Ann Thorac Surg 2000;69:1806-1810
© 2000 The Society of Thoracic Surgeons
Original articles: Cardiovascular
Near-infrared monitoring of myocardial oxygenation during ischemic preconditioning
Michio Kawasuji, MDa,
Masahiro Ikeda, MDa,
Naoki Sakakibara, MDa,
Susumu Fujii, MDa,
Shigeyuki Tomita, MDa,
Yoh Watanabe, MDa
a Department of Surgery (I), Kanazawa University School of Medicine, Kanazawa, Japan
Address reprint requests to Dr Kawasuji, Department of Surgery (I), Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa 920-8641, Japan
e-mail: kawasuji{at}med.kanazawa-u.ac.jp
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Abstract
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Background. Ischemic preconditioning has been advocated as a method of cardioprotection for minimally invasive direct coronary artery bypass. This study was performed to estimate the cardioprotective effect of ischemic preconditioning before ischemia by examining the changes in myocardial tissue oxygenation and also to examine whether adenosine triphosphate-sensitive potassium channel opener enhances the cardioprotective effect of ischemic preconditioning.
Methods. Myocardial ischemia was induced in three groups of 6 dogs by temporary occlusion of the left anterior descending coronary artery. Group 1 dogs received a 30-minute coronary occlusion and subsequent 3-hour reperfusion. Groups 2 and 3 dogs underwent three periods of 5-minute coronary occlusion and 5-minute reperfusion and then received 30-minute sustained ischemia and 3-hour reperfusion. In group 3, nicorandil was administered during the procedure. Myocardial oxygenation was measured using three-wavelength near-infrared spectroscopy. Myocardial blood flow was measured by the colored microsphere method.
Results. During ischemic preconditioning the myocardial tissue oxygen saturation decreased rapidly at coronary occlusion and increased at reperfusion. It was increased stepwise at the second and third coronary occlusion. Myocardial oxygen saturation during 30-minute sustained ischemia was significantly higher in groups 2 and 3 than in group 1 (p < 0.05). The myocardial tissue hemoglobin concentration showed similar changes to myocardial oxygen saturation. During 30-minute sustained ischemia, it was significantly higher in group 2 than in group 1 (p < 0.001), and it was significantly higher in group 3 than in groups 1 and 2 (p < 0.05). Regional myocardial blood flow showed no difference after 30 minutes of sustained ischemia among the three groups. Troponin-T levels were significantly lower in groups 2 and 3 than in group 1 (p < 0.01).
Conclusions. Ischemic preconditioning had beneficial effects on myocardial oxygenation during sustained ischemia, and the protected state of the myocardium could be monitored with the use of near-infrared spectroscopy. Ischemic preconditioning coupled with nicorandil administration might provide protection for minimally invasive direct coronary bypass.
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Introduction
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Minimally invasive direct coronary bypass grafting (MIDCAB) requires a temporary coronary occlusion during anastomosis of the vascular graft to the target vessel. This relatively short period of regional ischemia can cause myocardial injury. Ischemic preconditioning (IP) is a potent cardioprotective mechanism in which the heart is exposed to one or more short periods of sublethal ischemia, which attenuates cellular damage from a subsequent prolonged and otherwise lethal episode of ischemia [1, 2]. Ischemic preconditioning has been advocated as a method of cardioprotection for MIDCAB. It is not known whether IP effectively protects the myocardium from a short period of ischemia during MIDCAB. Because the standard endpoint of IP is the delay of lethal injury reducing infarct size [1], the cardioprotective effects of IP could not be estimated in advance of sustained ischemia and reperfusion. Several studies suggested that adenosine triphosphate (ATP)-sensitive potassium channels mediate IP as the end effector of protection [3–5]. It is not known whether the ATP-sensitive potassium channel opener enhances the cardioprotective effect of IP during MIDCAB. Three-wavelength near-infrared spectroscopy has been developed to measure tissue oxygen saturation and tissue hemoglobin concentration [6, 7]. This apparatus allows real-time monitoring of the changes in myocardial tissue oxygenation within the beating heart.
The purpose of this study was to examine changes in myocardial tissue oxygenation during the period of IP using near-infrared spectroscopy and to develop a new method for evaluating the cardioprotective effect of IP before sustained ischemia. This study also examined whether the ATP-sensitive potassium channel opener, nicorandil, enhanced the cardioprotective effect of IP.
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Material and methods
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Eighteen adult mongrel dogs weighing 9 to 14 kg were studied. The animals were anesthetized with intramuscular administration of ketamine hydrochloride (20 mg/kg) and intravenous sodium pentobarbiturate (30 mg/kg) and were mechanically ventilated with a volume respirator. The dogs received humane care in compliance with the "Principles of Laboratory Animal Care" (National Society for Medical Research) and the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health, NIH publication 85-23, revised 1985). A small left thoracotomy through the fourth intercostal space was done. A catheter was placed in the left atrium for microsphere blood flow determination. A tip-transducer catheter (Millar Instruments, Houston, TX) was placed in the left ventricle to measure pressure. The left anterior descending coronary artery was isolated distal to its first diagonal branch. The dogs were divided into three groups of 6 animals. In group 1, control dogs received a single period of coronary occlusion of 30 minutes and subsequent 3-hour reperfusion. In groups 2 and 3, dogs underwent three periods of 5-minute coronary occlusion and 5-minute reperfusion as the IP pretreatment and then received a 30-minute sustained occlusion and subsequent 3-hour reperfusion. In group 3, the ATP-sensitive potassium channel opener, nicorandil, was administered intravenously (100 µg/kg) and was continued (10 µg/kg per minute) during the IP and 30-minute ischemia. Lidocaine (1 mg/kg) was given to all dogs intravenously before coronary occlusion.
Myocardial tissue oxygenation was measured using a three-wavelength near-infrared spectroscope (PSA-IIIN; Biomedical Science, Kanazawa, Japan) [6, 7]. Near-infrared light passes through tissue with relative ease and is significantly absorbed by oxygenated and deoxygenated hemoglobin, which have distinctly different absorption spectra in the near-infrared region. On the basis of this difference, changes in the tissue concentration of hemoglobin can be measured by near-infrared spectroscopy. Because oxygenated hemoglobin and oxygenated myoglobin have essentially identical near-infrared absorption spectra, hemoglobin plus myoglobin (Hb) were added together. The near-infrared spectroscopy probe (PSP-15R; Biomedical Science) was attached to the anterior surface of the left ventricle distal to the left anterior descending coronary artery, avoiding the epicardial fat tissue. This probe contains three light-emitting diodes as light sources and three pairs of silicone photodiodes to detect the intensity of reflected light. The optical information from a myocardial tissue depth of 2.5 to 5.0 mm was obtained. The near-infrared signal was analyzed using a set of algorithms that solve for oxygenated and deoxygenated Hb. Oxygenated Hb divided by the sum of oxygenated and deoxygenated Hb corresponded to the tissue oxygen saturation (SO2). The method used in his study has been described in detail previously [6, 7].
Microsphere blood flow measurement was done on each dog at baseline before coronary occlusion and after 30 minutes of sustained ischemia. At each determination, approximately 6 x 106 colored microspheres (E-Z Trac, Los Angeles, CA) were injected into the left atrial catheter. At the same time, reference blood samples were withdrawn using a syringe pump at a constant rate through the femoral artery. After this procedure the heart was excised and was used for microsphere blood flow analysis. A central short axis slice was cut from the left ventricle. The circumferential segments were obtained from the territory of the left anterior descending coronary artery, which was defined as the ischemic area, and from the territory of the left circumflex coronary artery, which was defined as the normal area. These segments were further divided into endocardial and epicardial portions. The tissue samples and reference blood samples were digested with sodium hydroxide, and microspheres were reclaimed for measurement. Regional myocardial blood flow (Qm, mL/per minute) was calculated by the following equation:
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where Cm is the number of microspheres in 1 g of myocardial tissue, Cr is the number of microspheres in the reference sample, and Qr is the withdrawal rate of blood (mL/min). The endocardial and epicardial blood flows were averaged at each area.
The serum levels of troponin-T were measured by an enzyme-linked immunosorbent assay to assess myocardial injury. Samples were examined before coronary occlusion and after 3 hours of reperfusion.
Cumulative data are expressed as the mean ± the standard deviation. Statistical analysis was done with the Student t test and analysis of variance and Scheffe F test to detect significant (p < 0.05) differences between measured variables.
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Results
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There were no significant changes in the heart rate or left ventricular systolic pressure during IP, 30-minute sustained ischemia, and 3-hour reperfusion. The left ventricular end-diastolic pressure was significantly higher during coronary occlusion for IP and 30-minute sustained ischemia. There was no difference in the left ventricular end-diastolic pressure after 30 minutes of sustained ischemia or after 1 hour of reperfusion among the three groups (Table 1).
The baseline value of myocardial tissue SO2 was 74% ± 2% in all groups (Fig 1). In group 1, myocardial SO2 decreased rapidly at coronary occlusion and maintained a stable level of 58% ± 4% during the 30-minute sustained ischemia. During IP in groups 2 and 3, myocardial SO2 decreased rapidly during the first period of coronary occlusion and reached a level of 59% ± 5%, and it increased rapidly during the first period of coronary reperfusion and reached a level of 78% ± 5%. The level of myocardial SO2 increased stepwise at the second and third periods of coronary occlusion. The level of myocardial SO2 was significantly higher at the second and third periods of coronary reperfusion compared with the baseline value (p < 0.001). In groups 2 and 3, during the 30-minute sustained ischemia, myocardial SO2 maintained a level of 68% ± 4%, which was the same as that of the third coronary occlusion for IP. The level of myocardial SO2 during the 30-minute sustained ischemia was significantly higher in groups 2 and 3 than in group 1 (p < 0.05). Myocardial SO2 increased rapidly after reperfusion and then gradually decreased to the baseline level during the 3-hour reperfusion.
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Fig 1. Changes in myocardial tissue oxygen saturation (SO2). *p < 0.05 compared with group 1. (O = coronary occlusion; R = coronary reperfusion.)
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The baseline value of myocardial tissue Hb was 536 ± 55 g/L · mm in all groups (Fig 2). In group 1, myocardial Hb decreased rapidly at coronary occlusion and maintained a stable level of 304 ± 26 g/L · mm during the 30-minute sustained ischemia. During IP in groups 2 and 3, myocardial Hb decreased rapidly below the level of 400 g/L · mm at the first period of coronary occlusion. It increased rapidly at the first coronary reperfusion and reached a significantly (p < 0.001) higher level than the baseline (692 ± 101 and 760 ± 127 g/L · mm in groups 2 and 3, respectively). The level of myocardial Hb increased stepwise at the second and third periods of coronary occlusion. In groups 2 and 3, during the 30-minute sustained ischemia, myocardial Hb maintained levels of 418 ± 38 g/L · mm and 481 ± 44 g/L · mm, respectively, which were same as those of the third coronary occlusion for IP. The level of myocardial Hb during the 30-minute sustained ischemia was significantly higher in group 2 than in group 1 (p < 0.001), and it was significantly higher in group 3 than in groups 1 and 2 (p < 0.05). Myocardial Hb increased rapidly after reperfusion and then gradually decreased during the 3-hour reperfusion. Myocardial Hb at 2 and 3 hours of reperfusion was significantly higher in group 3 than in group 1 (p < 0.05).
Regional myocardial blood flow in the left anterior descending coronary artery area showed no difference at baseline among the three groups (1.07 ± 0.12, 1.08 ± 0.14, and 1.10 ± 0.11 mL/g per minute, in groups 1, 2, and 3, respectively). It showed no difference after 30 minutes of sustained ischemic among the three groups (0.19 ± 0.03, 0.18 ± 0.03, and 0.20 ± 0.04 mL/g per minute in groups 1, 2, and 3, respectively). Regional myocardial blood flow in the nonischemic left circumflex artery area showed no difference both at baseline and after 30 minutes of sustained ischemia among the three groups.
Serum troponin-T levels were less than 0.10 ng/mL in all groups. Troponin-T levels increased to 0.84 ± 0.14 ng/mL, 0.58 ± 0.21 ng/mL, 0.29 ± 0.17 ng/mL after 3 hours of reperfusion in groups 1, 2, and 3, respectively (Fig 3). Troponin-T levels were significantly lower in groups 2 and 3 than in group 1 (p < 0.01).
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Fig 3. Serum troponin-T levels before coronary occlusion (pre) and after 3-hour reperfusion (post). *p < 0.05 compared with group 1;  p < 0.001 compared with group 1. Differences between postreperfusion troponin-T levels of groups 2 and 3 did not reach statistical significance.
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Comment
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The major findings of this study were as follows: (1) Using three-wavelength near-infrared spectroscopy the cardioprotective effects of IP could be estimated before the period of sustained ischemia. (2) Ischemic preconditioning increased the levels of myocardial tissue SO2 and the myocardial Hb concentration during the 30-minute sustained ischemia and reduced the magnitude of myocardial injury after ischemia and reperfusion. (3) The ATP-sensitive potassium channel opener, nicorandil, enhanced the cardioprotective effects of IP.
The features characterizing the protected state of the preconditioned myocardium are a slower rate of ischemic metabolism and delayed onset of irreversible cell injury during sustained ischemia [1, 2]. Utilization of high-energy phosphates slowed markedly so that depletion of high-energy phosphate stores is delayed, even though anaerobic glycolysis is also slowed [2]. Reduced proton and catabolite accumulation during prolonged myocardial ischemia are prominent effects of IP [8]. Consequently, IP slows the development of acidosis during sustained ischemia [9, 10]. These effects could contribute to anti-infarct effect of IP. The present study found that the levels of myocardial tissue SO2 were higher at the second and third episodes of coronary occlusion during the period of IP. It is noteworthy that the preconditioned hearts maintained significantly higher levels of myocardial SO2 during 30-minute sustained ischemia compared with control hearts. This finding cannot be explained by increased collateral flow to the ischemic area. During the 30-minute sustained ischemia, there was no difference in regional myocardial blood flow at the ischemic left anterior descending artery of the preconditioned hearts compared with control hearts. Murray and colleagues [1] reported that the smaller infarcts occurring in preconditioned hearts were independent of levels of collateral flow. The difference in myocardial SO2 is considered to be caused by reduced energy consumption during sustained ischemia in the preconditioned hearts. Relatively high levels of myocardial SO2 during sustained ischemia might be a useful sign of the beneficial effects of IP. This is suggested by our result that myocardial injury evaluated by serum levels of troponin-T was significantly reduced in the preconditioned dogs compared with the control dogs.
The present study showed that the myocardial tissue Hb concentration was significantly higher at the first episode of coronary reperfusion in the preconditioned hearts and that is was further increased by the second and third episodes of coronary reperfusion. The increase in myocardial Hb is considered to be caused by reactive hyperemia after temporary ischemia [11]. Interestingly, myocardial Hb was increased also by subsequent episodes of coronary occlusion, and preconditioned hearts maintained higher levels of myocardial Hb during the 30-minute sustained ischemia compared with control hearts. Higher levels of myocardial Hb during ischemia and reperfusion might be related to continued vasodilatation in the preconditioned hearts. DeFily and Chilian [12] showed that ischemia and reperfusion significantly attenuated endothelium-dependent vasodilatation of coronary arterioles in the beating heart and that IP reduced the endothelial dysfunction of coronary arterioles after ischemia and reperfusion. Thourani and associates [13] suggested that postischemic regional blood flow defect was related to neutrophil accumulation in the ischemic area and found that postischemic endothelial dysfunction was attenuated by IP in a MIDCAB model [13].
The present study showed that the level of myocardial Hb during 30 minutes of sustained ischemia was higher in preconditioned hearts that received nicorandil than in preconditioned hearts without nicorandil. In addition, a significantly higher level of myocardial Hb was observed in the nicorandil group at each coronary occlusion during IP. These results suggest an additive effect of nicorandil to reactive hyperemia in the preconditioned hearts. Aversano and associates [14] reported that ATP-sensitive potassium channel mediates reactive hyperemia. A higher level of myocardial Hb combined with high myocardial SO2, ie, increased myocardial oxygenated Hb, might be advantageous during ischemia and during reperfusion, even though myocardial SO2 during 30-minute ischemia was the same in both preconditioned hearts.
There have been several protocols for IP [1, 4, 10, 12, 13]. Originally, four episodes of 5-minute coronary occlusion and reperfusion were used to achieve infarct size reduction with 40 minutes of ischemia [1, 2]. The present study showed that the level of myocardial SO2 increased stepwise during later episodes of 5-minute coronary occlusion. An increasing level of myocardial SO2 during IP could be a sign of the protected state. Myocardial SO2 in the third episode of coronary occlusion reached a plateau that was the same as the level for the 30-minute sustained ischemia. From the findings of our study, it appears that two episodes of brief coronary occlusion and reperfusion conferred better effects of IP. There are limitations in the extrapolation of findings in a canine model to human coronary circulation because dogs have more coronary collateral vessels than humans. The use of near-infrared spectroscopy in the intraoperative period may provide a sensitive indicator of myocardial ischemia. Although IP is time-consuming, its cardioprotective effect can be useful in patients in whom an endocoronary shunt cannot be placed despite severe myocardial ischemia.
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Accepted for publication November 30, 1999.
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Top
Abstract
Introduction
p < 0.05 compared with groups 1 and 2. (O = coronary occlusion; R = coronary reperfusion.)