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(Circulation. 1997;96:2239-2246.)
© 1997 American Heart Association, Inc.

Articles

Pharmacological Modulation of Pressure-Overload Cardiac Hypertrophy

Changes in Ventricular Function, Extracellular Matrix, and Gene Expression

Kit Wong, FRCS; Kenneth R. Boheler, PhD; Mario Petrou, FRCS; ; Magdi H. Yacoub, FRCS

From the Division of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.

Correspondence to Professor Sir Magdi Yacoub, Department of Cardiac Surgery, Royal Brompton Hospital, Sydney St, London SW3 6NP, UK.

Background Appropriate cardiac hypertrophy (CH) is necessary in several clinical settings, such as pulmonary artery banding in the two-stage arterial switch operation for transposition of the great arteries. Pressure-overload CH, however, produces ventricular dysfunction due to structural and molecular changes. The ß₂-adrenergic receptor agonist clenbuterol has been shown to induce CH without such adverse effects to the rat heart. This study was performed to determine its effects on left ventricular (LV) function, structure, and gene expression in pressure-overload CH.

Methods and Results Sprague-Dawley rats were assigned to one of four groups: 1, sham-operated (n=15); 2, banding of ascending aorta (n=22); 3, banding+clenbuterol (n=18); and 4, banding+thyroxine (n=17). At the end of 3 weeks, groups 2, 3, and 4 showed an increase in LV mass index of 49.7±5.1%, 66.1±3.8%, and 47.6±4.6%, respectively, relative to group 1. A subgroup with severe CH (>50%) in group 2 was found to have significantly impaired developed pressure and diastolic relaxation and an increase in passive stiffness, with significantly reduced LV expression of sarcoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) mRNA and increased LV collagen concentration. In comparison, similarly hypertrophied animals in groups 3 and 4 demonstrated improved developed pressure, normal relaxation and diastolic stiffness with normal collagen concentration, and a greater abundance of SERCA2a mRNA.

Conclusions Clenbuterol administration in conjunction with pressure overload produces a specific type of CH with preserved LV function. In addition, an increase in LV mass was associated with less fibrosis and greater expression of SERCA2a mRNA than banding alone.

Key Words: hypertrophy • pharmacology • collagen • sarcoplasmic reticulum

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