【观点】难治性心绞痛亟待新型治疗方法

Carl J Pepine 教授教授

机构： 佛罗里达大学医学院心血管医学部内科 介绍：

佛罗里达大学医学院心血管医学部内科Carl J Pepine 教授

随着人口的老龄化以及缺血性心脏病危险因素如高血压和糖尿病等情况的普及，患有难治性心绞痛的人群逐渐增大。这类患者生活质量较差，且数量不断增多，成为了一个重大的问题。随着数据的积累，如Povsic及其同事则表示，该问题对存活率的损害仅为中度，但对其他不良结局，如反复住院和医疗资源的应用等，则有非常大的损害。Povsic等通过设计良好的研究提供了重要的信息，确定了死亡率的预测因素，增加了我们对于难治性心绞痛的认识。预测因素包括年龄、射血分数、消瘦、多血管受累、心衰史及心率慢。有趣的是，心绞痛的严重程度及血管重建与死亡风险增高并不相关，但再次入院相关的花费超过$10,000/患者（2012年）。

该研究强调了我们迫切需要新型的治疗方案来治疗难治性患者。为此，我对于这类患者最有效的治疗药物是哌克昔林，这是一种线粒体肉碱脂酰转移酶-1抑制剂，可增强葡萄糖氧化，但该药未在美国上市。增强型体外反搏疗法（EECP）对于一些患者有效，但该疗法的作用并不持续。一些早期试验的结果显示，以CD34+细胞为中心的细胞疗法表现出不错的效果。之后，在一项对167例难治性心绞痛患者进行的双盲、随机II期研究中（ClinicalTrials.gov identifier: NCT00300053），我们记录到与安慰剂治疗相比，接受CD34+细胞治疗的患者的运动时间约成倍增加且心绞痛的发生频率减少了一半。近期，一项双盲随机试验（ClinicalTrials.gov number: NCT01205893）在104例难治性心绞痛患者中检测了经皮球囊膨胀支架——不锈钢冠状窦限流阀植入（基于Beck术）。与假手术对照组相比，手术患者的心绞痛分型及生活质量具有显著改善2。尽管产生这些早期获益的特定机制尚不明确，但这些结果支持了“冠脉微循环造成了，或许独立造成了难治性患者的缺血症状及体征”这一观点。冠脉微血管的发生或募集可改善缺血心肌的血流，而微循环或许是缺血治疗的理想治疗靶点，这有赖于更多研究去证实。

这些结果在无阻塞性心外膜CAD（此前有过或无血管重建）的难治性患者中引申出了这个问题。这类患者的数量难以估算。在诊断为临床稳定性CAD且接受过导管术的患者中，26 999例无阻塞性CAD，这提示略高于其筛选过人群的30%。我们的经验表示，患有非阻塞性CAD的这类患者中包含了约20%的难治性心绞痛人群，但由于缺少循证数据，他们成为了重大的治疗难题。新兴的观点认为，这些患者的冠脉微血管也发生了紊乱，因此这些患者或许将成为新型治疗方案的重要目标人群。

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The population with treatment-refractory angina appears to be growing as our population ages and risk conditions for ischemic heart disease like hypertension and diabetes increase in prevalence. This increasing number of patients with a poor quality of life makes this is an important issue. While accumulating data, like that of Povsic and colleagues, suggest only modest implications for impaired survival, other adverse outcomes, like repeated hospitalizations and health resource utilization, are very high. Povsic et al provide important information from a well-conducted study that advances our knowledge in refractory angina by identifying predictors of mortality. They included age, ejection fraction, leanness, multivessel involvement, heart failure history, and low heart rate. Interestingly, angina severity and revascularization were not associated with increased mortality risk, while costs related to rehospitalization exceeded $10,000/patient (in 2012 dollars).

This work emphasizes the critical need for novel therapeutics in refractory patients. To this end, the most effective medical therapy that I have worked with in these patients is perhexiline, a mitochondrial carnitine palmitoyltransferase-1 inhibitor that enhances glucose oxidation; however, it is not sold in the US. Enhanced external counterpulsation (EECP) works in some, but its benefit is not lasting. However, cell-based therapy centered on CD34+ cells has shown very encouraging results in several early trials. Then, in a double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053) of 167 patients with refractory angina, we documented an approximate doubling of exercise time and halving of angina frequency with CD34+cell therapy vs placebo.1 Very recently, percutaneous implantation of a balloon-expandable, stainless steel coronary sinus restrictor (based on the Beck procedure) was examined in a double-blind, randomized trial of 104 patients with refractory angina (ClinicalTrials.gov number: NCT01205893). There was significant improvement in angina class and quality of life compared with a sham-control group.2 Although specific mechanisms responsible for these early benefits are not known, these results support the notion that the coronary microcirculation contributes, perhaps independently, to symptoms and signs of ischemia in refractory patients. Development (or recruitment) of coronary microvessels could improve blood flow to ischemic myocardium, and, if this is proven in additional studies, the microcirculation may be a suitable therapeutic target for treatment of ischemia.

These results raise the question in refractory patients without obstructive epicardial CAD (with or without prior revascularization). The size of this population is difficult to estimate. Of patients who underwent catheterization for evaluation of clinically stable CAD, 26,999 did not have obstructive CAD, suggesting a little more than 30% of their screened population (Figure 1 in Povsic et al). Our experience suggests that these patients with nonobstructive CAD comprise ~20% of the refractory angina cohort, but they are a major management challenge due to lack of evidenced-based data. The emerging notion is that their coronary microvasculature is also disordered; so these cases may be an important future target for novel therapies.

Copyright © 2015 Elsevier Inc. All rights reserved.

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