Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
Int J Mol Sci. 2021 Mar 19;22(6):3145. doi: 10.3390/ijms22063145.
Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 10 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 10 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 10 cells each) can be fully replicated by a single combined dose of 3 × 10 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 10) and vehicle × 2; or (3) three doses of CPCs (1 × 10 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% ( < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant ( = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group ( = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (-32.7%, 182.6 ± 15.1 µm vs. 271.5 ± 27.2 µm, < 0.05, in the risk region and -28.5%, 148.5 ± 12.1 µm vs. 207.6 ± 20.5 µm, < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.
利用陈旧性心肌梗死导致的慢性缺血性心肌病的小鼠模型，我们之前发现，3 次给予 1×10 的 c-kit 阳性心肌细胞（CPC）比单次给予 1×10 的细胞更有效。本研究的目的是确定 3 次给予 CPC（每次 1×10 个细胞）的有益作用是否可以通过单次给予 3×10 的 CPC 完全复制。小鼠接受 60 分钟的冠状动脉闭塞；再灌注 90 天后，它们接受 3 次间隔 5 周的超声引导心室内输注：（1）载体×3；（2）一个 CPC 联合剂量（3×10）和载体×2；或（3）3 次 CPC 剂量（每次 1×10）。在联合剂量组中，左心室射血分数（LVEF）在第一次 CPC 输注后改善，但在第二次和第三次（载体）输注后没有改善。相比之下，在多次剂量组中，每次 CPC 输注后 LVEF 均增加；在最后的超声心动图中，LVEF 平均为 35.2±0.6%（<0.001 与载体组相比，27.3±0.2%）。在研究结束时，从预处理值开始，多次剂量组的 EF 总累积变化数值大于联合剂量组（6.6±0.6%比 4.8±0.8%），尽管差异无统计学意义（=0.08）。血流动力学研究表明，多次剂量组的几个 LV 功能参数数值大于联合剂量组（=0.08 表示 LVEF 的差异）。与载体相比，仅在多次剂量组中，心肌细胞横截面积减少（-32.7%，182.6±15.1 µm 与 271.5±27.2 µm，<0.05，在风险区域和-28.5%，148.5±12.1 µm 与 207.6±20.5 µm，<0.05，在非梗死区域）。在接受细胞治疗的两组中，LV 重量/体重比和 LV 重量/胫骨长度比均显著降低，表明 LV 肥大得到抑制；然而，仅在多次剂量组中，肺重量/体重比显著降低，提示肺充血减少。综上所述，这些结果表明，在患有慢性缺血性心肌病的小鼠中，单次给予 1 次剂量的 CPC 对 LV 功能和肥大的有益作用不能完全复制，尽管单次或 3 次给予的细胞总数相同。因此，是剂量的多次性，而不是细胞总数，决定了重复剂量方案的优越性。这项研究支持这样一种观点，即心力衰竭细胞治疗的疗效可以通过重复给药来增强。
