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Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure

¹First Department of Internal Medicine, ²Department of Laboratory Medicine, and ³Department of Pathology, Mie University School of Medicine, Tsu 514-8507, Japan

Submitted 18 May 2004 ; accepted in final form 15 July 2004

Angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor (ACEI) each act in a different manner to prevent myocardial fibrosis and left ventricular (LV) stiffness in animals with pathways in the heart for generating ANG II as well as ACE. A model of pacing-induced congestive heart failure (CHF) was used to test the central hypothesis that ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness to a greater extent than ARB or ACEI alone. Thirty-five dogs were assigned to the following treatment protocols on the 8th day of a 4-wk pacing schedule: 1) rapid ventricular pacing, 2) ARB (candesartan cilexetil, 1.5 mg·kg^–1·day^–1) with pacing, 3) ACEI (enalapril, 1.9 mg·kg^–1·day^–1) with pacing, 4) ARB (candesartan cilexetil, 0.75 mg·kg^–1·day^–1) + ACEI (enalapril, 0.95 mg·kg^–1·day^–1) with pacing, and 5) sham operation. The LV stiffness coefficient was significantly increased after rapid pacing but was significantly lower with ARB + ACEI than with ARB or ACEI alone. The collagen volume fraction and mRNA levels of collagen I and III, which were increased by rapid pacing, were significantly lower with ARB + ACEI than with ARB or ACEI alone. Thus ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness during the progression of CHF compared with ARB or ACEI alone.

congestive heart failure; angiotensin II; collagen I and III; rapid pacing