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Ann Thorac Surg 1998;65:54-58
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Early Detection of Cardiac Damage With Heart Fatty Acid-Binding Protein After Cardiac Operations

First Department of Surgery, Osaka University, Osaka, Japan

Accepted for publication October 3, 1997.

Dr Suzuki, First Department of Surgery, Osaka University Medical School, 2-2 Yamada-Oka, Suita, Osaka, 565, Japan.

	Abstract

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Background. It is still difficult to evaluate myocardial damage in the acute phase of reperfusion in cardiac operations. We investigated the clinical significance of human heart fatty acid-binding protein (HH-FABP) for detecting myocardial damage after cardiac operations earlier than creatine kinase MB isoform or troponin-T.

Methods. Blood samples from 20 patients who underwent coronary artery bypass grafting were collected serially after reperfusion to measure serum levels of creatine kinase-MB, troponin-T, and HH-FABP.

Results. Serum HH-FABP levels peaked earliest after reperfusion. In addition, the maximum serum HH-FABP level was predictable immediately after reperfusion. The maximum serum HH-FABP level correlated with the maximum serum creatine kinase-MB or troponin-T level, as well as with the aortic cross-clamp time or the maximum dose of catecholamines administered after reperfusion.

Conclusions. Measurements of HH-FABP allow for earlier evaluation of myocardial damage in the acute phase of reperfusion. Human heart fatty acid-binding protein may be a useful indicator of myocardial damage after cardiac operations.

	Introduction

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In cardiac operations, an early and accurate evaluation of myocardial damage in the acute phase of reperfusion would be clinically useful for perioperative patient management. According to such an indicator, we could earlier and more properly determine a dose of catecholamine administration or the need for employment of auxiliary circulation after the termination of cardiopulmonary bypass. The clinically available indicators, such as creatine kinase MB isoform (CK-MB) and troponin-T (TnT), have been reported to be very cardiospecific and also correlate well with the severity of myocardial damage [1][2][3][4][5][6]. However, serum levels of CK-MB or TnT after reperfusion peak slowly, and several hours are needed to reach maximum levels [4][5][6][7]. Therefore, these values are only useful for retrospective analysis of myocardial damage after an operation, but not for identifying immediate postoperative myocardial damage. The development of an early indicator of myocardial damage after cardiac operations is of major importance, especially for critical cases.

Heart fatty acid-binding protein (H-FABP) is believed to be involved in the transport of long-chain fatty acids from the sarcolemma through the cytoplasm to different sites of oxidation and esterification within the cell [8][9][10][11]. Heart fatty acid-binding protein is a small, hydrophilic protein (12 to 15 kDa), which is abundant in the cytoplasm of cardiomyocytes in its free forms. Therefore, H-FABP enters the blood and urine just after myocardial damage occurs, and the total amount of H-FABP leakage reflects the extent of the damage [12][13][14][15][16]. It has recently become possible to measure human H-FABP (HH-FABP) with an enzyme immunoassay kit that uses two different monoclonal antibodies specific for HH-FABP [17], and its usefulness for the early detection of acute myocardial infarction has recently been reported [18][19][20]. Here, we demonstrated that HH-FABP can indicate myocardial damage after a cardiac operation earlier than CK-MB or TnT.

	Patients and Methods

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Patient Population
Twenty adult patients who underwent elective coronary artery bypass grafting in Osaka University Hospital between November 1993 and March 1996 were evaluated for this study. The study group consisted of 11 men and 9 women, aged 38 to 76 years, with a mean ± standard error of the mean of 59.9 ± 2.4 years. Their preoperative cardiac index was 3.50 ± 0.09 L · min^-1 · m^-2. There were no patients whose cardiac hypertrophy exceeded 120 g/m² of left ventricular mass index. The myocardial protection was performed systemically in the same way for all patients. Cold blood cardioplegic solution was intermittently infused at an initial volume of 10 mL/kg body weight (blood:crystalloid = 2:1; K+ = 18 mmol/L; approximately 10°C, antegrade), followed by retrograde infusion (blood:crystalloid = 4:1) of 5 mL/kg body weight every 20 minutes accompanied by topical cooling to maintain myocardial temperature of less than 20°C. The number of coronary artery bypass grafts was 3.2 ± 0.7 per patient. The aortic cross-clamp time ranged from 77 to 142 minutes (mean, 105.8 ± 4.3 minutes), and the cardiopulmonary bypass time from 108 to 288 minutes (mean, 162.3 ± 8.8 minutes). Operative procedures such as cardiopulmonary bypass and clamping and declamping of the aorta were standardized.

Measurement of Samples
Informed consent was obtained from all patients before the operation in accordance with the procedures stipulated by our internal review board. Only the surgeons were informed that samples were being collected for this study, and other people administering anesthesia and postoperative management were blinded to it.

Arterial blood samples were collected before the operation and every 15 minutes for up to 2 hours after reperfusion, followed by collection at 3, 6, 9, 12, 18, 24, and 48 hours after reperfusion. The HH-FABP levels in these samples were measured using a sandwich enzyme immunoassay with two different anti–HH-FABP monoclonal antibodies [17]. Activity of CK-MB was measured with an immunoinhibitory assay, and TnT levels were quantified with an enzyme immunoassay.

Use of Catecholamine
Catecholamines were administered based on each patient’s blood pressure just after the termination of cardiopulmonary bypass on the same principle. A dose of 5 µg · kg^-1 · min^-1 of dopamine was infused initially. Subsequently, catecholamine doses were determined according to the patient’s hemodynamic condition.

Data Analysis
All data are expressed as mean ± standard error of the mean. Comparisons among the three groups were performed with the Kruskal-Wallis test for nonparametric and noncontinuous variables. All analyses were performed using the Statview 4.0 statistical package (Abacus Concepts Inc, Berkeley, CA). A p value of less than 0.05 was considered statistically significant.

	Results

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Clinical Outcomes
No release distress of cardiopulmonary bypass, death during operation, or in-hospital death were observed. No perioperative myocardial infarction occurred after the operation. All patients had stable hemodynamic data after cardiopulmonary bypass. No patient showed a significant change in electrocardiography such as a development of a new Q wave. No patient showed a new regional or global asynergy on echocardiography. No patient showed a significantly high value of serum CK-MB or TnT. The lowest cardiac index after cardiopulmonary bypass ranged from 2.07 to 3.11 L · min^-1 · m^-2 (mean, 2.58 ± 0.07 L · min^-1 · m^-2), and the maximum dose of catecholamines administered after cardiopulmonary bypass ranged from 5.0 to 15.0 µg · kg^-1 · min^-1 (mean, 8.9 ± 0.6 µg · kg^-1 · min^-1). Dopamine and dobutamine were the only catecholamines administered.

Time Course of Serum Levels of the Indicators
Individual data of the time course of serum HH-FABP levels after reperfusion are presented in Table 1. Serum HH-FABP levels were 1.9 to 5.5 ng/mL (mean, 3.8 ± 0.2 ng/mL) before the operation. They showed a sharp peak within 60 minutes after reperfusion in all patients (maximum serum HH-FABP levels ranged from 64.9 to 139.0 ng/mL; mean, 93.2 ± 5.4 ng/mL), then gradually normalized without double peak formation or a persistently high level (see Table 1; Fig 1). Serum CK-MB concentrations were 0 to 11 IU/L (mean, 2.8 ± 0.7 IU/L) before the operation. A slow increase was seen after reperfusion, but no discrete peak was observed within 90 minutes after reperfusion in any of the patients (maximum concentration range, 44 to 128 IU/L; mean, 75.7 ± 5.2 IU/L). Serum TnT levels were undetectable preoperatively in all patients, and after reperfusion, TnT levels increased more slowly than HH-FABP or CK-MB levels. None of the patients showed peak levels of serum TnT within 105 minutes after reperfusion (maximum levels, 0.95 to 5.41 ng/mL; mean, 2.76 ± 0.23 ng/mL). Some patients had double peaks or persistently high levels of CK-MB or TnT despite the absence of additional myocardial damage after the operation (see Fig 1).

View larger version (27K): [in this window] [in a new window]   Time course of serum human heart fatty acid-binding protein (HH-FABP), creatine kinase MB isoform (CK-MB), and troponin-T (TnT) levels after reperfusion in 20 patients undergoing coronary artery bypass grafting (shown as mean ± standard error of the mean). (pre = preoperation.)

View larger version (16K): [in this window] [in a new window]   Time needed to reach the maximum serum levels of indicators for myocardial damage. Data are shown as mean ± standard error of the mean (n = 20). (CK-MB = creatine kinase MB isoform; HH-FABP = human heart fatty acid-binding protein; TnT = troponin-T; *p < 0.0001.)

View larger version (21K): [in this window] [in a new window]   Serum human heart fatty acid-binding protein (HH-FABP) levels immediately after reperfusion plotted against maximum (max) serum HH-FABP levels.

View larger version (16K): [in this window] [in a new window]   (A) Maximum (max) serum creatine kinase MB isoform (CK-MB) levels plotted against maximum serum human heart fatty acid-binding protein (HH-FABP) levels. (B) Maximum serum troponin-T (TnT) levels plotted against maximum HH-FABP levels.

View larger version (16K): [in this window] [in a new window]   (A) Aortic cross-clamp time (AXC) and (B) maximum (max) dose of catecholamine administration after cardiopulmonary bypass plotted against maximum serum human heart fatty acid-binding protein (HH-FABP) levels.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

Maximum serum HH-FABP levels also showed a significant correlation with the serum HH-FABP levels immediately after reperfusion. This suggests that maximum serum HH-FABP levels can be predicted immediately after reperfusion, and thus serum HH-FABP may be quite useful for the early detection of myocardial damage after cardiac operations. However, it currently takes approximately 1 hour to measure HH-FABP with the sandwich enzyme immunoassay kit. The development of a quicker method for the determination of HH-FABP will make it possible to immediately determine and follow up myocardial damage after an operation. Development of a rapid and easy method for the quantification of HH-FABP with dry chemistry is currently underway.

A correlation between H-FABP levels and the severity of myocardial damage was reported previously in animal experiments [16]. Our report indicates that in the clinical setting, the maximum serum HH-FABP levels after reperfusion in cardiac operations correlate significantly with both serum CK-MB and TnT levels, which have been shown to correlate strongly with the severity of myocardial damage [3][5][6]. Moreover, we also demonstrated that the maximum serum HH-FABP level correlated significantly with aortic cross-clamp time and the maximum dose of catecholamines administered after cardiopulmonary bypass. Although statistically significant, each of these data may not be enough to prove the correlation. By putting these various data together, however, it is reasonable to assume that the maximal serum HH-FABP level reflects the severity of myocardial damage after the cardiac operation.

This study included no patients with severe myocardial damage who required hemodynamic support with intraaortic balloon pumps or adrenaline administration, because we encountered no such patients having coronary artery bypass grafting during this period. We experienced another 3 patients who required strict management because of perioperative myocardial infarction. They showed development of a new Q wave in electrocardiography, a new asynergy in echocardiography, and markedly high levels of serum CK-MB and TnT after operation. One underwent aortic and mitral valve replacements, tricuspid annuloplasty, and a maze procedure, 1 underwent coronary artery bypass grafting and left ventricular aneurysmectomy, and the third underwent mitral valve replacement. These patients showed remarkably high levels of serum HH-FABP (326, 390, 304 ng/mL, respectively). The pattern of their change in serum HH-FABP level after reperfusion was the same as those of the patients undergoing coronary artery bypass grafting without perioperative myocardial infarction. To determine the levels of HH-FABP that indicate clinically significant myocardial damage after a cardiac operation, further investigation with larger numbers of such critical patients will be required.

In this study, we highly selected our study group to exactly investigate whether serum HH-FABP reflects the myocardial damage in cardiac operations. However, it is also important to study the usefulness of HH-FABP in universal types of patients as a marker for myocardial damage. For this purpose, further investigation and accumulation of data are needed.

In summary, maximum serum HH-FABP levels probably reflected the severity of myocardial damage after cardioplegic arrest. These levels were observed soon after reperfusion and could be predicted at the acute phase after reperfusion. Therefore, HH-FABP may be an early indicator of myocardial damage after cardiac operations.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We express our deep appreciation to Dr Takao Tanaka (Third Division of the Department of Internal Medicine, Osaka Medical College) for his advice and permission to evaluate HH-FABP.

We thank Miss Kumiko Asayama and Dr Yasuhiko Ohkaru (Division of Laboratory Products, Dainippon Pharmaceutical Co, Ltd, Osaka, Japan) for their kind assistance of measurement of HH-FABP, CK-MB, and TnT.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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