Klaus Pethig

Mechanism of luminal narrowing in cardiac allograft vasculopathy : Inadequate vascular remodeling rather than intimal hyperplasia is the major predictor of coronary artery stenosis

BACKGROUND Despite increasing knowledge about degree and distribution pattern of intimal hyperplasia in cardiac allograft vasculopathy, coronary artery remodeling is only poorly understood in this disease. METHODS To evaluate vascular geometry, intravascular ultrasound was used to characterize 57 advanced lesions in 35 consecutive transplant recipients. Lumen, plaque, and vessel area in these target lesions were compared with proximal and distal reference sites. RESULTS AND CONCLUSIONS Vascular remodeling by compensatory local vessel enlargement (positive remodeling) and circumscript vascular constriction (negative remodeling) could be demonstrated. Plaque area in stenotic lesions was significantly increased compared with the mean reference site (5.6+/-3.0 mm2 versus 2.8+/-1.5 mm2, p < 0.001); however, inadequate compensatory enlargement rather than intimal hyperplasia was shown to be the most important predictor of luminal obstruction (r = 0.77, p < 0.001).

Long-term outcome of chronic hepatitis B in heart transplant recipients

BACKGROUND Hepatitis B is common in organ transplant recipients. It adversely affects the prognosis after liver and kidney transplantation. The long-term outcome of hepatitis B virus (HBV) infection in heart transplant recipients has not been studied before. METHODS Between July 1984 and June 1993, 436 patients underwent heart transplantation at the Hannover Medical School. A total of 345 patients survived for more than 1 year and were included in this study. Of these, 74 were found to be hepatitis B surface antigen (HBsAg)-positive during follow-up; 69 acquired HBV infection at known time points 25+/-17 months after transplantation, and 5 had already been infected before heart transplantation. Mean follow-up was 105 (range, 25-157) months. RESULTS Patients developed significant alanine aminotransferase (ALT) elevations after HBV infection, which peaked and then remained above normal. Preinfection levels of ALT were 15.4+/-6.4 U/L, peak values were 71.2+/-47.2 U/L, and mean values after HBV infection were 28.9+/-14.6 U/L. All patients remained HBsAg-positive. Thirteen patients (18%) became HBeAg-negative during follow-up, 10 with negative quantitative HBV-DNA assays. Mean HBV-DNA levels in the remaining patients were 292+/-267 (range, 0-978) pg/ml. Thirty-four patients died during follow-up (45.9%) compared to 78/271 (28.8%) in the control group (P=0.008). Six of the HBsAg-positive patients (17.1%) died of liver failure 6.2-10.6 years (mean, 8.6) after transplantation. Histology of 25 HBsAg-positive patients more than 5 years after infection revealed severe fibrosis or cirrhosis in 14 (56%), mild fibrosis in 9 (36%), and chronic hepatitis without fibroproliferation in 2 (8%). CONCLUSIONS Hepatitis B infection after heart transplantation leads to chronic liver disease in the majority of the affected patients, causing cirrhosis in more than 55% within the first decade after transplantation. Liver failure is a common cause of death in the infected group of patients. Active HBV vaccination is mandatory for all organ transplant candidates, in particular before heart transplantation.

Coronary artery stenting in cardiac allograft vascular disease

Cardiac allograft vascular disease is characterized by diffuse and multifocal heterogeneous myointimal hyperplasia with or without vascular remodeling. Catheter-based interventions are indicated in selected patients. This study documents our experience with percutaneous transluminal coronary angioplasty and coronary stents (n = 48) in a group of 27 patients 5.7 +/- 2.9 years after heart transplantation. Early and intermediate results were controlled by angiography and intravascular ultrasound. Conventional percutaneous transluminal coronary angioplasty resulted in a mild and mostly inadequate gain in luminal dimensions (lumen area: 3.17 +/- 0.92 mm2 to 3.70 +/- 1.21 mm2; minimal lumen diameter: 1.84 +/- 0.23 mm to 2.04 +/- 0.36 mm). Coronary stenting led to a further improvement of luminal gain (lumen area: 3.70 +/- 1.21 mm2 to 5.86 +/- 1.76 mm2; minimal lumen diameter: 2.04 +/- 0.36 mm to 2.53 +/- 0.38 mm). These results were stabilized by application of aspirin and ticlopidine only. There were no stent thromboses or bleeding complications, and early hospital discharge of the patients was possible. At follow-up (mean follow-up period 7.72 +/- 5.45 months (range 0.50 to 23.13 months) all patients were clinically event free. In six of 24 stented vessels (25%) in 16 patients, significant restenosis (>50%) was found by intravascular ultrasound (n = 20) or by angiography (n = 4) 6 months after stent placement. We conclude that in eligible cardiac allograft vascular disease lesions primary stenting may be the method of choice. However, further evaluation of the modalities of stent application and different stent designs with respect to long-term survival is necessary.

Mycophenolate mofetil for secondary prevention of cardiac allograft vasculopathy: influence on inflammation and progression of intimal hyperplasia☆

BACKGROUND Cardiac allograft vasculopathy (CAV) remains the single most important complication impairing long-term survival after heart transplantation (HTx). Intimal hyperplasia as a response to immunologic and non-immunologic injury is involved in the pathogenesis. Because improved immunosuppressive properties with mycophenolate mofetil (MMF) have been shown within the first year, beneficial effects on intimal hyperplasia and systemic inflammation might be found late after HTx as well. METHODS After a baseline examination with intravascular ultrasound (IVUS, volumetric assessment) 30 patients (2.0 +/- 1.1 years post-HTx) were prospectively randomized to receive either MMF (2 g/day) or to continue with azathioprine (AZA) as part of a triple immunosuppression protocol with cyclosporine and prednisolone. Markers of systemic inflammation and changes in vascular geometry were evaluated by IVUS after 1 year of follow-up. RESULTS With regard to inflammation, significantly lower values were found for high-sensitive C-reactive protein (CRP) in the MMF group (AZA 1.8 +/- 1.2 mg/liter. vs MMF 1.0 +/- 4.1 mg/liter, p = 0.02). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-6 and transforming growth factor (TGF)-beta did not differ between the groups. IVUS revealed no significant differences between groups. There was a weak trend toward a larger increase in plaque volume (AZA 13 +/- 43 mm(3) vs MMF 27 +/- 41 mm(3), p = 0.33), whereas MMF-treated patients tended to show a small increase in vessel dimensions (AZA +10 +/- 63 mm(3) vs MMF +50 +/- 87 mm(3), p = 0.17). CONCLUSIONS Changing immunosuppression from a standard AZA-based regimen to MMF resulted in a decrease in systemic inflammatory activity as indicated by levels of high-sensitive CRP. However, progression of intimal hyperplasia did not differ significantly, and the weak trend toward vascular enlargement could indicate some influence on vascular geometry.

Ten year survival after heart transplantation: palliative procedure or successful long term treatment?

OBJECTIVE To investigate the long term outcome and prognostic factors after heart transplantation. SETTING University hospital. SUBJECTS 120 heart transplant patients (98 male, 22 female; underlying disease: dilated cardiomyopathy in 69, coronary artery disease in 42, miscellaneous in nine) who had undergone heart transplantation between October 1984 and October 1987. Immunosuppressive treatment was comparable in all patients and rejection episodes were treated in a uniform manner. METHODS Functional status, quality of life, and potential predictors for long term survival were investigated. RESULTS Actuarial survival rates were 65% at five years and 48% at 10 years; 58 patients survived > 10 years. The major causes of death were cardiac allograft vasculopathy (39%), acute rejection (18%), infection (11%), and malignancy (11%). Long term survivors had good exercise tolerance assessed by the New York Heart Association classification: 47 (81%) in grade I/II; 11 (19%) in grade III/IV. Echocardiography showed good left ventricular function in 48 patients. On angiography, severe allograft vasculopathy was present in only 16 patients (28%). Renal function was only slightly impaired, with mean (SD) serum creatinine of 148.5 (84.9) μmol/l. Multiple potential predictors of long term survival were analysed but none was found useful. CONCLUSIONS Heart transplantation represents a valuable form of treatment. Survival for more than 10 years with a good exercise tolerance and acceptable side effects from immunosuppression can be achieved in about 50% of patients.

Myelodysplastic syndrome and acute myelogenous leukemia secondary to heart transplantation

Myelodysplastic syndrome and acute myelogenous leukemia secondary to radiotherapy, radiation exposure, and chemotherapy is a well-documented malignant stem cell disorder. The incidence and natural course of myelodysplastic syndrome and acute myelogenous leukemia after organ transplantation remains less thoroughly investigated. In our institution, 631 heart transplantations have been performed between 1983 and 1998. We report five patients (age, 22-63 years) with myelodysplastic syndrome (MDS) (n=1) or acute myelogenous leukemia (AML) (n=4) occuring 4-8 years after transplantation. Immunosuppression consisted uniformly of a combination of prednisone, cyclosporine, and azathioprine. Successful cytogenetic analysis was performed in three patients, showing typical cytogenetic abnormalities in each case. The course of AML was uniformly fatal. One patient with MDS, refractory anemia with excess of blasts according to the FAB criteria, is alive with transfusion dependency 32 months after diagnosis. MDS and AML may occur during immunosuppression after heart transplantation. Treatment results are poor in this subgroup of patients with secondary leukemia.

LMNA Mutations in Cardiac Transplant Recipients

Lamin A and C are components of the nuclear envelope, located at the nucleoplasmatic surface of the inner nuclear membrane within cells. Recently, mutations within LMNA encoding lamin A/C have been associated with various disease entities including cardiomyopathy. We screened heart transplant recipients suffering from dilated cardiomyopathy (DCM) with a positive family history of LMNA mutations. Four index patients and one relative belonging to four unrelated families carrying LMNA mutations were identified. The mutations p.Q355X and p.S22L have not been reported before, whereas p.R190W has already been reported in other studied DCM cohorts. In the patients of the present study, the mean age at manifestation of heart disease was 37.6 years (range 30–45 years), with progression to end-stage heart failure requiring transplantation at a mean age of 45.8 years (range 35–54 years). Three patients presented initially with atrial fibrillation. These data confirm the involvement of LMNA mutations in patients with DCM and extend the mutational spectrum of LMNA. The p.R190W mutation has been reported in different populations and may therefore be useful for analyzing the impact of a specific LMNA mutation on the phenotype of muscle disease.

Aerosolized iloprost for severe pulmonary hypertension as a bridge to heart transplantation

Preexisting pulmonary hypertension in pediatric patients is associated with poor outcome after cardiac transplantation because of donor right ventricular dysfunction. To avoid a combined heart-lung transplantation in a 17-year-old patient, we used an intensified pretreatment with intravenous prostacyclin and dobutamine combined with an inhalative therapy with the aerosolized prostacyclin-analog Iloprost. With this regimen, the patient was hemodynamically stabilized for the waiting period of 21 days after which an uneventful cardiac transplantation was performed.

Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms.

BACKGROUND Recently, homocysteine (HCY) levels have been suggested to be a risk factor in cardiac allograft vascular disease (CAVD). As plasma levels are partially under genetic control, we investigated the influence of the methylenetetrahydrofolate reductase (MTHFR) polymorphism on HCY levels and development of CAVD in heart transplant (HTX) recipients. METHODS Genotyping and assessment of fasting HCY levels were performed in a cohort of 146 HTX recipients and correlated to the onset and progression of CAVD, assessed by serial angiography. RESULTS Actuarial freedom from CAVD did not differ significantly between the genotypes. However, patients positive for CAVD presented with higher HCY levels than CAVD-negative individuals (21.0+/-9.4 vs. 18.2+/-6.6 micromol/L, P=0.046). CONCLUSIONS There is some evidence that plasma HCY might be involved in development of CAVD. However, polymorphism of the MTHFR gene could not be shown to be related to severity of allograft vascular disease.

Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295.

Background. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF-receptor (PDGFR) system has been linked to vascular smooth muscle cell migration and proliferation leading to allograft vasculopathy. This study describes the effect of the tyrphostin AG-1295, a specific PDGFR tyrosine-kinase inhibitor, on neointimal formation in this disease. Methods and Results. Rat aortic allografts transplanted from dark agouti (RT1av1) donors to Wistar-Furth (RT1u) recipients were assessed in a new treatment model for local drug delivery from polymeric carrier matrices precoated with AG-1295. Matrices were wrapped around the graft immediately after transplantation. The recipients received no background immunosuppression. At day 80 posttransplantation, intimal thickness in AG-1295–treated grafts was reduced when compared to controls (11.8±9.1% intimal thickness vs. 23.7±6.4% intimal thickness;P =0.042). This finding corresponded to inhibition of intimal PDGFR-&bgr; expression in AG-1295–treated grafts at day 20 posttransplantation (P =0.029 vs. allogeneic controls). Conclusions. The tyrphostin AG-1295 reduces neointimal formation in aortic allograft vasculopathy by inhibition of PDGFR-&bgr;–triggered tyrosine phosphorylation. Local drug release of specific tyrosine-kinase inhibitors from perivascularly co-implanted polymeric carrier matrices is effective in the prophylaxis of allograft vasculopathy under selected experimental conditions.