Despite appreciable advances with regards to current understanding of the molecular mechanisms governing chronic pressure and/or volume overload induce pathologic hypertrophy, pharmacological strategies for the clinical treatment of hypertrophic cardiomyopathy remain limited. In order to facilitate translation of recent mechanistic insights to the clinical setting, the current proposal intends to investigate hypertrophic cardiomyopathy within an innovative dimension. That being time. Obstructive sleep apnea and non-dipping hypertensive patients have an increased risk for the development of hypertrophic cardiomyopathy, which is associated with an inappropriate stress of the myocardium during the sleep phase. Conversely, exercise bouts (during the awake/active period) result in beneficial, physiologic growth of the myocardium. Collectively, these observations led us to hypothesize that the time of day at which the myocardium is challenged with hypertrophic stimuli markedly influences the remodeling response. Consistent with this hypothesis, preliminary studies in our laboratory show that isoproterenol induced cardiac growth and expression of hypertrophic markers (e.g., anf) to a greater extent when administered to mice at the beginning of the sleep/inactive phase (relative to the beginning of the awake/active phase). Regarding mechanism, we hypothesize that the cardiomyocyte circadian clock mediates time-of-day-dependent responsiveness of the heart to hypertrophic stimuli. Indeed, initial studies in our laboratory show that temporal suspension of the cardiomyocyte circadian clock at the beginning of the sleep/inactive period (i.e., CCM and CBK mice) results in a pro-hypertrophic phenotype, at gravimetric (e.g., biventricular weight), histological (i.e., myocyte cross sectional area), imaging (e.g., septal wall thickness), and transcriptional levels (e.g., anf and mcip1 induction). These observations have led to the following broad objective of this proposal: to test the innovative hypothesis that the cardiomyocyte circadian clock influences the responsiveness of the heart to pathologic and physiologic hypertrophic stimuli in a time-of-day-dependent manner, at transcriptional, post-translational, and functional levels. We plan to address this broad objective through completion of the following specific aims (SA): SA1 - Determine whether time-of-day-dependent pathologic ventricular remodeling in response to isoproterenol is mediated by the cardiomyocyte circadian clock;and SA2 - Elucidate whether the cardiomyocyte circadian clock modulates responsiveness of the myocardium to physiological hypertrophic growth. Successful completion of the proposed studies will not only unveil the cardiomyocyte circadian clock as a novel regulator of hypertrophic remodeling, but will also highlight a need to consider time-of-day when targeting distinct molecular mechanisms for clinical treatment of hypertrophic cardiomyopathy.
Despite the fact that many factors that induce hypertrophic growth of the heart oscillate in a time-of-day- dependent manner in both humans and animal models, relatively few studies have investigated how the timing of hypertrophic stimuli influences ventricular remodeling and contractile function/dysfunction. The current proposal outlines studies designed to investigate whether the time of day at which the heart is challenged with a hypertrophic stimulus significantly influences physiological versus pathological remodeling. Completion of the proposed studies will establish whether the cardiomyocyte circadian clock modulates responsiveness of the heart to hypertrophic stimuli that influence heart function/dysfunction, and may help to explain why non- dipping hypertensive and sleep apnea patients exhibit poorer clinical outcomes.
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