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Pathophysiology. 2002 Jun;8(3):183-192.

Early and persistent activation of myocardial apoptosis, bax and caspases: insights into mechanisms of progression of heart failure.

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Department of Medicine, Division of Cardiology, St. Michael's Hospital, Terrence Donnelly Heart Center, University of Toronto, 30 Bond Street, Ontario, M5B1W8, Toronto, Canada


The aim of this study was to test the hypothesis that persistent myocardial apoptosis contributes to progression of heart failure in a canine model of pacing-induced cardiomyopathy. Dogs were paced at 250 beats per minute for 1 week (n=9), 3 weeks (n=14) and 4 weeks (n=14) with normal dogs served as controls (n=12). Myocardial apoptosis was assessed by multiple methods including DNA fragmentation and in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, bax and bcl-2 protein expression, and caspase activity. Pacing produced a progressive increase in left ventricular (LV) end diastolic pressure (LVEDP) and plasma norepinephrine levels with no significant increase in LV mass. The number of apoptotic cells was markedly increased after 1 week of pacing and remained increased at 4 weeks of pacing with characteristic DNA laddering. The increase in apoptosis was associated with bax protein expression and caspase activation while there was no detectable changes in bcl-2 protein expression. The estimated total number of apoptotic cells correlated with cardiac output and LVEDP (r=-0.69 and 0.59, respectively, P<0.001). Plasma norepinephrine and bax protein expression correlated significantly with the estimated total number of apoptotic myocytes (r=0.62 and 0.42, respectively, P<0.01). In conclusion, an early and persistent activation of myocardial apoptosis and pro-apoptotic factors is likely an important mechanism that contributes to the progression of heart failure in canine pacing-induced cardiomyopathy.


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