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| Human Mesenchymal Stem Cell Transplantation in Canine Myocardial Infarction Model Results in Sympathetic Hyper-innervation and Proarrhythmia |
| 고려의대¹, 포천의대², Utah Valley Medical Center ³, Cedars-Sinai Medical Center⁴ |
| 박희남¹, 임홍의¹, 김진석¹, 김광일², 방영호¹, 주형준¹, 유지현¹, 김병수¹, Chun Hwang³, Peng-Sheng Chen⁴, 김영훈 ¹ |
Background Cardiac resynchronization therapy reduces morbidity and mortality in patients with heart failure, and mesenchymal stem cells (MSC) transplantation has a potential for the improvement of ventricular function, especially if it is applied during acute stage of myocardial infarction (AMI). However, the safety of combined left ventricular (LV) epicardial pacing (EpiP) and MSC transplantation in AMI has not been studied.
Methods and Results We explored the safety of human MSC (hMSC) transplantation in 15 canine model of with or without AMI or LV EpiP. AMI was made by ligation of proximal left circumflex coronary artery in open chest canine model, and positioned EpiP electrode on the peri-infarct zone (DDD mode, 3.5 V, minimal AV delay 150 ms). Implantable cardioverter defibrillator (ICD) was implanted in right ventricular endocardium to monitor ventricular arrhythmia. hMSC (1x107 in 1 mL, 5 sites) were injected subepicardially 15 mm separated from pacing electrode. We compared hMSC+EpiP+AMI (n=5), hMSC+EpiP (n=5), hMSC only (n=5), and sham operation (n=2) by ICD egm analysis and immunohistochemistry after 4 weeks of survival. Results: 1. 80% of hMSC+EpiP+AMI group, 60% of hMSC+EpiP group, 40% of hMSC only group, and none of control revealed spontaneous ventricular tachyarrhythmia (VT) episodes in stored ICD egm, and 60%, 40%, 20%, and none of each group died suddenly at 5.3±6.6 days after surgery, respectively. 2. Human nucleolin positive hMSC with vimenting positive meosdermal differentiation were observed at the subepicardial peri-infarct zone without any evidence of immune rejection. 3. The hMSC transplanted hearts expressed higher densities of tyrosine hydroxylase positive cardiac sympathetic nerves compared with control dog (0.32±0.28 % area vs. 0.00±0.02 % area, p<0.001).
Conclusion hMSC xenograft to canine AMI and EpiP model showed successful engraftment of hMSC without immune rejection. However, VT and sudden death those were associated with sympathetic hyper-innervation at the transplanted myocardium were frequently inevitable in this model.
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