經(jīng)皮導(dǎo)管去腎動脈交感神經(jīng)射頻消融術(shù)治療難治性高血壓研究進展

楊超英，陽慧，蘇雨江

(中南大學(xué)湘雅附屬?？卺t(yī)院海口市人民醫(yī)院心血管內(nèi)科，海南 ?？?570208)

·綜 述·

經(jīng)皮導(dǎo)管去腎動脈交感神經(jīng)射頻消融術(shù)治療難治性高血壓研究進展

楊超英，陽慧，蘇雨江

(中南大學(xué)湘雅附屬?？卺t(yī)院?？谑腥嗣襻t(yī)院心血管內(nèi)科，海南 ?？?570208)

高血壓是引起心腦血管死亡的重要基礎(chǔ)疾病，難治性高血壓是指服用包括利尿劑在內(nèi)的3種最佳劑量降壓藥后血壓仍難以達標(biāo)，或者需服用4種或以上降壓藥血壓才能達標(biāo)的高血壓。其引起并發(fā)癥更多，引起的心腦血管事件發(fā)生率和死亡率更高。就這一類型的高血壓，近幾年出現(xiàn)了一種新型的非藥物治療方法——經(jīng)皮導(dǎo)管去腎動脈交感神經(jīng)射頻消融術(shù)。本文就此治療方法做一簡要綜述。

難治性高血壓；去腎動脈交感神經(jīng)術(shù)；介入性治療；射頻消融術(shù)

難治性高血壓指在排除繼發(fā)因素改善生活方式的基礎(chǔ)上，應(yīng)用包括利尿劑在內(nèi)的足量合理的3種降壓藥物后血壓仍在目標(biāo)水平以上，或至少需要4種藥物血壓才能達標(biāo)[1]。難治性高血壓對患者危害極大，可導(dǎo)致嚴(yán)重的靶器官損傷和心血管風(fēng)險，如不接受治療生存年齡及生存質(zhì)量將遠遠低于正常人。難治性高血壓的治療在近幾年取得了巨大進步，經(jīng)皮導(dǎo)管去腎動脈交感神經(jīng)術(shù)(renal sympathetic denervation，RSD)是目前治療難治性高血壓的一大突破。本文就國內(nèi)外關(guān)于RSD治療難治性高血壓的研究進展作一綜述。

1 難治性高血壓流行及治療現(xiàn)狀

中國高血壓人群存在三高(發(fā)病率、死亡率、致殘率)三低(知曉率、治療率、控制率)的流行病學(xué)特點，其中約15%的高血壓患者不規(guī)律服藥，約75%的高血壓患者服藥但血壓控制不能穩(wěn)定在目標(biāo)水平。高血壓可導(dǎo)致嚴(yán)重的靶器官損傷和心血管風(fēng)險，人口老齡化加劇、環(huán)境惡化、人們精神壓力增大等因素的不斷作用，全世界每年有7百多萬人因高血壓死亡[2-4]。高血壓是影響人們生存質(zhì)量和危及生命的常見慢性基礎(chǔ)疾病之一，據(jù)2010年《中國高血壓指南》顯示，中國高血壓患病率呈增長趨勢，患病率約為20%，占全球高血壓患者總?cè)藬?shù)的20%。最新數(shù)據(jù)顯示，目前國內(nèi)高血壓患者已超過2億，估計至2025年將升至3億。其中難治性高血壓發(fā)病率約占高血壓發(fā)病率的10%[5-7]。比普通高血壓病有更高的靶器官受損發(fā)生率、心血管事件發(fā)生率及死亡率。研究證實，有效控制血壓能使心血管事件發(fā)生和死亡率減少8%～10%[8-9]；血壓不能穩(wěn)定在目標(biāo)水平患者發(fā)生腦卒中、心力衰竭、心肌梗死、腎功能不全等的風(fēng)險是血壓控制達標(biāo)者的2.3倍[10]。高血壓嚴(yán)重威脅著人類健康，為社會帶來了極大的負擔(dān)。難治性高血壓的治療主要為傳統(tǒng)的多種藥物聯(lián)合應(yīng)用，一般很難使難治性高血壓患者血壓穩(wěn)定在目標(biāo)水平，且存在藥物依從性問題。國內(nèi)國外學(xué)者不斷探索新的降壓措施，一種新型的非藥物治療方法——RSD應(yīng)運而生。

2 經(jīng)皮導(dǎo)管去腎動脈交感神經(jīng)術(shù)降壓機制

目前研究關(guān)于腎動脈交感神經(jīng)影響血壓的機制有兩種：(1)腎動脈交感神經(jīng)過度活躍引起腎素分泌過多致水鈉潴留、腎動脈收縮最終引起持續(xù)性血壓升高[11]；(2)腎傳入神經(jīng)通過神經(jīng)激肽受體途徑發(fā)出的信號傳到中樞神經(jīng)系統(tǒng)，同時傳到對側(cè)腎臟，使腎動脈交感神經(jīng)活性增強，發(fā)揮血管緊張性調(diào)節(jié)作用[12]。RSD從此機制中入手，通過導(dǎo)管頭端溫度及阻抗傳感監(jiān)測射頻能量釋放，透過腎動脈的內(nèi)、中膜選擇性毀壞外膜的腎動脈交感神經(jīng)纖維來降低腎動脈交感神經(jīng)活性，從而抑制交感神經(jīng)過度興奮達到降壓目的。在彈性部位進行溫控消融有效避免過熱導(dǎo)致的不必要組織損傷確保了此技術(shù)的安全性。通過對術(shù)后患者即刻行腎動脈造影未見血管狹窄、穿孔及血栓形成的數(shù)據(jù)資料統(tǒng)計，證實了RSD的安全性[6，13]。腎功能方面，多項臨床研究證實RSD不會引起腎小球濾過率的下降[13-14]。

3 經(jīng)皮導(dǎo)管去腎動脈交感神經(jīng)術(shù)臨床研究現(xiàn)狀

Symplicity HTN-3研究是設(shè)有假手術(shù)組，雙盲、多中心、前瞻性、隨機對照的大樣本關(guān)于RSD的臨床研究，樣本量達到535例[15]，此研究對照組與治療組處理區(qū)別在于對照組僅接受腎動脈造影檢查不予射頻消融，即所謂的假手術(shù)，治療組則使用美敦力Symplicity導(dǎo)管系統(tǒng)進行了RSD治療。2014年該研究結(jié)果顯示：術(shù)后6個月兩組間血壓下降差異無統(tǒng)計學(xué)意義，表明RSD對難治性高血壓的降壓效果并不優(yōu)于藥物治療；12個月后隨訪數(shù)據(jù)顯示，Symplicity導(dǎo)管系統(tǒng)治療難治性高血壓患者沒有發(fā)生嚴(yán)重并發(fā)癥，但未達到預(yù)期的主要臨床終點。許多學(xué)者對此困惑不解，追溯HTN-1研究和HTN-2研究的隨訪資料發(fā)現(xiàn)12個月后入組患者中也有13%～21%的患者收縮壓下降不足10 mmHg(1 mmHg=1.33 kPa)，而HTN-1研究隨訪3年的數(shù)據(jù)亦發(fā)現(xiàn)7.1%患者RDN治療無反應(yīng)[16-18]。HTN-3研究的陰性結(jié)果引來大片爭議，甚至影響到了后續(xù)的一系列關(guān)于RSD的研究，但仍有不少學(xué)者對RSD充滿信心。他們深入分析HTN系列研究發(fā)現(xiàn)：RSD可減少室性心律失常的發(fā)生頻率，尤其那些無結(jié)構(gòu)性心臟病的特發(fā)性心律失常的患者[19-20]；此外還有慢性腎臟病[21]、阻塞性睡眠呼吸暫停[22]、糖代謝受損[22]、心臟衰竭[23-24]、心房顫動[25-26]等也都能在RSD后獲益。國際心血管病雜志最新研究[27]發(fā)表：(1)雙腎單根腎動脈的患者接受RSD術(shù)后3個和6個月，24 h動態(tài)血壓及門診血壓持續(xù)顯著下降，尤其是夜間血壓下降明顯，這種血壓下降的幅度有明顯的臨床意義很可能與心腦血管事件發(fā)生率減少密切相關(guān)；(2)雙腎單根腎動脈患者接受RSD后血壓下降幅度明顯大于有單腎雙根腎動脈組；(3)術(shù)前和術(shù)后患者心率、血漿肌酐水平、腎小球濾過率變化均無明顯差異；(4)術(shù)后不到10%的患者需要加大藥物劑量控制血壓，約20%的患者反而減少了藥物劑量。此項研究為進一步證實RSD的安全性提供了依據(jù)，同時為研究RSD無反應(yīng)與腎動脈解剖結(jié)構(gòu)的相關(guān)性提供了參考。

RSD是目前治療難治性高血壓的一大突破。研究表明，RSD可降低全身交感神經(jīng)活性，并可治療其他以交感神經(jīng)系統(tǒng)的過度激活為特征的疾病[28]，如減少難治性高血壓患者房顫、室性心律失常的發(fā)生率[29-30]；逆轉(zhuǎn)難治性高血壓患者左室肥厚，改善心臟功能，改善動脈硬化[29，31-34]；減少難治性高血壓患者蛋白尿，改善其腎功能[12，21，35-36]；改善難治性高血壓血糖代謝，增加其胰島素敏感性[37-38]；減輕難治性高血壓患者上呼吸道阻塞，減少睡眠呼吸暫停綜合征的發(fā)生[22，38-39]；有病例報告報道RSD不僅使需血液透析的難治性高血壓患者平穩(wěn)降壓，還能減慢其腎素及血管緊張素轉(zhuǎn)化酶的分泌速度[40]；RSD對合并多囊卵巢綜合征的難治性高血壓患者也有治療作用[41]。

4 展 望

RSD具有安全、創(chuàng)面小、恢復(fù)快、手術(shù)時間短等優(yōu)勢，如果能替代藥物治療有望獲得更廣闊的前景。但現(xiàn)在RSD相關(guān)研究仍處于不成熟階段，這表現(xiàn)在以下幾個方面：在患者的選擇上需要腎動脈交感神經(jīng)活性敏感的難治性高血壓患者，怎么判斷腎交感神經(jīng)活性敏感，目前沒有評判指標(biāo)；技術(shù)方面，導(dǎo)管的材質(zhì)、消融點多少和部位的選擇等沒有參考標(biāo)準(zhǔn)；腎交感神經(jīng)具有再生能力，是否需要再次交感消融，多久后再次手術(shù)目前沒有這方面的研究報道；預(yù)后方面，由于這項技術(shù)開展的時間還不夠長，目前還沒有確切數(shù)據(jù)證實RSD對延緩難治性高血壓病病情進展及改善高血壓病預(yù)后有積極意義；評價RSD的有效性的指標(biāo)方面，據(jù)血壓的下降的幅度以及持久性來定義這項技術(shù)的有效性有待進一步考證[42]。此外其對難治性高血壓的治療效果是否優(yōu)于藥物治療存在爭議，因為有以上多種問題的存在，國內(nèi)這項技術(shù)并沒有普及，中國大部分地區(qū)都還沒有這門技術(shù)。雖然RSD病例數(shù)已經(jīng)從開展時的十多例發(fā)展到了現(xiàn)有的2萬多例，但RSD對難治性高血壓的研究仍處于不成熟階段，需要進一步探索。同時進一步研究RSD對合并有腎衰、糖尿病、心力衰竭、心律失常、多囊卵巢綜合征等疾病的難治性高血壓患者獲益的作用機制將會為此類患者的治療提供新的契機，開拓全新的領(lǐng)域。

[1]喬建文.四聯(lián)降壓藥物治療難治性高血壓68例療效觀察[J].海南醫(yī)學(xué),2013,24(19):2898-2899.

[2]中國高血壓防治指南修訂委員會.中國高血壓防治指南2010[J].中華心血管病雜志,2010,39(7):579-616.

[3]Blumenthal JA,Sherwood A,Smith PJ,et al.Lifestyle modification for resistant hypertension:The TRIUMPH randomized clinical trial [J].American Heart Journal,2015,170(5):986-994.

[4]Kearney PM,Whelton M,Reynolds K,et al.Global burden of hypertension:analysis of worldwide data[J].Lancet,2005,365(9455): 217-223.

[5]Calhoun DA,Jones D,Textor S,et al.Resistant hypertension:Diagnosis,evaluation,and treatment:A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research[J].Circulation,2008, 117(25):e510-e526.

[6]Esler MD,Bohm M,Sievert H,et al.Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial[J].European Heart Journal,2014,35(26):1752-1759.

[7]Giuseppe Mancia Chairperson RF,Chairperson Belgium KNSC,Josep Redon Section Co-Ordinator AZSC,et al.2013 ESH/ESC Guidelines for the management of arterial hypertension[J].European Heart Journal,2013,34(28):2159-2219.

[8]de la Sierra A,Segura J,Banegas JR,et al.Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring[J].Hypertension,2011,57(5): 898-902.

[9]Persell SD.Prevalence of Resistant Hypertension in the United States, 2003-2008[J].Hypertension,2011,57(6):1076-1080.

[10]Lobo MD,de Belder MA,Cleveland T,et al.Joint UK societies' 2014 consensus statement on renal denervation for resistant hypertension[J].Heart,2014,101(1):10-16.

[11]Prochnau D,Lauten A,Busch M,et al.Catheter-based radiofrequency ablation therapy of the renal sympathetic-nerve system for drug resistant hypertension in a patient with end-stage renal disease[J].International Journal of Cardiology,2012,154(2):e29-e30.

[12]Ewen S,Ukena C,Linz D,et al.The sympathetic nervous system in chronic kidney disease[J].Current Hypertension Reports,2013,15 (4):370-376.

[13]George L,Bakris MRRT,Sidney A,et al.12-Month blood pressure results of catheter-based renal artery denervation for resistant hypertension[J].JACC,2015,65(13):1314-1321.

[14]van Brussel PM,Eeftinck Schattenkerk DW,Dobrowolski LC,et al. Effects of renal sympathetic denervation on cardiac sympathetic activity and function in patients with therapy resistant hypertension[J]. International Journal of Cardiology,2016,202:609-614.

[15]A Controlled Trial of Renal.Denervation for resistant hypertension [J].N Engl J Med,2014,15(370):1393-1401.

[16]Henry Krum MPSP.Percutaneous renal denervation in patients with treatment-resistant hypertension:final 3-year report of the Symplicity HTN-1 study[J].Lancet,2014,383:622-629.

[17]Esler MD,Krum H,Schlaich M,et al.Renal sympathetic denervation for treatment of drug-resistant hypertension:One-year results from the symplicity HTN-2 randomized,controlled trial[J].Circulation, 2012,126(25):2976-2982.

[18]Krum H,Schlaich M,Whitbourn R,et al.Catheter-based renal sympathetic denervation for resistant hypertension:a multicentre safety and proof-of-principle cohort study[J].Lancet,2009,373(9671): 1275-1281.

[19]Winterfield JR,Mahapatra S,Wilber DJ.Catheter ablation of ventricular arrhythmias[J].Current Opinion in Cardiology,2013,28(3): 344-353.

[20]Chugh SS,Reinier K,Teodorescu C,et al.Epidemiology of sudden cardiac death:Clinical and research implications[J].Progress in Cardiovascular Diseases,2008,51(3):213-228.

[21]Dagmara Hering FMAS,Elisabeth A Lambert PASM,Schlaich AMP. Renal denervation in moderate to severe CKD[J].J Am Soc Nephrol,2012,23(7):1250-1257.

[22]Witkowski A,Prejbisz A,Florczak E,et al.Effects of renal sympathetic denervation on blood pressure,sleep apnea course,and glycemic control in patients with resistant hypertension and sleep apnea [J].Hypertension,2011,58(4):559-565.

[23]Davies JE,Manisty CH,Petraco R,et al.First-in-man safety evaluation of renal denervation for chronic systolic heart failure:Primary outcome from REACH-Pilot study[J].International Journal of Cardiology,2013,162(3):189-192.

[24]B?hm M,Ewen S,Kindermann I,et al.Renal denervation and heart failure[J].European Journal of Heart Failure,2014,16(6):608-613.

[25]Pokushalov E,Romanov A,Katritsis DG,et al.Renal denervation for improving outcomes of catheter ablation in patients with atrial fibrillation and hypertension:Early experience[J].Heart Rhythm,2014, 11(7):1131-1138.

[26]Linz D,van Hunnik A,Ukena C,et al.Renal denervation:effects on atrial electrophysiology and arrhythmias[J].Clinical Research in Cardiology,2014,103(10):765-774.

[27]Hering D,Marusic P,Walton AS,et al.Renal artery anatomy affects the blood pressure response to renal denervation in patients with resistant hypertension[J].International Journal of Cardiology,2016, 202:388-393.

[28]陽康,黃兵,廖凱,等.腎交感神經(jīng)刺激對全身交感神經(jīng)系統(tǒng)的影響[J].海南醫(yī)學(xué),2015,26(4):469-472.

[29]Mclellan AJA,Schlaich MP,Taylor AJ,et al.Reverse cardiac remodeling after renal denervation:Atrial electrophysiologic and structural changes associated with blood pressure lowering[J].Heart Rhythm, 2015,12(5):982-990.

[30]Liang Z,Shi X,Liu L,et al.Renal denervation suppresses atrial fibrillation in a model of renal impairment[J].PLoS One,2015,10(4): e124123.

[31]Hu J,Yan Y,Zhou Q,et al.Effects of renal denervation on the development of post-myocardial infarction heart failure and cardiac autonomic nervous system in rats[J].International Journal of Cardiology, 2014,172(3):e414-e416.

[32]Mahfoud F,Urban D,Teller D,et al.Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension:data from a multi-centre cardiovascular magnetic resonance imaging trial[J].European Heart Journal,2014,35(33):2224-2231.

[33]Sobotka PA,Krum H,B?hm M,et al.The role of renal denervation in the treatment of heart failure[J].Current Cardiology Reports,2012, 14(3):285-292.

[34]Brandt MC,Reda S,Mahfoud F,et al.Effects of renalsympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension[J].Journal of the American College of Cardiology,2012,60(19):1956-1965.

[35]Leong K T,Walton A,Krum H.Renal sympathetic denervation for the treatment of refractory hypertension[J].Annu Rev Med,2014, 65:349-365.

[36]Ott C,Mahfoud F,Schmid A,et al.Improvement of albuminuria after renal denervation[J].International Journal of Cardiology,2014,173 (2):311-315.

[37]Mahfoud F,Schlaich M,Kindermann I,et al.Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension:A pilotstudy [J].Circulation,2011,123(18): 1940-1946.

[38]Schlaich MP,Hering D,Sobotka P,et al.Effects of renal denervation on sympathetic activation,blood pressure,and glucose metabolism in patients with resistant hypertension[J].Frontiers in Physiology, 2012,3:3329-3331.

[39]Witkowski A,Prejbisz A,Florczak E,et al.Effects of renal sympa-thetic denervation on blood pressure,sleep apnea course,and glycemic control in patients with resistant hypertension and sleep apnea [J].Hypertension,2011,58(4):559-565.

[40]Di Daniele N,De Francesco M,Violo L,et al.Renal sympathetic nerve ablation for the treatment of difficult-to-control or refractory hypertension in a haemodialysis patient[J].Nephrology Dialysis Transplantation,2012,27(4):1689-1690.

[41]Schlaich MP,Straznicky N,Grima M,et al.Renal denervation:a potential new treatment modality for polycystic ovary syndrome?[J]. Journal of Hypertension,2011,29(5):991-996.

[42]Ripp TM,Mordovin VF,Pekarskiy SE,et al.Predictors of renal denervation efficacy in the treatment of resistant hypertension[J].Current Hypertension Reports,2015,17(12):225-288.

Researching progress of percutaneous radiofrequency catheter-based renal sympathetic denervation in the treatment of resistant hypertension.

YANG Chao-ying,YANG Hui,SU Yu-jiang.Department of Cardiovascular Medicine,Haikou Hospital Affiliated to Xiangya School of Medicine,Central South University,Haikou People's Hospital, Haikou 570208,Hainan,CHINA

Resistant hypertension is a special type of the high blood pressure,which is one of the basic diseases resulting in higher mortality and morbidity.Resistant hypertension is defined as blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes.Ideally,one of the agents should be a diuretic and all agents should be prescribed at optimal dose amount.It accompanies with more complications and higher incidence of cardiovascular events and mortality than other types of hypertension.Recently,there is a new type of non-pharmacological therapy,that is,percutaneous radiofrequency catheter-based renal sympathetic denervation.This review summarizes the research progress on the therapy.

Resistant hypertension;Renal sympathetic denervation;Interventional treatment;Radiofrequency

R544.1

A

1003—6350（2016）19—3194—04

10.3969/j.issn.1003-6350.2016.19.033

2015-12-31)

海南省自然科學(xué)基金（編號：SZR0506）

蘇雨江。E-mail：13078955322@163.com