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Time course of spirapril-induced structural and functional changes after myocardial infarction in rats followed with
W Zierhut1, M Rudin, E Robertson
1Sandoz Pharma Preclinical Research, Basel, Switzerland.
Abstract:
Structural alterations after myocardial infarction (MI) in rats are usually examined only after death of the experimental animal. Magnetic resonance imaging (MRI) allows repeated and noninvasive measurements of important structural [left ventricular (LV) mass, LV wall thickness, LV chamber radius] as well as function [LV end-systolic and LV end-diastolic volume, stroke volume (SV), ejection fraction (EF)] parameters for a prolonged period. We describe our experience in a series of experiments in rats. Three weeks after MI, infarct size (IS) was determined by MRI and the rats were divided into two groups with equal IS. Three weeks later, treatment with the angiotensin-converting enzyme (ACE) inhibitor spirapril (10 mg/kg in food) or placebo was started. In both groups, the first MRI scan taken before the treatment showed moderately dilated left ventricles and signs of impaired LV function, i.e., an increase in LV end-systolic and end-diastolic volume and decreased EF. After 3-week treatment, no significant differences with respect to heart structure and function were detected as compared with those of untreated animals. Prolonged treatment for 10 weeks with spirapril resulted in significant reduction of LV dilatation, LV mass, and LV end-systolic and end-diastolic volume, which was accompanied by improved EF. Hemodynamic examinations after treatment for 6 months showed, in contrast to control animals, no increase in right ventricular systolic pressure in animals receiving spirapril. Furthermore, histologic examination of perfusion-fixed hearts at the end of the study demonstrated more pronounced LV dilatation in control animals, thus confirming the in vivo MRI data. Delayed treatment with spirapril proved to have beneficial effects on structure and function of infarcted hearts within 10 weeks. Spirapril limited LV dilatation, reduced LV weight and LV end-systolic and end-diastolic volumes, and improved EF.
Insights
Delayed treatment with spirapril improved heart structure and function after myocardial infarction (MI) in rats. This angiotensin-converting enzyme (ACE) inhibitor limited left ventricular (LV) dilatation and improved ejection fraction (EF).
Area of Science:
- Cardiovascular Research
- Animal Models of Cardiac Disease
- Pharmacology
Background:
- Myocardial infarction (MI) leads to structural and functional cardiac alterations.
- Traditional methods for assessing these changes are invasive and terminal.
- Magnetic Resonance Imaging (MRI) offers a noninvasive approach for longitudinal studies.
Purpose of the Study:
- To evaluate the long-term effects of delayed spirapril treatment on post-MI cardiac remodeling in rats.
- To assess the efficacy of an angiotensin-converting enzyme (ACE) inhibitor in mitigating adverse structural and functional changes following MI.
Main Methods:
- Myocardial infarction was induced in rats, and infarct size was assessed using MRI.
- Rats were divided into groups receiving delayed treatment with spirapril or placebo.
- Cardiac structure and function were monitored noninvasively using serial MRI scans over 10 weeks.
- Hemodynamic and histological analyses were performed at study completion.
Main Results:
- Delayed treatment with spirapril for 10 weeks significantly reduced left ventricular (LV) dilatation, LV mass, and LV volumes compared to placebo.
- Improved ejection fraction (EF) was observed in the spirapril-treated group.
- Histological and hemodynamic data corroborated the MRI findings, showing less LV dilatation and preserved right ventricular systolic pressure in spirapril-treated rats.
Conclusions:
- Delayed administration of the ACE inhibitor spirapril demonstrates significant beneficial effects on cardiac structure and function in a rat model of MI.
- Spirapril effectively limits adverse left ventricular remodeling and improves systolic function post-MI.
- MRI is a valuable tool for noninvasive, longitudinal assessment of therapeutic interventions in experimental cardiac disease.