经导管肾动脉消融去神经对顽固性高血压的影响—临床分析和实验研究

发布时间：2018-05-03 07:05

本文选题：顽固性高血压 + 肾动脉消融去神经术　；参考：《重庆医科大学》2015年博士论文

【摘要】：背景：顽固性高血压(Resistant hypertension, RH)是临床上常见的心血管病之一,常合并有糖尿病、肥胖、慢性肾脏疾病和睡眠呼吸暂停综合征等多种疾病,增加心血管疾病风险,具有较高的致残率和致死率。许多研究显示,交感神经系统(Sympathetic nervous system, SNS)过度激活参与顽固性高血压发生和发展。经导管肾动脉消融去神经术(Catheter-based renal denervation, RDN)是近几年发展起来的用于治疗顽固性高血压的新方法,这种新方法理论上不仅可用于顽固性高血压人群,也可用于任何交感神经过度激活的疾病,因而成为现代医学关注的焦点之一。许多临床数据显示,RDN可有效降低顽固性高血压患者的血压；然而,2014年一项随机、单盲、多中心前瞻性对照临床试验—Symplicity HTN-3结果显示RDN治疗顽固性高血压并未取得显著的降压效果,这些结果提示RDN治疗顽固性高血压的有效性尚存在争议。目的：本研究从临床和实验两个方面进行评估：1、临床方面,以导管为基础的肾脏去神经术能否有效降低顽固性高血压患者的血压；2、实验方面,采用两种不同的导管实施RDN术,探讨这两种不同的导管对肾动脉周围神经毁损及肾动脉壁影响有无差别。方法：临床研究方面：依据纳入标准和排除标准,通过检索医学文献数据库,入选应用RDN治疗顽固性高血压的临床研究,以RDN后6月诊室收缩压和舒张压变化为主要观察终点,通过荟萃分析和系统评价的方法评估RDN治疗顽固性高血压的降压效应。实验研究方面：实验昆明犬10只,经有创血压及肾动脉造影评估后,右肾动脉采用盐水灌注导管(Saline-irrigated catheter, SIC)实施RDN；左肾动脉采用温控导管(Temperature-controlled catheter, TCC)实施RDN；术后6月,随访血压和肾动脉造影后留取动物标本进行常规组织病理学,病理特殊染色和电镜检测。评价的内容包括：(i)RDN基线和随访6月心率和血压变化；(ii) RDN基线和随访6月肾动脉变化(影像学)；(iii) RDN后肾动脉周围神经的常规组织病理学改变,及其两种导管肾动脉周围神经病理学差别；(iv) RDN后肾动脉周围神经的病理特殊染色改变,及其两种导管肾动脉周围神经的病理特殊染色差别；(v)RDN后肾动脉周围神经的电镜改变,及其两种导管肾动脉周围神经的电镜差别；(vi) RDN后两种导管肾动脉形态差别；(vii) RDN基线和随访6月儿茶酚胺代谢物水平的变化。结果：临床方面,通过对数据库Cochrane Library, PubMed和clinicaltrial.gov进行检索,最终32篇RDN的临床研究纳入进行荟萃分析；这32篇研究中,3篇研究是随机、对照临床试验,有7篇研究是有对照组的前瞻性观察试验,余下22篇研究是无对照组的前瞻性观察试验。本荟萃分析纳入的32篇研究中,其中26篇研究涉及3724例患者报道了RDN后6月收缩压的结果,22篇研究涉及2444个研究患者报道了RDN后6月舒张压的结果,统计结果显示RDN干预后6月能够降低收缩压23.32 mmHg(95% confidence interval[CI]:[-25.14,-21.50], p0.0001, Z=25.14)和舒张压9.11mmHg(95% confidence interval[CI]:[-11.00,-7.22],p0.0001,Z=9.45)。实验方面,(i)动物存活情况：共10只实验犬入组,4只被排除实验(1只肾动脉畸形,2只麻醉死亡,1只未达随访期),最后入选本研究6只实验犬； (ii)心率和血压：与基线相比,RDN后6月心率和血压均有下降趋势,但无显著差异；(iii)肾动脉造影：与基线相比,术后6月未观察到手术相关并发症如肾动脉狭窄；(iv)消融参数：消融时间、功率、消融数量、温度和阻抗在两种导管间无显著差别；(v)肾动脉周围的神经：HE结果显示,RDN后肾动脉周围可见神经纤维和轴突的变性及结缔组织增生；这些变化SIC组比TCC组更明显；快蓝染色和嗜银染色结果显示,RDN后肾动脉周围可见神经纤维和轴突的脱髓鞘、变性及结缔组织增生,这些变化SIC组比TCC组更明显；电镜检测结果显示,RDN后肾动脉周围可见神经纤维和轴突的空泡变性、电子致密物沉积、施旺细胞肥大和增生及结缔组织增生；这些变化SIC组比TCC组更明显；(vi)肾动脉周围神经密度：Image Pro Plus (IPP) 6.0图像半定量分析结果显示,RDN后肾动脉周围的神经密度改变与导管类型相关；此外,RDN后肾动脉周围的神经密度改变与神经距离肾动脉管腔的距离相关；(vii)肾动脉增生：Masson's三色染色结果显示,TCC消融组见明显的内膜增生,而肾动脉中膜较完整,相反,SIC消融组见明显的中膜增生；维多利亚蓝染色显示两组间肾动脉壁增生有明显差别,TCC组增生组织主要位于内弹力膜管腔侧,而SIC组增生组织主要位于内弹力膜与外弹力膜间；(viii)儿茶酚胺代谢物：与基线相比,RDN后6月儿茶酚胺代谢物均有下降趋势,但无显著差异。结论：临床研究荟萃分析结果提示RDN能够有效降低顽固性高血压患者随访6月的收缩压和舒张压。实验研究结果提示：(i)RDN能够部分损伤肾动脉周围神经；(ii)SIC消融去神经比TCC消融去神经程度更大、距离更深；(iii) SIC消融主要导致肾动脉中膜增生；而TCC消融主要导致肾动脉内膜增生。
[Abstract]:Background: Resistant hypertension (RH) is one of the most common cardiovascular diseases, often associated with diabetes, obesity, chronic renal disease and sleep apnea syndrome, which increase the risk of cardiovascular disease and have a high rate of disability and mortality. Many studies have shown that the sympathetic nervous system (Sympathe) Tic nervous system, SNS) excessively activation involved in the occurrence and development of refractory hypertension. Transcatheter renal artery ablation (Catheter-based renal denervation, RDN) is a new method developed in recent years for the treatment of refractory hypertension. This new method can be used not only in intractable hypertension, but also in people with refractory hypertension. Any hyperactivated sympathic disease has become one of the focus of modern medical attention. Many clinical data show that RDN can effectively reduce blood pressure in patients with refractory hypertension; however, a randomized, single blind, multicenter, prospective, controlled clinical trial in 2014 - Symplicity HTN-3 results show that RDN is not in the treatment of refractory hypertension The results suggest that the effectiveness of RDN in the treatment of refractory hypertension is still controversial. Objective: This study was evaluated from two clinical and experimental aspects: 1, clinically, whether the catheter based renal denervation can effectively reduce the blood pressure of intractable high blood pressure patients; 2, two kinds of experiments. RDN was performed by different catheters to explore the difference between the two different catheters for the damage of the peripheral nerve and the wall of the renal artery. Methods: clinical research: according to the inclusion criteria and exclusion criteria, the clinical study on the treatment of refractory hypertension by RDN was selected by retrieving the medical literature database, and the consulting room was collected in June after RDN. The change of systolic and diastolic pressure was the main point of observation, and the antihypertensive effect of RDN in the treatment of refractory hypertension was evaluated by meta-analysis and systematic evaluation. Experimental study: 10 Kunming dogs were tested by invasive blood pressure and renal arteriography, and the right renal artery was treated with Saline-irrigated catheter (SIC) by saline infusion catheter (SIC). The left renal artery was performed RDN by Temperature-controlled catheter (TCC). After the operation in June, blood pressure and renal arteriography were followed up for routine histopathology, pathological special staining and electron microscopy. The contents of the evaluation included: (I) RDN base line and follow up of heart rate and blood pressure in June; (II) RDN baseline and Follow up of renal artery change (imaging) in June; (III) the routine histopathological changes of the peripheral nerve of the renal artery after (III) RDN and the difference of neuropathological changes around the renal artery; (IV) the special pathological changes of the peripheral nerve after RDN and the special pathological staining difference of the peripheral nerve of the renal artery; (V) RDN after RDN Ultrastructural changes of the peripheral nerve of the renal artery and the electron microscope difference of the two kinds of catheterization of the renal artery; (VI) two types of renal artery morphological differences after RDN; (VII) RDN baseline and changes in the level of theamines metabolites in the follow-up 6 months. Results: the clinical aspects were examined by the data base Cochrane Library, PubMed, and clinicaltrial.gov. The final 32 RDN clinical studies were included in the meta-analysis; in the 32 studies, 3 were randomized, controlled clinical trials, 7 were prospective observation trials in the control group, and the remaining 22 were prospective observation trials in the non control group. In this meta analysis, 32 studies were included in this meta analysis, of which 3724 cases were involved in 26 studies. The results of the June systolic pressure after RDN were reported. The 22 study involved 2444 patients who reported the diastolic pressure of June after RDN. The results showed that the RDN intervention could reduce the systolic pressure by 23.32 mmHg (95% confidence interval[CI]: [-25.14, -21.50], P0.0001, Z= 25.14) and the diastolic 9.11mmHg (95% confidence) after the intervention. -7.22], P0.0001, Z=9.45). (I) the survival of (I) animals: a total of 10 experimental dogs and 4 excluded experiments (1 renal arteriovenous malformations, 2 anaesthetized deaths, 1 no follow-up period), and the last selected study of the experimental dogs; (II) heart rate and blood pressure: Compared with the baseline, the heart rate and blood pressure decreased in June, but no significant difference was found. (III) renal arteriography: compared with baseline, surgery related complications such as renal artery stenosis were not observed in June; (IV) ablation parameters: ablation time, power, ablation number, temperature and impedance between two types of catheters; (V) the nerve around the renal artery: HE results showed nerve fibers around the renal artery after RDN and The degeneration of axon and connective tissue hyperplasia in the group SIC were more obvious than that in the TCC group. The results of rapid blue staining and silver staining showed that the demyelination, denaturation and connective tissue proliferation around the renal artery were visible around RDN, and these changes were more obvious in the SIC group than in the TCC group; the results of electrical microscopy showed that the renal arteries were visible around RDN after RDN. Vacuolar degeneration of nerve fibers and axons, electron dense deposition, hypertrophy and hyperplasia of Schwann cells and connective tissue hyperplasia; these changes were more obvious in group SIC than in group TCC; (VI) the density of the peripheral nerve of the renal artery: the semi quantitative analysis of the Image Pro Plus (IPP) 6 image showed that the changes of the nerve density around the renal artery and the type of catheterization around the renal artery after RDN In addition, the changes of the nerve density around the renal artery after RDN were related to the distance from the nerve distance to the renal artery cavity; (VII) the renal artery hyperplasia: the Masson's tricolor staining results showed that the TCC ablation group showed obvious intimal hyperplasia, but the middle membrane of the renal artery was more complete, but the SIC melted group showed obvious mesangial hyperplasia; Vitoria blue staining showed that the renal artery was obvious. The proliferation of renal artery wall between the two groups was significantly different. The proliferative tissue in group TCC was mainly located in the inner elastic membrane, while the proliferative tissue in group SIC was mainly located between the inner elastic membrane and the outer elastic membrane; (VIII) the catecholamine metabolite: compared with the baseline, there was a decline in the metabolites of theamines in 6 months after RDN, but there was no significant difference. Conclusion: clinical research The results of the meta analysis suggest that RDN can effectively reduce the systolic pressure and diastolic pressure of the patients with refractory hypertension in June. The results of the experimental study suggest that (I) RDN can partially damage the peripheral nerve of the renal artery; (II) SIC ablation of the nerve is greater than TCC ablation, and the distance is deeper; (III) SIC ablation mainly leads to the increase of the renal artery membrane. TCC ablation is the main cause of renal artery intimal hyperplasia.

【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R544.1

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