Angiographic assessment of cardiac allograft vasculopathy: results of a Consensus Conference of the Task Force for Thoracic Organ Transplantation of the German Cardiac Society.

Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa=0.371, P<0.001). The kappa value for peripheral obliteration was 0.331 (P=0.001). Angiographic evaluation of cardiac allograft vasculopathy, particularly of diffuse and peripheral disease and remodeling, needs standardization. This should be performed in a downward compatible improvement process.

Prognostic impact of microvasculopathy on survival after heart transplantation: evidence from 9713 endomyocardial biopsies.

BACKGROUND: Epicardial vasculopathy has been shown to be associated with poor outcome after heart transplantation. We demonstrate that histologically proven stenotic microvasculopathy is a novel prognostic factor for long-term survival. METHODS AND RESULTS: In 9713 biopsies harvested within the first posttransplantation year from 873 patients (83% male; mean age, 49.1+/-0.6 years), light microscopic evaluations (x200) were performed for microvasculopathy, defined as stenotic endothelial and/or medial disease. Prevalence of severe epicardial vasculopathy was defined by presence of > or = 75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P<0.001). Endothelial disease (median [95% CI], 12.07 [10.69 to 13.44] versus 12.73 years [10.16 to 15.30]; P=0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P=0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P=0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6+/-1.4%, 86.9+/-2.3%, 75.5+/-3.1% versus 99.1+/-0.5%, 96.8+/-1.0%, 89.8+/-1.9%; P<0.0001). This finding was independent of epicardial transplant vasculopathy (P=0.0031). CONCLUSIONS: Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long-term survival after heart transplantation.

Beneficial effect of female gender on long-term survival after heart transplantation.

BACKGROUND: We aimed to test whether stenotic microvasculopathy affects the more beneficial course in female cardiac transplant recipients. METHODS: We studied 873 patients (35/151 premenopausal women aged < or =40 years) who underwent primary heart transplantation. In 7750 biopsies harvested within the first posttransplant year endothelial disease and stenotic microvasculopathy were evaluated by light microscopy (Hematoxylin and Eosin). Kaplan-Meier and Cox regression analyses were performed for major cardiac events (MACE; lethal myocardial infarction, sudden cardiac death, graft failure, and cardiac retransplantation). RESULTS: Stenotic microvasculopathy was found equally in men (38%) and women (39%). Allografts from premenopausal female-to-male transplants more frequently developed endothelial disease (78% vs. 65%; P=0.021) and stenotic microvasculopathy (46% vs. 28%, P=0.024). Beyond the first 5 posttransplant years women presented MACE less often than men, independently of donor gender and stenotic microvasculopathy (P=0.0001). Multivariate regression analysis found women to be at lower risk for MACE (Relative Risk [RR] 0.38; 95% Confidence Interval [CI] 0.17-0.81), whereas stenotic microvasculopathy (RR 2.15; 95% CI 1.42-3.26) and treated diabetes (RR 1.65; 95% CI 1.08-2.52) indicated a higher risk for MACE. CONCLUSIONS: Stenotic microvasculopathy has prognostic impact on survival of male and female cardiac recipients; however, it does not affect the more beneficial course of women in the long-term follow-up.

Non-HLA antibodies targeting vascular receptors enhance alloimmune response and microvasculopathy after heart transplantation.

BACKGROUND: Non-human leukocyte antigen antibodies (Abs) targeting vascular receptors are implicated in the pathogenesis of renal allograft vascular rejection and in progressive vasculopathy in patients with systemic sclerosis. METHODS: We prospectively tested in 30 heart transplant recipients the impact of Abs directed against endothelin-1 type A (ET(A)R) and angiotensin II type 1 receptors (AT(1)R, cell-enzyme-linked immunosorbent assay) at time of transplantation and during the first posttransplantation year on cellular and Ab-mediated rejection (immunohistochemistry, C3d, and immunoglobulins) and microvasculopathy in endomyocardial biopsy. RESULTS: Cellular rejection, Ab-mediated rejection, and microvasculopathy was found in 40% and 13%, 57% and 18%, and 37% and 40% of biopsies at 1 month and 1 year posttransplantation, respectively. Maximum levels of AT(1)R and ET(A)R Abs were higher in patients with cellular (16.5±2.6 vs. 9.4±1.3; P=0.021 and 16.5±2.5 vs. 9.9±1.9; P=0.041) and Ab-mediated rejection (19.0±2.6 vs. 10.0±1.3; P=0.004 and 19.4±2.7 vs. 9.0±1.7; P=0.002), as compared with patients who had no rejection. Patients with elevated AT(1)R Abs (53% [16/30]) or ETAR Abs (50% [15/30]; pretransplantation prognostic rejection cutoff >16.5 U/L) presented more often with microvasculopathy (both, 67% vs. 23%; P=0.048) than patients without. CONCLUSIONS: Elevated levels of AT(1)R and ET(A)R Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation.

Invasive pressure monitoring saves from tuberculous meningitis with fulminant generalized brain edema.

We report a 57-year old female patient with a rapid and dramatic dynamic of whole brain edema caused by tuberculous meningitis. After initiation of tuberculostatic medication, general condition of the patient worsened and finally she was intubated due to a progredient loss of consciousness and respiratory insufficiency. Repeated cerebral computer tomography (CCT) revealed a global brain edema with slit ventricles and a dramatic progress of generalized brain swelling. Highly interesting, a rapid expanded regime of brain pressure monitoring and treatment according to a neurosurgical intensive standard ICP/CPP management protocol, which was complemented by the tuberculostatic therapy and high dose steroid application, dramatically improved the general conditions, so that the patient is now in a general condition which corresponds that before the occurrence of tuberculous meningitis. Thus, it is mandatory in situations with a rapid progressive brain swelling caused by bacterial meningitis to consider an intensified cerebral monitoring and stratified treatment protocol in order to avoid the devasting effects of a long lasting increase in intracranical pressure.

Everolimus prevents endomyocardial remodeling after heart transplantation.

BACKGROUND: Endomyocardial remodeling is characterized by progressive fibrosis and scars and may develop after heart transplantation. The role of everolimus in preventing this process has not been evaluated as yet. METHODS: We prospectively studied 132 patients at baseline pretransplant and at 4 weeks, 1 year, and 3 years after heart transplantation. Fibrosis, scars (Zeiss Vision, in Sirius), and acute cellular rejection (hematoxylin-eosin) were studied in biopsy. Transplant vasculopathy was assessed by coronary angiography (focal stenoses, peripheral obliterations, negative vascular remodeling defined by peripheral obliterations, and diffusely narrowed proximal and mid vessel segments). RESULTS: Patients on everolimus versus patients on mycophenolate mofetil presented with significantly less fibrosis at 4 weeks (3.8%±0.3% vs. 5.5%±0.3%, P=0.007), 1 year (4.1%±0.3% vs. 4.8%±0.3%, P=0.015), and 3 years (4.2%±0.3% vs. 5.5%±0.7%, P=0.049) posttransplant and showed less scarring at 3 years posttransplant (19.9±1.9% vs. 31.9±4.6% vs. baseline biopsy 26.0±2.8%; P=0.017). Angiographic peripheral obliterations correlated with higher amounts of endomyocardial fibrosis. The negative correlation of everolimus and the positive correlation of peripheral obliterations with fibrosis were confirmed by regression analysis. Angiographic stenoses or acute cellular rejection had no effect on the development of fibrosis. Negative vascular remodeling in 1-year follow-up tended to be less frequent in everolimus-treated patients (24% vs. 76%; P=0.053). CONCLUSIONS: Everolimus prevents endomyocardial remodeling after heart transplantation and might have beneficial effects on vascular remodeling of epicardial coronary arteries too. Angiographic peripheral obliterations correlate with increased amounts of endomyocardial fibrosis, suggesting a relevant effect on microvascular perfusion.

Heart transplantation at the Deutsches Herzzentrum Berlin.

The Deutsches Herzzentrum Berlin is one of the largest transplant centers in Germany with more than 1700 transplant procedures, more than 170 being procedures in children, in patients from the beginning of life to 71 years of age. Survival rates during the early and intermediate follow-up are lower than in international data; however, long-term survival at 15 years or more is similar. Discrepant survival rates derive mainly from the organ shortage that resulted in the development of a different allocation system in Germany as compared to North America and in the increasing number of patients undergoing the bridge-to-transplant concept to move the patient to transplantability. Thus, the patient at highest risk of death while on the waiting list, who according to the ISHLT registry is also the patient at highest risk of death early post-transplant, is the candidate most likely to undergo transplantation in Germany. Unfortunately, the myth persists of solving the donor organ shortage by increasing the "fairness" of organ allocation. Major goals of our transplant program are: the introduction of non-invasive cellular rejection screening with the intramyocardial electrogram (IMEG) and echocardiography; to characterize microvasculopathy in biopsy as a novel and easily diagnosed marker for poor prognosis; to identify Quilty as a determinant for poor prognosis; to propose classifications for microvasculopathy and epicardial vasculopathy that consider the diffuse character of the disease; and to provide insights into the therapeutic options and potential clinical benefits of novel immunosuppressive strategies.

International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010.

The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.

Reduction of arteriosclerotic nanoplaque formation and size by n-3 fatty acids in patients after valvular defect operation.

BACKGROUND/METHODS: Coating a silica surface with the isolated lipoprotein receptor heparan sulfate proteoglycan (HS-PG) from arterial endothelium and vascular matrices, we could observe the very earliest stages of arteriosclerotic plaque development by ellipsometric techniques in vitro (patent EP 0 946 876). This so-called nanoplaque formation is represented by the ternary aggregational complex of the HS-PG receptor, lipoprotein particles and calcium ions. The model was validated in several clinical studies on statins in cardiovascular high-risk patients applying their native blood lipoprotein fractions. RESULTS: In 7 patients who had undergone a valvular defect operation, the reduction of arteriosclerotic nanoplaque formation in normal Krebs solution amounted to 6.1 +/- 2.3% (p < 0.0156) and of nanoplaque size to 37.5 +/- 13.2% (p < 0.0312), respectively, after a 3-month therapy with n-3 fatty acids (3 ..3 g daily, Ameu 500 mg). Additionally, the quotient oxLDL/LDL was lowered by 6.8 +/- 2.1% (p < 0.0166), the MDA concentration remained unchanged and the lipoprotein(a) concentration decreased by 15.8 +/- 5.6% (p < 0.0469) in the patients' blood. The concentration of the nanoplaque promoting particles VLDL and total triglycerides was diminished by 34.1 +/- 11.6% (p < 0.0469) and 26.7 +/- 10.8% (p < 0.0156), respectively. Furthermore, the ratio of the strongly atherogenic small dense to the total LDL cholesterol (LDL5+LDL6)/LDLtot decreased by 9.9 +/- 3.0% (p < 0.0174). CONCLUSIONS: A combinatorial regression analysis revealed a basis for a mechanistic explanation of nanoplaque reduction under n-3 fatty acid treatment. This effect was possibly due to the beneficial changes in lipid concentrations and an attenuation of the risk factors oxLDL/LDL and (LDL5+LDL6)/LDLtot.

Attenuation of transplant arteriosclerosis with clopidogrel is associated with a reduction of infiltrating dendritic cells and macrophages in murine aortic allografts.

BACKGROUND: Monotherapy with clopidogrel reduced the formation of transplant arteriosclerosis in a murine aortic allograft model. However, the underlying immunologic mechanisms are still unknown. METHODS: Fully major histocompatibility complex-mismatched C57BL/6 (H2b) donor aortas were transplanted into CBA.J (H2k) recipients and mice received different doses (1, 10, and 20 mg/kg) of clopidogrel, an antagonist of the P2Y12 ADP receptor on platelets, or control saline for 30 days. Blood was analyzed for changes in adhesion molecule and sCD40L concentrations by ELISA. Grafts were analyzed by histology, morphometry, and immunofluorescence on day 30 after transplantation. Intragraft cytokine mRNA production was analyzed by reverse-transcriptase polymerase chain reaction on day 14 after transplantation. RESULTS: Treatment with clopidogrel resulted in significantly decreased blood concentrations of sCD40L and P-selectin after transplantation. Cellular analysis of the aortic transplant revealed fewer numbers of infiltrating dendritic cells (CD205+) and macrophages (F4/80+) after application of clopidogrel, whereas T-cells within the graft were unaltered. In addition cellular P-/E-selectin, ICAM-1, and platelet-derived-growth-factor (PDGF)-beta surface expression were significantly reduced as compared with untreated controls. Intragraft mRNA expression confirmed these results and showed significant lower production of P-/E-selectin, ICAM-1, and PDGF-beta after treatment with clopidogrel. Antiglycoprotein-Ib and antiglycoprotein VI had no beneficial effect on the development of transplant arteriosclerosis. CONCLUSION: This report shows that application of clopidogrel after transplantation results in a reduction in adhesion molecule expression within the blood and transplant tissue and is associated with reduced transendothelial migration of dendritic cells and macrophages within the vascular wall.

Bronchogenic cyst of the interatrial septum presenting as atrioventricular block.

Bronchogenic cysts are congenital lesions that are a remnant from abnormal budding of the embryonic foregut. These cysts are usually single; most cases are either asymptomatic or present with respiratory symptoms. A 43-year-old woman presented with intermittent type II atrioventricular block during cholecystectomy. The cardiac evaluation including transthoracic and transesophageal echocardiography and magnetic resonance imaging revealed a cystic homogeneous mass within the interatrial septum. The patient underwent surgical resection of the mass and closure of the septal defect. Histopathology identified ciliated columnar epithelium, consistent with the diagnosis of a bronchogenic cyst.

Quilty indicates increased risk for microvasculopathy and poor survival after heart transplantation.

BACKGROUND: The impact of Quilty (sub-endocardial infiltration of lymphocytes) on the development of stenotic microvasculopathy and outcome after heart transplantation has not yet been evaluated. METHODS: Biopsies (n = 9,713) obtained within the first post-transplant year from 873 patients (722 men, age 49.3 +/- 0.3 years) were evaluated by light microscopy (hematoxylin-eosin) for Quilty and cellular rejection (ISHLT), stenotic microvasculopathy (luminal radius:medial thickness ratio <1) and endothelial disease (core diameter:cell diameter ratio < or =1). Risk factors for stenotic microvasculopathy were analyzed by logistic regression. Overall survival and freedom from graft failure (cardiac re-transplantation, myocardial infarction and sudden cardiac death) were estimated by the Kaplan-Meier method and tested using a Cox proportional hazard model. RESULTS: We found 1,830 (19%) Quilty-positive biopsies in 481 (55%) Quilty-formers and stenotic microvasculopathy in 866 (9%) biopsies of 379 (43%) patients. Evidence of Quilty (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.26 to 2.57) and endothelial disease (OR 4.98; 95% 95% CI 3.31 to 7.49) indicated higher risk, whereas post-transplant statin therapy was associated with lower risk for stenotic microvasculopathy (OR 0.68; 95% CI 0.48 to 0.97). Freedom from graft failure was lower in Quilty-formers (p = 0.0060) and even worse if patients suffered from both Quilty and stenotic microvasculopathy (p = 0.0017). Both factors were confirmed in multivariate regression analysis (stenotic microvasculopathy risk ratio [RR] 1.90, 95% CI 1.23 to 2.95; Quilty RR 1.77, 95% CI 1.11 to 2.82, p = 0.0430). CONCLUSIONS: Presence of Quilty indicates increased risk for stenotic microvasculopathy in biopsy early after heart transplantation. Both are associated with poor outcome due to graft failure.

A decade of percutaneous coronary interventions in cardiac transplant recipients: a monocentric study in 160 patients.

BACKGROUND: Transplant vasculopathy is a long-term complication of cardiac transplantation. Percutaneous transluminal coronary angioplasty (PCI) is a method of choice for local revascularization that is also increasingly used in heart transplant patients. METHODS: Between October 1989 and November 2006, 160 adult cardiac transplant recipients (19 women) with mean age at heart transplantation of 47 +/- 12 years underwent PCI in 502 coronary segments during 319 catheterizations (balloon only, 209; bare metal stents, 227, drug-eluting stents, 66). Concomitant medical therapy, procedural data, primary success, recurrence of stenosis, and cardiac events (cardiac death or repeat transplantation) were analyzed retrospectively. Multivariate Cox proportional hazards analysis was performed. RESULTS: Stents reduced early and mid-term recurrence of stenosis but had no impact on graft survival. Drug-eluting stents did not improve the restenosis rate. Immunosuppression with mycophenolate mofetil and concomitant treatment with statins and clopidogrel were significantly associated with reduced recurrence of stenosis and prolonged graft survival. Low steroid dosage was associated with a positive impact on graft survival. CONCLUSIONS: Stenting in heart transplant patients has no impact on graft survival despite high primary success and deferred recurrence of stenosis. Early reduction of steroids, immunosuppression by mycophenolate mofetil, and concomitant treatment with statins are likely to reduce recurrent stenosis and to improve graft survival in heart transplant patients needing PCI. Long-term treatment with clopidogrel deserves further assessment.

Observational study with everolimus (Certican) in combination with low-dose cyclosporine in de novo heart transplant recipients.

BACKGROUND/METHODS: This observational study reports on immunosuppression with cyclosporine (CsA) in 38 de novo heart transplant recipients receiving everolimus compared with 14 patients receiving mycophenolate mofetil (MMF). RESULTS: Mean (+/- SD) everolimus C0 blood levels remained stable within 5 to 7 ng/ml. Mean CsA C0 blood levels were reduced by 47%, from 240 +/- 57 ng/ml at 2 weeks post-transplant to 128 +/- 38 ng/ml at Month 6 and by 58% to 101 +/- 26 ng/ml at Month 12 in the everolimus group, compared to 18% from 246 +/- 54 ng/ml at 2 weeks post-transplant to 201 +/- 48 ng/ml at Month 6 and by 35% to 160 +/- 41 ng/ml in MMF patients. Efficacy was high with a rejection rate of 23.6% (everolimus) vs 28.5% (MMF) by Month 12. Mean pre-transplant serum creatinine levels of 1.67 +/- 0.59 mg/dl decreased to 1.53 +/- 0.57 mg/dl under everolimus and increased from 1.22 +/- 0.36 to 1.99 +/- 0.75 mg/dl in the MMF group by Month 12 post-transplant. However, calculated GFR declined in both groups by Month 12 (everolimus: from 71 +/- 29 to 57 +/- 27 ml/min/1.73 m2; MMF: from 73 +/- 22 to 44 +/- 24 ml/min/1.73 m2), with stabilization after 3 to 6 months in everolimus-treated patients and after 6 to 9 months in MMF-treated patients. CONCLUSIONS: Everolimus allows marked reduction of CsA exposure without significant loss of efficacy and also provides early protection of renal function.

Clopidogrel reduces the development of transplant arteriosclerosis.

BACKGROUND: Transplant arteriosclerosis, the hallmark feature of chronic rejection, is still the major limiting factor for the long-term success of heart transplantation. Platelets have been implicated to play a role in the pathogenesis of this disease. Therefore the aim of this study was to investigate whether platelet inhibition alone has a positive effect on the development of transplant arteriosclerosis. METHODS: Fully major histocompatibility complex-mismatched C57BL/6 (H2(b)) donor aortas were transplanted into CBA (H2(k)) recipients, and mice received different doses (1, 10, and 20 mg/kg) of clopidogrel or control saline as a daily intraperitoneal injection for 30 days. Blood was analyzed on days 2, 7, 14, and 30 by using a platelet aggregation test (adenosine diphosphate) for effectiveness of the treatment. Grafts were analyzed by means of histology and morphometry on day 30 after transplantation. RESULTS: When mice were treated daily with 1 mg/kg clopidogrel in the absence of any other immunosuppression, transplant arteriosclerosis was significantly reduced compared with that seen in saline-treated control animals (intimal proliferation of 66% +/- 9% [1 mg/kg clopidogrel] vs 77% +/- 5% [control], n = 7, P < or = .03). Daily application of 10 mg/kg and 20 mg/kg clopidogrel also significantly reduced the development of transplant arteriosclerosis compared with that seen in control animals (intimal proliferation of 61% +/- 11% [10 mg/kg clopidogrel] vs 54% +/- 10% [20 mg/kg clopidogrel] vs 77% +/- 5% [control], n = 8, P < or = .003). There was, however, no additional beneficial effect when compared with mice treated with 1 mg/kg clopidogrel (P = .06). Isografts did not show any signs of vascular lesions on day 30 after transplantation. CONCLUSION: These results demonstrate that monotherapy with clopidogrel can effectively reduce the formation of transplant arteriosclerosis in a murine aortic allograft model.

Small vessel disease after heart transplantation: impact of immunologic and nonimmunologic risk factors.

To determine risk factors for small vessel disease after heart transplantation (HTx), characteristics of donors and organ harvesting were evaluated in 246 HTx patients (205 male, 41 female, mean survival 5.4 years). In right ventricular endomyocardial biopsies (EMB, n = 5421) evidence of microvascular disease [endothelial cell (EC) swelling/vessel wall thickening] was evaluated by light microscopy (hematoxylin and eosin staining, x 200). Mild EC swelling/vessel wall thickening were found in 204 and 213 patients, severe EC swelling/vessel wall thickening were present in 23 and 142 patients respectively. Evidences of mild and severe acute cellular rejection were found in 2064 and 421 EMB respectively. Microvascular disease was positively correlated with mild acute rejection episodes (P < 0.05). EC swelling was more frequent in patients with donors dying of craniocerebral trauma. No correlations were present to further demographical data. Microvascular alterations after HTx seem to be the result of an immunologic conflict rather than to depend on nonimmunologic factors.