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J Thorac Cardiovasc Surg 1994;108:938-945
© 1994 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

Dynamics of energy metabolism in the transplanted human heart during reperfusion

Ryszard T. Smolenski, MD, PhD, Anne-Marie L. Seymour, MA, PhD, Magdi H. Yacoub, FRCS


Harefield, Middlesex, United Kingdom

Supported by British Heart Foundation grant No 91/167.

Received for publication Sept. 1, 1993. Accepted for publication July 12, 1994. Address for reprints: Magdi Yacoub, FRCS, Department of Cardiothoracic Surgery, Heart Science Centre, National Heart and Lung Institute at Harefield Hospital, Harefield, Middlesex UB9 6JH, United Kingdom.

Abstract

Reperfusion after ischemia of the heart generates further damage to the myocardium through a variety of mechanisms including free radical generation, calcium overload, and abnormalities of energetics. In this study, the uptake and release of metabolites involved in energy metabolism were investigated during 45 mintues of reperfusion of donor human heart after transplantation to evaluate the nature of the metabolic abnormalities and the time course of recovery. Analysis of coronary sinus and arterial blood samples in 11 transplant recipients showed the following: (1) In the first minute of reperfusion, lactate release was observed accompanied by an uptake of pyruvate, resulting in a markedly elevated lactate/pyruvate ratio. The pH value of coronary sinus blood was lower than that of arterial blood by 0.1 unit, inorganic phosphate was released, and a massive efflux of nucleotide catabolites was observed. Hemoglobin oxygen saturation of coronary sinus blood was almost equal to that of arterial blood, showing minimal myocardial oxygen extraction. Coronary flow was approximately 300 ml/min at reperfusion with minor changes in the first minute. (2) From the second minute onward, pyruvate was released for over 45 minutes, contrasting with the first minute of reperfusion. Lactate was significantly released for up to 10 minutes of reperfusion, but myocardial uptake of lactate was not restored by the end of the observation period. However, the lactate/pyruvate ratio in coronary sinus blood recovered at the onset of this phase. Both pH changes in coronary sinus blood and phosphate release were restored within 5 minutes, but release of nucleotide catabolites was still significant after 30 minutes of reperfusion. The oxygen saturation of hemoglobin in coronary sinus blood decreased gradually in a biphasic mode over the 45 minutes, indicating gradual restoration of myocardial oxygen uptake. Coronary flow measured for up to 10 minutes of reperfusion decreased to a minimal value of 200 ml/min in the third minute, followed by restoration of initial flow. These data highlight the profound alterations in energy metabolism that occur during reperfusion of the transplanted heart. These changes, which may result from the preceding ischemia and impaired oxidative metabolism at the onset of reperfusion, were partially reversed in the first minutes. However, impaired pyruvate and lactate use and underperfusion reflected by the release of purine catabolites persisted for a period of more than 30 minutes of reperfusion. (J THORACCARDIOVASCSURG1994;108:938-45)

Reperfusion after myocardial ischemia affects the viability of heart cells through a variety of mechanisms, including calcium overload and generation of free radicals.Go Go 1-5 However, the deterioration of glycolytic and oxidative metabolism has been also identified as a potential factor involved in myocardial injury. Results of animal studies have demonstrated an increase in fatty acid use and a depression of glucose, pyruvate, and lactate use during reperfusion.Go Go 6-9 However, contradictory data have been also presented.Go 10 Evidence also exists to suggest that ischemia does not modify substrate use.Go 11 The tricarboxylic acid cycle flux was reported to be slightly enhanced or unchanged in the postischemic heart.Go Go 12,13 Other studies, however, have shown a decrease in tricarboxylic acid activity, particularly during the initial phase of reperfusion.Go 14 Detailed studies on cellular respiration of the heart under conditions of various workloads have provided evidence of a reduced oxidative capacity in the postischemic heart together with markedly altered regulation of the mitochondrial respiration.Go 15 A no-reflow phenomenonGo 16 and inhibition of the pyruvate dehydrogenase complexGo Go 17,18 are other contributory factors to altered myocardial metabolism in the reperfusion phase.

Clinical studies on the alterations of myocardial energy metabolism during cardiac operations have shown that the rate of substrate uptake in the heart was slow after reperfusion,Go Go 19-21 with only partial recovery after 4 hours of reperfusion.Go 22 The profile of metabolic requirements during the early reperfusion phase in human beings has not been clearly defined. Control of the reperfusion environment can exert a profound effect on myocardial functionGo Go 23-27 and may have important implications for future therapeutic rationales.

The present study was undertaken to define the profile and time course of energy metabolism during reperfusion in the donor human heart after transplantation. The pattern of myocardial uptake and release of metabolites involved in energy metabolism were monitored by the analysis of coronary sinus and arterial blood. Results demonstrated profound alterations in oxidative metabolism during the initial phase of reperfusion with rapid reversal within the first few minutes. Impaired pyruvate and lactate use and underperfusion persisted for at least 30 minutes of reperfusion.

METHODS

The study was carried out during 11 heart or heart-lung transplantations performed at Harefield Hospital. Collection of human blood was approved by the local ethics committee. The donor organs during heart-lung transplantations were preserved by lowering the systematic temperature to 15° C before the donor organs were collected, followed by infusion of 0.5 L of cold blood potassium (26 mmol/L) cardioplegic solution and storage in cold donor blood. In the course of heart transplantations, 1 L of cold St. Thomas' Hospital No. 1 cardioplegic fluid was infused just after the heart was harvested, followed by storage at 4° C in Ringer's solution during transportation.Go 28 The mean duration of the preservation period was 185 ± 66 minutes (with a range of 69 to 292 minutes).

Coronary sinus and arterial blood collection and extraction
Coronary sinus blood (2 ml) was collected directly from the coronary sinus through a catheter introduced either from inside or outside the heart. The protocol of sample collection is presented in Fig. 1. Coronary sinus samples were collected just after removal of the aortic clamp (at reperfusion) and after 1, 2.5, 5, 10, 20, 30, and 45 minutes. Arterial blood samples were collected from the arterial line of the extracorporeal circuit at reperfusion and after 1, 10, 30, and 45 minutes. One portion (0.8 ml) of blood was mixed immediately (within seconds) with an equal volume of perchloric acid (1.3 mol/L) and the remainder was analyzed with a blood gas analyzer (Radiometer Medical A/s, Copenhagen, Denmark) for hemoglobin oxygen saturation, pH, and potassium concentration. Rapid mixing of blood with perchloric acid was found previously to be sufficient to prevent purine catabolite breakdown in blood under conditions of this study.Go 29 The blood samples mixed with perchloric acid were centrifuged in an Eppendorf microfuge (Eppendorf North America, Madison, Wis.) for 3 minutes at 4° C to remove protein precipitate. One part of the supernatant was directly used for lactate, pyruvate, and inorganic phosphate assay and the remainder was neutralized with tripotassium ortophosphate, 3 mol/L. The resultant supernatant was analyzed by high-performance liquid chromatography for purine catabolite content.



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  		Fig. 1. Protocol of coronary sinus and arterial sample collection during heart or heart-lung transplantations.

 
Analytic procedures
The lactate and pyruvate content was assayed by enzymatic methods with a Sigma diagnostic kit (procedure No. 726-UV/826-UV, Sigma Chemical Co., St. Louis, Mo.). Inorganic phosphate was determined by a malachite green colorimetric procedure.Go 30 Purine catabolites (adenosine, inosine, hypoxanthine, xanthine, and uric acid) were evaluated by a reversed-phase high-performance liquid chromatography method operating on a Merck-Hitachi liquid chromatograph (Hitachi Medical Corp., Tokyo, Japan) as described previously.Go 29 We did not observed any release of uric acid or xanthine, confirming absence of xanthine oxidoreductase in the human heart. The sum of adenosine, inosine, and hypoxanthine concentrations was thus taken as the measure of extent of myocardial nucleotide breakdown.

Measurement of coronary flow
Coronary flow was measured with a Nihon-Kohden electromagnetic flowmeter (Tokyo, Japan) in three patients undergoing heart transplantation. The flow probe was inserted into the coronary perfusion line. This perfusion line supplied arterial blood from the extracorporeal circuit, entering the aortic root between the heart and the aortic clamp. The coronary line was opened at the time of reperfusion of the heart, whereas the aortic clamp was left closed. As the aortic valve was known to be fully competent in all patients, the flow into the aortic root provided an accurate measure of coronary flow. Pressure in the aortic root was monitored continuously throughout the reperfusion period and was maintained between 80 and 100 mm Hg by adjusting the rate of flow through the coronary line of the bypass machine.

Statistics
All results are presented as means ± standard error of the mean. The significance of the differences between arterial and coronary sinus concentration of all measured metabolites was evaluated with a paired Student's t test. A value of p < 0.05 was considered to indicate a significant difference.

RESULTS

In the first minute of reperfusion, profound metabolic alterations were observed. As can be seen in Figs. 2 and 6, a release of lactate was observed, accompanied by the uptake of pyruvate, resulting in a marked elevation of the lactate/pyruvate ratio. The lactate concentration in the arterial blood was above normal range at the time of reperfusion. Figs. 3 and 6 show the release of inorganic phosphate, nucleotide catabolites, and hydrogen ions, which were also elevated during the initial phase of reperfusion. At this time oxygen saturation of hemoglobin in coronary sinus blood was almost equal to that in arterial blood (Figs. 4 and 6), indicating a minimal myocardial oxygen extraction. Coronary flow (Fig. 5) was 330 ml/min at reperfusion and remained unchanged within the first minute.





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  		Fig. 2. Coronary sinus and arterial concentrations of lactate (A), pyruvate (B), and lactate/pyruvate ratio (C) in the 45-minute period after aortic declamping following implantation of the human heart. Values are expressed as the mean ± standard error of the mean, n = 8 to 11. *p < 0.05 in comparison with arterial concentration.

 




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  		Fig. 3. Coronary sinus and arterial concentrations of inorganic phosphate (A), sum of adenosine, inosine, and hypoxanthine (B), and pH value (C) in the 45-minute period after aortic declamping following implantation of the human heart. Values are expressed as the mean ± standard error of the mean, n = 6 to 11. *p < 0.05 in comparison with arterial concentration.

 


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  		Fig. 4. Hemoglobin saturation of coronary sinus and arterial blood in the 45-minute period after aortic declamping following implantation of the human heart. Values are expressed as the mean ± standard error of the mean, n = 7. *p < 0.05 in comparison with arterial concentration.

 


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  		Fig. 5. Coronary flow during initial phase of reperfusion after implantation of the heart. Coronary perfusion pressure was maintained at 80 to 100 mm Hg. Values are presented as the mean ± standard error of the mean, n = 3.

 
From the second minute of reperfusion, pyruvate was released from the heart (see Figs. 2 and 6), resulting in a restoration of arterial lactate/pyruvate ratio. This efflux of pyruvate was observed over the remaining time of reperfusion while lactate was significantly released for up to 10 minutes of reperfusion but normal myocardial uptake of lactate was not restored. Phosphate and pH changes (see Fig. 3) in coronary sinus blood were restored within 5 minutes, but release of nucleotide catabolites was observed for up to 30 minutes. Oxygen saturation of hemoglobin in coronary sinus blood (see Figs. 4 and 6) decreased gradually in a biphasic mode over the 45 minutes, indicating restoration of myocardial oxygen uptake. Coronary flow (see Fig. 5), measured for up to 10 minutes of reperfusion, decreased initially but recovered rapidly to above 300 ml/min.

Transplanted hearts were in the arrested state in the initial phase of reperfusion and the majority regained normal sinus rhythm within the 30 minutes of reperfusion. Among those that required defibrillation, no obvious changes in metabolite release were observed. Between 30 and 40 minutes of reperfusion, at the time of termination of cardiopulmonary bypass, hearts had commenced ejection and started to perform mechanical work.

DISCUSSION

The results of this study identify significant alterations in myocardial bioenergetics after reperfusion of the donor human heart. A severe metabolic imbalance was observed in the first minutes, whereas prolonged abnormalities in pyruvate and lactate metabolism together with existence of underperfusion areas continued for more than 30 minutes of reperfusion.

Energetic imbalance in the first minutes of reperfusion
The release of lactate, phosphate, hydrogen ions, and purine catabolites indicates profound alterations in myocardial energy metabolism.Go Go 31-34 Although most of the release observed in this study may represent washout of metabolites accumulated during ischemia, some of the observations imply that there is delayed recovery of energetic homeostasis. In support of this view, myocardial oxygen extraction from blood was minimal in the first minutes of reperfusion (see Fig. 4). The relatively small variations in coronary flow (see Fig. 5) cannot account for this effect. Temperature variations during rewarming of the heart in the initial phase of reperfusion may inevitably slow down recovery of metabolic processes in the heart. However, the existence of other metabolic activities such as release of purine catabolites, which is mediated by a temperature-dependent membrane transport system,Go 35 or the uptake of pyruvate suggest that inhibition of oxidative metabolism is not an effect of low temperature. In addition, extraction of pyruvate in the initial phase of reperfusion suggests that cellular uptake of oxygen or respiration was impaired rather than the distribution of coronary flow. The high lactate/pyruvate ratio observed in the first minutes of reperfusion reflected a high cytosolic NADH/NAD ratioGo 33 which, under conditions of adequate oxygen supply, implies that respiratory chain activity is inhibited by factors other than oxygen delivery.

Reduced oxidative metabolism or tricarboxylic acid cycle flux has been reported during reperfusion in some animal studies,Go Go Go Go 14,15,36,37 but other experimental work has shown full recovery of these processes after ischemia.Go Go 12,13 This discrepancy suggests that restoration of oxidative metabolism and tricarboxylic acid activity after ischemia may depend on either experimental conditions or species differences. Most of the animal studies did not include sufficient time resolution of the events during reperfusion and did not reproduce routine clinical procedures such as cardioplegic arrest and hypothermia.






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  		Fig. 6. Arterial-coronary sinus differences in concentrations of lactate (A), pyruvate (B), purine catabolites (C), and oxygen saturation of hemoglobin (D) at different time of reperfusion after implantation of the human heart. Presented data are the average differences of the values reported in Figs. 2 to 4.

 
Prolonged alteration in pyruvate and lactate metabolism
The state of energetic imbalance continued in the heart only for the first minutes of reperfusion. However, persistent but less severe metabolic alterations were also observed in the later phases. Despite restoration of the lactate/pyruvate ratio by the third minute of reperfusion, substantial release of pyruvate without any uptake of lactate continued for up to 45 minutes of reperfusion. This is atypical of balanced myocardial metabolism, wherein these metabolites are used.Go 33 One possible explanation could be the inhibition of pyruvate dehydrogenase complex in the postischemic heart, a phenomenon previously demonstrated in animal studies.Go Go 17,18 This inhibition restricts entry of glycolytic end products—lactate and pyruvate—into the tricarboxylic acid cycle with their consequent release from the heart. Inhibition of lactate and pyruvate metabolism during reperfusion has also been demonstrated in intact heart studies in animals.Go Go 6-9 Alterations in lactate metabolism in the heart after transplantation were recognized shortly after the initiation of this procedure in human beings.Go 38 Recent studies on reperfusion after coronary artery bypass grafting have also demonstrated changes in substrate preference of the heart with a shift from fatty acid and lactate uptake toward amino acid use.Go Go 19-21 However, release of pyruvate has not been previously shown, suggesting that this type of metabolic alterations may be more pronounced after the long storage in deep hypothermia used during heart transplantations.

Is myocardial blood supply restored completely?
Metabolic alterations in response to ischemia and reperfusion of the transplanted heart may not be uniform because of altered flow distribution, temperature gradients in the heart, or the known enhanced susceptibility of the subendocardium.Go 39 One line of support for persistent underperfusion zones after restoration of coronary flow is the release of purine catabolites from the heart, which is not accompanied by enhanced lactate/pyruvate ratio in coronary sinus blood. This was observed from the fifth up to the thirtieth minute of reperfusion.

Clinical implications
The high lactate concentration and high lactate/pyruvate ratio in arterial blood at the time of reperfusion shown here may have deleterious effects on the reperfused myocardium, as has been found in a number of animal studies.Go Go 36,40 This suggests that application of pyruvate at the time of reperfusion, which would restore lactate/pyruvate ratio and exert other beneficial effects,Go Go Go 36,40-42 may improve the function of the reperfused human heart. Prolonged release of purine catabolites indicating existence of underperfused areas in the heart offers strong support for the use of coronary vasodilators at the time of reperfusion to correct flow alterations. Recent experimental studies on the isolated rat heart have demonstrated the beneficial effect of this intervention on the mechanical performance of the heart.Go Go 43,44 It is worthwhile noting that some compounds like dichloroacetate can activate the pyruvate dehydrogenase complex,Go Go 45,46 which can potentially ameliorate abnormalities in pyruvate metabolism observed in this study. Finally, the observed inefficiency of myocardial energetics in the initial phase of reperfusion strongly supports the concept of using glutamate/aspartate–enriched reperfusion cardioplegic solution, which has been shown to be beneficial in extensive studies on controlled reperfusion after ischemia.Go Go Go 23-27,47

In summary, the results presented here highlight a biphasic recovery of myocardial energetics in the donor human heart on reperfusion. Global and profound alterations evidenced by a high lactate/pyruvate ratio, massive release of nucleotide catabolites, phosphate, and hydrogen ion were reversed within the first minutes of reperfusion, but abnormalities in pyruvate metabolism persisted for at least 45 minutes. Continued release of purine catabolites suggest also the existence of regional underperfusion zones in the heart for at least 30 minutes of reperfusion. Therapeutic interventions aimed at correcting these abnormalities may enhance myocardial recovery.

Footnotes

*Nicotinamide adenine dinucleotide (reduced)/nicotineamide adenine dinucleotide. Back

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