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Title: The role of the renin angiotensin system in morbidity and mortality following orthotopic cardiac transplantation
Author: Walker, Antony H.
ISNI:       0000 0001 3552 3491
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2009
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Background. Thoracic organ transplantation is a recognized and established therapy for end stage cardio-pulmonary disease. Long-term survival of recipients is limited by chronic rejection (Graft coronary artery disease - GCAD, myocardial fibrosis and progressive ventricular dysfunction). Integral to GCAD is the development of neointimal hyperplasia. The renin-angiotensin system (RAS) has a significant role in the maintenance of fluid homeostasis. There is increasing evidence of a 'tissue' RAS being responsible for the local, autocrine control of an individual tissues development, maintenance and potential pathology. The insertion (1)/ deletion (D) of287 base pairs within intron 16 ofthe angiotensin converting enzyme (ACE) gene influences enzyme levels and activity. The D homozygote has been associated with left ventricular hypertrophy, acute myocardial infarction, ischaemic heart disease and hypertension. The role ofthis polymorphism in the transplant population remains controversial. The aim ofthis research was to investigate the role ofthe ACE polymorphism and 'postACE' proteins and cytokines following cardiac transplantation. Materials and Methods. Whole blood was collected from consented cardiac transplant recipients and DNA extracted using an established double lysis buffer method. Polymerase chain reaction (PCR) was performed to amplify the polymorphism-containing region ofDNA and the products separated using electrophoresis and visualised using ethidium bromide. Serum Angiotensin II and PDGF concentrations ofthe recipients were determined using sandwich ELISA. Vascular smooth muscle cells were cultured in varying concentrations ofPDGF and BrDU incorporation used to quantify cellular proliferation. Statistical analysis was undertaken using SPSS with p values less than 0.05 being taken as significant. Results. The D allele of the recipient was associated with greater ACE enzymatic activity. There was no significant influence ofthe ACE lID polymorphism on pre- or post-transplant clinical outcomes. ACE inhibitor therapy was associated with a reduction in ACE enzymatic activity. ANG II levels were significantly higher in individuals transplanted for ischaemic heart disease. In this population ACE inhibitor use was associated with significantly higher ANG II concentrations. Only PDGF BB was found in the serum of the study population with wide inter- and intra-recipient variability. The I allele was associated with lower serum PDGF BB concentrations. Neither ANG II nor PDGF BB concentrations had a significant influence on clinical outcome post-transplantation. PDGF induced proliferation of arterially derived vascular smooth muscle cells. Proliferation occurred within twelve hours of exposure to PDGF BB but after twenty-four hours proliferation was equal for all three isoforms. Discussion. Following orthotopic cardiac transplantation the RAS is influenced by recipient genotype. PDGF concentration is also influenced by the ACE lID polymorphism suggesting it as an effector protein of the RAS. Higher ANG II levels in those individuals transplanted for ischaemic heart disease may identify ANG II as a risk factor for atherosclerosis. The lack of association between genetic polymorphism, effector proteins (ANG II and PDGF) and clinical outcomes is likely secondary to the large number of interacting/confounding variables and risk factors present in this population (factor dilution model). ACE inhibition alters the ACE activity and our findings suggest that alternative 'non-ACE' pathways are more important in the formation ofANG II and PDGF.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available