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Biomedical subjects

James B Young

Publications and source records attributed to James B Young.

At least 19 recordsLinked to original sources
PubMed2003

Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient.

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<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (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.

Adult↗
PubMed2003

Importance of mitral valve repair associated with left ventricular reconstruction for patients with ischemic cardiomyopathy: a real-time three-dimensional echocardiographic study.

BACKGROUND: Left ventricular (LV) reconstruction surgery leads to early improvement in LV function in ischemic cardiomyopathy (ICM) patients. This study was designed to evaluate the impact of mitral valve (MV) repair associated with LV reconstruction on LV function 1-year after surgery in ICM patients assessed by real-time 3-dimensional echocardiography (3DE). METHODS AND RESULTS: Sixty ICM patients who underwent the combination surgery (LV reconstruction in 60, MV repair in 30, and revascularization in 52 patients) were studied. Real-time 3DE was performed and LV volumes were obtained at baseline, discharge, 6-month and >or=12-month follow-up. Reduction in end-diastolic volumes (EDV) by 29% and in end-systolic volumes by 38% were demonstrated immediately after surgery and remained at subsequent follow-up (P<0.0001). The LV ejection fraction significantly increased by about 10% at discharge and was maintained >or=12-month (P<0.0001). Although the LV volumes were significantly larger in patients with MV repair before surgery (EDV, 235+/-87 mL versus 193+/-67 mL, P<0.05), they were similar to LV volumes of the patients without MV repair at subsequent follow-ups. However, the EDV increased from 139+/-24 mL to 227+/-79 mL (P<0.01) in 7 patients with recurrent mitral regurgitation (MR). Improvement in New York Heart Association functional class occurred in 81% patients during late follow-up. CONCLUSIONS: Real-time 3DE demonstrates that LV reconstruction provides significant reduction in LV volumes and improvement in LV function which is sustained throughout the 1-year follow-up with 84% cardiac event free survival. If successful, MV repair may prevent LV redilation, while recurrent MR is associated with increased LV volumes.

Echocardiography, Three-Dimensional↗
PubMed2003

Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure.

OBJECTIVES: We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF). BACKGROUND: Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF. METHODS: In a double-blind fashion, 292 patients (cardiac index < or =2.5 l/min per m(2) and pulmonary capillary wedge pressure (PCWP) > or =15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured. RESULTS: After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m(2) with 50 and 100 mg/h and -3.9 mm Hg for each dose, respectively; p < 0.0001). This effect was maintained during the remaining infusion and for > or =6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related. CONCLUSIONS: Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h.

Aged↗
PubMed2003

Chemokine and receptor-gene expression during early and late acute rejection episodes in human cardiac allografts.

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.

Acute Disease↗
PubMed2003

Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial.

CONTEXT: Cardiac resynchronization therapy (CRT) through biventricular pacing is an effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown. OBJECTIVE: To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, parallel-controlled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high risk of life-threatening ventricular arrhythmias, and in NYHA class III (n = 328) or IV (n = 41) despite optimized medical treatment. INTERVENTIONS: Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on). MAIN OUTCOME MEASURES: The primary double-blind study end points were changes between baseline and 6 months in quality of life, functional class, and distance covered during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival, incidence of ventricular arrhythmias, and rates of hospitalization were also compared. RESULTS: At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (-17.5 [-21 to -14] vs -11.0 [-16 to -7], P =.02) and functional class (-1 [-1 to -1] vs 0 [-1 to 0], P =.007) than controls but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs 53 m [43-75], P =.36). Peak oxygen consumption increased by 1.1 mL/kg per minute (0.7-1.6) in the CRT group vs 0.1 mL/kg per minute (-0.1 to 0.8) in controls (P =.04), although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group and decreased by 11 seconds (-55 to 12) in controls (P<.001). No significant differences were observed in changes in left ventricular size or function, overall HF status, survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia termination capabilities were not impaired. CONCLUSIONS: Cardiac resynchronization improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function.

Aged↗
PubMed2003

Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure.

OBJECTIVES: We sought to define the characteristics of fluid retention after thiazolidinedione (TZD) initiation in patients with established heart failure (HF). BACKGROUND: Fluid retention associated with the use of TZD is commonly attributed to exacerbation of HF, which has led to the proscription of these potentially useful agents in patients with chronic HF. METHODS: We examined 111 consecutive diabetic patients with chronic systolic HF who were treated with TZD from January 1999 to June 2001. A retrospective chart review was performed to determine the incidence of fluid retention in this cohort. Physical signs of fluid retention were compared between TZD users and an age- and gender-matched control group of diabetic, non-TZD users with chronic HF who had fluid retention. Baseline clinical and echocardiographic data were compared between TZD users with and without fluid retention. RESULTS: Nineteen TZD users (17.1%) developed fluid retention, which reversed after drug withdrawal and presented predominantly as peripheral and not central edema. Comparing patients in the upper and lower tertiles of weight gain, more female patients and insulin users developed TZD-related fluid retention. However, there were no differences in the baseline New York Heart Association functional class or echocardiographic severity of cardiac dysfunction. CONCLUSIONS: Although fluid retention after treatment with TZD in diabetic patients with chronic systolic HF occurs, the mechanism is undefined. Fluid retention related to TZD tends to be peripheral and is usually reversible after drug withdrawal. No direct association between the risk of fluid retention and the baseline degree of severity of HF was observed.

Adult↗
PubMed2003

Severe renal dysfunction complicating cardiogenic shock is not a contraindication to mechanical support as a bridge to cardiac transplantation.

OBJECTIVES: This study investigated outcomes in patients with cardiogenic shock and severe renal dysfunction treated with ventricular assist devices (VAD) as a bridge to cardiac transplantation. BACKGROUND: Previous reports have documented poor survival in patients with cardiogenic shock and severe renal dysfunction treated with VAD. METHODS: We surveyed 215 consecutive patients who received a VAD from 1992 to 2000 and selected patients who had a serum creatinine > or =3.0 mg/dl at the time of VAD placement. Demographic, laboratory, and clinical outcome data were collected. RESULTS: Eighteen patients met the inclusion criteria. Mean serum creatinine at the time of VAD placement was 4.0 +/- 0.7 mg/dl (range 3.0 to 5.2 mg/dl). Seven patients required temporary renal support with continuous venovenous hemodialysis (CVVHD). Eleven patients underwent cardiac transplantation. At six months post-transplantation, mean serum creatinine was 2.0 +/- 0.6 mg/dl (range 1.3 to 3.5 mg/dl). None of the transplanted patients required subsequent renal support. Seven patients died with a VAD before transplantation. Three died early (<1 month) after VAD placement, and all three required CVVHD until death. Four patients survived for >1 month after VAD placement; all four had resolution of renal dysfunction with mean serum creatinine of 1.9 +/- 1.2 mg/dl (range 0.8 to 3.6 mg/dl) without the need for renal support. Overall 30-day and six-month survival after VAD placement, survival to transplantation, and survival one year post-transplantation were similar to patients without severe renal dysfunction. CONCLUSIONS: Contemporary use of VAD leads to resolution of severe renal dysfunction in most cardiogenic shock patients and comparable long-term outcomes to patients without renal dysfunction.

Adult↗
PubMed2003

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</=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.

Acute Disease↗
PubMed2003

Proposition: the benefit of cardiac transplantation in stable outpatients with heart failure should be tested in a randomized trial.

Recent data suggest that cardiac transplantation is associated with a survival benefit only in patients at high risk for dying of advanced heart failure without this procedure. To test the hypothesis that survival and quality of life advantages associated with cardiac transplantation exist in stable outpatients, a 3-stage approach is proposed: 1). to establish a database within the International Society for Heart and Lung Transplantation/United Network for Organ Sharing/Eurotransplant infrastructure that will provide an estimate of the survival benefit of heart transplantation in various heart failure risk strata by prospectively following cohorts of patients listed for heart transplantation; 2). to organize an international consensus conference that will define, based on the review of the Stage 1 data, the feasibility of a prospective randomized trial; and 3). pending consensus, to perform a clinical trial, perhaps with an augmented, randomized design that allocates cardiac transplantation to all patients at high risk for dying of heart failure while randomizing patients at low risk to either conventional treatment or cardiac transplantation. Generating such scientific evidence is important in light of today's donor organ crisis and the associated difficulties of equitable resource allocation.

Cohort Studies↗
PubMed2003

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.

Adult↗
PubMed2003

How to improve organ donation: results of the ISHLT/FACT poll.

BACKGROUND: Worldwide organ shortages remain a long-standing problem. Efforts to address this have ranged from attempts to improve public awareness to modified mandated choice systems; most have been unsuccessful. In the face of this intractable problem, increased consideration has been given to direct and indirect compensation, and in certain countries, black markets for organs have developed. To examine the attitudes of the transplant medical community regarding these issues, we surveyed members of the International Society for Heart and Lung Transplantation (ISHLT) in conjunction with the Foundation for the Advancement of Cardiac Therapies (FACT). METHODS/RESULTS: We asked for opinions about how to improve organ donation. Of 739 respondents, 75% supported presumed consent, and 39% identified it as the single best way to increase donation; improved public education was a distant second (18%). Seventy percent supported indirect compensation (e.g., payment of funeral expenses, donation to a charity of the family's choice), and 66% opposed direct compensation (e.g., tax credit, life insurance benefit). When asked whether next of kin should be consulted regarding organ donation, and 84.2% responded affirmatively. However, of these individuals, 77.2% did not think that consultation should be required if the potential donor already had signed a donor card. MEMBERSHIP: Our membership dramatically favors indirect over direct compensation as a way of increasing organ donation. The majority also favors the wishes of the individual over the family in determining donor status. However, presumed consent is the single best way to significantly improve organ donation, according to the majority of our respondents. More effort should be directed toward policy in these areas as opposed to improving public education, which has failed to yield satisfactory results.

Attitude of Health Personnel↗
PubMed2002

The prognostic value of estimated creatinine clearance alongside functional capacity in ambulatory patients with chronic congestive heart failure.

OBJECTIVES: The goal of this study was to determine the prognostic significance of estimated creatinine clearance (CrCl) in relation to 6-min walk distance in ambulatory patients with congestive heart failure (HF). BACKGROUND: Although measurement of renal function is integral to the management of chronic congestive HF, its prognostic implications are not well described and have not been formally evaluated relative to measures of functional capacity. METHODS: We analyzed outcomes of the 585 participants of the 6-min walk substudy of the Digitalis Investigation Group (DIG) trial. The CrCl was estimated using the Cockcroft-Gault equation. Predictors of all-cause mortality were identified using semiparametric Cox proportional hazards regression and completely parametric hazard analyses. RESULTS: Most subjects (85%) were New York Heart Association functional class II and III. Mean age was 65 (+/-12) years and mean ejection fraction (EF) 35% (+/-13%). There were 153 (26%) deaths during a median of 2.6 years of follow-up. Mortality by increasing quartiles of estimated CrCl was 37% (18 to 48 ml/min), 29% (47 to 64 ml/min), 18% (64 to 86 ml/min), and 21% (86 to 194 ml/min) with corresponding hazard ratios (HRs) relative to the top quartile of 2.1 (95% confidence interval [CI], 1.4 to 3.3), 1.6 (95% CI, 1.0 to 2.5), and 0.9 (95% CI, 0.5 to 1.5), respectively. In Cox regression analyses, independent predictors of mortality were estimated CrCl (adjusted HR [quartile 1:quartile 4] 1.5; 95% CI, 1.1 to 2.1), 6-min walk distance < or =262 m [adjusted HR, 1.63; 95% CI, 1.12 to 2.27]), EF, recent hospitalization for worsening HF, and need for diuretic treatment. Parametric (hazard) analysis confirmed consistent effects of estimated CrCl on mortality in several subgroups including that of patients with EF >45%. CONCLUSION: In ambulatory patients with congestive HF, estimated CrCl predicts all-cause mortality independently of established prognostic variables.

Aged↗
PubMed2002

Increased tissue factor expression predicts development of cardiac allograft vasculopathy.

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<0.004) in patients with CAV than those without CAV. In patients <2 years (0.87+/-0.48 years) posttransplantation (n=28) without evidence of CAV, the TF score was determined and patients were followed up prospectively. A high TF score had a positive predictive value of 78.6% for the development of CAV, and a low TF score had a negative predictive value of 100%. 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.

Adult↗
PubMed2002

Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28-29, 2001, Crystal City, Va.

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to approximately 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond approximately 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on "Maximizing Use of Organs Recovered From the Cadaver Donor" held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described.

Cadaver↗
PubMed2002

The gene expression fingerprint of human heart failure.

Multiple pathways are responsible for transducing mechanical and hormonal stimuli into changes in gene expression during heart failure. In this study our goals were (i) to develop a sound statistical method to establish a comprehensive cutoff point for identification of differentially expressed genes, (ii) to identify a gene expression fingerprint for heart failure, (iii) to attempt to distinguish different etiologies of heart failure by their gene expression fingerprint, and (iv) to identify gene clusters that show coordinated up- or down-regulation in human heart failure. We used oligonucleotide microarrays to profile seven nonfailing (NF) and eight failing (F) human hearts with a diagnosis of end-stage dilated cardiomyopathy. Biological and experimental variability of the hybridization data were analyzed, and then a statistical analysis procedure was developed, including Student's t test after log-transformation and Wilcoxon Mann-Whitney test. A comprehensive cutoff point composed of fold change, average difference, and absolute call was then established and validated by TaqMan PCR. Of 6,606 genes on the GeneChip, 103 genes in 10 functional groups were differentially expressed between F and NF hearts. A dendrogram identified a gene expression fingerprint of F and NF hearts and also distinguished two F hearts with distinct etiologies (familial and alcoholic cardiomyopathy, respectively) with different expression patterns. K means clustering also revealed two potentially novel pathways associated with up-regulation of atrial natriuretic factor and brain natriuretic peptide and with increased expression of extracellular matrix proteins. Gene expression fingerprints may be useful indicators of heart failure etiologies.

Adult↗
PubMed2002

Myocardial ischemic injury after heart transplantation is associated with upregulation of vitronectin receptor (alpha(v)beta3), activation of the matrix metalloproteinase induction system, and subsequent development of coronary vasculopathy.

BACKGROUND: Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin alpha(v)beta3) 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 alpha(v)beta3, 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 alpha(v)beta3 (3.2-fold, P<0.001), tissue factor (2.5-fold, P<0.001), and EMMPRIN (1.9-fold, P=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24+/-1.8% versus 14+/-1.1%, P<0.001) and zymographic activity of MMP-2 (1.4-fold, P<0.001), MMP-3 (1.2-fold, P<0.001), and MMP-9 (1.3-fold, 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 alpha(v)beta3, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.

Adult↗