Non-invasive detection of cardiac allograft rejection among heart transplant recipients using an electrocardiogram based deep learning model.

Aims: Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG). Methods and results: Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set (n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study (n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity. Conclusion: An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function.

Upregulation of Endothelin-1 May Predict Chemotherapy-Induced Cardiotoxicity in Women with Breast Cancer.

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Preoperative risk factors for mortality after biventricular assist device implantation.

BACKGROUND: A right ventricular assist device is a treatment option for patients with severe right ventricular failure after left ventricular assist device (LVAD) implantation. Recognition of risk factors for mortality after biventricular assist device (BiVAD) implantation is important for patient selection and optimal outcomes. METHODS: We reviewed our experiences between 1991 and 2005 in 44 patients who were supported by both an LVAD and a right ventricular assist device. RESULTS: Thirteen patients (30%) survived until heart transplantation, and 31 patients (70%) died while on support. The multivariate analysis shows that post-LVAD extracorporeal membrane oxygenation and worsening renal function are associated with the highest postoperative mortality. The univariate analysis also included previous thoracic surgery and ischemic cardiomyopathy as potential preoperative indicators for poor outcome after BiVAD implants. No differences were observed in the rates for the need of preoperative support with a ventilator, an intra-aortic balloon pump, or extracorporeal membrane oxygenation, or in the rates of postoperative complications between survivors and nonsurvivors. CONCLUSIONS: BiVAD implantation remains one of the challenges in treating severe heart failure. Previous cardiac surgery, elevated creatinine, and post-LVAD extracorporeal membrane oxygenation were risk factors for mortality after BiVAD implantation. Dialated Cardiomyopathy on the other hand was associated with a more favorable outcome.

Transplant vasculopathy is associated with increased AlloMap gene expression score.

The AlloMap gene expression test is used for the non-invasive detection of rejection in heart transplant recipients. We evaluated the impact of transplant vasculopathy on AlloMap gene expression analysis. A total of 69 heart transplant recipients, mean age 53 years, were evaluated at a mean 35 months post-transplant. AlloMap score was determined on the same day of the endomyocardial biopsies. Twenty patients had evidence of vasculopathy by coronary angiography (vasculopathy group). These were compared to the remaining 49 patients (control group). The vasculopathy group had a longer mean follow-up duration (48.7 vs 28.8 months, p < 0.01), lower left ventricular ejection fraction (51% vs 60%, p < 0.01) and increased use of sirolimus (40% vs 16%, p = 0.034) compared with controls. Using the logistic regression model and bagging bootstrap approach to adjust for the time factor and potential confounders, the vasculopathy group had a significantly higher AlloMap score than the control group (32.2 +/- 3.9 vs 26.1 +/- 6.5, p < 0.001). There was a correlation of AlloMap score with time after transplantation (r = 0.31, p = 0.01). We found transplant vasculopathy to be associated with increased AlloMap score.

Increased expression of angiotensin II type 1 receptor (AGTR1) in heart transplant recipients with recurrent rejection.

BACKGROUND: Angiotensin II receptor sub-type 1 (AGTR1) plays an important role in the regulation of the cellular immune process. We hypothesized that recurrent acute rejection is associated with increased gene expression of AGTR1 in human heart transplantation. METHODS: We identified a group of 14 heart transplant recipients who had recurrent acute cellular rejection (RAR), defined as three consecutive episodes of acute rejection (Grade > or =3A). These patients were matched to a control group (n = 15). mRNA gene expression of AGTR1 was measured in heart biopsy specimens of controls at 1 week post-transplant. AGTR1 mRNA was determined serially in the RAR group at baseline, each rejection episode, and after resolution of rejection. Angiotensin-converting enzyme (ACE) polymorphism was also evaluated. RESULTS: Both the control and RAR groups had similar mRNA AGTR1 expression at baseline. Compared with baseline, the RAR group had significantly increased mRNA expression of AGTR1 at the first episode of rejection (9-fold, p < 0.001), which increased further at the second episode (12-fold, p < 0.001) and peaked at the third episode (35-fold, p < 0.001). After resolution of rejection, AGTR1 expression was decreased significantly (p < 0.001), but remained elevated above baseline (6-fold, p < 0.001). No difference in ACE polymorphism was noted between the two groups. Compared with controls, the RAR patients had an increased incidence of hypertension, diabetes mellitus, chronic renal insufficiency and transplant vasculopathy during a mean follow-up period of 51.5 +/- 12 months. CONCLUSIONS: This is the first report to describe increased mRNA expression of AGTR1 in response to recurrent cellular rejection. Up-regulation of AGTR1 responds to treatment of rejection but not to complete recovery, a phenomenon that may potentially explain the link between rejection and subsequent clinical outcome.

Improved survival after acute myocardial infarction complicated by cardiogenic shock with circulatory support and transplantation: comparing aggressive intervention with conservative treatment.

BACKGROUND: The prognosis for patients with myocardial infarction has steadily improved, but remains poor for those developing cardiogenic shock. Utilization of re-vascularization, mechanical circulatory support and transplantation in these patients may improve survival. METHODS: We retrospectively analyzed the clinical outcome of 138 consecutive patients at the Cleveland Clinic from 1992 to 1998 who met the criteria for cardiogenic shock after acute myocardial infarction. All patients received intensive medical therapy and intra-aortic balloon pump support. Forty-three patients received intensive medical therapy (conservative group) and 95 patients were treated aggressively (aggressive group). The aggressive group comprised patients who were treated with percutaneous intervention/coronary artery bypass grafting (n = 77, re-vascularization group), and patients who received circulatory support/cardiac transplantation (n = 18). RESULTS: The baseline demographics and angiographic and hemodynamic features were comparable for the two groups. The in-hospital mortality rate was significantly reduced in the aggressive group compared with the conservative group (54% vs 81%, p = 0.002). The in-hospital mortality rate of the circulatory support/transplant group was markedly reduced compared with the conservative group (33% vs 81%, p < 0.001), and was also significantly lower than that of the re-vascularization group (33% vs 63%, p= 0.03). The aggressive group had a markedly improved 5-year survival compared with the conservative group (30% vs 6.2%, p = 0.003). CONCLUSIONS: These data suggest that an aggressive strategy, particularly left ventricular assist device support as a bridge to heart transplantation, may improve survival in post-myocardial infarction patients with cardiogenic shock.

The impact of donor gender on cardiac peri-transplantation ischemia injury.

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.

Peritransplant ischemic injury is associated with up-regulation of stromal cell-derived factor-1.

OBJECTIVES: We evaluated chimerism and stromal cell-derived factor-1 (SDF-1) expression in response to peritransplant ischemic injury following human heart transplantation. BACKGROUND: Myocardial ischemia has been shown to trigger mobilization of stem cells to the heart in animal experiments. METHODS: Between January 1998 and April 2002, a total of 114 male recipients received hearts from female donors. Of these 114 recipients, 26 had evidence of ischemic injury on their initial heart biopsies (ischemia group). These were compared to the remaining 88 patients (control group). Heart biopsy specimens obtained initially at one week and at one year after transplant were evaluated from 20 matched patients of each group for the presence of Y chromosome-containing nuclei. The SDF-1 messenger ribonucleic acid (mRNA) and protein expression were also evaluated on initial heart biopsy specimens. RESULTS: At one week, Y chromosome-containing nuclei were significantly increased in the ischemia group (0.68% vs. 0.04%; p < 0.0001) compared to the control group. These were positive for the stem cell factor receptor c-kit. A significant 3.3-fold increased mRNA expression (p = 0.001) and 2.8-fold increased protein expression (p = 0.01) of SDF-1 was noted in the ischemia group. At one year, Y chromosome was detected in 0.29% of cardiomyocyte nuclei in the ischemia group but none in the control group. The ischemia group had poorer survival and increased vasculopathy. CONCLUSIONS: This is the first report to describe chimerism and up-regulation of SDF-1 in human heart transplantation in response to ischemic injury.

Systemic activation of integrin alphaVbeta3 in donors with spontaneous intracerebral hemorrhage is associated with subsequent development of vasculopathy in the heart transplant recipient.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Systemic up-regulation of angiotensin II type 1 receptor in cardiac donors with spontaneous intracerebral hemorrhage.

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.

Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease.

OBJECTIVES: We evaluated whether the angiotensin II (Ang II) receptors from perioperation through one-year post-transplantation predict the transplant coronary artery disease (TCAD) progression. BACKGROUND: The role of Ang II receptors (type 1: AT(1)R; type 2: AT(2)R) in TCAD is uncertain. METHODS: We investigated 28 heart donors and the corresponding recipients. The levels of AT(1)R and AT(2)R messenger ribonucleic acid (mRNA) were examined in lymphocytes from the donor spleen and in the donor heart at one-week and one-year posttransplantation to determine their association with the progression of TCAD, measured as changes in maximal intimal thickness (CMIT) and plaque volume (CPV) by intravascular ultrasound (IVUS) examinations. RESULTS: The AT(1)R mRNA in lymphocytes from the donor spleen (CMIT: r = 0.73, p < 0.0001; CPV: r = 0.69, p < 0.0001) and in the donor hearts at one-week (CMIT: r = 0.52, p = 0.005; CPV: r = 0.56, p = 0.002) and at one-year (CMIT: r = 0.63, p < 0.0001; CPV: r = 0.43, p = 0.004) post-transplantation along with AT(2)R mRNA in the donor hearts at one-year post-transplantation (CMIT: r = 0.3, p < 0.0001; CPV: r = 0.53, p = 0.009) were univariate predictors, whereas AT(1)R mRNA in lymphocytes and in the donor hearts at one-year post-transplantation proved to be multivariate predictors of the progression of TCAD. CONCLUSIONS: These data suggest a role for Ang II receptors in the pathogenesis of TCAD and support a novel concept that TCAD may have its origin in the donor per se and may be modulated by the recipient's inherent biological factors.

Cardiac angiotensin II receptors as predictors of transplant coronary artery disease following heart transplantation.

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 > or = 0.3 mm over one year. The level of AT(1)R mRNA was associated with that of AT2R in transplanted hearts (regression coefficient=1.77, 95% CI 0.85-2.89, p<0.0001). AT1R and AT2R gene transcripts were univariate predictors of CMIT (AT1R: regression coefficient 0.10, 95% CI 0.06-0.14, p<0.0001; AT2R: regression coefficient 0.28, 95% CI 0.17-0.40, p<0.0001 ) or CPV (AT1R: regression coefficient 0.41, 95% CI 0.17-0.65, p<0.0001 ; AT2R: regression coefficient 1.25, 95% CI 0.49-2.01, p=0.002 ). By one year, 21 (46%) transplant recipients showed evidence of transplant vasculopathy and the rest did not. The vasculopathic group demonstrated a higher level of expression of cardiac AT1R than the non-vasculopathic group (3.7+/-2.9 vs 1.6+/-1.7 folds; p=0.006). The level of AT(1)R mRNA in transplanted heart was identified as a discriminator that predicted the development of transplant vasculopathy with a sensitivity of 75% and specificity of 83%. CONCLUSIONS: Cardiac Ang II receptor gene transcripts are associated with the progression of TCAD following heart transplantation. Only AT1R gene transcripts predicted the development of transplant vasculopathy in this preliminary study. These findings potentially support a role of Ang II receptors in the progression of TCAD following cardiac transplantation.

Does acute cellular rejection correlate with cardiac allograft vasculopathy?

BACKGROUND: 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. METHODS: 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, p < 0.0001) 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. CONCLUSIONS: 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.

Impact of donor spontaneous intracranial hemorrhage on outcome after heart transplantation.

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<0.0001). Compared with the Trauma group, the ICB group had an increased incidence of post-transplant graft dysfunction during the first week of transplant (10% vs. 3%, p=0.007), and higher incidence of interstitial myocardial fibrosis on their endomyocardial biopsies within 4 weeks of transplant (21% vs. 9%, p=0.0012). There was a trend towards an increased rate of allograft vasculopathy in the ICB group (competing risks adjusted hazard ratio 1.39, 95% CI 0.90-2.13, p = 0.14).

Sustained apoptosis in human cardiac allografts despite histologic resolution of rejection.

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.

Quilty lesions are associated with increased expression of vitronectin receptor (alphavbeta3) and subsequent development of coronary vasculopathy.

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 (alphavbeta3) 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 alphavbeta3, using immunohistochemistry staining and immunoblotting. RESULTS: Quilty lesions stained positive for alphavbeta3, and Western blot analysis showed a 1.3-fold (p = 0.004) increase in expression of alphavbeta3. 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 alphavbeta3 expression.

Chemokine and chemokine receptor gene expression indicates acute rejection of human cardiac transplants.

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)-gamma 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), 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

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.

BACKGROUND: 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. METHODS: 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). RESULTS: Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of alphavbeta3 (1.9-fold, p < 0.001), tissue factor (1.8-fold, p < 0.001), and EMMPRIN (1.5-fold, p < 0.001). 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. CONCLUSIONS: 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.

Computerized scoring of histopathology for predicting coronary vasculopathy, validated by intravascular ultrasound.

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 > or =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 < 560, n = 37), patients with high-risk biopsy scores (RY > or = 560, n = 103) had increased progression of coronary vasculopathy (CMIT, 0.59 +/- 0.29 vs 0.19 +/- 0.10 mm, p < 0.001) and worse 7-year event-free survival (60% vs 91%, 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.