Effect of low molecular weight heparin on coronary endothelial function in acute cellular heart transplant rejection.

R research interest has focused on the effects of heparin on allograft survival. In addition to anticoagulant properties, heparin has immunosuppressive effects and inhibitory effects on smooth muscle cell proliferation.1 Animal studies1–4 have shown that low doses of heparin devoid of anticoagulant activity extend the survival of skin allografts as well as heterotopic and xenographic cardiac allografts. The addition of low molecular weight heparin (LMWH) to cyclosporine immunosuppression reduced the frequency and severity of accelerated graft coronary disease and the extent of acute parenchymal rejection in a rat model of heterotopic heart transplantation.5 Because endothelial dysfunction has been proposed as a surrogate end point for the subsequent development of cardiac allograft vasculopathy,6 we undertook a pilot study to evaluate the effect of LMWH in addition to enhanced antirejection therapy on endothelium-dependent vasomotor responses in acute cardiac allograft rejection. • • • Thirteen orthotopic heart transplant recipients who had International Society for Heart and Lung Transplant grade III or IV acute allograft rejection7 confirmed by endomyocardial biopsy between July 1, 1995, and March 1, 1997, were screened for this randomized, parallel-design pilot study comparing the effects of standard therapy and LMWH with standard therapy alone on endothelium-dependent vasomotor responses. Exclusion criteria included age ,18 years, angiographically significant coronary stenosis (.50% luminal diameter narrowing), hemodynamically compromising rejection with systolic blood pressure ,90 mm Hg and/or cardiac index ,2.0 L/min/m, a major contraindication to anticoagulation such as life-threatening bleed in the previous 6 months, platelet count ,50,000 or prior allergic reaction to heparin. One patient was excluded from the study because of early hemodynamic complications from the rejection episode. Three patients refused consent. The remaining 9 patients with acute cellular allograft rejection underwent cardiac catheterization and vasomotor function testing within 18 hours of the histologic diagnosis of rejection, before initiation of any antirejection therapy. After vasomotor function testing, patients were randomized into 2 groups. All patients received enhanced immunosuppression with intravenous methylprednisolone 1,000 mg/day for 3 days. Four patients in group 1 received LMWH (Enoxaparin, Rhone-Poulenc Rorer, Collegeville, Pennsylvania) 2 mg/kg/day in 2 divided subcutaneous doses for 3 days in addition to methylprednisolone. Five patients in group 2 were treated with methylprednisolone alone. At the time of the next endomyocardial biopsy (10 6 3 days), all but 1 patient underwent repeat vasomotor function assessment. All study patients had received 3-drug (prednisone, cyclosporine, and azathioprine) immunosuppression with therapeutic drug levels and 1 in each group had received diltiazem for hypertension before the acute episode. All vasoactive medications were discontinued $12 hours before the study procedure. After coronary angiography from the femoral approach, all patients received 5,000 U of unfractionated heparin intravenously. Using an 8Fr wide lumen guiding catheter, a steerable 0.014-inch, 12-MHz Doppler guidewire (Flowire, Cardiometrics, Inc., Mountainview, California) and a 3.2Fr, 30-MHz intravascular ultrasound catheter (IVUS; Cardiovascular Imaging Systems, Inc., Sunnyvale, California) were positioned in the middle left anterior descending artery for simultaneous assessment of vascular structure and function in relation to coronary blood flow. Use of these 2 systems together has been previously reported.8,9 The Doppler transducer at the tip of the Flowire was positioned 5 to 10 mm distal to the tip of the imaging transducer to avoid interference with Doppler velocity signals caused by the IVUS catheter. Identical catheter positions on serial studies were confirmed by reference to branch vessels in 2 views. Simultaneous IVUS and Doppler recordings were made during intracoronary infusions of adenosine 16 mg, acetylcholine 60 mg, and nitroglycerin 200 mg as boluses. Time was allowed for coronary blood flow (CBF) and luminal diameter to return to baseline before administration of each agent. Doppler and IVUS signals were recorded on 1/2-inch videotape for off-line analysis. The interventional cardiologists that performed these studies were not blinded. Quantitative measurements of average peak velocity were made and CBF reserve was defined as the ratio of hyperemic to resting baseline average peak velocities. Vessel cross-sectional area was measured directly by tracing the lumen-wall interface from a single diastolic frame using the Cardiovascular ImagFrom the University of Florida College of Medicine, Division of Cardiovascular Medicine, Gainesville, Florida. This research was supported in part by the American College of Cardiology/Merck Research Fellowship Award, Bethesda, Maryland; the American Heart Association, St. Petersburg, Florida; Florida Affiliate Research Fellowship Award, and the Bracco Diagnostics/Society for Cardiac Angiography and Interventions Research Fellowship Award, Breckenridge, Colorado; and a grant from Rhone-Poulenc Rorer, Collegeville, Pennsylvania. Dr. Mills’ address is: Division of Cardiology, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195. Manuscript received September 13, 1999; revised manuscript received and accepted January 7, 2000.