<International Circulation>: What are the major problems that have not yet been resolved in renal denervation therapy?
Prof.  Caulfield: Probably the standout one is that we don’t know if it reduces mortality or morbidity. When you study small numbers of people， you don’t have enough people in the studies to make estimates as to whether it reduces stroke or heart attack. What we can say in both the Symplicity-1 and Symplicity-2 trials and indeed in some evidence with another technology made by St Jude， is that the falls in blood pressure are appreciable – between 25mmHg and 30mmHg systolic. These are quite big falls in blood pressure. There is only one drug that we have in clinical practice that can cause that much blood pressure lowering and that is spironolactone. That doesn’t even come close to some of the data that is more than the lowering capacity of spironolactone. So it is a treatment with promise. Blood pressure falls are likely to reduce risk of heart attack and stroke but we don’t actually know that. I am aware that at least one company is considering an outcomes study in high-risk patients so I suspect this will be answered in time but for the moment we don’t have that data.
《国际循环》：目前肾脏去交感神经治疗尚未解决的主要问题有哪些？
Caulfield教授：最主要的问题就是我们不知道其能否降低死亡率或发病率。相关研究都是在少量患者中进行的，研究未能纳入足够的患者来评估降低卒中或心肌梗死发病率。Symplicity-1试验、Symplicity-2试验以及St Jude所做的关于另一项技术的试验均显示，肾脏去交感神经治疗具有明显的降压作用，可使收缩压降低25 mmHg~30 mmHg。血压的降幅还是非常大的。目前，在我们的临床实践中，只有一种药物能使血压降幅达到这种程度，这就是螺内酯。甚至有数据提示，与螺内酯相比，其降压疗效更强。因此肾脏去交感神经治疗非常具有应用前景。血压的降低有可能减少心肌梗死及卒中的发病风险，但实际情况我们还尚不得知。据我所知，至少有一个公司正在考虑对高危人群肾脏去交感神经对上述结局的研究。我认为，未来这些问题都将得到解答。但是目前来说我们还没有相关数据。
<International Circulation>: Some studies have suggested that renal denervation therapy could bring benefits to patients with heart failure， diabetes， atrial fibrillation and ventricular arrhythmias. What is your opinion on the potential of renal denervation beyond resistant hypertension?
Prof.  Caulfield: The early proof of concept data in really small numbers (sometimes seven， sometimes ten and twelve patients) has looked at a variety of different characteristics. In hypertensives with insulin resistance， which is a common feature of hypertension， some of whom were diabetic， there was an improvement in blood glucose by about a 0.5mmol reduction post-renal denervation. These people did not have this treatment because they were diabetic or insulin resistant; they had it because they met the Symplicity criteria for resistant hypertension. But this collateral beneficial effect on glucose was noted. In a world with a burgeoning diabetes epidemic， there is potential for there being benefit beyond blood pressure.
In terms of heart failure， the study that is in the public domain is on seven patients and it is way too early to say whether it should be deployed but in the seven patients that were seen in the study， there were no untoward safety issues， no major blood pressure drop (they didn’t have resistant hypertension and their blood pressure was 112mmHg systolic)， but what they did have was an improvement in their ability to walk without breathlessness on a six-minute walk test. But with seven people you can’t really make any fixed comment. The larger study has been commissioned and is underway and we await the results of that.
In terms of atrial fibrillation and arrhythmias， an observation from the trials that have been conducted so far in resistant hypertension is that after you deliver the therapy， because it damps down the outflow of the sympathetic nerve firing from the brain， you get a reduction in heart rate. At the end of the day， it is an adaptation on an existing technology that is already used to treat atrial fibrillation. We use catheter-based ablation to actually stop atrial fibrillation. One theory is that as blood pressure is a really strong trigger to the swelling of the atria that can cause atrial fibrillation， if you treat patients with resistant hypertension could you reduce their risk of progression to atrial fibrillation? This is not by actually stopping the trigger point from the pulmonary vein from firing and triggering the atrial fibrillation， it is actually by reducing the stretch of the atria because of the hypertension. So you are actually treating hypertension and having a secondary potential benefit on atrial fibrillation. We have some promising data from animal models but no human data as yet. We need more data.
The other area that has been explored is in people with resistant hypertension who have obstructive sleep apnea. Typically these people are often very overweight and they have periods during the night when they snore a lot and stop breathing. What was seen in a sleep study from Poland with patients treated for resistant hypertension is that not only does the blood pressure get lowered but the number of apneic and hypopneic episodes i.e. the number of obstructive sleep apnea episodes， was reduced in the treated patients. There is some link between the two but we do not fully understand it at the present time.
These are areas that should be regarded from the point of view of physicians as areas of research endeavor for which we do not have current answers that will allow us to build confidence that we should give this as a treatment to patients with those conditions. For all of these other cardiovascular and metabolic characteristics， the honest answer is that we need more data.
　《国际循环》：有些研究提示肾脏去交感神经治疗能为心力衰竭、糖尿病、心房颤动及室性心律失常患者带来获益。您对其在难治性高血压外的应用前景有何看法？
Caulfield教授：早期研究在不同特征人群中开展了小样本量（有时7例，有时10例，有时12例）调查。高血压经常伴有胰岛素抵抗，这些患者中有一部分伴有糖尿病。有研究显示肾脏去交感神经治疗能使其血糖降低0.5 mmol/L。这些患者并不是因为糖尿病或胰岛素抵抗接受肾脏去神经术，而是由于其合并难治性高血压，符合Symplicity试验的入选标准。值得注意的是，肾脏去交感神经治疗对血糖具有有益效应。当今世界糖尿病不断流行，这种降压外获益具有非常大的发展潜力。
就心力衰竭而言，相关研究仅纳入7例患者（这些患者不伴有难治性高血压，平均收缩压仅为112 mm Hg），确定其是否应该被应用还为时尚早。在研究的7例心力衰竭患者中， 6分钟步行试验中无呼吸困难行走的能力改善，未发现血压显著降低，也未发现其他安全性问题。更大型的研究正在进行中，我们期待结果的公布。
就心房颤动和心律失常而言，难治性高血压的观察性数据显示，肾脏去交感神经治疗能降低心率，这是由于大脑交感神经冲动输出减弱。实际上，肾脏去神经术是现有心房颤动治疗技术的一种进化。我们应用导管消融来消除心房颤动。有一种理论认为，血压是促进心房扩大从而引发房颤的强力刺激因素，那么，肾脏去交感神经术治疗难治性高血压是否能降低房颤风险？该效应是因为其降低了高血压对心房的牵张，而不是消除肺静脉的触发。因此，虽然你治疗的是高血压，但却能为房颤带来继发性的潜在获益。虽然有关肾脏去交感神经治疗的动物模型结果令人兴奋，但目前尚无人类的相关数据。
另一个特殊人群是合并阻塞性睡眠呼吸暂停的难治性高血压患者。这些患者通常伴有超重，夜间经常出现打呼噜及呼吸停止现象。波兰一项对难治性高血压患者睡眠情况的研究显示，肾脏去交感神经治疗不仅能够降低患者的血压，还能减少呼吸暂停及低通气发作次数。也就是说治疗组患者阻塞性呼吸睡眠暂停的发作次数减少。两者之间存在一定的关联，但目前我们对其尚不完全了解。
从临床医生的角度来说，我认为这些是我们需要关注的领域，因为目前的研究尚未为我们充足的自信可以将肾脏去神经治疗应用于上述患者中。诚实地说，对其他心血管及代谢疾病而言，仍需更多的研究数据来阐明肾脏去交感神经治疗能否应用。