Cardiac Imaging for Regenerative Therapy and Tissue Engineering

Cardiovascular disease remains the number 1 cause of death worldwide. Over the past 20 years, therapies for treating cardiac disease have come of age and coronary heart disease in particular has seen a revolution in new treatments such as statins, stents and beta blockers. These therapies have slowed death rates and have shown potential to minimise ischemia induced atrophy following myocardial infarction. Crucially however, they are unable to recover lost heart function due to cardiomyocyte death, resulting in poor prognosis for patients. Myocardial regeneration therapy is a new strategy towards treating cardiac disease that engrafts regenerative cells and biomaterials to the myocardium to stimulate repair of tissue and restore contractile function. Cardiac regeneration therapy has made a rapid translation from preclinical research to clinical trials with the first trial in humans published in 2001. Clinical trials in the years since however have produced underwhelming results and there is a general consensus that further preclinical optimisation with powerful non-invasive imaging data will be key to the future success of regenerative medicine in humans. Magnetic resonance imaging is unparalleled in providing non-invasive multiparametric imaging of both global and regional cardiac structure and function. MRI provides high spatiotemporal resolution and multiple contrast mechanisms revealing information about molecular changes in the myocardium. These imaging abilities make MRI a versatile and powerful tool in the preclinical optimisation of cardiac regeneration therapies. Over the chapters presented in this thesis I have established a set of MR imaging techniques that enable valuable in vivo characterisation of cardiac function and structure in for use in studies of regenerative therapy. It is hoped that the methods developed over the course of this thesis aid in the uptake of imaging applications in studies of regenerative medicine and that the wide range of imaging tools demonstrated help to bring regenerative medicine closer to practical clinical therapy

Microbubbles in vascular imaging

Ultrasound is integral in diagnostic imaging of vascular disease. It is a common first line imaging modality in the detection of deep vein thrombosis (DVT) and carotid atherosclerosis. The therapeutic use of ultrasound in vascular disease is also clinically established through ultrasound thrombolysis for acute DVT. Contrast agents are widely used in other imaging modalities, however, contrast enhanced ultrasound (CEUS) using microbubbles remains a largely specialist clinical investigation with truly established roles in hepatic imaging only. Aim The aim of this thesis was to investigate diagnostic and therapeutic roles of CEUS in vascular disease. Diagnostically, carotid plaque characteristics were evaluated for stroke risk stratification in patients with carotid atherosclerosis. Therapeutically, microbubble augmented ultrasound thrombolysis was investigated in-vitro as a novel technique for acute thrombus removal in the prevention of post thrombotic syndrome. Methods A validated in-vitro flow model of DVT was adapted and developed for a formal feasibility study of microbubble augmented ultrasound thrombolysis. Two cross sectional studies of patients with 50-99% carotid stenosis were performed assessing firstly, plaque ulceration and secondly plaque perfusion using CEUS. Results Using commercially available microbubbles and ultrasound platform, significantly improved thrombus dissolution was demonstrated using CEUS over ultrasound alone in the in-vitro flow model of acute DVT. In particular, increased destruction of the thrombus fibrin mesh network was observed. CEUS demonstrated greater sensitivity than carotid duplex in the detection of carotid plaque ulceration with a trend toward symptomatic carotid plaques. A reduced plaque perfusion detected by both semi-qualitative and quantitative analysis was associated with a symptomatic status in patients with a 50-99% stenosis. Conclusion CEUS is a viable adjunct to vascular imaging with ultrasound. Microbubble augmented ultrasound thrombolysis is a feasible, non-invasive, non-irradiating intervention which warrants further investigation in-vivo. Carotid plaque CEUS may contribute to future scoring systems in stroke risk stratification but requires prospective validation.Open Acces