Martino Tami A, Young Martin E
Cardiovascular Research Group, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
J Biol Rhythms. 2015 Jun;30(3):183-205. doi: 10.1177/0748730415575246. Epub 2015 Mar 22.
Cardiac function and dysfunction exhibit striking time-of-day-dependent oscillations. Disturbances in both daily rhythms and sleep are associated with increased risk of heart disease, adverse cardiovascular events, and worsening outcomes. For example, the importance of maintaining normal daily rhythms is highlighted by epidemiologic observations that night shift workers present with increased incidence of cardiovascular disease. Rhythmicity in cardiac processes is mediated by a complex interaction between extracardiac (e.g., behaviors and associated neural and humoral fluctuations) and intracardiac influences. Over the course of the day, the intrinsic properties of the myocardium vary at the levels of gene and protein expression, metabolism, responsiveness to extracellular stimuli/stresses, and ion homeostasis, all of which affect contractility (e.g., heart rate and force generation). Over the past decade, the circadian clock within the cardiomyocyte has emerged as an essential mechanism responsible for modulating the intrinsic properties of the heart. Moreover, the critical role of this mechanism is underscored by reports that disruption, through genetic manipulation, results in development of cardiac disease and premature mortality in mice. These findings, in combination with reports that numerous cardiovascular risk factors (e.g., diet, diabetes, aging) distinctly affect the clock in the heart, have led to the hypothesis that aberrant regulation of this mechanism contributes to the etiology of cardiac dysfunction and disease. Here, we provide a comprehensive review on current knowledge regarding known roles of the heart clock and discuss the potential for using these insights for the future development of innovative strategies for the treatment of cardiovascular disease.
心脏功能及功能障碍呈现出显著的昼夜节律性振荡。日常节律和睡眠的紊乱都与心脏病风险增加、心血管不良事件及预后恶化相关。例如，流行病学观察结果凸显了维持正常日常节律的重要性，即夜班工作者患心血管疾病的发病率增加。心脏活动的节律性是由心脏外因素（如行为以及相关的神经和体液波动）与心脏内因素之间复杂的相互作用介导的。在一天当中，心肌的内在特性在基因和蛋白质表达、代谢、对细胞外刺激/应激的反应以及离子稳态等层面都会发生变化，所有这些都会影响心肌收缩力（如心率和力量产生）。在过去十年中，心肌细胞内的生物钟已成为调节心脏内在特性的关键机制。此外，有报告指出通过基因操作破坏该机制会导致小鼠患心脏病及过早死亡，这凸显了这一机制的关键作用。这些发现，再加上众多心血管危险因素（如饮食、糖尿病、衰老）会显著影响心脏生物钟的报告，引发了这样一种假说，即该机制的异常调节促成了心脏功能障碍和疾病的病因。在此，我们全面综述了关于心脏生物钟已知作用的现有知识，并探讨了利用这些见解为未来开发心血管疾病创新治疗策略的可能性。
