Cardiac diastolic dysfunction in conscious dogs with heart failure induced by chronic coronary microembolization

1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and 2 Division of Cardiology, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York Submitted 12 January 2006 ; accepted in final form 17 July 2006 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 intracoronary injections of microspheres (1.2 million, 90- to 120-µm diameter) for 24 ± 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/d t min ) 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 were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = be *EDV ) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient ( ) 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 plasminogen activator inhibitor-1 (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 development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE. coronary embolization; diastolic stiffness; plasminogen activator inhibitor-1 Address for reprint requests and other correspondence: W. Shen, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285