JAMA: 体外冲击波辅助治疗可以显著提高经冠脉自体骨髓单个核细胞移植治疗慢性心力衰竭的疗效

既往多个临床试验显示，经冠脉注射自体骨髓单个核细胞（BMCs）治疗心肌梗死后慢性心力衰竭的临床疗效非常有限，这可能和移植后细胞不能很好的向目标区域归巢有关。而体外冲击波治疗已被实验证实可以增加局部组织归巢诱导因子的表达，从而帮助目标组织增强对移植细胞的归巢作用。为了验证体外冲击波辅助是否可以提高细胞移植治疗的疗效，德国法兰克福大学医学院的Birgit Assmus博士等设计并开展了一项研究（CELLWAVE 试验），其研究结果发表在2013年4月17日出版的《美国医学会杂志》（JAMA）上。研究者发现，体外冲击波辅助经冠脉移植自体骨髓单个核细胞治疗，可以显著提高心肌梗死后慢性心力衰竭患者4个月后的左室射血分数（LVEF）。
CELLWAVE试验是一项随机、双盲、安慰剂对照的临床研究。共入选自2006年～2011年在法兰克福大学医学院就诊的103例心肌梗死后的慢性心力衰竭患者。所有入选患者首先单盲随机分为低剂量组（n=42）、高剂量组（n=40）和安慰剂组（n=21），分别应用体外冲击波预处理其左心室前壁。24小时后，接受冲击波治疗的患者再随机双盲分为经冠脉注射自体骨髓单个核细胞组和经冠脉注射安慰剂组；而接受安慰剂冲击波治疗组的患者则全部接受经冠脉自体骨髓单个核细胞移植治疗。研究的主要终点是治疗4个月后与基线水平相比，合并的体外冲击波（高、低剂量）+经冠脉细胞移植组与合并的体外冲击波（高、低剂量）+经冠脉安慰剂组的左室射血分数改变值；次要终点包括MRI对左心室局部功能情况的评估和不良临床事件的发生总数量。
研究结果显示：治疗4个月后与基线水平的左室射血分数变化，体外冲击波+经冠脉细胞移植组（3.2%，[95% CI, 2.0% to 4.4%]）较体外冲击波+经冠脉安慰剂组（1.0%，[95% CI, -0.3% to 2.2%]）有显著改善（P=0.02）。体外冲击波+经冠脉细胞移植组（3.6%，[95% CI, 2.0% to 5.2%]）对局部心室壁增厚的改善程度也显著优于体外冲击波+经冠脉安慰剂组（0.5%，[95% CI,-1.2% to 2.1%]）（P=0.01）。而临床主要不良心脏事件的总体发生数量，体外冲击波+经冠脉移植细胞组（n=32，n代表发生的总临床事件的数量）也较安慰剂冲击波+经冠脉细胞移植组（n=18）和体外冲击波+经冠脉安慰剂移植组（n=61）有显著降低（HR，0.58 [95% CI，0.40-0.85]； P=0.02）。
本研究发现，对于心肌梗死后的慢性心力衰竭患者，体外冲击波辅助经冠脉注射自体骨髓单个核细胞治疗与单纯体外冲击波治疗相比，可以显著提高患者4月后的左室射血分数水平（虽然这种改变的绝对值并不大）。但左室收缩功能的改善是否可以进一步带来患者临床预后的改善，则仍有待于未来的临床试验来证实。
与心力衰竭相关的拓展阅读：

• JCF：CARRESS-HF研究着眼于超滤治疗在急性失代偿期心力衰竭患者中的运用
• JAMA：阿利吉仑对心力衰竭住院患者无益
• Lancet：重组人松弛素-2Serelaxin治疗急性心力衰竭
• 心力衰竭患者醛固酮水平研究进展
• 张建： 急性心力衰竭诊治进展
• BMJ：绝经早期接受激素替代治疗(HRT)可显著降低心力衰竭风险
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Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial.
IMPORTANCE
The modest effects of clinical studies using intracoronary administration of autologous bone marrow-derived mononuclear cells (BMCs) in patients with chronic postinfarction heart failure may be attributed to impaired homing of BMCs to the target area. Extracorporeal shock wave treatment has been experimentally shown to increase homing factors in the target tissue, resulting in enhanced retention of applied BMCs.
OBJECTIVE
To test the hypothesis that targeted cardiac shock wave pretreatment with subsequent application of BMCs improves recovery of left ventricular ejection fraction (LVEF) in patients with chronic heart failure.
DESIGN, SETTING, AND PARTICIPANTS: The CELLWAVE double-blind, randomized, placebo-controlled trial conducted among patients with chronic heart failure treated at Goethe University Frankfurt, Germany, between 2006 and 2011.
INTERVENTIONS
Single-blind low-dose (n = 42), high-dose (n = 40), or placebo (n = 21) shock wave pretreatment targeted to the left ventricular anterior wall. Twenty-four hours later, patients receiving shock wave pretreatment were randomized to receive double-blind intracoronary infusion of BMCs or placebo, and patients receiving placebo shock wave received intracoronary infusion of BMCs. MAIN OUTCOMES AND MEASURES: Primary end point was change in LVEF from baseline to 4 months in the pooled groups shock wave + placebo infusion vs shock wave + BMCs; secondary end points included regional left ventricular function assessed by magnetic resonance imaging and clinical events.
RESULTS
The primary end point was significantly improved in the shock wave + BMCs group (absolute change in LVEF, 3.2% [95% CI, 2.0% to 4.4%]), compared with the shock wave + placebo infusion group (1.0% [95% CI, -0.3% to 2.2%]) (P = .02). Regional wall thickening improved significantly in the shock wave + BMCs group (3.6% [95% CI, 2.0% to 5.2%]) but not in the shock wave + placebo infusion group (0.5% [95% CI, -1.2% to 2.1%]) (P = .01). Overall occurrence of major adverse cardiac events was significantly less frequent in the shock wave + BMCs group (n = 32 events) compared with the placebo shock wave + BMCs (n = 18) and shock wave + placebo infusion (n = 61) groups (hazard ratio, 0.58 [95% CI, 0.40-0.85]; P = .02).
CONCLUSIONS AND RELEVANCE
Among patients with postinfarction chronic heart failure, shock wave-facilitated intracoronary administration of BMCs vs shock wave treatment alone resulted in a significant, albeit modest, improvement in LVEF at 4 months. Determining whether the increase in contractile function will translate into improved clinical outcomes requires confirmation in larger clinical end point trials.