Lars Christian Rump

Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.

BACKGROUND Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension. METHODS In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433. FINDINGS 106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment. INTERPRETATION Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients. FUNDING Ardian.

Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes

BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02). CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).

Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension A Pilot Study

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 A1c, 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 178/96±3/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by −28/−10 mm Hg (P<0.001) and −32/−12 mm Hg (P<0.001), respectively, in the treatment group, without changes in concurrent antihypertensive treatment. Three months after renal denervation, fasting glucose was reduced from 118±3.4 to 108±3.8 mg/dL (P=0.039). Insulin levels were decreased from 20.8±3.0 to 9.3±2.5 &mgr;IU/mL (P=0.006) and C-peptide levels from 5.3±0.6 to 3.0±0.9 ng/mL (P=0.002). After 3 months, homeostasis model assessment–insulin resistance decreased from 6.0±0.9 to 2.4±0.8 (P=0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL (P=0.012). 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.

Renal Hemodynamics and Renal Function After Catheter-Based Renal Sympathetic Denervation in Patients With Resistant Hypertension

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg (P for all <0.001), respectively, without significant changes in the control group. SBP reduction after 6 months correlated with SBP baseline values (r=−0.46; P<0.001). There were no renal artery stenoses, dissections, or aneurysms during 6 months of follow-up. Renal resistive index decreased from 0.691±0.01 at baseline to 0.674±0.01 and 0.670±0.01 (P=0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.

Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in Patients with Resistant Hypertension

Background— Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. Methods and Results— A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all <0.001), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (−10.1/−10.2/−11.7 mm Hg, P<0.001), diastolic BP (−4.8/−4.9/−7.4 mm Hg, P<0.001), maximum SBP (−11.7/−10.0/−6.1 mm Hg, P<0.001) and minimum SBP (−6.0/−9.4/−13.1 mm Hg, P<0.001) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response. Conclusions— RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00664638 and NCT00888433.

Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial

BACKGROUND Previous trials have demonstrated clinically significant and durable reductions in arterial pressure from baroreflex activation therapy (BAT), resulting from electrical stimulation of the carotid sinus using a novel implantable device. A second-generation system for delivering BAT, the Barostim neo™ system, has been designed to deliver BAT with a simpler device and implant procedure. METHODS BAT, delivered with the advanced system, was evaluated in a single-arm, open-label study of patients with resistant hypertension, defined as resting systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 medications, including ≥1 diuretic. Stable medical therapy was required for ≥4 weeks before establishing pretreatment baseline by averaging two SBP readings taken ≥24 hours apart. RESULTS Thirty patients enrolled from seven centers in Europe and Canada. From a baseline of 171.7 ± 20.2/99.5 ± 13.9 mm Hg, arterial pressure decreased by 26.0 ± 4.4/12.4 ± 2.5 mm Hg at 6 months. In a subset (n = 6) of patients with prior renal nerve ablation, arterial pressure decreased by 22.3 ± 9.8 mm Hg. Background medical therapy for hypertension was unchanged during follow-up. Three minor procedure-related complications occurred within 30 days of implant. All complications resolved without sequelae. CONCLUSION BAT delivered with the second-generation system significantly lowers blood pressure in resistant hypertension with stable, intensive background medical therapy, consistent with studies of the first-generation system for electrical activation of the baroreflex, and provides a safety profile comparable to a pacemaker.

Cardiovascular and Cerebrovascular Comorbidities of Hypokalemic and Normokalemic Primary Aldosteronism: Results of the German Conn’s Registry

CONTEXT Primary aldosteronism (PA) is associated with vascular end-organ damage. OBJECTIVE Our objective was to evaluate differences regarding comorbidities between the hypokalemic and normokalemic form of PA. DESIGN AND SETTING This was a retrospective cross-sectional study collected from six German centers (German Conns registry) between 1990 and 2007. PATIENTS Of 640 registered patients with PA, 553 patients were analyzed. MAIN OUTCOME MEASURES Comorbidities depending on hypokalemia or normokalemia were examined. RESULTS Of the 553 patients (61 +/- 13 yr, range 13-96), 56.1% had hypokalemic PA. The systolic (164 +/- 29 vs. 155 +/- 27 mm Hg; P < 0.01) and diastolic (96 +/- 18 vs. 93 +/- 15 mm Hg; P < 0.05) blood pressures were significantly higher in hypokalemic patients than in those with the normokalemic variant. The prevalence of cardiovascular events (angina pectoris, myocardial infarction, chronic cardiac insufficiency, coronary angioplasty) was 16.3%. Atrial fibrillation occurred in 7.1% and other atrial or ventricular arrhythmia in 5.2% of the patients. Angina pectoris and chronic cardiac insufficiency were significantly more prevalent in hypokalemic PA (9.0 vs. 2.1%, P < 0.001; 5.5 vs. 2.1%, P < 0.01). Overall, cerebrovascular comorbidities were not different between hypokalemic and normokalemic patients, however, stroke tended to be more prevalent in normokalemic patients. CONCLUSIONS Our data indicate a high prevalence of comorbidities in patients with PA. The hypokalemic variant is defined by a higher morbidity than the normokalemic variant regarding some cardiovascular but not cerebrovascular events. Thus, PA should be sought not only in hypokalemic but also in normokalemic hypertensives because high-excess morbidity occurs in both subgroups.

The Adrenal Vein Sampling International Study (AVIS) for Identifying the Major Subtypes of Primary Aldosteronism

CONTEXT In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.

Secondary rise in blood pressure after renal denervation.

In July, 2011, a 58-year-old man with type II diabetes and hypertension resistant to treatment was referred to our hospital for renal denervation. He had had hypertension for 30 years and his antihypertensive medication dose had been increased over several years. In 2001, he had a minor stroke, and in 2009, a carotid artery stent was implanted. On examination, his blood pressure was 170/90 mm Hg despite treatment with seven antihypertensive drugs (appendix). Resistant hypertension was confi rmed by 24 h ambulatory blood pressure measurement. He also had sleep apnoea which was treated with continuous positive airway pressure therapy. Aldosteronism, phaeochromocytoma, and renal artery stenosis were ruled out. Renal resistive indices (RI) on both sides were similar. Normal renal function with microalbuminuria was present. Magnetic resonance angiography (appendix) done before renal denervation showed early ramifi cation but no relevant stenosis on either side. In August, 2011, six ablations were applied on the left side (three in each branch) and six on the right side, including two at proximal superior positions 4 mm and 9 mm distal to the ostium (fi gure). Ablations were applied in a spiral pattern at a minimum distance of 5 mm. Renal artery alterations were not visible im mediately after denervation. Duplex sonography the next day did not show any abnormalities. 3 months later his blood pressure had decreased to 140/70 mm Hg. A routine follow-up duplex sonography showed turbulences and increased renal blood fl ow velocity on the right side. At this time no diff erences in RI were detectable, excluding