PHARMACOLOGICAL MODULATION OF PRESSURE-OVERLOAD CARDIAC-HYPERTROPHY -CHANGES IN VENTRICULAR-FUNCTION, EXTRACELLULAR-MATRIX, AND GENE-EXPRESSION

Background Appropriate cardiac hypertrophy (CH) is necessary in severa l clinical settings, such as pulmonary artery banding in the two-stage arterial switch operation for transposition of the great arteries. Pr essure-overload CH, however, produces ventricular dysfunction due to s tructural and molecular changes. The beta(2)-adrenergic receptor agoni st clenbuterol has been shown to induce CH without such adverse effect s to the rat heart. This study was performed to determine its effects on left ventricular (LV) function, structure, and gene expression in p ressure-overload CH. Methods and Results Sprague-Dawley rats were assi gned to one of four groups: 1, sham-operated (n = 15); 2, banding of a scending aorta (n = 22); 3, banding + clenbuterol (n=18); and 4, bandi ng + thyroxine (n=17). At the end of 3 weeks, groups 2, 3, and 4 showe d an increase in LV mass index of 49.7 +/- 5.1%, 66.1 +/- 3.5%, 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 develop ed pressure and diastolic relaxation and an increase in passive stiffn ess, with significantly reduced LV expression of sarcoplasmic reticulu m Ca2+-ATPase2a (SERCA2a) mRNA and increased LV collagen concentration . In comparison, similarly hypertrophied animals in groups 3 and 4 dem onstrated improved developed pressure, normal relaxation and diastolic stiffness with normal collagen concentration, and a greater abundance of SERCA2a mRNA. Conclusions Clenbuterol administration in conjunctio n 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 alon e.