Stem cell therapy in no-option critical limb ischemia patients

Abstract

Critical limb ischemia (CLI) is a severe form of peripheral arterial disease (PAD), characterised by severe stenoses and / or occlusion of the leg arteries, resulting in chronic ischemic rest pain and / or non-healing ischemic skin lesions. CLI is associated with high morbidity and reduced life expectancy. This thesis shows that CLI patients score extremely poor on every health dimension of commonly used quality of life (QoL) questionnaires. This poor QoL becomes particularly apparent when compared to the QoL of patients with milder forms of PAD or of patients with cardiovascular risk factors only. The QoL scores were calculated using a norm based scoring method, and may therefore serve as a reference for the increasing number of studies investigating new experimental therapies in CLI patients. The poor life expectancy of CLI patients is mainly due to high risks of cardiovascular events. To identify patients at the highest risk of such events, a prediction model that allows for a simple assessment of this risk is proposed. The prediction model may serve as a valuable tool in vascular secondary health care to select patients that could benefit from intensified treatment. With regard to limb salvage, treatment options for patients with CLI are limited: there is no effective pharmacological therapy available and approximately half of the patients is ineligible for traditional interventions aimed at revascularisation of the affected leg. Amputation often remains the only option to relieve symptoms, but is by itself associated with a poor prognosis. New treatment options are thus needed to ameliorate the burden of CLI. In the past decade, stimulating neovascularisation by means of stem / progenitor cell therapy has emerged as a new therapeutic strategy. Neovascularisation involves the mobilisation of endothelial progenitor cells (EPC) from the bone marrow (BM) towards the circulation. These EPC subsequently contribute to the sprouting of new blood vessels by direct incorporation and proliferation into the endothelial layer of existing blood vessels and by paracrine effects on mature endothelial cells. This thesis explores stem cell therapy as a novel treatment for CLI and describes the rationale and design of the ongoing JUVENTAS study, a large randomised, placebo-controlled, double-blind trial that investigates the clinical effects of stem cell therapy in CLI patients. Increasing evidence however suggests that EPC of CLI patients have impaired function, which may negatively affect the effectiveness of stem cell therapy. The JUVENTAS study therefore also encompasses fundamental research on cell characterisation and functional properties of progenitor cells of CLI patients. In this thesis we show that despite ischemic cues, circulating EPC levels do not increase in CLI patients. Together with the observed reduction in the levels of MMP-9 and soluble c-Kit in BM plasma, this is suggestive for a functional BM impairment, possibly due to reduced NO availability. Stem cell therapy is a promising novel treatment option in CLI, but its effectiveness remains to be confirmed by ongoing randomised clinical trials. Combined with treatments augmenting progenitor cell function, therapeutic neovascularisation may become a compelling new treatment option for no-option CLI patients.