背景:本研究调查了自体骨髓细胞(BMC)治疗严重肢体缺血(CLI)患者的结果和可能的预测因素。重点探讨了与BMC治疗疗效相关的临床背景和先前的他汀类药物和肾素-血管紧张素系统(RAS)作用剂药物治疗。
方法:在本研究中,我们回顾了33例(平均年龄64.9±10岁;31例男性)在血运重建失败或不可能后出现晚期CLI的患者。通过局部肌内应用用40mL自体BMC治疗。保肢和伤口愈合的患者(N=22)被认为是BMC治疗的应答者,并且将具有肢体抢救和完全缺血性伤口愈合的患者(N=13)定义为超应答者。采用Logistic回归模型筛选并确定预后因素,和接收器工作特性(ROC)曲线,线性回归,并绘制生存曲线以确定预测准确性,候选预测因子之间的相关性,以及严重截肢的风险。
结果:基于单变量回归分析,基线C反应蛋白(CRP)和经皮氧分压(TcPO2)值被确定为反应者的预后因素,而CRP值,踝肱指数(ABI),和骨髓来源的单核细胞(BM-MNCs)浓度被确定为超应答者的预后因素。ROC曲线下面积为0.768,表明移植前CRP>8.1mg/L具有良好的鉴别性,可作为阴性临床反应的预测因素。线性回归分析显示,基线CRP水平与移植骨髓中BM-MNCs浓度之间存在显着依赖性。在BMCs治疗前服用阿托伐他汀的患者(N=22)在BMCs移植后TcPO2显著改善,疼痛评分降低,与非阿托伐他汀组相比。他汀类药物治疗与严重截肢风险降低相关。然而,差异无统计学意义。与未使用他汀类药物治疗的患者相比,他汀类药物的使用还与移植骨髓中BM-MNC的浓度显着升高有关。使用RAS作用剂治疗的患者(N=20)在BMC移植后疼痛评分显着降低,与非RAS作用药物组相比。类似的结果,在BMC治疗前,阿托伐他汀和RAS作用药物治疗的患者(N=17)疼痛评分降低,TcPO2改善.Spearman相关结果显示CLI回归之间存在显著正相关,响应者,以及单独使用RAS作用剂或阿托伐他汀进行BMC移植前的先前治疗。
结论:CRP和TcPO2是反应者的预后因素,而CRP值,ABI,和BM-MNCs浓度被确定为超应答者的预测因素。在CLI患者中,阿托伐他汀治疗与骨髓浓缩物中BM-MNC的浓度显著增加以及BMC治疗后较高的TcPO2和较低的疼痛评分相关。同样,在BMCs治疗前,接受阿托伐他汀和RAS作用药物治疗的患者疼痛评分降低,TcPO2改善.在单独使用RAS作用剂或阿托伐他汀进行BMC移植之前,应答者与先前治疗之间的正相关是显着的。
BACKGROUND: The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with \"no-option\" critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy related to the therapeutic efficacy of BMCs treatment.
METHODS: In the present study, we reviewed thirty-three patients (mean age 64.9 ± 10 years; 31 males) with advanced CLI after failed or impossible revascularisation, who were treated with 40 mL of autologous BMCs by local intramuscular application. Patients with limb salvage and wound healing (N = 22) were considered as responders to BMCs therapy, and patients with limb salvage and complete ischemic wound healing (N = 13) were defined as super-responders. Logistic regression models were used to screen and identify the prognostic factors, and a receiver operating characteristics (ROC) curve, a linear regression, and a survival curve were drawn to determine the predictive accuracy, the correlation between the candidate predictors, and the risk of major amputation.
RESULTS: Based on the univariate regression analysis, baseline C-reactive protein (CRP) and transcutaneous oxygen pressure (TcPO2) values were identified as prognostic factors of the responders, while CRP value, ankle-brachial index (ABI), and bone marrow-derived mononuclear cells (BM-MNCs) concentration were identified as prognostic factors of the super-responders. An area under the ROC curve of 0.768 indicated good discrimination for CRP > 8.1 mg/L before transplantation as a predictive factor for negative clinical response. Linear regression analysis revealed a significant dependence between the levels of baseline CRP and the concentration of BM-MNCs in transplanted bone marrow. Patients taking atorvastatin before BMCs treatment (N = 22) had significantly improved TcPO2 and reduced pain scale after BMCs transplant, compared to the non-atorvastatin group. Statin treatment was associated with reduced risk for major amputation. However, the difference was not statistically significant. Statin use was also associated with a significantly higher concentration of BM-MNCs in the transplanted bone marrow compared to patients without statin treatment. Patients treated with RAS-acting agents (N = 20) had significantly reduced pain scale after BMCs transplant, compared to the non-RAS-acting agents group. Similar results, reduced pain scale and improved TcPO2, were achieved in patients treated with atorvastatin and RAS-acting agents (N = 17) before BMCs treatment. Results of the Spearman correlation showed a significant positive correlation between CLI regression, responders, and previous therapy before BMCs transplant with RAS-acting agents alone or with atorvastatin.
CONCLUSIONS: CRP and TcPO2 were prognostic factors of the responders, while CRP value, ABI, and BM-MNCs concentration were identified as predictive factors of the super-responders. Atorvastatin treatment was associated with a significantly increased concentration of BM-MNCs in bone marrow concentrate and higher TcPO2 and lower pain scale after BMCs treatment in CLI patients. Similarly, reduced pain scales and improved TcPO2 were achieved in patients treated with atorvastatin and RAS-acting agents before BMCs treatment. Positive correlations between responders and previous treatment before BMCs transplant with RAS-acting agents alone or with atorvastatin were significant.