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Cardiac diastolic dysfunction in conscious dogs with heart failure induced by chronic coronary microembolization
Robert M Gill1, Bonita D Jones, Angela K Corbly
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Insights
Congestive heart failure (CHF) impairs left ventricular (LV) diastolic function. Chronic coronary embolization (CCE) in dogs caused diastolic dysfunction, increased myocardial stiffness, and fibrosis, alongside reduced systolic function.
Area of Science:
- Cardiology
- Physiology
- Pathology
Background:
- Left ventricular (LV) diastolic dysfunction is a key feature of congestive heart failure (CHF).
- Understanding diastolic dysfunction mechanisms in heart failure models is crucial for therapeutic development.
Purpose of the Study:
- To investigate LV diastolic function in a canine model of CHF induced by chronic coronary embolization (CCE).
- To characterize changes in LV relaxation, passive viscoelastic properties, and myocardial structure post-CCE.
Main Methods:
- Induction of CHF in dogs via daily intracoronary microsphere injections over 24 +/- 4 days.
- Measurement of LV pressure and dimensions to assess systolic and diastolic function.
- Evaluation of LV passive viscoelasticity and regional myocardial stiffness, coupled with histological analysis for fibrosis and collagen content.
Main Results:
- CCE significantly depressed LV systolic function (dP/dt(min) decreased 25%).
- LV active relaxation was impaired (isovolumic relaxation constant and duration increased).
- LV chamber stiffness (alpha, k) and regional myocardial diastolic stiffness increased significantly (62-73%), associated with fibrosis and increased collagen I/III, and PAI-1 expression.
Conclusions:
- Chronic coronary embolization in dogs effectively models CHF with impaired LV diastolic relaxation and increased chamber stiffness.
- Myocardial fibrosis and altered collagen composition, along with PAI-1 activation, contribute to diastolic dysfunction in this CHF model.
Abstract:
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-microm diameter) for 24 +/- 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/dt(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(alpha*EDV)) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (alpha) 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.
