Ascione Raimondo, Bruno Vito D, Johnson Tom, Sammut Eva, Bond Andrew, Lopez-Baz Daniel, Deutsch Julia, Bailey Mick, Chiribiri Amedeo, Patel Ashish, Baker Andrew, Modarai Bijan
Faculty of Health Science, Bristol Heart Institute and Translational Biomedical Research Centre, University of Bristol, Bristol, United Kingdom.
Faculty of Health Science, Langford Vets and Translational Biomedical Research Centre, University of Bristol, Bristol, United Kingdom.
Front Cardiovasc Med. 2024 Aug 7;11:1427023. doi: 10.3389/fcvm.2024.1427023. eCollection 2024.
Human CD16 monocytes (hCD16 Ms) have proangiogenic properties. We assessed the feasibility, safety and efficacy of hCD16 Ms in a porcine model of myocardial infarction (MI).
A total of 27 female Large White pigs underwent MI with reperfusion and cardiac magnetic resonance (CMR). Five days later, animals received intramyocardial injections of hCD16 Ms in saline ( = 13) or saline only ( = 14). hCD16 Ms were selected from leucocyte cones. Feasibility/safety endpoints included injury at injected sites, malignant arrhythmias, cancer, haematoma, left ventricular (LV) dilatation, troponin release and downstream organ injury. Co-primary efficacy outcome included LV scar and ejection fraction (LVEF) at 30-day post-injections by CMR. Immunohistochemistry included neo-angiogenesis, fibrosis, markers of myofibroblast and inflammation. Four animals were excluded before injections due to untreatable malignant arrhythmias or lung injury. Median cell number and viability were 48.75 million and 87%, respectively. No feasibility/safety concerns were associated with the use of hCD16 Ms. The LV scar dropped by 14.5gr (from 25.45 ± 8.24 to 10.8 ± 3.4 gr; -55%) and 6.4gr (from 18.83 ± 5.06 to 12.4 ± 3.9gr; -30%) in the hCD16 Ms and control groups, respectively ( = 0.015). The 30-day LVEF did not differ between groups, but a prespecified sub-analysis within the hCD16 Ms group showed that LVEF was 2.8% higher and LV scar 1.9gr lower in the subgroup receiving a higher cell dose. Higher tissue levels of neo-angiogenesis, myofibroblast and IL-6 and lower levels of TGF-β were observed in the hCD16 Ms group.
The use of hCD16 Ms in acute MI is feasible, safe and associated with reduced LV scar size, increased tissue levels of neo-angiogenesis, myofibroblasts and IL-6 and reduced pro-fibrotic TGF-β at 30-day post-injections. A higher cell dose might increase the LVEF effect while reducing scar size, but this warrants validation in future studies.
人CD16单核细胞（hCD16 Ms）具有促血管生成特性。我们在猪心肌梗死（MI）模型中评估了hCD16 Ms的可行性、安全性和有效性。
总共27只雌性大白猪接受了MI再灌注和心脏磁共振成像（CMR）检查。五天后，动物接受心肌内注射hCD16 Ms生理盐水溶液（n = 13）或仅注射生理盐水（n = 14）。hCD16 Ms从白细胞层中选取。可行性/安全性终点包括注射部位损伤、恶性心律失常、癌症、血肿、左心室（LV）扩张、肌钙蛋白释放和下游器官损伤。共同主要疗效指标包括注射后30天通过CMR检测的LV瘢痕和射血分数（LVEF）。免疫组织化学检测包括新生血管生成、纤维化、肌成纤维细胞标志物和炎症。由于无法治疗的恶性心律失常或肺损伤，4只动物在注射前被排除。细胞数量中位数和活力分别为4875万个和87%。使用hCD16 Ms未发现可行性/安全性问题。hCD16 Ms组和对照组的LV瘢痕分别减少了14.5克（从25.45±8.24克降至10.8±3.4克；-55%）和6.4克（从18.83±5.06克降至12.4±3.9克；-30%）（P = 0.015）。两组间30天LVEF无差异，但在hCD16 Ms组内预先设定的亚组分析显示，接受较高细胞剂量的亚组LVEF高2.8%，LV瘢痕低1.9克。hCD16 Ms组观察到新生血管生成、肌成纤维细胞和IL-6的组织水平较高，而TGF-β水平较低。
在急性MI中使用hCD16 Ms是可行、安全的，并且在注射后30天与LV瘢痕大小减小、新生血管生成、肌成纤维细胞和IL-6的组织水平增加以及促纤维化的TGF-β水平降低相关。较高的细胞剂量可能会增加LVEF效应同时减小瘢痕大小，但这需要在未来研究中进行验证。
