetime adaptation. One way to attain an altered level of proteins is to reprogram gene expression, although posttranscriptional changes are also possible. The data at hand imply that on the whole, the contractile machinery-associated proteins in the acclimated phenotype are transcriptionally regulated. A large body of evidence links persistent alterations in the velocities of contraction and relaxation of the heart to the influence of thyroid hormones by their effect on the expression of genes coding for myosin isoforms, PLB, and SERCA (e.g., Ref. 12). In the hypothyroid state, for example, PLB is upregulated and SR-SERCA is downregulated. Effects of thyroxine on the transcription of several energizing metabolic proteins have also been implicated. Heat acclimation leads to a sustained drop in thyroid hormone levels (2, 6). Subjecting rats to heat acclimation together with maintenance of a euthyroid state blocks the phenomenology of the heat-acclimated cardiac phenotype (3, 6). We therefore suggest that the sustained drop in plasma thyroid hormones during acclimation is responsible, at least partially, for the observed adaptations in cardiac mechanical performance.
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Comparative aspects in thermal acclimation and cardiac performance
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Plasticity during thermal acclimation of the heart has been studied in several additional taxonomic groups, primarily in teleost fish. Despite basic differences between homeotherms, which adjust their body temperature within a very narrow range, and poikilotherms, which are able to tolerate a wide range of body temperatures depending on the ambient temperature, similar cellular targets are subject to thermal acclimation. In fish there is a similar effect of the transition to high ambient temperature on myosin heavy chain distribution, leading to predominance of the energy-efficient myosin upon warming. Likewise, mechanical restitution, at least in "athletic" fish, is slower in warm- than in cold-acclimated fish. Intrinsic adaptations in the myocyte, in excitation-contraction coupling, and in calcium-handling proteins make it possible to match activity to the environmental temperature. It is worth noting that in fish, SR is sparse and therefore the sarcolemma is the major adaptive target. Nevertheless, in the athletic fish, which has a higher beating rate upon warm acclimation, similar to the rat, SR calcium cycling may limit the rate of mechanical restitution at high pacing frequencies (for further reports, see Ref. 17). There are large species differences in cardiac acclimation ability among fish, depending on their activity pattern and ecophysiological adaptations. Calcium handling, however, plays an important role in all. Heat acclimation in homeotherms other than rats has been studied in only a few species. All show similar phenotypic responses. Because of the small number of species studied, acclimation plasticity of the myocyte across different evolutionary-adaptive homeotherm species to their particular environments is unknown.
"...in rat...heart, heat acclimation induces favorable adaptations..."
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Cross-tolerance between heat acclimation and impaired oxygen supply/demand ratio
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Acclimation to one environmental stressor may induce enhanced adaptation to additional, different stressors. This cross-reinforcement raises the possibility of the induction of adaptation to a stressor without any preexposure to that particular stressor. Levy et al. (10) have shown in rats that in the heart, heat acclimation induces favorable adaptations, allowing improved performance with less injury upon oxygen supply/demand mismatching. This is indicated by a decreased number of cases of ischemic contracture (IC, namely elevated passive ventricular pressure, which stems from an insufficient supply of ATP molecules to break down myosin-actin bonds) in the hearts of the heat-acclimated rat population, delayed onset of IC, better recovery of systolic and diastolic pressures upon reperfusion, and decreased infarct size. Some of these beneficial features, e.g., decreased number of cases of IC in a group or recovery of pulse pressure upon reperfusion, could also be achieved by exercise training. However, features such as delayed onset of IC and the enhanced recovery of the left intraventricular passive diastolic pressure upon reperfusion are specific to heat acclimation.
What, then, renders the heat-acclimated heart so well protected against oxygen deprivation/reperfusion insults? Species that routinely experience long periods of oxygen shortage in their life history (4) have acquired constitutive adaptations to endure aggressive hypoxia/reoxygenation stress. These adaptations can be divided into two categories: 1) those leading to metabolic depression and, in turn, energy sparing and 2) those upregulating the energetic efficiency of ATP-producing pathways. There are a host of additional physiological, biochemical, and molecular strategies, including alterations in membrane activity and enhanced cytoprotection, which complement the above-mentioned adaptations. The acclimatory responses seem to recapitulate the evolutionary adaptations. It is therefore likely that enhancement of protective signaling pathways, similar to those that have emerged through many generations of a species’ history under shortage of oxygen, underlies the cardioprotection achieved upon heat acclimation. Evidence for metabolic and cytoprotective adaptation has already been presented (2, 13).
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Metabolic adaptations and cardioprotection in the heat-acclimated heart
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During ischemia/hypoxia, energy conservation can be achieved either by matching energy requirements to a greatly curtailed supply of ATP or by increasing energy production efficiency. When enhanced glycolysis is the operating mechanism for increasing energy, constancy of intracellular pH must be protected. Levi et al. (10) showed that during total ischemia, heat-acclimated hearts display better preservation of global myocardial high-energy compounds and a shorter period of acidosis, followed upon reperfusion by improved recovery of high-energy phosphocompounds compared with nonacclimated hearts. Improvement in each of the above-mentioned parameters is known to lead to preservation of myocardial integrity and to enhancement of mechanical recovery during reperfusion. Thus improved energy status and delayed acidosis during ischemia attenuate several deleterious biochemical disturbances, e.g., sodium accumulation via sodium/hydrogen exchange, increased sodium-mediated calcium gain, and subsequent calcium-mediated rise in diastolic pressure and mitochondrial calcium overload during reperfusion (8).
We have indications that the delayed fall in ATP in the heat-acclimated ischemic heart is the result of energy sparing due to changes in the properties of cellular ATPases, e.g., myosin V3 predominance (vs. myosin V1 predominance before acclimation) or decreased sodium/potassium pump affinity for its substrate during ischemia and altered activity of glycolytic enzymes and glycogen levels, leading to slow, though continuous, ATP production. Although ischemia and oxygen deprivation cause the heart to shift to anaerobic energy production, during severe ischemia glycolysis is arrested by its own end product, thus leading, together with sodium and calcium accumulation, to the onset of IC and ischemic injury (1, 8). One important metabolic cardioprotective pathway developed during heat acclimation is mediated by the production of a larger pool of glycogen (glycogen breakdown may provide the heart with the glucose necessary for glycolysis) in conjunction with quantitatively increased glycolysis but at a slower rate, both allowing improved ATP availability with attenuated development of intracellular acidosis. In turn, longer preservation of cellular integrity is maintained. A sustained low thyroxine level (in addition to its effects on the contractile response) is probably associated with some of these metabolic features.
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Cytoprotection in the heat-acclimated heart
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An additional aspect of heat acclimation/ischemia crosstolerance is the cytoprotective role of heat shock proteins (HSPs), among which the HSP of 72 kDa (HSP72) has been the most extensively studied. These evolutionary-conserved protein species are induced in response to heat and a wide range of stressful stimuli. Their prior induction in response to mild stress provides protection against subsequent, more severe stress in a multifaceted mode. They function by chaperoning the correct folding of other proteins but are also involved in protective processes, such as degradation of abnormal proteins, cytoskeleton and mitochondria protection, inhibition of apoptosis, etc. Their protective role against cardiac ischemia was demonstrated unequivocally by using genetic manipulation to produce overexpression of single HSP species in both cells and mice (for further details, see Ref. 11). Heat-acclimated hearts constitutively maintain markedly higher reserves of the inducible HSP type HSP72 (by 200%) (13). Teleologically, the advantage of larger HSP reserves is an immediate protection without a need for time-consuming de novo protein synthesis. This conclusion is compatible with the finding that overexpression of HSP70 in mice renders ischemic tolerance and with our observations that the index for the severity of the stress (i.e., infarct size) measured subsequent to coronary occlusion is markedly smaller in the heat-acclimated heart and is increased upon HSP production blockade. An additional acclimatory phenomenon is the faster rate of increased hsp mRNA expression and the higher PO2 threshold sufficient for HSP production during ischemia. This dynamic molecular response may produce an outcome different from that obtained by constitutively high HSP expression.
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Conclusions
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Our data provide evidence that the process of heat acclimation confers long-term intrinsic circulatory adaptations to match peripheral hemodynamic load during both heat acclimation and heat stress. The manifestations of this adaptive response are multifaceted and stem primarily from reprogramming of gene expression. Persistent low thyroxine level, via its effect on transcriptional activation, appears to be an important mediator of the changes observed. Collectively, heat acclimation enhances cardiac work efficiency and increases cardiac reserves. It also confers cardioprotection upon ischemia/reperfusion insults, involving ionic (not described), metabolic, and cytoprotective adaptations.
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Acknowledgments
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Most of the research that provided the basis for this article was supported over the years by the U.S.-Israel Binational Science Foundation and was carried out in collaboration with G. Gerstenblith, M. Stern, and Y. Hasin. Their contribution is highly appreciated. I am also indebted to H. Sohmer, Hadassah Medical School, The Hebrew University, for valuable comments.
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Introduction
Systemic acclimatory changes:...
