Objectives: Noradrenaline released from sympathetic nerves is rapidly inactivated via the action of the noradrenaline transporter (NET). We aimed to determine whether a single nucleotide polymorphism (SNP) in the NET gene, rs7194256, was associated with blood pressure and plasma noradrenaline concentration in patients with resistant hypertension. Methods: Ninety-two consecutive patients with resistant hypertension participated in this study (age 62 ± 1.3 years, BMI 32 ± 0.6 kg/m2, mean ± SEM). Blood pressure was assessed using 24-h ambulatory blood pressure monitoring. Genotyping of rs7194256 (C/T) was performed using a predeveloped TaqMan SNP Genotyping Assay. Plasma catecholamines were analyzed using high-performance liquid chromatography. Results: There were no differences in anthropometric measures between those carrying a T allele or the CC genotype. Patients carrying a T allele had significantly higher SBP: 24-h mean 148 ± 2.6 vs. 140 ± 2.4; 24-h max 189 ± 3.2 vs. 179 ± 2.6; 24-h min 114 ± 3.0 vs. 105 ± 2.3; night mean 141 ± 3.0 vs. 131 ± 2.5; night max 170 ± 3.6 vs. 159 ± 3.1; night min 118 ± 3.4 vs. 109 ± 2.4 (all P < 0.05). T-allele carriers had a significantly higher arterial noradrenaline concentration: 573 ± 53 vs. 377 ± 35 pg/ml (P = 0.002) and lower ratio of the intraneuronal noradrenaline metabolite, 3,4-dihydroxyphenylglycol, to noradrenaline (3.01 ± 0.4 vs. 4.08 ± 0.3 pg/ml; P = 0.024). Conclusion: A SNP in the NET gene in patients with resistant hypertension is associated with higher plasma noradrenaline concentration and elevated SBP. Impaired NET function may be a contributor to the pronounced activation of the sympathetic nervous system characteristic of patients with resistant hypertension.

Objective: The reported variability in the BP response to renal denervation (RDN) has limited its clinical application. A selection of inappropriate patient cohorts (pathophysiology failure) and the inability to confirm that sufficient renal denervation has actually been achieved (technical failure) represent major obstacles. Here, we aimed to assess whether changes in the plasma concentration of chromogranin A (ChrA), a sympathetic nerve vesicular protein, could predict the blood pressure response to RDN. Design and method: Thirty one consecutive patients with resistant hypertension (65% males, age 61.7 ± 1.7 years, mean ± SEM) who underwent RDN (Symplicity® catheter) were included in this study. We analysed plasma concentrations of ChrA by ELISA. Samples from renal vein and renal artery were taken prior to (T0) and immediately after (T1) RDN. Associations between ChrA concentrations and venous and arterial noradrenaline (NA) concentrations, as well as NA spillover were analysed. Automated office systolic (SBP) and diastolic blood pressure (DBP) measurements were obtained before (T0) and 3 months (M3) after RDN using the Omron HEM-907 monitor. Results: Office BP decreased significantly at M3: SBP: 166.9 ± 3.95 vs 149.8 ± 5.43 mmHg (p = 0.0001), DBP: 89.9 ± 3.06 vs 84.5 ± 3.4 mmHg (p = 0.0045). Arterial ChrA at T0 was correlated with the change in SBP from baseline to M3 (T0-M3) (r = 0.45, p = 0.015). At T0, the arterio-venous ChrA gradient was correlated with SBP change (r = 0.43, p = 0.02). At T1, this gradient was correlated with SBP (r = 0.38, p = 0.04) and DBP change (r = 0.34, p = 0.066). The delta (T0-T1) arterial ChrA was inversely correlated with the DBP change at M3 (T0-M3) (r = −0.50, p = 0.006) but not with SBP. No correlation was found for NA and NA spillover with blood pressure change. These results suggest: 1) higher arterial ChrA concentrations at baseline predicted a more pronounced BP decrease in response to RDN, 2) an increase of ChrA after RDN, potentially explained by the release of the ChrA contained in sympathetic axons, predicted the DBP decrease. It means that an acute change of ChrA could help to confirm the success of the procedure. Figure. No caption available. Conclusions: ChrA might represent a predictor of BP response to RDN at M3. Further studies are needed to confirm these results.

Renal denervation (RDN) has been shown in several studies to reduce blood pressure (BP) in patients with resistant hypertension (RH). Data on potential biomarkers associated with BP changes remain scarce. We evaluated whether soluble vascular endothelial growth factor receptor (sVEGFR-1) is affected by the procedure. A total of 57 patients with RH participated in this study. BP and heart rate were recorded at baseline and at 3 months follow-up, at which time blood samples were collected to determine the levels of sVEGFR-1, VEGF-A, VEGF-C, nitric oxide (NO), soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1. None of the biomarkers had a predictive value that could identify responders vs non-responders to RDN. However, sVEGFR-1 concentration was dramatically reduced after RDN (5913±385 vs 280±57 pg ml−1, P<0.001). At the same time VEGF-A levels were significantly increased (10.0±3.0 vs 55.5±7.9 pg ml−1, P<0.001), without significant changes in VEGF-C. NO levels were significantly increased after RDN in the whole group (82.6±6.2 vs 106.9±7.8 μM, P=0.021). Interestingly, the elevation in NO levels at 3 months was only seen in patients who demonstrated a reduction in systolic BP of ⩾10 mm Hg (78.9±8.3 vs 111.6±11.7 μM, P=0.018). We report a significant reduction in sVEGFR-1 levels after RDN procedure, which was accompanied by a significant increase in VEGF-A concentration as well as NO. Changes in plasma cytokines were not quantitatively linked to magnitude of BP reduction. An RDN-induced reduction in sVEGFR-1 plasma levels and increase in VEGF-A would raise the VEGF-A/sVEGFR-1 ratio, thereby increasing VEGF-A bioavailability to act on its full-length receptor and may contribute to the BP-lowering effect potentially via NO-mediated pathways.

Background: Over-activation of renal sympathetic nervous system and low-grade systemic inflammation are thought to be common features of hypertension. Renal Denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been investigated. Aim: To determine the effect of RDN-induced sympathetic inhibition on monocyte activation and systemic inflammation in hypertensive patients. Methods: Peripheral blood was obtained from 42 patients who underwent RDN for uncontrolled blood pressure (BP) at baseline, at 3 months and 6 months post-procedure. Ambulatory BP, overall activation status of monocyte as well as monocyte subsets and inflammatory markers were assessed at each time point. Results: RDN significantly lowered 24-hour ambulatory BP at 3 months (150.5/81.0 mmHg to 144.7/77.9 mmHg), which was sustained at 6 months (144.7/78.6 mmHg). The overall monocyte activation was significantly decreased (3 months, 4079.4 MFI to 3182.0 MFI; 6 months, 3457.62 MFI) post-RDN, specifically in the subset of classical monocytes (6 months, 4696.8 MFI to 3958.8 MFI). In line with this, reduction of several inflammatory markers were observed, including monocyte-platelet aggregates at 3 months (34% [680 of 2000 monocyte events] to 11.85% [237 of 2000 monocyte events]) and plasma levels of MCP-1 (3 months, 144.9 pg/ml to 100.1 pg/ml; 6 months, 122.2 pg/ml), IL-1β (3 months, 18.3 pg/ml to 10.8 pg/ml; 6 months, 12.2 pg/ml), TNF-α (3 months, 167.5 pg/ml to 78.4 pg/ml; 6 months, 111.1 pg/ml), IL-12 (3 months, 59.8 pg/ml to 9.9 pg/ml; 6 months, 21.4 pg/ml) and IL-6 (3 months, 2.4 pg/ml to 1.5pg/ml; 6 months, 1.9 pg/ml). A positive correlation was observed between baseline muscle sympathetic nerve activity and monocyte activation (R=0.62) and changes observed at both time points (3 months, R=0.63; 6 months, R=0.88) post-procedure. Conclusions: Inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other circulating inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN.

Objective: We have previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. Obesity also contributes to hypertension. A number of adipocyte-derived factors (collectively termed ‘adipokines’) have been implicated in BP control. The aim of this study was to examine the effect of RDN on adipokines. In particular, whether BP reduction, associated with RDN treatment, has a favourable outcome on adipokine profile in patients with resistant hypertension (RH). Design and method: Fifty seven patients with RH undergoing RDN have been recruited for the study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m2, mean ± SEM). At recruitment the patients were on an average of 4.8 ± 2.1 antihypertensive drugs and were asked to refrain from changing their medication regimen for the duration of the study. Automated seated office BP measurements were taken with an Omron HEM-705 monitor at baseline and 3 months follow up visit. Leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were measured in plasma at baseline and 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight and heart rate remained unchanged. There were no significant differences in plasma leptin levels post RDN. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs 0.47 ± 0.04 mEq/l, p < 0.001). While there were no changes in resistin, adiponectin concentration was significantly higher after RDN (5654 ± 800 vs 6644 ± 967 ng/ml, p = 0.024). Conclusions: We have previously shown a decrease in BP following RDN. This is the first study to demonstrate that RDN is associated with potentially beneficial effects on the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via metabolic pathways.

Background: Over-activation of renal sympathetic nervous system is a common feature of hypertension. In addition, inflammatory innate immune cells such as monocytes have been shown to be elevated and associated with low-grade systemic inflammation. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension; however its effect on systemic inflammation has not been investigated. We developed a single-chain antibody (MAN-1) that detects monocyte activation by targeting the conformational change of integrin αмβ2 (CD11b/CD18). Aim: To determine whether RDN induced reduction in sympathetic nerve activity affects monocyte activation and inflammation in patients with hypertension. Methods: Forty hypertensive patients were recruited and peripheral blood was obtained before and after RDN. Monocyte and monocyte subset activation, inflammatory markers and ambulatory blood pressure were measured at baseline and at 3 and 6 months after RDN. Results: MAN-1 binding to monocytes significantly decreased at 3 months (p<0.01) and 6 months (p<0.01), indicative of a reduction in monocyte activation. In particular, classical monocyte subset activation was reduced at 6 months (p<0.05) after RDN. Monocyte-Platelet Aggregates were reduced at 3 months (p<0.01) but not at 6 months (p=0.1387). Plasma levels of MCP-1 (3 months p<0.0001; 6 months p=0.0747) and IL-1β (3 months p<0.05; 6 months p=0.2005) were also reduced after RDN. The ambulatory blood pressure was reduced from 152/81mmHg to 146/79mmHg (p<0.05). Conclusion: RDN induced reduction in renal sympathetic nerve activity is associated with reduced monocyte activation and inflammation in hypertensive patients.

BackgroundRenal denervation (RDN) has been shown to reduce blood pressure (BP), muscle sympathetic nerve activity (MSNA) and target organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The safety and efficacy of RDN in patients with multiple renal arteries remains unclear.MethodsWe measured office and 24-hour BP at baseline, 3 and 6months following RDN in 91 patients with RH, including 65 patients with single renal arteries bilaterally (group 1), 16 patients with dual renal arteries on either one or both sides (group 2) and 10 patients with other anatomical constellations or structural abnormalities (group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up.ResultsRDN significantly reduced office and daytime SBP in group 1 at both 3 and 6months follow-up (P<0.001) but not in groups 2 and 3. Similarly, a significant reduction in resting baseline MSNA was only observed in group 1 (P<0.05). There was no deterioration in kidney function in any group.ConclusionWhile RDN can be performed safely irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities is associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with RH. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was trend towards a greater BP reduction. Insufficient renal sympathetic nerve ablation may account for these differences.

Objective: Renal denervation (RDN) decreases blood pressure (BP), muscle sympathetic nerve activity (MSNA) and attenuates hypertension-induced organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The BP response to RDN and safety of RDN in patients with multiple renal arteries remains unclear. Design and method: This study examined office and 24-hour BP at baseline, 3 and 6 months following RDN in 91 patients with RH including 65 patients with single renal arteries bilaterally (Group 1), 16 patients with dual renal arteries on either one or both sides (Group 2) and 10 patients with other anatomical constellations (Group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up. Results: RDN significantly decreased office and daytime SBP in group 1 at 3 and 6 month follow-up (P < 0.001). In group 2, RDN decreased daytime SBP (P < 0.05) at 3 month follow-up. Group 3 decreased office SBP (P = 0.05), mean and night-time 24-hour SBP (P = 0.04) from baseline to follow-up. When patients in group 2 with dual renal arteries on either sides were categorized according to the left or right sides, there was a reduction in daytime SBP at 3 (P = 0.006) and 6 months (P = 0.02) post procedure in patients with dual renal arteries on the left and single renal artery on the right sides. A patient who received RDN in all 3 arteries (two right renal arteries, single left renal artery) substantially improved BP control. RDN significantly reduced MSNA in group 1 (P < 0.05) and individuals in group 3 but not in group 2. There was no deterioration in kidney function in either group. Conclusions: While RDN can safely be performed irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities appears to be associated with a more pronounced BP and MSNA reduction than the presence of dual renal arteries in patients with RH. Nevertheless, when patients with dual renal arteries received RDN in all arteries there was trend towards a greater BP reduction. Insufficient sympathetic renal nerve ablation may account for these differences.

Hypertension is an important risk factor in the development and progression of cardiovascular disease. Renal denervation (RDN) has been shown to reduce blood pressure (BP) and muscle sympathetic nerve activity in patients with resistant hypertension (RH) [ 1 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. Lancet. 2009; 373: 1275-1281 Abstract Full Text Full Text PDF PubMed Scopus (1763) Google Scholar , 2 Symplicity H.T.N.I. Esler M.D. Krum H. et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. Lancet. 2010; 376: 1903-1909 Abstract Full Text Full Text PDF PubMed Scopus (1851) Google Scholar ]. Irrespective of the effects of RDN on BP, there is little data to date to describe the impact of this procedure on other systems and organs.

Renal denervation (RDN) is associated with a sustained blood pressure (BP) reduction and inhibition of muscle sympathetic nerve activity (MSNA) in resistant hypertension (RH). The magnitude of the BP response to RDN varies between patients. This study examined whether RH patients treated with the centrally acting sympatholytic agent moxonidine (RH+MOX) may display a different response to RDN compared to patients not taking moxonidine (RH−MOX). Office BP was obtained at baseline, 3, 6 months after RDN in 33 RH+MOX (age: 61 ± 2 yrs; BMI 33 ± 1 kg/m2) and 32 RH-MOX patients (age: 61 ± 1 yrs; BMI 33 ± 1 kg/m2, mean ± SEM). MSNA was available from 18 RH+MOX and 13 RH-MOX at baseline, 3, 6 month follow-up. Baseline BP was 171/94 ± 3/2 mmHg in RH-MOX and 167/87 ± 3/3 mmHg in RH+MOX (p = 0.39 for difference in baseline BP). The change in SBP response to RDN was more pronounced in RH+MOX than in RH-MOX at three (difference between groups: 11.98 ± 2.11 mmHg, p < 0.05) and six month follow-up (19.24 ± 3.11 mmHg; p = 0.002) (group × visit interaction, p = 0.032). Baseline MSNA was similar between the two groups (47 ± 3 bursts/min vs 46 ± 3 bursts/min; p = 0.69). There was a similar reduction in MSNA at three (−5 ± 3 bursts/min vs −5 ± 2 bursts/min) and six months (−5 ± 3 bursts/min vs −4 ± 3 bursts/min) with RDN (p = 0.01 between visits; group × visit interaction p = 0.95). These findings indicate that the BP response to RDN is enhanced in patients receiving the centrally acting sympatholytic agent moxonidine. Whether the sympathetic response to moxonidine could be used as a tool to predict the BP response to RDN merits further investigation.

<正>已有研究证实经皮经导管射频消融去肾交感神经术(renal denervation,RDN)可降低难治性高血压患者血压,减低其肌肉交感神经活性(muscle sympathetic nerve activity,MSNA),而交感神经受抑制的潜在机制尚未可知。该研究旨在探讨RDN对难治性高血压患者血管收缩交感神经元的放电模式是否有特异性影响。方法:入选难治性高血压患者35例,在基线、随访3月时记录其标准诊室血压、单个神经元MSNA和多个神经元MSNA。其中25例患者行RDN(RDN组),其余10例继续原方案治疗(非RDN组)。RDN组和非RDN组患者平均使用(4.8±0.4)和(4.4±0.5)

Renal denervation (RDN) has been shown to reduce blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in resistant hypertension (RH). Whether sustained BP reduction with RDN is associated with concomitant sympathetic inhibition in the long-term is unknown. This study aimed to assess office BP and multi-unit MSNA at baseline and at three, six and 12 months following RDN in 25 patients (age: 59 ± 11years, BMI 32 ± 5 kg/m2, mean ± SD) with RH. Office baseline SBP and DBP averaged 171 ± 22/94 ± 16 mmHg despite the use of an average of 4.6 + 2.3 antihypertensive drugs. Baseline MSNA was 50 ± 11 bursts/min (79 ± 17 bursts/100 heartbeats) which is ∼2–3-fold higher than the levels typically seen in healthy subjects. RDN significantly decreased SBP and DBP by −14.6/−7.3, −19.1/−10.3 and −25.0/−13.5 mmHg (p < 0.001 for both SBP and DBP) at 3, 6 and 12 month follow-up, respectively. MSNA decreased by −9 ± 17, −9 ± 17 and −12 ± 18 bursts/100 heartbeats (p = 0.005) at 3, 6 and 12 months follow-up, respectively. The reduction in MSNA was sustained despite a further gradual fall of BP following RDN. These findings confirm sustained BP lowering after RDN and for the first time demonstrate sustained sympathetic inhibition up to one year post procedure in patients with RH. Our observations support the notion that afferent renal nerves play a critical role in resistant hypertension and demonstrate that these can be targeted therapeutically by RDN. The finding of sustained sympathetic inhibition in association with longer term BP reduction after RDN indicates that the potential re-growth of renal nerves, if any, is not of functional relevance, at least up to one year post-procedure.