Pharmacological modulation of pressure-overload cardiac hypertrophy: changes in ventricular function, extracellular matrix, and gene expression.
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.


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.
Wong
K
K
Division of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.
Boheler
K R
KR
Petrou
M
M
Yacoub
M H
MH
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis*; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D002976:Clenbuterol / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
D012333:RNA, Messenger; D003094:Collagen; D000252:Calcium-Transporting ATPases; D013974:Thyroxine; D002976:Clenbuterol