Effectiveness of beta-blockade in experimental chronic aortic regurgitation.
BACKGROUND
Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats.


RESULTS
Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, beta-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of beta1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented.


CONCLUSIONS
In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.
Plante
Eric
E
Groupe de Recherche sur les Valvulopathies, Centre de Recherche Hôpital Laval, Institut de Cardiologie de Québec, Université Laval, Quebec, Canada.
Lachance
Dominic
D
Gaudreau
Martin
M
Drolet
Marie-Claude
MC
Roussel
Elise
E
Arsenault
Marie
M
Couet
Jacques
J
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001022:Aortic Valve Insufficiency / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D002395:Catecholamines / Q000032:analysis; D048429:Cell Size / Q000187:drug effects; D002908:Chronic Disease; D004353:Drug Evaluation, Preclinical; D005353:Fibronectins / Q000032:analysis; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D009929:Organ Size; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis / Q000235:genetics; D013318:Stroke Volume; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D005353:Fibronectins; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D008790:Metoprolol