Esler教授是澳大利亚墨尔本贝克IDI心脏与糖尿病研究所的心脏病专家及医学家。其主要研究领域涉及交感神经系统、应激及其对心脏与血压的影响、高血压及心力衰竭的原因/治疗等，发明了研究人类内脏交感神经系统的同位素稀释法，是SYMPLICITY研究的首席研究员。

　　评估去神经化是否成功是肾脏去神经治疗必不可少的重要环节。但是，目前在人类研究中我们还尚未进行相关评估，究其原因还是受方法学的限制。鉴于技术方面存在的挑战，目前评估去神经化治疗成功与否的方法只有一种，那就是于治疗前后测量从肾神经发出的交感神经递质的释放速率即所谓的肾去甲肾上腺素溢出率。不过目前人类临床研究中，研究者都假定自己实施的去神经化治疗是成功的，均未对是否成功实施去神经化进行客观评估。近期对50例患者的数据分析显示，经导管射频消融去神经治疗的成功实施率仅为40%。这就意味着，实际上在临床研究中，我们可能仅对部分患者进行了充分的去神经化，而对部分患者的去神经化则并不充分和彻底。

　　SYMPLICITY HTN-3研究未能达到预设的有效性终点，很多人因此对肾脏去神经治疗的前景表示担忧。我认为，首先肾脏去神经治疗顽固性高血压的理论并没有问题；其次，该研究是一项大型、假手术对照、随机、双盲研究，设计良好；第三，很大一部分患者的肾脏去神经化治疗实施得并不成功可能才是导致部分患者对治疗无反应、研究未能达到预期阳性结果的真正原因。实际上，经导管射频肾脏去神经化治疗的操作是非常有技术难度的，设备（主要是消融导管）问题以及术者经验不足均可导致治疗失败。SYMPLICITY HTN-3研究采用的是单电极导管，难以实现360度全方位消融，且大多数术者并无这项新技术的实施经验，这可能是研究未达预设阳性结果的根源所在。就消融肾神经的能量来源而言，目前可选用的有射频能量及超声波能量两种。至于哪种能量消融更安全有效，则尚需进一步头对头对比研究来确定。SYMPLICITY HTN-3研究的意义在于激励我们发现和解决肾脏去神经治疗目前所存在的问题。

　　<International Circulation>: Dr. Esler，  we saw this whole session this morning at CIT about renal denervation and I think it is interesting that at an interventional meeting now we are seeing some more material being presented about this topic whereas before I would often see it more at hypertension meetings or general cardiology meetings.  Your talk this morning， one thing that was particularly interesting was that you mention the trials and the animal studies versus in humans and that in the human studies they really have not looked at whether or not they could have completely ablated the nerve.  First of all what are the limitations and why have they not done this in studies previously?  In human studies what are the limitations， why is this being done.

　　Dr. Esler: It is universally done in animal studies without exception and it clearly is essential to know if you have achieved the denervation.  The problem in the human studies is that there is only one state of the art method.  And that is what we have to measure the rate of release of the sympathetic transmitter from the renal nerves pre-treatment and at a certain period after treatment， so called renal noradrenalin spillover and that is a method that I developed in Melbourne and we have used for 30 years.  There were centers around the world using it but there were no others now because it is technically challenging.  It has not been available in the human trials and it meant that there’s just been no tests of denervation， it has been assumed it was adequate but when we actually have tested it and we now have a data base of 50 patients， we know it is only about 40% successful and differs a lot from patient to patient compared to 95% successful with surgical denervation.  That means it is very close to the margin.  Some patients you can do enough， some patients not enough and I think that is primarily what causes non response rather than not that the pathophysiology is not right which is suggested and could be true.  I think it is more likely that there has been technical failure.

　　<International Circulation>: You also mentioned that the real difficulty of these catheter denervation procedures， although it may appear simple， that it is actually difficult.  Do you have any view on when we look at failure of renal denervation procedures， do you think it is attributed to the device or do you think a lot of these could possibly be operator inexperience or training.  If this is the case how do we move forward and get over this particular barrier to applying this more widely.

　　Dr. Esler: I think it can be both， I think that the earlier catheters including the one used in the SYMPLICITY HTN-3 trial， are single electrode catheters that are very operator dependent in their application.  The newer designs typically have 4 electrodes and either a spiral design or at least spring open to get simultaneous contact with the wall so I think between a combination less than optimal design in the hands of people who may not be skilled and in SYMPLICITY HTN-3 I am sure that happened， whatever they said， that happened.  They used a single electrode catheter and it was done by people who had never done that before.  Now there is another problem， this has been amazingly safe and in SYMPLICITY HTN-3 the margin was they were after a safety endpoint of 9%， in other words， if 9 out of 10 were safe that was right.  It was 99 out of 100 who were safe so the new thinking is we have not given enough imaging.  We need a better catheter with model points of contact and it is safe to get better imaging and those 2 facets should get better denervation.

　　<International Circulation>: Although you mentioned that it appears to be really a class wide issue， in fact across these devices do we really know the differences between these different energies?  Is there one in particular that we might want to move and the future devices will go more towards that type of energy， with more ideal safety and efficacy?

　　Dr. Esler: It is a key question whether radiofrequency energy or ultrasonic energy will win out in the long run.  I say there may be a class effect but there is no head to head comparison of those 2 energy forms in the human study.  It is to be established whether one is better than the other and one may be better than the other but we do not know.  For example if ultrasound penetrated better I think it would probably be preferred but we do not know any of that at the moment.

　　<International Circulation>: With SYMPLICITY HTN-3 does this answer the questions?  Where do we go after this study， what is the next step because it seems we really still need answers.  What is the status now of post SYMPLICITY HTN-3?

　　Dr. Esler: That’s right the nihilist would say this is the end of the story.  It was a study that was designed that was so optimal， except it wasn’t.  It was done by novices that had never done it before， so a big study， sham， blinded， which is how it should be.  It is not a definitive study and what this has done is stimulated people all around the world， including me， to look at the science again and consider these questions.  Which energy form will be best?  We must include a measure of denervation in each study， how can we do that?  In fact I have a database at home I am working on which is effectiveness of denervation in 50 patients and I can look separately at the 2 kidneys.  There is a bilateral denervation and unilateral and then match that up against blood pressure response which will use ambulatory pressure in everybody， and all these patients pre-treatment will have measures of sympathetic activation; plasma noradrenalines， whole body noradrenaline release， nerve recording， and renal spillover so we can look at a patient and say ‘yes， the denervation was technically successful’， what predicted the outcome?  So far it has been impossible to predict the outcome because some of the failures to respond are technical failures， the kidneys have not been denervated.