左心室辅助装置的现状与未来

Left ventricular assist devices in Heart Failure
左室辅助装置（LVADs）在心力衰竭中的应用
Author: Janet Fricker
Sunday 2 September 2007

A paradigm shift in the concept of left ventricular assist devices (LVADs) in heart failure has occurred; now, devices are used not only as destination therapy and as a bridge to transplant, but also as a bridge to recovery.
左室辅助装置的概念在心力衰竭中已经发生了变化：LVADs不仅用为终末期治疗和过渡到心脏移植的桥梁，而且也是恢复的桥梁。
In a recent study, Emma Birks and Magdi Yacoub at Harefield Heart Science Centre, Imperial College, London, reported 70 per cent of heart failure (HF) patients taking a specific cocktail of drugs could recover (N Engl J Med 2006;355:1873-84).
在最近的研究中，伦敦皇家学院Harefield心脏学中心的Emma Birks和 Magdi Yacoub报道了接收特殊的药物鸡尾酒疗法的心力衰竭病人中70%可以恢复(N Engl J Med 2006;355:1873-84)。
“This is one of the most exciting current developments in cardiology,” said Yacoub. “We’re seeing dramatic changes in heart function, involving both biochemical and genetic changes. Patients are achieving good quality of life and it’s freeing up more donor hearts for the patients who aren’t eligible for this therapy.”
Yacoub说：“这是目前心脏病学的最令人兴奋的发展之一，我们看到了心脏功能的显著性变化，包括生物化学方面和遗传学上的变化。病人即将得到生活质量的提高，而对于适合于心脏移植的病人也可以得到更多的心脏。”


Too good to be true?

Critics, however, remain sceptical, saying these results “seem too good to be true”. In other series using LVADS as a bridge to recovery, recovery has only been observed in 5-24 % of patients. Many are withholding judgement until they see whether the results can be reproduced in a new USA study that uses the Harefield strategy.
然而，批评家仍怀疑，声称这些结果“太好了简直难以相信”。在另一项应用LVADs作为恢复桥梁的研究中，只发现了5-24 %的病人得以恢复。除非见到了这些应用Harefie措施的研究结果能够在一项新的美国研究中得以实现，很多人都不表态。
With 16 million HF patients in Europe and the USA, new strategies are indisputably needed. Transplantation offers the only effective treatment for the severest forms of HF, which affect about six per cent of patients, but the shortage of donor hearts has led to a search for alternatives. In the UK, for example, only 150 donor hearts are available each year for 15,000 patients aged less than 65 with stage D chronic HF.
欧洲和美国有1600万心衰病人，毫无疑问新的措施势在必行。心脏移植对最严重的心力衰竭患者提供了唯一的有效治疗措施，而这些最严重的心力衰竭只占病人总数的6%，但是器官来源的缺乏导致必须寻找替代途径。例如，在英国，每年有15000名65岁以下的慢性心力衰竭D级的病人需要接受心脏移植，但是，仅仅有150个供心可以应用。
Several studies have shown that using an LVAD to take the strain off the left ventricle (unloading) is associated with a reversal of the adverse biochemical changes (reverse remodelling) that have occurred during HF and an improvement in the heart’s function.
已有几项研究表明，使用LVAD以减轻左室的紧张度（减负荷），与在心力衰竭中产生的有害的生化改变（逆转重塑）的逆转和心功能的提高相关
The Harefield Recovery Protocol
Harefield恢复草案
In the past decade Yacoub has developed the Harefield Recovery Protocol, a unique strategy combining mechanical and pharmacological therapy, which he claims makes heart recovery more predictable following implantation of the LVAD. There are two distinct pharmacological phases.
在过去的十年间，Yacoub发展了Harefield恢复草案，一种将机械辅助和药物治疗相结合的独特的治疗方法，他声称随着LVAD的植入可以使心脏的恢复更有可预见性。有两种不同的药物治疗阶段。
The first involves the use of the drugs lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodelling.
第一个阶段包括药物赖诺普利，卡维地洛、螺内酯和洛沙坦的应用，以提高逆转重塑。
Then, once regression of left ventricular enlargement has been achieved, patients are administered clenbuterol, a β2-adrenergic-receptor agonist (abused by athletes to make muscles bigger) to produce cardiac muscle hypertrophy.
然后，一旦左室扩大得以控制，就给病人应用克伦特罗，一种β2肾上腺能受体激动剂（被运动员滥用，以使肌肉增强），来使心脏肥大。
“During prolonged mechanical unloading there have been suggestions that disuse atrophy occurs, in much the same way as if you rest a limb, muscles can waste away. The idea of clenbuterol is to prevent this from happening,” explains Yacoub.
Yacoub解释到：“在延长的机械性减负荷期间，有证据表明废用性萎缩的发生，就像你限制了一个肢体后肌肉消瘦一样。克伦特罗就是用来阻止这种情况的发生。”
In the Harefield study, 15 patients with severe heart failure due to non-ischaemic cardiomyopathy and no histologic evidence of active myocarditis underwent implantation, followed by the specific drug regimen. Eleven of 15 patients (73%) demonstrated sufficient cardiac recovery to have the device removed successfully (explantation) at a mean of 320 ±186 days after implantation. The cumulative rate for avoiding recurrent HF one and four years after the device was removed was 100% and 88.9% respectively for surviving patients.
在Harefield的研究中15名由非缺血性心肌病和无组织学证据的活动性心肌炎导致的严重心力衰竭接受了左室辅助装置的植入，随之接受特殊的药物用法。结果15名患者中有11位(73%)在植入后平均320 ±186天后恢复到足以将LVAD移除。对于这些生存的病人，在这种装置移除后1年和4年避免心力衰竭复发的累积率分别为100% and 88.9% 。

The LVAD Working Group study
LVAD工作组研究
The Harefield recovery results are considerably higher than anything previously reported. A recent study from the LVAD Working Group, a consortium of seven different US centres, found that only six out of 67 patients (9%) were able to undergo explantation (Circulation. 2007;115:2497-2505.)
Harefield的恢复结果较以前报道的任何结果相当地高。最近的一项研究来自由美国7所不同中心组成的LVAD工作组，该研究发现67名病人中只有6人(9%)能够移除该装置(Circulation. 2007;115:2497-2505.) 。
The study showed that although cellular recovery and improvements in ventricular function were observed for a number of patients (34% had an LVEF greater than 40% with reduced support), the degree of recovery was insufficient in most patients for removal. Principal investigator, Simon Maybaum (Montefiore Medical Center, Albert Einstein College of Medicine, NY), says: “This was a very different protocol from Harefield’s, making the two studies difficult to compare. We were observing the natural history of heart function with LVADs, and not introducing any additional interventions.”
该研究表明，尽管在许多病人（34%的病人随着辅助的降低LVEF大于40%）观察到细胞恢复和心室功能的提高，在多数病人中恢复程度仍不足以移除LVADs。主要调查者Simon Maybaum（纽约Albert Einstein医学院Montefiore医学中心）指出：“这与Harefield的方案迥异，这也导致了两个研究很难比较。我们观察了只有LVADs辅助而无其他额外干预的心脏功能的自然病史。”
Philip Poole-Wilson (Imperial College, London) regards the matter as unresolved. “In my view these papers don’t provide sufficient information about the initial clinical state of patients, making it hard to judge whether they would have recovered anyway with medical treatment or whether the assist device got these patients over a transient period of heart failure rather than being a treatment for established chronic heart failure. It’s quite possible we’re dealing with different patient populations – some of the Harefield patients might have recovered spontaneously.” He believes a randomised trial is needed to determine the precise individual benefits from the device, the medical treatment used and the effect of clenbuterol.
Philip Poole-Wilson（伦敦帝国学院）认为该问题仍未解决。“在我看来这些论文并没有为病人的初始临床状态提供充分的信息。他们（严重心力衰竭的病人）是经治疗后恢复，还是辅助装置只是使这些病人度过了心衰的短暂时期而非对已确诊的心力衰竭的一种治疗方法，这很难判断。很有可能我们处理了不同的病人——Harefield的一些病人可能自发地恢复了。”他相信需要进行随机试验以确定该装置的具体个体化益处、应用的医疗治疗手段和克伦特罗的效果。
“These patients were in end stage heart failure, suffering from cardiogenic shock – you just can’t randomise someone in the last minutes of life,” counters Yacoub.
Yacoub 回应到“这些病人处于终末期心力衰竭，遭受着心源性休克——你不能够对这些处于生命最终阶段的病人进行随机化。”

The next step...

The next step is a larger, multi-centre trial named the Harefield Recovery Protocol study (HARPS), where the protocol will be used in seven US centres and involve around 60 patients. If the data are found to be robust, a larger randomised study is planned, with one group given clenbuterol and the other not, to identify the exact role the drug plays in events. “It’s essential to be able to show we can reproduce our results in other centres using the same protocol,” said Yacoub.

In an editorial accompanying the initial NEJM paper, Dale Renlund and Abdallah Kfoury (LDS Hospital, Salt Lake City, UT) described the study as “tantalizing” but added : “To use legal parlance, …(they) have achieved ‘a preponderance of evidence’ but are not convincing ‘beyond a reasonable doubt’.” It is to be hoped that the new studies will provide the proof.
下一步……
下一步是进行名为Harefield恢复方案研究(HARPS)的更大的、多中心的临床试验，这项方案应用于美国7个研究中心，包括大约60名病人。如果发现数据确实可靠，将计划更大的随机研究，一组给与克伦特罗，而另一组则不应用该药物，目的在于明确这种药物发挥的具体作用。Yacoub. 声称“关键是能够显示应用相同的方案，我们能够在其它中心得到与我们相同的结果。”
在新英格兰杂志原文同期发表的一篇评论中，Dale Renlund 和 Abdallah Kfoury（犹他州盐湖城，LDS医院）指出，这项研究“很诱人”，但同时补充到：“套用法律的说法……（他们）达到了‘证据优势’而没有令人信服的‘无可置疑’”。有希望认为新的研究将提供证据。