J Appl Physiol 100: 1727-1732, 2006.
First published January 12, 2006; doi:10.1152/japplphysiol.01244.2005
8750-7587/06 $8.00
HIGHLIGHTED TOPICS
A Physiological Systems Approach to Human and Mammalian Thermoregulation
Frequency-dependent contractile response of isolated cardiac trabeculae under hypo-, normo-, and hyperthermic conditions
Nitisha Hiranandani,*
Kenneth D. Varian,*
Michelle M. Monasky, and
Paul M. L. Janssen
Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio
Submitted 29 September 2005
; accepted in final form 30 December 2005
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ABSTRACT
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The body is from time to time exposed to nonnormothermic conditions; both hypo- and hyperthermia can occur as a result of external (environment) or internal (pathogens, allergens) stressors. To preserve life under hypo- and hyperthermic conditions, adequate perfusion of vital organs is mandated. Although cardiac output regulation under hyperthermic conditions has been studied, the mechanical response of basic contractile function of the myocardium itself is incompletely understood. Accordingly, we set out to test mechanical output of isolated myocardium under hyperthermic conditions and to compare the results with the hypo- and normothermic response in the same tissue. We observed that, in absence of a frequency change, developed force decreased markedly. At a physiological normal stimulation rate of 6 Hz, developed force decreases to 67.2 ± 2.6% at 42°C compared with 37°C. In addition, twitch timing characteristics also accelerate, allowing for a faster relaxation; time from peak tension to 50% relaxation is 
23% faster (from 31.4 ± 2.6 to 24.4 ± 1.7 ms). Although this faster relaxation in turn prevents a steep increase in diastolic tension at high frequencies, the very fast calcium kinetics now prevent a more complete activation of the myofilaments, resulting in a lower twitch-force maximum at hyperthermic conditions. Even at maximal 
-adrenergic stimulation, developed force is well below levels reached at physiological temperature.
fever; force-frequency relationship; beta-adrenergic stimulation; isoproterenol; thermoregulation
THERMOREGULATION OF THE BODY occurs under normal physiological conditions, such that a normal body temperature is maintained even under most pathological states. However, the body is from time to time exposed to nonnormothermic conditions; both hypo- and hyperthermia can occur as a result of external (exposure, exercise, environment) or internal (pathogens, allergens) stressors. Because vital organs need to be kept functioning even when temperature of the body drops below or increases above the optimal temperature, delivery of nutrients and oxygen are a must under hyper- and hypothermic conditions, and thus cardiac contractile function needs to be adapted to provide an adequate circulation.
During hyperthermia (or heat stress), it is long known that heart rate increases, and sympathetic responses are upregulated. Faster heart rates, at least in healthy subjects, result in an increase in myocardial force production (7). All mammals, within their own physiological range of rates (i.e., adult human 1.3 Hz, rat 5–9 Hz), display a so-called positive force-frequency relationship (Bowditch effect) (3). As heart rate increases, so does contractile strength in humans (7), as well as other mammals (10, 11, 17). In addition to the increased force production at higher heart rates, the entire contraction is accelerated; both time to peak pressure (or force) and relaxation kinetics are speeding up in synergy with heart rate. The faster kinetics allows the heart to maintain a fast pacing rate without immediate diastolic fusion of successive contractions that can potentially cause a diastolic dysfunction.
Temperature also has a profound effect on myocardial function. In isolated myocardium, at constant frequency (or heart rate), increasing the temperature from room temperature to body temperature results in a profound loss of peak contractile force, whereas twitch kinetics speed up with temperature (9). However, changes in force production and twitch kinetics do not occur in parallel. Between 22.5 and 30°C, the loss of peak twitch force is minimal, whereas twitch kinetics speed up by a factor of two to three. In contrast, between 30 and 37°C, force drastically declines by a factor of two to three, but twitch kinetics only speed up by a small amount. Little, however, is known regarding contractile performance of the myocardium under hyperthermic conditions. In the whole heart, an increase above normal temperatures induced negative inotropism (15). However, cardiac output can be reduced by loss of myocardial contractility and/or insufficient filling. It remains unknown whether and how basic contractile performance of myocardial tissue is affected by hyperthermic conditions. Isolated cardiac muscle function has been extensively investigated under hypothermic conditions, but isolated myocardial contraction data obtained under hyperthermic conditions are altogether lacking. We hypothesize that, when temperature of the myocardium is increased above normal body temperature, twitch kinetics will accelerate and force development will decrease. Accordingly, we set out to investigate the influence of hyperthermia on the regulation of basic myocardial contraction, including at high heart rates. We observed that, in isolated myocardium subjected to 42°C, peak force development as well as -adrenergic-induced inotropism is reduced, whereas the force-frequency relationship shifts rightward to a higher frequency optimum.
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MATERIALS AND METHODS
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Muscle preparation.
Male LBN-F1 rats (175–225 g) were anesthetized using intraperitoneal injection of pentobarbital sodium (60 mg/kg). The chest cavity was opened by bilateral thoracotomy, and 1,000 U of heparin were injected into the heart at the apex. The heart was removed and immediately perfused with Krebs-Henseleit solution containing (in mM) 137 NaCl, 5 KCl, 1.2 MgSO4, 1.2 NaH2PO4, 20 NaHCO3, 10 glucose, and 0.25 CaCl2. Additionally, 20 mM 2,3-butanedione monoxime was added to the perfusate to minimize cutting damage, and to arrest the heart (12). The buffer solution was oxygenated continuously by bubbling with a mixture of 95% O2-5% CO2; this resulted in a pH of 7.32 at 37°C, with minimal change at different temperatures (7.30 at 32°C, and 7.34 at 42°C). After the blood was flushed out of the heart, the right ventricle was carefully opened and unbranched, and ultrathin trabeculae were carefully dissected as previously described (9, 14, 19). A small portion of the tricuspid valve was left attached to one end, and a block of ventricular tissue remained attached to the other end of the trabeculae to facilitate mounting the preparation onto the experimental setup. Muscle dimensions were measured (14) at x40 magnification (10-µm resolution), and they were 142 ± 16 µm wide, 82 ± 8 µm thick, and 1.70 ± 0.16 mm long (n = 9). It is imperative that these preparations are ultrathin; experimentally, it has been show that, at a temperature of 25°C, core hypoxia develops at preparations exceeding 200 µm (16), and at a temperature of 37°C this width has recently been determined to be only 150 µm (14). We realize that, at even higher temperature or frequency, this size limitation could be even smaller, and extrapolation of the previous two studies would potentially indicate that a hypoxic core could develop in preparations exceeding 130 µm. To avoid any potential complications of core hypoxia, we remained well below 100 µm for the thickness of our preparations (average of 82 µm), so they were in the order of four to five myocytes thick and thus had a maximal diffusion distance to the core of no more than three myocytes.
Protocols.
After mounting the preparation at 37°C in the experimental system, extracellular calcium concentration was raised to 1.5 mM, and point-stimulation (via hook and basket) was initiated by 2-ms-wide pulses at 120% threshold voltage (4–5 V) at an initial frequency of 4 Hz. The muscle was allowed to stabilize, and thereafter the muscle length was stretched until developed force was maximal or until an increase in developed force was accompanied by a disproportional increase in diastolic force. After stabilization (15–25 min), muscle length was adjusted if needed, and the experimental protocol was initiated when contractile parameters were stable. Only healthy muscles, defined by a positive force-frequency relationship between 4 and 8 Hz, as well as a minimal isometric developed force of at least 20 mN/mm2 at 32°C (4 Hz), were used for this study.
First, temperature was lowered to 32°C. After force had stabilized, data were collected. After collection of data at 6 and 8 Hz thereafter (again after forces had stabilized), frequency was returned to 4 Hz. Temperature was rapidly switched to 37°C, the muscle was allowed to stabilize at this new temperature, and this protocol was repeated, up to 10 Hz, and thereafter again at 42°C, with frequencies up to 12 Hz.
To test for cardiac reserve and -adrenergic responsiveness at 42°C, a separate set of trabeculae (n = 7) was subjected to an isoproterenol concentration-response protocol. Isoproterenol concentration was increased from 1 nM to 1 µM in semilog steps, and force responses were recorded at each concentration.
In a third set of experiments, intracellular calcium transients were measured after iontophoresis of the calcium indicator bis-fura-2 into the preparation. The dye-loading technique and protocol that allow for assessment of calcium transients at body temperature have been described previously (1, 6, 9, 17). Briefly, at room temperature, a micropipette filled with bis-fura-2 is introduced into a single myocyte near the center of the preparation, and a small negative current is applied to introduce the dye into the cytoplasm. Via gap junctions, this dye spreads to neighboring cells. Once the dye has uniformly spread, fluorescence intensity at 510 nm is measured under various conditions (temperature, frequency) during alternate exposure to 340- and 380-nm-wavelength excitation light. Intracellular calcium transients were recorded at various combinations of temperature and frequency.
Briefly, in two additional experiments, we tested whether the response to acidosis was preserved during hyperthermia. After assessment of a force-frequency relationship at 42°C, the pH of the perfusate was lowered from 7.34 to 7.00. At this lower pH, the force-frequency relationship was again measured.
Twitch contractions were continuously recorded throughout the experiment. Force development was normalized to the cross-sectional area of the trabeculae to allow for comparison between muscles of different diameters, including those from previously published work. Twitches were recorded at each experimental condition on stabilization. Data were collected and analyzed on- and offline using custom-written software (LabView, National Instruments). Data are expressed as means ± SE unless otherwise noted. Data were statistically analyzed using ANOVA or Students' t-tests (paired or unpaired) where applicable. A two-tailed value of P < 0.05 was considered significant.
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RESULTS
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Figure 1A shows the twitch force development at a stimulation frequency of 4 Hz under hypo-, normo-, and hyperthermic conditions. As can be clearly seen, peak twitch force development (Fdev) diminishes as temperature increases. In Fig. 1B, the average active isometric force development for nine trabeculae is depicted, as well as the kinetic parameters. Both time to peak tension and time from peak tension to 50% relaxation (RT50) are reduced on elevation of temperature.
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Fig. 1. A: twitch peak force development (Fdev) is reduced as temperature increases. At a stimulation rate of 4 Hz, Fdev is reduced, whereas twitch kinetics are accelerated. B: average data for Fdev, time to peak tension (TTP), and time from peak tension to 50% relaxation (RT50) at a frequency of 4 Hz and at various temperatures. Values are means ± SE; n = 9 trabeculae. *Significant increase vs. 37°C, P < 0.05. **Decrease vs. 37°C data, P < 0.05.
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The optimum of the force-frequency relationship depends highly on temperature (Fig. 2A). At 32°C, a small increase is observed in Fdev from 4 to 6 Hz, but a clear and significant loss of Fdev occurs between 6 and 8 Hz. At 8 Hz, contractions are too slow for force to completely return to unstimulated (diastolic) values, resulting in a slightly elevated diastolic force, thereby reducing Fdev. At body temperature, the frequency optimum is at 8 Hz. At this rate of contraction, relaxation is fast enough to allow a complete relaxation. At an even faster rate of 10 Hz (supraphysiological), a significant decline in Fdev is observed. At hyperthermic conditions, Fdev does not significantly decline between 8 and 10 Hz. In fact, even at a stimulation rate of 12 Hz, the decline is not significant. In several preparations, Fdev continues to increase when frequency was elevated from 10 to 12 Hz. Under all conditions, both an increase in temperature or frequency results in faster kinetics (reduction in RT50). However, at 42°C, this reduction in RT50, both relative and absolute, is less than at 32 and 37°C. In Fig. 2C, it can be more clearly seen that the optimal frequency shifts toward higher values when temperature is increased. For each temperature, forces are depicted as a fraction of the ones measured at 4 Hz. In Fig. 3 the twitch tracings of a typical force-frequency protocol are given under hyperthermic conditions; from 4 to 8 Hz force development significantly increases, and thereafter it remains fairly stable. Even at the supraphysiological frequency of 12 Hz, diastolic force is hardly elevated. In fact, even when stimulated at even higher rates, up to 20 Hz, only a small elevation of diastolic force is observed, and tension easily relaxed below 25% of maximal (not shown). In Fig. 3 it can be clearly seen that even up to 10 Hz, no elevation of diastolic force is found, indicating that the muscle can completely relax before the next twitch. At 12 Hz, a very small amount for diastolic force is observed, but this is much smaller than that at 10 Hz at 37°C.
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Fig. 2. A: Fdev varies with frequency and temperature. At 32°C, Fdev is optimal at 6 Hz, whereas this is 8 Hz at 37°C, and 10 Hz at 42°C. Diastolic force starts developing at 8 Hz (32°C), 10 Hz (37°C), and 12 Hz (42°C), respectively (data not shown). B: RT50 accelerates with both frequency and temperature. At 42°C, however, little acceleration is observed between 8 and 12 Hz. C: when expressed as fraction of Fdev at 4 Hz at each respective temperature, it can be seen more clearly that the higher the temperature, the more positive the force-frequency relationship is. It can be seen that at 32°C, the optimal frequency is 8 Hz, whereas it is 10 and 12 Hz for 37 and 42°C, respectively. Values are means ± SE; n = 9 trabeculae. *Significant increase vs. 37°C, **P < 0.05 a decrease vs. 37°C data.
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Fig. 3. Original force recording of a rat cardiac trabeculae at 42°C at various frequencies, spanning the in vivo range. An increase in frequency results in an increase in Fdev and in an acceleration of twitch kinetics. Only at 12 Hz a very mild diastolic force is observed.
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To test to what extend -adrenergic stimulation can increase isometric force under hyperthermic conditions, a concentration-response relationship was measured. In Fig. 4 it can be seen that at the higher concentration (maximal effect), of 1 µM isoproterenol, Fdev is clearly enhanced, while twitch kinetics are accelerated. In Fig. 4B the response of Fdev and RT50 shows the average values obtained for seven trabeculae.
To test whether the observed changes in force development are a result of altered calcium handling, intracellular calcium transients were assessed at various temperature and frequency. As can be seen in Fig. 5A, the amplitude of the calcium transient at a fixed frequency (depicted here is 6 Hz) is not much different, but the kinetics are faster; the decline of the calcium transient is greatly accelerated at higher temperatures. In Fig. 5B, both calcium transient and force development of a trabeculae at 42°C at 4 and 12 Hz are plotted. Clearly, the amplitude of the calcium transient is much higher at 12 Hz, while its kinetics are also faster. The resulting force traces reflect the same: a stronger contraction with a faster relaxation.
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Fig. 5. A: intracellular calcium transients at various temperature at a stimulation rate of 6 Hz. The amplitude of the calcium transient is only slightly increased at higher temperature, but the acceleration is clearly visible. B: at 42°C, both the calcium transient and force development are increased in amplitude and accelerated. Ratio (340/380), ratio of 340-nm-wavelength to 380-nm-wavelength excitation light.
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Lastly, we tested whether changes in pH could have an impact on cardiac contractility at 42°C. We observed the expected effect, a loss of force development combined with an increase in twitch kinetics. Interestingly, we did observe a very clear frequency-dependent effect of the influence of pH; the loss of force and acceleration of kinetics were much more profound at lower frequencies (4–8 Hz) than at higher ones (10 and 12 Hz) (Fig. 6).
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Fig. 6. At a temperature of 42°C, the response to lowering of the pH has an additive negative inotropic effect on twitch contractions in the lower and midfrequency range. Fdev was significantly lower at pH 7.0 vs. pH 7.34 at stimulation rates of 4–10 Hz, while simultaneously RT50 relaxation was abbreviated, indicative of faster twitch kinetics. At a rate of 12 Hz, which is supraphysiological, the loss of developed force and acceleration of twitch kinetics were smaller or absent. Values are means ± SE; n = 2–3 trabeculae.
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DISCUSSION
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We set out to study the mechanical function of isolated cardiac tissue under hyperthermic conditions. Isolated muscle preparations allowed us to study the contractile capacity of the heart (2, 18) without being hampered by altered loading conditions as prevail during hyper- and hypothermia. We found that the contractile force of isolated myocardium is significantly reduced when studied at a fixed pacing rate. In addition, we observed that the kinetics of the twitch contractions accelerate, and response to -adrenergic stimulation is maintained.
It has long been known that, under hypothermic conditions, isolated preparations display increased inotropy at the same pacing rate. In fact, most of the published data on contractility of isolated muscle preparations is carried out at temperatures below the physiological range, and its temperature dependency between room temperature and body temperature is well documented. In isolated trabeculae, our laboratory (9) and others (11) have previously shown that, although between 22.5 and 30°C little or no loss of inotropy (at 1 Hz) occurs, between 30 and 37°C a significant loss of developed force was found. We now add the finding that, on further increasing temperature, this negative inotropism persists. We observed this not only at very low stimulation rates but also at rates within the physiological range: at any frequency spanning the physiological rate for the rat, between 5 and 9 Hz, increasing temperature led to a loss of force development. To date, virtually no information is, however, available on the contractile response of isolated myocardium under hyperthermic conditions. In this study, we observed lower force development at constant rate that is in line with in vivo and whole heart studies that have observed negative inotropy on heat-stress studies (15).
However, because force is lost with increased temperature, the contractions accelerate, allowing for a faster relaxation. As a result, at higher frequencies the isolated myocardium can reach higher rates without diastolic dysfunction. In our data, we observed an increase in contractile strength when stimulation frequency was increased. This positive force-frequency behavior is observed across mammalian species, including rat (9, 11) and mouse (6), provided that the frequencies tested fall within each species' normal in vivo range. The magnitude of frequency-induced gain in contractility is also correlated to the size of the animal, and it is therefore relatively small in the rat and mouse, but nonetheless is positive. However, when frequencies are used outside the animal's normal heart rate range, negative staircases can be obtained. Indeed, even when large mammals are subjected to very low twitch frequencies, they too can show a negative staircase behavior, but this process should ideally not be termed force-frequency behavior, because it is not reflecting the normal physiological response of mammalian myocardium to increase heart rate but instead be regarded as a display of an inverse postrest behavior (13). In our data, the accelerate twitch kinetics that were observed at higher temperature allowed the already positive force frequency to be extended to higher ranges, resulting in increased development of force even when frequencies well exceeded the rates usually observed under normothermic conditions. Thus the loss of contractile force can be (partially) offset by the ability of the myocardium to achieve higher rates under hyperthermic conditions. This would be in close accordance to the response of the heart under hyperthermic condition; it has long been known that, when core body temperature increases, so does heart rate, especially under strenuous conditions (4). The positive force-frequency effect is thus clearly preserved, and even more pronounced at high temperature, while the fast relaxation allows the heart to sufficiently relax in between beats. Interestingly, in our experiments, at the very highest pacing rates, twitch kinetics were only slightly affected; between 8 and 12 Hz (and even as high as 20 Hz, which is well beyond the physiological rate), little further acceleration of the twitch kinetics was observed. Possibly, at these very high rates, cross-bridge cycling rates are approaching a maximal rate, imposing the rate-limiting step on cardiac relaxation.
Because of the loss of Fdev at any given frequency at 42°C, when isoproterenol, a -adrenergic agonist was applied, a significant gain of force development was observed. However, even at the highest and maximal concentrations 10–7–10–6 M, the force development did not reach the level that could be achieved at lower temperatures. Twitch kinetics further accelerated in presence of isoproterenol, with RT50 near, and even below, 20 ms. These very rapid contractions may be the underlying factor in twitch force-production reduction; the intracellular calcium transients are only a few milliseconds above the level needed for thin filament activation, and full activation of the thin filament can simply not be achieved in that time period.
The underlying mechanism of hyperthermia-induced loss of inotropy has likely to be sought in the altered calcium handling. Our calcium transient measurements indicated faster kinetics, likely reducing the time for myofilament activation. Unfortunately, within the short time span, intracellular calcium transients can be performed at supraphysiological temperatures (10–15 min) because of fast leakage of the dye, we could not calibrate the calcium signals, which takes >40 min. Thus we can only use the data as illustrative and indicative of kinetic direction. Although Kd and on-off rates of the dye may depend on temperature, at a given temperature in the same preparation, a faster fluorescence transient will always be indicative of faster calcium kinetics. There are numerous studies that have studied the kinetics of calcium-handling processes in myocardium. A common denominator in these studies is that hypothermia-induced gain of inotropy mainly stems from a slowed calcium transient, increasing the time for myofilament activation and resulting in not only increased force production but also in a prolongation of contraction. Indeed, in our data this is very clearly visible as well; the hypothermia data clearly show an increase in force (at a given frequency), in concert with slowed twitch kinetics. Our data now extend these previous observations to hyperthermic conditions. As temperature increases, kinetics further speed up and result in a further loss of inotropy in combination with faster twitch kinetics.
In addition to the acceleration of the twitch and loss of peak force due to the temperature itself, lowering the pH of the perfusate had a similar, but additive, effect; when pH was lowered from 7.34 to 7.00, at the lower end of the frequency rage (4–8 Hz), twitch kinetics were slightly faster, and loss of developed force was pronounced. This is in line with the observations that lowering pH has a desensitizing effects on the myofilaments (5, 8). Interestingly, at 10 and 12 Hz, this acidosis-induced loss of contractility was much less, and although these stimulation rates are supraphysiological under normothermic conditions, they could occur during hyperthermia, where prevailing heart rates are higher. At increasing frequency, relaxation rates are faster, and the molecular basis for frequency-dependent acceleration of relaxation is incompletely understood. It is conceivable that desensitization of the myofilaments is one of the underlying factors. Desensitization of the myofilaments would abbreviate relaxation, similar to the effect of -adrenergic stimulation-induced desensitization of the myofilaments. This desensitizing effect may aid in providing adequate relaxation at higher frequencies, and thus the pH-induced depression of myofilament calcium sensitivity may be less due to a common pathway to achieve this desensitization at higher frequencies.
In conclusion, under hyperthermic conditions myocardial contractile performance is markedly reduced compared with body temperature; isometric force development is lower at all frequencies spanning the physiological range. Both twitch and calcium transient kinetics are accelerated, whereas the positive force-frequency relationship is preserved and has shifted its optimum to higher frequencies, thereby being able to produce adequate force at the higher heart rates that generally prevail during hyperthermia.
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GRANTS
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This study was supported by National Heart, Lung, and Blood Institute Grant R01 HL-738616 (to P. M. L. Janssen).
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FOOTNOTES
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Address for reprint requests and other correspondence: P. M. L. Janssen, Dept. of Physiology and Cell Biology, The Ohio State Univ., 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210-1218 (e-mail: janssen.10{at}osu.edu)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
* N. Hiranandani and K. D. Varian contributed equally to this work. 
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Copyright © 2006 by the American Physiological Society.
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ABSTRACT
MATERIALS AND METHODS
) and acceleration of RT50 (
) in cardiac trabeculae at 42°C. Values are means ± SE; n = 7 trabeculae. Con, control; Base, baseline.