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Pharmacological modulation of pressure-overload cardiac hypertrophy: changes in ventricular function, extracellular
K Wong1, K R Boheler, M Petrou
1Division of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.
Insights
Clenbuterol, a beta2-adrenergic agonist, induces cardiac hypertrophy (CH) with preserved left ventricular (LV) function. This study shows clenbuterol-induced CH in rats had less fibrosis and more SERCA2a mRNA than pressure-overload CH alone.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Cardiac hypertrophy (CH) is essential in some clinical situations but can cause ventricular dysfunction.
- Pressure-overload CH leads to adverse structural and molecular changes.
- Beta2-adrenergic receptor agonists like clenbuterol may induce CH without negative effects.
Purpose of the Study:
- To investigate the effects of clenbuterol on left ventricular (LV) function, structure, and gene expression in pressure-overload CH.
- To compare clenbuterol-induced CH with pressure-overload induced CH.
Main Methods:
- Rats underwent sham operation, ascending aorta banding, or banding combined with clenbuterol or thyroxine treatment.
- Left ventricular (LV) mass index, developed pressure, diastolic relaxation, passive stiffness, collagen concentration, and SERCA2a mRNA expression were measured after 3 weeks.
Main Results:
- All treatment groups showed increased LV mass index compared to sham-operated rats.
- Severe CH induced by banding alone resulted in impaired LV function, increased stiffness, reduced SERCA2a mRNA, and higher collagen concentration.
- Clenbuterol and thyroxine treatments preserved LV function, improved relaxation and stiffness, and increased SERCA2a mRNA abundance.
Conclusions:
- Clenbuterol administration with pressure overload induces CH that preserves LV function.
- This specific type of CH is associated with reduced fibrosis and increased SERCA2a mRNA expression compared to banding alone.
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 beta2-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.