Ann Thorac Surg 2001;71:648-653
© 2001 The Society of Thoracic Surgeons
Original article: cardiovascular
Carnitine affects fatty acid metabolism after cardioplegic arrest in neonatal rabbit hearts
Takahiko Sakamoto, MDa,
Mitsuru Aoki, MDa,
Yasuharu Imai, MDa,
Shintaro Nemoto, MDa
a Department of Pediatric Cardiovascular Surgery, The Heart Institute of Japan, Tokyo Women’s Medical University, Tokyo, Japan
Accepted for publication August 21, 2000.
Address reprint requests to Dr Nemoto, Department of Medicine-Cardiology, Veterans Affairs Medical Center, Laboratories of Cardiac Molecular and Cellular Physiology, Baylor College of Medicine, 2002 Holcombe Blvd, Bldg 110, Rm 243, Houston, TX 77030
e-mail: snemoto{at}bcm.tmc.edu
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Abstract
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Background. Fatty acid (FA) metabolism and the contribution of carnitine to metabolism after cardioplegic arrest still remain unclear, especially in the neonatal heart where ß-oxidation is not a predominant source of adenosine triphosphate.
Methods. FA metabolism and the effects of carnitine administration were evaluated using a newborn (7-day-old) rabbit blood-perfused Langendorff model subjected to cold cardioplegic arrest. The hearts were divided into five groups; (1) perfused with unmodified diluted blood (n = 9), (2) subjected to 180 minutes of cold cardioplegic arrest and reperfused with the blood (n = 9), (3) subjected to the same ischemia and reperfused with the blood containing 40 µM/L (n = 9), (4) 0.5 mM/L (n = 5), and (5) 5 mM/L of carnitine (n = 5). During reperfusion, FA metabolism was assessed by iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid, a fatty acid. The myocardial time-radioactivity curve was then determined and a mathematical compartment analysis of the external detection was used to elucidate FA metabolism in the cardiac myocyte.
Results. Cold cardioplegic arrest resulted in significantly impaired FA metabolism following reperfusion. Compartment analysis suggested that FA activation in the cytosol and ß-oxidation were impaired. Carnitine supplementation in groups 3 and 4 improved FA metabolism during reperfusion. In contrast, supplementation in group 5 had no beneficial effect on FA metabolism.
Conclusions. These results suggest that FA metabolism is impaired after cold cardioplegic arrest and that carnitine supplementation may improve aerobic metabolism in neonates after open heart surgery.
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Introduction
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ß-oxidation of long-chain fatty acids (FA), which occurs in the mitochondria, is the most important and efficacious aerobic source of adenosine triphosphate (ATP) in the normal adult heart [1]. During normothermic no-flow ischemia, this highly aerobic FA oxidation is inhibited. Moreover, FA intermediates, such as fatty acyl-CoA, acyl-carnitine, and FA itself, readily accumulate in the ischemic tissue [2]. In this way, these intermediates increase ischemic injury by adenylate translocase and pyruvate dehydrogenase inhibition [3, 4], and by modifying the structure and function of membranes [5]. Although previous studies have examined FA metabolism during ischemia reperfusion in experimental isolated adult mammal hearts [6, 7] and in clinical practice [8], the results have been conflicting. There has been no precise study which examines FA metabolism after cardioplegic arrest, especially in the neonatal heart which shifts dramatically from predominantly using carbohydrates to predominantly using FA as an energy substrate after a few weeks of life [5, 9, 10]. The first purpose of the current study was to evaluate FA metabolism after cold cardioplegic arrest in neonatal rabbit hearts.
Carnitine has important roles in the FA metabolism, as well as carbohydrate oxidation in cardiac myocyte, including: 1) facilitation of ß-oxidation by transporting activated FA into the mitochondria [11]; 2) enhancement of the metabolic flux in the tricarboxylic acid cycle by sparing free CoA [1]; 3) activation of the transport of adenine nucleotides across the inner mitochondrial membrane by preventing adenylate translocase inhibition by long-chain acyl-CoA [12]; and 4) stimulation of activity of pyruvate dehydrogenase by decreaseing the acyl-CoA/CoA ratio, thus enhancing the oxidative utilization of glucose [13]. Although previous studies have demonstrated the beneficial effects of carnitine on cardiac functions in experimental isolated adult mammal hearts [14–16] and clinical practice [17], contributions of carnitine to the metabolism of the developing mammal especially following ischemia in the neonatal heart are still unclear. Accordingly, the second purpose of the current study was to investigate the effects of carnitine administration on FA metabolism after cold cardioplegic arrest in neonatal rabbit hearts.
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Material and methods
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Experimental preparation
An isolated blood-perfused Langendorff model was used. Briefly, 37 hearts from 7-day-old neonatal rabbits (Japanese white rabbit) were used because this model is thought to be a good representative of newborn hearts [18]. Rabbits were anesthetized with an intraperitoneal injection of 60 mg/Kg sodium pentobarbital and 100 IU heparin. When the rabbit totally lacked sensation, the thoracic cavity was opened and the heart was quickly excised and placed in ice-cold normal saline. The aorta was perfused at 40 cmH2O aortic pressure by gravity. Heparinized fresh homologous whole blood diluted with N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES) buffer (NaCl 123 mM/L, KCl 5 mM/L, MgSO4 1 mM/L, CaCl2 1.5 mM/L, sodium acetate 5 mM/L, and glucose 6 mM) at hematocrit 15% was used as perfusate and oxygenated with 100% oxygen. The perfusate and water bath were controlled at 37°C by heater-circulator except during the hypothermic phase, which was produced by circulating ice water.
Experimental protocol
After a 15-minute stabilization period, in the cardioplegic ischemia groups, the perfusate and water bath were cooled to 20°C. At 10 minutes after the start of cooling, when both temperatures reached 20°C, the heart was subjected to cold cardioplegic arrest by infusion of St. Thomas cardioplegic solution (NaCl 110 mM/L, NaHCO3 10 mM/L, KCl 16 mM/L, MgCl2 16 mM/L, and CaCl2 1.2 mM/L) every 30 minutes (3 ml initial dose and 1.5 ml following dose) and topical cooling. After 180 minutes of cold ischemia, reperfusion was begun with the perfusate at 20°C followed by rewarming to normothermia. All the animals in this study received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guideline for the Care and Use of Laboratory Animals" prepared by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).
Experimental groups
Experimental hearts were devided into five groups: (1) group C: control group, perfused without ischemia (n = 9); (2) group I: ischemia group, perfused after 180 minutes of the cardioplegic ischemia (n = 9); (3) group ICR: carnitine ischemia group, reperfused with the perfusate containing 40 µM/L of carnitine (normal plasma concentration of carnitine in neonatal rats) after 180 minutes of the ischemia (n = 9); (4) group ICR-10, and (5) group ICR-100: ischemia groups reperfused with the perfusate containing 0.5 mM/L and 5 mM/L of carnitine respectively (n = 5 in each group).
Measurements
After a 15-minute stabilization period or at the onset of reperfusion after cardioplegic arrest, 40 µCi of iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP) was injected as a bolus into the perfusion circuit 3 cm above the heart. The myocardial time-radioactivity curve was determined using a 1 x 1 inch NaI (TI) scintillation probe (Steffi, Raytest Inc, Straubenhardt, Germany) located 4 cm from the heart and fitted with a 7-mm thick lead shield. The count rate was recorded for 30 minutes from onset of the injection using a chromatointegrator (D-2500, Hitachi Co Ltd, Tokyo, Japan). At the end of the experiment, the radioactivity of the heart and the perfusate collected during the procedure were measured using a 2 x 2 inch NaI (TI) scintillator interfaced to a single channel analyzer (Ohyo Koken Kogyo Co, Tokyo, Japan). Myocardial radioactivity of 123I-BMIPP was evaluated as the percentage of the injection dose (%ID) and %ID per heart weight (%ID/g). Clearance was calculated as change of %ID/g per minute in early phase (30 seconds
1 minute) and late phase (530 minutes).
Mechanism of 123I-BMIPP accumulation in the myocardium
FA in coronary circulation are transported to the cytosol in the cardiac myocyte by simple diffusion. Afterwards, some of them are stored as triglycerides (TG) in the cytosol, and some of them are transfered by carnitine shuttle into the mitochondria where FA are metabolized through ß-oxidation. Otherwise, the rest of FA are released back to coronary circulation, which is "early back diffusion" (Fig 1). 123I-BMIPP is localized identically to natural FA. Moreover, since its ß-oxidation is delayed because of its methyl residue, 123I-BMIPP remains in the mitochondria for a long time [19, 20]. Therefore, using 123I-BMIPP is useful to measure myocardial FA metabolism in various settings, such as ischemia [21] and changes in metabolic substrate [22].
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Fig 1. Mechanism of iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP) accumulation in the myocardium, and a mathematical compartment analysis of the external detection to elucidate the fatty acid metabolism in the cardiac myocyte. (The kinetic constants: k(2,1) = activation of FA; k(3,2) = storage in TG pool; k(1,3) = lypolysis; k(4,2) = transfer into the mitochondria; k(5,4) = release of degradation products from the cardiac myocyte; and k(6,1) = release of 123I-BMIPP from the myocyte. PIPA = 123I-p-iodophenyldodecanoic acid, intermediate metabolite of 123I-BMIPP; TG = triglyceride pool in the cytosol.)
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Calculation
A mathematical compartment analysis of the external detection was used to elucidate the FA metabolism in the cardiac myocyte. This technique is potentially useful for estimating the intracellular metabolism and validated by comparison with actual experimental measurements [23]. To obtain quantitative information about 123I-BMIPP distribution in the different intracellular metabolic pathways, analysis of a cardiac time-radioactivity curve fitting by least squares method and calculating of parameters were performed using the SAMM II software package (version 1.0, SAMM Institute, University of Washington, Seattle, WA). A 6-compartment model is thought to be ideal in this experimental model (Fig 1). Each compartment is represented as follows: 1) free 123I-BMIPP in the cytosol; 2) 123I-BMIPP-CoA complex in the cytosol; 3) 123I-BMIPP in the TG pool; 4) 123I-BMIPP in the mitochondria; 5) and 6) 123I-BMIPP in coronary vessel. The kinetic constants that rule the fluxes between the various compartments are as follows: k(2,1) represents activation of FA; k(3,2) represents storage in TG pool; k(1,3) represents lypolysis; k(4,2) represents transfer into the mitochondria; k(5,4) represents release of degradation products from the cardiac myocyte; and k(6,1) represents release of 123I-BMIPP from the cell. The radio-activity in each compartment was calculated as the percentage of the total radioactivity at 30 minutes after injection of 123I-BMIPP.
Statistics
Data was expressed as mean ± standard error (SE) and analyzed by a statistical analysis system (Stat-View version 4.5, Abacus Concepts Inc, Berkeley, CA). Repeated measures of analysis of variance (ANOVA) was used for sequential, time-based measurements. A one-way ANOVA was used to compare parameters obtained from the compartment model analysis between groups. Data were further compared by the Student’s t test if ANOVA was significant. A p value less than 0.05 was considered to be significant.
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Results
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There were no significant differences in body weight and coronary blood flow (CBF) at baseline among the five groups (data not shown). Figure 2 demonstrates time-radioactivity curve expressed as %ID/g in groups C, I, and ICR. All groups had a peak within 1 minute after the injection of 123I-BMIPP. The %ID/g in group I was consistently lower than group C (ANOVA p < 0.01). And the %ID/g at 30 minutes after the injection of 123I-BMIPP in group I was significantly lower than group C (Table 1). On the other hand, there were no significant differences in the curve of %ID/g between ICR and C (Fig. 2 and Table 1).
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Fig 2. Time–radioactivity curve expressed as percentage of the injection dose per heart weight (%ID/g) in groups C, I, and ICR. (C = control; I = ischemia; ICR = carnitine ischemia.)
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Table 1 demonstrates the clearance of 123I-BMIPP calculated in early phase and late phase. In the clearance in early phase, which represents "early back diffusion," group I showed a significantly greater clearance than group C. However, examining clearance in the late phase, representing metabolized 123I-BMIPP in the cardiac myocyte, group I showed a significantly delayed clearance than group C. There were no significant differences between groups C and ICR.
Table 2 demonstrates the kinetic constant in the compartment model. The k(2,1) demonstrating activation of FA to acyl-FA, which is the first step in FA metabolism, was significantly lower in group I than in group C. There were no significant differences between groups C and ICR.
Table 2 demonstrates the radioactivity in each compartment calculated as the percentage of the total radioactivity in the heart and expressed as "q (%)." In group I, q3 (TG pool), q4 (mitochondria), and q5 (coronary vessels where degradation product of 123I-BMIPP was released) were significantly lower than in groups C and ICR. And q1 (cytosole) and q2 (acyl-BMIPP complex) in group I were also lower than in groups C and ICR (statistically insignificant). However, q6 (released 123I-BMIPP into coronary circulation without degradation) in group I was significantly greater than in groups C and ICR.
Change of %ID/g in group ICR10 showed the same pattern as in groups C and ICR, as shown in Figure 3 and Table 1. Moreover, the clearance and parameters of the compartment model in group ICR10 were same as those in groups C and ICR (statistically insignificant). On the other hand, the time-activity curve of %ID/g in group ICR100 showed the same pattern as that in Group I. And Group ICR100 had significantly lower parameters, such as k(2,1) and q2–5, than groups C, ICR, and ICR10 in the compartment model.
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Fig 3. Time–radioactivity curve expressed as percentage of the injection dose per heart weight (%ID/g) in groups C, I, ICR10, and ICR100. (C = control; I = ischemia; ICR10 = ischemia reperfused with 0.5 mM/L of carnitine; ICR100 = ischemia reperfused with 5 mM/L of carnitine.)
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Comment
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There were three major findings of this study of neonatal hearts. First, FA metabolism was significantly impaired during reperfusion after cardioplegia arrest. The compartment model analysis showed that activation of FA, in which acyl-FA is produced from free FA in the cytosol, was significantly impaired. In consequence, early back diffusion of 123I-BMIPP was increased, as was distribution of 123I-BMIPP into TG pool and mitochondrial matrix. Second, clearance of radioactivity in the late phase, which represents ß-oxidation in mitochondria, was consistently lower during the reperfusion than those in control. Moreover, the conpartment analysis showed that degradated 123I-BMIPP through ß-oxidation, which is released into coronary vessels from cardiac myocyte as shown in q5 fraction, was less during the reperfusion than control. Third, carnitine supplementation in physiologic concentration and 10 times physiologic concentration significantly improved FA metabolism during the reperfusion. The parameters of the compartment model returned within normal ranges. However, when carnitine was supplemented in 100 times physiologic concentration, a dose used in most of the previous studies [6], the impaired FA metabolism did not recover.
Previous studies examining FA metabolism during ischemia reperfusion have shown conflicting results. Increased FA oxidation has been shown to occur at the expense of glucose oxidation, resulting in a decreased recovery of both cardiac function and efficiency during reperfusion after simple zero-flow ischemia in the adult rat hearts [6, 7]. However this does not explain the accumulation of cytotoxic FA intermediates such as acyl-CoA and acyl-carnitine [2]. On the other hand, myocardial FA oxidation was depressed during reperfusion following coronary bypass surgery [8]. The difference in outcome of FA metabolism may stem from differences in types of ischemia, such as perfusate (crystalloid or blood), temperature (normothermia or hypothermia), and cardioplegic protection (with or without). We used a diluted blood-perfused model with cold cardioplegic arrest to better reflect the clinical setting during open heart surgery, and our results of FA metabolism in neonatal hearts agree with the latter finding [8].
The compartment model analysis showed that the FA activation in cytosol deteriorated significantly during the reperfusion. In consequence, early back diffusion of 123I-BMIPP was increased. Three possible mechanisms of this abnormality are: (1) suppression of long-chain fatty acyl-CoA synthetase, which activates FA into fatty acyl-CoA in the cytosol; (2) consequence of suppression in downstream FA activation where fatty acyl-CoA is transferred into the mitochondria by the carnitine-shuttle; and (3) a decrease in cytosolic FA binding protein, which facilitates cardiac uptake of long-chain FA and promotes their intracellular trafficking to sites of metabolic conversion [24]. Since carnitine supplementation in physiologic concentrations normalized the FA activation during the reperfusion in this study, the second possible mechanism seems most plausible.
Previous studies have demonstrated the beneficial effects of carnitine administration on left ventricular functional recovery after zero-flow global ischemia in adult rat isolated hearts [6, 16]. Carnitine was supplemented in 100 times physiologic concentration in the previous studies. One of the possible mechanisms of its beneficial effects might be stimulation of carbohydrate utilization and suppression of FA metabolism [6]. Our finding that the same high concentration of carnitine depressed FA metabolism during the reperfusion could support the possible mechanism even in the neonatal heart. This is especially important in the neonatal heart where carbohydrates are utilized as predominant energy substrates [5, 10]. On the other hand, in this study, we found that carnitine supplementation during the reperfusion in physiologic concentration and 10 times physiologic concentration normalized FA metabolism in neonatal hearts. It is known that the increased glucose oxidation by dichloroacetate may not be enough to alter the recovery of mechanical function in the neonatal zero-flow global ischemia-reperfusion rabbit heart [18], and free FA is still the preferred substance in the early reperfusion in the adult rat heart [17]. Therefore, FA metabolism could be one of the major sources of ATP after cardioplegic arrest even in the neonatal heart. However, effects of this normalization of FA metabolism by carnitine on cardiac performance and other aerobic metabolism, such as carbohydrate metabolism, still remain unclear, especially in the neonatal heart where the fatty acid metabolism is not mature but developing.
We concluded that fatty acid metabolism was impaired after cold cardioplegic ischemia in the blood-perfused neonatal rabbit heart. This depressed FA metabolism was restored well by carnitine supplement during reperfusion in low concentration. However, the supplement in high concentration failed to normalize the impaired FA metabolism. It is suggested that carnitine supplement might benefit aerobic metabolism in neonates after open heart surgery.
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Acknowledgments
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We gratefully thank Kenichi Morishita, BA, Yoshihiro Yamamichi, PhD, and Yoshifumi Shirakami, PhD, Central Research Laboratory of Nihon Medi-Physics Co, Ltd, for their technical assistance. 123I-BMIPP was generously provided by Nihon Medi-Physics Co, Ltd. This work was supported in part by the Japanese Ministry of Education, Science, and Culture (S.N. and M.A.).
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Abstract
Introduction
