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Ann Thorac Surg 2002;74:1208-1212
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Effects of hypothermia on myocardial substrate selection

Nathan F. Gilbert, MDa, Paul E. Meyer, MDa, M. Peter Tauriainen, MDa, Robert Y. Chao, MDa, Jayendra B. Patel, BSa, Craig R. Malloy, MDb,c, Michael E. Jessen, MD*a

a Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center at Dallas, and the Dallas Veterans Affairs Medical Center, Dallas, Texas, USA
b Department of Internal Medicine (Division of Cardiology), University of Texas Southwestern Medical Center at Dallas, and the Dallas Veterans Affairs Medical Center, Dallas, Texas, USA
c Department of Radiology, University of Texas Southwestern Medical Center at Dallas, and the Dallas Veterans Affairs Medical Center, Dallas, Texas, USA

Accepted for publication June 7, 2002.

* Address reprint requests to Dr Jessen, Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8879 USA
e-mail: michael.jessen{at}utsouthwestern.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Hypothermia lowers the metabolic rate and increases ischemic tolerance but the effects of temperature on myocardial substrate selection are not well defined.

Methods. Isolated rat hearts were perfused with physiologic concentrations of 13C labeled lactate, pyruvate, acetoacetate, mixed long-chain fatty acids, and glucose. Hearts were cooled over 5 to 10 minutes to one of four target temperatures (37°, 32°, 27°, or 17°C), then perfused for an additional 30 minutes, freeze-clamped, and extracted. 13C NMR spectra were obtained and substrate oxidation patterns were determined by isotopomer analysis.

Results. Although hearts in all groups were supplied with identical substrates, the percentage of acetyl-CoA oxidized within the citric acid cycle that arose from fatty acids decreased significantly from 53.8% ± 0.8% in the 37°C group to 33.1% ± 3.3% in the 17°C group. Lactate or pyruvate utilization increased from 3.3% ± 0.5% to 25.7% ± 3.6%, respectively (p < 0.05 by one-way ANOVA).

Conclusions. These data suggest that moderate hypothermia suppresses fatty acid oxidation and deep hypothermia significantly increases utilization of lactate and pyruvate. These effects may result from relative inhibition of catabolism of complex molecules such as fatty acids, or stimulation of pyruvate dehydrogenase. These effects on substrate metabolism may play a role in myocardial protection afforded by hypothermia.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Cardiac operations frequently subject the heart to a period of planned ischemia. Strategies to improve postischemic myocardial function include measures to reduce the energy requirements of the heart during ischemia, and measures to accelerate energy production or avoid free-radical mediated damage in the reperfusion period. Efforts to decrease myocardial energy requirements have involved reducing cardiac work with cardiopulmonary bypass or venting, diminishing cardiac mechanical and electrical activity with cardioplegic solutions, and cooling the heart with intracoronary solutions or topical techniques. Each of these methods reduces myocardial oxygen consumption, which has been used as a marker for myocardial metabolism [1–3].

Oxygen serves as the terminal electron receptor in the electron transport chain, reoxidizing NADH and FADH2 reduced during oxidative metabolism and generating high-energy phosphates such as adenosine triphosphate (ATP). As hypothermia slows oxidative metabolism, formation of reducing equivalents decreases and oxygen utilization falls. However, the number of reducing equivalents produced during complete oxidation varies among substrates [4], with greater numbers of reducing equivalents formed (and therefore greater amounts of oxygen consumed) through catabolism of fatty acids compared to carbohydrate fuels, when corrected for the amount of ATP generated. Therefore, simply measuring oxygen consumption does not provide a complete assessment of myocardial energy metabolism.

Hypothermia has been applied as a measure to protect the heart from ischemic damage for more than 40 years [5]. However, the effects of hypothermia on myocardial substrate selection are not well described. One study has suggested that the normal myocardial preference for fatty acids is increased under hypothermic conditions [6], but the study was performed with nonphysiologic levels of substrates. Another study in blood-perfused dog hearts measured greater oxidation of glucose than fatty acids (oleate) during hypothermia and after rewarming [7]. An understanding of the relative oxidation of substrates by the myocardium under hypothermic conditions is important because conditions that increase fatty acid use may lead to reduced functional recovery after rewarming [8] or after ischemia [9].

Recently the technique of 13C NMR isotopomer analysis has been applied to the study of complex metabolic problems in isolated hearts perfused with multiple substrates [10, 11]. This study used this method to evaluate the effect of hypothermia on myocardial substrate utilization in a model containing a combination of substrates at physiologic concentrations.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
13C-enriched compounds and perfusate composition
[3-13C]-sodium L-lactate, [3-13C]-sodium pyruvate, and [1,3-13C]-ethyl-acetoacetate were obtained from Isotec (Miamisburg, OH) or from Cambridge Isotope Labs (Andover, MA). [U-13C]-fatty acids and unenriched fatty acids were obtained from Martek (Columbia, MD). Unenriched L-lactate, pyruvate, glucose, ethyl-acetoacetate, and other chemicals were obtained from Sigma (St. Louis, MO).

Two different crystalloid perfusion solutions were prepared. Each solution consisted of a modified Krebs-Hensleit solution containing physiologic concentrations of electrolytes (in mM) [118 NaCl, 4.7 KCl, 1.2 MgSO4, 1.2 NaH2PO4, 22 NaHCO3, and 1.2 CaCl2] and substrates (in mM) [5.5 glucose, 1.2 lactate, 0.12 pyruvate, 0.17 acetoacetate, and 0.35 mixed fatty acids]. Purified bovine serum albumin was added to all solutions at a concentration of 7.5 g/L. These substrate concentrations were selected based on normal values measured in the fed, rested rat [12]. In one version of the crystalloid solution, the substrates were unlabeled. In a second version, the substrates were 13C labeled as noted above. Perfusion with the unlabeled solution allowed stabilization of the isolated heart before switching to labeled substrates for the period of interest.

Experimental animals
Adult male Sprague-Dawley rats weighing 280 to 300 g were given food and water ad libitum and used in an institutional-approved research protocol. All animals were cared for in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources (National Academy of Sciences) and published by the National Institutes of Health (National Institutes of Health Publication No. 86-23, revised 1985).

Perfusion technique
Rats were anesthetized with chloral hydrate (4%, 1 mL/100 g, IP) and heparinized (1000 U/100 g). Both superior vena cavae and the inferior vena cava were clipped and the heart was rapidly excised and perfused retrogradely via the aorta at a pressure of 100 cm H2O in a Langendorff preparation. Each perfusate solution was circulated in a water-jacket enclosed glass apparatus with roller pumps and gassed with 95% O2/5% CO2. The pulmonary artery was incised to allow exit and collection of coronary sinus effluent for determination of coronary flow (CF). Perfusate exiting the coronary sinus was not recirculated. The left atrial appendage was excised and a fluid-filled latex balloon was inserted across the mitral valve into the left ventricle for measurement of left ventricular function. The balloon was filled to obtain an end-diastolic ventricular pressure of 10 to 12 mm Hg. Hearts were not paced during the experiment. Left ventricular pressure was continuously monitored by the latex balloon. Measurements of mechanical function, including heart rate (HR) and left ventricular end-systolic pressure and end-diastolic pressure (LVESP and LVEDP) were recorded at 20, 30, 40, and 50 minutes.

Experimental protocol
Four experimental groups were studied. All hearts underwent an initial 20-minute stabilization period during which they were perfused with unlabeled substrates at 37°C. After stabilization, function was examined in each heart and the experiment was discontinued in hearts that did not reach a base line RPP (HR x [LVESP - LVEDP]) >= 24,000 mm Hg · bpm. About 5% of hearts did not meet this criterion. All acceptable hearts were then perfused with the solution containing 13C-labeled substrates for an additional 30 minutes. During the first 10 minutes of perfusion with labeled substrates, the temperature of the circulating waterbath was altered to reach one of four target temperatures. In group 1, temperature was maintained at 37°C. In other groups, temperature was lowered to 32°C (group 2), 27°C (group 3), or 17°C (group 4). Eight animals were studied in each group.

At the end of each perfusion period, nonventricular tissue was quickly trimmed. Hearts were then freeze-clamped with aluminum tongs, chilled in liquid nitrogen, extracted with cold perchloric acid, neutralized with KOH, freeze-dried, and dissolved in 0.5 mL of D2O for 13C NMR analysis.

13C NMR spectroscopy and analysis of spectra
Samples were placed in 5-mm tubes. Proton-decoupled 13C spectra were obtained at 100.3 MHz on a 9.4 T Bruker Omega spectrometer (Billerica, MA). Spectra were acquired using a 45 degree carbon pulse, collecting 10,000 to 15,000 data points over 22,000 to 26,000 Hz, with a 1.0-second delay between pulses. Relative multiplet areas in the glutamate carbon resonances were determined with the use of commercial software (Acorn NMR Inc, Fremont, CA).

Data were analyzed using the nonsteady-state technique as described previously [13]. This method determines the contributions of acetoacetate, lactate plus pyruvate, fatty acids, and unlabeled sources to acetyl-coenzyme A (acetyl-CoA) oxidized in the TCA cycle. Catabolism of the available substrates will yield acetyl-CoA in one of four specific isotope patterns: enriched in carbon 1 (if derived from acetoacetate), enriched in carbon 2 (if derived from lactate or pyruvate), enriched in both carbons 1 and 2 (if derived from fatty acids), or unenriched (if derived from glucose or from endogenous tissue sources such as glycogen or triglycerides). As acetyl-CoA enters the citric acid cycle these specific labeling patterns become reflected in the enrichment pattern of the glutamate carbons, which are easily distinguished in the 13C-NMR spectrum. The nonsteady-state analysis is advantageous because it does not require assumptions of metabolic and isotopic steady state [13], multiple substrates can be evaluated in a single experiment, and the sources of acetyl-CoA are easily distinguishable from examination of glutamate resonances (see Fig 1).



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  		Fig 1. Representative 13C NMR spectra of glutamate C4 from a heart perfused at 37°C (A) and one perfused with identical substrates at 17°C (B). C4 peaks resulting from lactate oxidation (L) are increased relative to those from fatty acid oxidation (F) at the lower temperature.

 
Statistical analysis
Statistical analysis was performed with commercially available software (SAS Institute Inc, Cary, NC). Metabolic results were compared using a one-way analysis of variance with the Student-Newman-Keuls test for differences between groups ({alpha} set to 0.05). The effect of perfusate temperature on mechanical function (RPP) was compared by repeated measures analysis of variance.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Effects of hypothermia on function and coronary flow
Cardiac performance remained stable in the normothermic group (group 1) throughout the perfusion interval. In the hypothermic groups, heart rate declined in proportion to the degree of cooling, with final heart rates of 189 ± 9, 117 ± 6, and 55 ± 4 beats per minute [mean ± SEM] in groups 2 to 4 respectively (see Fig 2A). In association with this negative chronotropic effect was an increase in developed pressure in hearts perfused at colder temperatures (see Fig 2B). The effect of temperature on rate-pressure product (defined above) is shown in Figure 2C. Coronary flow changed little with progressive hypothermia, averaging 19 ± 2, 16 ± 1, 18 ± 1, and 16 ± 2 mL/min [mean ± SEM] at the final experimental time point in groups 1 to 4 respectively. A group of hearts (n = 4) were perfused at the lowest temperature for 30 minutes then rewarmed to 37°C. These hearts returned to their base line functional status, suggesting that this model did not result in any significant ischemia or temperature-induced cardiac injury.



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  		Fig 2. Functional values recorded from each group over the experimental timecourse. Progressive hypothermia resulted in slower heart rate (A), higher developed pressure (B), and lower rate-pressure product (C). Results are expressed as mean ± SEM, n = 8 for each group. Heart rate was significantly different among all four groups. Developed pressure was similar between groups 3 and 4, but significantly different from all others. Rate-pressure product in group 4 was significantly different from all other groups by repeated measures analysis of variance. Open circles represent group 1 (37°C), triangles represent group 2 (32°C), squares represent group 3 (27°C), and filled circles represent group 4 (17°C).

 
Substrate selection profile
Under control conditions (group 1, 37°C) fatty acids and ketones were the dominant fuels oxidized by the heart, together generating more than 90% of the acetyl-CoA oxidized within the citric acid cycle. Substrate preferences changed as the temperature of the perfusate dropped below 32°C. Although there was no change in substrate oxidation patterns between 37°C and 32°C, at a perfusate temperature of 27°C, the contribution of fatty acids to acetyl-CoA oxidized within the citric acid cycle was significantly reduced (see Table 1). Lactate or pyruvate and unlabeled sources (representing glucose or endogenous substrates) began to replace fatty acids at this temperature although the increase was not statistically significant. At 17°C, the relative oxidation of lactate or pyruvate was significantly increased compared to values observed at 37°C, and fatty acid utilization was further depressed. The contribution of acetoacetate to acetyl-CoA remained constant throughout the entire temperature range studied. Utilization of glucose or endogenous stores was minor at all temperatures and did not significantly change with variations in temperature.


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  		Table 1. Percentage Contribution of Each Substrate to Acetyl-CoA Oxidized in the Citric Acid Cycle

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Effects of hypothermia on cardiac function
Hearts subjected to hypothermia exhibited significant changes in functional values. Specifically, developed pressure increased and heart rate fell with progressive hypothermia. This is consistent with the findings of Suga and associates [14], who reportd that hypothermia (to 29°C) increases contractility without altering the efficiency of contraction. The mechanism of increased contractility with hypothermia may relate to increased cellular calcium influx [15], and it is noteworthy that the temperature-induced alterations in calcium movement are affected by substrates, particularly fatty acids [16]. Increased calcium in endothelial cells may increase coronary vasomotor tone, which may account for the minor changes in coronary flow rates noted in the hypothermic groups. In this study, cooling was accomplished gradually (over 10 minutes) to avoid the known deleterious effects of rapid cooling contracture [17].

Selection of substrates for oxidation: effects of hypothermic perfusion
This analysis demonstrates that hypothermia independently alters patterns of substrate oxidation in the isolated heart. Oxidation patterns under normothermic conditions were similar to those reported by other investigators. Under deep hypothermic conditions, fatty acids provided less of the total acetyl CoA entering the TCA cycle compared with other substrates. At the lowest temperature studied, pyruvate and lactate increased their contribution to acetyl CoA to fill this void. The relative contributions of acetoacetate and unlabeled sources (which could include endogenous stores or exogenous glucose) did not change with variations in temperature.

The mechanism behind these changes in myocardial substrate selection are not defined. Hypothermia may cause primary suppression of fatty acid oxidation with a compensatory increase in carbohydrate metabolism. Alternatively, hypothermia’s primary effect may be to increase carbohydrate metabolism, resulting in a secondary suppression of fatty acid oxidation. One possible site of suppression of fatty acid catabolism could be inhibition of carnitine pamitoyl transferase I (CPT I), an enzyme known to have a central regulatory role in fatty acid metabolism [18]. CPT I facilitates transport of fatty acids into the mitochondria for oxidation; and inhibition of this enzyme has been shown to decrease fatty acid oxidation and increase carbohydrate (specifically glucose) oxidation [19].

Another possible mechanism for the observed increase in carbohydrate contribution to acetyl CoA could be stimulation of pyruvate dehydrogenase, either by inhibition of pyruvate dehydrogenase kinase, or stimulation of pyruvate dehydrogenase phosphatase, the two controlling enzymes of the pyruvate dehydrogenase complex. Activation of pyruvate dehydrogenase phosphatase occurs with increases in intracellular and intramitochondrial calcium [20], and a rise in cytosolic calcium at low temperature has been described [15, 21]. Interestingly, administration of dichloroacetate (DCA), which increases the ratio of active to inactive pyruvate dehydrogenase, causes similar alterations in myocardial substrate metabolism in an isolated rat heart model [10]. We note that the increase in lactate or pyruvate contribution cannot be explained by accumulation of lactate from anaerobic glycolysis. Any lactate derived by this route would be unlabeled and would not be included in the lactate contribution defined by NMR isotopomer analysis.

Methodology is important in evaluating substrate oxidation. Most prior studies have examined changes in substrate concentrations or oxygen content across the myocardium. Measuring arteriovenous differences in metabolite concentrations gives information on uptake of substrates, but does not necessarily equate to rates of complete oxidation as substrates may accumulate in the cell or be diverted to biosynthetic pathways. Measurements of oxygen consumption reflect overall oxidative metabolism under normal conditions, but if oxidative phosphorylation becomes uncoupled, the relationship between substrate oxidation, oxygen consumption and myocyte energetics is altered. Finally, measuring oxygen consumption does not provide information on substrate utilization patterns in the myocardium.

13C NMR isotopomer analysis offers advantages in evaluating substrate utilization. Because it measures changes in the glutamate spectrum, substrates must enter the citric acid cycle en route to complete oxidation to be recorded. Those taken up and not oxidized are ignored. Similarly, uncoupling oxidative phosphorylation will not change the relative substrate utilization patterns determined by isotopomer analysis. The technique has other advantages in that multiple substrates can be evaluated in a single experiment, isotopic and metabolic steady states are not required [13], and 13C has no radiation risk. This method is well-suited to the present study, where a more complete and physiologic complement of available substrates is provided.

Study limitations
This study was performed in an isolated heart with a crystalloid perfusate. Substrates were provided in carefully controlled concentrations that mimic those observed in the fed rat. However, surgery, anesthesia, heparinization and other factors may alter the concentrations found under clinical conditions. The model does not include catecholamines or other neurohormonal effectors which can alter substrate metabolism [9]. Isotopomer analysis determines the relative contributions of each available substrate to acetyl-CoA oxidized within the heart. Absolute flux measurements are not determined, but may be relevant under conditions where the overall metabolic rate is reduced. Finally, this study evaluated only changes in temperature, and extrapolation of these findings to scenarios that also involve cardioplegic arrest or ischemia may be inappropriate.

Clinical relevance
Hypothermia is commonly applied to myocardial protection strategies during cardiac surgery, and some successful clinical methods use continuous perfusion with cold blood as the major technique to preserve myocyte function [22]. This study demonstrates that lowering myocardial temperature significantly alters substrate utilization profiles in the myocyte. The suppression of fatty acid oxidation may have importance to myocardial recovery after ischemia and during rewarming, two conditions where high levels of fatty acid oxidation may translate to cardiac dysfunction [8, 23]. Also, studies that evaluate drugs or cardioplegia additives designed to alter myocardial metabolism should consider the independent effect of temperature on substrate utilization.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This research was supported by grants from the National Institutes of Health (RO1-HL57310 and P41-RR02584), the American Heart Association [96007740] and a Merit Review and Clinical Investigator Award of the Department of Veterans Affairs.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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