Faculty Bibliography

BACKGROUND: The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure. METHODS AND RESULTS: A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days -1, 1, and 3; long-term blockade consisted of MR1 given on days -1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43+/-7% and 50+/-12%, respectively (P=NS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19+/-3% (P<0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control (P<0.05). CONCLUSIONS: These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.

Asymmetric dimethylarginine (ADMA), a compound detectable in human plasma, is an endogenous inhibitor of NO synthase. Endothelial dysfunction is an early event in atherogenesis, and large-vessel atherosclerosis is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus. Fifty patients with type 2 diabetes mellitus were studied at baseline and 5 hours after ingestion of a high-fat meal. Plasma ADMA measured by using high-performance liquid chromatography increased from 1.04+/-0.99 to 2.51+/-2.27 micromol/L (P:<0.0005). Brachial arterial vasodilation after reactive hyperemia, a NO-dependent function, measured by high-resolution ultrasound, decreased from 6.9+/-3.9% at baseline to 1.3+/-4.5% (P:<0.0001). These changes occurred in association with increased plasma levels of triglycerides and very low density lipoprotein triglycerides, with reduced low density lipoprotein cholesterol and high density lipoprotein cholesterol, and with no changes in total cholesterol. The increase in plasma ADMA in response to a high-fat meal was significantly and inversely related to the decrease in percent vasodilation. In 10 of the subjects studied with a similar protocol on another day, no significant changes in the brachial artery flow responses or in plasma ADMA were observed 5 hours after ingestion of a nonfat isocaloric meal. The data suggest that ADMA may contribute to abnormal blood flow responses and to atherogenesis in type 2 diabetics

Rapid acquisition of echocardiographic images is critical for the predictive accuracy of stress echocardiography. Real-time 3-dimensional echocardiography (RT3D) allows review of several standard 2-dimensional images from a single volumetric data set. To assess the feasibility of RT3D for treadmill stress echocardiography, we performed treadmill stress RT3D on 20 volunteers (10 men and 10 women; mean age 32 +/- 6 years) with a device that uses a matrix phased-array transducer in a 60-degree pyramidal volume. Images are displayed as 2 steerable, intersecting B-scan sectors with adjustable C-scan planes parallel to the transducer face. At pre-exercise and immediate postexercise assessment, the volumetric data were obtained from apical and parasternal windows, respectively. Left ventricular segments were divided into 16 standard segments according to criteria defined by the American Society of Echocardiography. The use of both volume sets resulted in visualization of 98% of the segments at peak exercise. Even with only an apical volume set, 89% of the segments were adequately visualized. Image optimization and acquisition time at peak exercise was 35 +/- 18 seconds from the apical window and 50 +/- 28 seconds from the parasternal window. This preliminary study indicates that RT3D treadmill stress echocardiography is feasible and may be an important application of this new 3-dimensional device.

To test the hypothesis that real-time, 3-dimensional (3-D) echocardiography can obtain all standard 2-dimensional (2-D) views from acquisition of 2 volume sets, we scanned 45 patients (24 men, 21 women; mean age 49 +/- 17 years). This real-time 3-D device (VOLUMETRICS Medical Imaging, Durham, NC) uses a matrix phased array transducer in a 60 degree pyramidal volume. Images are displayed as 2 steerable, intersecting, conventional 2-D image sectors that can be oriented throughout 3-D space. By using this equipment, we were able to obtain 93.3% of standard views from a parasternal volume set and 85.2% of standard views from an apical volume set. The mean scanning time was 91 +/- 19 seconds for the parasternal volume set and 86 +/- 22 seconds for the apical volume set. We conclude that standard 2-D views can be obtained in the majority of patients by using this method. This equipment has the potential to substantially decrease the imaging time compared with the standard 2-D echocardiography.