本文選題：頑固性高血壓 + 腎動脈消融去神經術�。� 參考：《重慶醫(yī)科大學》2015年博士論文

【摘要】：背景：頑固性高血壓(Resistant hypertension, RH)是臨床上常見的心血管病之一,常合并有糖尿病、肥胖、慢性腎臟疾病和睡眠呼吸暫停綜合征等多種疾病,增加心血管疾病風險,具有較高的致殘率和致死率。許多研究顯示,交感神經系統(tǒng)(Sympathetic nervous system, SNS)過度激活參與頑固性高血壓發(fā)生和發(fā)展。經導管腎動脈消融去神經術(Catheter-based renal denervation, RDN)是近幾年發(fā)展起來的用于治療頑固性高血壓的新方法,這種新方法理論上不僅可用于頑固性高血壓人群,也可用于任何交感神經過度激活的疾病,因而成為現代醫(yī)學關注的焦點之一。許多臨床數據顯示,RDN可有效降低頑固性高血壓患者的血壓；然而,2014年一項隨機、單盲、多中心前瞻性對照臨床試驗—Symplicity HTN-3結果顯示RDN治療頑固性高血壓并未取得顯著的降壓效果,這些結果提示RDN治療頑固性高血壓的有效性尚存在爭議。目的：本研究從臨床和實驗兩個方面進行評估：1、臨床方面,以導管為基礎的腎臟去神經術能否有效降低頑固性高血壓患者的血壓；2、實驗方面,采用兩種不同的導管實施RDN術,探討這兩種不同的導管對腎動脈周圍神經毀損及腎動脈壁影響有無差別。方法：臨床研究方面：依據納入標準和排除標準,通過檢索醫(yī)學文獻數據庫,入選應用RDN治療頑固性高血壓的臨床研究,以RDN后6月診室收縮壓和舒張壓變化為主要觀察終點,通過薈萃分析和系統(tǒng)評價的方法評估RDN治療頑固性高血壓的降壓效應。實驗研究方面：實驗昆明犬10只,經有創(chuàng)血壓及腎動脈造影評估后,右腎動脈采用鹽水灌注導管(Saline-irrigated catheter, SIC)實施RDN；左腎動脈采用溫控導管(Temperature-controlled catheter, TCC)實施RDN；術后6月,隨訪血壓和腎動脈造影后留取動物標本進行常規(guī)組織病理學,病理特殊染色和電鏡檢測。評價的內容包括：(i)RDN基線和隨訪6月心率和血壓變化；(ii) RDN基線和隨訪6月腎動脈變化(影像學)；(iii) RDN后腎動脈周圍神經的常規(guī)組織病理學改變,及其兩種導管腎動脈周圍神經病理學差別；(iv) RDN后腎動脈周圍神經的病理特殊染色改變,及其兩種導管腎動脈周圍神經的病理特殊染色差別；(v)RDN后腎動脈周圍神經的電鏡改變,及其兩種導管腎動脈周圍神經的電鏡差別；(vi) RDN后兩種導管腎動脈形態(tài)差別；(vii) RDN基線和隨訪6月兒茶酚胺代謝物水平的變化。結果：臨床方面,通過對數據庫Cochrane Library, PubMed和clinicaltrial.gov進行檢索,最終32篇RDN的臨床研究納入進行薈萃分析；這32篇研究中,3篇研究是隨機、對照臨床試驗,有7篇研究是有對照組的前瞻性觀察試驗,余下22篇研究是無對照組的前瞻性觀察試驗。本薈萃分析納入的32篇研究中,其中26篇研究涉及3724例患者報道了RDN后6月收縮壓的結果,22篇研究涉及2444個研究患者報道了RDN后6月舒張壓的結果,統(tǒng)計結果顯示RDN干預后6月能夠降低收縮壓23.32 mmHg(95% confidence interval[CI]:[-25.14,-21.50], p0.0001, Z=25.14)和舒張壓9.11mmHg(95% confidence interval[CI]:[-11.00,-7.22],p0.0001,Z=9.45)。實驗方面,(i)動物存活情況：共10只實驗犬入組,4只被排除實驗(1只腎動脈畸形,2只麻醉死亡,1只未達隨訪期),最后入選本研究6只實驗犬； (ii)心率和血壓：與基線相比,RDN后6月心率和血壓均有下降趨勢,但無顯著差異；(iii)腎動脈造影：與基線相比,術后6月未觀察到手術相關并發(fā)癥如腎動脈狹窄；(iv)消融參數：消融時間、功率、消融數量、溫度和阻抗在兩種導管間無顯著差別；(v)腎動脈周圍的神經：HE結果顯示,RDN后腎動脈周圍可見神經纖維和軸突的變性及結締組織增生；這些變化SIC組比TCC組更明顯；快藍染色和嗜銀染色結果顯示,RDN后腎動脈周圍可見神經纖維和軸突的脫髓鞘、變性及結締組織增生,這些變化SIC組比TCC組更明顯；電鏡檢測結果顯示,RDN后腎動脈周圍可見神經纖維和軸突的空泡變性、電子致密物沉積、施旺細胞肥大和增生及結締組織增生；這些變化SIC組比TCC組更明顯；(vi)腎動脈周圍神經密度：Image Pro Plus (IPP) 6.0圖像半定量分析結果顯示,RDN后腎動脈周圍的神經密度改變與導管類型相關；此外,RDN后腎動脈周圍的神經密度改變與神經距離腎動脈管腔的距離相關；(vii)腎動脈增生：Masson's三色染色結果顯示,TCC消融組見明顯的內膜增生,而腎動脈中膜較完整,相反,SIC消融組見明顯的中膜增生；維多利亞藍染色顯示兩組間腎動脈壁增生有明顯差別,TCC組增生組織主要位于內彈力膜管腔側,而SIC組增生組織主要位于內彈力膜與外彈力膜間；(viii)兒茶酚胺代謝物：與基線相比,RDN后6月兒茶酚胺代謝物均有下降趨勢,但無顯著差異。結論：臨床研究薈萃分析結果提示RDN能夠有效降低頑固性高血壓患者隨訪6月的收縮壓和舒張壓。實驗研究結果提示：(i)RDN能夠部分損傷腎動脈周圍神經；(ii)SIC消融去神經比TCC消融去神經程度更大、距離更深；(iii) SIC消融主要導致腎動脈中膜增生；而TCC消融主要導致腎動脈內膜增生。
[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.

【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R544.1

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