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Ann Thorac Surg 2003;76:528-534
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Cardiomyocyte apoptosis and ischemic preconditioning in open heart operations

^a Division of Cardiac Surgery, Department of Surgery, Tampere University Hospital, Tampere, Finland
^b Department of Cardiac Surgery, Affiliated 1^st Hospital, Sun Yat-sen University, GuangZhou, China
^c Department of Cardiac Surgery, Turku University Hospital, Turku, Finland

Accepted for publication February 21, 2003.

^* Address reprint requests to Dr Tarkka, Clinic of Cardiac Surgery, Tampere University Hospital, 33521 Tampere, Finland
e-mail: matti.tarkka{at}tays.fi

	Abstract

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BACKGROUND: The aim of the present study was to ascertain the percentage of left apical myocardial apoptosis in three-vessel coronary artery bypass grafting patients quantitatively and the impact of ischemic preconditioning.

METHODS: Twenty-one patients with three-vessel disease who had elective coronary artery bypass grafting were randomized in a ratio of 2:1 to ischemic preconditioning (n = 14) or a control group (n = 7). The ischemic preconditioning protocol was established by two cycles of ascending aorta occlusion for 2 minutes followed by 3 minutes of reperfusion. Myocardial samples from the apex of the left ventricle were taken using a Tru-Cut needle before aortic cross-clamping and immediately after declamping. The percentage of apoptosis was analyzed by TUNEL methods. Data on hemodynamics and biochemical markers were collected.

RESULTS: Low levels of myocardial apoptosis were found before the operation (0.01% ± 0.00%). During the early reperfusion period, the percentage of myocardial apoptotic cells significantly increased (0.15% ± 0.05%, p = 0.008). Ischemic preconditioning significantly improved cardiac index and right ventricular ejection fraction recovery after the operation (p = 0.036 and 0.001 respectively, repeated measure) but had no effect on myocardial apoptosis before and after the operation (0.01 ± 0.00 versus 0.01 ± 0.00, p = 0.658 and 0.12% ± 0.04% versus 0.23% ± 0.14%, p = 0.302).

CONCLUSIONS: Cardioplegic myocardial ischemia during open heart operation was associated with induction of cardiomyocyte apoptosis in humans. Attenuation of postoperative cardiac dysfunction by ischemic preconditioning appeared to be independent of apoptosis.

	Introduction

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Apoptosis is an active, genetically controlled type of cell death with distinct morphologic and biochemical features [1, 2]. Morphologically it is characterized by chromatin condensation, shrinkage, and fragmentation of the cell into membrane-bound apoptotic bodies and rapid phagocytosis into neighboring cells without induction of the inflammatory response. The biochemical hallmark of apoptosis is degradation of DNA into internucleosomal fragments.

Cardiomyocyte apoptosis occurs in ischemic myocardial tissue injury and has been shown to occur in experimental [3–5] and human [6] acute myocardial infarction. Experimental studies have demonstrated the occurrence of cardiomyocyte apoptosis in global ischemic reperfusion [7–9], but the relevance of apoptosis in cardioplegic ischemia associated with open heart operation remains to be determined, particularly in humans. Ischemic preconditioning (IP) by brief, repeated episodes of ischemia and reperfusion provides cardiac protection during open heart operation [10–13]. Mechanisms of this effect have been investigated intensely. Several studies of experimental myocardial ischemia have shown that IP inhibits cardimyocyte apoptosis [14–17]. To clarify the role of apoptosis in cardiac protection provided by IP during cardiac operation, we studied the occurrence of cardiomyocyte apoptosis in left ventricular myocardium of patients who had coronary artery bypass grafting and compared IP with standard surgical procedure.

	Material and methods

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Patients
The Ethics Committee of Tampere University Hospital, Finland, approved the study design, and all patients gave an informed consent. Twenty-one patients with three-vessel coronary artery occlusive disease were randomized in a ratio of 2:1 to an IP (n = 14) and a control group (n = 7). Coronary artery occlusive disease was diagnosed in each patient by stress test electrocardiography and coronary artery angiography. All patients underwent elective coronary artery bypass grafting using sternotomy and cardiopulmonary bypass (CPB). In all patients, the left anterior descending artery was grafted using the left internal thoracic artery. The rest of the bypasses (median 4) were performed by using the radial artery (in 6 patients) and saphenous vein grafts. Emergency operations were not included in the study. One patient in the study group had a myocardial infarction within 90 days before the operation. Patients with additional cardiac diseases and severe noncardiac diseases were excluded from the study in both groups.

There were no statistically significant differences among the patients in the study and control groups in age, sex, New York Heart Association functional class, severity of stenosis in the diseased vessels, previous myocardial infarction, diabetes, or preoperative medication. The vessels bypassed, cross-clamping time, CPB time, and occurrence of ventricular fibrillation after cross-clamping release were similar in the IP and control groups (Table 1).

Anesthesia, cardiopulmonary bypass, and surgical technique
A standardized anesthetic technique was used with sufentanil, midazolam, and pancuronium. Cardiopulmonary bypass with nonpulsatile perfusion flow (2.2 to 2.4 L/m² per minute) was conducted using membrane oxygenators with arterial catheter filtration. Mild hypothermia (32°C) was maintained without topical cooling. Blood from the pump reservoir was mixed with crystalloid in a ratio of 4:1, yielding a cardioplegic solution with a 0.21 hematocrit value and a 21 mmol/L potassium concentration in the initial dose and 9 mmol/L in subsequent doses. In antegrade delivery, cardioplegia was administered at a pressure of 80 mm Hg, and in retrograde delivery the pressure was 30 to 40 mm Hg, with a minimum flow of 200 mL/minute. The initial high-potassium cardioplegia was given for 1.5 minutes antegrade then 2.5 minutes retrograde, at a temperature of 6° to 9°C. One minute was given retrograde and to the right coronary artery and circumflex artery area grafts after each distal anastomosis. Warm cardioplegia (37°C) was given retrograde for 3 minutes before release of the aortic cross-clamp.

Surgical techniques were the same for all patients. Aortic root and two-stage single venous cannule were used for CPB. A retrograde, self-inflating cardioplegia cannula (RC014, Research Medical Inc., Midvale, UT) with a pressure-monitoring port was introduced into the coronary sinus. A 9-gauge cannula was placed in the aortic root for antegrade cardioplegia or for venting during retrograde cardioplegia delivery. Distal anastomoses were made in the order right coronary artery, circumflex artery, and left anterior descending artery. Proximal anastomoses were constructed during cross-clamping, starting with the left-side grafts. Left internal thoracic artery to left anterior descending artery was used in all patients.

Measurements and treatment
Preoperative left ventricular ejection fraction was measured with M-mode echocardiogram. Heart rate, mean arterial pressure, central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were monitored. The cardiac index was calculated using standard formulas. Right ventricular ejection fraction and right ventricular end-diastolic volume index were measured with a fast-response volumetric thermister-tipped pulmonary artery catheter (93A-434H-7.5F; Baxter Health Care Corp., CA) and a microprocessor (Explorer; Baxter Health Care Corp., Edwards Division, CA) using thermodilution methods [17]. Hemodynamic data were collected at four time-points [1]: base line: before induction of anesthesia [2], 1 hour after declamping [3]; 6 hours after declamping [4]; at 8 o’clock on the first postoperative day. The mean value of three consecutive measurements at one time-point was registered.

Perioperatively, volume infusion was designed to maintain filling pressures at preoperative level and was optimized for actual heart performance. Inotropic agents (dopexamine or adrenaline) were used to maintain a cardiac index greater than 2.0 L/m² per minute. Amrinone with noradrenaline was used when dopexamine or adrenaline was insufficient to maintain the criteria. These were used after declamping and continued for at least 6 hours. Inotropic infusions were continued at the time-points of hemodynamic data measurement. Perioperative infarction was diagnosed if any new Q wave appeared with one third QRS height and for more than 0.04 second or CK-MB more than 100 µg/L.

Biochemical markers
Creatine kinase isoenzyme MB and cardiac troponin I
Blood samples were collected from the peripheral vessel before CPB, 5 minutes after cross-clamping release, 6 hours postoperatively, on the first postoperative day, and on the second postoperative day. Samples were collected in heparin-coated plastic tubes and centrifuged. Serum samples were measured with a Chiron ACS180^R analyzer (Chiron Dianostics Corp., East Walpole, MA) using a direct chemiluminescence method.

Myocardial biopsies: TUNEL assay
The late stages of apoptosis were detected with terminal deoxynucleotidyl transferase-mediated ddUTP nick-end labeling (TUNEL) assay as previously described [2, 6]. The TUNEL assay was standardized using serial tissue sections treated with DNase I (1 U/mL, 30 minutes in 37°C) to induce the formation of DNA strand breaks (positive control of apoptosis). To confirm optimal specificity and sensitivity of the assay for apoptosis, development of the immunohistochemical staining reaction caused by alkaline phosphatase was monitored by microscopy, and the reaction was interrupted at the moment when intense positive signal appeared in the corresponding DNase I–treated section. The number of TUNEL-positive cardiomyocytes was counted in multiple tissue sections of biopsies of 21 patients using light microscopy (magnification x400) with an ocular grid. The average number of microscopic fields (area of a field 0.06 mm²) analyzed was 31 ± 17 in biopsies obtained at the beginning of CPB and 22 ± 14 in samples obtained after CPB. Cardiomyocyte origin of the TUNEL-positive nuclei was confirmed by the presence of myofilaments surrounding the nucleus in TUNEL-stained sections and in selected sections by myosin antibody. The number of apoptotic cardiomyocytes was expressed as the proportion of TUNEL-positive myocyte nuclei from the total number of myocyte nuclei, which was obtained in the serial DNase I-treated control section. The average number of myocytes per microscopic field was 135 ± 23.

Histologic analysis
Myocardial tissue sections stained with Van Gieson were studied for the presence of fibrosis and signs of acute myocardial injury, such as loss of nuclei, eosinophilia, contraction bands, or cytoplasmic coagulation in myocytes and infiltration of inflammatory cells. Myocardial fibrosis was quantified by measuring the area of fibrosis in the total area of the tissue section using a computerized image analysis system.

Statistics
Statistical analyses were performed using the SPSS 9.0 statistical program (SPSS Inc, Chicago, IL). Two-sample Student’s t test (two-tailed) was used for continuous data, and Pearson’s ² test or Fischer’s exact test was used for categorical data when comparing variables between the two groups. Repeated measures analysis of variance was used to test repeated observation variables after the operation. Baseline values were used as a covariate when appropriate. Data are presented as mean ± standard error of the mean. Significance was assumed at a p value less than 0.05.

	Results

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Operative outcome and hemodynamics
Cardiac operation resulted in a transient decrease in cardiac index despite increased heart rate (Fig 1). Moreover, there was a marked and prolonged impairment of right ventricular function (Fig 2). Ischemic preconditioning significantly improved cardiac index and right ventricular ejection fraction recovery postoperatively (p = 0.036 and 0.001, respectively, analysis of variance for repeated measures (Figs 1 and 2). Other hemodynamic variables, namely heart rate, mean arterial pressure, central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right ventricular end-diastolic volume index were similar between IP and control groups before and after the operation (Table 2). The period of mechanical ventilation as well as the period of inotropic medication were shorter in IP patients than in controls (p = 0.003 and 0.676, respectively). Six patients in the IP group but none in the control group were free of inotropic agents (p = 0.032). Intraaortic balloon pump was not required in any patients. The length of stay in intensive care unit was similar in both groups (p = 0.091, Table 3).

View larger version (10K): [in this window] [in a new window]   Fig 1. Cardiac index (CI) in coronary artery bypass grafting (CABG) patients. Ischemic preconditioning (dotted line) significantly improved postoperative CI recovery (p = 0.036, analysis of variance for repeated measures). (POD = postoperative day.)

View larger version (10K): [in this window] [in a new window]   Fig 2. Right ventricular ejection fraction (RVEF) in coronary artery bypass grafting (CABG) patients. Ischemic preconditioning (dotted line) significantly improved postoperative RVEF recovery (p = 0.001, analysis of variance for repeated measures). (POD = postoperative day.)

View larger version (100K): [in this window] [in a new window]   Fig 3. A TUNEL-positive cardiomyocyte in a sample obtained during reperfusion after cardiopulmonary bypass. (A) The positive TUNEL reaction is visible as a dark staining in the nucleus (black arrow). (B) Immunohistochemical staining of the same cell with an antibody to cardiac myosin demonstrates the cardiomyocyte origin of the cell (white arrow).

Compared with the number of apoptotic cardiomyocytes before aortic cross-clamping, there were 15 cases among all patients (75%) in which an increased amount of apoptosis was found after aortic declamping. Elevation of apoptotic cell levels was found in 9 subjects in the IP group and 6 subjects in the control group (p = 0.613). Again, the elevation of myocardial apoptosis showed no correlation with the patient’s age, severity of vessel disease, length of cross-clamping or perfusion times, number of vessels bypassed, time required for respiratory support and stay in the intensive care unit, use of inotropic agents, CK-MB and CTnI, or hemodynamic recovery.

Histology
We did not find signs of cardiomyocyte necrosis in histologic analysis. Because cardiomyocyte apoptosis has been shown to occur at a high rate adjacent to the scars of old infarctions, we analyzed the amount of fibrosis in our samples. The percentage of area occupied by myocardial fibrosis was similar before and after the operation (6.62% ± 1.23% versus 6.36% ± 1.53%, p = 0.896). Similarly, there was no difference in the amount myocardial fibrosis between the IP and the control group before or after the operation (6.61% ± 1.71% versus 6.62% ± 1.11%, p = 0.999 and 6.30% ± 2.02% versus 6.49% ± 2.24%, p = 0.957).

Biochemical markers
Both CTnI and CK-MB increased significantly after the operation compared with preoperative levels (p < 0.001). No statistically significant differences were found in CTnI and CK-MB after the operation in IP or controls (0.680 and 0.501, respectively, repeated-measures analysis of variance (Figs 4 and 5).

View larger version (11K): [in this window] [in a new window]   Fig 4. Cardiac troponin I (CTnI) in coronary artery bypass grafting (CABG) patients. Cardioplegic ischemia and reperfusion significantly increased serum CTnI release. Similar amounts of CTnI were found in ischemic preconditioning (dotted line) and control (straight line) patients. (POD = postoperative day.)

View larger version (11K): [in this window] [in a new window]   Fig 5. Creatine kinase isoenzyme MB (CK-MB) in coronary artery bypass grafting (CABG) patients. Cardioplegic ischemia and reperfusion significantly increased serum cardiac tropinin I release. Similar amounts of CK-MB were found in ischemic preconditioning (dotted line) and control (straight line) patients. (POD = postoperative day.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Ischemic preconditioning by brief repeated episodes of ischemia offers cardiac protection against cardioplegic ischemia associated with open heart operation [12–15]. We hypothesized that the mechanism of this effect could be associated with inhibition of apoptosis. The beneficial effect of our IP protocol was demonstrated by attenuation of the depression of cardiac function postoperatively and more favorable postoperative clinical course, which is concordant with our previous findings [12]. However, we did not find significant differences in the amount of cardiomyocyte apoptosis between IP and control groups. Previously, several experimental studies showed that apoptosis is inhibited by IP [16–19]. The mechanisms of this effect have been shown to involve vacuolar proton ATPase [14], decreased accumulation of neutrophils capable of inducing apoptosis by inflammatory mediators [16], activation of nuclear factor kappa B (NFB) [17], induction of antiapoptotic Bcl-2 protein [17], caspase inhibition [21], mitochondrial ATP-dependent potassium channel and protein kinase C activation [22]. Previous study found that the activation of the vacuolar proton ATPase by protein kinase C during IP may attenuate intracellular acidification during metabolic inhibition, and thereby protects myocytes from apoptosis [14]. In our previous report, myocardial metabolic acidosis was not likely to be involved in the IP effect in CABG patients [23]. This might partly explain why our IP protocol does not bring about the attenuation of myocardial apoptosis. One recent report proved that delayed IP effect was mediated by ₁-adrenoceptor activation, which involved increased bcl_x:bax ratio to limit apoptotic cell death [24]. Our samples were taken during the very early reperfusion period and thus do not exclude the possibility of delayed IP effects on myocardial apoptosis. It is known that reperfusion can accelerate myocardial apoptosis [2–4, 14–17], the postoperative sample taken at 10 minutes of reperfusion is too short to reflect the full extent of apoptosis. In the present study, the degree of postoperative of apoptosis in the controls was almost twice as much as in the study group. It is possible that if the study population could be larger and the sample had been taken after a longer period of reperfusion, the difference might be more pronounced and significant. Further studies with later follow-up time would be needed to study the effects of delayed IP on apoptosis during open heart operation.

Apoptosis of cardiomyocytes has been implicated in the progressive loss of ventricular function in the failing heart [25–27]. In addition, it has been suggested that apoptosis might be related to prolonged reversible postischemic contractile dysfunction after myocardial ischemia and reperfusion called stunning [18, 19]. In human right atrium, release of cytochrome c from mitochondria correlated with the degree of cardiac dysfunction immediately after open heart operation [19]. We did not find a relationship between either clinical course of operation or cardiac function and the amount of apoptosis. This result does not necessarily mean that apoptosis does not play a role in stunning, because our quantitative methodology might not be sensitive enough to detect small differences in the amount of apoptosis. Myocardial biopsies obtained from the left ventricle of our patients were necessarily very small. Apoptosis has been shown to occur in a patchy distribution during acute myocardial ischemia [6, 9], and highest numbers of apoptotic cells have been found adjacent to scars of previous myocardial infarctions [6]. Thus, small samples may not reflect accurately the quantity of apoptosis in the whole left ventricle. Development of noninvasive methods to demonstrate apoptotic changes in vivo, such as those based on detection of externalization of the phosphatidyl serine with Annexin V, might be suitable tools to assess the extent of apoptosis in the entire left ventricle in future studies [28].

Ventricular myocardial biopsy is a possible endangered manipulation. Analysis of TUNEL-positive cells in the right ventricle might be more informative in correlation with postoperative right ventricular function. For the safety of the patients, only one postoperative biopsy was taken during the early reperfusion period. There is a lack of data on ventricular apoptosis in CABG patients, the study population was therefore calculated according to the power of our previous study on cardiac index. The small population investigated and postoperative sampling at the early reperfusion period could result in a type II error regarding the lack of effect of IP on apoptosis.

In conclusion, cardioplegic myocardial ischemia during open heart operation is associated with induction of apoptosis in left ventricular cardiomyocytes in human. Attenuation of postischemic cardiac dysfunction by IP appears to be independent of the amount of apoptosis.

	Acknowledgments

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The study was supported by the Research Foundation of Tampere University Hospital, the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, Finnish Foundation for Cardiovascular Research, and clinical research funds (EVO funds) of the Turku University Central Hospital.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jari Laurikka Erkki J. Pehkonen Timo Savunen Matti R. Tarkka Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, Z.-K. Articles by Tarkka, M. R. Search for Related Content PubMed PubMed Citation Articles by Wu, Z.-K. Articles by Tarkka, M. R. Related Collections Myocardial protection