Dissociation between cardiomyocyte function and remodeling with beta-adrenergic receptor blockade in isolated canine mitral regurgitation

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 295; no. 6; pp. H2321 - H2327
• Main Authors: Pat, Betty, Killingsworth, Cheryl, Denney, Thomas, Zheng, Junying, Powell, Pamela, Tillson, Michael, Dillon, A Ray, Dell'Italia, Louis J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2008
• Subjects: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists - pharmacology; Animals; Cell Shape - drug effects; Collagen - metabolism; Disease Models, Animal; Dogs; Female; Imaging, Three-Dimensional; Isoproterenol - pharmacology; Magnetic Resonance Imaging; Male; Metoprolol - analogs & derivatives; Metoprolol - pharmacology; Mitral Valve Insufficiency - drug therapy; Mitral Valve Insufficiency - metabolism; Mitral Valve Insufficiency - pathology; Mitral Valve Insufficiency - physiopathology; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Receptors, Adrenergic, beta-1 - metabolism; Stroke Volume - drug effects; Time Factors; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00746.2008

The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that beta1-adrenergic receptor blockade (beta1-RB) would attenuate LV remodeling after 4 mo of MR in the dog. beta1-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by beta1-RB. However, beta1-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171+/-5 microm, P<0.05) compared with normal (156+/-3 microm) and MR (165+/-4 microm) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73+/-0.31 vs. 5.02+/-0.26%, P<0.05) and normalized with beta1-RB (4.73+/-0.48%). In addition, stimulation with the beta-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% (P<0.05) in beta1-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, beta1-RB improved LV cardiomyocyte function and beta-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization.