Asian Cardiovasc Thorac Ann 1999;7:173-176
© 1999 Asia Publishing EXchange Pte Ltd
Ischemic Preconditioning Improves Protection with Cold Blood Cardioplegia
Li Guo Hu, MD,
Chen Shen Xi, MD,
Lu Er Xiong, MD,
Liu Qiu Qiu, BS,
Li Yuan Jian, MD
Department of Cardiothoracic Surgery
Xiangya Hospital
Hunan Medical University
Changsha, Hunan, People's Republic of China
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For reprint information contact: Li Guo Hu, MD Tel: 86 731 447 4411 Fax: 86 731 447 1339 email: liguohu{at}hotmail.com Department of Cardiothoracic Surgery, Xiangya Hospital, Hunan Medical University, Changsha 410008, Hunan People's Republic of China.
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Abstract
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This prospective randomized study was undertaken to test the hypothesis that ischemic preconditioning could improve myocardial protection with cold blood cardioplegia in patients undergoing valve replacement and to investigate the mechanism of ischemic preconditioning in human myocardium. After the institution of cardiopulmonary bypass, 20 patients undergoing double valve replacement were preconditioned with 2 cycles of 3 minutes of aortic crossclamping and 2 minutes of reperfusion before cardioplegic arrest. A further 20 patients served as controls. The hearts were arrested with blood cardioplegic solution at 4°C. In the perioperative period, blood samples were collected from the coronary sinus, samples of right atrial myocardial tissue were obtained, and cardiac function was measured. Ischemic preconditioning reduced oxygen free radial production, calcium overload, and myocardial ultrastructural damage, while the myocardial production of calcitonin gene-related peptide was increased to 95.3 ± 3.8 µg•L–1 compared with 61.2 ± 4.9 µg•L–1 in the controls. Cardiac index was also higher in the preconditioned patients at 2.8 L•min–1•m–2 compared to 2.3 L•min–1•m–2 in the controls. It was concluded that ischemic preconditioning enhanced cardioplegic protection in valve replacement patients by increasing the level of calcitonin gene-related peptide and decreasing oxygen free radicals.
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Introduction
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Modern myocardial preservation techniques have revolutionized cardiac surgery. Most of these techniques focus on extraneous factors such as the composition of the cardioplegic solution and temperature manipulation.1 However, it has been shown that ischemic preconditioning can be used as an intrinsic protective measure.2–4 Our recent research and that of others, has indicated that ischemic preconditioning may enhance myocardial protection in patients undergoing cardiac surgery.5–7 Although studies in humans are limited, the mechanism involved in ischemic preconditioning has been investigated in animals and there is increasing evidence that endo-genous myocardial protective substances play an important role. Preconditioning with ischemia or calcitonin gene-related peptide (CGRP) enhanced cardioplegic protection in isolated rat myocardium.8 CGRP is considered to be an endogenous myocardial protective substance.9 This study was designed to evaluate the effects of ischemic preconditioning prior to cold blood cardio-plegic arrest in double valve replacement patients and to investigate the mechanism of endogenous protection in terms of production of CGRP.
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Patients and Methods
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The clinical study was approved by both the University Scientific Association and the local ethics committee of Hunan Medical University. Written informed consent was obtained from each patient before the operation. Forty patients undergoing double valve replacement with mechanical prostheses were prospectively entered into this study. Anesthesia was uniform in all cases and consisted of a standard combination of fentanyl citrate and pancuronium bromide, maintained with intravenous propofol and inhalation of isoflurane. After endotracheal intubation, the lungs were ventilated with a volume-cycle respirator (Excel 210; Ohmeda, Madison, WI, USA). The left radial artery was catheterized to monitor arterial pressure. The right internal jugular vein was catheterized with a pulmonary arterial Swan Ganz catheter (Spacelabs, Inc., Redmond, WA, USA) to monitor hemodynamic data. The electrocardiogram and body temperature were recorded. Cardiopulmonary bypass (CPB) was established with a crystalloid-albumin-blood prime (Stockert, Munich, Germany) and a Sarns membrane oxygenator (Sarns, Inc., Ann Arbor, MI, USA). All patients received cold blood cardioplegia (4°C). Throughout the period of ischemia, cardioplegic solution was given every 20 minutes (the potassium chloride content was only half that of the initial cardioplegic solution). Moderate hypo-thermia was maintained during the period of cardiac arrest. Administration of heparin before cannulation and its subsequent post-bypass reversal with protamine sulfate were accomplished in the standard fashion.
The 40 patients were randomized into two equal groups. Group 1 underwent two cycles of ischemia by cross-clamping the aorta for 3 minutes (effective left ventricular decompression by intracardiac drainage) followed by 2 minutes of reperfusion (aortic declamping) under CPB. Group 2 underwent 10 minutes of CPB under the same conditions of flow and left ventricular venting. Double valve replacement was then carried out during aortic crossclamping and cardioplegic arrest. Fifty-eight bileaflet and 22 monoleaflet mechanical prosthetic valves were implanted; there was no significant difference between the two groups in terms of the type of prosthesis.
Blood samples were collected from a coronary sinus catheter before ischemia and after 30 minutes of reperfusion to measure the level of the MB-isoenzyme of creatine kinase with a reagent kit (Chongshong Co., Beijing, China). Blood samples were collected before ischemia, after ischemic preconditioning (or after 10 minutes of CPB in controls), and at the start of cardiac reperfusion, to measure calcitonin gene-related peptide (RIA, East-Asia Immune Institute, Beijing, China). Before CPB and 30 minutes after reperfusion (completion of CPB), hemodynamic data were recorded from the pulmonary artery catheter.
Before ischemia and 30 minutes after reperfusion, right atrial myocardial samples (100 to 150 mg) were collected to measure the levels of myocardial calcium, superoxide dismutase and malondialdehyde (T-SOD/MDA test kit; Nanjing Jiangzheng Biological Engine Institute, Nanjing, China), and to observe myocardial ultrastructure (Hitachi 600 electron microscope; Hitachi Corp., Tokyo, Japan). According to the semiquantitative methods of Schaper and colleagues,10 myocardial ultrastructural damage was recorded in a blinded manner. Intercellular junctions, intracellular and extracellular edema, mitochondria, nuclei, and myofibrils were assessed separately in each biopsy specimen by scoring from 0 (unchanged) to 3 (severe alterations). A total score between 5 and 10 was defined as moderate ultrastructural damage, above 10 was considered severe damage.
Results are presented as mean ± the standard error of the mean. Comparisons of the two groups were made by unpaired t test. Differences were considered significant when the value of p was less than 0.05.
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Results
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The major preoperative and intraoperative variables were similar in both groups (Table 1
). One patient in the control group was excluded from the blood sample measurements because of a problem with the coronary sinus catheter. There were no operative deaths (up to 30 days post-operatively) in either group. The mean cardiac index after 30 minutes of reperfusion was higher in group 1 than in group 2 (Table 2). Ischemic preconditioning reduced the production of oxygen free radicals; after 30 minutes of reperfusion, myocardial superoxide dismutase was significantly higher and malondialdehyde was significantly lower in group 1 compared to the control group (Table 2). Ischemic preconditioning decreased myocardial calcium and increased myocardial CGRP (Table 2). The mean level of CGRP was significantly higher in group 1 compared to group 2 immediately after ischemic pre-conditioning and after reperfusion (Table 3).
Electron microscopic observations in myocardial samples from the control group detected extensive mitochondrial swelling with disruption of the cristae, the myofibrils were relaxed and some were disrupted. In samples from group 1, the myofibrils were nearly normal, there was some mitochondrial swelling and disruption of the cristae but the ultrastructural damage was significantly less than in the control group (Tables 4 and 5). Clinical observations in the early postoperative period showed a lower incidence of ventricular arrhythmias in the patients who underwent ischemic preconditioning and the use of inotropic agents was less in this group (Table 6).
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Discussion
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Ischemic preconditioning has been used to enhance the tolerance of the myocardium to ischemia during cardiac surgery.5–7 Recently, Illes and Swoyer6 reported significant hemodynamic improvement after ischemic precondition-ing in a large series of patients undergoing cardiac surgery. On the other hand, Perrault and colleagues11 found that ischemic preconditioning did not enhance cardioplegic protection in cardiac surgery. It is possible that many factors could effect the results, such as preconditioning protocols, operative details, anesthesia, temperature and type of cardioplegia, and inotropic agents. In our study, ischemic preconditioning with two cycles of 3 minutes occlusion and 2 minutes reperfusion, which is applicable clinically, significantly augmented myocardial pre-servation in the setting of hypothermic arrest with cold blood cardioplegia in valve replacement patients.
Our results indicate that ischemic preconditioning reduced myocardial malondialdehyde formation and the con-sumption of myocardial superoxide dismutase after reperfusion. The benefits of ischemic preconditioning are thought to be mediated by an increase in antioxidant levels with consequently greater stability of the lipid membranes and enhanced resistance to reperfusion injury.12,13 Our previous studies on CGRP indicated that it provides endogenous myocardial protection.8,14 Ischemic or CGRP preconditioning improved isolated rat cardiac preservation with cold cardioplegia.8 The beneficial effect of CGRP on the myocardium may be due to inhibition of lipid peroxidation and reduction of calcium overload.15,16 Some studies suggested that ischemic preconditioning produces endogenous cardioprotection by activation of protein kinase C.17,18 CGRP has been shown to increase the activation of protein kinase C in adult mammalian ventricular myocytes.19 In our study, myocardial CGRP levels were significantly increased after ischemic pre-conditioning and we postulate that this produced a myocardial protective effect by activation of protein kinase C, leading to a reduction of calcium overload and inhibition of lipid peroxidation.
We concluded that ischemic preconditioning improved myocardial protection during cold blood cardioplegic arrest in valve replacement patients by increasing the production of myocardial CGRP and decreasing the formation of oxygen free radicals.
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Acknowledgments
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This work was supported by a grant from the Scientific Commission of Hunan Province in the People's Republic of China.
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References
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Abstract
Introduction
