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CLINICAL STUDIES

Pericardial fluid from patients with unstable angina induces vascular endothelial cell apoptosis

Atsushi Iwakura, MD^a, Masatoshi Fujita, MD, FACC, Koji Hasegawa, MD, Tatsuya Sawamura, MD, Ryuji Nohara, MD, Shigetake Sasayama, MD, FACC and Masashi Komeda, MD^a

^a Departments of Cardiovascular Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan
College of Medical Technology, Kyoto University, Kyoto, Japan
Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan
Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan

Manuscript received June 22, 1999; revised manuscript received December 16, 1999, accepted February 21, 2000.

Reprint requests and correspondence: Dr. Masatoshi Fujita, Professor, College of Medical Technology, Kyoto University, 53 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507 Japan
mfujita{at}kuhp.kyoto-u.ac.jp

OBJECTIVES

The purpose of this study was to investigate whether pericardial fluid from patients with unstable angina (UA) would modulate vascular endothelial cell survival.

BACKGROUND

Apoptosis of vascular endothelial cells promotes the coagulation process, playing an important role in the formation of coronary arterial thrombi. However, little is known about the mechanisms of vascular endothelial cell death in acute coronary syndrome. We hypothesized that factors inducing apoptosis are produced by the ischemic heart and accumulated in high concentrations in pericardial fluid.

METHODS

Pericardial fluid was obtained during coronary artery bypass surgery from patients with UA (group A, n = 8) and those with stable angina (group B, n = 23). A survival assay of F2 cells from a mouse vascular endothelial cell line was performed in the presence of 10% pericardial fluid from each patient.

RESULTS

Pericardial fluid levels of vascular endothelial growth factor were significantly higher in group A than in group B, indicating that group A had more ischemic insults than group B. Pericardial fluid from group A, but not from group B, markedly induced F2 cell death (cell survival relative to fetal bovine serum; group A: 33 ± 26% vs. group B: 91 ± 22%, p < 0.01). Cell death was associated with internucleosomal DNA fragmentation, a hallmark of apoptosis. Fractionation of pericardial fluid using a Centricon C-100 demonstrated that apoptosis-inducible activities exist in the Centricon C-100 retentates but not in the filtrates.

CONCLUSIONS

Factors that induce vascular endothelial cell apoptosis are secreted into the pericardial space from the hearts of patients with UA. These factors are large complexes or unknown new proteins larger than 100 kDa.

Abbreviations and Acronyms   ACS = acute coronary syndrome   FBS = fetal bovine serum   UA = unstable angina   VEGF = vascular endothelial growth factor

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