The Effect Of Catheter-Based Renal Denervation On Resistant Hypertension, Clinical Analysis And Experimental Research

Background:Resistant hypertension is one of the common clinical cardiovascular diseases which are associated with diabetes, obesity, chronic kidney diseases and obstructive sleep apnea and increases risk of cardiovascular disease with higher morbidity and mortality. Many studies have shown that the sympathetic nervous system (SNS) plays an important role in the development and progression of hypertension.In recent years, catheter-based renal denervation (RDN) has emerged as a new method to treat resistant hypertension. Theoretically, the new method can be used not only in patients with resistant hypertension also in patients with any excessive activation of SNS, and thus has become the focus of attention. Many clinical data show that RDN reduces blood pressure in patients with resistant hypertension. However, in 2014, a randomized, single-blind, multicenter, prospective, controlled clinical trial—Symplicity HTN-3 did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. These results have suggested that the effectiveness of RDN is still controversial.Purpose:This paper include two parts,namely the clinical analyses and experimental studies. In chlinical analysis, to investigate whether RDN has a significant effect on decreasing blood pressure (BP) in patients with resistant hypertension, a meta-analysis was performed. In experimental study, to investigate the effectiveness of RDN and the differences between TCC and SIC catheters, RDN was performed by using different catheters.Methods:In clinical analysis, to assess the effectiveness of RDN treatment for resistant hypertension, a meta-analysis was performed. According to inclusion and exclusion criteria, clinical studies on resistant hypertension were searched by the medical literature databases, and the primary end point is the changes of SBP and DBP at 6 months after RDN.In experimental research, the Kunming dogs (n= 10) were ablated after assessment of invasive blood pressure measurement and renal arteriography, and RDN was performed by using saline-irrigated catheter (SIC) in the right renal artery, while RDN was performed by using temperature-controlled catheter (TCC) in the left renal artery. The conventional histopathology, special staining, transmission electron microscopy (TEM) and renal angiography were performed at 6 months after RDN. The indicators included are as follows:(i) the changes of heart rate and blood pressure between baseline and follow-up; (ii) the changes in renal artery (Imaging/renal artery angiography) between baseline and follow-up; (iii) the conventional histopathology change of peri-renal arterial nerves and differences between two catheters 6 months after RDN; (iv) the special staining change of peri-renal arterial nerves and differences between two catheters at 6 months after RDN; (v) the TEM change of peri-renal arterial nerves and differences between two catheters at 6 months after RDN; (vi) the morphological differences of renal artery wall between two catheters at 6 months after RDN; (vii) the change values of catecholamine metabolites between baseline and follow-up.Results:In clinical analysis, according to the inclusion criteria and exclusion criteria,32 clinical studies on RDN were included in present meta-analysis. Of all 32 studies, three studies are randomized, controlled clinical trials; seven studies were prospective, observational study with control group; and the remaining 22 studies were prospective, observational studies without control group. Of all 32 studies included the present meta-analysis,26 studies involving 3724 cases of patients reported the results of SBP at 6 months after RDN,22 studies involving 2444 patients reported the results of DBP at 6 months. The statistical results show that RDN can reduce 23.32 mmHg of SBP (95% confidence interval [CI]:[-25.14,-21.50], p<0.0001, Z=25.14) and 9.11mmHg of DBP (95% confidence interval [CI]:[-11.00,-7.22], p<0.0001,Z=9.45).In experimental study,(i) Animal survival:a total of 10 dogs were enrolled, four were excluded [renal artery malformation(n=1), death of anesthesia(n=2), less than 6-month follow-up(n=1)], and finally six canines were included in present study; (ii) Heart rate and blood pressure:there is a trend toward a decrease between baseline and follow-up, but there was no statistical difference; (iii) Renal arteriography:procedure-related complications was observed both baseline and follow-up; (iv) Ablation parameters:there were no significant differences in ablation time, power, ablation, temperature and impedance between the two catheter; (v) The changes of nerves surrounding the renal artery:the results of H & E show that there is degeneration of nerve fibers and axon and connective tissue proliferation, and these changes are more apparent in SIC group than TCC group; fast blue and silver staining show that there is demyelination of nerve fibers, degeneration of nerve axon and connective tissue proliferation, and these changes are more apparent in SIC group than TCC group; the results of TEM show that there is degeneration of nerve fibers and axon, electron dense deposits, Schwann cell hypertrophy and hyperplasia and these changes are more apparent in SIC group than TCC group; (vi)Density changes of peripheral nerves around renal artery:semi-quantitative image analysis shows that the density changes of peri-renal arterial nerve are associated with the types of catheters and distance from peripheral nerve to the luminal surface of renal arteries; (vii) Renal artery hyperplasia:special staining show that Intimal hyperplasia was greater when the TCC was used, whereas medial hyperplasia was greater when the SIC was used; (viii)Catecholamine metabolite:there is a trend toward a decrease in catecholamine metabolite between baseline and follow-up, but there was no statistical difference.Conclusions:In clinical analysis, the results of meta-analysis suggest that RDN has a significant effect on decreasing SBP and DBP in patients with resistant hypertension 6 months after RDN.In experimental study, (i) RDN may partly cause nerve damage around the renal artery; (ii) SIC ablation is relatively more neural degeneration, deeper distance than TCC ablation; (iii) TCC ablation mainly may cause neointimal hyperplasia, whereas SIC ablation may mainly cause medial hyperplasia.