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Translational Applications of Circadian Rhythms in Cardiology: Chronotherapy and Chronobiomarkers in Cardiovascular Disease

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Title: Translational Applications of Circadian Rhythms in Cardiology: Chronotherapy and Chronobiomarkers in Cardiovascular Disease
Author: Tsimakouridze, Elena
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: Martino, Tami
Abstract: Cardiovascular physiologic parameters such as heart rate, blood pressure, and cardiac contractility exhibit circadian time-of-day variation. Underlying these rhythms is the circadian clock, a molecular mechanism coordinating rhythmic gene transcription and protein abundance over a 24 h cycle. Circadian rhythms play a role in the timing of onset of adverse acute cardiovascular events, and altered rhythms increase the risk of cardiovascular diseases. This thesis investigates the translational applications of circadian rhythms to cardiovascular disease. The first study identified novel gene time-of-day biomarkers of cardiovascular disease. Gene biomarker candidates exhibiting day/night variation were determined with a bioinformatics analysis of microarray data from heart samples collected over 24 h from mice with pressure-overload induced cardiac hypertrophy versus sham surgery (healthy) mice. The results revealed global gene expression changes in the top 300 biomarker candidates, which were pared to 20 genes by knowledge-based analysis. The validated genes were involved in cardiac metabolism and extracellular matrix remodeling pathways. Global profiling using microarray and bioinformatics approaches demonstrate differences in gene expression profiles day vs night and can be translationally applied to create chronobiomarker panels for cardiovascular disease. The second study investigates the role of the core circadian clock mechanism, the gene Clock in cardiovascular disease. The transverse aortic constriction model was used to induce cardiac hypertrophy in wild-type mice. Diurnal microarray analysis of wild-type mice with cardiac hypertrophy revealed 67 significantly upregulated genes in the middle of the light period as compared to control wild-type mice, including the negative regulator of calcineurin (Rcan1.4). Cardiac structure and function was impaired in wild-type mice after pressure-overload hypertrophy vs controls as assessed by echocardiography. The circadian clock in the heart plays an important role in adaptation to disease states with implications for heart patients with rhythm disturbances. The third chapter discusses leading-edge therapeutic applications of circadian biology to improve cardiovascular disease outcome. This discusses i) research and clinical chronotherapeutic approaches to cardiovascular disease; ii) research in genomic, proteomic, and metabolomic factors day versus night as chronobiomarkers of cardiovascular disease; and iii) novel chronobiology drugs directly modulating the molecular clock. Consideration of circadian rhythms has significant clinical potential to improve the management and treatment of cardiovascular and other diseases. Collectively, this thesis demonstrates the role of circadian rhythms in pathophysiologic processes and supports the novel strategy of targeting and maintaining normal circadian rhythms for heart disease.
Date: 2017-01
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