Rationale GDF11 (Growth Differentiation Factor 11) is a member of the transforming growth factor β (TGFβ) super family of secreted factors. A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH), and restoring GDF11 to normal levels in old mice rescued PCH. Objective To determine if and by what mechanism GDF11 rescues aging dependent PCH. Methods and Results 24-month-old C57BL/6 mice were given a daily injection of either recombinant (r) GDF11 at 0.1mg/kg or vehicle for 28 days. rGDF11 bioactivity was confirmed in-vitro. After treatment, rGDF11 levels were significantly increased but there was no significant effect on either heart weight (HW) or body weight (BW). HW/BW ratios of old mice were not different from 8 or 12 week-old animals, and the PCH marker ANP was not different in young versus old mice. Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle treated animals at baseline and remained unchanged at 1, 2 and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals. In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes (NRVM), to explore the putative anti-hypertrophic effects of GDF11, showed that GDF11 did not reduce NRVM hypertrophy, but instead induced hypertrophy. Conclusions Our studies show that there is no age-related PCH in disease free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.

Rationale: Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure. Objective: To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials. Methods and Results: CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surface marker profile, including high expression of CD61 and integrin β4 versus CDCs and MSCs. In addition, CBSCs were morphologically distinct and showed enhanced proliferation capacity versus CDCs and MSCs. CBSCs had significantly better survival after exposure to an apoptotic stimuli when compared with MSCs. ATP and histamine induced a transient increase of intracellular Ca 2+ concentration in CBSCs versus CDCs and MSCs, which either respond to ATP or histamine only further documenting the differences between the 3 cell types. Conclusions: CBSCs are unique from CDCs and MSCs and possess enhanced proliferative, survival, and lineage commitment capacity that could account for the enhanced protective effects after cardiac injury.

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.