Cardiac allograft vasculopathy : the role of immunosuppressive therapy

Vascular narrowing, or more correctly termed intimal hyperplasia, is a central feature of chronic rejection occurring in all allografts following heart transplantation. The aim of this thesis was to determine the effects of modem immunosuppressive agents on the development of intimal hyperplasia. Potential synergistic combinations that may potentiate their individual actions were then investigated. The introductory three chapters discuss the aetiology, molecular mechanisms and role of immunosuppressive therapy respectively. The experimental chapter describes the model and techniques employed throughout the study. Four results chapters detail the findings of the effects of immunosuppressive drugs and the potential of a novel anti- fibrotic agent on the development of intimal hyperplasia. The final chapter reviews the principal findings of the thesis and potential avenues for further investigation. The central findings of this thesis demonstrate clear differences in the effects of the drugs on intimal thickening following arterial injury. In summary, cyclosporin had no impact on early intimal hyperplasia but its prolonged administration was associated with a marked increase in intimal thickening compared to untreated controls. Tacrolimus inhibited early intimal thickening but had no significant effect at the end of the study period. However, treatment with either mycophenolate mofetil or rapamycin was associated with a significant reduction at both early and late time points, offering potential preferential alternatives to cyclosporine, which forms the mainstay of current immunosuppressive regimens. The novel anti-fibrotic agent Pirfenidone had a more potent early anti-proliferative effect on vascular smooth muscle cells compared to either mycophenolate mofetil or rapamycin. However treatment with Pirfenidone had no significant inhibitory effect on intimal thickening by 28 days. Treatment with all immunosuppressive agents was associated with a significant increase in intimal extracellular matrix deposition compared to untreated controls. This increase was most marked in the cyclosporin group. Pirfenidone however significantly decreased the deposition of extracellular matrix proteins at 28 days compared to all other treatment groups and untreated controls. Molecular analysis using reverse transcription polymerase chain reaction aimed to target potential mechanisms to account for the observed histological changes. Despite there being significant differences between treatment and control groups in the expression of all genes studied, there were no significant differences in gene expression between individual treatment regimens. Thus the molecular data failed to explain the histological changes observed between different treatment groups. The most marked reduction in intimal hyperplasia was observed in the Pirfenidone treated group at 14 days. However this benefit was not observed at 28 days and this warrants further investigation in a 'higher' model to assess whether this late increase relates to an upregulation of other pathways fundamental to vascular smooth muscle cell proliferation and extracellular matrix deposition or is a failure of the model that may or may not be observed in the human setting. The experimental data advocates a potential role for the use if alternative immunosuppressive drugs which may reduce the degree of vascular narrowing following arterial injury.