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(Circulation. 2004;109:1056-1061.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model

Isao Kondo, MD; Koji Ohmori, MD; Akira Oshita, MD; Hiroto Takeuchi, MD; Junji Yoshida, MD; Kaori Shinomiya, MD; Sachiko Fuke, DVM, MCs; Takeo Suzuki, MD; Katsufumi Mizushige, MD; Masakazu Kohno, MD

From the Second Department of Internal Medicine and the First Department of Surgery (T.S.), Kagawa University School of Medicine, Kagawa, Japan.

Correspondence to Koji Ohmori, MD, PhD, Second Department of Internal Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 Japan. E-mail komori{at}kms.ac.jp

Received May 7, 2003; de novo received September 22, 2003; revision received October 28, 2003; accepted October 31, 2003.

Background— Repetitive endomyocardial biopsies are necessary to monitor the effects of immunosuppressants after cardiac transplantation. Contrast ultrasound with microbubble targeting of leukocytes detects acute leukocyte infiltration. We examined whether leukocyte-targeted myocardial contrast echocardiography (MCE) could provide for the quantitative assessment of acute cardiac rejection.

Methods and Results— Hearts from Brown Norway rats or Lewis rats were transplanted into other Brown Norway rats. Isografts and groups of allografts either untreated or treated with cyclosporin A (CsA) at a low dose (3 mg · kg^-1 · d^-1) or high dose (10 mg · kg^-1 · d^-1) from 3 days before transplantation were compared at posttransplantation day 3. Echocardiography-derived left ventricular wall thickening was comparable among the 4 groups. Myocardial blood flow assessed with MCE, relating pulsing intervals with signal intensity (SI), was slightly decreased only in untreated allografts. However, myocardial SI (in gray levels) obtained after a 10-minute period allowing microbubble–leukocyte interactions after contrast injection exhibited a clear gradient in these groups (12±2 in untreated allografts, 9±5 in allografts treated with low-dose CsA, 6±3 in allografts treated with high-dose CsA, and 2±1 in isografts, P<0.001). The pattern of difference in SI among the groups agreed well with that in ED-1–positive cell (macrophage) count (25±7, 12±4, 5±3, and 1±0 cells per high-power field, respectively, P<0.001), which correlated with CD3-positive cell (T lymphocyte) count (33±5, 22±5, 9±4, and 1±0 cells per high-power field, respectively, P<0.001).

Conclusions— Leukocyte-targeted MCE can noninvasively assess the degree of rejection in transplanted hearts by directly revealing the magnitude of intramyocardial infiltration of macrophages and T lymphocytes.

Key Words: rejection • leukocytes • cyclosporine • echocardiography

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