Abstract 2191: Chronic Partial Unloading Improves β-adrenergic Response and Normalizes Gene Expression in Failing Rat Hearts
Introduction: Chronic complete unloading induces left ventricular (LV) atrophy and depression of contractile function. However, the effects of chronic partial unloading are not known; here they were studied on failing rat hearts by using heterotopic heart-lung transplantation model.
Methods: Heart failure was induced in Lewis rats by ligating the left anterior descending artery. After 4 weeks, infarcted hearts were transplanted into the abdomen of recipient rats by anastomosing donor ascending aorta to recipient abdominal aorta and donor pulmonary artery to recipient inferior vena cava (complete unloading, n=7). The infarcted hearts and lungs were harvested and transplanted into the abdomen of the recipient rats by anastomosing donor ascending aorta to recipient abdominal aorta, therefore LV was partially loaded with coronary venous blood (partial unloading, n=8). Normal (n=8) and infarcted (failing, n=8) hearts without transplantation were used as controls. Papillary muscle (PM) function and gene expression were studied at 2 or 4 weeks after transplantation.
Results: Developed tension (DT) of posterior PM increased in partially and completely unloaded hearts (2-week) compared with failing hearts (0.15 ± 0.03 and 0.12 ± 0.04 g/mm2 vs. 0.02 ± 0.003 g/mm2 respectively, p<0.05). However, in 4-week unloaded hearts, DT decreased in partial and complete groups (72.8% and 80.8% of 2-week values). In 4-week, but not in 2-week models, the inotropic response to isoproterenol (10−7mol/L) from baseline significantly improved in partially unloaded hearts, but not in completely unloaded and failing hearts (33.4 ± 8.5% vs. 10.1 ± 2.9% and 11.5 ± 2.2%, p<0.05). The mRNA expressions of brain natriuretic peptide (BNP), β1 and β2-adrenergic receptors (β1 and β2-AR) were normalized in partially unloaded (2 and 4-week) hearts. In completely unloaded hearts, BNP was normalized in 2-week and increased in 4-week; β1 -AR was decreased in both 2 and 4-week compared with normal hearts; β2-AR was normalized in 2-week but decreased in 4-week.
Conclusions: We conclude that chronic partial unloading caused a time-dependent depression of contractile function, but improved β-adrenergic response and normalized BNP, β1 and β2-AR gene expressions in failing rat hearts.