PubMed Health⌕ Search

Biomedical subjects

N Yonan

Publications and source records attributed to N Yonan.

At least 19 recordsLinked to original sources
PubMed2006

Cyclosporine profiling with C2 and C0 monitoring improves outcomes after heart transplantation.

BACKGROUND: Cyclosporine (CsA) level at 2 hours post-dose (C2) is a more sensitive marker for rejection risk than trough (C0) level. A combination of C2 and C0 monitoring may prove optimal. METHODS: We compared efficacy and safety outcomes among 28 de novo heart transplant patients in whom both C2 and C0 monitoring were undertaken (Group 1), with a single CsA profile at Weeks 2 to 6, versus 28 historic controls monitored by only C0 (Group 2). Patients received anti-thymocyte globulin (ATG) induction with CsA, steroids and azathioprine maintenance therapy. RESULTS: The CsA microemulsion dose was significantly higher in Group 1 than Group 2 up to 3 months post-transplant. Mean C2 values in Group 1 at 3 and 12 months were 1,248 +/- 328 ng/ml and 1,039 +/- 362 ng/ml, respectively. One patient in Group 1 and 7 in Group 2 (25%) discontinued CsA, either due to CsA-related neurotoxicity or two or more episodes of early rejection. At 12 months, graft and patient survival were 100% in both groups. Six patients in Group 1 (21%) and 11 in Group 2 (39%) had at least one episode of biopsy-proven acute rejection (not significant). Over the first 12 months post-transplant, the proportion of biopsies showing Grade 3 rejection was 5% in Group 1 and 11% in Group 2 (p < 0.002). Gloerular filtration rate (GFR) was significantly lower in Group 1 than Group 2 at both 3 and 12 months. CONCLUSIONS: Combined use of C2 and C0 monitoring results in improved efficacy versus C0 monitoring alone. Regular measurement of C2 levels should be undertaken in de novo heart transplant recipients.

Adult↗
PubMed2005

Angiotensin converting enzyme insertion/deletion polymorphism does not influence postcardiac transplantation hypertension onset or progression.

BACKGROUND: The angiotensin converting enzyme insertion deletion polymorphism (ACE I/D) has been associated with much cardiovascular pathology, including posttransplantation hypertension. Hypertension is a significant cause of morbidity and mortality after cardiac transplantation. We investigated the influence of the ACE I/D polymorphism on posttransplantation hypertension. METHODS: A total of 211 heart transplant recipients and 154 corresponding donors were genotyped for the ACE I/D polymorphism by polymerase chain reaction. ACE enzymatic activity was measured by spectrophotometric kinetic analysis. Sitting systolic and diastolic blood pressures were recorded at 3 consecutive visits, and the mean was calculated. Clinical data, including demographics and medication, were collected for all recipients. Results were analyzed by the chi-square test and analysis of variance, taking a p value of <0.05 to be significant. RESULTS: A total of 41.7% of the subjects were hypertensive (diastolic blood pressure >90 mm Hg) at the time of the study, with 79.6% taking at least one antihypertensive agent. We found no difference between the number of antihypertensive agents, cyclosporin dose and level, renal function, or systolic blood pressure for the different recipient or donor genotypes. We also found no significant correlation between ACE enzymatic activity and systolic or diastolic blood pressure. CONCLUSIONS: Our study of 211 recipients and 154 corresponding donors is the largest investigation of this polymorphism in a cardiac transplantation population. We found no apparent relationship between the ACE genotype (of either donor or recipient) and systemic hypertension (absolute measurements and the number or dose of antihypertensive agents used).

Alleles↗
PubMed2005

Donor heart selection: Wythenshawe experience.

BACKGROUND: The decline in the number of suitable donor hearts has led to an increasing interest in the use of previously unacceptable donors. This study aimed to evaluate the outcome of recipients of donor hearts considered medically unsuitable for transplantation at this center that were used in other centers in the United Kingdom. METHODS: Forty donor hearts (group 1) were declined by Wythenshawe Hospital and used in other units in the United Kingdom in the period extending from April 1998 to March 2003. One hundred four hearts (group 2) were transplanted at Wythenshawe Hospital during the same period. Donors and recipient data were obtained from the United Kingdom Cardiothoracic Transplant Audit database. Mortality in both groups was analyzed using SPSS software. RESULTS: Mortality in patients receiving grafts from group 1 donors was significantly higher than in group 2 (P < .0009). Of the early deaths in this group 50% (6 of 12) were the result of graft failure. These donors were receiving high doses of inotropes, had ischemic time exceeding 3.5 hours, and the grafts were transplanted into high-risk patients. CONCLUSION: Hearts declined on medical grounds by one center should be evaluated with caution before being considered suitable for transplantation, especially when more than one adverse factor is present.

England↗
PubMed2005

Donor CCR5 Delta32 polymorphism and outcome following cardiac transplantation.

BACKGROUND: Chemokines regulate the recruitment and trafficking of leukocytes during an immune response. Animal models have shown correlations between chemokine production and leukocyte infiltration during allograft rejection. Also, antagonism of chemokine receptors in transplant models has produced prolonged graft survival. Individuals homozygous for a 32 base pair deletion in the CC chemokine receptor 5 (CCR5) gene have an inactive receptor. Renal transplant recipients homozygous for the deletion have been shown to survive significantly longer than those heterozygous or homozygous for the wild type allele. CCR5 ligands are upregulated during allograft rejection aiding infiltration of leukocytes. We investigated the influence of CCR5Delta32 polymorphism on outcome following human cardiac transplantation. METHODS: Recipients and corresponding donors were genotyped for CCR5Delta32 polymorphism using polymerase chain reactions. RESULTS: We found no correlation between recipient genotype and outcome following transplantation. However, there was a significant correlation between donor genotype and mortality in patients transplanted for a nonischemic condition (DD = n/a, ID = 4%, II = 25%, P = .0014). CONCLUSIONS: The induction of CCR5 expression in endomyocardial biopsy tissue is known to correlate with leukocyte graft infiltration. We suggest that donor CCR5 may be more important for leukocyte trafficking during rejection than recipient CCR5 expression. The CCR5 gene is highly conserved, and due to the small population available for this study, more work is required from other centers.

Base Sequence↗
PubMed2005

CD4-veCD8-ve CD30+ve T cells are detectable in human lung transplant patients and their proportion of the lymphocyte population after in vitro stimulation with donor spleen cells correlates with preservation of lung physiology.

INTRODUCTION: Survival following lung transplantation is less than 50% at 5 years, mainly due to immune-mediated chronic rejection. Recently a novel subset of T cells, CD4-veCD8-ve CD30+ve, so-called double negative (DN) CD30+ve T cells, has been described and shown to be responsible for tolerance in an animal model of skin transplantation. METHODS: We investigated 18 lung transplant recipients for the presence of DN CD30+ve T cells in resting peripheral blood and also following in vitro stimulation of recipient peripheral blood mononuclear cells (PBMCs) with donor spleen cells. RESULTS: Small percentages (0.2% to 6%) of DN T cells are detectable in resting PBMCs of human transplant patients (n = 18), but these did not correlate with allograft function, acute rejection episodes, HLA mismatch, or CMV status. On repeated stimulation of recipient PBMCs (two exposures) in vitro by donor spleen cells (2:1 ratio stimulators to responders) the percentage of DN CD30+ve T cells within the lymphocyte pool correlated with preservation of allograft lung function (both for FEV(1), P = .009, and FEF(25-75), P = .036) and was inversely correlated with grade of chronic rejection. On repeated exposure of recipient PBMCs to donor spleen cells with a 1:1 ratio the percentage of DN CD30+ve T cells correlated with the number of acute rejection episodes of grade 2 or greater. The total number of HLA mismatches correlated with the percentage DN CD30+ve T cells present after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio). The number of mismatches at the B locus inversely correlated with the percentage of DN CD30+ve T cells after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio; P = .031, n = 18). CONCLUSION: Percentages of DN CD30+ve T cells present following repeated stimulation of recipient PBMCs by donor spleen cells correlated with preservation of graft function following lung transplantation.

Antigens, CD↗
PubMed2005

The effects of ACE inhibition on serum angiotensin II concentration following cardiac transplantation.

AIMS: ANGII mediates vascular neointimal formation through smooth muscle cell stimulation and enhanced production of growth factors leading to increased arterial medial layer thickness, which is a characteristic of transplant arteriosclerosis. ACE inhibition is known to be of benefit to patients with cardiovascular risk factors. We aimed to determine the effect of ACE inhibitor therapy on ACE enzymatic activity and serum ANGII levels following cardiac transplantation. METHODS: A total of 43 serum samples from eight transplant recipients were used for analysis. Samples were taken monthly from the date of transplant for the initial 6 months. ANGII was measured using sandwich ELISA. ACE enzymatic activity was measured using spectrophotometric kinetic analysis. RESULTS: There was a significant reduction in ACE enzymatic activity among individuals treated with ACE inhibitor therapy (18.0 +/- 16.6 vs 31.8 +/- 23.4, P = .008). We found significantly higher ANGII serum levels in patients receiving ACE inhibitor therapy compared to those not (2.4 +/- 2.1 vs 8.0 +/- 7.4, P = .002). There was also a significant positive correlation between ACE enzymatic activity and ANGII serum level (coefficient 0.332, P = .03). CONCLUSIONS: Our results suggest an effective ACE independent pathway for ANGII conversion. Chymase can convert ANGI with higher affinity than ACE. Also, chymase is stored in mast cells, which infiltrate the myocardium following transplantation. This data indicate that pharmacological chymase inhibition may be a possible therapeutic strategy following transplantation.

Adult↗
PubMed2005

The distribution of cardiac macrophages in myocardial ischaemia and cardiomyopathy.

AIMS: Recent evidence has implicated the macrophage as an effector cell in the inflammatory processes in transplant rejection, as well as cardiac disease, including coronary atherosclerosis. Although the latter is a vascular disease, the entire myocardium is affected. We have previously demonstrated the presence and distribution of macrophages in the 'normal' human heart. In this paper the distribution of myocardial macrophages, in the various chambers of the failing human heart, from cases of coronary atheroma and cardiomyopathy undergoing heart transplantation is documented. METHODS AND RESULTS: Tissue blocks were removed at specific sites taken from six cases with ischaemic heart disease (IHD) (four males, two females, age range 54-62 years), and four cases with idiopathic dilated cardiomyopathy (IDCM) (three males, one female, age range 18-49 years). These were compared with hearts from five cases of sudden death, unrelated to heart disease. Sections were stained with a CD68 pan macrophage marker. Positive cells were enumerated in 20 random fields. Results were analysed using a generalized linear modelling method using a Poisson distribution. Macrophages were identified within the interstitium and often close to blood vessels in all hearts. Macrophages from IHD hearts demonstrated the most intense staining and were often larger and more elongated than those found in 'normal' control hearts. Macrophages were also often degranulated and staining was diffuse in the interstitium. Overall, there were significantly more macrophages in most areas from IHD hearts than from IDCM hearts or control hearts (P < 0.001). CONCLUSIONS: Significantly more macrophages were found in all four chambers in diseased hearts compared with controls. Macrophage numbers were higher in the atria than in ventricles in the diseased myocardium. This study suggests selective recruitment of macrophages into the atria in the disease states studied.

Adolescent↗
PubMed2004

The influence of donor age on transplant coronary artery disease and survival post heart transplantation: is it safe to extend donor age?

BACKGROUND: Due to the increasing demand for suitable cardiac donor organs, acceptance criteria need to be re-evaluated. We retrospectively analyzed the effect of donor age on survival following cardiac transplantation. METHOD: Three hundred thirty-five cardiac transplant recipients and corresponding donor data were reviewed using SPSS. RESULTS: Seventy-two recipients had early posttransplant angiography or postmortem data available. The mean donor age of recipients with evidence of graft coronary artery disease (32.5 +/- 11.7 years) was significantly higher than that of recipients free of transplant coronary artery disease (TCAD) (24.8 +/- 9.4 years; P=.003). Recipient of organs from donors aged less than 50 years were less likely to develop TCAD than those of donors aged over 50 years (odds ratio 0.333; 95% CI 0.239-0.465; P=.044). TCAD also occurred much earlier posttransplantation in recipients of organ from donors over 50 years (mean time 6.5 years; median 5.0 years) than those of donors under 50 years (mean time 12.7 years; median 14.0 years). CONCLUSION: We observed no increase in mortality associated with cardiac donors over 50 years. However, increased donor age was associated with an increased incidence of TCAD.

Adult↗
PubMed2004

A novel polymorphism of the gene encoding furin, a TGF-beta1 activator, and the influence on cardiac allograft vasculopathy formation.

BACKGROUND: Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-beta1 (TGF-beta1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-beta1 activation. We investigated for polymorphism within the promoter region of the gene for furin (fur). Allelic variation of the fur gene, in conjunction with TGF-beta1 polymorphism, was subsequently related to the development of CV. METHODS AND RESULTS: The fur gene promoter region (position -1199 to +39) was analysed by SSCP and sequencing. A C/T single nucleotide substitution polymorphism at position -231* was identified. Using PCR the fur and TGFB1 genotypes were identified in 115 cardiac transplant recipients. CV was diagnosed at routine surveillance post-transplant coronary angiography. Fur polymorphism had no influence on vasculopathy development; median time to diagnosis, *C/C homozygotes, 2.27 years (2.10-4.32), *C/T heterozygotes 2.97 years (2.09-4.24), *T/T homozygotes 2.65 years (2.33-4.08), (P=0.95). Allelic variation did not influence Kaplan Meier actuarial analysis of disease onset (P=0.54). Ninety-three percent of recipients were high TGF-beta1 producers. We used fur polymorphism to substratify patients with the +915*G/G TGFB1 (high producing) allele. Fur polymorphism did not influence CV development within this TGF-beta1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing. CONCLUSIONS: We have described a novel polymorphism at position -231* in the gene encoding furin. The fur -231* single nucleotide polymorphism in isolation, or in conjunction with TGFB1 polymorphism, is not useful as a genetic risk marker for cardiac transplant associated coronary vasculopathy.

Adult↗
PubMed2004

Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of coronary vasculopathy following cardiac transplantation. The TGFB1 gene contains polymorphisms at positions +915* (Arg25Pro) and +869* (Leu10Pro) which may influence TGF-beta1 expression. We investigated the relationship between the development of coronary vasculopathy and the prevalence of these alleles in a cardiac transplant population. METHODS: Vasculopathy was diagnosed at routine surveillance post-transplant coronary angiography. Using sequence-specific polymerase chain reaction we identified the TGFB1 +915* and +869* genotypes in 147 cardiac transplant recipients and 134 cardiac donors. RESULTS: TGFB1 +915*C allele carriers (low producers) made up 10.5% of the recipient population but were significantly less likely to develop coronary vasculopathy (P=0.03). Median time to diagnosis was 6.0 years (3.9-8.72) in +915*C allele carriers compared to 2.75 years (2.10-4.22) in *G/G homozygotes (p=0.002). Pre- and 1 year post-transplant clinical variables were equivalent between the two groups. Multivariate analysis identified the recipient +915*G/G genotype (hazard ratio 2.96 (95% CI, 1.09-9.98); p=0.039), donor age (hazard ratio 1.05 (95% CI, 1.02-1.09); p=0.008) and number of acute rejection episodes of ISHLT grade 3 or greater in the first year (hazard ratio 1.12 (95% CI, 1.01-1.23); p=0.03) as significant predictors of vasculopathy. The recipient TGFB1 +869*, and both alleles in the donor, had no influence on vasculopathy development. CONCLUSIONS: Recipient TGFB1 +915* genotype influences the development of cardiac transplant-related coronary vasculopathy. This gives an important insight to the pathophysiology of the disease. On the contrary, donor TGFB1 +915* and TGFB1 +869* polymorphisms do not appear to be important and cannot be used as genetic risk factors.

Coronary Angiography↗
PubMed2002

The effect off-pump coronary artery bypass surgery on in-hospital mortality and morbidity.

OBJECTIVE: Off-pump coronary artery bypass (OPCAB) surgery is being increasingly reported to show better outcomes compared to conventional on bypass grafting. We examined the effect of OPCAB on in-hospital mortality and morbidity, while adjusting for patient and disease characteristics, in four institutions in the North West of England. METHODS: Between April 1997 and March 2001, 10,941 consecutive patients underwent isolated coronary artery bypass surgery at these four institutions. Of these, 7.7% were performed off-pump. We used logistic regression to examine the effect of OPCAB on in-hospital mortality and morbidity after adjusting for potentially confounding variables. RESULTS: The crude odds ratio (OR) for death (off-pump versus on-pump coronary bypass grafting) was 0.48 (95% confidence interval, CI 0.26-0.92; P=0.023). After adjustment for all major risk factors, the OR for death was 0.59 (95% CI 0.31-1.12; P=0.105). Off-pump patients had a substantially reduced risk of post-operative stroke (0.6 versus 2.3%, respectively; adjusted OR 0.26 (95% CI 0.09-0.70; P=0.008) and a significant reduction in post-operative hospital stay. Other morbidity outcomes were similar in both groups. CONCLUSIONS: Off-pump coronary artery bypass incurs no increased risk of in-hospital mortality. In contrast, there is a significant reduction in morbidity in patients undergoing off-pump coronary bypass grafting when compared to that performed on cardiopulmonary bypass.

Aged↗
PubMed2002

Tumour necrosis factor alpha gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction?

BACKGROUND: Tumour necrosis factor alpha (TNF alpha) is implicated in the pathophysiology of heart failure. Plasma TNF alpha is raised in patients with myocardial dysfunction in proportion to the symptoms. OBJECTIVE: To determine whether this genetic variant is over represented in heart transplant recipients. PATIENTS: 175 heart transplant recipients and a control group of 212 healthy volunteers were studied. The reason for transplantation was severe symptomatic myocardial dysfunction in all cases. METHODS: The TNF alpha genotype was determined by polymerase chain reaction and gel electrophoresis. The populations were compared for their fit to Hardy-Weinberg equilibrium by calculating the expected frequencies of each genotype and comparing them to the observed values. A chi(2) test was used to determine the significance of the difference between the observed and expected values. RESULTS: No differences were found in the frequency of the TNF2 allele between all heart transplant recipients taken together (54/175, 31%) and healthy volunteers (58/212, 27%). A higher proportion of TNF2 allele carriers was present in cardiac recipients with a pretransplant diagnosis of viral mediated or idiopathic heart failure than in those with ischaemic myocardial dysfunction (26/69 (37.7%) v 28/106 (26.4%), p = 0.03). PATIENTS with a non-ischaemic aetiology had a higher prevalence of TNF2 than healthy volunteers (26/69 (37.7%) v 58/212 (27%), p = 0.05). CONCLUSIONS: The TNF2 allele is overrepresented in patients with end stage non-ischaemic myocardial dysfunction. This may represent a genetic predisposition in a small subset of patients who could respond favourably to anti-TNF alpha treatment.

Biomarkers↗
PubMed2001

Tumor necrosis factor-alpha gene polymorphism and death due to acute cellular rejection in a subgroup of heart transplant recipients.

Irreversible acute rejection of the transplanted heart usually has a fatal outcome. Predicting which recipients are most likely to reject might allow closer monitoring and modification of treatment protocols to prevent graft loss. Recipients genetically predisposed to produce more TNF-alpha are those who suffer the most acute rejection episodes. Here we show that TNF-alpha genotype is strongly associated with death due to acute cell-mediated heart transplant rejection (Chi-square = 28.57, p < 0.0001). This subgroup of recipients should be given optimally tissue matched transplants and should be treated with the most effective immunosuppressive regimens.

Acute Disease↗
PubMed2001

Transforming growth factor beta and myocardial dysfunction following heart transplantation.

OBJECTIVE: We analyzed the role of transforming growth factor-beta (TGF-beta), a fibrogenic cytokine, in the development of left ventricular diastolic dysfunction following heart transplantation. METHODS: We studied 152 heart transplant recipients who had survived for at least 24 months. We compared histopathological findings (staining of endomyocardial biopsy specimens using Hematoxylin Eosin and polyclonal antibodies), left ventricular function (Doppler echocardiography) and clinical course (NYHA status). Patients are classified into group A (n=56 recipients) with immunohistochemical TGF-beta staining score >7 and group B (n=96 recipients) with a staining score <7. RESULTS: Doppler echocardiographic evaluation demonstrated greater impairment of left ventricular diastolic function in recipients with higher TGF-beta staining score. The average mitral deceleration time was 129+/-6 ms for recipients group A compared to 167+/-15 ms in group B. While the mean isovolumic relaxation time was 65+/-8 ms for patients in group A compared with 82+/-6 ms for recipients in group B (P=0.0004 and 0.005, respectively). Immunohistochemical scoring correlated inversely with both mitral deceleration and isovolumic relaxation times (r=-0.74, P=0.0004 and r=-0.66, P=0.004, respectively). Mean NYHA status was 2.7+/-1.3 for group A compared to 1.17+/-0.4 in group B was (P=0.002). Five years follow-up revealed persistent left ventricular diastolic impairment for recipients with higher immunohistochemical staining score. Mitral deceleration time and isovolumic relaxation time were 118+/-11 and 62+/-7 ms for group A compared to 156+/-12 and 80+/-5 ms for group B, P=0.006 and P=0.01, respectively. The actuarial development of subsequent coronary artery disease (> 50% stenosis) was 17 and 29% for recipients in group A compared to 4 and 6% for recipients in group B at 3 and 5 years follow-up, respectively (P=0.01 and P=0.005, respectively). CONCLUSIONS: TGF-beta expression in cardiac allografts is associated with impaired graft function and limited survival. The pathogenesis of diastolic dysfunction may be an aberrant repair process following rejection due to increased TGF-beta expression in transplant recipients.

Biopsy↗