1 Third Department of Cardiology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
2 Department of Pathology, Evangelismos Hospital, Athens, Greece.
J Cardiovasc Pharmacol Ther. 2019 Jan;24(1):70-77. doi: 10.1177/1074248418784287. Epub 2018 Jul 30.
Cardiosphere-derived cells (CDCs) have yielded promising efficacy signals in early-phase clinical trials of ischemic and nonischemic cardiomyopathy. The potential efficacy of CDCs in acute myocarditis, an inflammatory cardiomyopathy without effective therapy, remains unexplored. Given that CDCs produce regenerative, cardioprotective, anti-inflammatory, and anti-fibrotic effects (all of which could be beneficial in acute myocarditis), we investigated the efficacy of intracoronary delivery of CDCs in a rat model of experimental autoimmune myocarditis.
Lewis rats underwent induction of experimental autoimmune myocarditis by subcutaneous footpad injection of purified porcine cardiac myosin supplemented with Mycobacterium tuberculosis on days 1 and 7. On day 10, rats were randomly assigned to receive global intracoronary delivery of 500 000 CDCs or vehicle. Global intracoronary delivery was performed by injection of cells or vehicle into the left ventricular (LV) cavity during transient occlusion of the aortic root. Rats were euthanized 18 days after infusion. Cardiac volumes and systolic function were assessed by serial echocardiography, performed on days 1, 10, and 28. Myocardial inflammation, T-cell infiltration, and cardiac fibrosis were evaluated by histology.
Experimental autoimmune myocarditis was successfully induced in 14/14 rats that completed follow-up. Left ventricular ejection fraction (LVEF) and volumes were comparable on days 1 and 10 between groups. CDC infusion resulted in increased LVEF (81.5% ± 3% vs 65.4% ± 8%, P < .001) and decreased LV end-systolic volume (43 ± 15 vs 100 ± 24 μL, P < .001) compared to placebo administration at 18 days post-infusion. Cardiosphere-derived cell infusion decreased myocardial inflammation (7.4% ± 7% vs 20.7% ± 4% of myocardium, P = .007), cardiac fibrosis (16.6% ± 13% vs 38.1% ± 3% of myocardium, P = .008), and myocardial T-cell infiltration (30.4 ± 29 vs 125.8 ± 49 cells per field, P = .005) at 18 days post-infusion compared to placebo administration.
Intracoronary delivery of CDCs attenuates myocardial inflammation, T-cell infiltration, and fibrosis while preventing myocarditis-induced systolic dysfunction and adverse remodeling in rats with experimental autoimmune myocarditis.
心脏球来源细胞（CDCs）在缺血性和非缺血性心肌病的早期临床试验中显示出有前景的疗效信号。在没有有效治疗方法的炎症性心肌病——急性心肌炎中，CDCs 的潜在疗效仍未得到探索。鉴于 CDCs 具有再生、心脏保护、抗炎和抗纤维化作用（所有这些在急性心肌炎中都可能有益），我们研究了冠状动脉内输注 CDCs 在实验性自身免疫性心肌炎大鼠模型中的疗效。
Lewis 大鼠通过在第 1 天和第 7 天经皮足底注射纯化的猪心肌肌球蛋白并用结核分枝杆菌进行皮下诱导实验性自身免疫性心肌炎。在第 10 天，大鼠被随机分配接受 500,000 个 CDCs 或载体的冠状动脉内输注。通过在主动脉根部短暂闭塞期间将细胞或载体注入左心室（LV）腔来进行冠状动脉内输注。输注后 18 天处死大鼠。通过连续超声心动图在第 1、10 和 28 天评估心脏容积和收缩功能。通过组织学评估心肌炎症、T 细胞浸润和心脏纤维化。
在完成随访的 14 只大鼠中，成功诱导了实验性自身免疫性心肌炎。在第 1 天和第 10 天，两组之间的左心室射血分数（LVEF）和容积均相似。与安慰剂相比，CDC 输注可使 LVEF 增加（81.5%±3%比 65.4%±8%，P<0.001），LV 收缩末期容积减少（43±15 比 100±24μL，P<0.001）在输注后 18 天。与安慰剂相比，心脏球来源细胞输注可减少心肌炎症（心肌的 7.4%±7%比 20.7%±4%，P=0.007）、心脏纤维化（心肌的 16.6%±13%比 38.1%±3%，P=0.008）和心肌 T 细胞浸润（30.4±29 比 125.8±49 个细胞/视野，P=0.005）在输注后 18 天。
冠状动脉内输注 CDCs 可减轻心肌炎症、T 细胞浸润和纤维化，同时预防实验性自身免疫性心肌炎大鼠的心肌收缩功能障碍和不良重塑。
