Improvement In Hemodynamic Performance, Exercise Capacity, Inflammatory and Apoptotic Profiles After Intra-coronary Delivery of Mesenchymal Stem Cells (MSC) in an Experimental Model of Hypertrophic Cardiomyopathy
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Objectives: Cell transplantation is a novel promising strategy for the treatment of end-stage heart failure. MSC have been found to improve hemodynamic performance in experimental animal models of ischemic heart failure. In a rat model of hypertrophic cardiomyopathy, we studied the hemodynamic and molecular effects of intra-coronary delivery of MSC.
Methods: Sprague-Dawley rats underwent aortic banding and were followed by echocardiography for development of heart failure. After a decrease in fractional shortening of 25% from baseline, intra-coronary randomized injection of MSC (n=28) or PBS (n=20) was performed. Serial echocardiography was performed to identify reverse remodeling. Hemodynamic assessment, swim testing to exhaustion and measurement of inflammatory markers was performed prior to sacrifice on post-operative day 7, 14, 21 or 28. Left ventricular protein analysis including apoptotic markers (bax and bak), mitogen-activated protein kinases (MAPKs; p38, erk, and jnk) and matrix metalloproteinase 3 (MMP-3) was performed.
Results: MSC injection improved systolic function in the MSC group compared to the control group (mean ± SD, max dP/dt 3048 mmHg/s ± 230 vs. 2169 ± 97 at 21 days, and 3573 ± 741 vs. 1363 ± 322 at 28 days, p<0.001). LVESD was significantly reduced at 28 days in the MSC group compared to the control group (7.0 ± 0.2 vs. 7.4 ± 1.5 mm, p=0.01). Time to exhaustion was similarly increased in the MSC group compared to controls (407 ± 34 seconds vs. 264 ± 24 seconds at 21 days, and 487 ± 35 seconds vs. 306 ± 27 seconds at 28 days, p<0.001). Serum levels of IL-l, IL-6, TNF-α and BNP-32 were significantly decreased in MSC treated animals (Table 1; 21 and 28 days shown). Levels of the pro-apoptotic markers bax and bak, the MAPKs erk, p38 and jnk and MMP-3 were also found to be improved in the MSC group.| MARKER | 21 DAYS | 28 DAYS |
| Control | MSC | Control | MSC |
| IL-1 (pg/ml) | 37.15 ± 0.76 | 33.86 ± 0.63* | 41.08 ± 1.36 | 32.40 ± 1.17* |
| IL-6 (pg/ml) | 205.80 ± 5.76 | 171.34 ± 2.03* | 228.58 ± 8.25 | 167.83 ± 6.02* |
| TNF-α (pg/ml) | 19.38 ± 0.61 | 15.59 ± 0.67* | 26.10 ± 1.99 | 14.64 ± 1.20* |
| BNP-32 (pg/ml) | 30.08 ± 0.26 | 21.11 ± 1.80* | 36.85 ± 3.24 | 19.84 ± 3.08* |
| bax (level/actin) | 1.15 ± 0.04 | 1.02 ± 0.01* | 1.36 ± 0.09 | 1.00 ± 0.01* |
| bak (level/actin) | 1.37 ± 0.02 | 1.15 ± 0.07* | 1.57 ± 0.09 | 1.07 ± 0.11* |
| erk (level/actin) | 1.19 ± 0.01 | 1.02 ± 0.03* | 1.29 ± 0.07 | 1.04 ± 0.05* |
| p38 (level/actin) | 1.16 ± 0.03 | 1.02 ± 0.04* | 1.29 ± 0.03 | 1.01 ± 0.05* |
| jnk (level/actin) | 1.24 ± 0.02 | 1.06 ± 0.03* | 1.33 ± 0.06 | 1.07 ± 0.06* |
| MMP3 (level/actin) | 1.38 ± 0.04 | 1.14 ± 0.05* | 1.53 ± 0.08 | 1.09 ± 0.10* |
| * p<0.01 for comparison of Control Group Vs. Mesenchymal Stem Cell Group |
Conclusions: In this model of hypertrophic cardiomyopathy, intra-coronary delivery of mesenchymal stem cells during heart failure improved hemodynamic performance, ventricular remodeling and maximal exercise tolerance. MSC transplantation was associated with improvement in markers of systemic inflammation, volume overload, ventricular apoptosis and extracellular matrix remodeling. These effects were most remarkable at 21 and 28 days following injection. This study suggests a potential use of this treatment strategy for the management of hypertrophic heart failure.
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