Ann Thorac Surg 1996;62:762-768
© 1996 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Myocardial Substrate Oxidation During Warm Continuous Blood Cardioplegia
Terje S. Larsen, PhD,
Øivind Irtun, MD, PhD,
Terje K. Steigen, MD, PhD,
Thomas V. Andreasen,
Dag Sørlie, MD, PhD
Departments of Medical Physiology and Surgery, Faculty of Medicine, University of Tromsø, Tromsø, Norway
Accepted for publication April 29, 1996.
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Abstract
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Background. Although long-chain fatty acids are a major energy substrate utilized by the myocardium, changes in the substrate balance toward a predominating fatty acid utilization could jeopardize the myocardium during cardiac operative procedures.
Methods. In the present study myocardial substrate utilization was examined during warm continuous blood cardioplegia (4 hours, 37°C), using pigs undergoing cardiopulmonary bypass. Hearts were perfused antegradely in a closed extracorporeal circuit in which cardioplegic donor blood (hematocrit, 22%) containing 14C-glucose and 3H-oleate was delivered to the heart. Arterial and coronary sinus blood samples were taken at intervals for determination of plasma concentrations of energy substrates, as well as glucose and oleate oxidation rates (14CO2 and 3HOH production).
Results. The concentration of fatty acids in the cardioplegic perfusate did not change significantly during the cardiac arrest period. The mean concentration of glucose showed a 30% decline (not significant), whereas the lactate concentration increased from a starting value of 3.12 ± 0.27 to 6.31 ± 0.72 mmol/L at the end (mean ± standard error of the mean; n = 8; p< 0.05). Only fatty acid levels showed a significant (positive) arterial-coronary sinus difference. Myocardial oxidation of oleate varied between 302 ± 71 and 650 ± 66 nmol•min-1•heart-1, whereas the range of variation for glucose oxidation was 144 ± 64 to 355 ± 107 nmol•min-1•heart-1. However, the changes in fatty acid levels and glucose oxidation rates during the cardiac arrest period were not statistically significant. We calculated that overall glucose oxidation accounted for less than 5% of the total aerobic energy production.
Conclusions. The present results demonstrate overreliance on fatty acids as a source of energy during warm continuous blood cardioplegia, consistent with a condition of myocardial insulin resistance.
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Introduction
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The introduction of warm heart surgery has focused on the cardioprotective potential offered by warm continuous blood cardioplegia, which implies proper oxygenation of the myocardium during the plegic period. This strategy is attractive, recognizing that myocardial oxygen consumption during normothermic cardioplegic arrest is about 10% of that in beating hearts [1]. Thus, during warm continuous cardioplegic perfusion the myocardial energy requirements should be balanced by aerobic metabolism, avoiding the processes leading to metabolic and structural derangements that are associated with cardioplegic strategies where coronary (nutritional) flow is interrupted [2, 3].
Warm continuous blood cardioplegia was, however, introduced clinically without any experimental testing [4], and even today only limited information is available regarding structural and functional changes of the myocardium with this procedure. In particular, information regarding the oxidative metabolism, which contributes by far the largest amount of energy to the myocardium, is lacking. Moreover, the choice of energy substrate (fat versus carbohydrates) by the heart, both during and after cardioplegia, has not been clarified. This knowledge is important to argue why one cardioplegic strategy may be superior to another, and it should create a rationale for improvement of current cardioplegic strategies. The aim of the present study was therefore to examine myocardial supply and oxidation of the major energy substrates, ie, fatty acids and glucose, during 4 hours of warm continuous blood cardioplegia, using pentobarbital-anesthetized pigs. This model, which includes a separate extracorporeal circuit with oxygenator and pump for the heart alone, mimics the set-up used for human cardiac operations, and was recently established in our laboratory by Irtun and associates [5].
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Material and Methods
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Animal Preparation
Eight domestic pigs (Norwegian native breed) of either sex (47 to 54 kg) were used in the study. They 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.
An intramuscular injection of 1,000 mg of ketamine (Ketalar; Parke-Davis, Morris Plains, NJ) and 2 mg of atropine (Hydro Pharma, Oslo, Norway) was given as premedication. The animals were anesthetized by isofluoran inhalation, followed by continuous infusion of pentobarbital (Pentothal-Natrium; Abbott Laboratories, North Chicago, IL) via the left external jugular vein. The infusion rate was 30 mg•kg-1•h-1 for the first 30 minutes and 6 mg•kg-1•h-1 thereafter. Fentanyl (0.5 mg•h-1) (Leptanal; Janssen, Beerse, Belgium) was given for analgesia. Saline solution (0.9% NaCl) mixed with 5% glucose (1:1) was administered (20 mL•kg-1•h-1) for basal fluid replacement through the same line. A tracheostomy was performed, and the pigs were artificially ventilated with a mixture of nitrous oxide (50%) and oxygen (50%) by a volume-regulated ventilator (Servo 900; Elema-Schønander, Stockholm, Sweden). Arterial blood gases were regularly checked on an automatic blood gas analyzer (ABL 3; Radiometer, Copenhagen, Denmark), and ventilation volume was adjusted so that carbon dioxide tension and pH were within normal ranges (3.5 to 5.7 mm Hg and 7.34 to 7.47, respectively). Urine was continuously drained through a cystostoma.
The chest was opened by a median sternotomy, and the pericardium was incised and cradled. The hemiazygos vein, which in the pig drains directly into the coronary sinus, was ligated to exclude admixture of systemic venous blood with coronary sinus blood. Blood samples were taken from the root of the aorta and the coronary sinus for measurements of chemical and radioactive metabolite levels.
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Systemic Hemodynamic Measurements
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Systemic hemodynamic measurements were performed before and after cardioplegia, and will be published elsewhere. They are mentioned here to indicate the instrumentation of the animals. Left ventricular pressure was recorded by a microtip pressure transducer catheter (Millar Instruments Inc, Houston, TX) inserted into the left ventricle via a high-speed drill biopsy hole in the apex. A Swan-Ganz catheter was introduced through the right external jugular vein and floated into position in the pulmonary artery for measurements of central venous pressure, wedge pressure, pulmonal arterial pressure, and central temperature. Arterial blood pressure and heart rate were measured with a fluid-filled polyethylene catheter inserted 40 cm upstream into the descending aorta via the left femoral artery and connected to a pressure transducer (Transpac, Abbott, Ireland).
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Determination of Substrate Oxidation
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Daily, an ethanolic mixture of 3H-labeled oleic acid (potassium salt) and 14C-labeled glucose was dried under a stream of N2. The dried substrates were subsequently redissolved in 50 mL of plasma obtained from the pig to give a final radioactivity of 3.4 µCi/mL and 27.4 µCi/mL of 14C-labeled glucose and 53H-labeled oleic acid, respectively. A bolus of the labeled substrates was added to the cardioplegic perfusate, followed by a continuous infusion of 4 mL•h-1, corresponding to 13.6 µCi•h-1 (14C-labeled glucose) and 109.6 µCi•h-1 (3H-labeled oleic acid).
The content of 3H2O in plasma was determined by vacuum sublimation, as described by Midwood [6]. The 14CO2 content of the blood was assessed by a diffusion method, as described by Wisneski and associates [7]. Briefly, 1 mL of blood (duplicate samples from aorta and coronary sinus) was drawn into an airtight syringe and transferred via a 21-gauge needle into the outer well of a double-chambered, rubber-stopped glass tube. The outer well contained 1.0 mL 1 mol/L H2SO4, whereas the center well contained 1 mL 1 mol/L NaOH that trapped released 14CO2 as NaH14CO3. Aliquots of NaOH (with trapped CO2) or plasma water (with 3H2O) were then mixed with scintillation fluid, and the radioactivity was determined on a beta-scintillation counter (Packard 1900 TR Liquid Scintillation Analyzer; Packard Instruments BV-Chemical Operations, Groningen, the Netherlands).
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Experimental Protocol
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Cardiopulmonary bypass was performed under systemic hypothermia (26°C) with cross-clamping of the aorta and pulmonary artery and snaring of both venae cavae for 4 hours. During this time the hearts were antegradely perfused with cardioplegic blood solution, which was administered in the aortic root through a 9F aortic cardioplegic needle (Fig 1
). The cardioplegic blood solution was prepared by mixing 200 mL of St. Thomas' solution no. 2 [8] with 800 mL of fresh blood from a donor pig. This mixture was supplied with 16 mmol KCl and 5,000 IU of heparin, resulting in a final K+ concentration of 24 mmol•L-1 and a hematocrit of 22%. The solution was oxygenated and heated to 37°C, using a separate oxygenator (Babyvox; Baxter, San Juan, Puerto Rico). Perfusion pressure was regulated at 70 to 75 mm Hg, resulting in coronary flow rates between 94 ± 5 and 112 ± 4 mL•min-1 at the various observation times during the cardioplegic period. The myocardium was drained through a catheter inserted into the right ventricle via the pulmonary artery, and the cardioplegic blood returned to the oxygenator (see Fig 1). A vent was placed in the left ventricle to remove blood originating from noncoronary collaterals, thebesian drainage, and leakage through the aortic valve (70 to 200 mL•h-1).
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Fig 1. . Cardiopulmonary circuit and the cardioplegic circuit for continuous warm blood cardioplegia. The cardioplegic solution consisted of 200 mL of St. Thomas' solution mixed with 800 mL of blood from a donor pig (final hematocrit, 22%). Heparin was added to a final concentration of 5,000 IU/L, and potassium was adjusted to 24 mmol/L. (Inf. v.cava = inferior vena cava; LA = left atrium; RA = right atrium; Sup. v.cava = superior vena cava.)
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Ten minutes after cross-clamping and subsequently at 1-hour intervals arterial and coronary sinus blood was collected into preheparinized 10-mL plastic syringes and transferred to plastic tubes, which were immediately cooled on ice water. The tubes were centrifuged within 3 to 4 minutes, and the plasma was subsequently divided into portions, which were stored at -20°C for later analysis of plasma metabolite levels. Samples were also taken at these times for measurements of substrate oxidation and myocardial oxygen consumption. At the end of the cardiac arrest period the cardioplegic infusion was stopped and the aorta and pulmonary artery were declamped and perfused with systemic blood. All pigs were weaned from bypass and reperfused for 1 hour.
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Chemical Analysis
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Plasma lipids were extracted by the method of Folch and associates [9], and the free fatty acids were separated from other lipid components by a solid phase extraction system (Varian Int, Harbor City, CA). The fatty acids were quantified by gas chromatography as their methyl esters, using heptadecanoic acid as internal standard.
Plasma glucose was analyzed spectrophotometrically by the glucose oxidase method (Boehringer Mannheim, GmbH), whereas analysis of lactate was carried out according to Passoneau [10].
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Calculations
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Calculation of the myocardial oxidation of 3H-labeled oleic acid and 14C-labeled glucose was based on the difference in 3H2O and 14CO2 content between simultaneously sampled coronary sinus and arterial blood, the specific activities of the radioactive substrates, and the cardioplegic flow.
The oxygen content in blood (mL•100 mL blood-1) was calculated according to the following formula: Hb•SO2•1.34•10-2 + 0.024•PO2, where Hb is the hemoglobin concentration (in g•100 mL-1), SO2 is saturation of hemoglobin with O2 (in %), PO2 is partial pressure of oxygen (in kPa), the constant 1.34 is the oxygen binding capacity for hemoglobin (in mL•g-1), and 0.024 is the solubility constant of oxygen in blood at 37°C (in mL•100 mL-1•kPa-1). Myocardial oxygen consumption (mL•min-1•heart-1) was calculated from myocardial blood flow and arteriocoronary sinus differences in oxygen content.
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Specific Materials
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L-Lactic dehydrogenase (L-lactate:NAD oxidoreductase, EC 1.1.1.27) was purchased from Sigma Chemical Company (St. Louis, MO). 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 GmbH, Dreieich-Dreieichchain, 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 (adenosine triphosphate: D-hexose 6-phosphotransferase, EC 2.7.1.1) were obtained from Boehringer Mannheim GmbH, Mannheim, Germany.
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Statistical Analysis
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Data are presented as mean ± standard error. Statistical evaluation of the data was performed using one-way analysis of variance, followed by a paired two-tailed Student's t test, when F values indicated statistical difference, applying Bonferroni's method for simultaneous multiple comparisons.
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Results
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Energy Metabolite Levels in the Cardioplegic Circuit
The concentration of glucose in the cardioplegic solution showed a 30% overall reduction during the 4-hour cardioplegic perfusion (from 7.45 to 5.20 mmol/L; not significant), with the highest rate of decline occurring during the first 2 hours (Fig 2A). The difference in glucose concentration between arterial and coronary sinus blood was minimal, except for the measurements after 3 and 4 hours, when slightly lower values were obtained in the coronary sinus than in the arterial line (not statistically significant).
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Fig 2. . Concentrations of glucose (A), total free fatty acids (B), lactate (C), and oleate (D) in the cardioplegic perfusate during 4 hours of warm continuous blood cardioplegia. The perfusate was composed as described in Figure 1 . Note lack of arterial-coronary sinus difference for glucose and lactate. Results are mean ± standard error of the mean (n = 8).
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Free fatty acid (FFA) concentrations were some 25% less than starting values (not significant) at the end of the cardiac arrest period. Moreover, FFA values obtained from coronary sinus blood were consistently lower than those from arterial blood, except at 4 hours, when similar FFA values were obtained from the two sampling locations (Fig 2B). Oleic acid accounted for 32% (28% to 36%) of the total plasma FFA pool, and the changes in the plasma concentrations of this particular fatty acid (which was used to calculate fatty acid oxidation) showed an almost identical pattern as that of the total FFA pool (Fig 2D).
The concentration of lactate in the cardioplegic solution increased from a starting value of 3.12 ± 0.27 to 6.31 ± 0.72 mmol/L (p < 0.05). The major increase took place during the first hour of perfusion. There was virtually no difference in lactate concentration between arterial and coronary sinus blood at any time during the perfusion period (Fig 2C).
Substrate Oxidation
A prominent oxidation of oleic acid was observed throughout the whole cardiac arrest period, ranging between 353 ± 71 and 650 ± 66 nmol•min-1•heart-1. Glucose oxidation ranged between 144 ± 64 and 355 ± 107 nmol•min-1•heart-1. However, the changes in fatty acid, as well as glucose oxidation rates during the cardiac arrest period, were not statistically significant (Table 1). On a molar basis, the ratio between glucose and oleate oxidation showed values between 0.40 ± 0.11 and 1.23 ± 0.35. Taking into account that the average contribution of oleic acid to the total FFA pool was 32%, this observation indicates that glucose oxidation contributed very little to the overall energy production. Assuming adenosine triphosphate yields of 136 and 36 moles per mole of fatty acid and glucose, respectively, we calculated that glucose oxidation accounted in average for less than 5% of the total aerobic energy production (Table 2). Moreover, average adenosine triphosphate production from fatty acids and glucose over the 4-hour cardiac arrest period was approximately 13% of that seen in parallel studies on normothermic beating hearts (Larsen TS, et al, unpublished).
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Table 1. . Myocardial Oxidation of Oleate and Glucose, as well as the Ratio Between Glucose and Oleate Oxidation, During 4 Hours of Warm Continuous Blood Cardioplegiaa
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Table 2. . Myocardial Adenosine Triphosphate Production During Warm Continuous Blood Cardioplegia Based on the Mean Oxidation Rates from Table 1a
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Although oxidation of lactate was not measured in this study, the absence of a distinct arteriocoronary sinus difference of this metabolite indicates that oxidation of lactate is not a major contributor to energy production under the present conditions.
Table 3 shows that myocardial oxygen consumption stabilized at values between 1.1 and 1.4 mL•min-1 • heart-1 during the cardiac arrest period, corresponding to approximately 10% of values reported for beating hearts.
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Table 3. . Concentration of Hemoglobin, Partial Pressure of Oxygen, and Percent Saturation of Hemoglobin With O2 in Arterial and Coronary Sinus Blood
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Measurements of left ventricular pressure, its maximum first derivative, and mean arterial pressure (Table 4) showed that myocardial function was somewhat depressed after reperfusion, as compared with the precardioplegic values.
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Table 4. . Hemodynamic Variables During the Stabilization Period Before Cardioplegic Arrest and 60 Minutes After Reperfusion (n = 7)
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Comment
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The present study demonstrates that myocardial oxidative energy production was preserved during the present conditions of warm continuous blood cardioplegia. The energy was, however, derived almost exclusively from fatty acid oxidation, whereas utilization of carbohydrates (glucose and lactate) was negligible. Throughout the experimental period a significant increase in lactate concentration in the cardioplegic solution was observed, which was paralleled by a decline in the concentration of glucose.
The initial rates of oxidation obtained after 5 minutes of cardiac arrest, both for glucose and oleate, were somewhat lower (though not significantly lower) than those obtained later during the cardioplegic period. This finding may reflect dilution of labeled substrates by endogenous substrates at a time when exchange between these pools had not reached steady state. The total amount of adenosine triphosphate derived from glucose and oleate oxidation as calculated was approximately 13% of what we have found in beating pig hearts in parallel experiments (Larsen TS, et al, unpublished). The energy production in the cardioplegic hearts matched the myocardial oxygen consumption, which was slightly more than 10% of values reported for beating hearts [11].
Normally, the substrate preference of the heart is determined by the availability of substrates in the blood, so that when the concentration of carbohydrates is high after a carbohydrate-rich meal, carbohydrate oxidation is the dominating oxidative energy source, whereas in the fasted state free fatty acids become the choice of substrate [12]. The present observation of overreliance on fatty acid oxidation as a source of energy was, however, not related to excess of fatty acids in the cardioplegic solution, because the fatty acid concentration was within the lower physiologic range. More likely, the predominant fatty acid oxidation was a consequence of depressed glucose oxidation, and not related to stimulation of fatty acid oxidation per se. Of particular interest in this respect is that (1) although myocardial glucose uptake is not insulin-dependent, it is certainly stimulated by insulin [12] and (2) insulin resistance, caused by the systemic neuroendocrine stress response, has been reported after surgical procedures on the heart [13]. Thus, the decrease in glucose concentration in the cardioplegic solution to values around 4 mmol/L during the initial phase of the perfusion period, combined with myocardial insulin resistance, may in part explain the low glucose oxidation by the plegic heart.
Changes at the intracellular level may also be involved. For instance, elevated intramitochondrial acetyl coenzymeA/coenzymeA ratios, which are observed in the presence of high fatty acid concentrations, result in inhibition of the pyruvate dehydrogenase complex [14, 15], and consequently in depressed glucose oxidation. Although fatty acid levels were within the normal physiologic range in the present study, the potential existence of a myocardial insulin resistance combined with a predominant fatty acid utilization may be equivalent to a high fat condition. Besides, the high levels of lactate in the cardioplegic circuit will equilibrate with the intracellular milieu, and may in turn influence key enzymes in the glycolytic pathway due to elevation in the reduced form/oxidized form ratio of nicotinamide adenine dinucleotide [16]. These mechanisms, in addition to low glucose concentration in the cardioplegic solution and insulin resistance, may account for the observed depression of glucose oxidation. Apparently, the arrested heart can cope with this metabolic condition, but one should keep in mind recent evidence emphasizing beneficial effects of carbohydrates and amino acids after cardiac operations [13, 17, 18], while fatty acid oxidation may be harmful [19, 20]. Utilization of fatty acids increases oxygen consumption [21], jeopardizes calcium control [22], and reduces mechanical recovery after ischemia and hypothermia [23, 24].
It should be stressed that lactate that accumulated in the cardioplegic solution during the experimental period was unlikely to be of myocardial origin, primarily because the hearts were perfused continuously with oxygenated blood and also because there was no arteriocoronary sinus difference with respect to lactate content. The obvious explanation for the increase in lactate concentration, as well as the decline in glucose level, is anaerobic metabolism of glucose by erythrocytes, which obtain more than 90% of their energy from anaerobic catabolism of glucose [25]. Another source could be introduction of lactate from the systemic circulation via noncoronary collaterals. We believe, however, that this is of minor importance, primarily because systemic lactate concentrations were considerably less than in the cardioplegic circuit.
Under certain conditions, such as during exercise or lactate infusion [12], lactate may serve as an important source of energy for the heart after oxidation to pyruvate and transfer into the tricarboxylic acid cycle as acetyl coenzyme A units. Under the present conditions, where the hearts were perfused with oxygenated blood and lactate was abundant in the perfusate, one would expect a considerable lactate utilization by the heart. Yet uptake of lactate was not detectable. Again, low pyruvate dehydrogenase activity might be a plausible candidate to explain this finding. On the other hand, myocardial lactate utilization and oxidation are difficult to evaluate because the heart may simultaneously take up and release lactate.
In conclusion, this study demonstrates that fatty acid oxidation is the primary source of energy during warm continuous blood cardioplegia. The correspondingly low carbohydrate utilization may be related to insulin resistance, as well as enzyme inhibition due to elevations in the tissue level of lactate and the reduced form/oxidized form ratio of nicotinamide adenine dinucleotide. Continuance of this predominant fatty acid oxidation into the reperfusion period is believed to impair recovery of mechanical function of the heart, and interventions that can shift metabolism away from fatty acid oxidation toward glucose oxidation [18] should be considered. Of particular interest is the use of glucose or amino acids, or both, which are frequently included in the crystalloid fraction of warm blood cardioplegia mixtures during cardiac arrest [18, 26]. The present results are consistent with a condition of myocardial insulin resistance, and may provide a rationale for such treatments. Carefully controlled experiments are needed, however, to determine the effects of glucose and amino acid supplementation with respect to both myocardial substrate utilization and mechanical function during reperfusion.
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Acknowledgments
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The expert assistance from the technical staff at the Department of Medical Physiology and the Department of Surgery is gratefully acknowledged.
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Footnotes
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Address reprint requests to Dr Larsen, Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway.
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References
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Abstract
Introduction
