Incidence Of Cardiac Allograft Vasculopathy Research Articles

Temporal changes in myocardial endothelial nitric oxide synthase expression following human heart transplantation

Background: The incidence of cardiac allograft vasculopathy increases with time after heart transplantation. Allograft vasculopathy is associated with endothelial dysfunction and reduced endothelium-dependent nitric oxide-mediated vascular effects. In this study, temporal changes in endothelial nitric oxide synthase (NOS3) expression in human myocardial biopsies were investigated during the first 3 years after heart transplantation. Methods: In each patient ( n = 7), the immunohistochemical presence of NOS3 and inducible nitric oxide synthase were examined in serial biopsies taken at 1, 4, and 26 weeks and at 1, 2, and 3 years after transplantation. Results: Endothelial nitric oxide synthase was present in vascular endothelial cells in all biopsies at the time of transplantation. A rapid fall within the first months in the number of NOS3-positive biopsies was observed, with a possible difference in the rate of disappearance among the capillaries, the arterial endothelium, and the venous endothelium. After 2 years, very little NOS3 could be detected. Inducible nitric oxide synthase was present in vascular smooth muscle cells throughout the study period and did not change. Conclusion: Endothelial nitric oxide synthase immunoreactivity is gradually lost after heart transplantation. These changes may be responsible for the coronary endothelial dysfunction often seen after human cardiac transplantation.

Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.

Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.

Long term results of hyperimmunoglobulin CMV-prophylaxis in 377 heart transplant recipients

Because of the immunosuppression required, heart-transplant (HTX) recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, gastroenteritis, and a syndrome of fever, hepatitis, and leukopenia. We performed a retrospective analysis to evaluate the efficiency of prophylactic administration of a CMV hyperimmunoglobulin (Cytotect, Biotest, Germany) to prevent CMV-induced disease in aggressively immunosuppressed HTX-patients. 377 consecutive patients, who underwent HTX at our institution between Aug 90 and Dec 96 were studied. Cytotect was given intravenously at a dose of 1,5mg per kilogram of bodyweight pre-TX and on post-TX day 1, 7, 14, 21, and 28 as sole CMV prophylaxis. All patients received quadruple immunosuppressive therapy. They were monitored for CMV immediate early antigen on peripheral blood cells, urine sediments and in throat washings, the presence of serum CMV-IgM/IgG and clinical evidence of CMV related symptoms. The study population was categorized into 4 groups according to donor and recipient CMV-serologic status at the time of transplantation (D+/R+, D+/R-, D-/R+, D-/R). Estimates of patient survival were computed using the Kaplan-Meier method, with differences between the groups determined by means of the log rank- and Wilcoxon test. In addition, we compared the incidence of cardiac allograft vasculopathy (CAV) and infection. During the first 5 years after HTX CMV illness occurred in 81 patients (21.5%). A comparison between the groups showed a significantly increased risk for CMV disease in allograft recipients from a seropositive donor (p=0.0003) (D+/R+ 38.5%, D+/R-39.7%, D-/R+14.1%, D-/R-7.7%). A total of 6 deaths from CMV-disease were observed, all of which in CMV antibody-negative recipients (D+/R- n=4, D-/R- n=2) due to a primary infection. This translated into a significantly worse survival of CMV- recipients compared to CMV+ patients (p=0.0052). Both the incidences of CAV (p=0.049) and overall infection (p=0.0034) were found to be higher in CMV+ recipients. Under prophylactic treatment with hyperimmunoglobuline the incidence of CMV disease among aggressively immunosuppressed heart transplant recipients is very low, comparable to the more invasive treatment with ganciclovir. Since fatal CMV disease in CMV- recipients of seropositive donors could not be prevented with Cytotect we recommend the additional use of prophylactic ganciclovir in this CMV-mismatched population.

Cardiac allograft vasculopathy in heart transplant recipients: a bacteriosclerosis by chlamydia pneumoniae?

Background: Cardiac allograft vasculopathy (CAV) is an accelerated progressing coronary syndrome characterized by diffuse and multifocal myointimal hyperplasia and represents an important factor limiting long-term survival after heart transplantation. Recently there has been evidence for the pathophysiologic importance of chronic infection with Chlamydia pneumoniae (CP) in development of coronary heart disease. However, there is no information concerning a possible association of chronic CP infection and incidence of cardiac allograft vasculopathy in heart transplant recipients.

Graft vasculopathy and tolerance: does the balance of Th cells contribute to graft vasculopathy?

Cardiac allograft vasculopathy (CAV) is sometimes observed even though the allograft may survive indefinitely. In this study, we examined whether or not the preferential activation of Th2-type cells prevents the development of CAV. Hearts from C57BL/10 mice were transplanted heterotopically into the abdominal cavities of C3H.He recipient mice, and monoclonal antibodies (mAbs) to T-cell receptor (TCR) alphabeta or CD80/CD86 were administered after transplantation. The incidence of CAV was then examined histologically. To investigate the relative Th1/Th2 balance, the levels of IFNgamma and IL4 in the transplanted hearts were measured. Indefinite heart graft survival was observed in mice treated with either the anti-TCRalphabeta or anti-CD80/CD86 mAbs and these mice accepted donor-type (C57BL/10) skin grafts but rejected those from a third party (BALB/c). Evidence of CAV was found in the mice treated with the anti-TCRalphabeta mAb, but CAV did not develop in the mice treated with anti-CD80/CD86 mAbs. Preferential activation of Th2-type cells was dominant in the tolerant mice treated with anti-TCRalphabeta mAb, but it was not dominant in the tolerant mice treated with anti-CD80/CD86 mAbs. These findings suggest that the dominance of Th2-type cells does not prevent allograft vasculopathy.

Impact of chronic infection with chlamydia pneumoniae on incidence of cardiac allograft vasculopathy.

Chronic infection with Chlamydia pneumoniae (CP) is associated with development of coronary disease. However, little information exists concerning CP infection and impact on posttransplant cardiac allograft vasculopathy (CAV). A total of 202 patients were investigated 5.5+/-3.1 years after cardiac transplantation (46.5+/-11.0 years; 169 male, 33 female). Assessment of CAV was performed by annual coronary angiograms. Chlamydia serology (IgG/IgA) was performed using micro-immunofluorescence. Statistics comprised analysis of variance and Kaplan-Meier analysis. A total of 152 patients were CAV positive. Elevated titers were present in 45% (IgG) and 72.8% (IgA) of patients. Generally, serostatus was not associated with development of CAV when evaluated over the total postoperative interval. However, after month 14 there was a significant trend toward lower actuarial freedom from CAV in patients with elevated IgA titers. CP seems not to play a significant role in the development of CAV early after heart transplantation but might be a predicting risk factor after the first postoperative year.

Does University of Wisconsin solution harm the transplanted heart?

Background University of Wisconsin solution (UW) has been shown to be an effective preservative for the cardiac allograft. Recently, the high potassium content of UW has been implicated in causing coronary endothelial damage, allegedly contributing to development of cardiac allograft vasculopathy (CAV) and eventually to poorer survival. Methods We examined our experience using UW for preservation of cardiac allografts between 1990 and 1994 ( n = 94), and compared these to hearts preserved with the lower potassium-containing Stanford solution used at our center between 1986 and 1990 ( n = 65). Indices of graft function, ischemic injury, CAV incidence, CAV severity, and survival were evaluated. Results The 2 groups were similar in age, gender, diagnosis, donor inotropic support, donor-recipient weight ratio, incidence of acute graft failure, and cytomegalovirus seroconversion. UW-preserved hearts came from older donors (30.5 vs 24.1 years, p < .001), and were transplanted into more status 1 recipients (56% vs 22%, p < .001), consistent with current trends. Mean ischemic time of UW-preserved hearts was significantly longer (184 vs 155 minutes, p < .005) although time required to wean from bypass was less (45.5 vs 73.8 minutes, p < .001) and there was a trend towards less inotropic requirement. CPK-MB release was less with UW preservation (63 vs 87 μg/dL, p = .001). Three years after transplantation, both groups were similar in the incidence of CAV (UW, 27.3%; STNF, 37.5%; p = 0.27), and also the severity of CAV ( p = 0.78). Deaths attributed to CAV were equal in each group (UW, 11.4% vs STNF, 10.7%; p = 0.79). Kaplan-Meier survival analysis revealed equivalent survival curves ( p = 0.26). Conclusions We conclude that UW is a safe and effective myocardial preservative, allowing longer ischemic times with equivalent graft function. Our data suggest that when UW is used for cardiac allograft preservation, both CAV and survival are comparable to the experience with other preservatives containing lower concentrations of potassium.

Cardiac allograft vasculopathy: IgM antibody responses to donor-specific vascular endothelium.

We have previously demonstrated that heightened cell-mediated immunity to donor-specific endothelium was associated with an increased incidence of cardiac allograft vasculopathy (CAV) at 1 year postcardiac transplantation. We further demonstrated that the development of IgG antibody directed to donor-specific HLA antigens was extremely uncommon and, furthermore, had no relationship to the development of CAV. Subsequent studies have demonstrated a correlation between IgM antibody directed against endothelial cell antigens and the development of CAV. Accordingly, recipient serum obtained between 6 and 8 weeks (early) and 1 year (late) after transplantation were reacted with recombinant human interferon (rhIFN)-gamma pretreated donor-specific human aortic endothelial cells (HAECs) in 10 recipients with and 10 recipients without CAV at 1 year after transplantation. HAEC IgM binding was assessed by flow cytometry and complement fixation and HAEC lysis was measured using standard chromium release assays. Seven of 10 and 5 of 10 patients with CAV had IgM detected by flow at early and late time points, respectively (14+/-2 and 16+/-5 mean channel shift), whereas 5 of 10 and 6 of 10 patients without CAV had IgM detected by flow at early and late time points, respectively (15+/-4 and 14+/-3 mean channel shift). This finding was not different between groups. Despite between 50% and 70% of all patients having detectable IgM binding to ECs, no patient's serum was cytotoxic to its donor-specific HAECs. We conclude that IgM antibody to endothelial cells is common (at low titers) after transplantation. This antibody is not cytotoxic and in this study provided no discrimination between those with and without chronic rejection.