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Background-Hypertension is associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. We investigated the effect of catheter-based renal sympathetic denervation on glucose metabolism and blood pressure control in patients with resistant hypertension. Methods and Results-We enrolled 50 patients with therapy-resistant hypertension. Thirty-seven patients underwent bilateral catheter-based renal denervation, and 13 patients were assigned to a control group. Systolic and diastolic blood pressures, fasting glucose, insulin, C peptide, hemoglobin A 1c , calculated insulin sensitivity (homeostasis model assessment-insulin resistance), and glucose levels during oral glucose tolerance test were measured before and 1 and 3 months after treatment. Mean office blood pressure at baseline was 178/96Ϯ3/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by Ϫ28/Ϫ10 mm Hg (PϽ0.001) and Ϫ32/Ϫ12 mm Hg (PϽ0.001), respectively, in the treatment group, without changes in concurrent antihypertensive treatment. Three months after renal denervation, fasting glucose was reduced from 118Ϯ3.4 to 108Ϯ3.8 mg/dL (Pϭ0.039). Insulin levels were decreased from 20.8Ϯ3.0 to 9.3Ϯ2.5 IU/mL (Pϭ0.006) and C-peptide levels from 5.3Ϯ0.6 to 3.0Ϯ0.9 ng/mL (Pϭ0.002). After 3 months, homeostasis model assessment-insulin resistance decreased from 6.0Ϯ0.9 to 2.4Ϯ0.8 (Pϭ0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL (Pϭ0.012). There were no significant changes in blood pressure or metabolic markers in the control group. Conclusions-Renal denervation improves glucose metabolism and insulin sensitivity in addition to a significantly reducing blood pressure. However, this improvement appeared to be unrelated to changes in drug treatment. This novel procedure may therefore provide protection in patients with resistant hypertension and metabolic disorders at high cardiovascular risk. Clinical Trial Registration-URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00664638 and NCT00888433.

Abstract-Percutaneous renal sympathetic denervation by radiofrequency energy has been reported to reduce blood pressure (BP) by the reduction of renal sympathetic efferent and afferent signaling. We evaluated the effects of this procedure on BP and sleep apnea severity in patients with resistant hypertension and sleep apnea. We studied 10 patients with refractory hypertension and sleep apnea (7 men and 3 women; median age: 49.5 years) who underwent renal denervation and completed 3-month and 6-month follow-up evaluations, including polysomnography and selected blood chemistries, and BP measurements. Antihypertensive regimens were not changed during the 6 months of follow-up. Three and 6 months after the denervation, decreases in office systolic and diastolic BPs were observed (median: Ϫ34/Ϫ13 mm Hg for systolic and diastolic BPs at 6 months; both PϽ0.01). Significant decreases were also observed in plasma glucose concentration 2 hours after glucose administration (median: 7.0 versus 6.4 mmol/L; Pϭ0.05) and in hemoglobin A1C level (median: 6.1% versus 5.6%; PϽ0.05) at 6 months, as well as a decrease in apnea-hypopnea index at 6 months after renal denervation (median: 16.3 versus 4.5 events per hour; Pϭ0.059). In conclusion, catheter-based renal sympathetic denervation lowered BP in patients with refractory hypertension and obstructive sleep apnea, which was accompanied by improvement of sleep apnea severity. Interestingly, there are also accompanying improvements in glucose tolerance. Renal sympathetic denervation may conceivably be a potentially useful option for patients with comorbid refractory hypertension, glucose intolerance, and obstructive sleep apnea, although further studies are needed to confirm these proof-of-concept data. (Hypertension. 2011;58:559-565.)

Sympathetic activation contributes to the progression of CKD and is associated with adverse cardiovascular outcomes. Ablation of renal sympathetic nerves reduces sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function, but whether this approach is safe and effective in patients with an estimated GFR (eGFR) , 45 ml/min per 1.73 m 2 is unknown. We performed bilateral renal denervation in 15 patients with resistant hypertension and stage 3-4 CKD (mean eGFR, 31 ml/min per 1.73 m 2 ). We used CO 2 angiography in six patients to minimize exposure to contrast agents.Estimated GFR remained unchanged after the procedure, irrespective of the use of CO 2 angiography. Mean baseline BP 6 SD was 174622/91616 mmHg despite the use of 5.661.3 antihypertensive drugs. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were 234/214, 225/211, 232/215, and 233/219 mmHg, respectively. Night-time ambulatory BP significantly decreased (P,0.05), restoring a more physiologic dipping pattern. In conclusion, this study suggests a favorable short-term safety profile and beneficial BP effects of catheter-based renal nerve ablation in patients with stage 3-4 CKD and resistant hypertension.

for the Symplicity HTN-2 Investigators Background-Renal sympathetic nerve activation contributes to the pathogenesis of hypertension. Symplicity HTN-2, a multicenter, randomized trial, demonstrated that catheter-based renal denervation produced significant blood pressure lowering in treatment-resistant patients at 6 months after the procedure compared with control, medication-only patients.Longer-term follow-up, including 6-month crossover results, is now presented. Methods and Results-Eligible patients were on Ն3 antihypertensive drugs and had a baseline systolic blood pressure Ն160 mm Hg (Ն150 mm Hg for type 2 diabetics). After the 6-month primary end point was met, renal denervation in control patients was permitted. One-year results on patients randomized to immediate renal denervation (nϭ47) and 6-month postprocedure results for crossover patients are presented. At 12 months after the procedure, the mean fall in office systolic blood pressure in the initial renal denervation group (Ϫ28.1 mm Hg; 95% confidence interval, Ϫ35.4 to Ϫ20.7; PϽ0.001) was similar to the 6-month fall (Ϫ31.7 mm Hg; 95% confidence interval, Ϫ38.3 to Ϫ25.0; Pϭ0.16 versus 6-month change). The mean systolic blood pressure of the crossover group 6 months after the procedure was significantly lowered (from 190.0Ϯ19.6 to 166.3Ϯ24.7 mm Hg; change, Ϫ23.7Ϯ27.5; PϽ0.001). In the crossover group, there was 1 renal artery dissection during guide catheter insertion, before denervation, corrected by renal artery stenting, and 1 hypotensive episode, which resolved with medication adjustment. Conclusions-Control patients who crossed over to renal denervation with the Symplicity system had a significant drop in blood pressure similar to that observed in patients receiving immediate denervation. Renal denervation provides safe and sustained reduction of blood pressure to 1 year. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00888433.

SummaryAnimal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney’s somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics—insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders.