Arterial hypertension defeated? Attacked from another angle

Background/Introduction Three recently published sham-controlled studies proved the efficacy of renal denervation (RDN) in hypertensive patients. However, there it is still unclear which patients should be selected for RDN. Purpose This study seeks to clarify which patient subgroups benefit most from radiofrequency RDN by analysing a nationwide multicentre registry database. Methods This is a post-hoc analysis from the multicentre Austrian Transcatheter Renal Denervation Registry hosted by the Austrian Society of Hypertension. We correlated change of systolic blood pressure (BP) after RDN to gender and presence/absence of comorbidities. Bivariate correlation and multiple linear regression analyses were performed. Results 291 patients (43% female, median age 64 years) undergoing RDN between April 2011 and September 2014 were included in this analysis. Mean baseline ambulatory 24-hour BP (systolic/diastolic) was 150±18/89±14 mmHg and mean baseline office BP was 170±16/94±14 mmHg. After RDN, mean ambulatory 24-hour BP reduction was 9±19/6±16 mmHg. The following features were associated with a good response to RDN: high baseline systolic ambulatory BP (ρ=0.53, p<0.001), high baseline diastolic office BP (ρ=0.40, p<0.001), female gender (ρ=0.10, p=0.049), absence of diabetes mellitus (DM, ρ=0.11, p=0.033), and absence of peripheral arterial disease (ρ=0.17, p=0.002). Multivariate analysis identified high baseline systolic ambulatory BP, female gender and absence of DM as independent predictors for systolic ambulatory BP reduction (systolic ambulatory BP: HR 5.83 [95% CI 4.83–6.83], p<0.001; absence of DM: HR 5.82 [2.04–9.60], p=0.003; female gender: HR 5.07 [1.46–8.68], p=0.006), although women and patients without DM had lowest baseline ambulatory BP. Furthermore, both women and patients without DM used significantly less antihypertensives after RDN (female vs male: 4.0±1.3 vs 4.4±1.3, p=0.002; no DM vs DM: 4.0±1.3 vs 4.6±1.3, p<0.001). Figure 1 Discussion Ambulatory BP reductions after RDN were substantially more pronounced in female and in non-diabetic patients despite lower baseline BP. It is concluded that in terms of efficacy female patients and non-diabetics might be more suitable for RDN. Acknowledgement/Funding The Austrian Renal Denervation Registry was funded by the Austrian Society of Hypertension.

The diagnosis of resistant hypertension is made when a patient's blood pressure(BP)is not under control after taking appropriate lifestyle measures and treatment with optimal or best-tolerated doses of 3 antihypertensive medications (a diuretic should be 1 component) for at least 4 weeks or 4 drugs are required to control BP. The inadequate BP control is confirmed by BP measurements of office and out-of-office (ambulatory BP monitoring and Home BP monitoring). Resistant hypertension lacks effective treatment. As a treatment method of resistant hypertension, the pathophysiology of renal sympathetic denervation(RDN) has been confirmed by basic research. Although early studies using the first-generation came to different conclusions, recent clinical trials have reached a positive result with a radiofrequency ablation system of the second-generation.However, the evaluation method for the activity of the renal sympathetic nerve is not clear so that it is hard to accurately screen out the patients who are appropriate for RDN. The clinical application of RDN is still controversial.

In The Journal of Clinical Hypertension, Tino Naduvathumuriyil and colleagues report the results of their single-center registry on the effects of renal denervation (RDN) in resistant hypertension patients. They report that a total of 50 resistant hypertension patients underwent RDN using three different systems. The data from their registry showed that office blood pressure (BP) reductions following RDN were sustained throughout the follow-up periods of up to 3 years. Mean office BP was reduced from 170.6/93.4 mm Hg at baseline to 144.2/84.6 mm Hg at 36 months. Mean changes in office systolic and diastolic BP after 36 months were −26.4 and −8.8 mm Hg (95% CI: −34.6 to −18.2 and −13.5 to −4.2 mm Hg, n = 28), respectively. Patients at the very highest BP level—greater than 180 mm Hg systolic at baseline—appeared to benefit the most from the procedure at three years. Based on office BP, 100% and 82% of patients with grade 3 hypertension were responders at 24 and 36 months, respectively. Additionally, the proportion of patients with an office systolic BP ≥ 180 mm Hg dropped from 30% at baseline to 7.4% at 3 years. Although plasma creatinine increased from 90.6 μmol/L (95% CI: 82.1-99.0 μmol/L) at baseline to 102.1 μmol/L (95% CI: 95.8-108.3 μmol/L) at 36 months (P = .007), no long-term safety concerns were observed following the RDN procedure. The study is an important evidence around RDN as a safe, effective, and long-lasting BP-lowering therapy. The Global SYMPLICITY Registry is the largest study documenting the long-term safety and effectiveness of the Medtronic renal denervation systems in a real-world setting in patients with uncontrolled hypertension.1 This single-center study, as a useful supplement to the Global SYMPLICITY Registry, reconfirmed the long-term efficacy of lowering blood pressure in RDN. The recently published randomized, sham-controlled SPYRAL HTN-OFF MED (Efficacy of catheter-based renal denervation in the absence of antihypertensive medications [SPYRAL HTN-OFF MED Pivotal]: a multicentre, randomised, sham-controlled trial)2 and (Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications [SPYRAL HTN-OFF MED]: a randomised, sham-controlled, proof-of-concept trial),3 SPYRAL HTN-ON MED (Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial),4 and RADIANCE SOLO (Endovascular ultrasound renal denervation to treat hypertension [RADIANCE-HTN SOLO]: a multicentre, international, single-blind, randomised, sham-controlled trial)5 trials documented significant and consistent reductions in both office and ambulatory BP in patients with and without concomitant antihypertensive medication, while results are short term. Although the sample size is relatively small, the encouraging findings of this single-center registry support to the clinical application of RDN, a legitimate antihypertensive strategy, for uncontrolled hypertension. This single-center registry showed a substantial reduction in office BP after RDN using 3 different catheter-based radiofrequency ablation systems: the Symplicity RDN system from Medtronic, the EnligHTN RDN system from St. Jude Medical/Abbott, and the Vessix RDN system from Boston Scientific. This first comparison of 3 different radiofrequency ablation RDN systems reveals novel findings. Although the average BP reductions were modest and the number of patients was small, head-to-head comparison showed an advantage for Vessix RDN system perhaps because of the more complete renal nerve ablation. At present, there are a variety of RDN devices with different technologies, but different devices should have different effects. Both radiofrequency and ultrasound endovascular RDN systems have proven clinical efficacy for the treatment of hypertension. The Radiosound-HTN comparative trial has shown that RDN using endovascular ultrasound afforded superior reduction in ambulatory systolic BP in comparison with radiofrequency ablation system.6 Questions that remain open and require further evidence in future studies relate to the long-term safety and efficacy of both the radiofrequency ablation devices and that of other devices with different technologies in larger cohorts. A head-to-head comparison may be useful to determine the potential superiority of all the devices. Selection of suitable patients for RDN therapy is the key to the success of RDN. The ultimate litmus test is to identify responders and nonresponders to RDN therapy. The problem remains unresolved. In this small sample study, patients with grade 3 or higher hypertension had a better response, while the BP response was variable. Although more patients demonstrated BP reduction with RDN than with the sham procedure, there were changes seen in either direction for both groups in SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED, and RADIANCE SOLO trials. In any case, following the positive SPYRAL HTN-OFF MED Pivotal data, these new data provide additional evidence on the safety and efficacy of RDN to help manage uncontrolled hypertension, with study patients experiencing meaningful blood pressure reductions out to several years. None disclaimers.

Objective: The blood pressure (BP) lowering effect of renal sympathetic denervation (RDN) in treatment resistant hypertension (TRH) shows variation among the few randomized studies. The duration of antihypertensive effect and long-term effect and safety of RDN require further follow-up. We aimed to report the office and ambulatory (BP) changes and long-term safety at 12-month follow-up. Design and Method: Patients with apparent TRH (n = 65) were referred specifically for RDN and those with secondary and spurious hypertension (n = 26) were excluded. TRH was defined as office systolic BP>140 mmHg despite maximally tolerated doses of at least 3 antihypertensive drugs including a diuretic. Additionally, ambulatory daytime systolic BP > 135 mmHg following witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP, indicating poor drug adherence. Patients with true TRH were randomized and underwent RDN with Symplicity catheter (n = 9) versus adjusted drug treatment (n = 10). Results: 24-hour ambulatory systolic and diastolic BPs in the drug adjustment group changed from 151 ± 13/84 ± 7 mmHg (±SD) at baseline to 131 ± 12/75 ± 5 mmHg at 12 months (p < 0.0005 for all), and in the RDN group from 149 ± 9/89 ± 7 to 141 ± 11/83 ± 5 mmHg (p = 0.07 and p = 0.04, respectively). The absolute difference in change between groups in systolic BP was significantly higher in favor of the drug adjustment group (p = 0.01). Office, daytime and nighttime ambulatory BPs changed in parallel to the 24-hour ambulatory BPs. However 2 patients in RDN group considered as a responder since they have sustained reduction of 24-hour ambulatory systolic BP by more than 15 mmHg. There were no significant changes in renal arteries assessed by MRI or CT scans after 12 months follow-up. No deterioration of renal function was found. Conclusions: RDN has inferior BP lowering effects compared to adjusted drug treatment in patients with TRH. However, RDN is safe and this encourages future research to identify characteristics of patients who might respond to RDN.

Renal denervation (RDN) is a catheter-based intervention to treat patients with resistant hypertension. The biological effects of RDN are not fully understood, and randomized controlled trials have generated conflicting evidence. This report presents data from the Swedish Registry for Renal Denervation, an investigator-driven nationwide registry. To assess the safety and efficacy of RDN on patients with resistant hypertension in a real-world clinical setting. This nationwide database contains patient characteristics, procedural details, and follow-up data on all RDN procedures performed in Sweden. Consecutive procedures between 2011 and 2015 were included. The data analysis consists of 252 patients (mean age 61 ± 10 years, 38% women; mean 4.5 ± 1.5 antihypertensive drugs). Office SBP and DBP and 24-h ambulatory blood pressure (BP) decreased 6 months after RDN (176 ± 23/97 ± 17 to 161 ± 26/91 ± 16 mmHg, both P < 0.001; and 155 ± 17/89 ± 14 to 147 ± 18/82 ± 12 mmHg, both P < 0.001). Significant office and ambulatory BP reductions persisted throughout the observation period of 36 months. Major procedure-related vascular complications occurred in four patients. Renal function and number of antihypertensive drugs were unchanged during follow-up. In this complete national cohort, RDN was associated with a sustained reduction in office and ambulatory BP in patients with resistant hypertension. The procedure proved to be feasible and associated with a low-complication rate, including long-term adverse events.

Metabolic effects two years after renal denervation in insulin resistant hypertensive patients. The Re-Shape CV-risk study

HomeHypertensionVol. 60, No. 6Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Dec 2012https://doi.org/10.1161/HYP.0b013e31827adfa9Hypertension. 2012;60:1367NHE3-Inhibition in the Gut and Hypertension (page 1560)High intestinal sodium absorption is 1 mechanism of hypertension and constipation. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of sodium absorption in the gut. SAR218034 is an orally nonabsorbable specific NHE3 inhibitor. Inhibition of intestinal NHE3 by SAR218034 increased feces sodium-excretion and reduced urinary sodium-excretion, while absolute sodium balance and serum sodium-concentration was not changed. Reduced intestinal sodium absorption by SAR218034-treatment was associated with increased feces water content and reduction in systolic blood pressure. Angiotensin-converting enzyme inhibition by ramipril plus NHE3 inhibition resulted in an additive blood pressure lowering effect. Selective inhibition of NHE3-mediated sodium absorption in the gut has the potential to reduce high blood pressure and can be safely combined with angiotensin-converting enzyme inhibitor treatment. In addition, NHE3 inhibition in the gut may display a laxative effect in elderly patients suffering from constipation. These results show that SAR218034 inhibiting intestinal NHE3-mediated sodium absorption has potential as a representative of a new class of antihypertensive drugs. Intestinal NHE3 inhibitors may be particularly useful as an adjunct to other therapies. The real potential of the NHE3 inhibitor is to help accomplish a truly low salt-intake from the gut, because it is difficult to sufficiently reduce salt in the human diet.Quality of Life After Renal Denervation (page 1479)Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure in patients with treatment resistant hypertension. In this issue of Hypertension, Lambert et al present data indicating that subjective health-related quality of life, as assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey, is markedly diminished in patients with treatment resistant hypertension. Three months after renal denervation, the 36-Item Short-Form Health Survey mental component summary score improved, with the change being driven by increases in the vitality, social function, role emotion, and mental health domains. No change occurred in the physical component summary score. The changes in 36-Item Short-Form Health Survey scores were not related to the magnitude of blood pressure reduction. Although the authors could not exclude the possibility of a placebo effect, the potential mechanisms underlying their observations are intriguing. Preclinical studies have demonstrated that sensory renal afferent nerves can influence the firing rate of medullary and hypothalamic neurones and that renal afferent denervation prevents the development of hypertension and an increase in norepinephrine turnover in the posterior and lateral hypothalamic nuclei and the locus coeruleus. The majority of brain norepinephrine is located in the locus coeruleus, which, together with its hypothalamic and amygdala projections, is linked with behavioral responses involving autonomic activation. Whether the improvement in health-related quality of life that occurred after renal denervation is sustained and has a biological basis associated with reduction in sympathetic tone remains unknown but does merit further attention.Blood Pressure Tracking Over the Life Course (page 1393)Although prior studies have shown that blood pressure steadily increases with age, there are limited longitudinal data characterizing the pattern of blood pressure tracking over the life course. Furthermore, the extent to which risk factors influence blood pressure tracking is not well understood. Therefore, we used multilevel modeling to analyze blood pressure measurements performed serially, over a period of up to 28 years, in participants of the Framingham Heart Study. On the basis of data collected from >21 700 person-observations, we observed that risk factors such as greater body mass index and higher heart rate were associated with an increase in all component measures of blood pressure. However, dyslipidemia was primarily associated with increased mean arterial pressure, a measure of steady-state load, whereas diabetes mellitus and smoking were predominantly associated with higher pulse pressure, representing pulsatile load. Notably, age-related increases in pulse pressure were more pronounced in women compared with men overall. The differential impact of select risk factors on elevation in the individual components of blood pressure underscores distinct regulation of these measures over the life course. Further research is needed to investigate the mechanisms underlying these observations and, in turn, the extent to which targeted interventions may attenuate the typical trajectory of blood pressure progression with aging. Previous Back to top Next FiguresReferencesRelatedDetails December 2012Vol 60, Issue 6 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/HYP.0b013e31827adfa9 Originally publishedDecember 1, 2012 PDF download Advertisement

Percutaneous Renal Sympathetic Denervation: 2013 and Beyond

Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial

Objective The aim of this study was to describe and compare echocardiographic findings before renal sympathetic denervation (RDN) and 6 and 24 months after the procedure. Materials and methods Patients with treatment resistant hypertension (TRH) were included in this non-randomised intervention study. RDN was performed by a single experienced operator using the Symplicity Catheter System. Echocardiographic measurements were performed at baseline, and after 6 and 24 months. Results The cohort consisted of 21 patients with TRH, with a mean systolic office blood pressure (BP) of 163 mmHg and mean diastolic BP 109 mmHg. Mixed model analysis showed no significant change in left ventricular (LV) mass index (LVMI) or left atrium volume index (LAVI) after the RDN procedure. Higher LVMI at baseline was significantly associated with greater reduction in LVMI (p < 0.001). Relative wall thickness (RWT) increased over time (0.48 mm after two years) regardless of change in BP. There was a small but significant reduction in LV end-diastolic (LVIDd) and end-systolic (LVIDs) diameters after RDN, with a mean reduction of 2.6 and 2.4 mm, respectively, after two years. Progression to concentric hypertrophy was observed only in in patients who did not achieve normal BP values, despite BP reduction after RDN. Conclusion There was no reduction of LV mass after RDN. We found a small statistically significant reduction in LVIDd and LVIDs, which together with increase in RWT can indicate progression towards concentric hypertrophy. BP reduction after RDN on its own does not reverse concentric remodelling if target BP is not achieved.

The human sympathetic nervous system has an important regulatory role.In its dysfunctional hyperexcitatory state, it can lead to multiple pathologies.The renal sympathetic nerves play a significant role in these pathological states.Percutaneous renal sympathetic denervation (RSDN) allows for safe minimally invasive selective denervation of the renal sympathetic nerves.RSDN has been shown to be safe and efficacious in blood pressure reduction in earlier nonblinded SYMPLICITY HTN-1 and -2 trials.In Europe, it is approved for a select group of truly resistant severe essential hypertension.However, its real efficacy is now in doubt with the blinded SYMPLICITY HTN-3 trial that showed no significant difference in change in office and mean 24-h ambulatory systolic blood pressure between RSDN and sham-procedure arms.This review will look at the potential targets for percutaneous RSDN-heart failure, cardiac arrhythmias and kidney disease, sleep-disordered breathing and insulin resistance.

Background and Aims Arterial hypertension is a significant cause of cardiovascular morbimortality worldwide. Adequate blood pressure control constitutes a crucial tool to prevent the enduring end-organ damage inflicted by hypertension and, consequently, its high burden of disease. Resistant hypertension may be particularly challenging to address: in this field, denervation of the renal sympathetic nerves is developing as a promising despite controversial therapy. Our goal was to study long-term outcomes in a cohort of patients with resistant hypertension submitted to renal denervation. Method We conducted a retrospective, single-centre study amongst patients with resistant hypertension who underwent renal denervation between July 2011 and July 2022. All patients routinely underwent blood and urine testing, 24-hour ambulatory blood pressure monitoring (ABPM) and echocardiographic evaluation every 6 to 12 months after the procedure. We collected several demographic, clinical and laboratory variables, and analysed outcomes at 5 years of follow-up using SPSS software. Results 78 patients were submitted to renal denervation in our centre, 53% of which (n = 41) were male. There were no reported complications related to the procedure. At 5 years of follow-up, there were different types of responders. In ABPM, 61% of the patients showed a decrease in mean systolic blood pressure (SBP), with a median reduction of 16 mmHg (IQR 16.5). In 46% of patients, there was a reduction in albumin/creatinine ratio (ACR), with a median decrease of 17.63 mg/g (IQR 120.67). Before renal denervation, 30 patients (38.5%) had an ACR above 30 mg/g, while after 5 years the number of patients with ACR in this range was 21 (26.9%). In echocardiographic evaluation, 70% of the patients evidenced a decrease in left ventricular mass index (LVMI) with a median reduction of 20 g/m2 (IQR 41). These results are summarised in Figure 1. In total, 70% of the patients were considered responders to renal denervation, either through a reduction in mean SBP in ABPM, in LVMI, in ACR or simultaneously in all three variables. Additionally, the reduction in mean SBP in ABPM, LVMI and ACR proved to be independent variables, both in Spearman tests and binary logistic linear regression (nonsignificant p-values). 77% of the patients were prescribed less antihypertensive drugs after follow-up, with a median reduction of 2 drugs (IQR 2). Conclusion Our study identified a significant percentage of responders to renal denervation, evidenced by an improvement in one or more variables associated with blood pressure control and hypertension-mediated end-organ damage, without any safety issues to report. It is also important to emphasize that the observed reduction in ACR and LVMI was independent of the reduction in SBP. This finding suggests that renal denervation might have a direct effect on albuminuria and left ventricular hypertrophy, instead of solely as an indirect result of the control of blood pressure. Hence, while further studies are necessary to support this evidence, the results nevertheless raise hope for the therapeutic potential of renal denervation in patients with resistant hypertension.

Over one-third of Canadians with hypertension do not achieve recommended blood pressure (BP) targets despite availability of effective treatments. Renal sympathetic nerve denervation (RDN) is a recently approved, minimally invasive treatment for hypertension being offered in multiple Canadian centers. How best to implement this procedure in contemporary Canadian clinical practice remains unclear. Herein, we provide a Canadian hypertension specialist viewpoint on use of RDN in Canada. We review the rationale for, and evidence supporting, the use of RDN and discuss, using two clinical cases, its potential therapeutic role. We note that RDN has effectively lowered BP in multiple, sham-controlled, randomized clinical trials and has a favourable safety profile. Economic modeling estimates that it is cost-effective in the Canadian context. Conversely, the BP lowering effect is relatively modest; no well-established method to pre-identify responders exists; cardiovascular endpoint data supporting use of RDN are lacking; and no clear funding model is currently in place in Canada. Accordingly, we suggest that use of RDN be reserved for willing patients with severely elevated BP despite the use of first-line conventional therapies who have had secondary causes excluded. Examples include patients with resistant hypertension or moderate or severe hypertension and multiple drug intolerance syndrome. In view of its recent approval and known operator-dependency, RDN should be offered solely through programmatic, multidisciplinary collaboration between hypertension specialists and experienced interventionalists using a shared decision-making approach with the patient. Funding deployment should target such programs and sites should carefully monitor their outcomes to confirm comparability to the published literature.

Orthostatic function after renal sympathetic denervation in patients with resistant hypertension

Catheter-Based Renal Denervation in ADPKD: Just for Pain Control?