|Durgan, David - BAYLOR COLLEGE MED|
|Egbejimi, Oluwaseun - BAYLOR COLLEGE MED|
Submitted to: Circulation
Publication Type: Abstract Only
Publication Acceptance Date: July 20, 2006
Publication Date: October 31, 2006
Citation: Durgan, D.J., Egbejimi, O., Young, M.E. 2006. Circadian rhythms in myocardial metabolism and function [abstract]. Circulation. 114(18):134. Technical Abstract: Circadian rhythms in myocardial function and dysfunction are firmly established in both animal models and humans. For example, the incidence of arrhythmias and sudden cardiac death increases when organisms awaken. Such observations have classically been explained by circadian rhythms in neurohumoral factors, such as sympathetic stimulation. However, it is becoming increasingly clear that the intrinsic properties of the heart fluctuate over the course of the normal day. The purpose of the present study was to characterize fully circadian rhythms in myocardial metabolism and contractile function ex vivo, thereby exposing the intrinsic properties of the heart. Hearts were isolated from male Wistar rats (housed in 12h:12h light:dark cycle; lights on at 9AM) at 9AM, 3PM, 9PM, and 3AM, and perfused in the working mode with 5mM glucose plus 0.4mM oleate. Following 20min perfusion at baseline workload (100mmHg afterload), hearts were challenged with a 20-min 'work-jump' (140mmHg afterload plus 1muM epinephrine). Under basal conditions, cardiac power, oxygen consumption, and efficiency remained constant at all times investigated. Despite constant function, myocardial substrate selection exhibited marked circadian rhythms, with highest rates of glucose oxidation (GO) at 9PM (60% higher compared to 3PM; p<0.05), and highest rates of oleate oxidation at 9AM (30% higher compared to 9PM; p<0.05). Responsiveness of the heart to the 'work-jump' also exhibited circadian rhythmicity, with greatest cardiac power at 9AM (29% higher compared to 9PM; p<0.05). Despite lowest contractile function at 9PM, hearts subjected to the 'work-jump' exhibited highest rates of GO at this time (49% higher compared to 3PM; p<0.05). Increased myocardial GO at 9PM was mirrored by increased pyruvate dehydrogenase (PDH) activity at this time (143% higher compared to 9AM; p<0.05). This was likely driven by decreased PDH kinase 4 expression just prior to the light-to-dark transition. The data expose marked circadian rhythms in myocardial metabolism and function, which persist ex vivo. We speculate that decreased responsiveness of the heart to a 'work-jump' upon awakening may contribute to increased cardiovascular pathophysiological events observed in humans at this time.