Abstract 1870: Differential Effects of Exercise Training and Beta-Blocker Therapy on Cardiac Function and Calcium Reuptake in a Genetic Model of Cardiomyopathy Induced by Sympathetic Hyperactivity
Both beta-blocker (BB) therapy and exercise training (ET) are known to improve heart failure (HF) patient outcome. However, the mechanism underlying their isolated beneficial effects on left ventricular (LV) function is not fully understood.
Aim. To study the isolated effect of ET and BB on LV function and expression of proteins involved intracellular calcium regulation (ICR) in mice lacking α2A and α2C adrenoceptor subtypes (KO). These mice present sympathetic hyperactivity associated with HF and 50% mortality rate by 7 mo of age.
Methods. We studied a cohort of congenic KO (n=40) and a wild type (WT, n=40) control mice (from 5–7 mo of age). They were randomly assigned to receive metoprolol (165 mg/kg by gavage, 7 days/wk), saline, or ET (8-wk running sessions of 60 min, 5 days/wk). Cardiac contractility was evaluated by echocardiography, and cardiomyocyte width and cardiac collagen fraction (CC) by light microscopy. The protein expression of SERCA2, phospholamban (PLN), phospho-Ser16-PLN, Na+-Ca2+ exchanger (NCX), and phosphatase 1 (PP1) were evaluated by Western blott.
Results. KO displayed 30% decreased fractional shortening (FS) associated with reduced SERCA2/PLN ratio with no changes in phospho-Ser16-PLN, and increased NCX and PP1 when compared with WT. In addition, cardiomyocyte width (23%) and CC (3 fold) were increased. ET increased FS, which was paralleled by improved ICR represented by 112% increased SERCA2/PLN ratio, 92% phospho-Ser16-PLN, and normalized NCX and PP1expression. Cardiomyocyte width was reduced in KO mice after ET, while CC was not changed, neither mortality rate. Metoprolol improved FS in KO mice, which was associated with reverse cardiac remodeling and by less extension to an improved ICR. Metoprolol reduced cardiomyocyte width and CC to WT levels. This response was associated with 35% reduction in mortality rate. In addition, metoprolol restored SERCA2/PLN ratio and NCX expression but it did not change phospho-Ser16-PLN and PP1 expression.
Conclusion These findings provide direct evidence for differential mechanisms by which ET and BB improve cardiac function in HF. While ET improves LV function by restoring ICR, BB mainly reverses cardiac remodeling mortality rate associated with HF-induced sympathetic hyperactivity.