Abstract 336: Cardiomyocyte-specific Deletion of the Mineralocorticoid Receptor attenuates Cardiac Dilatation and Dysfunction after Myocardial Infarction
Background: Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with left ventricular (LV) dysfunction and heart failure after myocardial infarction (MI); however, the underlying mechanisms are still under investigation. We investigated LV remodeling after MI in mice with cardiomyocyte-specific deletion of the MR gene (MRMLCCre) which were generated using a conditional MR allele (MRflox) in combination with a transgene expressing Cre recombinase under control of the myosin light chain (MLC2a) gene promoter.
Methods and Results: Wild-type (WT) and MRMLCCre mice underwent coronary artery ligation. Transthoracic echocardiography was performed at days 1, 7, and 56. Moreover, at 56 days the mice were subjected to LV hemodynamic and volume measurements and hearts were removed for histology. Sham-operated WT and MRMLCCre mice showed similar cardiac morphology and function. MI size was similar between study groups (WT 51 ±1%; MRMLCCre 50 ±1%). LV end-diastolic (ED) and end-systolic (ES) area were significantly reduced while fractional shortening was significantly improved in MRMLCCre mice after MI compared to WT-MI animals. In addition, LV filling pressure, LV pressure isovolumic decay, LVES and LVED volumes were significantly lower in the MRMLCCre mice after MI than in WT. Attenuation of cardiac dilation and failure in MRMLCCre mice was associated with reduced myocyte cross-sectional area and collagen accumulation in the surviving myocardium.
Conclusions: Myocyte-specific deletion of the MR gene protects against adverse cardiac remodeling and contractile dysfunction in ischemic heart failure, suggesting that clinical benefits of MR blockade in patients with heart failure after MI may be mediated at least in part via a cardiomyocyte-dependent mechanism.