Application Of Synchrotron Microangiography To Functional Imaging Of Coronary Vessels In Vivo

Abstract

Heart failure (HF) can be defined as a state in which the heart is unable to generate sufficient cardiac output to maintain normal body function. It can be caused by a variety of diseases or conditions that impair or overload the heart. HF usually develops slowly, often over many years (chronic HF), but it can also occur with rapid onset (acute HF). While mortality from acute myocardial infarction (MI) and chronic HF resulting from MI is on the decline in many countries, there is a secondary epidemic of HF with preserved ejection fraction (HFpEF) due at least partly to the global epidemic of obesity and diabetes. Additionally, various conditions, including hypertension, obesity, diabetes mellitus, sleep apnea, and coronary vascular disease (especially acute MI) are considered to accelerate the progression of HFpEF to end-stage HF. Early diagnosis and prevention of HF is a crucial strategy for reducing cardiac remodeling and the other adverse compensatory pathophysiological changes associated with all subtypes of HF. This strategy is thus critical for improving survival of patients with HF. Assessment of coronary vascular function is a useful research tool to evaluate therapies for chronic HF, because coronary vascular disease or dysfunction are common causes of HF. Micro- angiography is a novel and minimally invasive technique for evaluation of coronary vascular function. In the experiments described in this thesis, synchrotron based microangiography was used to evaluate the efficacy of several therapies aimed at preventing the development of HF after MI. At the same time, micro-angiography was used to determine coronary vascular function in rodent models with various risk factors for development of HF, such as intermittent hypoxia, insulin resistance and vasospasm. This approach was aimed towards improving our understanding of the contributions of these risk factors to coronary vascular dysfunction and the progression of HF. In the studies described in this thesis, we found that a regenerative therapy that combined stem cells with endogenous sources of angiogenic factors had a better potential to prevent and treat HF than either treatment as a monotherapy. The efficacy of combined therapy appeared to be due to its ability to increase and re-established coronary blood flow by increasing the number of functional coronary microvessels in the infarcted heart. In contrast, we found that a pharmacological therapy, the prostacyclin analogue ONO-1301, did not produce consistent and significant benefits in the rodent model of chronic HF we studied. We also found that risk factors for HF, such as insulin resistance and intermittent hypoxia, have additive effects on coronary function by exacerbating endothelial dysfunction. However, these two risk factors appear to affect coronary circulation through different mechanisms. Therefore, the strategies for preventing the onset of HFpEF and the progression of chronic HF should not only be directed towards amelioration of symptoms, but should also be directed towards minimizing risk factors for HF. In conclusion, in studies of rodents, using synchrotron microangiography, we were able to demonstrate how risk factors for HF and novel potential treatments for HF affect the function of the coronary circulation. These studies provide novel insights into the mechanisms that drive progression of coronary dysfunction, particularly the relative roles of major risk factors for HF. They also demonstrate that it is possible to assess the efficacy of potential therapies for HF in preclinical studies by evaluating coronary function in vivo.