Cardiovascular Functional Alterations in Chronic Kidney Disease
Cardiovascular disease is a major life-limiting complication in patients with Chronic Kidney Disease (CKD). The development of cardiovascular disease during renal impairment involves striking multitiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vasculature, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD). Failure of this integrated system collectively contribute to impairment of cardiovascular functional capacity. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The problem is that the natural history and progression of cardiovascular functional alterations across the CKD spectrum is largely unknown. Additionally, few studies have examined the molecular mechanisms of the failing heart underlying functional impairment in patients with CKD. The overall aim of this thesis is to define cardiovascular functional changes in patients across the CKD spectrum and to examine the physiologic and molecular mechanisms involved. To accomplish this, I utilize state-of-the-art cardiopulmonary exercise testing (CPET) to examine ventilatory exercise response indices of cardiovascular functional capacity across the CKD spectrum. Using CPET, I first examine cardiovascular functional changes and the determinants involved in patients with mild-to-moderate CKD (chapter 2) and then in patients with advanced CKD on dialysis (chapter 3). To further determine organ-specific alterations underlying functional impairment at the level of the heart, I examined myocardial cytoskeletal changes in explanted human hearts from patients on dialysis, ex vivo and performed further in vitro studies to determine the molecular mechanisms involved (chapter 4). In summary, the thesis presents for the first time evidence that impairment in cardiovascular functional capacity occurs early in CKD, and that cardiovascular functional capacity is severely impaired by the time patients reach dialysis-dependency. Additionally, the study demonstrates that hearts from patients on dialysis exhibit severe cytoskeletal impairment underlying functional impairment, it describes the role of the focal adhesion pathway in regulating these changes and unveils novel therapeutic targets.
Chronic Kidney Disease, cardiopulmonary exercise testing, CPET
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