THE THERAPEUTIC USE OF ADULT AUTOLOGOUS BONE MARROW DERIVED CELLS IN ISCHAEMIC CARDIOMYOPATHY

Abstract

The effect of combined cytokine and cell therapy in ischaemic cardiomyopathy is unclear. Meta-analyses suggest improved cardiac function with cell therapy. The optimal cell delivery route remains unclear. The mechanism of effect on cardiac function with cell therapy remains to be elucidated. This thesis aims to address these unanswered questions. Chapter 1 introduces cell therapy in ischaemic cardiomyopathy. Chapter 2 details the methods. This thesis can be divided into three projects. The first project investigates whether granulocyte-colony stimulating factor (G-CSF) alone or in combination with intracoronary (IC) or intramyocardial (IM) injection of autologous bone marrow-derived cells (BMC) improves cardiac function as well as functional and biochemical parameters in patients with ischaemic cardiomyopathy. Chapter 3 details the results of the study which suggests an improvement in cardiac function, patient functional characteristics and biochemical parameters in patients who received IM BMC therapy along with G-CSF. The second and third projects assess the mechanisms by which improvements in cardiac function and/or symptoms may have occurred. The second study looked at the association between various pro- and anti-inflammatory cytokines as well as pro-angiogenic cytokines with G-CSF/cell therapy. Chapter 4 details the results of the cytokine sub-study. Important signals were observed including a reduction in certain pro-inflammatory cytokines (e.g. MCP-1, IL-8 and IL-1b) and an increase in the pro-angiogenic cytokine VEGF in the group with a significant improvement in cardiac function at 1 year i.e. the IM BMC group. The third project (chapter 5) looked at myocardial scar, diastolic function and cell characteristics in relation to G-CSF/cell therapy and cardiac function. The results highlighted important correlations including a significant association between colony-forming unit granulocyte-macrophage counts and improvement in cardiac function in the IM BMC group. Lastly, in chapter 6, I discuss the findings and the implications of the research in everyday practice.