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Ann Thorac Surg 1998;65:1235-1240
© 1998 The Society of Thoracic Surgeons

Glucose and Fatty Acid Oxidation by the In Situ Dog Heart During Experimental Cooling and Rewarming

^a Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
^b Department of Anesthesiology, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway

Accepted for publication November 21, 1997.

Address reprint requests to Dr Steigen, Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Reduced myocardial function after hypothermia may be metabolic in origin, but the relationship between myocardial metabolism and the various components of hypothermia-mediated dysfunction has not been thoroughly investigated.

Methods. In the present study we measured myocardial uptake and oxidation of glucose and oleate in mongrel dogs undergoing cooling to 25°C followed by rewarming to 37°C, using radiolabeled substrates.

Results. Segment work index declined from 39.3 ± 5.1 to 15.1 ± 2.4 mm Hg in response to cooling from 37° to 25°C and did not recover completely on rewarming (27.2 ± 4.2 mm Hg, p < 0.05). Oleate uptake declined from 3,251 ± 619 to 1,043 ± 356 nmol · min^-1 · 100 g^-1 (p < 0.05) when the dogs were cooled from 37° to 25°C. Simultaneously, oxidation rate fell from 1,089 ± 158 to 354 ± 83 nmol · min^-1 · 100 g^-1 (p < 0.05). On rewarming, oleate uptake was restored to prehypothermic values, whereas its rate of oxidation remained depressed (480 ± 129 nmol · min^-1 · 100 g^-1; p < 0.05). Uptake and oxidation of glucose also declined significantly during cooling. However, both uptake and oxidation of glucose recovered fully on rewarming.

Conclusions. The results of the present study demonstrate a reduced capacity to oxidize fatty acids by the myocardium during rewarming after hypothermia.

	Introduction

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Resuscitation after prolonged, deep hypothermia (experimental or accidental) often fails, probably as a result of cardiovascular dysfunction, including cardiac arrhythmias. It is likely that hypothermia-induced cardiac injury is in part metabolic in origin, but the relationship between myocardial metabolism and the various components of hypothermic injury has not been thoroughly investigated.

A better understanding of how temperature per se affects myocardial metabolism and function is of great importance for the development of rational treatments of accidentally hypothermic victims, for developing new cardioplegic solutions, and for preservation of hearts for transplantation. In addition, this knowledge will be important in the current debate about which of the two methods, cold or warm cardioplegia, is the optimal choice for myocardial protection during cardiac operations.

Mjøs and associates [1] reported that rat hearts perfused with high concentrations of free fatty acids showed impaired mechanical function during rewarming from hypothermia. Hearts given glucose as the sole substrate, on the other hand, recovered close to 100% of mechanical function. These authors further suggested that the fatty acid-induced loss of mechanical function was mediated through an altered calcium homeostasis. An improved posthypothermic function was also observed when oxfenicine (L-(+)-p-hydroxyphenylglycine; Sigma Chemical Co, St. Louis, MO), a known inhibitor of fatty acid oxidation in cardiac muscle, was present in the perfusion medium. In a previous study from our laboratory [2] on isolated rat hearts, we have shown that hypothermia per se causes a net calcium uptake and that this effect is aggravated by high concentrations of fatty acids. These results suggest that hypothermia-induced cardiac injury is in part induced by metabolic changes, especially changes in the balance between fatty acids and carbohydrates.

A first step, therefore, would be to determine which energy substrate is preferred by the heart during hypothermia and rewarming. In a previous study from our laboratory [3] on isolated rat hearts perfused with a constant supply of both fatty acids and glucose, it was shown that fatty acid oxidation dominated over glucose oxidation in the hypothermic state. However, experimental data obtained from isolated rat hearts perfused with a crystalloid perfusate may not be directly applicable to hearts perfused with blood. The purpose of the present study, therefore, was to determine the effect of hypothermia and rewarming per se on the myocardial substrate utilization in an intact dog model, emphasizing changes in the rates of uptake and oxidation of glucose and fatty acids. Body temperature was controlled with heat exchangers introduced into the esophagus and the lower bowels. This model has been used extensively in our laboratory and has shown to be stable at 37°C with respect to hemodynamics and metabolism.

	Material and methods

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Animal preparation
Eight mongrel dogs (15 to 24 kg) were anesthetized with 30 mg/kg sodium pentobarbital, followed by a continuous infusion of 3.5 mg · kg^-1 · min^-1. All animals were treated according to the guidelines on accommodation and care of animals formulated by the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes. The dogs were placed in the right supine position and ventilated through a cuffed endotracheal tube by a volume-controlled ventilator (Servo Ventilator 900, Siemens Elema, Stockholm, Sweden) with continuous monitoring of airway pressure. The ventilator was set to a tidal volume of 15 mL/kg, and the frequency was adjusted to maintain normocapnia (arterial carbon dioxide tension, 30 to 35 mm Hg). The heart was thereafter exposed through a midsternal split and suspended in a pericardial cradle.

Hemodynamic recordings
Limb lead ECG was recorded continuously throughout the experiment to detect arrhythmias. Left ventricular systolic pressure (LVSP) and end-diastolic pressure (LVEDP) were measured by a microtransducer catheter (Dräger Medical Electronics, Best, the Netherlands) which was inserted into the left ventricle through the right carotid artery. Mean aortic pressure was measured by a Statham P23 Db pressure transducer (Statham Instruments Inc, Oxnard, CA) connected to a fluid-filled catheter inserted into the thoracic aorta through a femoral artery. Myocardial blood flow was measured by the hydrogen washout technique [4, 5], ie, a catheter equipped with a H₂-sensitive platinum electrode was placed in the coronary sinus for repeated measurements of myocardial blood flow. Core temperature was continuously monitored using temperature sensors placed in the thoracic aorta. To calculate segment work index [6] we used piezoelectric crystals; one pair of discoid crystals was placed in the midmyocardium in the region supplied by the anterior descending artery. The crystals were mounted on T-shaped shafts and implanted at the desired depth (about 8 mm from the epicardium) through stab wounds. The crystals were connected to a dimension meter to measure regional contraction and relaxation of the myocardium [7]. Ultrasound was emitted from one crystal and received by the other and the distance between the two crystals was determined on the basis of the transmission time. Segment work index (WI) was determined by the formula , where SL_d is diastolic segment length and SL_s is systolic segment length. The measured parameters were recorded on a Gould ES 2000 recording system (Gould Inc Recording Systems, Cleveland, OH).

Cooling and rewarming regimens
Body temperature control was achieved by heat exchange tubing introduced into the esophagus and the lower bowels. The animals were cooled successively to 31° and 25°C and then rewarmed to 31° and 37°C, each step lasting 80 to 90 minutes. When the actual temperature was reached it was kept at this value for 15 minutes after which measurements and sampling were performed. The whole procedure lasted 336 ± 13 minutes (equally divided between cooling and rewarming).

Preparation and infusion of radioactive substrates
Daily, a mixture of oleic acid (potassium salt) labeled with radioactive hydrogen (³H) and glucose labeled with radioactive carbon (¹⁴C) in ethanol was dried under a stream of N₂. The dried substrates were subsequently redissolved in 45 mL plasma obtained from the dog to give a final radioactivity of 2.2 µCi/mL and 8.9 µCi/mL of [¹⁴C]glucose and [³H]oleic acid, respectively. The labeled substrates were administered intravenously by means of an infusion pump; a priming infusion of 30 mL/h were given during the first 15 minutes, after which the infusion rate was reduced to 8 mL/h, corresponding to 17.6 µCi/h ([¹⁴C]glucose) and 71.2 µCi/h ([³H]oleic acid).

In the normothermic (37°C) control condition, ie, 45 minutes after the start of tracer infusion, and at each additional temperature indicated in the data tables, simultaneous coronary sinus and thoracic aorta samples were obtained for determination of chemical and radioactive concentrations of substrates. The samples were collected into heparinized 10-mL plastic syringes and transferred to plastic tubes that were immediately cooled in ice water. The tubes were centrifuged within 3 to 4 minutes, and the plasma was subsequently divided in portions and stored at -20°C until later analysis.

Chemical analysis
Plasma lipids were extracted by the method of Folch and associates [8], and the free fatty acids were separated from other lipid components using Bond Elut aminopropyl columns (Analytichem Int, Harbor City, CA) as described by Tracy [9]. The fatty acids were derivatized to their phenacyl esters according to Durst and coworkers [10] and quantified by high performance liquid chromatography (Waters HPLC unit; Waters Inc, Milford, MA) as described by Halgunset and colleagues [11], using heptadecanoic acid as internal standard.

Plasma glucose was analyzed spectrophotometrically by the glucose oxidase method (Boehringer Mannheim, GmbH, Mannheim, Germany), whereas analysis of lactate in plasma was carried out according to Passoneau [12].

Myocardial substrate oxidation
Calculation of the myocardial oxidation of [³H]oleic acid and [¹⁴C]glucose was based on the difference in ³H₂O and ¹⁴CO₂ content between simultaneously sampled coronary sinus and arterial blood, as well as the coronary blood flow. The content of ³H₂O was determined by vacuum sublimation of 1 mL plasma, as described by Midwood [13]. Blood ¹⁴CO₂ content was assessed by a diffusion method, as described by Wisneski and associates [14]. Briefly, 1 mL blood (duplicate samples from aorta and coronary sinus) was drawn into an airtight syringe and transferred by a 21-gauge needle into the outer well of a double-chambered, rubber-stopped glass tube. The outer well contained 0.5 mL 1 mol/L H₂SO₄, whereas the center well contained 1 mL 1 mol/L NaOH that trapped the released ¹⁴CO₂ as NaH¹⁴CO₃. Aliquots of NaOH (with trapped CO₂) or plasma water (with ³H₂O) were then mixed with scintillation fluid (Ultima Gold XR), and the radioactivity was determined on a beta-scintillation counter (Packard 1900 TR Liquid Scintillation Analyzer; Packard Instruments BV-Chemical Operations, Groningen, the Netherlands).

Chemicals
L-Lactic dehydrogenase (L-lactate:NAD oxidoreductase, EC 1.1.1.27) was purchased from Sigma Chemical Company (St. Louis, MO). HPLC-grade methanol and acetonitrile were obtained from Rathburn Chemicals Ltd. (Walkerburn, Scotland). Radioactive oleate (NET-289 [9,10-³H(N)]-oleic acid) and glucose (NEC-042X D [¹⁴C(U)]-glucose) were from NEN Research Products (Du Pont, Deutschland, GmbH, Dreieich, Germany), both at a radiochemical purity of 99%. Glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP 1-oxidoreductase, EC 1.1.1.49) and hexokinase (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1) were obtained from Boehringer Mannheim GmbH. All other chemicals used were from Sigma or from Merck a/s, Oslo, Norway.

Statistical analysis
Data are presented as means ± the standard error. Differences were considered significant at the 95% confidence level. Data analysis was made by analysis of variance with repeated measures followed by Fisher’s least significant difference method of multiple range analysis when F values indicated statistical difference.

	Results

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Hemodynamic parameters
All hemodynamic parameters fell significantly during cooling, except left ventricular end diastolic pressure, which showed a slight increase (Table 1). After rewarming, WI, left ventricular systolic pressure, maximum rate of increase of left ventricular pressure, and myocardial blood flow were significantly lower as compared with their baseline values (p < 0.05). Heart rate returned to essentially the same value as measured before cooling, whereas left ventricular end-diastolic pressure did not change. Except for sporadic ventricular ectopic beats, no arrhythmias were observed during the experimental course.

	Comment

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It is generally accepted that hypothermia used in combination with cardioplegic arrest of the heart is protective to the myocardium, because hypothermia per se significantly reduces myocardial metabolism and retards deterioration of the heart function [15]. Nevertheless, there are major disadvantages with the introduction of hypothermia, including its effects on membrane stability [16], enzyme function [17], tissue calcium accumulation [2], and cellular volume regulation [18]. In accordance with previous studies on experimental hypothermia the current study demonstrated that rewarming after profound hypothermia in dogs is associated with depressed cardiovascular function. Thus, after rewarming the WI was almost 30% less than the prehypothermic control value. Other studies in our laboratory [19] indicate that this phenomenon could in part be related to a reduced coronary flow rate and an increased coronary resistance.

The current results may also indicate that hypothermia has deleterious effects on myocardial metabolism. Thus, the aerobic energy production of the myocardium was reduced after rewarming because of a reduction in the fatty acid oxidation capacity, which was not compensated by a corresponding increase in the oxidation of carbohydrates. Very little is known regarding the influence of hypothermia and rewarming on the metabolic status in the heart. In fact, most of our knowledge on this topic comes from the vast experience with clinical hypothermia, ie, cold cardioplegia used for cardiac arrest during heart operations. Evaluation of these studies is often complicated by the fact that the experimental protocol, in addition to hypothermia, also includes an ischemic component. Myocardial substrate preferences have been reported to change after both ischemia [20] and cardioplegia. Teoh and colleagues [21] reported an inability of the human heart to oxidize exogenous fatty acids during reperfusion after cold cardioplegic arrest for coronary bypass operation. In a follow-up study Teoh and colleagues suggested that lactate was the preferred substrate for myocardial oxidative metabolism after cardioplegic arrest [22]. However, no information was provided regarding the mechanical function of the hearts in that study. In the current study we did not observe any significant changes in lactate extraction during the course of the experiment, and it is therefore unlikely that the reduction in fatty acid oxidation after cooling was compensated by increased lactate oxidation.

In contrast to previous studies involving cold cardioplegia, which have demonstrated elevated arterial concentrations of FFA, glucose, and lactate [21, 23], we were not able to demonstrate significant changes in the levels of FFA either during hypothermia or after rewarming. This may reflect species differences as previously pointed out by Nesbakken [24]. Moreover, plasma glucose concentration was significantly lower at 25°C compared with prehypothermia and returned to baseline, prehypothermic values after rewarming. Probably, the discrepancy between our results and other studies with respect to the plasma concentrations of energy substrates could also be related to the fact that cardiopulmonary bypass per se introduces changes in catecholamine metabolism.

A slight, but statistically significant, increase in the arterial concentration of lactate was noted during hypothermia and after rewarming, which was probably related to peripheral anaerobic metabolism. Positive arterial–coronary sinus differences in lactate were obtained throughout the whole experimental period. Although we did not measure glycolysis directly, this finding could be taken as an indication that anaerobic metabolism plays a minor role in energy production during hypothermia. This may also explain why cold cardioplegic arrest during bypass operations [21] may induce other metabolic responses than those seen in our model.

In the present study, oxidation of fatty acids was significantly reduced after hypothermia and rewarming, whereas glucose oxidation returned to prehypothermic control values. Clearly, the reduction in fatty acid oxidation after hypothermia and rewarming, as indicated by the lower production of ³H₂O, reflects a reduced ß-oxidation of fatty acids in the mitochondria. This conclusion follows the fact that the hydrogen atoms removed during the dehydrogenation step in the ß-oxidation spiral are recovered as ³H₂O in the respiratory chain.

The reduced fatty acid oxidation was not related to reduced myocardial uptake of fatty acids from the circulation, because fatty acid uptake by the myocardium was fully recovered on rewarming. In fact, the myocardial fatty acid uptake recovered despite a clear reduction in the myocardial blood flow, which implies a posthypothermic increase in the fatty acid extraction. Furthermore, the observation that myocardial ¹⁴CO₂ production returned to prehypothermic values after rewarming shows that oxidation of acetyl-CoA to CO₂ and H₂O by the tricarboxylic acid cycle in the mitochondria was not affected by the hypothermic insult. This observation would exclude accumulation of acetyl-CoA in the mitochondria, and thus the possibility for feedback inhibition of the enzymes in the ß-oxidation pathway. Most likely, therefore, the lowered fatty acid oxidation capacity observed in rewarmed myocardium is related to a limited entry of fatty acids to the fatty acid oxidation system, situated in the inner matrix compartment of the mitochondria. Probably, the hypothermic insult may have caused changes (lateral phase transitions) in the phospholipid bilayer of the mitochondrial membranes, which in turn would affect the transfer of fatty acids across the mitochondrial membrane.

It is well-documented that myocardial contractile work is an important determinant of oxidative metabolism of the heart. In the present study we calculated a 21% reduction in the total oxidative energy production, taking into account that oleate comprised 37% of the plasma FFA pool, and assuming an ATP production rate of 136 for fatty acids and 36 for glucose oxidation. This correlated fairly well with the 30% reduction in WI after rewarming. This observation raises the question whether the depression in myocardial fatty acid oxidation observed after hypothermia and rewarming was a direct consequence of the parallel reduction in myocardial work. In our opinion, this is not the case, because one would expect the reduction in cardiovascular function to affect both glucose and fatty acid metabolism [25, 26]. Therefore, a reduction in deep body temperature to 25°C in dogs seems to cause a defect in the ß-oxidation of fatty acids in the myocardium, whereas the oxidative metabolism of glucose is unaffected.

In a previous study from our laboratory [3] on isolated rat hearts exposed to 15°C hypothermic perfusion, it was found that fatty acid oxidation rates returned to essentially the same values as those observed under steady-state normothermic conditions. Another observation in this study was that the rat hearts expressed a preference for fatty acids as oxidative substrate during hypothermia. In the current study on dogs, a reduction in body temperature from 37° to 25°C caused a 67% reduction in oleate oxidation and a 57% reduction in glucose oxidation. This finding may indicate a shift in the myocardial metabolism of hypothermic dogs in the opposite direction of that observed for the rat hearts, ie, a preference for glucose as oxidative energy substrate in the hypothermic state. The explanation for the differences in metabolic response to hypothermia between isolated rat hearts and in situ dog hearts could be related to species differences, as well as the duration and extent of hypothermic period. Another important factor is that in our study on isolated rat hearts we had a high level of oleate in the perfusion medium (0.6 mmol/L oleate complexed to 1% albumin is approximately equivalent to 1.8 mmol/L oleate complexed to 3% albumin) whereas in the current study the plasma levels of FFA were less than 0.4 mmol/L. It has been shown by Crass and associates [25] and Saddik and Lopaschuk [27] that oxidation of glucose is markedly inhibited by high levels of fatty acids. In addition, Langendorff-perfused rat hearts lack any nervous and hormonal influence and perform very little external work. Thus, their metabolic potential is not fully expressed, and therefore any defects in myocardial metabolism could be masked in this model.

A more difficult question to answer is whether reduction in the WI after rewarming is related to the defective fatty acid oxidation. Certainly, the reduced fatty acid oxidation represents a considerable deficit in aerobic ATP production, and should for this reason alone be considered as a possible mechanism for the reduced myocardial performance. In addition, because fatty acid uptake showed almost identical values before and after hypothermia, one would expect that the reduced fatty acid oxidation in the rewarmed state would cause accumulation of triacylglycerol and amphiphilic lipid intermediates. These intermediates have been suggested to jeopardize cardiovascular function by changing the excitability of the myocardial cells [28, 29] or by inducing intracellular energy-wasting (futile) cycles [30].

In conclusion, in situ dog hearts show a marked reduction in substrate oxidation and WI during hypothermia. Glucose oxidation, but not fatty acid oxidation, recovered to prehypothermic values when the hearts were subsequently rewarmed. Posthypothermic work indices were also considerably lower than those measured before hypothermia. It is suggested that the reduced fatty acid oxidation seen in the posthypothermic state may lead to accumulation of harmful lipid intermediates or induction of energy-wasting cycles, and that this could explain the reduced cardiovascular function after rewarming.

	Acknowledgments

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The expert technical assistance of bioengineers Elisabeth Børde and Helga-Marie Bye is gratefully acknowledged.

	References

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