Abstract 253: Restoring GDF11 to Normal Levels in Old Mice Has no Effect on Cardiac Structure and Function

Abstract

Rationale: GDF11 (Growth Differentiation Factor 11) is a member of the TGFβ super family of secreted factors, which play an important role in the regulation of cell processes including proliferation, differentiation, death, adhesion, and migration. Recently it was shown that circulating GDF11 levels fall with aging and this change is associated with pathological cardiac hypertrophy (PCH). Restoring GDF11 to normal levels was shown to rescue PCH. Objective: To determine if we can confirm the hypothesis that correcting the levels of a single factor, GDF11, determines aging related PCH. Methods and Results: We used the study design described by Loffredo et al, 2013. Investigators were blinded to treatment group. 24 month old C57BL/6 male mice were given a daily injection of recombinant GDF11 at 0 .1mg/kg or vehicle for 28 days. GDF11 bioactivity was confirmed in-vitro. After treatment, GDF11 levels were significantly increased but there was no difference in heart weight (HW) to body weight (BW) ratio (4.74 vs 4.70) between GDF11 and vehicle treated old mice. HW/BW ratios of old mice were not different from12 week-old animals (4.56) and the PCH markers ANP and BNP were not different in young verses old mice. Before GDF11 treatment there were no significant differences in ejection fraction (46 versus 46 %), internal ventricular dimensions (4.33 vs 4.28 mm), and septal wall thickness (0.72 versus 0.78 mm) between GDF11 and vehicle treated groups. All structural and functional parameters remained unchanged at 1, 2 and 4 weeks of treatment. Strain analysis showed no significant difference in radial or longitudinal strain. Invasive hemodynamics performed at time of sacrifice also showed no significant differences in max dP/dt (6499.17 vs 6011.95 mmHg/s) or min dP/dt (-6551.73 vs -6214.33 mmHg/s) between GDF11 and vehicle treated animals respectively. Conclusions: There is no significant age-related PCH in C57Bl6 mice. GDF11 injections had no effects on cardiac structure or function in old male C57BL/6 mice. Our results question the idea that there is age-related PCH in disease free C57BL6 mice and question the findings that restoring GDF11 in old mice has any effect on cardiac structure or function.