Leukocyte-targeted myocardial contrast echocardiography can assess the degree of acute allograft rejection in a rat cardiac transplantation model.

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 x kg(-1) x d(-1)) or high dose (10 mg x kg(-1) x 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.