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Donor spontaneous intracerebral hemorrhage (ICH) is a potential risk factor for morbidity and mortality after cardiac transplantation. We hypothesized that donor ICH is associated with systemic up-regulation of angiotensin II receptor type 1 (AT1R). We evaluated mRNA expression of AT1R and AT2R in donor spleen lymphocytes and in heart biopsies from 20 recipients of hearts from donors with spontaneous ICH which were compared with 20 recipients from trauma donors. Heart biopsies showed 4.7-fold increased mRNA expression of AT1R (p < 0.0001) in the ICH group compared with the Trauma group. The ICH group also showed 2.6-fold (p < 0.01) increased mRNA expression of AT1R in the donor spleen lymphocytes, suggesting the presence of systemic activation before transplantation. At 1 year, the ICH group had increased coronary vasculopathy by vascular ultrasound. Using multivariate regression analysis, mRNA expression of AT1R in the donor spleen lymphocytes was found to be a strong independent predictor of transplant vasculopathy (odds ratio = 4.397, CI = 1.243-15.553, adjusted p = 0.02). This is the first report to describe splenic up-regulation of AT1R in the presence of spontaneous ICH and its association with subsequent development of transplant vasculopathy.

Flail mitral leaflet (FML) is a common complication of mitral valve prolapse, often leading to severe mitral regurgitation (MR) and left ventricular dysfunction. In the absence of timely surgical correction, survival is significantly impaired. Early recognition of FML and identification of risk factors is important because early intervention increases the chances of survival.We studied 123 patients undergoing mitral valve surgery for severe MR caused by myxomatous disease. Chart review, echocardiography, and tensile testing were performed.Thirty-eight patients had FML, and 85 patients had non-flail mitral leaflet (non-FML). Patients with FML were younger (53.7 +/- 1.8 vs 59.3 +/- 1.4 years, P =.02), had more severe MR (3.89 +/- 0.04 vs 3.76 +/- 0.04, P =.02), were less likely to be in New York Heart Association class III or IV heart failure (5% vs 20%, P =.037), and were less likely to have bileaflet mitral valve prolapse (5% vs 38%, P.001) than non-FML patients. Valve tissue from patients with FML had less stiff chordae (23.5 +/- 3.6 vs 59.1 +/- 11.7 Mpa, P =.006) that tended to have a lower failure stress (3.8 +/- 0.9 vs 9.6 +/- 2.2 Mpa, P =.07) and had more extensible leaflets (56.4% +/- 7.9% vs 42.9% +/- 2.7% strain, P =.04) compared with that of non-FML patients.The development of FML may result from intrinsic tissue abnormalities and is associated with a distinct subset of the myxomatous population. Identification of such clinical characteristics in this population and knowledge of an implicit mechanical abnormality of valve tissue may further the argument for early surgical correction.

It is possible, but unproven, that hepatitis C (HCV) infection accelerates atherosclerosis. We evaluated the hypothesis that donor HCV seropositivity predicts mortality and the development of coronary vasculopathy in cardiac transplant recipients.Thirty-four cardiac transplant recipients who were seronegative for HCV at the time of transplantation received hearts from HCV-seropositive donors. We compared the mortality and the incidence of vasculopathy in this group of patients (study group) with a group of 183 successive heart transplant recipients (control group) with no evidence of HCV in the donor or in the recipient.After transplantation, 75% of the HCV-seronegative patients who received hearts from HCV-seropositive donors had detectable and persistent viremia (presence of HCV-RNA by reverse-transcription polymerase chain reaction). After a mean follow-up of 4.2 +/- 1.9 years, mortality was 2.8-fold greater in the study group than in controls (95% confidence interval [CI], 1.3-5.7; p = 0.006). The risk of having any vasculopathy after a mean follow-up of 3.4 +/- 1.6 years and after adjustment for other significant risk factors was 3-fold greater (hazards ratio, 3.08; 95% CI 1.52-6.20; p = 0.001) in the HCV group compared with controls. The risk of developing advanced vasculopathy was much greater in the study group compared with controls (hazard ratio, 9.4; 97% CI, 3.3-26.6; p =0.0001). The risk of mortality (p = 0.005) and vasculopathy (p =0.0001) was greatest in patients with combined donor HCV seropositivity and the presence of antibodies against donor B cells by flow cytometry.We conclude that donor hepatitis-C virus seropositivity is an independent risk factor for increased mortality and for the development of accelerated allograft vasculopathy after cardiac transplantation. These observations may have implications for the use of HCV-positive donors in heart transplant recipients.

Background— Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy. Methods and Results— We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P P P =0.016) increased mRNA expression of MMP-2 and 1.7-fold ( P =0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P =0.01; 95% CI, 1.24 to 4.69). Conclusions— This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.

Background. We investigated the occurrence of apoptosis during and after resolution of cardiac allograft rejection. Apoptosis could play different roles in graft survival depending on the target cells; thus, we also determined the cell types involved. Methods. Endomyocardial biopsy specimens were evaluated during the first 6 months after transplantation as follows: group I, no current or prior rejection; group II, during an episode of moderate rejection; and group III, histologic resolution after an episode of moderate rejection. Results. Groups II and III showed significantly increased apoptotic activity, indicated by increased caspase-8 and caspase-3 activity; however, activated caspase-3 was undetectable in group I. Activated caspase-3 was detected only in groups II and III. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling was detected in groups II and III but not group I and predominantly in inflammatory cells. Conclusions. Increased caspase activity and apoptosis of infiltrating cells not only occurs during acute cardiac allograft rejection but persists after histologic resolution. Thus, programmed cell death occurs beyond the period of histologic resolution and may play a role in regulation of the rejection process.

Introduction: Depolarizations similar to those from the sinus node have been documented from the pulmonary veins after isolation procedures. We assessed the hypothesis that sinus node-like tissue is present in the pulmonary veins of humans. Methods and Results: Pulmonary vein tissue was obtained from five autopsies (four individuals with a history of atrial fibrillation and one without a history of atrial arrhythmias) and five transplant heart donors. Autopsy veins were fixed in formaldehyde and processed for light microscopy to identify areas having possible conductive-like tissue. Areas requiring additional study were extracted from paraffin blocks and reprocessed for electron microscopy. Donor specimens were fixed in formaldehyde for histologic sections and glutaraldehyde for electron microscopy. Myocardial cells with pale cytoplasm were identified by light microscopy in 4 of the 5 autopsy subjects. Electron microscopy confirmed the presence of P cells, transitional cells, and Purkinje cells in the pulmonary veins of these cases. Conclusion: Our report is the first to show the presence of P cells, transitional cells, and Purkinje cells in human pulmonary veins. Whether these cells are relevant in the genesis of atrial fibrillation requires further study. (J Cardiovasc Electrophysiol, Vol. 14, pp. 803-809, August 2003)

Objectives This biochemical study compared the extracellular matrix of normal mitral valves and myxomatous mitral valves with either unileaflet prolapse (ULP) or bileaflet prolapse (BLP). Background Myxomatous mitral valves are weaker and more extensible than normal valves, and myxomatous chordae are more mechanically compromised than leaflets. Despite histological evidence that glycosaminoglycans (GAGs) accumulate in myxomatous valves, previous biochemical analyses have not adequately examined the different GAG classes. Methods Leaflets and chordae from myxomatous valves (n = 41 ULP, 31 BLP) and normal valves (n = 27) were dried, dissolved, and assayed for deoxyribonucleic acid, collagen, and total GAGs. Specific GAG classes were analyzed with selective enzyme digestions and fluorophore-assisted carbohydrate electrophoresis. Results Biochemical changes were more pronounced in chordae than in leaflets. Myxomatous leaflets and chordae had 3% to 9% more water content and 30% to 150% higher GAG concentrations than normal. Collagen concentration was slightly elevated in the myxomatous valves. Chordae from ULP had 62% more GAGs than those from BLP, primarily from elevated levels of hyaluronan and chondroitin-6-sulfate. Conclusions The GAG classes elevated in the myxomatous chordae are associated with matrix microstructure and elastic fiber deficiencies and may influence the hydration-related “floppy” nature of these tissues. These abnormalities may be related to the reported mechanical weakness of myxomatous chordae. The biochemical differences between ULP and BLP confirm previous mechanical and echocardiographic distinctions.

Background: Quilty lesions are common after heart transplantation; however, their relationship to vasculopathy has not been described. We tested the hypothesis that Quilty lesions are associated with increased expression of vitronectin receptor (αvβ3) and the subsequent development of coronary vasculopathy. Methods: A total of 140 heart transplant recipients underwent coronary intravascular ultrasound at baseline and at 1 year after transplantation, and we measured the change in coronary maximal intimal thickness. Endomyocardial biopsy specimens taken within 8 weeks after transplantation showed Quilty lesions in 54 of 140 (39%) patients (Quilty group). We compared these results with the remaining 86 of 140 patients (61%) who had no evidence of Quilty lesions during the same period (control group). We evaluated 10 endomyocardial biopsy specimens from each group for αvβ3, using immunohistochemistry staining and immunoblotting. Results: Quilty lesions stained positive for αvβ3, and Western blot analysis showed a 1.3-fold ( p = 0.004) increase in expression of αvβ3. Compared with control, the Quilty group tended to have a greater incidence of post-transplant ischemic injury complicated by fibrosis (54% vs 38%, p = 0.08) and a greater reported incidence of "previous biopsy site" during the first 4 weeks after transplantation (48% vs 32%, p = 0.06). At 1 year, the Quilty group had a significant increase in the change in coronary maximal intimal thickness seen with intravascular ultrasound (0.54 ± 0.34 vs 0.42 ± 0.28 mm, p = 0.038). Conclusions: This is the first report to describe the association of Quilty lesions with coronary vasculopathy and its association with increased αvβ3 expression.

BACKGROUND The expression levels of several chemokine genes in heart allografts correlate with histologic rejection grade. Potential molecular differences between early and late rejection (grade > or =2) episodes were examined by testing chemokine and receptor-gene expression. METHODS Expression of inducible protein (IP)-10, monokine induced by IFN-gamma (Mig), interferon inducible-T cell alpha chemoattractant (I-TAC), regulated on activation normal T-cell expressed and secreted(RANTES), and their receptors CXCR3 and CCR5 was tested in 60 endomyocardial biopsies from 24 patients using quantitative (Taqman) real-time polymerase chain reaction (PCR). The biopsies were taken in the first 3 months or from the 9th to the 12th month following transplantation. RESULTS IP-10, Mig, RANTES, CXCR3, and CCR5 expression levels were increased in the later versus earlier biopsies (P< or =0.01) despite no change in histologic rejection-grade status. CONCLUSION These results demonstrate significantly increased expression of T-cell chemoattractants in heart allografts during later rejection when compared with episodes occurring shortly after transplantation. The findings suggest increased intensity of inflammation in rejection occurring at later times posttransplant that are revealed by molecular analyses of the graft.

We describe a patient who developed multi-organ failure with reactive hemophagocytic syndrome secondary to disseminated histoplasmosis 8 months after orthotopic heart transplantation. The patient responded fully to a prolonged course of therapy with amphotericin B and remains free of recurrence. Disseminated histoplasmosis and reactive hemophagocytic syndrome have rarely been described in the setting of cardiac transplantation and never before in combination.

Purpose To report the clinicopathologic findings after submacular removal of choroidal neovascular membranes (CNV) treated with verteporfin ocular photodynamic therapy. Design Interventional case series. Methods Retrospective review of eight eyes of eight patients who underwent submacular surgery for CNV after having previously received verteporfin ocular photodynamic therapy for presumed ocular histoplasmosis (one patient), age-related macular degeneration ([AMD] three patients) pathologic myopia (two patients), punctate inner choroiditis (one patient), and idiopathic CNV (one patient). All cases had undergone ocular photodynamic therapy with verteporfin using standard protocols. Six of eight patients suffered a submacular hemorrhage after ocular photodynamic therapy, and two of eight patients refused further ocular photodynamic therapy. All patients subsequently had submacular surgery with removal of the CNV. One membrane was routinely processed, sectioned, and stained with hematoxylin and eosin. Five membranes were stained with toluidine blue for light microscopic examination. Semithin (1.0 μm) sections were cut and stained with uranyl acetate-lead citrate for transmission electron microscopy. Results Choroidal neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29 days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic) after verteporfin ocular photodynamic therapy. Histopathologic and ultrastructural examination showed areas of vascular occlusion at 3 days that were not seen at later time points. All specimens had patent CNV. There were signs of vascular damage with extravasated erythrocytes and fibrin, pigment clumping in cells, and inflammatory cells in all but the 3-day specimen. Conclusions This case series presents data only from patients who refused repeat treatment with ocular photodynamic therapy or who developed submacular hemorrhage after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days after verteporfin ocular photodynamic therapy showed partial vascular occlusion that was not present in later specimens. These later specimens demonstrated evidence of vascular damage. Verteporfin ocular photodynamic therapy does not appear to lead to permanent and complete occlusion of the CNV. Thus, treatments that lead to permanent closure of CNV without damage to the retinal pigment epithelium and sensory retina are still needed.

Background. Factors directing T-cell infiltration into allografts during acute rejection remain poorly defined. Chemokines have been shown to mediate leukocyte recruitment into allografts in animal models of rejection. The goal of this study was to test the presence and levels of chemokine and receptor gene expression in serial endomyocardial biopsy specimens from heart transplant patients and to correlate the levels observed with histopathologic rejection grade. Methods. Three hundred sixteen serial endomyocardial biopsy specimens from 30 heart transplant patients were obtained during the clinically scheduled surveillance heart biopsy program. The follow-up period was 1 year. The expression of interferon (IFN)-γ inducible protein (IP)-10, monokine induced by IFN-γ (Mig), interferon-inducible T-cell alpha chemoattractant (I-TAC), regulated on activation normal T-cell expressed and secreted (RANTES), monocyte chemotactic protein (MCP)-1, interleukin (IL)-8, and the receptors CXCR3 and CCR5 were tested using quantitative, real-time polymerase chain reaction. Biopsy samples were examined histologically to assign rejection grade. Results. Expression of IP-10, Mig, I-TAC, RANTES, CXCR3, and CCR5, but not MCP-1 and IL-8, increased significantly in both grade 2 and grade 3 rejection (P ≤0.0096). These increases returned to normal after treatment with pulse steroid therapy to treat the rejection episode. Conclusion. The expression of IP-10, Mig, I-TAC, RANTES, CXCR3, and CCR5 in cardiac allografts significantly correlates with the presence and grade of acute rejection.

Background — Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin α v β 3 ) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models. Methods and Results — Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for α v β 3 , tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of α v β 3 (3.2-fold, P P P =0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24±1.8% versus 14±1.1%, P P P P =0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54±0.1 versus 0.26±0.06 mm; P =0.031). Conclusions — Myocardial ischemic injury after cardiac transplantation is associated with upregulation of α v β 3 , tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.

Objectives This study was undertaken to test the hypothesis that transplant coronary vasculopathy (CV) is associated with increased myocardial protein expression of both tissue factor (TF) and integrin αvβ3. Background The vitronectin receptor (integrin αvβ3) and TF have recently been found to play a key role in apoptotic cell death and vascular endothelial cell injury. Methods A total of 77 heart transplant recipients underwent simultaneous endomyocardial biopsy and intravascular ultrasound (IVUS) at one year of transplant. Patients with pre-existing donor coronary atherosclerosis (n = 35) or with acute rejection (grade >1A, n = 10) at the time of the IVUS were excluded from the analysis. The remaining 32 patients constitute the cohort of the present study. A computerized biopsy score was derived based on the duration and severity of cellular rejection. Both TF and αvβ3 expression in the heart biopsy specimens were evaluated by immunoperoxidase histochemistry and Western blot analysis. Results Patients with CV (n = 24) had increased expression of αvβ3 (2.7-fold, p = 0.003) and TF (7.9-fold, p = 0.04) compared with patients without evidence of vasculopathy (n = 8). In the absence of myocardial fibrosis, αvβ3 expression correlated significantly with the cellular rejection score (r = 0.58, p = 0.02). Conclusions Transplant vasculopathy is associated with increased expression of both TF and αvβ3. The significant correlation of αvβ3 with cellular rejection suggests an important role for this integrin in serving as a mechanistic link between cellular rejection and vasculopathy.

The vitronectin receptor (integrin alphavbeta3), a cell-surface adhesion receptor, has been shown to play a significant role in endothelial cell migration, apoptosis, atherosclerosis, and T-lymphocyte activation. This study was undertaken to test the hypothesis that cardiac allograft rejection is associated with increased expression of alphavbeta3. We also determined whether fibronectin receptor (alpha5beta1) and tissue factor are up-regulated in the presence of acute cellular rejection. We evaluated endomyocardial biopsy specimens with histologic evidence of different degrees of acute cellular rejection (grade 0, n = 10; grade 1A, n = 10; grade 2, n = 10; grade 3A, n = 10). Biopsies were obtained 2-4weeks after cardiac transplantation. Immunoperoxidase staining was performed for alphavbeta3, tissue factor, and alpha5beta1, and protein levels were further determined by Western blot analysis. Specimens with grade 2 and grade 3A rejection showed positive staining of alphavbeta3 in lymphocytic aggregates and vascular endothelial cells. By immunoblotting, we identified significantly increased expression of alphavbeta3 in the presence of acute rejection, grade 2 (3-fold, p = 0.01) and grade 3A (3.6-fold, p = 0.005) compared to grade 0 and 1 A specimens. There was no evidence of increased expression of alpha5beta1 or tissue factor. Acute cellular rejection, a process characterized by T-lymphocyte activation and release of inflammatory cytokines, is associated with increased expression of alphavbeta3.

Background —Cardiac papillary fibroelastoma (CPF) is a primary cardiac neoplasm that is increasingly detected by echocardiography. The clinical manifestations of this entity are not well described. Methods and Results —In a 16-year period, we identified patients with CPF from our pathology and echocardiography databases. A total of 162 patients had pathologically confirmed CPF. Echocardiography was performed in 141 patients with 158 CPFs, and 48 patients had CPFs that were not visible by echocardiography ( Conclusions —CPFs are generally small and single, occur most often on valvular surfaces, and may be mobile, resulting in embolization. Because of the potential for embolic events, symptomatic patients, patients undergoing cardiac surgery for other lesions, and those with highly mobile and large CPFs should be considered for surgical excision.

Hypogammaglobulinemia (HGG) has been reported after solid organ transplantation and is noted to confer an increased risk of opportunistic infections.In this study, we sought to assess the relationship between severe HGG to infection and acute cellular rejection following heart transplantation.Between February 1997 and January 1999, we retrospectively analyzed the clinical outcome of 111 consecutive heart transplant recipients who had immunoglobulin G (IgG) level monitoring at 3 and 6 months post-transplant and when clinically indicated.Eighty-one percent of patients were males, mean age 54 +/- 13 years, and the mean follow-up period was 13.8 +/- 5.7 months. Patients had normal IgG levels prior to transplant (mean 1137 +/- 353 mg/dl). Ten percent (11 of 111) of patients developed severe HGG (IgG350 mg/dl) post-transplant. The average time to the lowest IgG level was 196 +/- 125 days. Patients with severe HGG were at increased risk of opportunistic infections compared to patients with IgG350 mg/dl (55% [6 of 11] vs. 5% [5 of 100], odds ratio = 22.8, p0.001). Compared to patients with no rejection, patients who experienced three or more episodes of rejection had lower mean IgG (580 +/- 309 vs. 751 +/- 325, p = 0.05), and increased incidence of severe HGG (33% [7 of 21] vs. 2.8% [1 of 35], p = 0.001). The incidence of rejection episodes per patient at 1 year was higher in patients with severe HGG compared to patients with IgG350 (2.82 +/- 1.66 vs. 1.36 +/- 1.45 episodes/patient, p = 0.02). The use of parenteral steroid pulse therapy was associated with an increased risk of severe HGG (odds ratio = 15.28, p0.001).Severe HGG after cardiac transplantation may develop as a consequence of intensification of immunosuppressive therapy for rejection and hence, confers an increased risk of opportunistic infections. IgG level may be a useful marker for identifying patients at high risk.

Purpose: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a limitation of this technique. Arterial wall cell proliferation is a component of restenosis preventable with intravascular brachytherapy. This study attempts to locate the sites of cellular proliferation after PTCA so as to aid the optimization of this therapy. Methods and Materials: Autopsy records from January 1, 1985 through December 31, 1995 were reviewed, and 27 patients who received PTCA prior to death were identified who also had evidence of PTCA on histologic examination of the arterial sections. The sections were subjected to immunohistochemical staining for proliferating cell nuclear antigen (PCNA) to detect the proliferating cells in the arterial sections, followed by image analysis to determine the proliferative index (PI) of all regions and layers of the section. Results: The PI did not differ significantly according to vessel region (plaque, plaque shoulder, or portion of vessel wall with lowest plaque burden), vessel layer (intima, media, adventitia), or evidence of prior PTCA. There was a trend toward a higher PI in young lesions. Conclusion: Cell proliferation in the vascular wall after PTCA was found throughout the treated arterial section’s axial plane, not only in the periluminal region.

ARVC is a cardiomyopathy in which the right ventricular myocardium is replaced by fibroadipose tissue. Males are affected slightly more often than females and, in those cases which are familial, the pattern of inheritance is usually autosomal dominant with incomplete penetrance. We examined the hearts of two sisters, ages 17 and 14, with no family history of heart disease. The older sibling, who was previously considered healthy, died suddenly, while the younger sibling developed congestive heart failure and received a cardiac transplant. An autopsy of the older sibling and examination of the younger sibling's excised heart revealed severe examples of ARVC with minor differences. A thick cap of fibroadipose tissue covered most, if not all, of each right ventricle and was transmural in some areas. Microscopically, left ventricles contained extensive myocyte disarray and multifocal fibrosis. The coronary arteries displayed intimal hyperplasia with disruption of the internal elastic lamina, similar to fibromuscular dysplasia. These two cases comprise a unique familial grouping in a polymorphic disease. Despite the male predominance and autosomal dominant inheritance in ARVC, the only members affected in this family were female, and an autosomal dominant pattern of inheritance, even with incomplete penetrance, would be unusual. In addition, we identified changes in the coronary arteries similar to fibromuscular dysplasia and corroborated recently reported changes in the left ventricle of patients with ARVC, providing evidence that this disease, in its most severe form, involves the entire heart.

Objective: Concern about the durability of small homograft cardiac valves has been expressed by surgeons, and evidence has been found that homograft valves evoke a recipient immune response. We reviewed our experience with homograft valves for evidence of rejection. Methods: A search of our files revealed 11 homograft cardiac valves removed at reoperation and one at autopsy. Six valves were from adults, five were from infants, and one was from a 13-year-old child. Immunohistochemical studies with antibodies against smooth muscle actin, CD20, CD43, CD34, and CD68 were performed on the homografts containing inflammatory infiltrates. These valves happened to be the valves from the five infants. These five valves were also stained with Gram and Gomori's methenamine silver stains. Results: The failed homografts from the adults and 13-year-old child showed leaflet calcification, fibrosis, and degeneration, but no inflammation. The valves from the infants all failed in less than 8 months. The valve leaflets were thickened, and the valve leaflets and aortic sleeves contained a hyperplastic intimal layer with numerous spindle cells positive for smooth muscle actin embedded in a glycosaminoglycan matrix. The homografts contained multiple foci of inflammation consisting of T lymphocytes (in all five infant valves) and B lymphocytes (in three of the five infant valves). Special stains for organisms were negative. Conclusions: Rapid failure plus lymphocytic infiltration in valve leaflets and aortic sleeves is consistent with rejection. The hyperplastic intima is similar to coronary arteries in transplant-associated vascular disease. Our observations are consistent with other reports of rapid failure of homograft valves in this age group. (J Thorac Cardiovasc Surg 1998;115;111-7)

This article reviews the theories regarding the causes of lymphocytic myocarditis, including viral and immunologic (cellular versus humoral) causes. Also covered is the relationship of dilated cardiomyopathy to myocarditis, the familial predilection for dilated cardiomyopathy in some cases, shortcomings of the various modalities for diagnosing lymphocytic myocarditis, and the occurrence of lymphocytic myocarditis in association with systemic illnesses. Lastly, treatment options for myocarditis are explored.

Background Allograft vasculopathy is a major risk factor for mortality following cardiac transplantation. Several immune and nonimmune factors have been evaluated as risk factors for the development of coronary vasculopathy. Objective We evaluated the influence of donor gender on the progression of coronary vasculopathy in heart transplant recipients. Methods Eighty-nine heart transplant recipients (67 men, 22 women of mean age: 56 ± 12 years) underwent serial volumetric intravascular ultrasound analysis (IVUS) at baseline (within 1 month) and at 1 year after transplantation. Patients were divided into four groups in relation to the donor–recipient gender status: female–female, n = 17; female–male, n = 28; male–female, n = 5; male–male, n = 39. Ultrasound images were recorded during an automated pullback and with an equal number of slices (average = 22 per coronary vessel). The measured IVUS indices for the left anterior descending artery were: change in maximal intimal thickness, average intimal area, total plaque volume, and intimal index. Results Patients were similar in baseline characteristics. At 1 year after transplantation, IVUS indices of coronary vasculopathy were significantly increased among recipients of female allografts ( P Conclusion Heart transplant recipients of female allografts display increased coronary vasculopathy progression.

To determine the incidence and morphologic features of acute vascular rejection (AVR) in cardiac transplant patients who have not received OKT3 induction therapy, we performed immunofluorescence (IF) staining for Clq and C3c on 341 endomyocardial biopsies from 135 patients. Each AVR biopsy, defined by positive IF, was further evaluated for C4c, C5, IgG, IgM, and IgA. Light and electron microscopy were also performed. The clinical features of each case were reviewed. A total of 29 biopsies from 6 recently transplanted patients (1993) and 10 biopsies from 4 long-term transplants (pre-1993) had IF evidence of AVR. All patients with AVR had linear vascular deposits of various complement components and immunoglobulins. Of the 6 recently transplanted patients, 4 were multiparous females. The male had a single episode of AVR. IF patterns were variable between and within patients. Clq and C3c were the most consistently detected complement components. IgM was the most frequently detected antibody. Of the 10 cases of AVR, 6 occurred within the first month post-transplant. Myocyte necrosis was present in all cases with cardiac dysfunction. Patients with early onset AVR had more recurrences and one fatality. There was one fatality in the long-term transplant group. Concomitant grades 0 to 4+ cellular rejection did not correlate with results of IF or clinical severity. The incidence of AVR in non-OKT3-treated patients is 7%. Of the early onset patients, 66% are multiparous females, indicating the possible importance of prior sensitization. IF patterns are not predictive of outcome. AVR may be asymptomatic, but early onset predicts a difficult clinical course and is detected only by IF screening.

Transplant-associated vascular disease (TAVD) is a major cause of late mortality after cardiac transplantation. To elucidate the evolution of TAVD, the autopsy histopathology of five cardiac allograft recipients who died ≥12 months posttransplantation was studied semiquantitatively. Vessel cross sections were analyzed for size, proliferative lesions, inflammation, lipid, and thrombi. The type of inflammatory cells in the vessels were characterized by immunohistochemistry, and the activation state of the vessel endothelium was characterized by immunohistochemistry for HLA-DR and inducible endothelial leukocyte adhesion proteins [endothelial leukocyte adhesion molecule-1 (SLAM-1) and vascular cell adhesion molecule-1 (VCAM-1)]. The mean posttransplantation interval was 27.2 months (range 12-40). TAVD was present in all five patients and was the cause of death in four of five. The percentage of vessels with proliferative lesions increased progressively with the duration of survival after transplantation. Both arteries and veins contained proliferative lesions, but more arteries than veins were involved at all time points. Large veins and large arteries had a significantly higher proportion of proliferative lesions than small veins (p < 0.04) and small arteries (p < 0.06), respectively. Inflammatory lesions were more prevalent in arteries than veins, 55.7% versus 10.9% (p < 0.001). The inflammatory vascular lesions were comprised principally of T lymphocytes, with smaller numbers of B lymphocytes and macrophages. The endothelium of arteries and veins expressed HLA-DR as well as VCAM-1, but stains for ELAM-1 showed only focal expression. By linear regression, intimal/medial inflammation decreased with time (r = -0.81, p < 0.06) and adventitial inflammation increased with time (r = +0.98, p < 0.001). Lipid-containing lesions were observed in 13.0% of arterial cross sections and were not seen in veins. Lipid containing arterial lesions increased progressively with both time and vessel size, but, in contrast to proliferative and inflammatory lesions, were not seen at any time interval in veins or small arteries. In summary, TAVD is an inflammatory and proliferative process that involves arteries more than veins, and is more prevalent in large vessels and at greater posttransplantation intervals. Vascular T cell inflammation, intimal proliferation, and an activated endothelial cell phenotype appear to be closely related in the development of TAVD.

As the ages of patients undergoing cardiac operations have increased, noncardiac causes of death have increased. To identify these causes of death, we analyzed the autopsy findings in 221 patients undergoing myocardial revascularization or valve operations between 1982 and 1989. Mean age was 65.6 ± 9.5 years and the range was from 32 to 94 years; 130 patients (58.8%) were male. Autopsies were complete in 129 patients (58.4%) and limited to the chest and abdomen in the remainder. Embolic disease was identified in 69 patients (31.2%). Atheroemboli or abnormalities consistent with atheroemboli were identified in 48 patients (21.7%). Fourteen patients had thromboembolism and 7 had disseminated intravascular coagulation. The prevalence of atheroembolic disease increased dramatically from 4.5% in 1982 to 48.3% in 1989 (p = 0.001). Atheroembolic disease was found in the brain in 16.3% of patients, spleen in 10.9%, kidney in 10.4%, and pancreas in 6.8%. Thirty (62.5%) of the 48 patients had multiple atheroembolic sites. Atheroemboli were more common in patients undergoing coronary artery procedures (43/165; 26.1%) than in those undergoing valve procedures (5/56; 8.9%) (p = 0.008). There was a high correlation of atheroemboli with severe atherosclerosis of the ascending aorta. Atheroembolic events occurred in 46 of 123 patients (37.4%) with severe disease of the ascending aorta but in only 2 of 98 patients (2%) without significant ascending aortic disease (p horac C ardiovasc S urg 1992;103:1104-12)

The influence of coronary artery stenoses on patient survival and event-free survival is known, but no studies have reported the long-term outcome of patients with stenoses in saphenous vein bypass grafts. We retrospectively studied 723 patients who underwent a postoperative angiographic study that documented a stenosis of 20% to 99% in at least one saphenous vein graft and who did not undergo reoperation or percutaneous transluminal coronary angioplasty within 1 year after that catheterization. The mean follow-up interval was 83 months (range 1 to 237 months). For comparison, a group of 573 patients who underwent a postoperative catheterization that did not show any vein graft stenosis were also followed up. Cox regression analyses were used to identify predictors of late survival, reoperation-free survival, and event-free survival. For the entire group of patients with stenotic vein grafts, moderate or severe impairment of left ventricular function (p less than 0.001), interval between operation and catheterization (p less than 0.001), older age (p = 0.001), triple-vessel or left main coronary artery disease (p = 0.004), and stenosis of the vein graft to the left anterior descending coronary artery (p = 0.09) were associated with decreased late survival. Patients with an operation-to-catheterization interval greater than or equal to 5 years were at particularly high risk, and multivariate analyses of that subgroup confirmed that a stenotic graft to the left anterior descending artery was a strong predictor of decreased survival (p less than 0.001), decreased reoperation-free survival (p less than 0.001), and decreased event-free survival (p less than 0.001). Patients greater than or equal to 5 years postoperatively with greater than or equal to 50% stenosis of vein grafts to the left anterior descending artery had survival of 70% and 50% at 2 and 5 years after catheterization, compared with 97% and 80% for those with greater than or equal to 50% stenosis of the native left anterior descending artery (p = 0.002). Late vein graft stenoses are more dangerous than native coronary stenoses. Late stenoses in saphenous vein grafts to the left anterior descending coronary artery predict a high rate of death and cardiac events and are an indication for reoperation.

Three nonelderly patients without hypertension whose clinical and radiologic features otherwise resembled Binswanger's subcortical arteriosclerotic encephalopathy underwent biopsy of the hyperintense periventricular lesions seen on magnetic resonance imaging. The pathologic findings of the periventricular lesions consisted of gliosis with mild rarefaction and edema of the white matter. All patients had a sclerosing vasculopathy of unknown cause, which involved numerous small vessels within the periventricular lesions. The vessels stained negatively for amyloid, amyloid precursors, desmin, vimentin, keratin, immunoglobulin, and complement. On electron microscopy, small arteries, arterioles, venules, and capillaries were characterized by swollen astrocytic foot processes surrounding the vessels; dense, perivascular collagen packing; crystalline arrays of filaments within basement membrane; giant lipid-laden lysosomes within perivascular cells; and narrowing of the vascular lumina. Similar changes were not seen in a control group of 19 patients. The pathologic features of the vessels in these cases are distinct from the vasculopathy associated with Binswanger's subcortical arteriosclerotic encephalopathy. We suggest that a spectrum of vasculopathies may be associated with dementia and periventricular hyperintense lesions on magnetic resonance imaging.

Cardiac amyloidosis typically presents with diastolic heart failure, but asymmetrical septal hypertrophy with outflow tract obstruction has been described. We illustrate the case of a 71-year-old woman with biopsy-proven cardiac amyloidosis and severe medical comorbidities with refractory severe heart failure who had asymmetric septal hypertrophy, systolic anterior motion (SAM) of the mitral valve, and a resting left ventricular outflow tract gradient of 86 mm Hg, increasing to 102 mm Hg on Valsalva maneuver. She underwent percutaneous transluminal septal myocardial ablation (PTSMA) with a dramatic resolution of her SAM and outflow tract obstruction, confirmed by intracavitary pressure wire measurements. PTSMA is technically feasible in this context, and correction of outflow tract obstruction may represent a new therapeutic target in cardiac amyloidosis.

Schwannoma is a slow growing solitary tumor that preferentially involves spinal nerve roots, and sympathetic, cervical, and vagus nerves. There are several clinico-pathologic variants of schwannoma, including schwannoma with a degenerative change (ancient schwannoma), cellular schwannoma, plexiform schwannoma, epithelioid schwannoma, and melanotic schwannoma. About 10% of cases of schwannomas are associated with multi-system disorders such as neurofibromatosis, schwannomatosis, multiple meningiomas, and Carney complex. Schwannoma rarely present as an intraocular tumor and is often misdiagnosed as malignant melanoma. Immunohistochemical positivity with S-100 stain and demonstration of long-spaced collagen (Luse bodies) are helpful in establishing the diagnosis. In this article, we review the clinical and histopathological findings of a sporadic plexiform pigmented schwannoma involving the iris, ciliary body, and the choroid.

Objectives We evaluated the impact of spontaneous intracranial bleeding (ICB) in the donor on transplant coronary vasculopathy using serial intravascular ultrasound examinations. Materials and methods Between January 1995 and December 2000, 72 recipients underwent cardiac transplantation from donors who had experienced spontaneous ICB (ICB group). Their findings using serial intravascular ultrasound analysis at baseline (within 1 month) and 1 year after transplantation were compared with 90 recipients who had undergone transplantation from trauma donors (trauma group). Results Compared with the Trauma group, the ICB group showed increased coronary intimal thickness (0.55 ± 0.33 vs 0.39 ± 0.3 mm; P = .034), plaque volume (3.84 ± 2.5 vs 2.28 ± 1.65 mm 3 ; P = .015) and plaque burden (7.4 vs 2%) at 1 year after transplantation. Conclusions Donor spontaneous ICB is associated with significantly increased coronary vasculopathy.

Background Cardiac allografts from female donors have been shown to be associated with increased risk of transplant vasculopathy. However, the influence of donor gender on peri-transplantation ischemic injury has not been evaluated. Methods A total of 361 patients (mean age, 52 ± 10 years) underwent cardiac transplantation between January 1998 and December 2002. Patients were divided into 4 groups according to their donor–recipient gender status: Group A, male–male, 156; Group B, male–female, 37; Group C, female–male, 114; and Group D, female–female, 54. Serial right ventricular endomyocardial biopsy specimens were evaluated for ischemic injury during the first 4 weeks after transplantation. Results Patients were similar in baseline characteristics. An increased incidence of ischemic injury complicated by fibrosis (12.9%, p = 0.03) and subsequent development of transplant vasculopathy (Kaplan-Meier 6-year freedom from vasculopathy, 53.4%; p = 0.012) was noted in Group D. No survival difference was observed among the 4 groups, however. In Group D (F–F), 2 patients underwent retransplantation and 2 patients underwent revascularization. Conclusions The transplantation of a female cardiac allograft into a female recipient is associated with increased risk of ischemic injury complicated by fibrosis and subsequent transplant vasculopathy.

Background We have previously shown that the preemptive use of cytomegalovirus (CMV) immunoglobulin (Ig) replacement (CytoGam) decreases the incidence of opportunistic infections in cardiac transplant recipients with severe hypogammaglobulinemia. However, the impact of Ig replacement in moderately hypogammaglobulinemic patients is unknown. Methods Periodic monitoring of the IgG levels was done in 300 heart transplant recipients. Moderate hypogammaglobulinemia (IgG, 350–500 mg/dl) developed in 56 patients (18.6%). Thirty-three patients declined randomization but agreed to have their IgG levels monitored. Twenty-three patients were randomized to placebo ( n = 10) or CytoGam ( n = 13) at 105 ± 63 days after transplantation. Results The baseline characteristics were similar. A significant reduction in CMV infection was noted in the CytoGam Group compared with the Placebo Group (15.4% [2/13] vs 60% [6/10], p = .039). Among patients who declined randomization, CMV infection developed in 13 (39.4%) of 33, and 6 (46.1%) of the 13 progressed to severe hypogammaglobulinemia. A trend for reduction in the average episodes of ≥grade 2 rejection during the 6-month period after randomization was noted in the CytoGam group (0.4 ± 0.6 vs 1.4 ± 1.3, p = 0.065). Conclusions The preemptive use of CytoGam decreases the incidence of CMV infection in patients with moderate hypogammaglobulinemia. A larger randomized study is needed to substantiate these results.

Recipients of hearts from donors with spontaneous intracerebral hemorrhage (ICH) are at increased risk of allograft vasculopathy compared with trauma donors. We have recently shown that the vitronectin receptor (integrin alpha(V)beta3) is upregulated in transplant vasculopathy. We hypothesized that donor ICH is associated with systemic activation of alpha(V)beta3 in the donor before transplantation.We evaluated mRNA expressions of alpha(V)beta3 (TaqMan PCR) in endomyocardial biopsy samples at 1-week post-transplant in 20 recipients from ICH donors and 20 recipients from trauma donors. To investigate whether systemic activation of alpha(V)beta3 was present in the donor before transplantation, alpha(V)beta3 expression was also evaluated in the corresponding donor spleen lymphocytes. All patients underwent serial coronary intravascular ultrasound to evaluate for coronary vasculopathy. The baseline characteristics were similar except for increased donor age in the ICH Group.The ICH Group showed significant increased mRNA expression of alpha(V)beta3 in the heart biopsy samples (3.8-fold, p = 0.012) and in the corresponding donor spleen lymphocytes (3.5-fold, p = 0.014) compared with the Trauma Group. At 1 year, the ICH Group also showed increased progression of coronary vasculopathy. Multivariate regression analysis found that donor lymphocytic alpha(V)beta3 mRNA expression was independently associated with increased risk of vasculopathy (odds ratio, 1.9; 95% CI, 1.21-3.98, p = 0.03).Our report demonstrates the presence of systemic activation of alpha(V)beta3 in donors with spontaneous intracerebral hemorrhage and its association with the subsequent development of allograft vasculopathy in the recipient.

Donor cause of death has been suggested to have a significant impact on cardiac transplant morbidity and mortality. Our objective was to evaluate the impact of donor spontaneous intracranial bleeding on clinical outcome after heart transplantation. A group of 160 recipients underwent cardiac transplantation from donors with spontaneous intracranial bleeding (ICB group). These were compared with 197 recipients who were transplanted from trauma donors (Trauma group). A higher 4-year mortality rate was noted in the ICB group (24% vs. 14%, p=0.015). ICB as a cause of donor death was an independent predictor of recipient mortality (adjusted hazard ratio 2.02, 95% CI 1.27-3.40, p

Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophy in vitro. In this report, we present data on the pathophysiological significance of myotrophin in vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophy versus transition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.

We describe the first case of prosthetic valve endocarditis due to a Streptomyces sp. The patient presented with fever, cutaneous embolic lesions, and bacteremia 3 months after aortic valve replacement. Treatment required valve replacement and a long course of parenteral imipenem.

Fifty-five patients with cardiac allografts were studied by electron beam computed tomography for coronary calcification (EBCT CC) and coronary arteriography, and from the latter, a coronary index was calculated using the size, degree of obstruction, and linear extent of disease of each vessel. There was a significant correlation between EBCT CC score and coronary index, but receiver-operating characteristic (ROC) analysis demonstrated unsatisfactory performance of EBCT CC, and 6 patients had no coronary calcification despite having very abnormal coronary indexes. There are pathologic differences between coronary allograft vasculopathy and atherosclerosis, and correspondingly, EBCT CC has limited usefulness in the cardiac transplant population.

Aims We tested the hypothesis that cardiac angiotensin II (Ang II) receptor gene transcription may predict the development of transplant coronary artery disease (TCAD) following heart transplantation. Methods and results We examined the gene transcripts of Ang II type 1 (AT1R) and type 2 receptors (AT2R) in endomyocardial biopsy specimens from 50 heart transplant recipients. The progression of TCAD was measured as change in maximal intimal thickness (CMIT) and change in plaque volume (CPV) by intravascular ultrasound (IVUS) examinations from baseline to one year after transplantation. The development of transplant vasculopathy was defined as a CMIT of ⩾0.3 mm over one year. The level of AT1R mRNA was associated with that of AT2R in transplanted hearts (regression coefficient=1.77, 95% CI 0.85–2.89, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P{

Bioprosthetic heart valves used to replace both the mitral and aortic valves in humans have a life span of 10-15 years. We performed uniaxial tensile tests on explanted failed porcine bioprostheses that came from both the mitral and aortic position and freshly fixed porcine aortic valves (PAV). The results showed that the explants had significantly different mechanical properties from the freshly fixed PAV. Comparison of explants from the mitral and aortic positions revealed no differences. The changes measured in the bioprostheses indicate that they have lost some of their elasticity as well as their ultimate strength.

It is unclear how the process of myxomatous disease leads to mitral valve regurgitation. We performed mechanical and biochemical tests to measure the differences between leaflets and chordae from myxomatous and normal human mitral valves. Uniaxial tensile tests and assays for uronic acid (glycosaminoglycans or GAGs) indicated that the myxoid tissues were more extensible, had lower stiffness and failure strength, and increased GAG concentration. Additional DNA assays suggest that the cells in myxoid valves are producing higher levels of GAGs than normal. Furthermore, all differences between the myxoid and normal tissues were far more pronounced in the chordae than in the leaflets. These findings support reported observations that myxoid-related chordal rupture is the leading cause of mitral valve regurgitation.

Previous studies of the association between acute cellular rejection and cardiac allograft vasculopathy (CAV) have yielded conflicting conclusions. We explored a possible association between acute cellular rejection and the extent of CAV, and we found a potential confounding variable that may obscure such an association.We investigated 140 patients (mean age, 51 +/- 11 years) who underwent serial intravascular ultrasound examinations at baseline and at 1 year after heart transplantation to assess CAV as change in maximal intimal thickness (CMIT). Patients were classified according to the presence or absence of biopsy-proven myocardial fibrosis. We used a standard biopsy-scoring system and a novel biopsy-scoring system, developed in our institution, to assess acute cellular rejection. Using univariate analysis, we found that CMIT was not associated with acute cellular rejection in the overall patient population (n = 140). However, we observed a correlation between CMIT and acute cellular rejection (standard method, r = 0.30, p = 0.01; novel method, r = 0.51, p0.0001) in patients who had no evidence of ischemic injury or fibrosis in their biopsy specimens (n = 57). Step-wise multiple regression showed that the rejection score derived from our novel method was associated more closely with the CMIT than was that derived from the traditional method.This data indicate that the presence of myocardial fibrosis masks an actuarial association between acute cellular rejection and the development of de novo allograft vasculopathy. As previously suspected, myocardial fibrosis is a marker for non-immune-mediated graft injury independently associated with an increased incidence of CAV.

A cascade of inflammatory reactions characterize acute vascular rejection after heart transplantation. This study was undertaken to test the hypothesis that acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system.Acute vascular rejection developed in 14 heart transplant recipients within 2 weeks of transplantation, confirmed by immunofluorescence (AVR group). We compared these patients with 10 transplant recipients who had no evidence of acute vascular rejection or peritransplant ischemic injury (control group). We evaluated endomyocardial biopsy specimens for alphavbeta3, tissue factor, and extracellular matrix metalloproteinase inducer (EMMPRIN).Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of alphavbeta3 (1.9-fold, p0.001), tissue factor (1.8-fold, p0.001), and EMMPRIN (1.5-fold, p0.001). All patients in the AVR group received plasmapheresis; 11 of 14 patients had evidence of ischemic necrosis on biopsy specimens, and 3 of 14 patients experienced hemodynamic compromise and graft dysfunction and died within 3 weeks of transplant. Another patient died at 10 months after transplant.Acute vascular rejection is associated with up-regulation of alphavbeta3, tissue factor, and activation of the matrix metalloproteinase induction system, which may contribute to the lethal morbidity associated with this disease.

Background— Cardiac allograft vasculopathy (CAV) limits the long-term success of cardiac transplantation. The incidence of CAV is increased in patients with elevated plasma levels of oxidized lipids or fibrin deposition within right heart biopsy (RHB) specimens. The present study investigated whether tissue factor (TF), the expression of which is regulated by oxidized lipids, is upregulated in patients with CAV. Methods and Results— A TF score was developed to quantify TF expression in RHB specimens from 63 consecutive patients undergoing routine annual posttransplantation RHB and coronary angiography. In patients >2 years (3.0±0.8 years) posttransplantation (n=35), a high TF score was observed with greater frequency (75% versus 26%, P Conclusions— These data demonstrate that early TF expression predicts subsequent development of CAV. Increased TF expression could link the elevated levels of oxidized LDL and fibrin deposition known to precede CAV. These findings suggest that TF may play a role in the pathophysiology of CAV and could offer a potential prognostic tool and a novel target for the prevention of CAV, possibly with antioxidants or inhibitors of the TF pathway.

Background Allograft coronary vasculopathy results from a complex interplay between immunologic and non-immunologic factors. We devised a computerized biopsy scoring method based on histopathology to predict the development of coronary vasculopathy. Methods One hundred forty heart transplant recipients underwent serial intravascular ultrasound analysis at baseline (within 1 month) and at 1 year after transplantation and were evaluated for development of coronary vasculopathy (change in coronary maximal intimal thickness, CMIT). We evaluated serial endomyocardial biopsy specimens for cellular rejection, vascular rejection, ischemia, and fibrosis. In a mathematical model, we computed a biopsy score in each patient based on the duration and severity of histopathology. Results We found a significant correlation between biopsy score (RY) and progression of coronary vasculopathy ( r = 0.54, p = 0.001). Using a sensitivity analysis method, an RY value of ≥560 predicted development of coronary vasculopathy with a sensitivity of 86%, specificity of 62%, and diagnostic accuracy of 80%. Compared with patients with low-risk biopsy scores (RY n = 37), patients with high-risk biopsy scores (RY ≥ 560, n = 103) had increased progression of coronary vasculopathy (CMIT, 0.59 ± 0.29 vs 0.19 ± 0.10 mm, p p = 0.01). Conclusion The biopsy score is an effective method for predicting the development of coronary vasculopathy and for predicting outcome in cardiac transplant recipients.

Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation necessitating surgical correction. Unileaflet prolapse (ULP), usually involving the posterior leaflet, is more common than bileaflet prolapse (BLP), which is more difficult to repair. Little is known about clinical, echocardiographic, and biomechanical differences between ULP and BLP. In this study, biomechanical testing was performed on mitral valve leaflets and chordae obtained at operation for severe mitral regurgitation. Preoperative clinical characteristics and echocardiographic measurements were obtained on surgical patients (ULP = 88, BLP = 37). Men outnumbered women by a factor of 4:1 in ULP, and by 3:1 in BLP. Patients with BLP were younger (53.2 +/- 1.7 vs 59.5 +/- 1.1 years) than those with ULP, and this difference was greater in women (48.9 +/- 2.5 vs 62.9 +/- 2.2 years). BLP patients were less likely to be hypertensive, and more likely to undergo valve replacement rather than repair. Echocardiography showed that BLP leaflets were longer and thicker than ULP leaflets. The severity of mitral regurgitation was similar in both groups, although ULP patients had a much higher incidence of flail leaflets (45% vs 5% in BLP). Mechanical strength of chordae was greater in BLP than in ULP, although leaflet strength was similar. The increased chordal strength in BLP may be responsible for less flail. In patients with MVP and severe mitral regurgitation requiring surgery, ULP and BLP are distinct entities with substantial differences in the population affected, in echocardiographic manifestations including prevalence of flail, in chordal mechanics, and in the likelihood of surgical repair.

Background — Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy. Methods and Results — Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection ( P =0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, P =0.002), lower mean episodes of acute rejection (≥ grade 2) during the first 3 months of transplant (1.09±0.66 versus 1.86±1.6, P =0.048), and more common vasculopathy at 2 years (50% versus 15%, P =0.02), and they tended to have worse survival (83.2% versus 100%, P =0.058). Conclusions — Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.