Research status and frontiers of renal denervation for hypertension: a bibliometric analysis from 2004 to 2023.

BACKGROUND: Renal Denervation (RDN) is a novel non-pharmacological technique to treat hypertension. This technique lowers blood pressure by blocking the sympathetic nerve fibers around the renal artery, then causing a decrease in system sympathetic nerve excitability. This study aimed to visualize and analyze research hotspots and development trends in the field of RDN for hypertension through bibliometric analysis. METHODS: In total, 1479 studies were retrieved on the Web of Science Core Collection (WoSCC) database from 2004 to 2023. Using CiteSpace (6.2.R4) and VOSviewer (1.6.18), visualization maps were generated by relevant literature in the field of RDN for hypertension to demonstrate the research status and frontiers. RESULTS: The number of publications was found to be generally increasing. Europe and the United States were the first countries to carry out research on different techniques and related RDN clinical trials. The efficacy and safety of RDN have been repeatedly verified and gained increasing attention. The study involves multiple disciplines, including the cardiovascular system, peripheral vascular disease, and physiological pathology, among others. Research hotspots focus on elucidating the mechanism of RDN in the treatment of hypertension and the advantages of RDN in appliance therapy. Additionally, the research frontiers include improvement of RDN instruments and techniques, as well as exploration of the therapeutic effects of RDN in diseases with increased sympathetic nerve activity. CONCLUSION: The research hotspots and frontiers reflect the status and development trend of RDN in hypertension. In the future, it is necessary to strengthen international collaboration and cooperation, conduct long-term clinical studies with a large sample size, and continuously improve RDN technology and devices. These measures will provide new options for more patients with hypertension, thereby improving their quality of life.

Randomized Trials of Renal Denervation for Uncontrolled Hypertension: An Updated Meta-Analysis.

BACKGROUND: Despite optimal medical therapy, a significant proportion of patients' blood pressure remains uncontrolled. Catheter-based renal denervation (RDN) has been proposed as a potential intervention for uncontrolled hypertension. We conducted an updated meta-analysis to assess the efficacy and safety of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off antihypertensive medications. METHODS AND RESULTS: Online databases were searched to identify randomized clinical trials comparing efficacy and safety of RDN versus control in patients with uncontrolled hypertension. Subgroup analyses were conducted for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking US Food and Drug Administration approval. Fifteen trials with 2581 patients (RDN, 1723; sham, 858) were included. In patients off antihypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory (-3.70 [95% CI, -5.41 to -2.00] mm Hg), office (-4.76 [95% CI, -7.57 to -1.94] mm Hg), and home (-3.28 [95% CI, -5.96 to -0.61] mm Hg) systolic blood pressures was noted. In patients on antihypertensive medications, a significant reduction was observed in 24-hour ambulatory (-2.23 [95% CI, -3.56 to -0.90] mm Hg), office (-6.39 [95% CI, -11.49 to -1.30]), home (-6.08 [95% CI, -11.54 to -0.61] mm Hg), daytime (-2.62 [95% CI, -4.14 to -1.11]), and nighttime (-2.70 [95% CI, -5.13 to -0.27]) systolic blood pressures, as well as 24-hour ambulatory (-1.16 [95% CI, -1.96 to -0.35]), office (-3.17 [95% CI, -5.54 to -0.80]), and daytime (-1.47 [95% CI, -2.50 to -0.27]) diastolic blood pressures. CONCLUSIONS: RDN significantly lowers blood pressure in patients with uncontrolled hypertension, in patients off and on antihypertensive medications, with a favorable safety profile. The efficacy of RDN was consistent in sham-controlled trials and contemporary trials using US Food and Drug Administration-approved devices.

Investigations of Laser-Assisted Renal Denervation for Treatment of Resistant Hypertension.

BACKGROUND AND OBJECTIVES: Renal denervation (RDN) is an emerging surgical treatment for resistant hypertension. However, the current RDN using radiofrequency can cause undesirable thermal damage to the medial and luminal layers due to direct contact between the arterial lumen and energy source. The aim of this study is to evaluate the feasibility of the new laser-assisted RDN by exploring the potential treatment conditions. METHODS: For ex vivo testing, six different treatment conditions (10 and 20 W applied for delivery of 300, 450, and 600 J) were tested on the porcine liver and renal artery (RA) by using a continuous wave 1064 nm laser wavelength. The ablated area in the liver tissue was measured to estimate the extent of the coagulated area. Histological evaluation was performed on the treated RA tissues to confirm the extent of thermal nerve damage. RESULTS: The ablated depth, length, and area in the liver tissue increased with laser power and total energy. According to the histological results, 20 W groups yielded more significant damage to the RA nerves than 10 W groups at the total energy of 300 J (0.0 ± 0.0 mm for 10 W vs. 2.9 ± 1.0 mm for 20 W), 450 J (1.9 ± 0.6 mm for 10 W vs. 6.8 ± 1.5 mm for 20 W), and 600 J (2.9 ± 0.4 mm for 10 W vs. 7.3 ± 0.8 mm for 20 W). The treated RA exhibited insignificant medial injury in depth (medial thinning ≤ 25%), and no difference in the medial thinning was found among the six groups (p = 0.4). CONCLUSION: The current study demonstrated that the 1064 nm laser at 20 W with delivery of 450 J could effectively damage the RA nerves with no or minimal injury to the surrounding tissue. The proposed laser-assisted RDN may enhance physiological effects with insignificant complications in in vivo situations. Further in vivo studies will be conducted to validate the current findings by evaluating the extent of blood pressure reduction and norepinephrine changes after the laser-assisted RDN on a large animal model.

Patient-Specific Factors Predicting Renal Denervation Response in Patients With Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: The accurate selection of patients likely to respond to renal denervation (RDN) is crucial for optimizing treatment outcomes in patients with hypertension. This systematic review was designed to evaluate patient-specific factors predicting the RDN response. METHODS AND RESULTS: We focused on individuals with hypertension who underwent RDN. Patients were categorized based on their baseline characteristics. The primary outcome was blood pressure (BP) reduction after RDN. Both randomized controlled trials and nonrandomized studies were included. We assessed the risk of bias using corresponding tools and further employed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the overall quality of evidence. A total of 50 studies were ultimately included in this systematic review, among which 17 studies were for meta-analysis. Higher baseline heart rate and lower pulse wave velocity were shown to be associated with significant antihypertensive efficacy of RDN on 24-hour systolic BP reduction (weighted mean difference, -4.05 [95% CI, -7.33 to -0.77]; weighted mean difference, -7.20 [95% CI, -9.79 to -4.62], respectively). In addition, based on qualitative analysis, higher baseline BP, orthostatic hypertension, impaired baroreflex sensitivity, and several biomarkers are also reported to be associated with significant BP reduction after RDN. CONCLUSIONS: In patients with hypertension treated with the RDN, higher heart rate, and lower pulse wave velocity were associated with significant BP reduction after RDN. Other factors, including higher baseline BP, hypertensive patients with orthostatic hypertension, BP variability, impaired cardiac baroreflex sensitivity, and some biomarkers are also reported to be associated with a better BP response to RDN.

Efficacy and Safety of Radiofrequency-Based Renal Denervation on Resistant Hypertensive Patients: A Systematic Review and Meta-analysis.

INTRODUCTION: New therapies for resistant hypertension (RH), including renal denervation (RDN), have been studied. AIM: Access the safety and effectiveness of radiofrequency-based RDN vs pharmacological treatment for RH. METHODS: A thorough literature search was conducted across PubMed, EMBASE, and the Cochrane databases, focusing on studies that compared the effects of radiofrequency-based RDN versus pharmacological treatment for RH. Treatment effects for binary and continuous endpoints were pooled and used, respectively, odds-ratio (OR) and mean differences (MD) with 95% confidence intervals (CI) to analyze continuous outcomes. RESULTS: In the 10 included studies, involving 1.182 patients, 682 received radiofrequency-based RDN. The follow-up period ranged from 6 to 84 months. Analysis revealed that the RDN group had a significant reduction in office systolic blood pressure (BP) (MD - 9.5 mmHg; 95% CI - 16.81 to - 2.29; P = 0.01), office diastolic BP (MD - 5.1 mmHg; 95% CI - 8.42 to - 2.80; P < 0.001), 24 h systolic BP (MD - 4.8 mmHg; 95% CI - 7.26 to - 2.42; P < 0.001). For 24 h diastolic BP RDN did not have a significant reduction (MD - 2.3 mmHg; 95% CI - 4.19 to - 0.52; P = 0.012). The heterogeneity between the studies was high, visible in the funnel and Baujat plots. The OR was non-significant for non-serious adverse events, but also clinically significant for hypertensive crises and strokes for the RDN group. CONCLUSIONS: While the pharmacological regimen of 3 or more anti-hypertensive, including a diuretic, still be the first-line option for RH treatment, our results support that radiofrequency-based RDN is superior in reducing global BP and is safe.

Overview of the 2023 FDA Circulatory System Devices Advisory Panel meeting on the Recor Paradise Ultrasound-Based Renal Denervation System.

Hypertension continues to be a prominent, avoidable factor contributing to major vascular issues on a global scale. Even with lifestyle adjustments and more aggressive medical treatments, maintaining optimal blood pressure levels remains challenging. This challenge has driven the emergence of device-oriented approaches to address hypertension. To assess the safety and efficacy of the Recor Paradise Ultrasound Renal Denervation System, the Circulatory System Devices Panel was convened by the US Food and Drug Administration (FDA). This manuscript provides a condensed overview of the information put forth by the sponsor and the FDA, along with an account of the considerations and conversations that took place during the meeting.

Controversies related to renal artery denervation and devices.

PURPOSE OF REVIEW: This review article discusses the controversies, strengths, and limitations of the current literature on renal artery denervation in the management of resistant hypertension, as well as the future directions of this intervention. RECENT FINDINGS: There have been conflicting data from the different randomized control trials assessing the efficacy of renal artery denervation in the management of resistant hypertension. SUMMARY: Renal artery denervation is achieved by ablating the sympathetic nerves surrounding the renal arteries using endovascular ultrasound, radiofrequency, or alcohol. Our review article highlights that renal artery denervation is generally effective in improving blood pressure in patients with resistant hypertension. The Food and Drug Administration (FDA) has recently approved the ReCor Medical Paradise system, and the Symplicity Spyral RDN systems for renal artery denervation.

Long-Term Safety and Efficacy of Transcatheter Microwave and Radiofrequency Denervation in a Chronic Ovine Model.

BACKGROUND: Transcatheter renal denervation (RDN) has had inconsistent efficacy and concerns for durability of denervation. We aimed to investigate long-term safety and efficacy of transcatheter microwave RDN in vivo in normotensive sheep in comparison to conventional radiofrequency ablation. METHODS AND RESULTS: Sheep underwent bilateral RDN, receiving 1 to 2 microwave ablations (maximum power of 80-120 W for 240 s-480 s) and 12 to 16 radiofrequency ablations (180 s-240 s) in the main renal artery in a paired fashion, alternating the side of treatment, euthanized at 2 weeks (acute N=15) or 5.5 months (chronic N=15), and compared with undenervated controls (N=4). Microwave RDN produced substantial circumferential perivascular injury compared with radiofrequency at both 2 weeks [area 239.8 (interquartile range [IQR] 152.0-343.4) mm2 versus 50.1 (IQR, 32.0-74.6) mm2, P <0.001; depth 16.4 (IQR, 13.9-18.9) mm versus 7.5 (IQR, 6.0-8.9) mm P <0.001] and 5.5 months [area 20.0 (IQR, 3.4-31.8) mm2 versus 5.0 (IQR, 1.4-7.3) mm2, P=0.025; depth 5.9 (IQR, 1.9-8.8) mm versus 3.1 (IQR, 1.2-4.1) mm, P=0.005] using mixed models. Renal denervation resulted in significant long-term reductions in viability of renal sympathetic nerves [58.9% reduction with microwave (P=0.01) and 45% reduction with radiofrequency (P=0.017)] and median cortical norepinephrine levels [71% reduction with microwave (P <0.001) and 72.9% reduction with radiofrequency (P <0.001)] at 5.5 months compared with undenervated controls. CONCLUSIONS: Transcatheter microwave RDN produces deep circumferential perivascular ablations without significant arterial injury to provide effective and durable RDN at 5.5 months compared with radiofrequency RDN.

Effect of Alcohol-Mediated Renal Denervation on Blood Pressure in the Presence of Antihypertensive Medications: Primary Results From the TARGET BP I Randomized Clinical Trial.

BACKGROUND: Renal denervation (RDN) has demonstrated clinically relevant reductions in blood pressure (BP) among individuals with uncontrolled hypertension despite lifestyle intervention and medications. The safety and effectiveness of alcohol-mediated RDN have not been formally studied in this indication. METHODS: TARGET BP I is a prospective, international, sham-controlled, randomized, patient- and assessor-blinded trial investigating the safety and efficacy of alcohol-mediated RDN. Patients with office systolic BP (SBP) ≥150 and ≤180 mm Hg, office diastolic BP ≥90 mm Hg, and mean 24-hour ambulatory SBP ≥135 and ≤170 mm Hg despite prescription of 2 to 5 antihypertensive medications were enrolled. The primary end point was the baseline-adjusted change in mean 24-hour ambulatory SBP 3 months after the procedure. Secondary end points included mean between-group differences in office and ambulatory BP at additional time points. RESULTS: Among 301 patients randomized 1:1 to RDN or sham control, RDN was associated with a significant reduction in 24-hour ambulatory SBP at 3 months (mean±SD, -10.0±14.2 mm Hg versus -6.8±12.1 mm Hg; treatment difference, -3.2 mm Hg [95% CI, -6.3 to 0.0]; P=0.0487). Subgroup analysis of the primary end point revealed no significant interaction across predefined subgroups. At 3 months, the mean change in office SBP was -12.7±18.3 and -9.7±17.3 mm Hg (difference, -3.0 [95% CI, -7.0 to 1.0]; P=0.173) for RDN and sham, respectively. No significant differences in ambulatory or office diastolic BP were observed. Adverse safety events through 6 months were uncommon, with one instance of accessory renal artery dissection in the RDN group (0.7%). No significant between-group differences in medication changes or patient adherence were identified. CONCLUSIONS: Alcohol-mediated RDN was associated with a modest but statistically significant reduction in 24-hour ambulatory SBP compared with sham control. No significant differences between groups in office BP or 6-month major adverse events were observed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02910414.

Opportunities and Limitations of Renal Denervation: Where Do We Stand?

Hypertension is a primary contributor to cardiovascular disease, and the leading risk factor for loss of quality adjusted life years. Up to 50% of the cases of hypertension in the United States remain uncontrolled. Additionally, 8%-18% of the hypertensive population have resistant hypertension; uncontrolled pressure despite 3 different antihypertensive agents. Recently, catheter-based percutaneous renal denervation emerged as a method for ablating renal sympathetic nerves for difficult-to-control hypertension. Initial randomized (non-sham) trials and registry analyses showed impressive benefit, but the first sham-controlled randomized controlled trial using monopolar radiofrequency ablation showed limited benefit. With refinement of techniques to include multipolar radiofrequency, ultrasound denervation, and direct ethanol injection, randomized controlled trials demonstrated significant blood pressure improvement, leading to US Food and Drug Administration approval of radiofrequency- and ultrasound-based denervation technologies. In this review article, we summarize the major randomized sham-controlled trials and societal guidelines regarding the efficacy and safety of renal artery denervation for the treatment of uncontrolled hypertension.

Ultra-long-term efficacy and safety of catheter-based renal denervation in resistant hypertension: 10-year follow-up outcomes.

BACKGROUND: Randomized sham-controlled trials have confirmed the efficacy and safety of catheter-based renal denervation in hypertension. Data on the very long-term effects of renal denervation are scarce. AIMS: This study evaluates the 10-year safety and efficacy of renal denervation in resistant hypertension. METHODS: This prospective single-center study included patients with resistant hypertension undergoing radio-frequency renal denervation between 2010 and 2012. Office blood pressure, 24-h ambulatory blood pressure, antihypertensive medication, color duplex sonography, and renal function were assessed after 1-, 2- and 10-years. RESULTS: Thirty-nine patients completed the 10-year follow-up (mean follow-up duration 9.4 ± 0.7 years). Baseline office and 24-h ambulatory systolic blood pressure were 164 ± 23 mmHg and 153 ± 16 mmHg, respectively. After 10 years, 24-h ambulatory and office systolic blood pressure were reduced by 16 ± 17 mmHg (P < 0.001) and 14 ± 23 mmHg (P = 0.001), respectively. The number of antihypertensive drugs remained unchanged from 4.9 ± 1.4 to 4.5 ± 1.2 drugs (P = 0.087). The estimated glomerular filtration rate declined within the expected range from 69 (95% CI 63 to 74) to 60 mL/min/1.73m2 (95% CI 53 to 68; P < 0.001) through 10-year follow-up. Three renal artery interventions were documented for progression of pre-existing renal artery stenosis in two patients and one patient with new-onset renal artery stenosis. No other adverse events were observed during the follow-up. CONCLUSION: Renal denervation was safe and sustainedly reduced ambulatory and office blood pressure out to 10 years in patients with resistant hypertension.

Role of dynamic road-mapping in renal denervation procedures.

Dynamic road-mapping (DRM) (Dynamic Coronary Roadmap; Philips) offers a real-time, dynamic overlay of the coronary tree on fluoroscopy.

Impact of renal denervation on cardiac remodeling in resistant hypertension: A meta-analysis.

Twelve studies involving 433 patients were included. After RDN treatment, LVMI decreased by 13.08 g/m2 (95% confidence interval [CI]: -18.38, -7.78; p < .00001), PWTd decreased by 0.60 mm (95% CI: -0.87, -0.34; p < .00001), IVSTd decreased by 0.78 mm (95% CI: -1.06, -0.49; p < .00001), and LVEF increased by 1.80% (95% CI: 0.71, 2.90; p = .001). However, there were no statistically significant improvements in LVIDd (95% CI: -1.40, 0.24; p = .17) and diastolic function (E/A) (95% CI: -0.04, 0.14; p = .28). Drug treatment for resistant hypertension (RH) is challenging. Renal denervation (RDN) is one of the most promising treatments for RH. Although studies have shown RDN can control blood pressure, the impacts of RDN on cardiac remodeling and cardiac function are unclear. This meta-analysis evaluated the effect of RDN on cardiac structure and function in patients with RH. PubMed, Embase, and Cochrane were used to conduct a systematic search. The main inclusion criteria were studies on patients with RH who received RDN and reported the changes in echocardiographic parameters before and after RDN. Echocardiographic parameters included left ventricular mass index (LVMI), end-diastolic left ventricular internal dimension (LVIDd), left ventricular end-diastolic posterior wall thickness (PWTd), end-diastolic interventricular septum thickness (IVSTd), E/A, and left ventricular ejection fraction (LVEF). Data was analyzed using RevMan. Twelve studies involving 433 patients were included. After RDN treatment, LVMI decreased by 13.08g/m2 (95%confidence interval [CI]: -18.38, -7.78, p < .00001), PWTd decreased by 0.60mm (95% CI: -0.87, -0.34, p < 0.00001), IVSTd decreased by 0.78mm (95% CI: -1.06, -0.49, p < .00001), and LVEF increased by 1.80% (95% CI: 0.71, 2.90, p = .001). However, there were no statistically significant improvements in LVIDd (95% CI: -1.40, 0.24, p = .17) and diastolic function (E/A) (95% CI: -0.04, 0.14, p =.28). This meta-analysis finds that RDN can improve left ventricular hypertrophy and ejection fraction in patients with RH but has no significant effect on LVIDd and diastolic function. However, more studies are warranted due to the lack of a strict control group, a limited sample size, and research heterogeneity.

Histological examination of renal nerve distribution, density, and function in humans.

BACKGROUND: Renal denervation is optimised when guided by knowledge of nerve distribution. AIMS: We aimed to assess sympathetic nerve distribution along the renal arteries, especially in post-bifurcation vessel segments. METHODS: Renal arteries and surrounding tissue from 10 body donors were collected and examined histologically. Immunohistochemical staining was used to analyse nerve distribution and to identify afferent and efferent sympathetic nerves. RESULTS: A total of 6,781 nerves surrounding 18 renal arteries were evaluated. The mean lumen-nerve distance of the left renal artery (2.32±1.95 mm) was slightly greater than the right (2.29±2.03 mm; p=0.161); this varied across the arteries' courses: 3.7±2.3 mm in proximal segments, 2.5±2.0 mm in middle segments, 1.9±1.6 mm in distal prebifurcation segments and 1.3±1.0 mm in post-bifurcation segments (p<0.001). The number of nerves per quadrant was highest in the proximal segments (13.7±18.6), followed by the middle (9.7±7.9), distal prebifurcation (8.0±7.6), and distal post-bifurcation (4.3±4.0) segments (p<0.001). Circumferentially, the number of nerves was highest in the superior (7.8±9.4) and the ventral (7.6±13.1) quadrants (p=0.638). The mean tyrosine hydroxylase (TH) to calcitonin gene-related peptide (CGRP) ratio increased from proximal (37.5±33.5) to distal (72.0±7.2 in the post-bifurcation segments; p<0.001). Thirty-eight neuroganglia were identified along 14 (78%) renal arteries. CONCLUSIONS: Nerves converge to the renal arteries' lumen in the distal segments and along branches, resulting in the lowest number of nerves per quadrant and the shortest lumen-nerve distance in the distal post-bifurcation segments. Efferent nerves occur predominantly, and the ratio of efferent to afferent nerves continues to increase in the vessels' course.

Renal nerve stimulation identifies renal innervation and optimizes the strategy for renal denervation in canine.

BACKGROUND: Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. METHODS: The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. RESULTS: The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). CONCLUSIONS: RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN.

Translational value of preclinical models for renal denervation: a histological comparison of human versus porcine renal nerve anatomy.

BACKGROUND: Preclinical models have provided key insights into the response of local tissues to radiofrequency (RF) renal denervation (RDN) that is unobtainable from human studies. However, the anatomic translatability of these models to the procedure in humans is incompletely understood.  Aims: We aimed to compare the renal arterial anatomy in normotensive pigs treated with RF-RDN to that of human cadavers to evaluate the suitability of normotensive pigs for determining the safety of RF-RDN. METHODS: Histopathologic analyses were performed on RF-treated renal arteries in a porcine model and untreated control renal arteries. Similar analyses were performed on untreated renal arteries from human cadavers.  Results: In both human and porcine renal arteries, the median number of nerves was lower in the more distal sections (the numbers in the proximal, middle, distal, 1st bifurcation, and 2nd bifurcation sections were 65, 58, 47, 22.5, and 14.7 in humans, respectively, and 39, 26, 29, 16.5, and 9.3 in the porcine models, respectively). Renal nerves were common in the regions between arteries and adjacent veins, but only 3% and 13% of the renal nerves in humans and pigs, respectively, were located behind the renal vein. The semiquantitative score of RF-induced renal arterial nerve necrosis was significantly greater at 7 days than 28 days (0.98 vs 0.75; p=0.01), and injury to surrounding organs was rarely observed. CONCLUSIONS: The distribution of nerve tissue and the relative distribution of extravascular anatomic structures along the renal artery was similar between humans and pigs, which validates the translational value of the normotensive porcine model for RDN.

Histological evidence supporting the durability of successful radiofrequency renal denervation in a normotensive porcine model.

BACKGROUND: Sustained blood pressure reductions after radiofrequency (RF) renal denervation (RDN) have been reported to 3 years in patients with uncontrolled hypertension. However, mechanistic data to support procedural durability are lacking. We aimed to quantify the long-term nerve anatomic and functional effects of RF RDN in a preclinical model. METHODS: Bilateral RF RDN was performed in 20 normotensive swine. Renal tissue samples were obtained in the RDN-treated groups at 7 ( n  = 6), 28 ( n  = 6), and 180 days ( n  = 8) postprocedure for quantification of cortical norepinephrine (NE) levels and renal cortical axon density. Tissue fibrosis, necrosis and downstream nerve fiber atrophy (axonal loss) were also scored for each sample. Three additional untreated groups ( n  = 6, n  = 6 and n  = 8, respectively) served as control. RESULTS: Pathologic nerve changes were characterized by necrosis in the ablated region at 7 days that partially resolved by 28 days and fully resolved at 180 days. Axonal loss was apparent within and downstream to the ablation regions and was evident at 7, 28 and 180 days in the main vessel and branch vessels. Consequently, renal cortical axon density and corresponding cortical NE levels were significantly reduced at 7 days in the RDN vs. control group and remained suppressed at 180 days. CONCLUSIONS: Reductions in renal NE, cortical axon density and downstream axonal loss caused by axonal destruction persisted through 180 days post-RDN in a normotensive swine model. These results suggest functional nerve regrowth after RF RDN is unlikely and support published clinical evidence that the procedure results in durable blood pressure reduction.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction in isolated renal artery.

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) repressively regulates protein translation through phosphorylating eEF2. We previously showed that expression and activity of eEF2K are increased in isolated mesenteric arteries from spontaneously hypertensive rats (SHR) contributing to development of essential hypertension. Furthermore, we have recently shown that 7-Amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide (A484954), a selective eEF2K inhibitor, induces endothelium-dependent relaxation in isolated mesenteric arteries from SHR inducing an antihypertensive effect. In order to test the hypothesis that inhibition of eEF2K activity induces vasodilatation by suppressing sympathetic nerve activity, we examined the effects of A484954 on perivascular sympathetic nerve stimulation-induced contraction in isolated renal artery from normotensive and hypertensive rats. Electrodes were placed near the isolated renal arteries that were applied with transmural nerve stimulation (TNS). Then, contraction of the arteries was isometrically measured. A484954 inhibited TNS-induced contraction. The A484954-mediated inhibition of TNS-induced contraction was significantly prevented by NG-nitro-L-arginine methyl ester. In SHR isolated renal artery, TNS-induced contraction was enhanced compared with normotensive Wistar rats. Furthermore, A484954-mediated inhibition of TNS-induced contraction in SHR was enhanced compared with Wistar rats. In conclusion, this study demonstrates for the first time that A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction at least in part perhaps through nitric oxide (NO) release from NO-operating nerve.