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EXPERIMENTAL STUDY

Angiotensin II receptor blockade does not improve left ventricular function andremodeling in subacute mitral regurgitation in the dog

Gilbert J. Perry, MD^*, Chih-Chang Wei, PhD^*, Gerald H. Hankes, DVM, PhD, S. Ray Dillon, DVM, Patricia Rynders, DVM, Rupak Mukherjee, PhD, Francis G. Spinale, MD, PhD and Louis J. Dell’Italia, MD^*,*

^* Birmingham Veterans Affairs Medical Center, University of Alabama, Department of Medicine, Division of Cardiovascular Disease, Birmingham, Alabama, USA
Auburn College of Veterinary Medicine, Auburn, Alabama, USA
Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA

Manuscript received December 31, 2000; revised manuscript received December 13, 2001, accepted January 30, 2002.

^* Reprint requests and correspondence: Dr. Louis J. Dell’Italia, University of Alabama at Birmingham, Department of Medicine, Division of Cardiology, 834 MCLM, 1918 University Boulevard, Birmingham, Alabama 35294, USA.
dellitalia{at}physiology.uab.edu

OBJECTIVES: We hypothesized that angiotensin II type-1 (AT₁) receptor blocker (AT₁RB) would prevent adverse left ventricular (LV) remodeling and LV dysfunction when started at the outset of mitral regurgitation (MR).

BACKGROUND: Little is known regarding the efficacy of AT₁RB treatment of MR.

METHODS: Mitral regurgitation was induced by chordal disruption in adult mongrel dogs. Six normal dogs (NLs) were compared to six untreated MR dogs (MR) and seven dogs treated with the receptor blocker irbesartan (MR+AT₁RB) started 24 h after induction of MR (60 mg/kg p.o. b.i.d.) and continued for three months.

RESULTS: Treatment with AT₁RB decreased systemic vascular resistance but did not significantly improve cardiac output, LV end-diastolic dimension (LVEDD) or LVEDD/wall thickness compared to untreated MR dogs. Resting isolated cardiomyocyte length increased in MR versus NLs and was further increased in AT₁RB dogs. Left ventricular end-systolic dimension increased to a greater extent from baseline in AT₁RB dogs versus untreated MR dogs (29 ± 9% vs. 12 ± 6%, p < 0.05), despite a significantly lower LV peak systolic pressure in AT₁RB dogs. Plasma-angiotensin (ANG) II was elevated greater than threefold in both MR and MR+AT₁RB versus NLs. In contrast, intracardiac ANG II was increased greater than twofold in MR dogs versus NLs, but was normalized by AT₁RB.

CONCLUSIONS: The use of AT₁RB decreased systemic vascular resistance and attenuated local expression of the renin-angiotensin system but did not prevent adverse LV chamber and cardiomyocyte remodeling. These results suggest that blockade of the AT₁ receptor does not improve LV remodeling and function in the early myocardial adaptive phase of MR.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   ANG   angiotensin   ANOVA   analysis of variance   AT1   angiotensin II type-1 receptor   AT2   angiotensin II type-2 receptor   AT1RB   angiotensin II type-1 receptor blocker   CHF   congestive heart failure   LV   left ventricle/ventricular   LVEDD   left ventricular end-diastolic dimension   LVESD   left ventricular end-systolic dimension   LVESS   left ventricular end systolic stress   LVESV   left ventricular end systolic volume   MR   mitral regurgitation   NL   normal dogs   RAS   renin-angiotensin system

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