Intrinsic Diurnal Variations in Cardiac Metabolism and Contractile Function

Abstract

Abstract-Diurnal variation of cardiac function in vivo has been attributed primarily to changes in factors such as sympathetic activity. No study has investigated previously the intrinsic properties of the heart throughout the day. We therefore investigated diurnal variations in metabolic flux and contractile function of the isolated working rat heart and how this related to circadian expression of metabolic genes. Contractile performance, carbohydrate oxidation, and oxygen consumption were greatest in the middle of the night, with little variation in fatty acid oxidation. The expression of all metabolic genes investigated (including regulators of carbohydrate utilization, fatty acid oxidation, and mitochondrial function) showed diurnal variation, with a general peak in the night. In contrast, pressure overloadinduced cardiac hypertrophy completely abolished this diurnal variation of metabolic gene expression. Thus, over the course of the day, the normal heart anticipates, responds, and adapts to physiological alterations within its environment, a trait that is lost by the hypertrophied heart. We speculate that loss of plasticity of the hypertrophied heart may play a role in the subsequent development of contractile dysfunction. Key Words: function Ⅲ gene expression Ⅲ metabolism Ⅲ perfusions Ⅲ rat C ells are able to anticipate, respond, and adapt to fluctuations in their environment. Anticipation is achieved through self-sustained intracellular clocks, providing advantageous priming of the cell in preparation to a given stimulus. 1 The response of any cell is dictated by the level of the stimulus, as well as the sensitivity to that stimulus. The latter is affected by both intracellular (genotype, circadian clocks) and extracellular (eg, neuronal and humoral factors) influences. The resultant adaptation can be either immediate (alterations in preexisting proteins) or prolonged (changes in gene and protein expression) depending on the length of exposure to the stimulus.The heart, not unlike other organs, possesses both internal clocks and the ability to respond to external stimuli, both of which could potentially influence gene expression, metabolism, and function. [2][3][4] It is well known that the onset of heart failure, myocardial infarction, and sudden death is greatest in the early hours of the morning. 5-7 For this reason, several studies have investigated diurnal variation in cardiac function in vivo, in both rodents and humans, and have correlated findings with fluctuations in neurohumoral influences. 5,8 -11 However, to date, no study has either postulated or investigated whether the intrinsic properties of the heart fluctuate during the day, or whether loss of synchronization between the presence of a stimulus (eg, sympathetic activity) and responsiveness of the heart plays a role in the development of contractile dysfunction.We set out to characterize the diurnal variation in contractile function and metabolic flux of the heart in the absence of confounding extracardiac influences by using the isolat...

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