Rationale: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.Objective: To compare the safety and efficacy of two doses of allogeneic bone marrow-derived human mesenchymal stem cells (hMSC) identically delivered in patients with ischemic cardiomyopathy (ICM).Methods and Results: Thirty patients with ICM received in a blinded manner either 20 million (20M, n=15) or 100 million (100M, n=15) allogeneic hMSCs via transendocardial injection (10 0.5 cc injections/patient). Patients were followed for 12-months for safety and efficacy endpoints. There were no treatment-emergent serious adverse events (SAE) at 30 days or treatment related SAEs at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% CI, 6.9%, 50.0%) in 20M and 13.3% (95% CI, 3.5%, 43.6%) in 100M (p=0.58). Worsening heart failure re-hospitalization was 20.0% (95% CI, 6.9%, 50.0%) in 20M and 7.1% (95% CI, 1.0%, 40.9%) in 100M (p=0.27). Whereas scar size reduced to a similar degree in both groups: 20M by -6.4g (IQR, -13.5g, -3.4g, p=0.001) and 100M by -6.1g (IQR, -8.1g, -4.6g, p=0.0002), the ejection fraction (EF) improved only with 100M by 3.7 units (IQR, 1.1, 6.1, p=0.04). NYHA class improved at 12 months in 35.7% (95% CI, 12.7%, 64.9%) in 20M and 42.9% (95% CI, 17.7%, 71.1%) in 100M. Importantly, pro-BNP increased at 12 months in 20M by 0.32 log pg/mL (95% CI, 0.02, 0.62, p=0.039), but not in 100M (-0.07 log pg/mL; 95% CI, -0.36, 0.23, p=0.65; between group p=0.07).Conclusions: Although both cell doses reduced scar size, only the 100M dose increased EF. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action, and enhance planning of pivotal Phase III trials.Clinical Trial Registration: NCTO2013674 [https://clinicaltrials.gov/ct2/show/NCT02013674]

基本原理：细胞剂量和浓度在对基于细胞的心力衰竭治疗的表型反应中起着至关重要的作用。目的：比较两种剂量的异基因骨髓来源的人间充质干细胞（hMSC）在缺血性心肌病（ICM）患者中的安全性和有效性。方法和结果：30 名 ICM 患者通过经心内膜注射（10 0.5 cc 注射/患者）以盲法方式接受 2000 万（20M，n=15）或 1 亿（100M，n=15）同种异体 hMSCs。对患者进行了 12 个月的安全性和有效性终点随访。在 30 天时没有治疗出现的严重不良事件 (SAE) 或在 12 个月时与治疗相关的 SAE。主要不良心脏事件发生率为 20.0% (95% CI, 6.9%, 50.0%) 在 20M 和 13.3% (95% CI, 3.5%, 43.6%) 在 100M (p=0.58)。恶化的心力衰竭再住院率为 20.0% (95% CI, 6.9%, 50.0%) 在 20M 和 7.1% (95% CI, 1.0%, 40.9%) 在 100M (p=0.27)。而两组的疤痕大小减少到相似程度：20M x -6.4g (IQR, -13.5g, -3.4g, p=0.001) 和 100M x -6.1g (IQR, -8.1g, -4.6g, p = 0.0002），射血分数（EF）仅在 100M 时提高了 3.7 个单位（IQR，1.1, 6.1, p=0.04)。NYHA 等级在 12 个月时改善了 35.7% (95% CI, 12.7%, 64.9%) 在 20M 和 42.9% (95% CI, 17.7%, 71.1%) 在 100M。重要的是，pro-BNP 在 12 个月时在 20M 中增加了 0.32 log pg/mL（95% CI，0.02，0.62，p=0.039），但在 100M 中没有增加（-0.07 log pg/mL；95% CI，-0.36， 0.23，p=0.65；组间 p=0.07)。结论：虽然两种细胞剂量都减少了疤痕大小，但只有 100M 剂量增加了 EF。这项研究强调了细胞剂量在细胞治疗反应中的关键作用。确定最佳剂量和给药方式对于推进该领域、破译作用机制和加强关键 III 期试验的规划至关重要。临床试验注册：NCTO2013674 [https://clinicaltrials.gov/ct2/show/NCT02013674]