Treatment-resistant Hypertensive Patients Research Articles

Abstract 129: Role Of Human T Cells In Experimental Hypertension And Hypertensive Kidney Damage

Animal studies suggest that adaptive immunity, in particular T cells contribute to the development hypertension. Due to the complex pathophysiological interactions in vivo, the impact of human T cells in the development of hypertension and hypertensive kidney damage is still unknown. To investigate the impact of human T cells, we transferred T cells from treatment resistant hypertensive patients (TRH) and healthy controls (controls) into immunodeficient NOD.Cg-Prkdcscid H2-K1tm1Bpe H2-D1tm1Bpe Il2rgtm1Wjl/SzJ (NSG-(KbDb)null) mice to establish a humanized mouse model. Hypertension was induced by angiotensin (Ang)II (500ng/kg/min) infusion for 14 days. PBMCs from RHT or controls were transferred to NSG-(KbDb) null mice. After ensuring T cell engraftment, blood pressure (BP) was measured by radiotelemetry. At baseline, systolic BP did not differ, however, systolic BP in response to AngII was increased in NSG-(KbDb) null mice receiving PBMCs from TRH compared to controls (week 1: 133±6 vs. 162±3mmHg, p<0.01; week 2: 141±6 vs. 158±7mmHg, n=5-6, p<0.05). Moreover, endothelial-dependant vasorelaxation was significantly impaired in isolated perfused kidneys of NSG-(KbDb) null mice receiving PBMCs from TRH compared to controls. Proportions of effector memory CD4 and Th17 CD4 cells in the spleens and kidneys of NSG-(KbDb) null mice engrafted with PBMCs from TRH were significantly higher compare to controls. Furthermore, renal mRNA expression of TNFα derived from human T cells (p<0.05) and renal perivascular T cell infiltration were significantly higher in NSG-(KbDb) null mice engrafted with PBMCs from TRH compared to controls. Overnight incubation of aortic rings with human TNFα impaired endothelial-dependen vasorelaxation compared to untreated aortic rings (p<0.01). Finally, NSG-(KbDb) null mice engrafted with PBMC from TRH were treated with the TNFα inhibitor etanercept. TNFα inhibition attenuated the systolic BP response to AngII compared to untreated mice (132±1 vs. 160±2mmHg, n=6, p<0.01).The present results suggest that pro-inflammatory cytokines released by T cells from patients with TRH directly influence the development of hypertension and therefore may have a pathophysiological relevance in the genesis of human hypertension.

Quality of life following renal sympathetic denervation in treatment-resistant hypertensive patients: a two-year follow-up study

Objective. Hypertension is a significant health burden. In the last 10 years, renal sympathetic denervation has been tested as a potential treatment option for a select group of patients with treatment-resistant hypertension. The aim of this study was to broadly assess the quality of life in patients undergoing renal sympathetic denervation with two years’ follow-up. Materials and methods. Patients with treatment-resistant hypertension being treated by hypertension specialists were eligible for inclusion in this study. Bilateral renal sympathetic denervation was performed with the Symplicity Catheter System. Quality of life was measured using standardised questionnaires (Short Form 36, 15 D and a single-item question) and an open question before denervation, after six months and after two years. Results. A total of 23 patients were included. The typical participant was male, 53 years, had a mean office blood pressure of 162/108 mmHg, body mass index of 32 kg/m2, and was prescribed 4.8 blood pressure lowering drug classes. At baseline, both physical and mental aspects of quality of life were affected negatively by the treatment-resistant hypertension. Over time, there were modest improvements in quality of life. The largest improvements were seen at six months. Simultaneously, the mean number of blood pressure lowering drug classes was reduced to 4.2. Conclusion. Following renal sympathetic denervation treatment, some aspects of health related quality of life showed an improved trend during follow-up. The observed improvement may reflect the impact of a reduced number of blood pressure lowering drug classes. Clinical Trial Number registered: NCT01630928

MO093: Dietary Sodium Restriction Reduces Nocturnal Blood Pressure in Treatment Resistant Hypertensive Patients

Abstract BACKGROUND AND AIMS High blood pressure (BP) is an essential contributor to the risk of cardiovascular disease (CVD) and death. Hence, diagnosing and treating patients with high BP is paramount if the number of cardiovascular related death should be reduced. High nocturnal BP and blunting of normal nocturnal BP decrease have stronger correlation to the risk of CVD than high day time BP. Lowering nocturnal BP is assumed to reduce the risk of CVD. Patients with treatment resistant hypertension (TRH) represent a subgroup of hypertensive patients characterized by lack of BP control despite antihypertensive treatment. These patients are at particular risk of CVD and target organ damage. Patients with TRH are more likely to experience BP increase as a response to sodium loading than other individuals. Lifestyle modification is an important treatment angle in hypertensive patients. It is, in particular, central to reduce sodium intake, as high sodium intake increases the risk of TRH. Thus, in this study we aimed to analyse if self-performed dietary sodium restriction could be implemented in patients with TRH. Moreover, we aimed to analyse the effect of this attempted restriction on nocturnal BP and 24 h BP, on plasma levels of BNP and nitric oxide, and on body water content. METHOD Patients with TRH from 20 to 70 years with normal renal function were invited for participation in this cross-over interventional study. Patients were screened with 24 h ambulatory BP monitoring initiated after observed intake of usual antihypertensive medication, and they were included if 24 h systolic BP/diastolic BP ≥ 130/80 mmHg. Study participation included two periods of 14 days; a standard period with usual diet and an interventional period with instructed dietary sodium restriction and handed-out sodium-reduced bread. For both periods, all antihypertensive medication was dosed and handed out and ingested in the morning. At the end of each period, patients were examined with 24 h BP monitoring, 24 h urine collection (sodium excretion), blood samples (nitric oxide and BNP) and bioimpedance measurement (body water content). RESULTS Baseline characteristics of the fifteen included patients are shown in Table 1. Eleven of the patients were male. Patients had been treated for hypertension for a mean of 12.5 (7) years and excreted a mean of 11.2 grams of salt at baseline [192 (86) mmol sodium]. All patients but one reduced sodium excretion at follow up. Table 2 shows the effect of sodium restriction on BP, nitric oxide, BNP and body water content. Sodium excretion was reduced to 91 mmol/24 h, which equals 5.3 g of salt. BP (24 h, day and nocturnal) decreased significantly as well as body water content and plasma levels of BNP. These changes were, however, not correlated. Plasma levels of nitric oxide increased, but it was not related to the changes in BP. Nocturnal fraction of 24 h sodium excretion increased after sodium restriction; however, this was not correlated to changes in nocturnal BP. Renal function and urinary potassium excretion both remained unchanged. Four patients experienced side effects; three reported newly onset dizziness at follow-up; two of them had 24 h BP reduction > 10 mmHg systolic. One patient had increased creatinine and potassium at follow-up. CONCLUSION In a population of 15 treatment resistant hypertensive patients, we demonstrated that self-performed dietary sodium restriction could be implemented. Urinary sodium excretion was reduced significantly to 5.3 g/24 h. Nocturnal BP was reduced significantly; dipping status was, however, unchanged. Increased plasma levels of nitric oxide may be evidence of improved endothelial function. Hence, by the local vasodilating effect, NO may be one of the involved mechanisms in BP decrease following a sodium restriction. Reduced extracellular water content and BNP may be other explainable effects of BP reduction after inducing sodium restriction.

Renal nerve stimulation: complete versus incomplete renal sympathetic denervation

Purpose Blood pressure (BP) reduction after renal sympathetic denervation (RDN) is highly variable. Renal nerve stimulation (RNS) can localize sympathetic nerves. The RNS trial aimed to investigate the medium-term BP-lowering effects of the use of RNS during RDN, and explore if RNS can check the completeness of the denervation. Material and methods Forty-four treatment-resistant hypertensive patients were included in the prospective, single-center RNS trial. The primary study endpoint was change in 24-h BP at 6- to 12-month follow-up after RDN. The secondary study endpoints were the acute procedural RNS-induced BP response before and after RDN; number of antihypertensive drugs at follow-up; and the correlation between the RNS-induced BP increase before versus after RDN (delta [Δ] RNS-induced BP). Results Before RDN, the RNS-induced systolic BP rise was 43(±21) mmHg, and decreased to 9(±12) mmHg after RDN (p < 0.001). Mean 24-h systolic/diastolic BP decreased from 147(±12)/82(±11) mmHg at baseline to 135(±11)/76(±10) mmHg (p < 0.001/<0.001) at follow-up (10 [6–12] months), with 1 antihypertensive drug less compared to baseline. The Δ RNS-induced BP and the 24-h BP decrease at follow-up were correlated for systolic (R = 0.44, p = 0.004) and diastolic (R = 0.48, p = 0.003) BP. Patients with ≤0 mmHg residual RNS-induced BP response after RDN had a significant lower mean 24-h systolic BP at follow-up compared to the patients with >0 mmHg residual RNS-induced BP response (126 ± 4 mmHg versus 135 ± 10 mmHg, p = 0.04). 83% of the patients with ≤0 mmHg residual RNS-induced BP response had normal 24-h BP at follow-up, compared to 33% in the patients with >0 mmHg residual RNS-induced BP response (p = 0.023). Conclusion The use of RNS during RDN leads to clinically significant and sustained lowering of 24-h BP with fewer antihypertensive drugs at follow-up. RNS-induced BP changes were correlated with 24-h BP changes at follow-up. Moreover, patients with complete denervation had significant lower BP compared to the patients with incomplete denervation.

DOES ALDOSTERONE VIA MINERALOCORTICOID RECEPTORS AND ENAC PROMOTE INTERLEUKIN-17 PRODUCTION IN LYMPHOCYTES?

Objective: Despite availability of antihypertensive therapeutic strategies, 20% of hypertensive patients remain resistant towards conventional treatment. Studies have shown that interleukin 17 (IL-17) from Th17 lymphocytes may be an important factor in the pathophysiology of hypertension. IL-17 plasma concentration is increased in hypertensive type 2 diabetes (T2D) patients compared to non-hypertensive diabetes patients. In vitro studies have shown the epithelial sodium channel ENaC to be expressed in lymphocytes. Activation of the mineralocorticoid receptor (MR) promotes pro-inflammatory Th17 lymphocyte differentiation in a spironolactone-sensitive way. We therefore hypothesized that aldosterone and ENaC may promote IL-17 production in lymphocytes ex vivo and from T2D hypertensive and kidney transplant patients in vivo. Design and method: Treatment resistant hypertensive T2D patients were included in a randomized double blinded study where patients were allocated to receive either spironolactone or placebo for 16 weeks (n = 116). After a two-week wash-out period the patients were included in an open label non-controlled follow-up study receiving amiloride for 8 weeks (n = 60). In a third randomized double blinded study, kidney transplant patients were allocated to receive either placebo or spironolactone for 1 year (n = 80). Plasma samples were available from all trials before and after intervention. Key cytokines involved in Th17 differentiation (IL-17, IL-6, IL-1β, IL-10, IFN-γ, TNF-α) were measured in plasma samples from the three interventional studies using ELISAs from Mesoscale. Results: Spironolactone intervention in T2D hypertensive patients lead to a decrease in plasma IFN-γ and IL-6. Amiloride intervention in the same patient group showed with a decrease in plasma IL-6 and TNF-α and an increase in IL-10 levels Conclusions: Spironolactone and amiloride treatment of hypertensive and kidney transplant patients had no effect on IL-17 concentrations in plasma. Spironolactone suppressed the cytokines IFN-γ and IL-6, whereas amiloride decreased the levels of IL-6 and TNF-α and cause an increase in the anti-inflammatory cytokine IL-10. Since these are key cytokines of macrophage activation, MR and ENaC may be relevant for monocyte-macrophage activation. Future ex vivo experiments will be performed to elucidate the effect of amiloride and spironolactone on cytokine release from Th17 cells and macrophages.

OP.7A.02] SUSTAINED REDUCTION OF BLOOD PRESSURE WITH BARORECEPTOR ACTIVATION THERAPY

Objective: Baroreflex Activation Therapy (BAT) is a novel technique for treating patients with resistant hypertension. Although short-term studies have demonstrated that BAT lowers blood pressure, long-term results have not yet been reported. The aim of the present study is to assess the long-term efficacy and safety of BAT. Design and method: Long-term follow-up data on blood pressure and heart rate were analyzed from all patients who have been included in one of the three BAT trials that focused on treatment-resistant hypertensive patients. These trials were the US feasibility study, the DEBut-HT trial and the pivotal trial. The first two were non-randomized, observational trials in the US and Europe respectively. In the pivotal trial patients were randomized to either immediate BAT or deferred BAT (six months after implantation). All patients who have received an implant were followed with regular visits. Results: Altogether, 383 patients were available for analysis: 143 of these had completed five years of follow-up and 48 patients had completed six years of follow-up. In the entire cohort, systolic blood pressure fell from 179+24 mmHg to 144+28 mmHg (p < 0.0001) while diastolic pressure dropped from 103+16 mmHg to 85+18 mmHg (p < 0.0001). The data further demonstrate that the greatest fall in pressure already occurs within 6 months following device implant. The blood pressure lowering effect of BAT is greater than average in patients with signs of heart failure, and less than average in patients with isolated systolic hypertension. The percentage of patients in whom systolic blood pressure at the end of follow-up had fallen below 140 mmHg was greatest in those with unilateral right-sided stimulation. In about 25% of patients it was possible to reduce the number of medications from a median of 6 to a median of 3. Temporary side effects, related to either the surgical procedure or to cardiovascular instability, do occur, but they do not require specific measures and resolve over time. Conclusions: After a follow-up of 5 years, BAT is safe and maintains its efficacy for persistent reduction of blood pressure in patients with resistant hypertension.

Sustained Reduction of Blood Pressure With Baroreceptor Activation Therapy: Results of the 6-Year Open Follow-Up.

Baroreflex activation therapy is a novel technique for treating patients with resistant hypertension. Although short-term studies have demonstrated that it lowers blood pressure, long-term results have not yet been reported. The aim of the present study is to assess the long-term efficacy and safety of baroreflex activation therapy. Long-term follow-up data were analyzed from all patients who had been included in 1 of the 3 trials that focused on treatment-resistant hypertensive patients. Altogether, 383 patients were available for analysis: 143 of these had completed 5 years of follow-up and 48 patients had completed 6 years of follow-up. In the entire cohort, office systolic blood pressure fell from 179±24 mm Hg to 144±28 mm Hg (P<0.0001), whereas office diastolic pressure dropped from 103±16 mm Hg to 85±18 mm Hg (P<0.0001). Heart rate fell from 74±15 beats per minute to 71±13 beats per minute (P<0.02). The effect of baroreflex activation therapy is greater than average in patients with signs of heart failure and less than average in patients with isolated systolic hypertension. In ≈25% of patients, it was possible to reduce the number of medications from a median of 6 to a median of 3. Temporary side effects, related to either the surgical procedure or the cardiovascular instability, do occur, but they do not require specific measures and resolve over time.After a follow-up of 6 years, baroreflex activation therapy maintains its efficacy for persistent reduction of office blood pressure in patients with resistant hypertension without major safety issues.

Effects of Renal Denervation Documented in the Austrian National Multicentre Renal Denervation Registry.

Renal denervation (RDN) is a new procedure for treatment-resistant hypertensive patients. In order to monitor all procedures undergone in Austria, the Austrian Society of Hypertension established the investigator-initiated Austrian Transcatheter Renal Denervation (TREND) Registry. From April 2011 to September 2014, 407 procedures in 14 Austrian centres were recorded. At baseline, office and mean 24-h ambulatory blood pressure (ABP) were 171/94 and 151/89 mmHg, respectively, and patients were taking a median of 4 antihypertensive medications. Mean 24-h ABP changes after 2–6 weeks, 3, 6 and 12 months were -11/-6, -8/-4, -8/-5 and -10/-6 mmHg (p<0.05 at all measurements), respectively. The periprocedural complication rate was 2.5%. Incidence of long-term complications during follow-up (median 1 year) was 0.5%. Office BP and ABP responses showed only a weak correlation (Pearson coefficient 0.303). Based on the data from the TREND registry, ambulatory blood pressure monitoring in addition to office BP should be used for patient selection as well as for monitoring response to RDN. Furthermore, criteria for optimal patient selection are suggested.

Acute Response to Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients With Resistant Arterial Hypertension.

Bilateral bipolar electric carotid sinus stimulation acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant arterial hypertension but is no longer available. The second-generation device uses a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We hypothesized that the second-generation device acutely lowers BP and MSNA in treatment-resistant hypertensive patients. Eighteen treatment-resistant hypertensive patients (9 women/9 men; 53±11 years; 33±5 kg/m(2)) on stable medications have been included in the study. We monitored finger and brachial BP, heart rate, and MSNA. Without stimulation, BP was 165±31/91±18 mm Hg, heart rate was 75±17 bpm, and MSNA was 48±14 bursts per minute. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited interindividually variable changes in systolic BP (-16.9±15.0 mm Hg; range, 0.0 to -40.8 mm Hg; P=0.002), heart rate (-3.6±3.6 bpm; P=0.004), and MSNA (-2.0±5.8 bursts per minute; P=0.375). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (systolic BP, -6.3±7.0 mm Hg; range, 2.8 to -14.5 mm Hg; P=0.028 and heart rate, -1.5±2.3 bpm; P=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) were correlated (r(2)=0.329; P=0.025). In our patient cohort, unilateral unipolar electric baroreflex stimulation acutely lowered BP. However, side effects may limit efficacy. The approach should be tested in a controlled comparative study.

Abstract P152: Acute Effect of Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients with Treatment-Resistant Arterial Hypertension

Electrical carotid sinus stimulation has been developed for treatment of resistant arterial hypertension. The first-generation device (Rheos™) relying on bilateral placement of bipolar electrodes acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) but is no longer available. The second-generation device (Neo™) utilizes a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We tested acute effects of the latter on BP and MSNA. We studied 18 treatment-resistant hypertensive patients (9 women, 53±11 years, 34±5 kg/m 2 ) on stable medication who had been implanted with the second-generation device. We assessed acute BP (oscillometry), heart rate (HR, ECG), and MSNA (microneurography) responses to electrical stimulation in the supine position. Without stimulation, BP was 165±31/91±18 mmHg, HR was 75±17 bpm, and MSNA was 48±14 bursts/min. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited variable changes in systolic BP (SBP: -16.9±15.0 mmHg, range: 0.0 to -40.8 mmHg, p=0.002), HR (-3.6±3.6 bpm, p=0.004), and MSNA (-1.9±5.3 bursts/min, p=0.194). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (SBP: -6.3±7.0 mmHg, range: 2.8 to -14.5 mmHg, p=0.028; HR: -1.5±2.3 bpm, p=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) tended to be correlated (r 2 =0.202, p=0.093). In our patient cohort, unilateral unipolar electrical baroreflex stimulation acutely lowered BP. Side effects may limit efficacy. The novel approach should be tested in a controlled comparative study.

Device-based approaches for renal nerve ablation for hypertension and beyond.

Animal and human studies have demonstrated that chronic activation of renal sympathetic nerves is critical in the pathogenesis and perpetuation of treatment-resistant hypertension. Bilateral renal denervation has emerged as a safe and effective, non-pharmacological treatment for resistant hypertension that involves the selective ablation of efferent and afferent renal nerves to lower blood pressure. However, the most recent and largest randomized controlled trial failed to confirm the primacy of renal denervation over a sham procedure, prompting widespread re-evaluation of the therapy's efficacy. Disrupting renal afferent sympathetic signaling to the hypothalamus with renal denervation lowers central sympathetic tone, which has the potential to confer additional clinical benefits beyond blood pressure control. Specifically, there has been substantial interest in the use of renal denervation as either a primary or adjunct therapy in pathological conditions characterized by central sympathetic overactivity such as renal disease, heart failure and metabolic-associated disorders. Recent findings from pre-clinical and proof-of-concept studies appear promising with renal denervation shown to confer cardiovascular and metabolic benefits, largely independent of changes in blood pressure. This review explores the pathological rationale for targeting sympathetic renal nerves for blood pressure control. Latest developments in renal nerve ablation modalities designed to improve procedural success are discussed along with prospective findings on the efficacy of renal denervation to lower blood pressure in treatment-resistant hypertensive patients. Preliminary evidence in support of renal denervation as a possible therapeutic option in disease states characterized by central sympathetic overactivity is also presented.

Role of renal sensory nerves in physiological and pathophysiological conditions.

Whether activation of afferent renal nerves contributes to the regulation of arterial pressure and sodium balance has been long overlooked. In normotensive rats, activating renal mechanosensory nerves decrease efferent renal sympathetic nerve activity (ERSNA) and increase urinary sodium excretion, an inhibitory renorenal reflex. There is an interaction between efferent and afferent renal nerves, whereby increases in ERSNA increase afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes to maintain low ERSNA to minimize sodium retention. High-sodium diet enhances the responsiveness of the renal sensory nerves, while low dietary sodium reduces the responsiveness of the renal sensory nerves, thus producing physiologically appropriate responses to maintain sodium balance. Increased renal ANG II reduces the responsiveness of the renal sensory nerves in physiological and pathophysiological conditions, including hypertension, congestive heart failure, and ischemia-induced acute renal failure. Impairment of inhibitory renorenal reflexes in these pathological states would contribute to the hypertension and sodium retention. When the inhibitory renorenal reflexes are suppressed, excitatory reflexes may prevail. Renal denervation reduces arterial pressure in experimental hypertension and in treatment-resistant hypertensive patients. The fall in arterial pressure is associated with a fall in muscle sympathetic nerve activity, suggesting that increased ARNA contributes to increased arterial pressure in these patients. Although removal of both renal sympathetic and afferent renal sensory nerves most likely contributes to the arterial pressure reduction initially, additional mechanisms may be involved in long-term arterial pressure reduction since sympathetic and sensory nerves reinnervate renal tissue in a similar time-dependent fashion following renal denervation.

Bilateral or unilateral stimulation for baroreflex activation therapy.

Previous trials have shown that in patients with resistant hypertension device-based baroreflex activation therapy (BAT) can substantially reduce blood pressure. However, the fact that electrodes had to be implanted bilaterally may be a drawback for further development of the technique. In this study, we explored whether unilateral stimulation would produce comparable results as bilateral stimulation. In the Pivotal trial, treatment-resistant hypertensive patients were randomized to receive either immediate BAT or deferred BAT, that is, 6 months after implantation. We adjusted stimulation parameters individually so as to provide optimal baroreflex activation. Unilateral stimulation was applied unless bilateral stimulation resulted in a greater blood pressure reduction. When we pooled the 6-month data for the group with immediate BAT and the 12-month data for the group with deferred BAT, a total of 215 patients had been stimulated on one side only (127 at the right side and 88 at the left side), whereas 80 patients had been stimulated bilaterally. Although blood pressure and heart rate did not differ between the 2 groups at baseline, all these variables were significantly lower in the unilateral than in the bilateral group after the 6-month period. When we compared the effect of right-sided stimulation with those of either left-sided or bilateral stimulation, we found right-sided stimulation to be the most effective. We conclude that unilateral and in particular right-sided BAT has a more profound effect on blood pressure than bilateral or left-sided BAT. http://www.clinicaltrials.gov. Unique identifier: NCT00442286.

Role of the Sympathetic Nervous Activity in Hypertension-Update in 2013

Many reviews focused on the role of sympathetic nervous activity in hypertension have been published. Recently a new treatment, radiofrequency renal denervation for the treatment of resistant hypertension has been developed and examined in several clinical trials such as the Symplicity HTN and EnligHTN studies. In the Symplicity HTN-1 study the efficacy for lowering blood pressure remained satisfactory at 3 years follow up and many ancillary ameliorative effects have been reported including cardiovascular, psychosocial, and metabolic effects. The purpose of this review is to provide the current findings on the relationships between sympathetic nerve activity and hypertension, especially focus on the importance of renal sympathetic nervous activity for the onset and development of hypertension. In addition, the methods to assess sympathetic nervous activity are reviewed. The renal denervastion was developed for the treatment-resistant hypertensive patients, and excessive confidence of the efficacy and safety existed by the end of 2013, although several issues on the efficacy and safety were reported in 2014. Furthermore, long-term efficacy and impact on renal function have been unclear. Those issues have to be clear for clinical usage. This review will also address the recent data from the renal denervation. Keywords: Hypertension, sympathetic nervous activity, symplicity-1 study.

Rationale and design of the Investigator-Steered Project on intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) trial

The SYMPLICITY studies showed that renal denervation (RDN) is feasible as novel treatment for resistant hypertension. However, RDN is a costly and invasive procedure, the long-term efficacy and safety of which has not yet been proven. Therefore, we designed the INSPiRED trial to compare the blood pressure lowering efficacy and safety of RDN vs usual medical therapy. INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert hypertension centres in Belgium. Eligible patients, aged 20–69 years old, have a 24-h ambulatory blood pressure of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTNTM, SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic blood pressure and in glomerular filtration rate as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. Follow-up will continue up to 36 months after randomization. INSPiRED is powered to demonstrate a 10-mmHg difference in systolic blood pressure between randomized groups with a two-sided p-value of 0.01 and 90% power. It will generate long-term efficacy and safety data, identify the subset of treatment-resistant hypertensive patients responsive to RDN, provide information on cost-effectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers.Trial registration: ClinicalTrials.gov identifier: NCT01505010.

Improvement of albuminuria after renal denervation

The primary objective of this study was the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in treatment-resistant hypertensive patients. In addition, patients were stratified according their UACR at baseline into micro- (30-300 mg/g, n=37) and macroalbuminuria (≥ 300 mg/g, <2,200 mg/g, n=22). Increased albuminuria indicates cardiovascular and renal damage in hypertension. RDN emerged as an innovative interventional approach to reduce blood pressure (BP) and may thus reduce albumin urinary excretion. Fifty-nine treatment-resistant hypertensive patients with elevated UACR at baseline underwent catheter-based RDN using the Symplicity Flex™ catheter (Medtronic Inc., Santa Rosa, CA). In the whole and pre-specified subgroups both office and 24-h ambulatory BP were significantly reduced 6 months after RDN. In parallel, a significant reduction in UACR occurred in all patients (160 (65-496) versus 89 (29-319) mg/g creatinine, p<0.001) and in both subgroups (microalbuminuria: 83 (49-153) versus 58 (17-113) mg/g creatinine, p=0.001; macroalbuminuria: (536 (434-1483) versus 478 (109-1080) mg/g creatinine, p<0.001). In accordance, the prevalence of micro- and macroalbuminuria decreased significantly. Regression analysis revealed a modest positive relationship between the decrease of UACR and the fall of systolic BP (β=0.340, p=0.039) independent of renal function. Renal function remained unchanged after RDN. In summary, following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria decreased in treatment-resistant hypertensive patients. Since albuminuria is an independent renal and cardiovascular risk factor, our findings suggest a reduction of renal and cardiovascular risk in these patients.

Blood pressure and neurohormonal responses to renal nerve ablation in treatment-resistant hypertension

Catheter-based renal nerve ablation is a novel therapy for treatment-resistant hypertension. Although the precise mechanism is unknown, a reduction in global sympathetic tone and renal sympathetic tone, potentially resulting in a decrease in renin, may account for the antihypertensive effect. In 17 patients (mean age 51.2 ± 9.4 years) with treatment-resistant hypertension (antihypertensive drugs 4.7 ± 1.3), office and ambulatory blood pressure (BP) measurements and circulating concentrations of catecholamines, renin, aldosterone and endothelin-1 were measured at baseline and 6 and 12 months after ablation. Office BP was measured for 1 h at 5-min intervals using an automatic device. Office BP (164.7 ± 27.7/102.3 ± 19.3 mmHg) decreased by 5.7 ± 18.8 mmHg (P = 0.11) systolic and by 2.6 ± 10.7 (P = 0.33) mmHg diastolic after 6 months, whereas after 12 months decreases were 12.7 ± 16.0 mmHg (P = 0.007) and 7.3 ± 11.9 mmHg (P = 0.02). Heart rate, 24-h (151.8 ± 12.6/94.2 ± 10.3 mmHg) and day and night ambulatory BP did not change, after either 6 or 12 months. Of the neurohormones, only plasma noradrenaline (397 pg/ml, interquartile range 268-461 pg/ml) decreased by 128 ± 167 pg/ml (P = 0.008) after 6 months, whereas other neurohormones remained unchanged. Forty-seven percent of patients had at least 10 mmHg decrease in 24-h ambulatory SBP. In these responders, office and ambulatory BP tended to be higher than in nonresponders, but neurohormones or changes after ablation between responders and nonresponders did not differ. Renal nerve ablation in treatment-resistant hypertensive patients had a moderate effect on office BP and is associated with a decrease in plasma noradrenaline but not in renin. The absent decrease in renin may imply that the intensity of efferent renal denervation achieved with the number of ablations applied was insufficient.

Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe

Scanty information is available on the clinical characteristics of resistant hypertension in Central and East European countries. The Blood Pressure (BP) control rate and CArdiovascular Risk profilE (BP-CARE) study allowed us to assess the prevalence and the main clinical features of resistant hypertension in this population. The study was carried out in 1312 treated hypertensive patients living in nine Central and East European countries. Four hundred and twenty-three patients had apparent resistant hypertension, of whom 168 had pseudo-resistant hypertension (noncompliant/white-coat) and 255 were true treatment-resistant hypertension patients (TRH). Clinical BP values in TRH amounted to 157.4±16.9/91.8±10.0 mmHg despite the daily use of 3.6±0.7 drugs. Their 24-h BP values were 149.5±16.5/97.5±9.8 mmHg. Compared to controlled hypertensive patients (n=368) and uncontrolled nonresistant hypertensive patients (n=521), TRH were older with a greater prevalence of women. They showed a higher rate of previous cardiovascular events and a very high cardiovascular risk profile. Estimated glomerular filtration rate was significantly lower in TRH as compared to controlled hypertensive patients and uncontrolled nonresistant hypertensive patients. Overall, target organ damage was more frequently detected in TRH than in controlled hypertensive patients and uncontrolled nonresistant hypertensive patients. The factor most frequently associated with TRH was severity of hypertension followed by age, total cholesterol, BMI and history of heart failure. The present study provides evidence that the prevalence of TRH in Central and East European countries is similar to that found in Western Europe and USA. It also shows the very high cardiovascular risk of TRH and the elevated association of this condition with obesity, renal failure, organ damage and history of cardiovascular events.

Quality of Life After Renal Denervation

To the Editor: Lambert et al1 recently reported that the quality of life of 62 treatment-resistant hypertensive patients, as assessed by the Medical Outcomes Study 36-Item Short-Form Health Survey and Beck Depression Inventory-II, improved 3 months after renal sympathetic denervation. All patients had been enrolled in the authors’ ongoing research into the effectiveness of renal denervation, without any reason given why they were selected to assess quality of life. These patients must have received more than usual attention. Lambert et al1 admit that in a purely observational study they could not exclude a placebo effect on the subjective self-assessment of …

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries