Author
DURGAN, DAVID - BAYLOR COLLEGE MED | |
FISCHER, MELANIE - UNIV ALBERTA | |
EGBEJIMI, OLUWASEUN - BAYLOR COLLEGE MED | |
Bray, Molly | |
CHOW, CHI-WING - ALBERT EINSTEIN COLL MED | |
DYCK, JASON - UNIV ALBERTA | |
Young, Martin |
Submitted to: Circulation
Publication Type: Abstract Only Publication Acceptance Date: 7/20/2006 Publication Date: 10/31/2006 Citation: Durgan, D.J., Fischer, M., Egbejimi, O., Bray, M.S., Chow, C., Dyck, J.R., Young, M.E. 2006. Circadian rhythms in fatty acid-induced depression of myocardial contractile function: Potential mediation by the circadian clock within the cardiomyocyte [abstract]. Circulation. 114(18):211. Interpretive Summary: Technical Abstract: Circadian rhythms in susceptibility to cardiovascular (CV) pathologic events (e.g., arrhythmias, myocardial infarction) are well established. These phenomena have been explained largely by diurnal variations in neurohumoral influences, such as sympathetic activity. Circadian clocks are intracellular molecular mechanisms capable of altering sensitivity of cells to environmental stimuli over the course of the day. Fatty acids (FAs) decrease myocardial efficiency and contractile function. We hypothesized that increased susceptibility of the heart to FA-induced contractile dysfunction upon awakening may contribute to increased risk of CV pathologic events observed at this time. 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 ex vivo with 5mM glucose, plus 0.4, 0.8, or 1.2 mM oleate. Following 20min perfusion at baseline workload (100mmHg afterload), hearts were challenged with a 'work-jump' (140mmHg afterload plus 1uM epinephrine). Oleate reduced cardiac power and efficiency for hearts perfused at 3PM, in a concentration-dependent manner (e.g., 1.8-fold higher cardiac power for hearts perfused with 0.4mM versus 1.2mM oleate; p<0.01). This effect was exacerbated by the 'work-jump'. In contrast, cardiac function was not influenced by FA availability at 9AM, 9PM, or 3AM, at basal workload. For hearts perfused with 1.2mM oleate, the 'work-jump' caused severe contractile dysfunction at all times of the day. Hearts were next isolated from wild-type and transgenic (in which the circadian clock is impaired specifically within the cardiomyocytes) mice at 9PM, and perfused ex vivo (5mM glucose, 1.2mM palmitate, 50mmHg afterload for basal workload, 80mmHg afterload plus 300nM isoproteronol for 'work-jump'). The 'work-jump' resulted in a rapid depression of cardiac power for wild-type hearts. However, cardiac power was completely unaffected by the 'work-jump' for transgenic hearts, suggesting that the circadian clock mediates the time-dependent effects of FAs on contractile function depression. We speculate that equivalent susceptibility of the human heart to FAs may contribute to increased contractile dysfunction observed upon awakening. |