Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation in the dog.
OBJECTIVE
We hypothesized that angiotensin II type-1 (AT(1)) receptor blocker (AT(1)RB) 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 AT(1)RB 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+AT(1)RB) started 24 h after induction of MR (60 mg/kg p.o. b.i.d.) and continued for three months.


RESULTS
Treatment with AT(1)RB 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 AT(1)RB dogs. Left ventricular end-systolic dimension increased to a greater extent from baseline in AT(1)RB dogs versus untreated MR dogs (29 +/- 9% vs. 12 +/- 6%, p < 0.05), despite a significantly lower LV peak systolic pressure in AT(1)RB dogs. Plasma-angiotensin (ANG) II was elevated greater than threefold in both MR and MR+AT(1)RB versus NLs. In contrast, intracardiac ANG II was increased greater than twofold in MR dogs versus NLs, but was normalized by AT(1)RB.


CONCLUSIONS
The use of AT(1)RB 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 AT(1) receptor does not improve LV remodeling and function in the early myocardial adaptive phase of MR.
Perry
Gilbert J
GJ
Birmingham Veterans Affairs Medical Center, University of Alabama, Department of Medicine, Division of Cardiovascular Disease, Birmingham, Alabama 35294, USA.
Wei
Chih-Chang
CC
Hankes
Gerald H
GH
Dillon
S Ray
SR
Rynders
Patricia
P
Mukherjee
Rupak
R
Spinale
Francis G
FG
Dell'Italia
Louis J
LJ
D000407:Alabama; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D053818:Chymases; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006352:Heart Ventricles / Q000201:enzymology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008944:Mitral Valve Insufficiency / Q000188:drug therapy*; D044140:Receptor, Angiotensin, Type 1; D012083:Renin / Q000097:blood / Q000187:drug effects; D012697:Serine Endopeptidases / Q000097:blood; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000803:Angiotensin I; D012697:Serine Endopeptidases; D053818:Chymases; D012083:Renin