Lupton, Emily; (2024) Multimodal Imaging of Cardiovascular Diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cardiovascular diseases are the leading cause of death worldwide. Hypertension affects 1.1 billion people globally and is a significant risk factor of cardiovascular disease. Therapeutic interventions can prevent or reduce metabolic and physiological changes caused by cardiovascular diseases. To monitor and enhance the efficacy of therapies it is important that non-invasive methods for measuring the structural and molecular properties of the heart are developed. This thesis develops and applies a range of novel imaging methods to small animal models of cardiovascular diseases, and gives unique insights into how different modalities can generate complimentary data in relevant models. Photoacoustic imaging is a relatively new imaging modality that can be used to assess blood oxygen saturation in deep tissue. Unmanaged hypertension can lead to cardiac hypertrophy and reduced angiogenesis which limits oxygen supply to the heart and organs. Here, photoacoustic imaging has been applied for the first time in a spontaneously hypertensive rat model to measure oxygenation changes in the hind limb. The method has then been applied to an angiotensin II induced cardiac hypertrophy mouse model to measure cardiac blood oxygen saturation. To examine the application of photoacoustic imaging for the assessment of therapies, a group of angiotensin II mice were treated with losartan. The findings suggest that photoacoustic imaging can measure the differences in blood oxygen saturation seen in cardiovascular diseases and can be used to monitor the efficacy of therapies. Hypertension is a significant risk factor of myocardial infarction. Many imaging modalities are used clinically for diagnosis, prognosis and monitoring of therapies. These techniques are available preclinically and provide insight into cardiac function and viability. Here, ¹⁸F-FDG positron emission tomography has been optimised for imaging myocardial infarction in mice. Then ¹⁸F-FDG positron emission tomography, late gadolinium enhanced magnetic resonance imaging, manganese enhanced magnetic resonance imaging and micro computed tomography have been compared for evaluation of cardiac function, infarct size and left ventricle mass in a mouse model of myocardial infarction. These comparisons will direct future studies on cardiac function. Diffuse fibrosis contributes to poor prognosis in cardiac hypertrophy and myocardial infarction, but is difficult to quantify and often relies on biopsy. Methods have been developed to measure extracellular volume fraction with computed tomography but this is yet to be applied in mice. Here, a micro computed tomography method has been used to examine cardiac fibrosis in myocardial infarction mice, angiotensin II induced cardiac hypertrophy mice, and angiotensin II mice treated with losartan. These measurements have been validated with magnetic resonance imaging and histological assessment of collagen fractional area. The findings suggest that micro computed tomography extracellular volume fraction is sensitive to changes in diffuse fibrosis in disease and can evaluate the success of antifibrotic therapies in mice. Overall, this thesis has developed, applied and compared multiple imaging modalities to animal models of angiotensin II induced cardiac hypertrophy and myocardial infarction, and has generated important new insights into the strengths and weaknesses of commonly used modalities and highlighted potential translational applications of each method.

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