PubMed Health⌕ Search

Biomedical subjects

M H Yacoub

Publications and source records attributed to M H Yacoub.

At least 91 records · Page 5Linked to original sources
PubMed2000

Significant frequencies of T cells with indirect anti-donor specificity in heart graft recipients with chronic rejection.

BACKGROUND: The purpose of this study was to determine whether T cells with indirect allospecificity could be detected in heart transplant recipients with chronic rejection. METHOD AND RESULTS: Human T-cell clones were used to determine the most effective way to deliver major histocompatibility complex alloantigens for indirect presentation. Seven allograft recipients with evidence of progressive, chronic rejection were selected. Four heart graft recipients with no evidence of chronic rejection were used as controls. Peripheral blood T cells and antigen-presenting cells from the recipients were cultured with frozen/thawed stored donor cells or major histocompatibility complex class I-derived synthetic peptides in limiting dilution cultures and then compared with controls using tetanus toxoid and frozen/thawed third-party cells with no human leukocyte antigens in common with the donor. In 5 of 7 patients analyzed who had chronic rejection, elevated frequencies of T cells with indirect, anti-donor specificity (iHTLf) were detected. No such elevated iHTLf were detected in recipients without chronic rejection. DISCUSSION: iHTLf can be obtained from human transplant recipients, which supports the contention that the indirect pathway is involved in chronic transplant rejection.

Animals↗
PubMed2000

Cardiac myosin autoantibodies and acute rejection after heart transplantation in patients with dilated cardiomyopathy.

OBJECTIVES: To determine whether humoral autoimmune responses associated with dilated cardiomyopathy (DCM) influence the postoperative clinical course following cardiac transplantation. METHODS: ELISA levels of preformed cardiac myosin (CM) autoantibodies (Abs) in patients with a pretransplant diagnosis of dilated cardiomyopathy (DCM) (n=64) and ischemic heart disease (IHD, n=53) were correlated with cardiac rejection, immunosuppression, and the incidence of endocardial infiltrates after transplantation. RESULTS: Alpha- and beta-CM autoantibody (IgG and IgM) levels were similar in DCM and IHD patients but were statistically higher than in controls. Distribution of preformed (beta-CM) IgM-Abs in patients with and without rejection in the first postoperative year differed in the two groups. DCM patients rejected earlier P=0.006, and the frequency of rejection at 3 months was statistically higher than in IHD patients. Frequency and reactivity of IgM-Abs in DCM patients with rejection [International Society for Heart and Lung Transplant (ISHLT) grade I and above] was 28% compared with 7% in rejection-free patients, P<0.05. IgM-positive patients had a greater frequency and severity of rejection episodes and required more immunosuppression. These patients had rejection earlier than Ab-negative patients, P<0.009. There was no correlation between antibody status and rejection in IHD patients or with IgG in either group. Distribution of IgG subclass differed in the two diseases. DCM patients had significantly higher IgG3 reactivity; 70% of this activity was present in patients who developed moderate rejection. IgG3-positive patients experienced more frequent rejections, as well as a greater incidence of grade 3A/B rejection as the first episode, than did Ab-negative patients (50% vs. 15%), P<0.05. Frequency of endocardial infiltrates was statistically higher in IgG3-positive patients. CONCLUSION: Proinflammatory characteristics of preformed IgG3 and IgM antibodies in DCM patients may influence the frequency and severity of cardiac rejection after transplantation.

Acute Disease↗
PubMed2000

Asymmetric redirection of flow through the heart.

Through cardiac looping during embryonic development, paths of flow through the mature heart have direction changes and asymmetries whose topology and functional significance remain relatively unexplored. Here we show, using magnetic resonance velocity mapping, the asymmetric redirection of streaming blood in atrial and ventricular cavities of the adult human heart, with sinuous, chirally asymmetric paths of flow through the whole. On the basis of mapped flow fields and drawings that illustrate spatial relations between flow paths, we propose that asymmetries and curvatures of the looped heart have potential fluidic and dynamic advantages. Patterns of atrial filling seem to be asymmetric in a manner that allows the momentum of inflowing streams to be redirected towards atrio-ventricular valves, and the change in direction at ventricular level is such that recoil away from ejected blood is in a direction that can enhance rather than inhibit ventriculo-atrial coupling. Chiral asymmetry might help to minimize dissipative interaction between entering, recirculating and outflowing streams. These factors might combine to allow a reciprocating, sling-like, 'morphodynamic' mode of action to come into effect when heart rate and output increase during exercise.

Adult↗
PubMed2000

Risk of lymphoid neoplasia after cardiothoracic transplantation. a cohort study of the relation to Epstein-Barr virus.

BACKGROUND: Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased. METHODS: The risk of lymphoid neoplasia was assessed in a cohort of 1563 patients who underwent cardiothoracic transplantation at Harefield Hospital, UK from 1980 to 1994 and were followed until December 1995. EBV antibody was assessed in the patients before transplantation, and lymphoid neoplasms were assessed for EBV RNA and latent EBV gene expression. RESULTS: Thirty cases of LPD occurred during follow-up. One lymphoma of unknown EBV status occurred. There were also six cases of EBV-negative non-Hodgkin's lymphoma (EBV-negative NHL), a highly significant excess over expectations from the general population rates of NHL (standardized incidence ratio 10.2 [95% confidence interval, 4.6-22.8]). The risk of LPD was significantly 10-fold raised in individuals who were EBV seronegative before transplantation; independently of this, it decreased steeply with age at transplantation and was greatest in the first year after transplantation. The risk was significantly raised in young seronegative recipients if the donor was older than the recipient. EBV-negative NHL occurred entirely in men 45 years old and older who were EBV seropositive before transplantation, and risk was not related to duration since transplantation. CONCLUSIONS: The risk factors found for LPD accord with EBV etiology and with greater hazard from primary infection than from reactivation. A second non-Hodgkin's lymphoid neoplasm, not related to EBV, seems also to be a consequence of transplantation and immunosuppression but is unlikely to be due to first infection by a ubiquitous agent. Its etiology and prevention need investigation separately from LPD.

Adolescent↗
PubMed2000

Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension.

The hypothesis for this study was that increased local expression of vascular angiotensin-converting enzyme (ACE) may contribute to the arterial remodelling which accompanies pulmonary hypertension, since angiotensin II (ANG II) is an important mediator of pulmonary vascular cell growth. The expression of ACE was studied by immunohistochemistry in paraffin-embedded lung sections from adults undergoing heart-lung transplantation for severe primary (n=6) and secondary (n=7) pulmonary arterial hypertension (PH), compared with age-matched controls (n=11). An antigen retrieval technique was used prior to incubating sections with the anti-ACE monoclonal antibody, CG2, or the endothelial marker, monoclonal anti-CD31. In control lungs, the highest level of ACE immunostaining was seen in the alveolar capillary endothelium, with less intense staining in small intra-acinar pulmonary arteries and relatively little staining in larger preacinar arteries. ACE immunostaining was virtually absent in lymphatics and veins. In both primary and secondary PH, there was an increase in ACE immunostaining in the endothelium of intra-acinar peripheral pulmonary arteries compared with control lungs, extending to the level of alveolar ducts, as confirmed by semi-quantitative analysis. The increase in endothelial ACE expression in the intra-acinar arteries of patients with primary and secondary PH is consistent with the hypothesis that locally increased production of ANG II may contribute to the process of pulmonary vascular remodelling.

Adult↗
PubMed2000

Identification of cis-acting DNA elements required for expression of the human cardiac troponin I gene promoter.

The human cardiac troponin I (TnIc) gene exhibits both cardiac-specific and developmentally regulated expression. The structure and expression of this gene as well as the identification of putative regulatory elements have been described previously. This study shows that a minimal promoter containing 98 bp of sequence is sufficient to drive transcription in neonatal rat cardiac myocytes. This region contains several putative cis -regulatory elements including an Initiator element surrounding the start site of transcription, an A/T-rich (TATA/MEF-2) element, two GATA elements and a cytosine-rich region containing overlapping CACC box and Sp1 elements. Using electrophoretic mobility shift assays (EMSAs) this study demonstrates the binding of MEF-2, Oct-1, and recombinant TBP to the A/T-rich element and of GATA-4 to both GATA elements. The CACC/Sp element binds the zinc finger transcription factors Sp1 and Sp3 in addition to an unidentified complex present in neonatal rat cardiac myocytes. Mutation of each of these sites has a deleterious effect on promoter activity as assayed by transient transfection into cardiac myocytes. The data suggest that transcriptional activity of the human TnIc gene can be driven by a compact promoter region and that within this region GATA, MEF-2 Sp1 and CACC box-binding factors are required for optimal activity. Furthermore, a comparison with data obtained for identical elements in the promoters of rodent TnIc genes identifies differences between species which may be of consequence for species-specific promoter function.

Animals↗
PubMed2000

Heterotopic cardiac transplantation and Batista operation.

We report the case of an infant who was first seen with dilated cardiomyopathy at the age of 3 1/2 months and 2 months later, successfully underwent heterotopic cardiac transplantation in combination with partial left ventriculectomy. The benefits of combining both procedures in such a young infant particularly with regard to containment of early graft dysfunction, reduction of respiratory problems, and weight mismatch are discussed.

Cardiac Surgical Procedures↗
PubMed2000

Age dependence of heat stress mediated cardioprotection.

BACKGROUND: To study the influence of age on heat stress cardioprotection, functional recovery, nucleotide concentrations, and heat stress protein 70 (Hsp70) levels were compared in the heat stressed (HS) and control (C) hearts at different ages, in a protocol mimicking donor heart preservation for transplantation. METHODS: Control and heat stressed (24 hours before experiment) rat hearts were divided into three age groups: (I) 1 month, (Y) 4 months, and (M) 16 months (n = 6). Left ventricle balloon catheter was used to determine systolic and end-diastolic pressure/volume relations before and after 4 hours of cardioplegic arrest at 4 degrees C. Another identical set of isolated hearts underwent 5 minutes of normoxic perfusion to obtain preischemic Hsp70 content and metabolite concentrations. RESULTS: The postischemic recovery was highest in group HS-Y as compared to C-Y, HS-I, C-I, HS-M, and C-M. There were no differences in preischemic adenine nucleotides or creatine metabolite concentrations between the three age groups. In contrast, the nicotinamide adenine dinucleotide (oxidized form) (NAD+) and nicotinamide adenine dinucleotide phosphate (oxidized form) (NADP+) concentrations were significantly raised in group HS-Y. Hsp70 content was increased in all HS groups with no difference between the age groups. CONCLUSIONS: Improved postischemic functional recovery after cardioplegic arrest was observed in the young adult HS hearts. This was associated with highest NAD+ and NADP+ concentrations and did not correlate with increased Hsp70 content.

Aging↗
PubMed2000

Expression and function of angiotensin converting enzyme, chymase, and angiotensin II in the human radial artery and internal thoracic artery.

BACKGROUND: The potential role of the local renin-angiotensin system to differentially affect radial artery and internal thoracic artery graft performance has not been examined. METHODS: Contractile responses to angiotensin I and II in the radial artery and the internal thoracic artery were examined in vitro. The expression function, and localization of angiotensin receptors, angiotensin converting enzyme, and chymase were studied in radial artery and internal thoracic artery segments. RESULTS: Angiotensin I and II contractions were significantly greater (p < 0.05) in the radial artery compared to the internal thoracic artery. In both arteries, angiotensin II responses were mediated via the AT1 receptor. Messenger RNA transcripts for angiotensin-converting enzyme and chymase were detected in both arteries. Angiotensin-converting enzyme was localized to luminal and vaso vasorum endothelial cells and smooth muscle cells in both vessels, while chymase was colocalized with mast cells in adventitial and medial layers. An angiotensin converting enzyme or a chymase inhibitor singularly had no effect on angiotensin I contractions, however, when combined, a marked inhibition of the angiotensin I response was observed in both vessels. CONCLUSIONS: Our results illustrate the complexities which exist within the local renin angiotensin system and suggest that clinical trials which may modulate the system are warranted.

Aged↗
PubMed2000

Anatomy of the muscular subpulmonary infundibulum with regard to the Ross procedure.

BACKGROUND: To clarify the precise anatomical relationship of the muscular subpulmonary infundibulum. METHODS: Eleven hearts were dissected, and microscopic sections taken through the arterial trunks of a 37-week-old fetus and of a neonate. The anatomy was also investigated during operative Ross procedures. RESULTS: The sinotubular junctions of the pulmonary and aortic roots cross obliquely. The leaflets of the pulmonary valve are lifted away from the ventricular septum by the free-standing subpulmonary infundibulum, whereas the aortic valve is deeply wedged between the atrioventricular junctions. The muscular infundibulum spirals around the aortic root, being longest below the right-facing aortic sinus and shortest below the left. The first septal perforating artery pierces the septum below the shortest part of the infundibulum, sometimes within a millimeter of the pulmonary valvar hinge, but a muscular sleeve lifts the pulmonary leaflets from the septal musculature. CONCLUSIONS: The pulmonary valvar leaflets are supported entirely by free-standing musculature, having no direct relationship with the ventricular septum. This makes possible the Ross procedure.

Adult↗
PubMed2000

Transplant atherosclerosis: role of phenotypic modulation of vascular smooth muscle by nitric oxide.

Occlusive accelerated atherosclerosis of coronary grafts is the predominant factor that limits longevity of heart transplant recipients. This form of vascular disease affects both the large epicardial and the smaller intramyocardial vessels, leading to characteristic clinical presentation that necessitates the use of sophisticated techniques for their accurate detection. Accelerated atherosclerosis after transplantation is a multifactorial disease with many events contributing to its progression. The initial vascular injury associated with ischemia-reperfusion appears to aggravate preexisting conditions in the donor vasculature in addition to activation of new immunological and nonimmunological mechanisms. Throughout these events, the endothelium remains a primary target of cell- and humoral-mediated injury. Changes in the vascular intima leads to alterations in vascular smooth muscle cell (VSMC) physiology, resulting in VSMC phenotypic modulation with the orchestration of a broad spectrum of growth and inflammatory reactions, which might be a healing response to vascular injury. Endogenous nitric oxide (NO) pathways regulate a multiplicity of cellular mechanisms that play a major role in determining the structure and function of the vessel wall during normal conditions and during remodeling associated with accelerated atherosclerosis. Recently identified signaling pathways, including mitogen-activated protein kinase, cGMP-dependent protein kinase, phosphatidylinositol 3-kinase, and transcriptional events in which nuclear factor kappa B and activator protein 1 take part, can be associated with NO modulation of cell cycle perturbations and phenotypic alteration of VSMC during accelerated atherosclerosis. This article reviews recent progress covering the aforementioned matters. We start by summarizing the clincal aspects and pathogenesis of accelerated atherosclerosis associated with transplantation, including clinical presentation and detection. This summary is followed by a discussion of the multiple factors of the disease process, including immunological and nonimmunolgical contributions. The next section focuses on cellular responses of the VSMCs relevant to lesion formation, with special emphasis on classical and recent paradigms of phenotypic modulation of these cells. To examine the influence of NO on VSMC phenotypic modulation and consequent lesion development, we briefly overview characteristics of NO production in the normal coronary vascular bed and the changes in endogenous NO release and activity during atherosclerosis. This overview is followed by a section covering molecular mechanisms whereby NO regulates a range of signaling pathways, transcriptional events underlying cell cycle perturbation, and phenotypic alteration of VSMC in accelerated atherosclerosis.

Animals↗