Incidence of acute cellular rejection and non-cellular rejection in cardiac transplantation.

BACKGROUND: Rejection continues to be one of the leading causes of death during the first year after cardiac transplantation. With the advent of more potent immunosuppressive therapies, the incidence of graft rejection has been reported to be decreasing. Yet, this trend has not been well established due to differences in the interpretation of and the protocols for endomyocardial biopsy specimens. Additionally, the incidence of humoral (noncellular) rejection has not been adequately addressed. METHODS: Six thousand one hundred thirty endomyocardial biopsy specimens in 487 cardiac transplant recipients during the first year posttransplantation from 1990 to 2000 were reviewed to assess the incidences of acute cellular and treated noncellular rejection episodes. Cellular rejection was defined as ISHLT grades 3-4; noncellular rejection as a 20% decrease in echo LVEF, cardiac index <2.0, and/or inotropic support associated with ISHLT grades 0-2 necessitating treatment. RESULTS: The incidence of noncellular rejection has remained relatively unchanged at approximately 20% (P=nonsignificant for all years); in contrast, there has been a significant decrease (P <.001) in the incidence of cellular rejection from 54% to 5%. CONCLUSION: The incidence of noncellular rejection in cardiac transplant recipients has remained unchanged through the 1990s despite improved immunosuppressive therapies, which have significantly decreased the incidence of acute cellular rejection. There appears to be a need for newer immunosuppressive agents to effectively treat noncellular rejection. Clinical trials using allograft rejection as a major endpoint will need to increase the enrollment of patients to achieve adequate power to demonstrate differences between study groups.

Cardiac function after eight hour storage by using polyethylene glycol hemoglobin versus crystalloid perfusion.

Efforts to extend myocardial preservation for transplantation by crystalloid perfusion have been limited by edema and compromised function. We hypothesized that hypothermic perfusion preservation with a polyethylene glycol (PEG) conjugated hemoglobin solution may extend preservation times. The purpose of this study was to compare cardiac function after continuous perfusion by using a hypocalcemic, normokalemic crystalloid perfusate with and without the addition of PEG-hemoglobin (Hb). The hearts of 20 anesthetized and ventilated New Zealand White rabbits were harvested after cold cardioplegic arrest. Group I (n = 10) hearts were continuously perfused with a hypocalcemic, normokalemic 3% bovine PEG-Hb solution at 20 degrees C and 30 mm Hg for 8 hours. Group II (n = 10) hearts were continuously perfused with an identical crystalloid solution without PEG-Hb for 8 hours under the same conditions as group I hearts. Cardiac function was measured with a left ventricular force transducer after transfer to a standard crystalloid Langendorff circuit at 37 degrees C and an aortic root pressure of 59 mm Hg. After 8 hours of perfusion preservation, heart rate was similar for groups I and II (p = not significant [NS]). Coronary blood flow after and during preservation was similar between PEG-Hb and crystalloid preserved hearts (p = NS). Left ventricular developed pressure, peak dP/dt, and peak -dP/dt were superior in hearts preserved with PEG-Hb. Percent water of total ventricular weight was 82.0% for group I and 81.6% for group II (p = NS). Continuous perfusion preservation of rabbit hearts for 8 hours with a hypocalcemic normokalemic PEG-Hb based solution at 30 mm Hg and 20 degrees C yields left ventricular function that is superior to perfusion with a similar crystalloid solution without PEG-Hb, despite similar myocardial edema and coronary flow. Extended cardiac perfusion preservation with this PEG-Hb based solution deserves further study, including comparison with traditional cardioplegic preservation solutions.

Pretransplant panel reactive-antibody screens. Are they truly a marker for poor outcome after cardiac transplantation?

BACKGROUND: The effect of pretransplant sensitization on outcome after cardiac transplant has been controversial. Sensitization, defined as a positive panel-reactive antibody (PRA) screen in patients awaiting transplant, represents circulating antibodies to a random panel of donor lymphocytes (usually T lymphocytes). The significance of pretransplant circulating antibodies to B lymphocytes has not been reported, and many centers disregard its use. METHODS AND RESULTS: We retrospectively reviewed the pretransplant PRA screens for 311 patients who underwent cardiac transplant at our institution. The PRA screen was performed by use of the lymphocytotoxic technique treated with dithiothreitol to remove IgM autoantibodies. Patients with PRA > or = 11% against T or B lymphocytes had significantly lower 3-year survival (T lymphocytes, 39%; B lymphocytes, 56%) than those patients with PRA = 0% and PRA = 1% to 10% (T lymphocytes, 76% and 78%; B lymphocytes, 78% and 74%, respectively) (P < .001). For this high-risk group, the rejection episode tended to occur earlier than in those patients with PRA = 0% and PRA = 1% to 10% (T lymphocytes, 2.3 versus 4.0 and 3.8 months; B lymphocytes, 2.1 versus 4.1 and 3.4 months, respectively), and there were more clinically severe rejections that required OKT3 therapy. CONCLUSIONS: Cardiac transplant patients with pretransplant T- and/or B-lymphocyte PRA > or = 11% despite negative donor-specific crossmatch at the time of transplant appear to have earlier and more severe rejection with significantly lower survival after transplant surgery. Modification of immunosuppression in these high-risk patients may be warranted.

Effect of pravastatin on outcomes after cardiac transplantation.

BACKGROUND: Hypercholesterolemia is common after cardiac transplantation and may contribute to the development of coronary vasculopathy. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to be effective and safe in lowering cholesterol levels after cardiac transplantation. Cell-culture studies using inhibitors of HMG-CoA reductase have suggested an immunosuppressive effect. METHODS: Early after transplantation, we randomly assigned consecutive patients to receive either pravastatin (47 patients) or no HMG-CoA reductase inhibitor (50 patients). RESULTS: Twelve months after transplantation, the pravastatin group had lower mean (+/- SD) cholesterol levels than the control group (193 +/- 36 vs. 248 +/- 49 mg per deciliter, P < 0.001), less frequent cardiac rejection accompanied by hemodynamic compromise (3 vs. 14 patients, P = 0.005), better survival (94 percent vs. 78 percent, P = 0.025), and a lower incidence of coronary vasculopathy in the transplant as determined by angiography and at autopsy (3 vs. 10 patients, P = 0.049). There was no difference between the two groups in the incidence of mild or moderate episodes of cardiac rejection. In a subgroup of study patients, intracoronary ultrasound measurements at base line and one year after transplantation showed less progression in the pravastatin group in maximal intimal thickness (0.11 +/- 0.09 mm, vs. 0.23 +/- 0.16 mm in the control group; P = 0.002) and in the intimal index (0.05 +/- 0.03 vs. 0.10 +/- 0.10, P = 0.031). In a subgroup of patients, the cytotoxicity of natural killer cells was lower in the pravastatin group than in the control group (9.8 percent vs. 22.2 percent specific lysis, P = 0.014). CONCLUSIONS: After cardiac transplantation, pravastatin had beneficial effects on cholesterol levels, the incidence of rejection causing hemodynamic compromise, one-year survival, and the incidence of coronary vasculopathy.