Papers by Norman Ratliff III
The Lancet, Aug 1, 2002
A 28-year-old man had a cardiac arrest upon finishing a marathon in October, 2000. When he collap... more A 28-year-old man had a cardiac arrest upon finishing a marathon in October, 2000. When he collapsed at the finish line, he was found to be in ventricular fibrillation, and a 45 min resuscitation effort including multiple defibrillations and intravenous epinephrine eventually restored ...
Circulation, Sep 10, 2002
Background-Cardiac allograft vasculopathy (CAV) limits the long-term success of cardiac transplan... more 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 Ͼ2 years (3.0Ϯ0.8 years) posttransplantation (nϭ35), a high TF score was observed with greater frequency (75% versus 26%, PϽ0.004) in patients with CAV than those without CAV. In patients Ͻ2 years (0.87Ϯ0.48 years) posttransplantation (nϭ28) 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. (Circulation. 2002;106: 1379-1383.
The Lancet, 2002
A 28-year-old man had a cardiac arrest upon finishing a marathon in October, 2000. When he collap... more A 28-year-old man had a cardiac arrest upon finishing a marathon in October, 2000. When he collapsed at the finish line, he was found to be in ventricular fibrillation, and a 45 min resuscitation effort including multiple defibrillations and intravenous epinephrine eventually restored ...
The Journal of Thoracic and Cardiovascular Surgery, 1996
We sought to determine whether cardiac transplant recipients who required a bridge to transplanta... more We sought to determine whether cardiac transplant recipients who required a bridge to transplantation with an implantable left ventricular assist device had a different outcome than patients who underwent transplantation without such a bridge. Methods: A retrospective study of 256 cardiac transplants from 1992 to 1996 included 53 patients who received the HeartMate left ventricular assist device and 203 patients who had no left ventricular assist device support. Results: Left ventricular assist device transplants increased from 8% of all transplants in 1992 (n = 63) to 32% in 1995 (n = 65) and 43% in 1996 (n = 14 year to date). Patients with and without left ventricular assist device had similar age and sex distributions. Left ventricular assist device recipients were larger (body surface area 1.96 vs 1.86 m 2, p = 0.004). They were more likely to have ischemic cardiomyopathy (70% vs 45%, p = 0.001) and type O blood group (51% vs 34%, p = 0.06). All patients with left ventricular assist device and 42% of those without had undergone previous cardiac operations by the time of transplantation (mean number per patient 1.5 vs 0.3, p < 0.001). More patients in the left ventricular assist device group had anti-HLA antibodies before transplantation (T-cell panel reactive antibody level > 10% in 66% of left ventricular assist device group vs 15% of control group, p < 0.0001). Waiting time was longer for the left ventricular assist device than for patients in status I without a left ventricular assist device (median 88 vs 37 days, p = 0.002). There was no difference in length of posttransplantation hospital stay (median 15 days for each) or operative mortality (3.8% vs 4.4%). Mean follow-up averaged 22 months. No significant difference was found in Kaplan-Meier survival estimates. One-year survival was 94% in the left ventricular assist device group and 88% in the control group (difference not significant). Comparison of posttransplantation events showed no significant difference in actuarial rates of cytomegalovirus infection (20% vs 17%) or vascular rejection (15% vs 12%) at 1 year of follow-up. Similar percentages of patients were free from cellular rejection at 1 year of follow-up (12% vs 22%, p = 0.36). Conclusions: Left ventricular assist device support intensified the donor shortage by including recipients who otherwise would not have survived to transplantation. Bridging affected transplant demographics, favoring patients who are larger, have ischemic cardiomyopathy, have had multiple blood From the
The Journal of Thoracic and Cardiovascular Surgery, 1998
Transmyocardial laser revascularization (TMLR) is an investigational procedure designed to allow ... more Transmyocardial laser revascularization (TMLR) is an investigational procedure designed to allow perfusion of ischemic myocardium with oxygenated blood directly from the left ventricle (LV) through microscopic channels created with a carbon dioxide laser. TMLR is currently being offered to patients who are unsuitable candidates for coronary bypass operations or percutaneous transluminal coronary angioplasty and who have severe angina refractory to medical treatment. In 1965, Sen and associates 1 discovered that the reptilian myocardium is perfused by channels that radiate from a single ventricle into the surrounding muscle with only a thin shell of myocardium being supplied by coronary arteries. Sen's group attempted to reproduce the reptilian model of myocardial perfusion by performing transmyocardial acupuncture. Today, transmyocardial acupuncture has been replaced by the development of high-energy carbon dioxide lasers that create transmyocardial channels in beating hearts without cardiopulmonary bypass (TMLR). Clinical studies of TMLR have reported decreased angina, increased treadmill tolerance, and an increase in relative subendocardial perfusion of laser-treated areas as measured by nuclear studies and positron emission tomographic scans 3, 6, and 12 months after the operations. Recently, a large 1:1 randomized prospective clinical study comparing TMLR to continued medical management in patients with symptomatic, end-stage coronary artery disease reported improved event-free survival, angina class, and quality of life after TMLR.* Patients and methods. We performed three autopsies at the Cleveland Clinic Foundation on patients who had From the
Journal of the American College of Cardiology, 2003
Journal of the American College of Cardiology, 2005
We evaluated chimerism and stromal cell-derived factor-1 (SDF-1) expression in response to peritr... more 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. 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 chromosomecontaining nuclei. The SDF-1 messenger ribonucleic acid (mRNA) and protein expression were also evaluated on initial heart biopsy specimens. At one week, Y chromosome-containing nuclei were significantly increased in the ischemia group (0.68% vs. 0.04%; p Ͻ 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 ϭ 0.001) and 2.8-fold increased protein expression (p ϭ 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. (
Journal of the American College of Cardiology, 1990
A retrospective analysis was performed to determine the surgical outcome and long-term follow-up ... more A retrospective analysis was performed to determine the surgical outcome and long-term follow-up of patients with documented cystic medial necrosis of the aorta. Ninetythree patients were diagnosed as having cystic medial necrosis at the Cleveland Clinic betweeu July 1%3 and December 1987 (72% men aged 26 to 77 years, mean 55). Patients who met the standard diagnostic criteria for Marfan's syndrome were deliberately excluded. Sixty-eight percent of tbe patients had a diastolic murmur and chest roentgenogram revealed a dilated aortic arch in 58% and cardiomegaly in 63%. Cardiac catheterization in 76 patients demonstrated aortic root dilation in 78% aortic regurgitation in 72%, aortic diition in 32% and coronary artery diiase in 32%. Ninety patients underwent surgery including composite graft repair with reimplautation of the coronary arteries in 34%. Follow-up, obtained on 90 (97%) of the 93 patients, Fmm the Department of Carut~pvs,, cweland Clinic Foundation. Cleveland. Ohio.
Journal of the American College of Cardiology, 2002
We sought to assess the influence of peritransplant ischemia and fibrosis on the development of a... more We sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome. BACKGROUND Allograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia. One hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n ϭ 32), ischemia (n ϭ 24), fibrosis (n ϭ 62) or vascular rejection (n ϭ 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up. Patients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p ϭ 0.008) and lowest average episodes of cellular rejection (1.7 Ϯ 1.4, p ϭ 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness ϭ 0.59 Ϯ 0.28 mm, p Ͻ 0.0001) and poor seven-year event-free survival (49%, p ϭ 0.01). CONCLUSIONS The development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy. (
Journal of the American College of Cardiology, 2003
This biochemical study compared the extracellular matrix of normal mitral valves and myxomatous m... more 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. Leaflets and chordae from myxomatous valves (n ϭ 41 ULP, 31 BLP) and normal valves (n ϭ 27) were dried, dissolved, and assayed for deoxyribonucleic acid, collagen, and total GAGs. Specific GAG classes were analyzed with selective enzyme digestions and fluorophoreassisted carbohydrate electrophoresis. 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. (
Journal of the American College of Cardiology, 2004
We evaluated whether the angiotensin II (Ang II) receptors from perioperation through one-year po... more 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. 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. The AT 1 R mRNA in lymphocytes from the donor spleen (CMIT: r ϭ 0.73, p Ͻ 0.0001; CPV: r ϭ 0.69, p Ͻ 0.0001) and in the donor hearts at one-week (CMIT: r ϭ 0.52, p ϭ 0.005; CPV: r ϭ 0.56, p ϭ 0.002) and at one-year (CMIT: r ϭ 0.63, p Ͻ 0.0001; CPV: r ϭ 0.43, p ϭ 0.004) post-transplantation along with AT 2 R mRNA in the donor hearts at one-year post-transplantation (CMIT: r ϭ 0.3, p Ͻ 0.0001; CPV: r ϭ 0.53, p ϭ 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. (
Journal of the American College of Cardiology, 2004
Background. Plasma lipids are suggested as modulators of inflammation. Enteral nutrition (EN) of ... more Background. Plasma lipids are suggested as modulators of inflammation. Enteral nutrition (EN) of patients with cardiac cachexia (CC) may change plasma lipids and therefore alter inflammation. Methods. We assessed the effects of EN on plasma lipids, body fat content by DEXA, and cytokines (all in pg/mL). 29 pts with CC (all weight loss>7,5%, 4 female, BM=21,7±2 kg/m 2 , NYHA 2,7±0,5, LVEF 24±9%) were randomized 3:1 to EN of 600 kcal/day (added between main meals) (ingredients per 600 kcal: proteins-20g, carbohydrates-72g, fat-26g) or placebo (clouding agent: 12 kcal/day). 3 pts died: 1-sudden cardiac death, 2-due to pump failure, 1 was transplanted. Remaining 19 patients (15 M, 4 F, age: 49±15y) were receiving nutrition, 6 patients placebo. Before nutrition (v1), directly after its withdrawal, that is 6 weeks after baseline (v2) and 12 weeks thereafter (v3), we performed DEXA, assessed plasma lipids, cytokines and quality of life by Minnesota score. Results. Responses noticed in patients receiving EN are shown in the table (paired ttest, NS=p>0.1). Conclusions. In patients with CC, EN increased body weight, which was mainly fat mass. This response was associated with opposite changes of plasma lipids that increased, and inflammatory cytokines that decreased.
Journal of Cardiac Failure, 2003
Background: Left ventricular assist devices (LVADs) have demonstrated the ability to improve card... more Background: Left ventricular assist devices (LVADs) have demonstrated the ability to improve cardiac function to such an extent that 15% of our patients were ultimately weaned from LVAD instead of undergoing heart transplantation. However, predictive parameters have still not been found. Methods: In the serum of 6 patients with dilated cardiomyopathy circulating concentration of carboxy-terminal propeptide of type I collagen (PICP), amino-terminal propeptide of type I and III collagen (PINP, PIIINP), and type I collagen telopeptide (ICTP) were measured by a radioimmunoassay. Echocardiographic examination was undertaken at the time the serum samples were collected. Left ventricular ejection fraction (LVEF) and left ventricular end-diastolic dimension (LVIDd) were the functional parameters used in this study. Results: The changes in serum concentration showed that PIIINP increased constantly during LVAD support in those patients who could not be weaned (at implantation 0.99 Ϯ 0.26, at transplantation 6.9 Ϯ 2.4 micro g/ml). In contrast PICP (at implantation 170.9 Ϯ 70.9, at weaning 203.2 Ϯ 80.2 micro g/l) and PINP (at implantation 15.5 Ϯ 3.5, at weaning 50.9 Ϯ 22.9 micro g/l) increased in the group of patients who were successfully weaned. The concentration of PICP and PINP increased in early stages (2 months) of LVAD support in the serum of patients who could be weaned later on. PIIINP showed a linear increase over time in the serum of the later transplanted patients. A statistically significant correlation between the serum peptides and the cardiac function parameters was found for PICP and PINP. At the time of implantation there was no significant difference found between the peptide concentration in serum of patients who were weaned and those who were not weaned. ICPT showed no significant differences between the two groups. Conclusions: The increase of PINP and PICP, representing collagen type I synthesis, may be a sign of reversion of maladaptive remodeling. However, the constant increase of PIIINP, representing collagen type III synthesis, may relate to poorer prognosis with regard to improvement of cardiac function.
European Journal of Cardio-Thoracic Surgery, 1998
Objective: Use of flow cytometry cross-matching for measurement of donor-specific alloreactivity ... more Objective: Use of flow cytometry cross-matching for measurement of donor-specific alloreactivity and monitoring anti-donor antibodies is well established. This study was performed to determine (1) its accuracy as a marker of vascular rejection, (2) its correlation with posttransplant outcome and (3) its ability to monitor highly sensitized patients requiring antibody removal with plasma exchange. Methods: Serial serum samples from 99 heart transplant recipients were examined for the presence of anti-donor antibodies of the IgG class that were reactive with T and/or B cryopreserved donor lymphocytes. A sub-group of 20 HLA sensitized patients required plasma exchange to remove the anti-HLA antibodies and were monitored with flow cytometry cross-matching to assess the degree of antibody removal. Results: Positive T-cell reactions were observed in 26 patients and positive B-cell reactions in 54. Twenty patients had vascular rejection. A significantly larger number of patients with a positive flow cytometry cross-match had vascular rejection (42% versus 12% for T-cell reactions, and 32% versus 7% for B-cell reactions; P = 0.002 each). Of the patients who had vascular rejection, 11 had a positive T-cell reaction (flow cytometry cross-match sensitivity of 55%), and 17 had a positive B-cell reaction (sensitivity of 85%). Of the 79 patients who did not develop vascular rejection, 64 had a negative T-cell reaction (specificity of 81%), and 42 had a negative B-cell reaction (specificity of 53%). The actuarial 2year survival estimates were significantly higher in patients with negative T-cell reactions (90% versus 75%; P = 0.04), and B-cell reactions (95% versus 78%; P = 0.02). In the highly sensitized subgroup (n = 20) the effectiveness of plasma exchange to decrease anti-HLA antibody reactivity was a strong predictor of outcome. For patients in whom plasma exchange (PE) reduced anti-donor reactivity, 1-year survival was 87% compared to 25% in those whom PE did not reduce the level of antibody binding as assessed with flow cytometry cross-matching (P Ͻ 0.0001). Conclusions: Flow cytometry cross-matching provides a valuable marker for the detection of vascular rejection after cardiac transplantation. Quantitative measurements may allow evaluation of the efficacy of treatment modalities employed in the management of vascular rejection in an attempt to improve outcome.
European Heart Journal, 2004
Aims We tested the hypothesis that cardiac angiotensin II (Ang II) receptor gene transcription ma... more 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. We examined the gene transcripts of Ang II type 1 (AT 1 R) and type 2 receptors (AT 2 R) 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 P 0.3 mm over one year. The level of AT 1 R mRNA was associated with that of AT 2 R in transplanted hearts (regression coefficient ¼ 1.77, 95% CI 0.85-2.89, P < 0:0001). AT 1 R and AT 2 R gene transcripts were univariate predictors of CMIT (AT 1 R: regression coefficient 0.10, 95% CI 0.06-0.14, P < 0:0001; AT 2 R: regression coefficient 0.28, 95% CI 0.17-0.40, P < 0:0001) or CPV (AT 1 R: regression coefficient 0.41, 95% CI 0.17-0.65, P < 0:0001; AT 2 R: regression coefficient 1.25, 95% CI 0.49-2.01, P ¼ 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 AT 1 R than the non-vasculopathic group (3.7 AE 2.9 vs 1.6 AE 1.7 folds; P ¼ 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 AT 1 R gene transcripts predicted the development of transplant vasculopathy in this preliminary study.
Circulation, 2003
Background— Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the prog... more 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 ...
Circulation, 2002
Background— Cardiac allograft vasculopathy (CAV) limits the long-term success of cardiac transpla... more 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 pos...
Circulation, 2002
Background — Myocardial ischemic injury after heart transplantation is associated with subsequent... more 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....
American Journal of Transplantation, 2002
The vitronectin receptor (integrin avb3), a cell-surface adhesion receptor, has been shown to pla... more The vitronectin receptor (integrin avb3), 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 avb3. We also determined whether fibronectin receptor (a5b1) 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 Ω 10; grade 1A, n Ω 10; grade 2, n Ω 10; grade 3A, n Ω 10). Biopsies were obtained 2-4 weeks after cardiac transplantation. Immunoperoxidase staining was performed for avb3, tissue factor, and a5b1, and protein levels were further determined by Western blot analysis. Specimens with grade 2 and grade 3A rejection showed positive staining of avb3 in lymphocytic aggregates and vascular endothelial cells. By immunoblotting, we identified significantly increased expression of avb3 in the presence of acute rejection, grade 2 (3-fold, p Ω0.01) and grade 3A (3.6-fold, p Ω0.005) compared to grade 0 and 1A specimens. There was no evidence of increased expression of a5b1 or tissue factor. Acute cellular rejection, a process characterized by T-lymphocyte activation and release of inflammatory cytokines, is associated with increased expression of avb3.
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Papers by Norman Ratliff III