去肾交感神经术治疗高血压的研究进展
Research Progress of Renal Sympathetic De-nervation for Treatment of Hypertension
DOI: 10.12677/ACM.2023.1392014, PDF, HTML, XML,   
作者: 王文涛, 邹航:西安医学院研究生工作部,陕西 西安;陕西省人民医院心血管内二科,陕西 西安;寿锡凌*:陕西省人民医院心血管内二科,陕西 西安
关键词: 去肾交感神经术高血压Renal Sympathetic Denervation Hypertension
摘要: 去肾交感神经术是近十几年来出现的一种新的基于器械的降压治疗方式。但SYMPLICITY HTN-3试验表明去肾交感神经术并不能显著降低患者的血压,使得这项技术的有效性遭受质疑。近期一些新的研究结果似乎更支持这项技术应用于高血压患者的降压治疗。本文就该项技术治疗高血压的临床疗效及面临的问题作一综述。
Abstract: Renal sympathetic denervation is a new antihypertensive therapy based devices in recent years. However, the Symplicity HTN-3 research shows that renal sympathetic denervation could not sig-nificantly reduce the blood pressure, which calls into question the effectiveness of this technique. Recently, some new research results seem to support the application of this technique in the anti-hypertensive treatment of patients with hypertension. This article reviews the clinical efficacy and problems of this technique in the treatment of hypertension.
文章引用:王文涛, 邹航, 寿锡凌. 去肾交感神经术治疗高血压的研究进展[J]. 临床医学进展, 2023, 13(9): 14396-14403. https://doi.org/10.12677/ACM.2023.1392014

1. 引言

高血压是心血管疾病最主要的危险因素,同时也是世界范围内导致死亡的主要原因 [1] 。降压治疗已被证明可以显著降低心血管事件的发生风险,但是目前高血压的治疗现状却不容乐观。有研究显示,高血压的治疗率在高收入国家和中低收入国家分别为55.6%和29.0%,而控制率仅为28.4%和7.7% [2] 。血压控制不佳与治疗依从性差及药物抵抗等这些原因相关,为此人们开始寻求非药物性干预措施来改善这种不利局面。去肾交感神经术(renal denervation, RDN)是过去十几年中发展最为迅速的一项器械降压治疗的新技术,开展了广泛的临床研究 [3] ,但相关研究结果之间存在着一些差异。本文从RDN治疗高血压的基本原理、临床证据及面临的问题等方面作一综述。

2. RDN治疗高血压的基本原理

肾脏在血压调节中发挥着重要的双向机制 [4] 。肾交感传入神经分布在肾盂、肾血管等部位,当感受到局部的牵张刺激或化学刺激后,将信号传入中枢神经系统,使全身交感活性增加,升高血压 [5] 。同时中枢神经系统的下丘脑室旁核(paraventricular nucleus, PVN)和延髓头端腹外侧区(rostral ventrolateral medulla, RVLM)会输入下行兴奋性信号增加肾交感传出神经的活动 [5] 。去甲肾上腺素(NE)是肾交感传出神经释放的主要激素,与肾血管平滑肌的α-1受体结合导致入球小动脉收缩,肾小球滤过率降低;与颗粒细胞膜上的β-1受体结合,刺激肾素的合成和分泌,增加血浆中血管紧张素Ⅱ和醛固酮的水平,导致外周血管收缩和水钠潴留;与肾小管上皮细胞表面的α受体结合,激活Na+/H+转运体,促进水钠重吸收增加 [5] 。正常生理状态下,肾交感传入神经对交感传出神经存在负反馈抑制,以避免血压持续升高 [6] 。但是在高血压患者中,这种负反馈调节功能减弱,导致肾传出和传入神经的持续激活 [7] 。RND通过破坏位于肾动脉外膜的肾交感传出和传入神经,减弱肾脏和中枢神经系统之间的这种联系,从而降低血压 [8] [9] 。

3. RDN治疗高血压的临床证据

3.1. 第一代RDN临床研究

SYMPLICITY HTN-1试验是一项原理验证研究。招募了153例重度难治性高血压患者(定义为服用3种及以上降压药物,包括一种利尿剂,收缩压 ≥ 160 mmHg)使用单电极射频导管对肾交感神经进行消融。诊室血压在第3、6、9和12个月分别降低了21/10 mmHg、22/11 mmHg、24/11 mmHg和27/17 mmHg [10] 。对88例患者完成了36个月的随访,36个月时诊室收缩压和舒张压降低32/14 mmHg。此外,超过93%的患者在36个月时SBP下降超过10 mmHg [11] 。SYMPLICITY HTN-1试验表明,在难治性高血压患者中,以导管为基础的去肾交感神经术可使血压持续降低,且安全性良好。

SYMPLICITY HTN-2试验是一项前瞻性、多中心、随机对照试验,共纳入106例难治性高血压患者随机分配到RDN组(n = 52)或对照组(n = 54),两组的基础降压药物相同。RDN组6个月时平均诊室血压降低了32/12 mmHg,而对照组诊室血压无明显变化,组间差异为31/11 mmHg [12] 。

虽然包括SYMPLICITY HTN-1和SYMPLICITY HTN-2试验在内的多项随机开放标签的试验结果都证明了RDN降压治疗的有效性 [3] ,但仍存在样本量小、未设置假手术对照组,未对所有的患者进行动态血压监测,试验未采取盲法等缺点 [13] 。为了解决上述不足,SYMPLICITY HTN-3试验应运而生。该研究在美国的90个中心纳入535名难治性高血压患者,以2:1的比例随机分配到RDN组与假手术组。6个月时,两组诊室收缩压的平均值相对于基线血压都发生明显降低,但是组间比较无明显差异(−2.39 mmHg,95% CI −6.89至2.21,P = 0.26),未达到主要疗效终点。24小时动态收缩压的组间差异甚至更小(−1.96 mmHg,95% CI −4.97至1.06,P = 0.98) [13] 。

SYMPLICITY HTN-3试验的并未证明RDN优于药物治疗,与先前的SYMPLICITY HTN-1,2结果差异巨大。对该试验进行了广泛的事后分析表明可能造成次阴性结果的原因包括:1) 患者选择不充分,纳入了部分继发性高血压患者 [14] ;2) 抗高血压药物变化不受控制,39%的患者在随访期间改变了降压药物的种类和剂量 [15] ;3) 消融点数和消融模式对降压效果也有着巨大影响,SYMPLICITY HTN-3试验的消融点数显著低于全球SYMPLICITY注册研究,并且由于使用单电极导管,约3/4的患者未接受双侧四象限消融,造成了消融不充分 [15] ;4) 对肾交感神经的解剖发现,远端肾动脉及分支肾动脉也存在肾交感神经分布,而SYMPLICITY HTN-3试验只对肾动脉主干进行消融 [16] ;5) 手术医生的经验不足,超过一半的操作者施行例数 ≤ 2次,施行例数 ≤ 1例者占34% [15] 。

DENERHTN试验也是一项前瞻性、随机对照试验,共纳入101名难治性高血压患者,在经历了4周标准化抗高血压治疗后,随机分配至标准化阶梯降压治疗(standard stepped-care antihypertensive treatment, SSAHT)组和RDN联合SSAHT组。6个月时,RDN组日间动态收缩压降低了15.8 mmHg,对照组降低了9.9 mmHg,两组间的差异为−5.9 mmHg (95% CI −11.3至−0.5,P = 0.0329),达到了主要疗效终点。夜间动态收缩压和24小时动态收缩压也较基线时明显降低,组间差异显著 [17] 。与SYMPLICITY HTN-3试验试验相比,DENERHTN试验中患者的同质性更高,白天、夜间及24小时动态收缩压下降幅度更大,提示患者用药依从性更好,这可能是造成两项试验结果差异的原因 [17] 。DENERHTN试验结果表明,对于难治性高血压患者RDN联合SSAHT比单独规范化药物治疗更能降低动态血压,如果可以长期维持这种额外的降压作用,可能有助于降低心血管事件发病率。

3.2. 第二代RDN临床研究

SYMPLICITY HTN-3试验的失败使RDN的临床应用进入了停滞期。人们重新评估了目前对RDN认识的差异、未满足的需求和未来临床试验的重点,提出了对未来随机对照试验的建议:包括改进手术器械和手术方法、选择最佳患者、将动态血压作为主要研究终点、控制药物影响、致盲和假对照等 [18] [19] [20] 。按照这些建议启动了SPYRAL HTN全球临床试验和RADIANCE-HTN试验的研究。

SPYRAL HTN全球临床试验计划被设计为一系列平行的可行性研究,旨在评价患者在缺乏(SPYRAL HTN-OFF MED [21] )和存在(SPYRAL HTN-ON MED [22] )抗高血压药物的情况下,RDN的降压效果。试验的改进包括:招募轻中度高血压患者(定义为诊室收缩压 ≥ 150 mmHg且<180 mmHg,舒张压 ≥ 90 mmHg,24小时平均动态收缩压 ≥ 140 mmHg且<170 mmHg)、使用新一代的Symplicity Spyral多电极导管,对主肾动脉及直径在3~8 mm之间的分支血管及副肾动脉进行四个象限消融、动态血压作为主要研究终点、使用毒理学分析监测用药依从性等 [19] [23] 。

SPYRAL HTN-OFF MED试验中311例患者被随机分配到RDN组(n = 166)或假手术组(n = 165)。研究结果显示,3个月时,RDN组与假手术组24小时动态收缩压差异为−3.9 mmHg (95% CI −6.2至−1.6),诊室收缩压的差异为−6.5 mmHg (95% CI −9.6至−3.5) [24] 。更重要的是,RDN组24小时内血压持续下降,而假手术组24小时血压没有显著变化 [24] 。SPYRAL Pivotal试验的结果表明,RDN可以有效降低24小时动态血压和诊室血压,并且这种降压效果持续存在。

SPYRAL HTN-ON MED研究中患者接受一致的三联疗法降压,80例患者随机分配到RDN组(n = 38)或假手术组(n = 42)。在6个月时,RDN组24小时动态SBP的变化为−9.0 mmHg (95% CI −12.7至−5.3),而假手术组为−1.6 mmHg (95% CI −5.2至2.0) [22] 。3年的随访显示,24小时收缩压和舒张压从基线到36个月时持续降低,随着时间推移,RDN组血压下降幅度更大 [25] 。36个月时,RDN组与假手术组动态收缩压调整后的组间差异为−10 mmHg (95% CI −16.6至−3.3,P = 0.0039) [25] 。与假手术组相比,RDN组的平均24小时收缩压、早晨收缩压、白天收缩压和夜间收缩压都显著降低 [25] ,这可能会降低心血管疾病的发病率和死亡率。比较RDN组和假对照组动态收缩压每小时的变化,发现RDN组在24小时内的降幅更大,动态舒张压的结果与收缩压类似 [25] 。SPYRAL HTN-ON MED研究进一步证明RDN可以产生临床上有意义的血压降低,并且与治疗的依从性无关。考虑到这一技术的长期安全性和有效性,可以将其作为一种辅助的降压治疗方式。

RADIANCE-HTN [26] 也是一项多中心、盲法、随机、假对照试验,旨在评估超声的去肾神经术(Paradise TM Renal Denervation System)在没有(RADIANCE-HTN SOLO)或存在(RADIANCE-HTN TRIO)降压药物的情况下对高血压患者的降压效果。

RADIANCE-HTN SOLO研究中患者在停用降压药物治疗4周后,筛选出合并收缩–舒张期高血压的患者(定义为日间动态血压 ≥ 135/85mmHg且<170/105mmHg),随机分配至RDN组(n = 74)或假手术组(n = 72)。主要研究终点是2个月时白天收缩压的变化。与假手术组相比,2个月时,RDN组白天动态收缩压显著降低,组间差异为−6.3 mmHg (95% CI −9.4至−3.1,P = 0.0001) [27] 。在2个月的主要研究终点结束后如患者的平均家庭血压仍 ≥ 135/85mmHg,则需接受了标准化的阶梯降压治疗。随访至6个月时,RDN组65%的患者和假手术组85%的患者需要重新开始药物治疗,但治疗的降压效果仍继续维持,组间差异为−4.3 mmHg (95% CI −7.9至−0.6,P = 0.024),且RDN组患者的用药负担更低 [28] 。从6个月至12个月为非盲期,与假手术组相比,RDN组服用的降压药物更少,降压效果在12个月时依然存在(日间动态收缩压较基线下降16.5 ± 12.9 mmHg)。然而两组间白天动态收缩压的差异不在显著(−2.3 mmHg;95% CI −5.9至1.3,P = 0.201) [29] ,这可能与假手术组的患者在这一时期接受了强化降压治疗相关。

RADIANCE-HTN TRIO研究对难治性高血压患者使用标准的三联药物(CCB + ARB + 噻嗪类利尿剂)治疗4周后,白天动态血压 ≥ 135/85 mmHg的患者随机分配到RDN组(n = 69)或假手术组(n = 67)。2个月时,RDN组白天动态收缩压显著低于假手术组,组间差异为−4.5 mmHg (95% CI −8.3至−0.3,P = 0.016),RDN组每小时的收缩压都有降低且降幅度更大 [30] 。在2个月主要终点结束后,有持续性血压升高的患者加用降压药物开始标准化的阶梯降压治疗。6个月时,RDN组和假手术组血压下降程度相似,但是RDN组需要的额外药物更少 [28] 。

REQUIRE试验也是一项随机、单盲、假对照试验,使用Paradise超声去肾神经系统对患者进行交感神经消融。招募了来自亚洲的143名难治性高血压患者,随机分配到RDN组(n = 72)或假手术组(n = 71)。3个月时,两组的24小时动态血压较基线降低,但组间无明显差异(−0.1 mmHg,95% CI −5.5至−5.3,P = 0.971),诊室收缩压和家庭收缩压差异也不显著 [31] 。导致这一结果原因包括未标准化降压药物、未完全致盲、未监测药物治疗依从性、未完全排除原发性醛固酮增多症的患者等。

与第一代研究的异质性结果相反,第二代研究的一致性结果提供了RDN治疗高血压的最终生物学证据,即无论伴随或不伴随抗高血压药物治疗,RDN均能持续降低患者的血压,结束了关于RDN治疗高血压疗效的争议。

4. RDN治疗高血压存在的几点疑问

4.1. RDN的长期有效性和安全性

长期有效性和安全性的数据主要来自注册研究。GSR (Global Symplicity Registry)是最大的一项前瞻性、开放标签的注册研究,对1742例患者完成3年随访,RDN术后收缩压持续下降,24小时收缩压较基线降低8.9 ± 20.1 mmHg,诊室收缩压降低16.5 ± 28.6 mmHg [32] 。RADIANCE-HTN SOLO研究对146例患者完成了1年随访,结果显示RDN组术后血压较基线显著降低,与对照组差异不明显,但在服药种类、数量、剂量都显著低于假手术组 [29] 。SPYRAL HTN-ON MED研究对80例患者随访3年,RDN组动态血压较基线时显著减低,并且组间差异显著,而两组的药物负担是相似的 [25] 。虽然上述研究结果表明RDN的降压效果具有持久性,但是与海量的药物降压临床试验相比,RDN在降压持久性方面的数据还是显得单薄。目前美敦力计划开展GSR-DEFINE研究,纳入5000例患者随访5年,我们期待这一结果能为RDN的长期疗效提供更多证据。安全性方面,RDN后每年约0.2%患者植入支架,其他围术期不良事件和术后30天内的意外事件几乎没有 [32] [33] ,因此可以肯定的说RDN具有良好的安全性。

4.2. RDN对心血管结局的影响

对17项前瞻性观察研究的荟萃分析表明RDN可以改善高血压介导的靶器官损伤 [34] ,但目前未有RCT研究评估RDN对心脑血管事件发生率的直接影响。抗高血压药物的临床试验表明 [35] [36] [37] ,诊室收缩压降低5~10 mmHg可使主要心血管事件发生率减少10%~20%,卒中发生率减少13%~26%。而这种保护作用源于血压降低本身,与降压手段无明显关系,因此推测RDN可以改善高血压患者的预后。

4.3. RDN的最佳人群

临床循证学证据表明,约有1/3的高血压患者RDN后无降压反应 [38] ,甚至血压不降反升 [21] 。RDN的降压反应定义为术后诊室收缩压下降幅度 > 10 mmHg,或动态收缩压降幅 > 5 mmHg [20] 。因此根据患者的临床特征选择适合的手术对象十分重要。基线血压水平越高RDN后降压反应越大,这是目前唯一被认可的预测因子 [39] 。既往认为年轻患者(< 65岁)RDN术后降压反应更显著 [13] ,但近期的研究显示年龄不是对RDN血压反应的预测因子 [40] 。与年龄相关的是动脉硬度的改变,研究认为动脉刚性可作为RDN后血压反应不良的预测因素 [6] 。早期研究发现与合并收缩期–舒张期高血压患者相比,单纯收缩期高血压患者在RDN后血压降低不太明显 [41] ,然而最近的GSR研究 [40] 和RADIOSOUND-HTN研究 [42] 显示这两类高血压人群平均24小时收缩压下降没有差异。其他一些获益人群的临床特征包括,较高的基线心率、夜间动态血压的平均值和标准差更高、血浆肾素活性更高、以及存在阻塞性睡眠呼吸暂停等,但这些尚未得到证实 [3] 。

4.4. RDN如何实现精准消融

目前对交感神经的消融策略是基于对肾交感神经解剖学认知而进行的范围性消融。要想实现肾交感神经精准消融,需要一项可以实时检测神经功能技术。目前常用侵入性神经显微造影、血浆去甲肾上腺素和肾素浓度测定等方法因自身局限性并不适用于术中对肾交感神经功能的实时评估 [6] 。Amsterdam [43] 和Mompeo [44] 等人研究了肾动脉周围的神经解剖结构,发现了三种神经类型:交感、副交感和传入神经成分,对这三种类型的神经给予电刺激会造成血压的升高、降低或不变 [45] 。因此人们设想使用电刺激标测这些消融的热点(交感点)、冷点(副交感点)和中性成分,然后对这些部位精准消融,选择性的去除交感神经。目前的动物实验和临床试验已经证明这项技术的可应用性 [46] [47] [48] 。由我国学者设计的SMART研究 [49] 是一项前瞻性、多中心、单盲、随机对照试验,旨在评估靶向去肾交感神经术治疗未受控制的高血压患者的安全性和有效性,我们期待这一研究结果早日问世,可以更好的指导我们对肾交感神经进行更为精准的消融。

5. 小结与展望

RDN是一项非常有前景的辅助降压治疗的新方式,与传统降压药物相比,RDN降压作用与药代动力学、依从性和给药方案无关,而且具有全天候24小时的降压效果,可以降低心血管事件的发生风险,改善患者的预后结局。但是目前仍有一些问题亟待解决,例如最适患者的选择、如何实现精准消融等。相信随着更多大型研究的展开,新技术的不断出现,RDN最终将会为高血压的治疗带来新的解决方案。

参考文献

NOTES

*通讯作者。

参考文献

[1] (2018) Global, Regional, and National Comparative Risk Assessment of 84 Behavioural, Environmental and Occupation-al, and Metabolic Risks or Clusters of Risks for 195 Countries and Territories, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. The Lancet, 392, 1923-1994.
[2] Mills, K.T., Bundy, J.D., Kelly, T.N., et al. (2016) Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies from 90 Countries. Circulation, 134, 441-450.
https://doi.org/10.1161/CIRCULATIONAHA.115.018912
[3] Lauder, L., Azizi, M., Kirtane, A.J., et al. (2020) Device-Based Therapies for Arterial Hypertension. Nature Reviews Cardiology, 17, 614-628.
https://doi.org/10.1038/s41569-020-0364-1
[4] 王捷. 2021年欧洲高血压学会关于经导管去肾交感神经术立场文件的解读: 经导管去肾交感神经术真的要来了! [J]. 中国介入心脏病学杂志, 2021, 29(10): 554-557.
[5] Osborn, J.W., Tyshynsky, R. and Vulchanova, L. (2021) Function of Renal Nerves in Kidney Physiology and Pathophysiology. Annual Review of Physiology, 83, 429-450.
https://doi.org/10.1146/annurev-physiol-031620-091656
[6] 胡鑫渝, 周浩, 李丹, 等. 聚焦去肾交感神经术发展的关键——患者选择与精准消融[J]. 中国介入心脏病学杂志, 2023, 31(3): 213-218.
[7] Tanaka, S. and Okusa, M.D. (2020) Crosstalk between the Nervous System and the Kidney. Kidney International, 97, 466-476.
https://doi.org/10.1016/j.kint.2019.10.032
[8] Hering, D., Marusic, P., Walton, A.S., et al. (2014) Sustained Sympathetic and Blood Pressure Reduction 1 Year after Renal Denervation in Patients with Resistant Hypertension. Hy-pertension, 64, 118-124.
https://doi.org/10.1161/HYPERTENSIONAHA.113.03098
[9] Hering, D., Lambert, E.A., Marusic, P., et al. (2013) Substantial Reduction in Single Sympathetic Nerve Firing after Renal Denervation in Patients with Resistant Hy-pertension. Hypertension, 61, 457-464.
https://doi.org/10.1161/HYPERTENSIONAHA.111.00194
[10] Krum, H., Schlaich, M., Whitbourn, R., et al. (2009) Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension: A Multicentre Safety and Proof-of-Principle Cohort Study. The Lancet, 373, 1275-1281.
https://doi.org/10.1016/S0140-6736(09)60566-3
[11] Krum, H., Schlaich, M.P., Sobotka, P.A., et al. (2014) Per-cutaneous Renal Denervation in Patients with Treatment- Resistant Hypertension: Final 3-Year Report of the Symplicity HTN-1 Study. The Lancet, 383, 622-629.
https://doi.org/10.1016/S0140-6736(13)62192-3
[12] Esler, M.D., Krum, H., Sobotka, P.A., et al. (2010) Renal Sympathetic Denervation in Patients with Treatment-Resistant Hypertension (The Symplicity HTN-2 Trial): A Random-ised Controlled Trial. The Lancet, 376, 1903-1909.
https://doi.org/10.1016/S0140-6736(10)62039-9
[13] Bhatt, D.L., Kandzari, D.E., O’neill, W.W., et al. (2014) A Controlled Trial of Renal Denervation for Resistant Hypertension. The New England Journal of Medicine, 370, 1393-1401.
https://doi.org/10.1056/NEJMoa1402670
[14] Persu, A., Jin, Y., Baelen, M., et al. (2014) Eligibility for Renal Denervation: Experience at 11 European Expert Centers. Hypertension, 63, 1319-1325.
https://doi.org/10.1161/HYPERTENSIONAHA.114.03194
[15] Kandzari, D.E., Bhatt, D.L., Brar, S., et al. (2015) Predictors of Blood Pressure Response in the Symplicity HTN-3 Trial. European Heart Journal, 36, 219-227.
https://doi.org/10.1093/eurheartj/ehu441
[16] Mahfoud, F., Tunev, S., Ewen, S., et al. (2015) Impact of Lesion Placement on Efficacy and Safety of Catheter-Based Radiofrequency Renal Denervation. Journal of the American College of Cardiology, 66, 1766-1775.
https://doi.org/10.1016/j.jacc.2015.08.018
[17] Azizi, M., Sapoval, M., Gosse, P., et al. (2015) Optimum and Stepped Care Standardised Antihypertensive Treatment with or without Renal Denervation for Resistant Hypertension (DENERHTN): A Multicentre, Open-Label, Randomised Controlled Trial. The Lancet, 385, 1957-1965.
https://doi.org/10.1016/S0140-6736(14)61942-5
[18] Mahfoud, F., Böhm, M., Azizi, M., et al. (2015) Proceedings from the European Clinical Consensus Conference for Renal Denervation: Considerations on Future Clinical Trial Design. European Heart Journal, 36, 2219-2227.
https://doi.org/10.1093/eurheartj/ehv192
[19] Kandzari, D.E., Kario, K., Mahfoud, F., et al. (2016) The SPYRAL HTN Global Clinical Trial Program: Rationale and Design for Studies of Renal Denervation in the Absence (SPYRAL HTN OFF-MED) and Presence (SPYRAL HTN ON-MED) of Antihypertensive Medications. American Heart Journal, 171, 82-91.
https://doi.org/10.1016/j.ahj.2015.08.021
[20] Mahfoud, F., Schmieder, R.E., Azizi, M., et al. (2017) Proceedings from the 2nd European Clinical Consensus Conference for Device-Based Therapies for Hypertension: State of the Art and Considerations for the Future. European Heart Journal, 38, 3272-3281.
https://doi.org/10.1093/eurheartj/ehx215
[21] Townsend, R.R., Mahfoud, F., Kandzari, D.E., et al. (2017) Cathe-ter-Based Renal Denervation in Patients with Uncontrolled Hypertension in the Absence of Antihypertensive Medications (SPYRAL HTN-OFF MED): A Randomised, Sham-Controlled, Proof-of-Concept Trial. The Lancet, 390, 2160-2170.
https://doi.org/10.1016/S0140-6736(17)32281-X
[22] Kandzari, D.E., Böhm, M., Mahfoud, F., et al. (2018) Effect of Renal Denervation on Blood Pressure in the Presence of Antihypertensive Drugs: 6-Month Efficacy and Safety Re-sults from the SPYRAL HTN-ON MED Proof-of-Concept Randomised Trial. The Lancet, 391, 2346-2355.
https://doi.org/10.1016/S0140-6736(18)30951-6
[23] Böhm, M., Townsend, R.R., Kario, K., et al. (2020) Ra-tionale and Design of Two Randomized Sham-Controlled Trials of Catheter-Based Renal Denervation in Subjects with Uncontrolled Hypertension in the Absence (SPYRAL HTN-OFF MED Pivotal) and Presence (SPYRAL HTN-ON MED Expansion) of Antihypertensive Medications: A Novel Approach Using Bayesian Design. Clinical Research in Cardiology, 109, 289-302.
https://doi.org/10.1007/s00392-020-01595-z
[24] Böhm, M., Kario, K., Kandzari, D.E., et al. (2020) Efficacy of Catheter-Based Renal Denervation in the Absence of Antihypertensive Medications (SPYRAL HTN-OFF MED Pivotal): A Multicentre, Randomised, Sham-Controlled Trial. The Lancet, 395, 1444-1451.
https://doi.org/10.1016/S0140-6736(20)30554-7
[25] Mahfoud, F., Kandzari, D.E., Kario, K., et al. (2022) Long-Term Efficacy and Safety of Renal Denervation in the Presence of Antihypertensive Drugs (SPYRAL HTN-ON MED): A Randomised, Sham-Controlled Trial. The Lancet, 399, 1401-1410.
https://doi.org/10.1016/S0140-6736(22)00455-X
[26] Mauri, L., Kario, K., Basile, J., et al. (2018) A Multinational Clinical Approach to Assessing the Effectiveness of Catheter-Based Ultrasound Renal Denervation: The RADIANCE-HTN and REQUIRE Clinical Study Designs. American Heart Journal, 195, 115-129.
https://doi.org/10.1016/j.ahj.2017.09.006
[27] Azizi, M., Schmieder, R.E., Mahfoud, F., et al. (2018) Endovascular Ultrasound Renal Denervation to Treat Hypertension (RADIANCE-HTN SOLO): A Multicentre, International, Sin-gle-Blind, Randomised, Sham-Controlled Trial. The Lancet, 391, 2335-2345.
https://doi.org/10.1016/S0140-6736(18)31082-1
[28] Azizi, M., Schmieder, R.E., Mahfoud, F., et al. (2019) Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control after Randomization to Endo-vascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial. Circulation, 139, 2542-2553.
https://doi.org/10.1161/CIRCULATIONAHA.119.040451
[29] Azizi, M., Daemen, J., Lobo, M.D., et al. (2020) 12-Month Results from the Unblinded Phase of the RADIANCE- HTN SOLO Trial of Ultrasound Renal Denervation. JACC: Cardiovascular Interventions, 13, 2922-2933.
https://doi.org/10.1016/j.jcin.2020.09.054
[30] Azizi, M., Sanghvi, K., Saxena, M., et al. (2021) Ultrasound Renal Denervation for Hypertension Resistant to a Triple Medication Pill (RADIANCE-HTN TRIO): A Randomised, Multi-centre, Single-Blind, Sham-Controlled Trial. The Lancet, 397, 2476-2486.
https://doi.org/10.1016/S0140-6736(21)00788-1
[31] Kario, K., Yokoi, Y., Okamura, K., et al. (2022) Cathe-ter-Based Ultrasound Renal Denervation in Patients with Resistant Hypertension: The Randomized, Controlled REQUIRE Trial. Hypertension Research: Official Journal of the Japanese Society of Hypertension, 45, 221-231.
https://doi.org/10.1038/s41440-021-00754-7
[32] Mahfoud, F., Böhm, M., Schmieder, R., et al. (2019) Effects of Renal Denervation on Kidney Function and Long-Term Outcomes: 3-Year Follow-Up from the Global SYMPLICITY Registry. European Heart Journal, 40, 3474-3482.
https://doi.org/10.1093/eurheartj/ehz118
[33] Townsend, R.R., Walton, A., Hettrick, D.A., et al. (2020) Review and Meta-Analysis of Renal Artery Damage Following Percutaneous Renal Denervation with Radiofrequency Renal Artery Ablation. EuroIntervention, 16, 89-96.
https://doi.org/10.4244/EIJ-D-19-00902
[34] Kordalis, A., Tsiachris, D., Pietri, P., et al. (2018) Regression of Or-gan Damage Following Renal Denervation in Resistant Hypertension: A Meta-Analysis. Journal of Hypertension, 36, 1614-1621.
https://doi.org/10.1097/HJH.0000000000001798
[35] Thomopoulos, C., Parati, G. and Zanchetti, A. (2014) Ef-fects of Blood Pressure Lowering on Outcome Incidence in Hypertension. 1. Overview, Meta-Analyses, and Me-ta-Regression Analyses of Randomized Trials. Journal of Hypertension, 32, 2285-2295.
https://doi.org/10.1097/HJH.0000000000000378
[36] Ettehad, D., Emdin, C.A., Kiran, A., et al. (2016) Blood Pressure Lowering for Prevention of Cardiovascular Disease and Death: A Systematic Review and Meta-Analysis. The Lancet, 387, 957-967.
https://doi.org/10.1016/S0140-6736(15)01225-8
[37] (2021) Pharmacological Blood Pressure Lowering for Pri-mary and Secondary Prevention of Cardiovascular Disease across Different Levels of Blood Pressure: An Individual Participant-Level Data Meta-Analysis. The Lancet, 397, 1625-1636.
[38] Townsend, R.R. and Sobotka, P.A. (2018) Catheter-Based Renal Denervation for Hypertension. Current Hypertension Reports, 20, Article No. 93.
https://doi.org/10.1007/s11906-018-0896-5
[39] Messerli, F.H., Bangalore, S. and Schmieder, R.E. (2015) Wil-der’s Principle: Pre-Treatment Value Determines Post-Treatment Response. European Heart Journal, 36, 576-579.
https://doi.org/10.1093/eurheartj/ehu467
[40] Mahfoud, F., Mancia, G., Schmieder, R., et al. (2020) Renal Dener-vation in High-Risk Patients with Hypertension. Journal of the American College of Cardiology, 75, 2879-2888.
https://doi.org/10.1016/j.jacc.2020.04.036
[41] Mahfoud, F., Bakris, G., Bhatt, D.L., et al. (2017) Reduced Blood Pressure-Lowering Effect of Catheter-Based Renal Denervation in Patients with Isolated Systolic Hypertension: Data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. European Heart Journal, 38, 93-100.
https://doi.org/10.1093/eurheartj/ehw325
[42] Fengler, K., Rommel, K.-P., Lapusca, R., et al. (2019) Renal Dener-vation in Isolated Systolic Hypertension Using Different Catheter Techniques and Technologies. Hypertension, 74, 341-348.
https://doi.org/10.1161/HYPERTENSIONAHA.119.13019
[43] Van Amsterdam, W.A.C., Blankestijn, P.J., Goldschmeding, R., et al. (2016) The Morphological Substrate for Renal Denervation: Nerve Distribution Patterns and Parasympathetic Nerves. A Post-Mortem Histological Study. Annals of Anatomy, 204, 71-79.
https://doi.org/10.1016/j.aanat.2015.11.004
[44] Mompeo, B., Maranillo, E., Garcia-Touchard, A., et al. (2016) The Gross Anatomy of the Renal Sympathetic Nerves Revisited. Clinical Anatomy, 29, 660-664.
https://doi.org/10.1002/ca.22720
[45] Kiuchi, M.G., Esler, M.D., Fink, G.D., et al. (2019) Renal Denervation Up-date from the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review. Journal of the Ameri-can College of Cardiology, 73, 3006-3017.
https://doi.org/10.1016/j.jacc.2019.04.015
[46] Liu, H., Chen, W., Lai, Y., et al. (2019) Selective Renal Denervation Guided by Renal Nerve Stimulation in Canine. Hypertension, 74, 536-545.
https://doi.org/10.1161/HYPERTENSIONAHA.119.12680
[47] Chinushi, M., Izumi, D., Iijima, K., et al. (2013) Blood Pressure and Autonomic Responses to Electrical Stimulation of the Renal Arterial Nerves before and after Ablation of the Renal Artery. Hypertension, 61, 450-456.
https://doi.org/10.1161/HYPERTENSIONAHA.111.00095
[48] De Jong, M.R., Adiyaman, A., Gal, P., et al. (2016) Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory Blood Pressure Response after Renal Denervation. Hypertension, 68, 707-714.
https://doi.org/10.1161/HYPERTENSIONAHA.116.07492
[49] Wang, J., Sun, N., Ge, J., et al. (2023) Rationale and Design of Sympathetic Mapping/Ablation of Renal Nerves Trial (SMART) for the Treatment of Hypertension: A Prospective, Multicenter, Single-Blind, Randomized and Sham Procedure-Controlled Study. Journal of Cardiovascular Translational Research, 16, 358-370.
https://doi.org/10.1007/s12265-022-10307-z