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1 Eli Lilly and Company, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: shenw2{at}wyeth.com.
Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intra-coronary injections of microspheres (90-120 mm diameter, 1.2 million) for 24±4 days, resulting in significant depression of cardiac systolic function. After CCE, LV dP/dtmin decreased by 25±2% (P<0.05), and LV isovolumic relaxation constant and duration increased by 19±5% and 25±6%, respectively (both P<0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties was evaluated from the LV end-diastolic pressure-volume relationship (EDP = ae
*EDV ) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (a) increased by 62±10% (P<0.05) and the stiffness constant (K) increased by 66±13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70±25% and 63±24% (both P<0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of PAI-1 protein expression. Thus, along with depressed LV systolic function; there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with the development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.
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