Abstract 19549: Aging Mice Maintain LV Function and Exhibit Less Remodeling, Dilation and Mortality in Pressure Overload Cardiomyopathy via Adaptive Extracellular Matrix Changes and Induction of Autophagy
Introduction: Prior studies suggesting worse outcomes with aging after transverse aortic constriction (TAC) have not corrected for differences in aortic size between young and aging mice. Creating the same surgical TAC in young and aging mice causes a disproportionately greater degree of constriction in aging mice, resulting in bias against the aging mice.
Methods and Results: Ascending aortic cross-sectional area (CSA) was 28% larger in aging mice (18-month old; 2.22±0.22 mm2) than in young mice (3-month old; 1.73±0.13 mm2:p<0.01). We performed TAC to result in a similar 92% reduction in CSA. Comparable hemodynamic effects in the young and aging mice were confirmed by demonstrating similar trans-TAC pressure gradient, increase in arterial elastance and BNP upregulation in the left ventricle (LV). Aged mice demonstrate more LV fibrosis and hypertrophy than young at baseline, yet echocardiography every 2 weeks showed progressive LV hypertrophy and dilation in young (n=15) and aging (n=15) mice, but to a greater degree in young. Pressure-volume loop analysis demonstrated a significant drop in stroke work index and in the slope of the end-systolic pressure volume relationship (Ees) in young mice, indicating reduced inotropy and an inability to augment systolic function. Conversely, aging mice showed an increased Ees with a significant rise in developed pressure and less of a drop in stroke work index, demonstrating increased inotropy. Interestingly, there was significantly less mortality in the aging group (0% vs 50%; log rank p<0.01). Early after TAC, aging hearts exhibit a cardioprotective MMP expression profile and increased autophagy (3.2-fold increase in MMP3 and 1.5-fold increase in MMP12; p<0.01), whereas young mice showed no change. TIMP1 expression increased more in aging than young (8.6-fold vs 4.3-fold; p<0.01). Despite less baseline autophagy, aging hearts demonstrated an increase in LC3II:I ratio (p<0.01) and beclin-1 expression (p<0.05) after TAC.
Conclusions: Young mice exhibit exaggerated LV remodeling, inability to augment systolic function and increased mortality following TAC compared to aging mice. Greater baseline fibrosis or induction of adaptive cellular and matrix changes may protect the aging mice from LV dilation and death.
Author Disclosures: B.M. Coulter: None. X. Geng: None. J. Hwang: None. J. Ye: None. R. Sievers: None. Y. Yeghiazarians: None. R. Lee: None. A. Boyle: None.
- © 2014 by American Heart Association, Inc.