为学·RDN｜肾神经标测在去肾神经术前、术中及术后的应用：信迈
2022-08-25 10:29

本栏目主要介绍由国际知名学者Richard R. Heuser, Markus P. Schlaich和Horst Sievert主编的RDN领域权威教科书《Renal Denervation: Treatment and Device-Based Neuromodulation（去肾神经术：神经调节的器械疗法）》，其中特邀江苏省人民医院/美国哥伦比亚大学王捷教授撰写重要章节“Sensing Renal Nerve Activity Before, During and After Denervation: SyMap（肾神经标测在去肾神经术前、术中及术后的应用：信迈案例）”，专门阐述了肾神经标测/选择性消融的理论基础、研究证据和临床实践。下面详细介绍该章节内容。

*通讯：

王捷博士，邮箱:jw147@columbia.edu，jay329329@yahoo.com。
苏州信迈医疗器械有限公司联合创始人，中国。

Abstract

The safety and efficacy of renal denervation (RDN) for the treatment of hypertension have been repeatedly confirmed by a number of studies. However, an approximately 30% non-responder rate was consistently observed among various energies-based RDN. This phenomenon might result from non-selective, global RDN as different nerve types are innervated around the renal artery and futile, even wrong, ablations of non-sympathetic nerves could cause detrimental effects. Thus, a readout for mapping renal nerves and selective sympathetic denervation before, during and after RDN is an urgent/unmet clinical need for this therapy. Results of recent studies demonstrated solid anatomy, physiology and histology evidences to support renal electronic stimulation as a tool for renal mapping and selective denervation. Using renal stimulation, we should be able to identify proper sites for RDN, monitor the effects of RDN and confirm an effective RDN before, during and after the procedure, respectively. With a newly developed renal mapping/selective denervation system, we are conducting a pivotal trial to test the safety and efficacy of selective renal sympathetic denervation to treat uncontrolled hypertension.  

Keywords: Renal denervation, Hypertension, Renal nerve activity, Sympathetic nerves, Renal stimulation, Mapping renal nerves, Selective sympathetic denervation, Renal mapping/ selective system, SyMap, SMART Study

摘要

去肾神经术（RDN）治疗高血压的安全性和有效性已经被多项研究反复证实。然而，无论采用何种能量形式（超声或者射频），总有近30%的患者对消融治疗无反应。造成这种现象的可能原因在于肾动脉周围分布着不同类型的神经，如果消融时不加以辨别，乃至错误地对副交感神经进行消融，就无法确保手术效果，甚至产生副反应。因此，在RDN术前、术中和术后标测肾神经活性，进而选择性去除肾交感神经，是目前RDN临床应用中的迫切需求。近年来的多项研究，从解剖学、生理学和组织学等多个层面为肾神经电刺激的临床应用奠定了坚实的理论基础，充分证实其作为神经标测和选择性消融工具的可靠性。借助肾神经电刺激，可以实现术前指导选择性消融位点、术中监测消融效果、术后验证消融疗效。目前本团队已成功研发一款肾神经标测/选择性消融系统，并牵头开展一项注册临床研究，旨在证实肾神经标测/选择性消融治疗未控制高血压的有效性和安全性。

关键词：去肾神经术、高血压、肾神经活性、交感神经、肾神经刺激、肾神经标测、选择性去肾神经、肾神经标测/选择性消融系统、信迈医疗、SMART研究。

The Achilles Heel of the Field: Lack of Readouts to Indicate Efficient Renal Sympathetic Denervation 

The concept of RDN to treat hypertension can be traced back to 1950s, in a large scale of study by Smithwick and Thompson who showed that blood pressure (BP), mortalities and survival rates of hypertensive patients were significantly improved by thoracolumbar splanchnicectomy [1], demonstrating the effectiveness of RDN on hypertension. Because of severe side effects of the surgical RDN and developments of pharmaceutical therapies, the surgical approach to denervate renal nerves was fired from clinical practice. Although sophisticated drug therapies have been available for hypertension, new therapies for the disease are still an unmet clinical need since social and economic burdens of this disease have become more severe in recent years, and the issues of drug compliance and drug resistance are never really addressed. There are 70[2], 150[3], and 245[4] million hypertensive patients in US, EU countries and China, respectively, and the uncontrolled rate is very high. Krum et al. brought a new hope for RDN in 2009, these investigators performed a proof-of-concept study to denervate renal nerves by a dedicated catheter in patients with resistant hypertension and demonstrated that interventional device-based RDN could lead to a significant reduction in BP with excellent safety profiles[5]. Since then, a series of clinical studies have proved the efficacy and safety of RDN to treat hypertension[6-10]. However, Symplicity HTN-3[11], the first double-blinded, randomized, sham controlled trial showed that the BP difference between RDN and sham group was not observed at 6 months. Investigators realized that two major factors interfered with the effects of device-based RDN on BP and led to the failure of the Symplicity HTN-3 study: poor drug compliance during the trial, and lack of a readout before, during and after RDN to confirm an effective renal sympathetic denervation[12]. Newly initiated Spyral Global Off-Med and On-Med studies after the failure of Symplicity HTN-3 trial partially addressed the issue of drug compliance by both patients who enrolled in the study and did not take any antihypertensive drugs or who followed a restricted drug regimen during the study[6,9,10]. Both studies further confirmed the efficacy and safety of RDN but the amplitude of office systolic BP reduction was moderate: around 10mmHg, because 20-30% patients were so-called no-responders whose BP was not decreased or even increased after RDN[6,9,10]. This may counteract BP-lowering effects achieved by RDN. This phenomenon was consistently observed across various energies-based RDN devices reported so far. Per Townsend and Sobotka[13], either radiofrequency ablation or ultrasound ablation had an over-all success rate of about 63%. These approximately 30% non-responder rates were also observed among patients with alcohol-mediated RDN, Mahfoud et al reported that decreases of ≥5 and ≥10 mm Hg in office systolic BP at 6 months were recorded in 70% and 61% of patients, respectively[14]. Townsend and Sobotka believed that the ~30% non-responder rates may reflect either technical failures or suboptimal patient selection given the lack of predictors for BP-lowering success. It becomes apparent that a decreasing non-responder rate is a major issue that needs to be addressed. As Esler pointed out, failure to test an effective renal sympathetic denervation "represents the Achilles heel of the field"[15]. Thus, indicators before, during and after the RDN procedure to predict and confirm a successful sympathetic denervation are an urgent unmet clinical need for this therapy. 
本领域的重要缺陷：缺乏判断实施有效去肾交感神经术的可读取指标
去肾神经术治疗高血压的概念可以追溯到1950年代，由Smithwick和Thompson教授完成的大规模临床试验发现，相对于常规药物治疗，胸腰椎段内脏神经切除术能更加有效控制患者血压，改善死亡率和存活率，初步证实RDN治疗高血压的有效性。随着高血压药物治疗方案的逐渐问世，肾交感神经外科切除术由于其并发症风险较高，逐渐退出临床应用。尽管已有先进完善的药物疗法可用于治疗高血压，但近年来该疾病的社会和经济负担逐渐加大，而且药物的依从性和耐药性问题从未得到真正解决，因此寻求该疾病的新疗法仍然是临床治疗迫切需要的。在美国、欧盟国家和中国分别有7千万[2]、1.5亿[3]和2.45亿[4]百万的高血压患者，其中血压控制不佳的患者比例非常高。2009年，Krum等牵头完成的概念验证研究表明，通过导管消融方式进行肾交感神经去除术，可显著降低顽固性高血压患者的血压水平，且具有良好的安全性，这一发现为RDN术带来了新的曙光[5]。此后，一系列临床研究证明了RDN治疗高血压的有效性和安全性[6-10]。然而，第一个双盲、随机、对照实验Symplicity HTN-3[11]显示，RDN治疗组和假手术对照组在随访的六个月内血压变化没有出现显著性差异。随后研究人员意识到主要有两个因素干扰了经导管行RDN对血压的作用并导致了Symplicity HTN-3研究的失败:试验期间患者服药依从性差和缺乏术前、术中和术后肾交感神经的标测指标，从而无法证实消融效果[12]。在Symplicity HTN-3试验失败后，新启动的Spyral Global Off-Med和On-Med研究在试验期间部分地解决了未服用任何抗压药和遵循标准用药方案患者在药物依从性方面地问题[6,9,10]。两项研究均进一步证实了RDN治疗的有效性和安全性，但收缩压降低幅度一般：约降低了10mmHg,但其中还有20-30%的患者对治疗无反应，甚至经RDN治疗后血压不降反升。上述现象一定程度上削弱了RDN治疗高血压的有效性。且在迄今为止进行的多项临床研究中，均观察到类似结果。Townsend和Sobotka[13]的研究显示射频消融或超声消融的总体成功率为63%。Mahfoud等研究发现，采用酒精消融进行RDN术，术后6个月随访时，收缩压降低≥5mmHg和≥10mmHg的比例分别为70%和61%，仍有30%的患者对治疗无反应[14]。Townsend和Sobotka认为，这持续存在的30%无反应率，说明由于缺乏有效的监测手段，使得手术效果的评估和患者的选择方面存在一定缺陷。显然，降低无应答率是一个需要解决的主要问题。正如Esler指出的那样，缺乏肾交感神经去除效果的评价指标是该领域中的重要缺陷[15]。因此，寻找RDN术前、术中和术后的肾神经标测指标，来预测和确认手术效果，是RDN临床应用中的迫切需求。
Mapping Renal Nerves by Renal Stimulation: Anatomy, Physiology and Histology Evidences
Recent developments based on studies of anatomy, physiology and histology in this field made mapping renal nerves and selective RDN possible. van Amsterdam et al. and Mompeo et al. [16,17]examined neural anatomy structures around renal artery and revealed three nerve types: sympathetic, parasympathetic and afferent nerve components (Figure 1); however, Kuichi et al. had different views about the types of these nerves and named these nerves as "pressor nerves", "depressor nerves" and "neutral nerves" depending upon whether BP was increased, decreased or unchanged in responses to electronic stimulation[12]. We[18-20] and other investigators[21,22] have demonstrated that systemic hemodynamics in particular, BP, was increased, decreased or unchanged once an electronic stimulation was delivered to the renal artery, respectively. The direction of change in BP due to the stimulation depends upon which type of renal nerves was activated. We [18] named the sites which increased BP when stimulated as "hot spots", representing sympathetic dominant innervations, the sites which lowered BP when simulated as "cold spots", representing parasympathetic dominant innervations, and locations along the renal artery which do not show hemodynamic effects when stimulated as "neutral spots," which may present no innervations or well balanced sympathetic and parasympathetic innervations (Figure 2). Mapping sympathetic/pressor nerves or hot spots for selective ablations could expect to cause a significant fall in BP whereas ablations of parasympathetic/depressor nerves or cold spots may result in no effects or even an increase in BP [23, 18], and neutral spots should not be ablated [12]. Results from clinical trials did show that increased BP in some patients after RDN at a 6-month follow-up [6, 9,10] and it may be due to wrong ablations of cold spots.  As Tsioufis et al [23] pointed out, renal nerve fibers vary significantly regarding types, numbers and sizes, as well as their distance from the lumen in the proximal and distal segments of renal artery mainstream and branches. Several recent studies [19-25] have illustrated BP responses to renal nerve stimulation in corresponding to the different nerve distributions around renal artery and provided convincing evidences of anatomy, physiology and histology for the rationales of renal mapping guided by renal nerve stimulation. Regarding the concept of different BP responses to discrete site stimulations, we have demonstrated a substantial reduction in both BP[20,26] and serum norepinephrine levels in Chinese Kunming dogs, a canine model with a spontaneous high sympathetic tone, after ablating the sites which caused significant rises in BP evoked by renal nerve stimulation, and we confirmed that the BP-lowering effects were proportional to the increases in BP by the stimulation. Histological evidence implied that these sites were innervated by nerve bundles containing sympathetic fibers[19,20] and that the amplitudes of increases in BP to renal stimulation were proportionally determined by the total area and number of renal nerves in stimulated sites (Figure 3).  Renal stimulation can be also used to assess whether a successful RDN is achieved. After a successful RDN, BP response to stimulation should be significantly blunted; otherwise, it suggests an inadequate denervation at the target sites and a second ablation on the same site will be needed.
Thus, renal nerve stimulation and changes in BP in response to the stimulation have been believed to have very promising potential for mapping renal nerves in order to selectively denervate sympathetic nerves and avoid futile ablations.
通过电刺激标测肾神经：解剖学、生理学和组织学证据
该领域解剖学、生理学和组织学研究的最新进展使标测肾神经和有选择性的去除肾交感神经成为可能。Van Amsterdam和Mompeo[16,17]等通过解剖学研究发现，肾动脉周围分布有三种不同类型神经：交感神经，副交感神经和其他神经类型(图1)；

图1.A组显示了人右肾的肾交感肾丛。(A)前视图和(B)后视图。Ag（肾上腺），Arg（主动脉神经节），Coe（腹腔神经节），CoT（腹腔干），Ig（肾下神经节），LC（腰神经对肾丛的分支），Pg（肾后神经节）、RK（右肾）、SMg（肠系膜上神经节）、SP（胸内脏神经）。

B组显示了相同动脉和节段的免疫组织学染色结果。左上角是动脉的管腔。(a)TH，交感神经标记，(b) NOS，副交感神经标记，(c)CGRP，传入神经标记，(d)PGP（一般标记。TH（酪氨酸羟化酶），NOS（一氧化氮合酶），CGRP（降钙素基因相关肽）、PGP（蛋白质基因产物 9.5）。经Van Amsterdam和 Mompeo等人的许可改编[16,17]。
然而Kuichi等人对这些神经类型的分类有不同的看法，他们根据对神经进行电刺激后引起的血压变化[12]，根据血压的反应是升高、降低还是不变，将这些神经命名为“加压神经”、“减压神经”和“中性神经”。我们[18-20]和其他研究人员[21,22]已经证明，电刺激肾动脉后，全身血流动力学改变，尤其是血压的变化，血压是升高、降低还是不变取决于刺激的肾神经类型。我们[18]将刺激后血压升高的部位命名为“热点”，代表是肾交感神经支配的部位；将刺激后血压降低的部位命名为“冷点”，代表是肾副交感神经支配的部位；将刺激后血压不变的部位命名为“中性点”，这可能是没有神经支配或者刺激后该部位的交感和副交感活性恰好互相平衡（图2）。
图2.选择性与全肾脏去神经支配的理论框架：红点代表“热点” - 加压点。这些神经在受到刺激后会升高血压。这些点是肾脏去神经支配的理想目标。绿点代表“冷点”——降压点，在受到刺激后会降低血压。黄色的神经纤维对血压生理学的贡献是中性的，并且在受到刺激时不显示血流动力学效应。经Fudim等人许可改编[18]。
对交感神经/加压神经或热点进行选择性消融可能会使血压显著下降，而对副交感神经/减压神经或冷点进行消融可能无影响，甚至有可能会导致血压升高[18,23]，同样也不应该对中性点进行消融[12]。确实有研究发现，RND术后六个月随访时，部分患者的血压不降反升，可能就是由于错误消融“冷点”所致[6,9,10]。正如Tsioufis所指出的[23]，在肾动脉主干和分支的近端及远端，所分布的肾神经纤维类型、数量、大小，以及距离管腔远近都有很大差异。最近的几项研究[19-25]说明了刺激肾神经引起的血压变化情况与肾动脉周围分布的不同类型神经相对应，这为经刺激标测肾神经的方式提供了解剖学、生理学和组织学上的理论支持。关于肾动脉刺激与血压之间的相关性[20,26]，我们借助昆明犬完成了生理性验证研究。昆明犬是一种具有自发性高交感神经活性的动物[19,20]，刺激其肾动脉周围神经可引起血压升高，对该部位进行消融后昆明犬的血压和血清去甲肾上腺素水平显著降低，且消融后血压下降程度与刺激后血压升高的幅度呈正相关。组织学证据也表明，这些部位由交感神经束进行支配，并且血压升高的幅度与受刺激部位肾交感神经[19，20]分布的面积和数量成正相关。因此，肾神经刺激可以用于验证肾交感去除术的手术效果（图3）。
图 3. 受刺激时血压显着升高的强反应部位 (SRS) 与受刺激时血压升高幅度较小的弱反应部位 (WRS) 之间的神经分布差异。A和B，SRS 和 WRS 的代表性 Masson 染色图像。红色箭头表示肾神经束，黑色箭头表示消融区域。SRS中肾神经的总面积（C）/数量（D）大于WRS。SRS 和 WRS 之间从管腔到神经的距离 (E) 没有差异。经刘等人许可改编[20]。
如果术中成功去除了某部位的交感神经，那么再次刺激时血压的变化幅度应该明显减弱；否则说明该部位的申请去除不充分，需要进行二次消融。因此，肾神经刺激和相应的血压变化有望成为一种有效的标测方法，用于指导选择性肾交感神经去除术，避免无效消融。
Using BP Response Patterns to Identify Hot Spot, Cold Spot and Neutral Spot
Based on the heterogeneous physiology of sympathetic and parasympathetic fibers, variant proportions of sympathetic and parasympathetic fibers produce different phenotypes of BP responses when stimulated. As we have discussed previously, [20] the same bundle may contain different types of nerves such as sympathetic and parasympathetic (or sympathetic inhibitory) fibers. The changes of BP in response to electronic stimulation are an integrated physiological event, depending upon which nerve fibers are dominant at this particular site. If a parasympathetic dominant site is futilely denervated, it may partly neutralize the BP drop caused by sympathetic denervation or even augment the BP. Thus, we propose that the net effects of RDN on BP involve the rebalance between the sympathetic and parasympathetic systems due to the procedure. Clearly, identifying BP patterns when stimulated could be a key for renal mapping and selective RDN. 
通过刺激后血压的不同变化模式识别热点、冷点和中性点
基于交感神经和副交感神经在生理功能上的差异性，不同比例的交感神经和副交感神经纤维在受到刺激后会出现不同的血压变化模式。正如我们之前所讨论的[20]，同一纤维束中可能包含不同类型的神经，例如交感神经和副交感神经（或交感抑制神经）纤维。电刺激引发的血压变化是一个综合后的生理事件，它取决于在该特定部位占主导地位的神经类型。如果去除了某部位的副交感神经，这可能会使该部位副交感神经降血压的效果降低，甚至引起血压升高。因此，我们称RDN对血压的最终影响取决于该部位交感神经和副交感神经平衡后占主导地位的神经类型。
Animal Data:
In animal studies, we [19] observed at least five patterns of BP responses which might potentially help us to distinguish sympathetic or parasympathetic-dominant sites (Figure 4). 

Pattern 1：BP immediately increased to its plateau in responses to renal nerve stimulation, maintained at a steady and elevated status during the stimulation, indicating that the renal sympathetic nerve is dominant in this site. We presumed that electrical stimulation signals were transmitted to the central nerve system (CNS) via afferent fibers and increased central sympathetic activity, leading to an increasing central sympathetic output to the entire body. It caused a series of physiological effects, including peripheral vasoconstriction, increases in myocardial contractility and cardiac output, resulting in BP elevation. Efferent nerve fibers in the same bundle were also captured by electronic simulation; the efferent sympathetic signals to kidneys participated the elevation of BP by renal artery contraction, release of renin from juxtaglomerular cells, and by increasing tubular sodium and water reabsorption. Overall, this pattern of BP response represents a hot spot and an ablation is needed. 

According to the character of increased BP response and its quick response to stimulation, we named this pattern as Sympathetic Dominant/Rapid Response. A typical original tracing of BP in this pattern is shown in Pattern 1, Figure 4. 

Pattern 2：BP was transiently declined below baseline and then increased to achieve a steady and elevated status above baseline in responses to renal stimulation. We believed that this pattern represents simultaneous activations of sympathetic and vagal nerves. Because the transmitted speed of vagal fibers to the CNS is faster than that of afferent nerves, the BP firstly decreases and then gradually increases. The net effect results in elevated BP, indicating that the impacts of sympathetic nerves on BP are more dominant than those of vagal nerves. This site is a hot spot and should be ablated. 

Because of the increased but delayed elevation of BP, this pattern is named as Sympathetic Dominant/Slow Response, showing in Pattern 2, Figure 4. 

Pattern 3：BP immediately decreased below baseline in responses to renal stimulation and maintained at the low level in a steady status during the stimulation. This pattern represents a site with dominant parasympathetic nerves, which belongs to a cold spot and should not be ablated.  Ablation of such sites may lead to inhibition of parasympathetic nerve activity and promotion of sympathetic nerve activity, resulting in BP elevation.   

We named this pattern as Parasympathetic Dominant/Rapid Response and an example of such a pattern is shown in Pattern 3, Figure 4. 

Pattern 4：BP was transiently declined below baseline in response to renal stimulation and then went up but stayed a level below baseline during the stimulation. This pattern of BP also represents simultaneous activation of sympathetic and parasympathetic nerves; however, the integrated effects of these two nerve types maintain BP at a low level, indicating the dominant function of parasympathetic nerves. This is a cold spot and should not be ablated.   

Since BP achieves a low level at a steady state in a slow manner, the pattern is named as Parasympathetic Dominant/Slow Response, an example is shown in Pattern 4, Figure 4.

Pattern 5：BP was fluctuated around baseline level in response to renal stimulation but the fluctuation was within 5 mmHg beyond or below baseline during the stimulation.  This pattern represents a site in which there is no renal nerve or a well balanced and integrated function between sympathetic and parasympathetic nerves. Since BP was not changed, this site plays a minor role in BP regulation and, therefore, presents a neutral spot and should not be ablated. 

This pattern of BP is named as Neutral Response. An example of this pattern is shown in Pattern 5, Figure 4. 

动物实验数据
在动物研究中，我们观察到至少五种刺激后血压变化模式[19]，这可能有助于我们去区分该部位占主导地位的神经类型是交感神经还是副交感神经（图4）。

模式一：肾神经刺激后血压立即升高直至平台期，并在刺激过程中始终保持稳定升高状态，这表明在该部位肾交感神经占主导地位。我们认为，电刺激信号通过传入纤维进入并激活中枢神经系统，引起全身中枢神经系统冲动传递增强。这产生了一系列生理作用，使外周血管收缩、心肌收缩增强和心输出量增加，从而导致血压升高。同一纤维束中的传出纤维的电子信号也被捕获；传出到肾脏交感神经的信号使肾动脉收缩、肾小球旁细胞释放肾素和肾小管水钠的重吸收作用增加，从而导致血压升高。总的来说，呈现这种血压变化模式的位点就是“热点”，该处需要进行消融。

根据血压升高和其对刺激反应快速的特点，我们将这种模式命名为交感神经主导/快反应。此模式中血压的原始记录图如图4中的模式一。

模式二：肾神经刺激后血压短暂下降至低于基线，然后升高至高于基线的状态保持稳定。我们认为这种模式同时激活了交感神经和迷走神经。因为迷走神经传入神经向中枢神经系统传递冲动的速度比交感神经快，所以血压先下降后才逐渐上升。两者作用的净效果表现为血压升高，这说明交感神经对血压的影响比迷走神经的大。这个部位是一个热点并且需要进行消融。

因为这种模式表现为血压延迟性升高，因此它被命名为交感神经主导/慢反应。此模式中血压的原始记录图如图4中的模式二。

模式三：肾神经刺激后血压立即降低并保持在基线以下。该模式代表此部位是副交感神经占主导地位，属于冷点，不应进行消融。这些部位的消融可能导致副交感神经活动被抑制并促进交感神经兴奋，从而导致血压升高。我们将这种模式命名为副交感神经主导/快反应。此模式中血压的原始记录图如图4中的模式三。

模式四：肾神经刺激后血压短暂下降到基线以下，然后逐渐升高，但最终仍稳定在基线以下。这种血压变化模式也表示交感神经和副交感神经同时被激活；然而这两种神经类型作用后的综合效果是将血压维持在一个较低的水平，这说明副交感神经占主导作用。这是一个冷点部位，不应进行消融。由于血压是缓慢变化并最终稳定在基线以下，所以该模式被命名为副交感神经主导/慢反应。此模式中血压的原始记录图如图4中的模式四。

模式五：肾神经刺激后血压在基线水平附近波动，但在刺激期间的波动幅度在基线水平上下5mmHg以内。这种模式代表此处是无肾神经或是交感神经和副交感申请平衡支配的部位。由于血压没有变化，说明该部位调节血压的作用较小，是一个中性点，不应进行消融。这种血压模式被称为中性反应。此模式中血压的原始记录图如图4中的模式五。

图 4. 动物对肾神经刺激反应的不同类型的血压 (BP) 模式。改编自 Tan 等人[19] 。
Preliminary Human Data:
BP response patterns due to renal stimulation are more complicated in a clinical setting. We have observed at least six different patterns in responses to renal stimulation representing hot, cold and neutral spots, respectively. To best illustrating these patterns, graphs are shown in Figure 5. Here, the elevation or reduction in BP was defined as the change of systolic BP (SBP) once it was ≥5mmHg from baseline.

Pattern 1: SBP is directly increased from baseline and maintained at an elevated level. This pattern is easily assessed as a hot spot and needs to be ablated.

Pattern 2: SBP fluctuated in the manner of repeatedly increasing and then decreasing, or vice versa; however, the overall increases in SBP were above baseline more than 5mmHg. We believe that baroreflex plays a big role in the fluctuations of BP. This is a hot spot and needs an ablation.

Pattern 3: SBP transiently decreased below baseline and then increased beyond baseline, and was maintained at an elevated steady level. This is a hot spot and needs to be ablated. 

Pattern 4: SBP is persistently decreased below baseline during renal stimulation. This is a cold spot and should avoid ablation.

Pattern 5: SBP transiently increased beyond baseline then decreased persistently below baseline when renal stimulation was performed. This is a cold spot and should avoid for ablation.

Pattern 6: SBP did not change much in response to renal stimulation and fluctuated around baseline. This is a neutral spot and should not ablate.     

Apparently, the response patterns of BP to renal stimulation in human are more complicated than in animals. Although the underlying mechanisms responsible for these patterns are not fully understood and need to be further revealed; analyzing and distinguishing these BP response patterns to renal stimulation will help operators to identify nerve types and determine sites to ablate or not ablate.

初步人体研究数据：
在临床试验中，由肾神经刺激引起的血压变化模式更为复杂。我们观察到至少六种不同的血压变化模式，分别代表热点、冷点和中性点。这六种具体的血压变化模式见图五。在这里，我们定义血压（收缩压）的有效升高或降低要比基线≥5mmHg。

模式一：收缩压从基线水平直接升高并保持在一个较高的水平。这种模式很容易识别出此部位是热点，需要进行消融。

模式二：收缩压从基线升高到一定水平后并在较高的水平反复上下波动；然而，收缩压升高的总体趋势超过5mmHg。我们认为这种压力反射在血压的调节中有着重要的作用。这是一个热点部位，需要进行消融。

模式三：收缩压短暂下降到基线以下然后开始上升，最终稳定保持在高于基线的水平。这是一个热点部位，需要进行消融。

模式四：在肾神经刺激期间收缩压持续下降到基线以下。这是一个冷点部位，不应进行消融。

模式五：当进行肾脏刺激后，收缩压迅速升高超过基线，然后持续下降至低于基线。这是一个冷点部位，不应进行消融。

模式六：收缩压对肾脏刺激反应没有太大变化，并在基线水平附近波动。这是一个中性点部位，不应进行消融。

显而易见，人体内血压的变化模式比动物更为复杂。然而导致这些变化模式的潜在机制尚未完全清晰，仍需要进一步研究揭示。分析和区分这些血压对肾脏刺激反应的变化模式将有助于术者确定神经类型并有选择地对交感神经主导的部位进行消融。

图 5. 人体对肾神经刺激反应的不同类型的血压模式。
Renal Mapping and Ablation System 
The combined renal mapping and ablation system developed by SyMap Medical (Suzhou), Ltd (Suzhou, China) is consisted of a dedicated electromapping/ablation SyMapCath I™ catheter and a SYMPIONEER S1™ Stimulator/Generator [27]. The stimulation/ablation catheter has a steer tip and is within a sheath that can be manipulated to go forward/back and turn 90 degrees in the sheath via a catheter handle. The sheath can be used for contrast injection (Panel A, Figure 6) as this design provides conveniences for operators without using additional accessories. The stimulator/generator can perform both electronic stimulation and RF ablation with the catheter (Panel B, Figure 6). This system could facilitate appropriate patient selection through screening for candidates whose BP is driven by renal sympathetic nerve activity. This would allow the operators to target only optimal ablation sites (hot spots/sympatho-stimulatory) while minimizing damage to cold spots/sympatho-inhibitory sites, with documentation of technical success through the loss of systemic BP changes when stimulated again after RDN. 
肾神经标测/消融系统
由中国苏州信迈医疗器械有限公司开发的肾神经标测和消融系统，由专用的射频消融SyMapCath I™导管和SYMPIONEER S1™刺激器[27]组成。位于鞘内的刺激/消融导管的引导尖头端，可以通过操纵手柄使其前进/后退和实现90°转动。导管还可用于注射造影剂（板块A，图6），这种设计提高了导管的操控性，无需再使用其他附件。刺激/消融导管可同时完成相应位点神经刺激和射频消融（板块B，图6）。该系统可以帮助筛选出由肾交感神经主导的合适患者。有助于术者正确识别消融位点（热点/交感神经支配部位），同时最大限度地降低对冷点及中性点的损伤。在RDN之后，可以再次刺激此部位标测血压变化，如果血压无变化，则说明此处去肾交感神经成功。
图 6. 苏州SyMap医疗有限公司开发的肾神经标测和消融系统，由 SyMapCath ITM 导管 (A) 和 SYMPIONEER S1TM 刺激器/发生器 (B) 组成。
SMART Study and Preliminary Results
The ongoing Sympathetic Mapping/Ablation of Renal Nerves Trial (SMART Study, ClinicalTrials.gov ID: NCT02761811) aims to evaluate the safety and efficacy of targeted renal sympathetic denervation using the system in patients with pharmacotherapy and uncontrolled hypertension for at least 6 months, and then after standardized antihypertensive drug therapy (at least two classes of drugs) for at least 28 days while office systolic BP is still ≥ 150mmHg and ≤180mmHg. 

Two major questions need to be answered after RDN procedure: How much blood pressure will be decreased and how many antihypertensive drugs will be taken less? The current designs of clinical trials are focused on the former and data have emerged for this question; the latter, however, has not been answered or even paid enough attention. We believed that changes of antihypertensive drugs should be a major clinical endpoint for RDN trials. The views of Weber et at. supported our ideas and they pointed out that an important endpoint for RDN trials is to test whether patients receiving the procedure have a reduced need for additional antihypertensive drugs in order to achieve optimal treatment targets [28]. In a clinical setting, the design using reduction in BP as a major clinical endpoint has a challenge to be taken: convincing patients to follow drug compliance even as their BP is still ≧150mmHg after RDN, and this is particularly difficult to maintain drug compliance for patients in sham group during a six-month follow-up period. If patients in sham group take any antihypertensive drugs to manage their high BP, the difference of office systolic BP between RDN and sham group could be compromised since the efficacy of global RDN is around 10 mmHg [6,9,10]. 

Thus, we designed dual primary endpoints at 6 months after RDN for SMART study:

1.The control rates of office systolic blood pressure (SBP<140mmHg);

2. The composite index of antihypertensive drugs.

The Composite Index is derived from the numbers of antihypertensive drugs and doses of the medications as below:     

Drug Composite Index = Weights × (sum of doses) .

Weights is the number of classes of antihypertensive drugs. 

One standard dose is defined as 1, a half dose is defined as 0.5, and double dose is defined as 2.  

For instance, if a patient takes one dose of an angiotensin II receptor blocker and one dose of a calcium blocker, this patient's Drug Composite Index is: 2×(1+1)=4. 

Via this trial, we will be able to tell patients and physicians how many antihypertensive drugs are taken less after RDN. 

During the RDN procedure, renal mapping and selective denervation are performed. Renal nerve stimulation is delivered for 60 seconds at 15mA, 20 Hz and pulse duration of 5ms, and hot spots are ablated for two minutes at 8-10 watts and 50℃. If an unsatisfied RDN is found，which can be confirmed by a post procedure stimulation and BP response remains, a repeat RDN is needed on the same site.  

This is a prospective, multicenter, single blind, randomized and controlled trial, and patients will be informed, given consent and entered into a screening process. During the screening period, patients will receive a standardized antihypertensive drug treatment for at least 28 days and office BP is still ≥ 150mmHg, and ≤180mmHg, and meet the inclusion and exclusion criteria. These patients will conduct renal artery angiography and are allocated to either renal sympathetic nerve denervation group or renal artery angiography group by a randomizing system in a 1:1 ratio (220 patients, 110 pairs). Patients with office BP that haven’t achieved an ideal level (<140 mmHg) three months after RDN will titrate doses and/or classes of antihypertensive drugs according to a predefined standardized medication regimen until their office BP <140 mmHg. All medications are provided by the study sponsor (SyMap Medical (Suzhou), Ltd.) and titrated antihypertensive drugs must be only chosen from the standardized drug regimen (Table 3). The class/dose and order to titrate antihypertensive drugs are rigorously defined. Physicians who perform post-procedure patient management and physicians who perform RDN procedures are blind to each other.  Patients will be followed for 7 days after the procedure or at discharge from hospital, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months and 12 months. Urine samples will be collected at the end of each screening, 3 months, 6 months and 12 months to monitor and maintain the antihypertensive drug compliance of these patients. 

Preliminary data from SMART Study were presented at CRT 2017 (Washington DC) [29] and TCT 2019 (San Francisco, USA) [30], and confirmed some of the theoretical groundwork and preliminary data laid out as above. In ten patients with uncontrolled hypertension, only 54% of sites were responsive to renal stimulation with BP elevation (hot spots) (Table 1). Maybe most importantly, stimulation resulted in a BP drop in 16% of sites (systolic BP − 16 mmHg, diastolic BP −4 mmHg, and mean BP− 7 mmHg in average) (Table 2) and no BP response to stimulation in 29% of sites. Ablation of the hot spots prevented BP elevation with repeat stimulation intra-procedurally, which confirmed an effective RDN. Otherwise, a second ablation would be needed on the same site. Long-term outcomes in the full study cohort are still pending. Similar attempts to develop a mapping system were also made by Rainbow/Pythagoras (Israel). Preliminary results were recently presented by Mahfoud, Tsioufis, and Damen at EuroPCR 2017 and confirmed a heterogeneous response to a renal nerve stimulation based on locations of stimulations, with a tendency towards higher BP elevation and higher levels of energy in more proximal renal artery locations [23, 31]. The continued development of appropriate tools to test the renal nerve contribution to elevated BP confirms the technical success of RDN, and in the end allows targeted RDN, which appears to be in close reach.

The promise of a targeted, selective sympathetic RDN opens up a number of possibilities which could address the limitations previously experienced with the conventional approach of unselective or global RDN. Dedicated clinical studies will need to prove the safety and efficacy of the selective RDN approach on long term BP reduction. 

SMART研究和初步结果
肾神经标测/选择性消融临床试验（SMART研究）是一项前瞻性、多中心、单盲法、随机对照研究（ClinicalTrials.gov ID: NCT02761811），旨在探究新型的肾神经标测/消融系统治疗未控制高血压的效果。入选患者的高血压病史至少6个月，经过至少28天规范化药物治疗（至少2种药物）后，诊室收缩压（SBP）仍≧150mmHg且≤180mmHg。

RDN手术治疗后需要回答的两个主要问题：血压会降低多少？可以减少服用多少降压药物？目前RDN临床试验的研究重心主要集中在前者，并且已经获得了针对这个问题的有效数据，然而后者还没有获得结果，甚至没有得到足够的重视。而我们认为降压药种类/剂量的调整应该是RDN临床试验的关键点。Weber等人也支持我们的想法，他们指出，RDN临床试验的重点是要测试接受该治疗的患者是否可以减少对额外降压药的需求，并达到最佳治疗目标[28]。在临床试验中，将血压降低作为临床试验成功的评估仍然面临着一个挑战：即说服血压仍≥150mmHg的假手术组患者在六个月随访期间内遵循药物依从性，这是尤其困难的。如果假手术组患者随意服用任何剂量的降压药去控制血压，则RDN手术组和假手术组之间的收缩压差异可能会受到影响，全球RDN手术治疗的效果大约可以使血压降低10mmHg[6,9,10]。因此，在SMART研究中，我们对RDN治疗六个月后设定了两个主要评价终点：

1.诊室收缩压的达标率（诊室收缩压<140mmHg）；

2.服用抗高血压药物的复合指数。

药物复合指数由以下抗高血压药物种类和剂量得出：

药物复合指数=权重×（剂量总和）

权重是抗高血压药物的种类

一个标准剂量定义为1，半剂量定义为0.5，双倍剂量定义为2。

例如，如果一个患者服用了一种标准剂量的血管紧张素 II 受体阻滞剂和一种标准剂量的钙阻滞剂，则该患者的药物综合指标为：2×(1+1)=4。

通过这项试验，我们可以告诉医生和患者怎样评估在RDN手术治疗后可以少服用多少抗高血压药物。

在进行RDN手术过程中，会进行肾神经标测和选择性去除肾交感神经。肾神经冲动会以 15mA,20 Hz和5ms的脉冲刺激传递60s，在 8-10 瓦和 50℃下消融热点需要两分钟。当对同一部位进行再次刺激时，如果仍然出现明显血压变化，说明该位点的肾交感神经去除不彻底，需要进行二次消融。

SMART研究是前瞻性、多中心、单盲的随机对照试验，对于拟入组的所有患者都要获取其知情同意，患者有权决定是否进入筛选过程。在筛选期间，患者在接受至少28天的标准化降压药物治疗后，如果血压仍≥150mmHg且≤180mmHg，则符合纳入标准。这些患者将进行肾动脉血管造影，并按照1:1的比例（220 名患者，110 对）随机分配到去肾神经术组或肾动脉血管造影组。在RDN手术治疗三个月后，根据预定义的标准化用药综合指标，对血压未达到理想水平(<140 mmHg)的患者调整降压药的剂量和类型，直至血压低于140mmHg。所有药物均由研究申办方（苏信迈医疗有限公司）提供，抗高血压药物调整只能从标准化用药方案中选择（表3）。

方案严格规定了抗高血压药物的种类/剂量和调整顺序。实施RDN手术和术后管理由不同医师完成，且两组医师之间保持盲态。患者术后出院时或术后7天、术后1个月、2个月、3个月、4个月、5个月、6个月、9个月和 12个月进行随访。在术后3个月、6个月和12个月进行随访时收集尿液，以评估和管控患者服药依从性。
SMART研究的初步数据已在CRT 2017(美国华盛顿)[29]和TCT 2019(美国旧金山)[30]会议上报告，为上述RDN理论基础和初步研究提供了部分证据。从10例未控制高血压患者的手术数据看，所有肾动脉标测位点中，出现血压升高（即“热点”）的比例仅占54%(表1)。
更重要的是，16%的刺激位点出现血压下降（收缩压降低16mmHg，舒张压降低4mmHg，平均动脉压平均7mmHg）（表2）；还有29%的刺激位点不会引起血压波动。如果热点部位消融充分，则术后再次刺激时不应出现血压波动，否则说明该位点消融不充分，需要重复消融。该研究仍在继续长期随访，期待结果。
SBP：收缩压；DBP：舒张压；MAP：平均动脉压。

Rainbow/Pythagoras公司（以色列）也在着手研发类似的标测/消融系统产品。Mahfoud、Tsioufis和Damen最近在EuroPCR 2017上也发表了初步结果，证实了肾动脉不同位置电刺激带来的生理性变化存在异质性，在肾动脉近端位置刺激，更容易引起血压升高和神经活性增强[23,31]。肾神经标测工具的研发，将有助于评估相应部位肾神经活性和血压升高之间的关系，为确保RDN手术疗效奠定基础，最终实现通过选择性去除肾交感神经治疗高血压的目的，而且我们距离这一目标越来越近了。

肾神经标测/选择性去肾神经术的出现，克服了传统非选择性消融RDN技术的局限性；然而，该术式治疗高血压的长期安全性和有效性如何，还有待于进一步研究加以证实。

向上滑动阅览

References

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Figure Legends

Figure 1. Panel A shows the renal sympathetic renal plexus of a human right kidney. (A) Anterior view and (B) posterior view. Ag (adrenal gland), Arg (aorticorenal ganglion), Coe (coeliac ganglion), CoT (coeliac trunk), Ig (renal inferior ganglion), LC (contribution of the lumbar chain to the renal plexus), Pg (renal posterior ganglion), RK (right kidney), SMg (superior mesenteric ganglion), SP (thoracic splanchnic nerves).

Panel B shows stained slides of the same artery and segment for immuno-histological markers. The upper left corner is the lumen of the artery. (a) TH, marker for sympathetic, (b) NOS, marker for parasympathetic, (c) CGRP, marker for afferent, (d) PGP, marker for general marker. TH (tyrosine hydroxylase), NOS (nitric oxide synthase), CGRP (calcitonin gene related peptide), PGP (Protein Gene Product 9.5).

Adapted with permission from van Amsterdam et al. (16) and Mompeo et al. (17).

Figure 2. Theoretical framework for selective vs global renal denervation: red lines/dots represent “hot spots” - pressor spots. These are nerves that raise the blood pressure when stimulated. These spots are the ideal targets of renal denervation. Green line/spots represent “cold spots” - inhibitory spots, which lower the blood pressure when stimulated. The nerve fibers in yellow are neutral in their contribution for blood pressure regulation and do not show hemodynamic effects when stimulated. 

Adapted with permission from Fudim et al. (18) 

Figure 3. Difference in nerve distribution between strong-response site (SRS) which increased blood pressure significantly when stimulated, and weak-response site (WRS) which increased blood pressure much less when stimulated. A and B, Representative Masson staining image for SRS and WRS. The red arrows indicated renal nerve bundle, and the black arrows indicated ablation area. The total area (C) /number (D) of renal nerves in SRS were greater than that in WRS. There was no difference in distance (E) from lumen to nerve between SRS and WRS. 

Adapted with permission from Liu et al. (20). 

Figure 4. The different types of blood pressure patterns in responses to renal stimulation in dogs.

Adapted from Tan et al (19)

Figure 5. The different types of BP patterns in responses to renal stimulation in human.

Figure 6. Renal Mapping and Ablation System developed by SyMap Medical Ltd., consisted of SyMapCath ITM catheter (A) and SYMPIONEER S1TM Stimulator/Generator (B).  

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