Abstract 16539: Amelioration of Cardiac Alternans by Human Mesenchymal Stem Cells
In the setting of heart disease, cell therapy utilizing mesenchymal stem cells (MSCs) has demonstrated some antiarrhythmic benefit. However, the mechanisms of this benefit are unclear since MSC are thought to act primarily by indirect signaling (i.e. paracrine). Cardiac alternans, a known cause of arrhythmias, can be mediated indirectly by signaling pathways that regulate intracellular calcium (Ca2+) cycling. Therefore, we hypothesized that MSCs can suppress cardiac alternans by paracrine action on Ca2+ cycling.
Methods: Ca2+ transient alternans (Ca2+ ALT) and calcium transient duration (CaD) were measured in human myocyte monolayers derived from iPS cells (hCMs) using optical mapping techniques. Measurements were performed at baseline and then during oxidative stress (H2O2) to simulate disease conditions. This was repeated when hCMs were co-cultured (48-72 h) with human MSCs (hMSCs) in direct contact or indirect contact to test for paracrine action (hMSC/hCM = 2000/50000 cells).
Results: During oxidative stress, Ca2+ ALT (68.6±3au) and CaD (711±17ms) measured in hCMs alone were significantly increased compared to baseline (29.5±3.9au and 647±16ms, respectively, p<0.001, n=24). During oxidative stress, hMSCs in direct contact (n=18) significantly decreased Ca2+ ALT (1.9±1.9au, p<0.001) and CaD (487±12ms, p<0.001) measured in hCMs compared to that in the absence of hMSCs. Importantly, hMSCs with indirect contact (n=18) also significantly decreased Ca2+ ALT (12.2±3au, p<0.001) and CaD (588±13ms, p<0.001), suggesting a paracrine mediated mechanism of alternans suppression that is associated with Ca2+ cycling.
Conclusion: Cardiac alternans measured in human myocyte monolayers in the setting of oxidative stress was ameliorated by human MSCs both in direct and indirect contact, suggesting a paracrine mechanism of action. This finding demonstrates, for the first time, how stem cell therapy might be antiarrhythmic by paracrine action on cardiac alternans.
- © 2013 by American Heart Association, Inc.