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The Critical Role of Circadian Rhythms in the Pathophysiology of Cardiovascular Disease

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Title: The Critical Role of Circadian Rhythms in the Pathophysiology of Cardiovascular Disease
Author: Alibhai, Faisal
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: Martino, Tami
Abstract: Cardiovascular physiology exhibits circadian rhythms in number of parameters including heart rate, blood pressure, and myocardial contractility. Disruption of circadian rhythms alters cardiovascular rhythms and increases the risk of cardiovascular disease. However, the pathophysiological mechanisms responsible are poorly understood. This thesis investigates the role of circadian rhythms in the pathophysiology of cardiovascular disease. Study 1 demonstrates that short term circadian rhythm disruption following myocardial infarction alters the inflammatory response post-myocardial infarction. Although rhythms were only disturbed for 5 days, disruption impaired scar formation and worsened long-term outcome. Maintenance of rhythms facilitated proper infarct healing and better outcome. The circadian mechanism factor CLOCK plays a key role in regulating inflammatory responses as ClockΔ19/Δ19 mice (which lack a functional circadian mechanism) exhibit increased macrophage infiltration post-myocardial infarction. This has important implications for patients recovering in intensive care units where circadian rhythm disturbances are common. Study 2 shows that male ClockΔ19/Δ19 mice develop age-dependent cardiovascular disease characterized by cardiac hypertrophy, fibrosis, impaired vascular responses, and reduced cardiac function. Development of disease in ClockΔ19/Δ19 mice is associated with increased activation of AKT and mTOR signalling. Pharmacological modulation of the circadian mechanism reduced AKT activation and heart weight in a Clock-dependent manner. These results support CLOCK as a regulator of cardiac growth and suggest that pharmacological modulation of the circadian mechanism is a novel approach for treating cardiovascular disease. Study 3 shows that female ClockΔ19/Δ19 mice are protected from the development of age-dependent heart disease. In contrast to the males, female ClockΔ19/Δ19 mice maintain normal heart size with age. Although CLOCK disruption altered diurnal activity and food intake, female ClockΔ19/Δ19 mice maintain normal glucose tolerance as well as normal cardiac and liver substrate uptake. Further examination of cardiac metabolism shows that female ClockΔ19/Δ19 hearts have altered lipid profiles compared to male mice, which may limit myocyte loss and preserve mitochondrial function with age. Lastly, a protective role for ovarian hormones is shown as ovariectomized ClockΔ19/Δ19 mice develop increased LV dilation compared to ovariectomized WT mice by 8 months. Collectively these studies demonstrate novel and important roles of circadian rhythms in the pathophysiology of cardiovascular disease.
Date: 2016-09
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