Aims The development of cell therapy as a widely available clinical option for ischaemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery. Methods and results Pigs with chronic ischaemic cardiomyopathy induced by myocardial infarction received one or three intravenous doses of allogeneic bone marrow mesenchymal stromal cells (MSCs) or placebo 35 days apart. Rigour guidelines, including blinding and randomization, were strictly followed. A comprehensive assessment of left ventricular (LV) function was conducted with three independent methods (echocardiography, magnetic resonance imaging, and haemodynamic studies). The results demonstrate that three doses of MSCs improved both load-dependent and independent indices of LV function and reduced myocardial hypertrophy and fibrosis; in contrast, one dose failed to produce most of these benefits. Conclusions To our knowledge, this is the first study to show that intravenous infusion of a cell product improves LV function and structure in a large animal model of chronic ischaemic cardiomyopathy and that repeated infusions are necessary to produce robust effects. This study, conducted in a clinically relevant model, supports a new therapeutic strategy based on repeated intravenous infusions of allogeneic MSCs and provides a foundation for a first-in-human trial testing this strategy in patients with chronic ischaemic cardiomyopathy.

中文翻译：

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间充质基质细胞的静脉输注在慢性缺血性心肌病的猪模型中具有累积有益效应


目的 细胞疗法作为缺血性心肌病广泛可用的临床选择的发展受到当前细胞递送方法侵入性的阻碍。此外，移植后细胞的快速消失为使用重复细胞剂量提供了令人信服的理由，然而，到目前为止，临床试验中尚未这样做，因为它不适用于侵入性方法。这项转化研究的目的是测试静脉途径对细胞递送的治疗效用。方法和结果 心肌梗死诱导的慢性缺血性心肌病猪接受 1 或 3 次静脉注射同种异体骨髓间充质基质细胞 （MSCs） 或安慰剂，间隔 35 天。严格遵循严格的指南，包括盲法和随机化。使用三种独立方法 （超声心动图、磁共振成像和血流动力学研究） 对左心室 （LV） 功能进行全面评估。结果表明，三剂 MSCs 改善了 LV 功能的负荷依赖性和独立指数，减少了心肌肥大和纤维化;相比之下，一剂未能产生大部分这些益处。结论 据我们所知，这是第一项表明静脉输注细胞产物可改善慢性缺血性心肌病大型动物模型中的 LV 功能和结构的研究，并且需要反复输注才能产生强大的效果。这项研究在临床相关模型中进行，支持一种基于反复静脉输注同种异体 MSC 的新治疗策略，并为在慢性缺血性心肌病患者中测试该策略的首次人体试验奠定了基础。