No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial
Abstract
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.
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.
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.
Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients.
Ardian.
... Catheter-based neuroablative strategies have been utilized in the management of several conditions mediated by the autonomic nervous system when control remains elusive including hypertension and atrial fibrillation [18][19][20][21]. The Symplicity HTN-1 and Symplicity HTN-2 studies demonstrated dramatic reductions in blood pressure in the systolic range of 30 mmHg compared to a nonblinded control group [18,22]. ...
... Catheter-based neuroablative strategies have been utilized in the management of several conditions mediated by the autonomic nervous system when control remains elusive including hypertension and atrial fibrillation [18][19][20][21]. The Symplicity HTN-1 and Symplicity HTN-2 studies demonstrated dramatic reductions in blood pressure in the systolic range of 30 mmHg compared to a nonblinded control group [18,22]. These findings resulted in a growing enthusiasm in the hypertension community with a consequent expanding procedural indications and technology evolution. ...
Background
Cardioneuroablation has been emerging as a potential treatment alternative in appropriately selected patients with cardioinhibitory vasovagal syncope (VVS) and functional AV block (AVB). However the majority of available evidence has been derived from retrospective cohort studies performed by experienced operators.
Methods
The Cardioneuroablation for the Management of Patients with Recurrent Vasovagal Syncope and Symptomatic Bradyarrhythmias (CNA-FWRD) Registry is a multicenter prospective registry with cross-over design evaluating acute and long-term outcomes of VVS and AVB patients treated by conservative therapy and CNA.
Results
The study is a prospective observational registry with cross-over design for analysis of outcomes between a control group (i.e., behavioral and medical therapy only) and intervention group (Cardioneuroablation). Primary and secondary outcomes will only be assessed after enrollment in the registry. The follow-up period will be 3 years after enrollment.
Conclusions
There remains a lack of prospective multicentered data for long-term outcomes comparing conservative therapy to radiofrequency CNA procedures particularly for key outcomes including recurrence of syncope, AV block, durable impact of disruption of the autonomic nervous system, and long-term complications after CNA. The CNA-FWRD registry has the potential to help fill this information gap.
... резистентна хипертония, ренална денервация, амбулаторно мониториране на артериалното налягане, вариабилитет на артериалното налягане, товар на артериалното налягане, артериален еластицитет I In recent years, there has been a signifi cant interest in renal denervation as a possibility to optimize blood pressure control among patients with resistant arterial hypertension [1]. Randomized trials have clearly demonstrated the capabilities of the methodology among patients without and those taking multiple antihypertensive agents [2][3][4][5][6][7][8][9][10][11][12]. This was accompanied by clarifi cation of diagnostic algorithms in patients with resistant hypertension, exclusion of secondary causes of hypertension, optimization of therapeutic approaches and assessment of adherence to antihypertensive therapy [13]. ...
... Apart from changes in offi ce and home arterial pressure, 24-hour ambulatory blood pressure monitoring (24h ABPM) is currently the standard in the diagnostic algorithm and the monitoring of the eff ect of applied therapeutic regimens. As a consequence, in the majority of controlled trials in resistant hypertension, it was the change in 24-hour systolic blood pressure that emerged as the main primary effi cacy endpoint [2][3][4][5][6][7][8][9][10][11][12][13]. Diff erent criteria have been proposed -more than 5 or more than 10 mmHg reduction in 24-hour systolic arterial pressure to evaluate a favorable therapeutic response in serial follow-up after successful renal denervation. ...
The aim of the study was to evaluate the long-term effect of renal sympathetic denervation (RSD) on 24h ambulatory blood pressure measurement (ABPM) and blood pressure load (BP load) in patients with resistant hypertension. The study included 32 patients with treatment-resistant hypertension and performed successful RSD. The effect of renal denervation was significant both in terms of daytime, nighttime and 24-hour arterial pressure, with the most pronounced effect on nocturnal blood pressure. In addition to mean BP reduction we found out a significant improvement of weighted 24 h SD and BP load during follow-up. A long-term effect of the RSD, reported as a reduction in 24-hour systolic blood pressure above 10 mm Hg at month 12, was found in 22 patients (68.8%). In multivariate regression analysis, two parameters remained predictive for successful renal denervation – higher nighttime systolic blood pressure (OR 0.9, 95% CI 0.8-1.005, p = 0.05) and lower pulse pressure (OR 1.13, 95% CI 1.01-1.26, p = 0.03).
... The intervention was largely written off by the clinical community and device industry in 2014, when the shamcontrolled SYMPLICITY HTN-3 trial failed to show a significant BP reduction in the intervention group in comparison to the control group [39]. The results came as a considerable surprise, after the publication of several highly promising proof-of-concept and randomised, open-label studies [40][41][42][43][44][45][46]. The lack of effect in the SYMPLICITY HTN-3 trial ...
... The intervention was largely written off by the clinical community and device industry in 2014, when the sham-controlled SYMPLICITY HTN-3 trial failed to show a significant BP reduction in the intervention group in comparison to the control group [39]. The results came as a considerable surprise, after the publication of several highly promising proof-of-concept and randomised, openlabel studies [40][41][42][43][44][45][46]. The lack of effect in the SYMPLICITY HTN-3 trial could be attributed to a number of factors, importantly procedural technique and incomplete denervation, high rate of drug changes and lack of adherence to treatment [47,48]. ...
Uncontrolled arterial hypertension is a major global health issue. Catheter-based renal denervation has shown to lower blood pressure in sham-controlled trials and represents a device-based, complementary treatment option for hypertension. In this situation assessment, the authors, who are practicing experts in hypertension, nephrology, general practice and cardiology in the Republic of Ireland, discuss the current evidence base for the BP-lowering efficacy and safety of catheter-based renal denervation with different modalities. Although important questions remain regarding the identification of responders, and long-term efficacy and safety of the intervention, renal denervation has the potential to provide much-needed help to address hypertension and its adverse consequences. The therapeutic approach needs to be multidisciplinary and personalised to take into account the perspective of patients and healthcare professionals in a shared decision-making process.
... RDN therapy using radiofrequency energy, ultrasound energy, or chemical ablation has emerged as a viable treatment option for resistant hypertension that targets sympathetic signaling at a proximal point in this highly pathological signaling cascade. 16,56,57 We postulated that implementing this device-mediated intervention would provide more sustained and powerful sympathoinhibitory effects on cardiorenal signaling in HFpEF. Through our investigation, we were able to elucidate that: (1) early treatment of HFpEF with RDN significantly improves cardiovascular (2) the beneficial effects of RF-RDN in HFpEF are likely mediated by a renal-centric mechanism; (3) one mechanism for the observed benefit is through downregulation of renal NLRP3-mediated IL-1β synthesis; and (4) RDN failed to provide the same benefit when performed in later-stage HFpEF disease in the ZSF1 obese rat. ...
Background
The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF).
We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression.
Methods and Results
Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF‐RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF‐RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF‐RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF‐RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial‐dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1β, and expression of profibrotic mediators. RF‐RDN failed to exert beneficial effects when administered in the 20‐week‐old HFpEF cohort.
Conclusions
Our data demonstrate that early RF‐RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF‐RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.
... In a short period of time after the procedure, small irregularities of the wall of the renal artery were observed, which could be attributed to spasm or oedema. [23][24][25] All those complications are very rare including renal artery iatrogenic dissection. 26 Seven (13%) patients during Symplicity HTN-2 who underwent RDN had transient intraprocedural bradycardia requiring atropine; none had any consequences. ...
Renal denervation (RDN) as a method of treating arterial hypertension (AH) was introduced in Croatia in 2012. A multidisciplinary team and a network of hospitals that diagnose and treat patients with severe forms of AH were established, and a very strict diagnostic-treatment algorithm was prepared. At monthly meetings patients with truly resistant hypertension who were candidates for RDN were discussed. According to the 2021 ESH position statement and 2023 ESH guidelines, RDN is considered an alternative and additional, not a competitive method of treating patients with various forms of AH which must be performed by following a structured procedure and the patient’s preference should be considered. In view of the changes in the global scientific community, the Croatian Hypertension League brings this consensus document on RDN conducted with radiofrequency-based catheter, the only currently available method in Croatia. In this document, exclusion and inclusion criteria are shown, as well as three groups of patients in whom RDN could be considered. The new diagnostic-treatment algorithm is prepared and follow-up procedure is explained. In Croatia, RDN is reimbursed by the national insurance company, thus pharmacoeconomic analyses is also shown. Criteria required by an individual centre to be approved of RDN are listed, and plans for prospective research on RDN in Croatia, including the Croatian registry for RDN, are discussed.
... Renal denervation (RDN) was implemented as a treatment option in resistant HTN substantiated by the experimental and clinical evidence of the reduced central sympathetic activity [11] and, consequently, significant BP drop. In the last decade, RDN overcame the rise and fall, related to the promising results of the first trials SYMPLICITY HTN-1 and − 2 [12,13] followed by a disclaimer due to the first negative results of the shamcontrolled randomized SYMPLICITY HTN-3 Trial. The latter [14] failed to prove a significant antihypertensive effect of the RDN procedure. ...
Purpose
In a cohort, observational prospective trial, we assessed the long-term dynamics of sleep-disordered breathing in patients with resistant hypertension after renal denervation and their association with blood pressure change at remote follow-up.
Materials and methods
Twenty-eight patients with stable hypertension who were recruited for endovascular radiofrequency renal denervation in 2012–2019 and had valid both baseline and follow-up sleep study, were included in the analysis. All patients underwent physical examination, anthropometry, office and ambulatory blood pressure measurements, blood and urine tests, kidney visualization, and full polysomnography before and within 12–36 months after renal denervation.
Results
The average follow-up comprised 30.1 ± 8.4 months. At long-term follow-up, no significant changes in creatinine level, estimated glomerular filtration rate, body mass index were registered. There was a significant increase in sleep apnea severity indices: the mean change in apnea-hypopnea index comprised 9.0(-21.1;25.2) episodes/h, in oxygen desaturation index 6.5(-16.8;35.9) episodes/h, in the average SpO 2 -1.7(-5.6;1.9)%. Over 12-month follow-up, there were no significant differences in blood pressure response in patients with and without sleep apnea. The baseline apnea-hypopnea and oxygen desaturation indices and the mean SpO 2 were associated with the circadian blood pressure profile at follow-up, but did not correlate with the blood pressure response.
Conclusions
Although the severity of sleep apnea worsens at > 12 months follow-up after renal denervation, this is not associated with hypertension exaggeration.
... The results of early, open-label RDN uncontrolled studies and even randomized trials were spectacular, and, in retrospect, too good to be true. 4 pandemic, which has had a major impact on the outcomes of many studies. 14 ...
... With the rapid development of interventional techniques in recent years, transcatheter renal denervation (RDN) has emerged as a potential approach for BP lowering. The unblinded clinical trials SYMPLICITY HTN-1 and HTN-2 have indicated significant decreases in systolic BP (SBP) 6 months after RDN, by 25 mmHg and 33 mmHg, respectively [12,13]. However, the blinded and sham-controlled SYMPLICITY HTN-3 trial has demonstrated no significant differences in SBP and 24-hour ambulatory SBP at 6 months between patients who underwent RDN and sham surgery. ...
Hypertension is a major global public health concern whose disease burden affects an estimated 1.4 billion people worldwide and is associated with 10.8 million deaths annually. Despite substantial advances in medical care, the prevalence of hypertension has markedly increased, owing to population aging; poor treatment adherence; and increases in risk factors, such as excessive salt intake, and overweight and obesity. Consequently, the disability-adjusted life years have increased by 40%, primarily because of elevated risk of stroke, coronary atherosclerosis, heart failure, and kidney failure. Major outstanding problems associated with the treatment and management of hypertension include determining optimal blood pressure targets, developing innovative antihypertensive medications and devices, and implementing effective and feasible hypertension management strategies. To address these challenges, numerous clinical trials are currently underway. This article highlights the most influential ten clinical studies on hypertension in 2022. The rational use of antihypertensive medications is concluded to be important for effective hypertension management. Important considerations include medication types and dosing times; optimal blood pressure targets; the development of new drugs and therapeutic devices; specific community characteristics, such as village doctor-led care; and healthful diets.
... The first percutaneous approach was the radiofrequency-based renal denervation (rRDN) demonstrating favorable effects in resistant hypertension. 3,4 The more recent development of an ultrasound-based renal denervation (uRDN) technology uses acoustic energy to create circumferential ablation patterns with simultaneous endovascular cooling via an irrigated balloon aiming at an improved ablation depth and completeness 5 and might therefore have the potential to increase the effectivity when compared with rRDN. ...
BACKGROUND
Renal denervation has proven its efficacy to lower blood pressure in comparison to sham treatment in recent randomized clinical trials. Although there is a large body of evidence for the durability and safety of radiofrequency‐based renal denervation, there are a paucity of data for endovascular ultrasound–based renal denervation (uRDN). We aimed to assess the long‐term efficacy and safety of uRDN in a single‐center cohort of patients.
METHODS AND RESULTS
Data from 2 previous studies on uRDN were pooled. Ambulatory 24‐hour blood pressure measurements were taken before as well as 3, 6, 12, and 24 months after treatment with uRDN. A total of 130 patients (mean age 63±9 years, 24% women) underwent uRDN. After 3, 6, 12, and 24 months, systolic mean 24‐hour ambulatory blood pressure values were reduced by 10±12, 10±14, 8±15, and 10±15 mm Hg, respectively, when compared with baseline ( P <0.001). Corresponding diastolic values were reduced by 6±8, 6±8, 5±9, and 6±9 mm Hg, respectively ( P <0.001). Periprocedural adverse events occurred in 16 patients, and all recovered without sequelae.
CONCLUSIONS
In this single‐center study, uRDN effectively lowered blood pressure up to 24 months after treatment.
... RDN is an endovascular technique that utilizes RF energy to eliminate sympathetic nerves that pass through the renal artery, accomplished in a minimally invasive manner [80] . Initially designed for refractory hypertension treatment, the effectiveness of this strategy in lowering blood pressure is debated due to mixed outcomes in clinical trials involving patients with hypertension [80][81][82][83] . Despite the controversy, RF-RDN may have cardiovascular benefits that extend beyond blood pressure reduction. ...
Heart failure, a condition that arises from numerous cardiovascular disorders, is a primary contributor to mortality related to cardiovascular disease. Typically noticed in heart failure is heightened sympathetic activity coupled with diminished parasympathetic activity. The autonomic nervous system governs the heart’s neurological regulation through opposing functions of its sympathetic and parasympathetic components, which regulate conduction velocity, heart rate, coronary blood flow, and contractile force. Promising treatments for heart failure include inhibiting the sympathetic nerve’s overactivity and restoring parasympathetic activity in the heart. In this review, we describe neural modulation approaches that have potential to assist in the management of heart failure.
This systematic review and meta-analysis was conducted to assess the randomized controlled trial (RCT) evidence available for renal denervation (RDN) in uncontrolled arterial hypertension. Twenty-five RCTs met the eligibility criteria for the systematic review, and 16 RCTs were included in the meta-analysis. The results of the random effects meta-analysis estimated a mean difference of −8.5 mmHg [95% confidence interval (CI) −13.5 to −3.6] for office SBP, −3.6 mmHg (95% CI −5.2 to −2.0) for 24 h SBP and −3.9 mmHg (95% CI −5.6 to −2.2) for ambulatory daytime SBP in favour of RDN compared with control (medication and/or sham-only) at primary follow-up. Similarly favourable results were observed across a range of prespecified subgroup analyses, including treatment-resistant hypertension. This meta-analysis suggests that the use of RDN in uncontrolled hypertension leads to consistent reductions in blood pressure. Reductions appear to be statistically consistent in the presence or absence of medications and in populations resistant to the use of three medications.
Importance
Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed.
Objective
To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm.
Data Sources
Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison.
Study Selection
Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity.
Data Extraction and Synthesis
Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020.
Main Outcomes and Measures
End points were examined in prespecified subgroups: patient-reported or health care professional–assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality.
Results
Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional–assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, −0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, −0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, −0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, −0.52 to 0.57; P = .91), or recurrent bleeding events (OR, −0.12; 95% CI, −1.11 to 0.88; P = .88).
Conclusions and Relevance
The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional–assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.
Hypertension is a risk factor for the development of heart failure and has a negative impact on the survival of these patients. Although patients with these two conditions usually take different antihypertensive medications, some patients do not achieve adequate blood pressure control and their hypertension becomes resistant or refractory. In this scenario, percutaneous renal denervation has emerged in recent years as an alternative to achieve blood pressure control goals. We present the case of a 53-year-old woman with a medical history of essential hypertension, hypercholesterolemia, unipolar depression, and diabetes, who was diagnosed with dilated cardiomyopathy with reduced left ventricular ejection fraction (33%). Despite the initiation of multiple antihypertensive medications and placement of a cardiac resynchronization therapy pacemaker, the patient remained hypertensive with a left ventricular ejection fraction of 40%. At that time, percutaneous renal denervation was performed without complications, and one year after the procedure, the patient had improved better blood pressure control and the left ventricular ejection fraction increased to 51%. This case illustrates one of the clinical scenarios in which it has been suggested that renal denervation may be more beneficial, as in the situation of patients with refractory hypertension and heart failure.
The cardiovascular continuum from the hypertensive state to decompensated heart failure has seen in the last decade a great improvement not only in pharmacological therapy but also in the device-based treatment. This aspect is particularly evident for the great development of devices useful to improve contractility and hemodynamic of the heart and for the important evolution in left ventricular assist devices. In hypertensive patients, the evolution has been concentrated on devices capable of interfering with the pathophysiologic mechanisms that sustain blood pressure, i.e., adrenergic tone and baroreflex mechanism. The chapter will briefly depict the principal innovative devices developed for treating these pathophysiologic conditions.
Uncontrolled hypertension is considered as one of the most important cardiovascular risk factors. Recently, catheter-based techniques using mainly radiofrequency or thermal energy brought to light the concept of renal denervation (RDN) as a viable therapeutic option in cardiovascular medicine. During the last decade, several single-arm studies have shown significant reduction in blood pressure among patients with uncontrolled hypertension. Although the early proof of concept studies showed a surprisingly great blood pressure reduction with RDN, the largest sham-controlled study (SYMPLICITY HTN-3) failed to confirm similar findings. Since then, both basic and clinical research took place and results have been taken into consideration careful design of modern devices and procedures used in the RDN era.
Prospective observational studies have suggested that RDN is associated with target organ damage (TOD) regression. Thus, in this chapter we present a systematic review and meta-analysis, which evaluates the effect of RDN on target organ damage by pooling currently available data and investigates its relation to BP-lowering following RDN. Seventeen studies (n = 698 patients) were incorporated in the present meta-analysis thus examining the following outcomes of interest: left ventricular mass index (LVMI), left atrial volume index (LAVI), E to A wave velocities of trans-mitral inflow (E/A) and E wave velocity to Em velocity from tissue Doppler imaging (E/Em), central augmentation index (AIx), and carotid−femoral pulse wave velocity (PWV). It is of great concern that the improvement of the abovementioned factors concerning left ventricle after RDN might play a crucial role in the prevention of heart failure in hypertensive patients.
Renal Artery Sympathetic Denervation (RDN) can lower blood pressure. Different ablation catheters (single electrode, multi‐electrode) have different scopes of ablation (renal artery main stem and branches). Few studies have compared the advantages and disadvantages of different ablation catheters and different procedures in terms of antihypertensive efficacy. To compare the efficacy and safety of 3D reconstruction radiofrequency ablation (3DRA) and basket multi‐electrode radiofrequency ablation (BMRA) in Renal Artery Sympathetic Denervation. Fifty‐three patients with Refractory hypertension (RHT) were divided into BMRA, ( n = 28) and 3DRA( n = 25). BMRA group used a stereobasket multi‐electrode ablation catheter with a controlled ablation temperature of 60°C and an ablation time of 120 s per site. 3DRA group used a NavStar pressure‐monitored perfusion monopolar ablation catheter with a controlled ablation temperature of 40°C, an ablation time of 40 s per site, and an ablation energy of 12 W. Baseline and RDN parameters and complications were compared in both groups. Home and 24 h ambulatory blood pressure, type of anti‐hypertensive medication taken, and serum creatinine were followed up at 1, 3, 6, 12, and 24 months after the RDN. There were no differences in baseline characteristics between the two groups. (23.14 ± 2.00)months of follow‐up in the BMRA group resulted in a total of (25.86 ± 8.61) loci ablation. (19.28 ± 7.40)months of follow‐up in the 3DRA group resulted in a total of (21.04 ± 6.47)loci ablation. Home SBP was significantly lower in both groups at 1 month after RDN treatment compared to baseline(H‐SBP/mmHg: BMRA 149.9 ± 10.59 vs. baseline 168.36 ± 12.76; 3DRA 152.6 ± 14.91 vs. 164.89 ± 12.96, both p < .05). The proportion of people with 24 h ambulatory SBP attainment was significantly higher in both groups and was maintained for 24 months. At each follow‐up time point, there were no differences in home and 24‐h flow SBP, DBP, or Scr between the two groups. There were two cases of severe renal artery complications from implanted vascular stents and one case of femoral artery pseudoaneurysm in the 3DRA group. At follow‐up, 1 (1.9%) patient in the 3DRA group died of unexplained death and 1 (1.9%) patient developed heart failure, and 1 (1.9%) patient in the BMRA group died of unexplained death. Basket multi‐electrode radiofrequency ablation and 3D reconstruction radiofrequency ablation of the renal artery applied to RDN have comparable efficacy in reducing systolic blood pressure.
Background
This case‐control study aimed to determine whether there were differences between patients with essential hypertension with accessory renal arteries (ARAs) and those without ARAs.
Methods and Results
The enrolled patients with essential hypertension were divided into the ARA group (n=200) and control group without ARAs (n=238). After propensity matching, 394 patients (197 in each of the 2 groups), were included. The 24‐hour BP (4.33/2.43 mm Hg) and daytime BP (4.48/2.61 mm Hg) of patients in the ARA group were significantly higher than those of the control group ( P <0.05). The flow‐mediated dilation was lower in the ARA group (5.98±2.70 versus 5.18±2.66; P <0.05). In correlation analysis, the horizontal plasma aldosterone concentration had the highest correlation with 24‐hour, daytime, and nighttime systolic BP ( r =0.263, 0.247, and 0.243, respectively; P <0.05) and diastolic BP ( r =0.325, 0.298, and 0.317, respectively; P <0.05). As for multivariate regression analysis, plasma aldosterone concentration was a significant risk factor for elevated 24‐hour, daytime, and nighttime systolic BP (β=0.249 [95% CI, 0.150–0.349], 0.228 [95% CI, 0.128–0.329], and 0.282 [95% CI, 0.187–0.377], respectively; P <0.05) and elevated diastolic BP (β=0.289 [95% CI, 0.192–0.385], 0.256 [95% CI, 0.158–0.353], and 0.335 [95% CI, 0.243–0.427], respectively; P <0.05). Direct renin concentration was also a risk factor for 24‐hour and daytime BPs, whereas heart rate was a risk factor correlated with 24‐hour, daytime, and nighttime diastolic BP (all P <0.05). For the mixed‐effects model for repeated measures, the results were similar to results of the multivariate regression analysis (all P <0.05).
Conclusions
ARAs could contribute a higher BP of patients with essential hypertension and might promote the development of essential hypertension. The mechanism might be related to overactivation of the renin‐angiotensin‐aldosterone system and sympathetic nervous system.
Les méthodes d’évaluation des effets des médicaments restent une référence scientifique incontournable. La prise de conscience de l’importance de facteurs d’efficacité non spécifiques, à l’œuvre dans les interventions thérapeutiques médicamenteuses ou non, interroge sur les possibilités de mobiliser ces facteurs, notamment dans la relation de soin. Les réflexions sur les processus d’autoguérison mettent en lumière l’importance d’un cadre méthodologique spécifique, objet de cet article. Nous passons au crible les grands traits de la méthodologie d’évaluation et leur rôle propre dans la maîtrise des facteurs de confusion et des biais. Cette analyse nous permet de proposer un cadre d’évaluation des interventions thérapeutiques et de leurs composantes, à l’œuvre dans les processus d’autoguérison, comme l’effet placebo. Notre analyse précise les conséquences de l’évaluation en ouvert, conduit à proposer une nouvelle échelle de niveau de preuve de l’efficacité des thérapeutiques, ainsi qu’une procédure pour individualiser l’estimation du bénéfice d’une intervention issue d’essais thérapeutiques. La nouvelle échelle dissocie l’apport des méta-analyses et des essais cliniques, et souligne l’importance de la conduite des essais d’évaluation en insu. Le cadre d’évaluation proposé apporte un référentiel commun aux travaux sur l’autoguérison et ses mécanismes ou composantes. Ce cadre doit être mis à l’épreuve dans les travaux à venir de l’IRIA.
The following text provides a brief summary of pivotal non-randomized and randomized non-sham controlled trials followed by a more detailed description of randomized sham-controlled trials of renal denervation in the treatment of hypertension.
Uncontrolled hypertension is considered as one of the most important cardiovascular risk factors. Recently, catheter based techniques using mainly radiofrequency or thermal energy brought to light the concept of renal denervation (RDN) as a viable therapeutic option in cardiovascular medicine. During the last decade, several single arm studies have shown significant reduction in blood pressure among patients with uncontrolled hypertension (Krum et al. Lancet. 373:1275–1281, 2009; Symplicity HTN-2 Investigators et al., Lancet 376:1903–1909, 2010; Worthley et al., Eur Heart J 34:2132–2140, 2013). Although the early proof of concept studies showed a surprisingly great blood pressure reduction with renal denervation, the largest sham-controlled study (SYMPLICITY HTN-3) failed to confirm similar findings. Since then, both basic and clinical research took place and results have been taken into consideration in the careful design of modern devices and procedures used in the renal denervation era. Thus, in this chapter we present a systematic review and meta-analysis, which examine results of sham-controlled studies using especially modern technologies and procedures. The meta-analysis included six sham-controlled studies that used radiofrequency or ultrasound-based devices to achieve successful renal denervation.
Introduction
Hypertension is the leading cause of death in the cardiovascular system. Indeed, untreated hypertension can affect one's general health, but medicine can help hypertensive people reduce their chance of developing high blood pressure. However, secondary hypertension remains an unresolved illness.
Areas covered
This review will go through the typical and unusual device-based therapies for resistant hypertension that have arisen in recent years. Further to that, the innovations developed in device-based RH treatment will be covered, as well as the research and studies assessing these novel technologies.
Expert opinion
The innovative device-based techniques that target resistant hypertension provide a potential therapy that has been backed by a number of studies and clinical trials, whereas pharmacological non-adherence and increased sympathetic activity are recognized to be the primary causes of resistant hypertension. Nevertheless, some limitations will be critical for the future of these RH systems, with the device's design and larger RCTs playing a significant role in determining whether a position in routine treatment could be warranted.
Advances in medical research have resulted in a better understanding of the pathogenic mechanisms involved and the adverse outcomes associated with metabolic diseases such as diabetes mellitus (DM) and metabolic syndrome (MetS). Sympathetic overdrive commonly present in these conditions, has been proven to play a key role in the perturbation of cardio-metabolic homeostasis, targeting which therefore is as an attractive therapeutic approach to restore impaired metabolism. Indeed, healthier lifestyle intervention strategies including calorie restriction and increased exercise have been shown to exert their beneficial effects at least in part by reducing sympathetic overdrive. The pharmacological approaches, though effective, result in variable responses in different patient cohorts and long-term efficiency may be limited by medication intolerance and non-adherence. Renal denervation, a catheter-based intervention applied locally to ablate the renal sympathetic nerves for the therapeutic management of resistant hypertension, demonstrated salutary metabolic outcomes. Here, we review the mechanisms that contribute to the beneficial metabolic effects associated with renal denervation in the context of diabetes mellitus and MetS and discuss the potential for these approaches to be embedded in clinical practice.
Renal denervation (RDN) is an effective treatment for resistant hypertension (HTN) but does not always result in lower blood pressures. New techniques to assess the success of RDN and measure sympathetic nerve activity may allow for improved patient selection for RDN, documentation of procedural technical success, and evaluation of patients in whom there is a late loss of clinical benefit. A number of potential surrogates, including blood and urinary biomarkers, recordings of nerve activity, and continuous monitoring to assess oscillations in heart rate and blood pressure, have been identified and evaluated. Assessing the effectiveness of RDN requires careful differentiation of technical success (i.e., effective ablation of nerve signaling in the renal arteries) and clinical outcomes (including surrogate endpoints such as left ventricular hypertrophy and “hard” outcomes such as mortality). In this chapter, we review the relevant renal artery anatomy and procedural characteristics of RDN; appraise the existing literature studying the value of surrogate markers for both technical success and clinical outcomes for RDN across multiple organ systems including cardiovascular, renal, and endocrine; and explore the relevance of these biomarkers as they relate to the potential applications of RDN for resistant HTN as well as alternative disease processes including atherosclerosis, heart failure, arrhythmia, chronic kidney disease, and the metabolic syndrome.
The prevalence of obstructive sleep apnea (OSA) in general population varies from 5 to 10%. OSA is the most common disease associated with resistant hypertension, diagnosed in 64% of patients. The potential pathophysiologic mechanisms of OSA in hypertensive patients is nocturnal rostral fluid shift, hyperaldosteronism and increased sympathetic activity, consistently evident in OSA patients. The potential impact of renal sympathetic denervation (RDN) on sleep apnea course was reported in two human studies. The first study included 10 patients with resistant hypertension and OSA. The second study was small, single center, randomized trial which recruited 60 patients with true resistant hypertension coexisting with moderate-to-severe OSA. In both studies significant systolic blood pressure reduction and sleep apnea course improvement was observed. Based on these two studies results it should be emphasized that RDN influences key mechanisms regulating sympathetic activation. These results have shown that catheter-based renal sympathetic denervation may not only lower systolic blood pressure in resistant hypertensive patients with sleep disordered breathing but also improve sleep apnea severity, but the number of recruited patients was small.
Renal sympathetic denervation is a new treatment option for patients with hypertension. Catheter-based renal denervation has demonstrated efficacy and safety in initial clinical trials; however, after the first randomized sham-controlled pivotal trial failed to show the efficacy of the technology, the frenzy in the field ended and most of the device manufacturers dropped out of development. Although newer generation randomized sham-controlled trials have shown promising results which was a result of better understanding of the renal anatomy and improvements in device design, many questions remain unanswered in this field. Preclinical studies using animal models are helping researchers and clinicians to find answers to many of these questions. Generally, larger animals such as pig, dog, or sheep are needed for the preclinical studies with preference for the swine model due to its renovascular anatomy being similar to that of humans. A semi-quantitative ordinal grading system is useful, when the changes of nerves, renal artery, and peri-arterial soft tissue induced by renal denervation are evaluated.
Kidney-related pain syndromes while relatively rare, are debilitating for sufferers and associated with a substantial reduction in quality of life. Our understanding of the underlying causes and mechanisms have improved but therapeutic options and management of this complex condition remain a clinical challenge. Current treatment approaches are mostly empirical and include a wide range of multi-disciplinary strategies such as physical therapy, local and systemic analgesia, interventional, and surgical approaches usually flanked by psycho-behavioral therapy, and other strategies. Novel approaches such as catheter-based renal denervation target the pain-mediating afferent sensory nerves directly, has been proposed as a valuable treatment option for kidney-related pain syndromes.
The kidney functions as a finely tuned sensor to balance body fluid composition and filter out waste through complex coordinated mechanisms. This versatility requires tight neural control, with innervating efferent nerves playing a crucial role in regulating blood flow, glomerular filtration rate, water and sodium reabsorption, and renin release. In turn sensory afferents provide feedback to the central nervous system for the modulation of cardiovascular function. However, the cells targeted by sensory afferents and the physiological sensing mechanisms remain poorly characterized. Moreover, how the kidney is innervated during development to establish these functions remains elusive. Here, we utilized a combination of light-sheet and confocal microscopy to generate anatomical maps of kidney sensory and sympathetic nerves throughout development and resolve the establishment of functional crosstalk. Our analyses revealed that kidney innervation initiates at embryonic day (E)13.5 as the nerves associate with vascular smooth muscle cells and follow arterial differentiation. By E17.5 axonal projections associate with kidney structures such as glomeruli and tubules and the network continue to expand postnatally. These nerves are synapsin I-positive, highlighting ongoing axonogenesis and the potential for functional crosstalk. We show that sensory and sympathetic nerves innervate the kidney concomitantly and classify the sensory fibers as calcitonin gene related peptide (CGRP)+, substance P+, Trpv1+, and Piezo2+, establishing the presence of Piezo2 mechanosensory fibers in the kidney. Using retrograde tracing, we identified the primary dorsal root ganglia, T10-L2, from which Piezo2+ sensory afferents project to the kidney. Taken together our findings elucidate the temporality of kidney innervation and resolve the identity of kidney sympathetic and sensory nerves.
The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve ac- tivity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention.
Methods: 30 young, healthy, sodium loaded, non-obese males were exposed to − 15 mmHg LBNP, − 30 mmHg LBNP, − 15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response.
Results: All intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; − 15 mmHg: − 3.1 ± 0.9 %, − 30 mmHg: − 2.9 ± 0.6 %, − 15 mmHg + aslikiren: − 1.8 ± 0.6 %). − 15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters.
Conclusion: Sympathetic stimulation for 90 min via LBNP at − 30 mmHg LBNP compared to − 15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.
Aim. To study the initial state of adrenergic reactivity and the five-year dynamics of the beta-adrenergic reactivity index of erythrocyte membranes and the manifestation of the antihypertensive effect of the procedure for radiofrequency destruction of sympathetic structures of the renal artery in patients with resistant arterial hypertension. Subjects and methods. The analysis included 42 patients with resistant arterial hypertension (RH). The renal denervation (RD) procedure of the kidneys was performed by endovascular bilateral transcatheter radiofrequency ablation of the renal arteries. The study of 24-hour blood pressure monitoring (BPM) and the determination of -adrenoreactivity of erythrocytes (-ARM) by changes in the osmoresistance of erythrocyte membranes were performed initially, 1 week, 6 months, 1, 2, 3 and 5 years after RD. Patients retrospectively, at a follow-up period of 6 months after RD, were divided into responders (decrease in blood pressure by 10 or more mm Hg) and non-responders (decrease in blood pressure less than 10 mm Hg). Results. 6 months after the RD, the number of responders was 28 people (66.7%), after 5 years - 31 people (73.8%). At the time of inclusion in the study, the median -ARM in the group of non-responders was not significantly higher than in the group of responders. After 6 months after the RD procedure, the -ARM indicator in the non-responder group was significantly lower than in the responder group (p = 0.043). With further follow-up in the group of responders, an increase in the median -ARM was noted, which reached significant differences relative to the baseline values in the group at follow-up periods of 1 year (p = 0.036) and 5 years (p = 0.004) after RD. The change in the -ARM indicator in the non-responder group was wavy in nature, the changes did not reach the significance criteria. Conclusion. Renal denervation in 73.8% of cases is accompanied by a stable antihypertensive response for 5 years of observation and an increase in -ARM, which may indicate the implementation of compensatory mechanisms in conditions of increasing activity of the sympathoadrenal system in response to a decrease in blood pressure.
Following second-generation randomized trials, there is evidence that renal denervation (RDN) decreases blood pressure (BP), although to a lesser extent than suggested in the initial controlled and observational studies. The recent publication of the 36-month follow-up of the Symplicity HTN-3 trial has raised expectations, suggesting increasing, late benefits of the procedure, despite initially negative results. These findings come after those obtained at 36 months in the sham-controlled trial SPYRAL HTN-ON MED and in the Global Symplicity Registry. However, they are susceptible to biases inherent in observational studies (after unblinding for sham-control) and non-random, substantial attrition of treatment groups at 36 months, and used interpolation of missing BPs. More importantly, in SPYRAL HTN-ON MED and Symplicity HTN-3, long-term BP changes in patients from the initial RDN group were compared with those in a heterogeneous control group, including both control patients who did not benefit from RDN and patients who eventually crossed over to RDN. In crossover patients, the last BP before RDN was imputed to subsequent follow-up. In Symplicity HTN-3, this particular approach led to the claim of increasing long-term benefits of RDN. However, comparison of BP changes in patients from the RDN group and control patients who did not undergo RDN, without imputation of BPs from crossover patients, does not support this view. The good news is that despite the suggestion of sympathetic nerve regrowth after RDN in some animal models, there is no strong signal in favour of a decreasing effect of RDN over time, up to 24 or even 36 months. Still, current data do not support a long-term increase in the effect of RDN and the durability of RDN-related BP reduction remains to be formally demonstrated.
Radiofrequency-based renal denervation is a safe and effective way of lowering blood pressure, a common condition associated with high cardiovascular risk. Several catheters have been developed to administer energy to the renal arteries and their side branches, thereby modulating sympathetic renal activity. The Symplicity Flex™ and Symplicity Spyral™ are first- and second-generation devices, respectively, for radiofrequency-based renal denervation. There is a continuous need to further improve and adjust interventional antihypertensive therapies. Several randomized controlled trials have been conducted to investigate the safety and efficacy of these catheters and most were able to show radiofrequency-based renal denervation to be feasible, safe and effective in lowering blood pressure in hypertensive patients with and without concomitant antihypertensive medication. Herein, the authors discuss the pathophysiologic concepts of renal denervation and its procedural approaches, report catheter designs, summarize clinical trials outcomes and, finally, discuss real-world evidence.
High salt intake induces hypertension and enhances stroke onset. However, whether an increase in brain sodium exposure itself is harmful and has poor prognosis remains unknown. Therefore, we employed hypertensive rats that underwent intracerebroventricular (ICV) infusion of sodium for 28 days and evaluated stroke onset and related cytotoxic brain injuries. Forty-seven spontaneously hypertensive stroke-prone (SHRSP) and 39 normotensive rats (Wistar Kyoto rats [WKY]) underwent persistent ICV infusion of the following four solutions: artificial cerebrospinal fluid, 0.9%, 2.7%, and 9% saline for 28 days. We evaluated stroke onset and all-cause mortality between SHRSP and WKY at each ICV sodium concentration as the primary endpoints. Our secondary objective was to explore histological brain injuries associated with SHRSP induced by high sodium ICV. The results indicated that ICV infusion of 2.7% and 9% sodium showed a significant increase in stroke onset, decrease in body weight, and increase rate of brain water content in SHRSP compared to WKY. Increased blood pressure was not observed for ICV infusion of high sodium, while serum sodium concentration was significantly increased in SHRSP compared to WKY. Histological evaluations revealed that higher sodium infusion significantly increased the number of activated microglia, superoxide, neuronal cell loss, and microbleeds compared to WKY and SHRSP with 0.9% sodium. We conclude that persistent exposure to high sodium in the brain is one of the risk factors for stroke onset upregulating cerebral microbleeds and oxidative stress in hypertensive rats.
Purpose of Review
To provide an update and review approaches to the treatment of resistant hypertension (RH) with a focus on emerging potential therapies.
Recent Findings
Resistant hypertension is defined as a blood pressure that remains elevated above a patient’s individualized target despite the concurrent use of 3 antihypertensive agents of different classes including a diuretic or use of 4 or more antihypertensive agents. Patients with RH have an increased risk of adverse cardiovascular and renal outcomes. Most RH is attributed to apparent RH and is not true RH. True RH is a diagnosis of exclusion after apparent RH has been excluded. Treatment of RH is challenging, and blood pressure goal is often difficult to achieve. Currently several new therapies have emerged with forthcoming data that provide promise for improved blood pressure control in those with resistant hypertension.
Summary
Once RH has been diagnosed, patients should be on standardized therapy that includes agents from three different classes including a diuretic with addition in most cases of a mineralocorticoid as a fourth line agent. There are newer agents in development currently being studied in clinical trials including dual endothelin receptor antagonists and aldosterone synthase inhibitors that appear to be efficacious. Other approved medications including SGLT2 inhibitors and non-steroidal mineralocorticoids such as finerenone also need to be incorporated into treatment paradigms. Renal denervation with catheter based devices is another potential promising treatment option in this population.
Resistant hypertension is associated with an exceedingly high cardiovascular risk, and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline‐recommended therapy. While spironolactone is widely considered as the preferable fourth‐line agent, its broad application is limited by its side effect profile, especially off‐target steroid receptors‐mediated effects, and hyperkalaemia in at‐risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist aprocitentan, the aldosterone synthase inhibitor baxdrostat, and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter‐based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This narrative review will summarise the recently published evidence on novel antihypertensive agents and renal denervation in the context of resistant hypertension.
Purpose of review
Hypertension is a condition characterized by increased sympathetic activity and the autonomic nervous system. Resistant hypertension, a condition with a prevalence of 10% to 20% in the general hypertensive population, is more likely to experience poor outcomes and adverse cardiovascular events. Renal sympathetic denervation (RDN), a minimally invasive, catheter-based percutaneous intervention, has been considered for treating this condition. Clinical trials have used various catheters, such as the Symplicity Spyral catheter, Vessix Renal Denervation system, and Paradise endovascular ultrasound renal denervation system.
Recent findings
After the first randomized clinical trials examining the effectiveness and safety of RDN for lowering blood pressure in hypertensive patients, new clinical trials have used various catheters based on radiofrequency, such as the Spyral catheter, Vessix Renal Denervation system, or based on radiofrequency as the Paradise endovascular ultrasound renal denervation system. Positive results on this trials have shown that endovascular RDN (radiofrequency energy or high focused ultrasound energy) could be considered as a treatment option for uncontrolled resistant hypertension.
Summary
Therefore, endovascular RDN (radiofrequency energy or high focused ultrasound energy) could be considered as a treatment option for uncontrolled resistant hypertension, which can be considered as an alternative to increasing medication. Nevertheless more data are needed, mainly in cardiovascular outcomes. RDN should be performed in experienced and specialized centers with a multidisciplinary team, and the benefits and risks of RDN should be addressed in a shared-decision-making process.
Introduction:
We previously completed a trial of renal pelvic denervation for treating hypertension that reduced blood pressure by the 2-month primary endpoint. However, information on the durability of effectiveness is a critical requirement for device therapy and we now report data up to 12 months.
Methods:
This was an open label single-arm feasibility study in patients with increased blood pressure despite taking an average of 2.7 medications. The key endpoint reported here was ambulatory blood pressure at 12 months following renal pelvic denervation.
Results:
In the 17 patients (mean age 56) studied, there was a reduction from the baseline of 148 + 8.7 mmHg in the primary endpoint of mean daytime systolic blood pressure at 12 months of 19.1 (26.7, 11.6) mmHg, P<0.001, as compared with the 2-month result of 19.4 (24.9, 14.0) mmHg. The 24-hour systolic blood pressure fell by 19.3 (26.7, 11.9), P<0.001, and nighttime systolic fell by 18.7 (27.5, 9.8), P<0.001, mmHg at 12 months. Diastolic pressures also fell significantly from baseline at 12 months. As well, automated office systolic blood pressure was reduced from the baseline of 156.5 + 12.3 by 24.8 (33.2. 16.8) mmHg, P<0.001, at 12 months as compared with 22.4 (31.5, 13.3) at 2-months. . All blood pressure changes at 12 months were not different from those at 2 months, thus confirming the durability of the procedure. There were no serious procedural, clinical or laboratory adverse events related to the intervention. Serum creatinine fell from 1.03 + 0.22 to 0.82 + 0.16 mg/dl and estimated glomerular filtration rate rose from 79.6 + 17.8 to 96.3 + 16.4 ml/min/1.73m2 by 12 months, again sustaining effects seen at 2 months.
Discussion/conclusion:
These findings provide evidence that the significant blood pressure-lowering effects of renal pelvis denervation are durable and safe for at least one year and provide the basis for a pivotal randomized blinded trial to further define the safety and effectiveness of this procedure.
Hypertension remains the leading cause of death worldwide. Despite advances in drug-based treatment, many patients do not achieve target blood pressure. In recent years, there has been an increased interest in invasive hypertension treatment methods. Long-term effects and factors affecting renal denervation effectiveness are still under investigation. Some investigators found that the renal arteries’ morphology is crucial in renal denervation effectiveness. Accessory renal arteries occur in 20–30% of the population and even more frequently in patients with resistant hypertension. Diversity in renal vascularization and innervation may complicate the renal denervation procedure and increase the number of people who will not benefit from treatment. Based on previous studies, it has been shown that the presence of accessory renal arteries, and in particular, the lack of their complete denervation, reduces the procedure’s effectiveness. The following review presents the anatomical assessment of the renal arteries, emphasizing the importance of imaging tests. Examples of imaging and denervation methods to optimize the procedure are presented. The development of new-generation catheters and the advancement in knowledge of renal arteries anatomy may improve the effectiveness of treatment and reduce the number of patients who do not respond to treatment.
Pharmacologic therapies remain the treatment of choice for patients with essential hypertension, as endorsed by international guidelines. However, several cases warrant additional modalities, such as invasive antihypertensive therapeutics. The major target of these interventions is the modulation of the sympathetic nervous system, which is a common pathophysiologic mechanism in essential hypertension. In this narrative review, we elaborate on the role of invasive antihypertensive treatments with a focus on renal denervation, stressing their potential as well as the drawbacks that prevent their widespread implementation in everyday clinical practice. In the field of renal denervation, several trials have shown significant and sustained reductions in the level of office and ambulatory blood pressure, regardless of the type of energy that was used (radiofrequency or ultrasound). Critically, renal denervation is considered a safe intervention, as evidenced by follow-up data from large clinical trials. Baroreflex activation therapy may result in enhanced parasympathetic nervous system activation, thus lowering blood pressure levels. Along the same lines, carotid body ablation could also produce a significant antihypertensive effect, which has not been tested in appropriately designed randomized trials. Moreover, cardiac neuromodulation therapy could prove efficacious by altering the duration of the atrioventricular interval in order to regulate the preload of the left ventricle and, therefore, lower blood pressure.
Background:
Radiofrequency or ultrasound renal denervation (RDN) has shown conflicting results when used as an adjunctive option for hypertension management in randomized controlled trials (RCTs).
Methods:
We searched Pubmed, MEDLINE, and other online databases for RCTs comparing RDN versus sham-control procedures in patients with uncontrolled or resistant hypertension. The endpoints of interest were 24-h ambulatory (AMB) blood pressure (BP), daytime AMB BP, and office BP. We performed a random-effects meta-analysis using the inverse variance method to estimate mean difference (MD) with a 95% confidence interval (CI).
Results:
Nine studies with 1643 patients were included in the final analysis. The mean follow-up was 5 months. As compared with the sham-controlled group, RDN was associated with a significant decrease in 24-h AMB BP (systolic [MD -4.20; 95% CI -5.36 to -3.03; p < 0.00001], diastolic [-2.38; -3.42 to -1.35]), and daytime AMB BP (systolic: -5.11; -6.75 to -3.47, diastolic: -2.88; -3.91 to -1.85). Similarly, office BP was reduced with RDN (systolic: -5.46; -7.12 to -3.81; diastolic: -3.17; -4.23 to -2.12) when compared with placebo.
Conclusion:
Our meta-analysis shows that RDN is associated with a significant reduction in the 24-h AMB BP, daytime AMB BP, and office BP.
Catheter-based renal artery denervation (RAD) is entering a new era. After the disappointing results of SYMPLICITY-HTN 3 trial in year 2014, several technical and methodological advancements led to execution of important SHAM-controlled randomized trials with promising results. Now, the 2023 ESH Guidelines give RAD a class of recommendation II with a Level of Evidence B. Currently, catheter-based RAD has two main areas of application: (a) Hypertensive patients who are still untreated, in whom RAD is a sort of a first-line treatment; (b) Difficult-to-control or true resistant hypertensive patients. Notably, randomized SHAM-controlled trials met their primary end-point in both these conditions. So far, we do not dispose of established predictors of the antihypertensive response to RAD. Some data suggest that younger patients with systo-diastolic hypertension, absence of diffuse atherosclerosis and evidence of sympathetic nervous system overactivity experience a better BP response to the procedure. We reviewed the available data on catheter-based RAD and included an updated meta-analysis of the results of the available SHAM-controlled trials. Overall, the reduction in 24-h systolic blood pressure (BP) after RAD exceeded that after SHAM by 4.58 mmHg (95% CI 3.07-6.10) in untreated patients, and by 3.82 mmHg (95% CI 2.46-5.18) in treated patients, without significant heterogeneity across trials, patient phenotype (untreated versus treated patients) and technique (radiofrequency versus ultrasound). There were no important safety signals related to the procedure. Notably, some data suggest that RAD could be an effective additional approach in patients with atrial fibrillation and other conditions characterized by sympathetic nervous system overactivity.
Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating alpha-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49 degrees C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 +/- 900 and 4,870 +/- 670%.s (area under the curve ARNA vs. time). Renal pelvic perfusion with norepinephrine increased ARNA 1,870 +/- 210%.s. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8 +/- 1 to 16 +/- 1 pg/min, and PGE(2) release, from 77 +/- 11 to 161 +/- 23 pg/min, suggesting a role for PGE(2) in the norepinephrine-induced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE(2). PGE(2) enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Interaction between ERSNA and ARNA is modulated by norepinephrine, which increases and decreases the activation of the renal sensory nerves by stimulating alpha(1)- and alpha(2)-adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE(2).
The presence of cardiac reinnervation in humans after cardiac transplantation has been widely debated, based on the application of differing methods for the assessment of neuronal function. Some of these techniques have been rather indirect; consequently, the time course and extent of cardiac reinnervation remains uncertain.
To test for the presence of cardiac reinnervation after transplantation, we examined neurochemical (radiolabeled norepinephrine [NE] kinetics) and functional markers (power spectral analysis, heart rate response to exercise) of cardiac sympathetic nerve integrity in 15 cardiac transplantation recipients and 25 healthy control subjects of similar age. Cardiac transplantation subjects were studied 9 weeks to 8 years after cardiac transplantation (10 "early" patients < 18 months and 5 "late" patients > 2 years after cardiac transplantation). At rest, cardiac NE spillover was markedly attenuated early after transplantation (11.2 +/- 18.3 pmol/min) compared with subjects late after transplantation (105 +/- 11 pmol/min, P < .01) or in healthy control subjects (103 +/- 15 pmol/min, P < .01). Heart rate variability (measured by total spectral power) was significantly reduced in cardiac transplantation recipients compared with control subjects (59.4 +/- 30 vs 1673 +/- 516 milliseconds squared; P < .05), with evidence of a trend toward increasing spectral power late after transplantation. During exercise, the cardiac NE spillover was significantly lower in early cardiac transplantation recipients when compared with control subjects (163 +/- 50 vs 1876 +/- 418 pmol/min, P < .01). Late cardiac transplantation subjects showed a response intermediate (1080 +/- 254 pmol/min) between that of the early cardiac transplantation and control groups. However, measurements of the neuronal reuptake process for NE (assessed by the fractional extraction of plasma labeled NE across the heart and tritiated dihydroxyphenylglycol release) were significantly depressed in both early and late cardiac transplantation subjects.
The present study demonstrates a partial restoration of cardiac sympathetic nerve function in humans up to 8 years after heart transplantation.
The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.
Background: Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR). Objective: To develop an equation to predict GFR from serum creatinine concentration and other factors. Design: Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease. Patients: 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample ; the remaining 558 patients constituted the validation sample. Methods: The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample. Results: To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively. Conclusion: The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
Over 11 million Americans have both diabetes and hypertension-comorbid diseases that strongly predispose people to both renal as well as cardiovascular (CV) injury. Hypertension substantially contributes to CV morbidity and mortality in people with diabetes. Diabetes is the most common cause of end-stage renal disease in the United States. Furthermore, hypertension and diabetes are particularly prevalent in certain populations, such as African-Americans and Native Americans. Since the 1994 Working Group Report on Hypertension and Diabetes, a large body of clinical trial data has affirmed the original blood pressure goal of less than 130/85 mmHg recommended to preserve renal function and reduce CV events in people with hypertension and diabetes. Data that are more recent have emerged, however, to support an even lower diastolic blood pressure goal, ie, 80 mmHg, in order to optimally preserve renal function and reduce CV events in people with diabetic nephropathy. A review of clinical trials indicates that more than 65% of people with diabetes and hypertension will require two or more different antihypertensive medications to achieve the new suggested target blood pressure of 130/80 mmHg. The purpose of this report is to update the previous recommendations with a focus on level of blood pressure control, proteinuria reduction, and therapeutic approaches to achieve these goals. We provide an evidence-based approach, integrating data from the major clinical trials that were designed as randomized prospective, long-term studies that had as a primary endpoint either progression of diabetic nephropathy or reduction in CV events. This report also addresses socioeconomic and cultural barriers that hinder achievement of blood pressure goals. Lastly, the report discusses approaches to resolve cultural barriers, both physician- and patient-derived, that interfere with achievement of lower blood pressure goals. (C) 2000 by the National Kidney Foundation, Inc.
Hypertensive cardiovascular disease remains one of the foremost problems facing medicine today. It has been estimated that one-fourth of the adult population of this country has high blood pressure1 and that the complications of this condition account for more deaths annually than does cancer. Hypertension is of particular importance because it is responsible for many deaths and much premature disability in young and middle-aged persons. It is highly desirable, therefore, to lower the mortality for such a disease.
Many forms of therapy have been used in an effort to control hypertension. The principal ones may be classified under three headings: (1) diets low in sodium and fat, (2) drugs with a hypotensive or sedative effect, and (3) surgery. The form of surgical therapy that has been used most extensively is intervention on the sympathetic nervous system. There are many data in the literature concerning the short-term effects of various
Background: Renal sympathetic hyperactivity is seminal in the progression of hypertension (HTN). Catheter-based renal sympathetic denervation (RDN) has been shown to significantly reduce blood pressure in patients with hypertension (HTN). Durability of effect at 2-years using this novel technique has never been reported.
Methods: A cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic) was originally reported in the Lancet. We report longer term data on these patients and similar patients subsequently treated with the catheter-based renal denervation in non-randomized studies. Office blood pressure (BP) data and safety data were available at 1, 3, 6, 12, 18 and 24 months post-procedure. eGFR at 3 and 12 months were available.
Results: 117 pts were treated with catheter-based RDN at 17 centers in Australia, Europe, and the US. Mean age was 57±11 yrs, 40% were female, 33% diabetic, 22% with CAD. Baseline values include mean office BP 176/98 ± 17/14 mmHg, mean of 5.0 anti-HTN medications, and eGFR 82 ± 19 mL/min. The procedure lasted a median of 38 minutes. Four acute procedural complications occurred: three groin pseudoaneurysms and one renal artery dissection, all managed without further sequelae. Post-procedure office BPs were reduced by 20/11, 24/10, 24/12, 25/12, 29/17, and 33/14 mmHg at 1, 3, 6, 12, 18, and 24 months respectively. At 3-months the eGFR had changed by -1.4 mL/min (95% CI: -4.6 to 1.7), and at 12-months the eGFR had changed by -2.8 mL/min (95% CI: -6.4 to 0.8). One patient required stenting of a renal artery ostial stenosis that was present at baseline but grew by 6 months; no radiofrequency energy had been delivered in this location. Otherwise, there were no late adverse events associated with the therapy.
Conclusions: Catheter-based RDN results in a substantial reduction in BP sustained to at least 2 years, without significant adverse events, in patients with resistant HTN. The changes in eGFR are better than the natural history reported in similar patients.
Measurements of the plasma concentration of noradrenaline, or more specifically the rate at which noradrenaline enters plasma, provide a useful guide to sympathetic nervous system function in humans. The overall rate of release of noradrenaline to plasma gives an overview of sympathetic nervous system activity (integrated nerve firing rate), detecting generalized changes, whether occurring as a reflex response, produced by drugs, or accompanying disease processes. The pattern of sympathetic nervous activation, however, is not delineated, only the net change in neurotransmitter release. Measurement of regional rates of noradrenaline release allows the clinical assessment of organ-specific sympathetic nervous tone, and consequently more penetrating analysis of sympathetic nervous system pathophysiology in disease states. The major problem in interpreting regional noradrenaline spillover measurements lies in the difficulty in differentiating those changes in noradrenaline spillover due to altered nerve firing, from those due to extraneous factors which might also affect spillover, such as the possible influence of blood flow on noradrenaline washout.
(C) Lippincott-Raven Publishers.
Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on disease morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document. Indeed, since 2000, the Statistical Update has been cited more than 6500 times in the literature (including citations of all annual versions). In 2008 alone, the various Statistical Updates were cited approximately 1300 times (data from ISI Web of Science). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas. For this year's edition, the Statistics Committee, which produces the document for the American Heart Association, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant papers from the literature over the past year. In future years, the Committee plans for the Statistical Update to be a major source for monitoring both cardiovascular health and disease in the population, with a focus on progress toward achievement of the American Heart Association's 2020 Impact Goals. In addition, future Statistical Updates will begin to incorporate the vast amounts of data becoming available from large population-based efforts to study the genetics of cardiovascular disease (CVD). Below are a few highlights from this year's Update.
Translational medicine is concerned with the translation of research discoveries into clinical applications for the prevention, diagnosis, and treatment of human diseases. Here we briefly review the research concerning the role of the renal sympathetic nerves (efferent and afferent) in the control of renal function, with particular reference to hypertension. The accumulated evidence is compelling for a primary role of the renal innervation in the pathogenesis of hypertension. These research discoveries led to the development of a catheter-based procedure for renal denervation in human subjects. A proof-of-principle study in patients with hypertension resistant to conventional therapy has demonstrated that the procedure is safe and produces renal denervation with sustained lowering of arterial pressure.
Sympathetic nervous system responses typically are regionally differentiated, with activation in one outflow sometimes accompanying no change or sympathetic inhibition in another. Regional sympathetic activity is best studied in humans by recording from postganglionic sympathetic efferents (multiunit or single fiber recording) and by isotope dilution-derived measurement of organ-specific norepinephrine release to plasma (regional "norepinephrine spillover"). Evidence assembled in this review indicates that sympathetic nervous system abnormalities are crucial in the development of cardiovascular disorders, notably heart failure, essential hypertension, disorders of postural circulatory control causing syncope, and "psychogenic heart disease," heart disease attributable to mental stress and psychiatric illness. These abnormalities involve persistent, adverse activation of sympathetic outflows to the heart and kidneys in heart failure and hypertension, episodic or ongoing cardiac sympathetic activation in psychogenic heart disease, and defective sympathetic circulatory reflexes in disorders of postural circulatory control. An important goal for clinical scientists is translation of knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this "mechanisms-to-management" transition is at differing stages of development with the different conditions. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension, perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on demonstration of activation of the renal sympathetic outflow. With psychogenic heart disease and postural syncope syndromes, knowledge of the neural pathophysiology is emerging, but clinical translation remains for the future.
To the Editor: The renal sympathetic nerves have been identified as a major contributor to the complex pathophysiology of hypertension in both experimental models and in humans.1 Patients with essential hypertension generally have increased efferent sympathetic drive to the kidneys, as evidenced by elevated rates of renal norepinephrine spillover, defined as the amount of transmitter that escapes neuronal uptake and local metabolism and thus “spills over” into the circulation. Hypertension is also characterized by an increased rate of sympathetic-nerve firing, possibly modulated by afferent signaling from renal sensory nerves.2–4 A 59-year-old male patient with long-standing essential hypertension that was . . .
Renal sympathetic hyperactivity is associated with hypertension and its progression, chronic kidney disease, and heart failure. We did a proof-of-principle trial of therapeutic renal sympathetic denervation in patients with resistant hypertension (ie, systolic blood pressure >/=160 mm Hg on three or more antihypertensive medications, including a diuretic) to assess safety and blood-pressure reduction effectiveness.
We enrolled 50 patients at five Australian and European centres; 5 patients were excluded for anatomical reasons (mainly on the basis of dual renal artery systems). Patients received percutaneous radiofrequency catheter-based treatment between June, 2007, and November, 2008, with subsequent follow-up to 1 year. We assessed the effectiveness of renal sympathetic denervation with renal noradrenaline spillover in a subgroup of patients. Primary endpoints were office blood pressure and safety data before and at 1, 3, 6, 9, and 12 months after procedure. Renal angiography was done before, immediately after, and 14-30 days after procedure, and magnetic resonance angiogram 6 months after procedure. We assessed blood-pressure lowering effectiveness by repeated measures ANOVA. This study is registered in Australia and Europe with ClinicalTrials.gov, numbers NCT 00483808 and NCT 00664638.
In treated patients, baseline mean office blood pressure was 177/101 mm Hg (SD 20/15), (mean 4.7 antihypertensive medications); estimated glomerular filtration rate was 81 mL/min/1.73m(2) (SD 23); and mean reduction in renal noradrenaline spillover was 47% (95% CI 28-65%). Office blood pressures after procedure were reduced by -14/-10, -21/-10, -22/-11, -24/-11, and -27/-17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. In the five non-treated patients, mean rise in office blood pressure was +3/-2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively. One intraprocedural renal artery dissection occurred before radiofrequency energy delivery, without further sequelae. There were no other renovascular complications.
Catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension. Prospective randomised clinical trials are needed to investigate the usefulness of this procedure in the management of this condition.
Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure.
We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. RESULTS. The mean (+/- SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58 +/- 3 vs. 23 +/- 3 bursts per minute, P < 0.01). In contrast, the rate of sympathetic-nerve discharge was similar in the patients receiving hemodialysis who had undergone bilateral nephrectomy (21 +/- 6 bursts per minute) and the normal subjects. The rate of sympathetic-nerve discharge in the patients receiving hemodialysis who had not undergone nephrectomy was also significantly higher (P < 0.01) than that in the patients with bilateral nephrectomy, and it was accompanied in the former group by higher values for vascular resistance in the calf (45 +/- 4 vs. 22 +/- 4 units, P < 0.05) and mean arterial pressure (106 +/- 4 vs. 76 +/- 14 mm Hg, P < 0.05). The rate of sympathetic-nerve discharge was not correlated with either plasma norepinephrine concentrations or plasma renin activity.
Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.
To study disturbances in sympathetic nervous system function in patients with alcoholic cirrhosis and the effect of clonidine on such disturbances.
Cross-sectional physiologic and neurochemical evaluation of patients with cirrhosis and of healthy controls; an uncontrolled trial of intravenous clonidine in the cirrhotic patients.
Forty-four hospitalized patients with biopsy-proven alcoholic cirrhosis and 31 healthy controls.
Intravenous clonidine.
Radiotracer-derived measures of norepinephrine release to plasma, central hemodynamics, wedge hepatic vein pressure, and measures of renal function.
In patients with cirrhosis, clonidine reduced previously elevated norepinephrine overflow rates for the whole body, kidneys, and hepatomesenteric circulation. This sympathetic inhibition was accompanied by the following potentially clinically beneficial effects: the lowering of renal vascular resistance (median reduction, 24%; 95% CI, 14% to 31%), the elevation of glomerular filtration rate (median increase, 27%; CI, 14% to 39%), and the reduction of portal venous pressure (median reduction, 25%; CI, 18% to 32%). The norepinephrine and hemodynamic responses to graded clonidine dosing (1, 2, and 3 micrograms/kg body weight intravenously) indicated that the sympathetic outflow to the hepatomesenteric circulation was more sensitive to pharmacologic suppression with clonidine than was the sympathetic outflow to the systemic circulation.
The sympathetic nerves to the kidneys, heart, and hepatomesenteric circulation are stimulated in patients with cirrhosis. Clonidine inhibits these activated sympathetic outflows differentially, which could possibly provide a basis for the selective pharmacologic treatment of portal hypertension in patients with cirrhosis.
Increased efferent renal sympathetic nerve activity could facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the deoxycorticosterone acetate-salt-treated rat, which suggests that these responses result from, at least in part, loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in humans. The efferent renal sympathetic nerves play a diminishing role once hypertension is established in these models. Renal denervation in established one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not caused by changes in renin activity or sodium excretion but is associated with decreased sympathoadrenal activity. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. Interruption of afferent renal fibers also appears to be the mechanism by which renal denervation prevents or reverses the normal increase in arterial pressure seen after aortic baroreceptor deafferentation in the rat.
The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 +/- 68 pg/ml (mean +/- SE) compared with 211 +/- 21 pg/ml in 15 subjects without heart failure (p less than .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 +/- 9 vs 5 +/- 1 ng/min; p less than .002) and renal (202 +/- 45 vs 66 +/- 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 +/- 38 pg/ml compared with 71 +/- 12 pg/ml in control subjects (p less than .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications.
Efferent renal innervation is composed of postganglionic sympathetic fibers to the renal arterioles, juxtaglomerular apparatus, and renal tubules. Increased efferent renal sympathetic nerve activity results in increased renal vascular resistance, renin release, and sodium retention. These responses from enhanced renal sympathetic activity contribute to normal cardiovascular homeostasis but could also facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the DOCA-salt-treated rat, suggesting that these responses are due, at least in part, to loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in man. Recent studies indicate that the kidney is a sensory organ with mechano-receptive and chemoreceptive afferent renal nerves involved in renorenal and cardiovascular regulation. Renal denervation in established one-kidney one-clip and two-kidney one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not due to change in renin activity or sodium excretion but is associated with decreased activity of the sympathetic nervous system. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. The role of the afferent renal nerves in renovascular hypertension in humans warrants further study.
Increased activity of the sympathetic nervous system has been described in chronic renal failure, but its role in the genesis and maintenance of hypertension associated with this condition has not been established. The kidney has an intense network of chemoreceptors and baroreceptors that send impulses to the brain. To what extent activation of these receptors by the scarred kidney or the uremic milieu may contribute to this model of hypertension is unknown. In the present study, we evaluated the effect of bilateral dorsal rhizotomy on the development of hypertension and neuroadrenergic activity in the anterior, lateral, and posterior hypothalamic nuclei, in the locus ceruleus, and in the nucleus tractus solitarius of Sprague-Dawley rats that underwent 5/6 nephrectomy or were sham operated. Neuroadrenergic activity was determined by calculating norepinephrine turnover rate after inhibition of norepinephrine synthesis with alpha-methyl-DL-p-tyrosine methyl ester hydrochloride. The endogenous norepinephrine concentration was significantly greater in the posterior and lateral hypothalamic nuclei and the locus ceruleus, but not in the nucleus tractus solitarius, and the anterior hypothalamic nuclei of uremic rats compared with control rats. In rats with chronic renal failure and sham rhizotomy, the turnover rate of norepinephrine in the posterior (15.3 +/- 1.61 nmol.g-1.h-1) and lateral hypothalamic nuclei (11.7 +/- 2.12 nmol.g-1.h-1) and in the locus ceruleus (26.6 +/- 2.42 nmol.g-1.h-1) was significantly faster (P < .01) than in rats with renal failure and dorsal rhizotomy (4.1 +/- 0.51, 4.7 +/- 0.77, and 5.1 +/- 1.13 nmol.g-1.h-1, respectively) or control animals with or without rhizotomy.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Previous histological studies have demonstrated partial reinnervation of the human transplanted kidney. However, it remains unknown whether this reinnervation is of any functional significance.
2. The effects of noradrenaline infusion (2 μgh−1kg−1) and lower body negative pressure (−27 mmHg) on renal haemodynamics, sodium excretion and tubular function were investigated in 25 renal transplant recipients and 10 normal subjects. Sixteen of the transplant recipients had all been transplanted for more than 27 months, and nine had all been transplanted for less than 2 months.
3. After an overnight fast, the subjects were water-loaded, and clearance studies were performed with a 1 h baseline period, a 1 h period with noradrenaline infusion, another 1 h baseline period, and a final 1 h period with lower body negative pressure.
4. During noradrenaline infusion the relative decrease in effective renal plasma flow, glomerular filtration rate and clearance of lithium and sodium was significantly more pronounced in the long-term transplanted patients than in the control subjects.
5. Lower body negative pressure only depressed the glomerular filtration rate significantly in the control subjects. Further, the relative decrease in effective renal plasma flow and clearance of lithium and sodium was significantly greater in the control subjects than in the two groups of transplanted patients.
6. The present study thus demonstrated that in short- and long-term transplanted kidneys in man, supersensitivity to circulating noradrenaline and an inadequate response to lower body negative pressure was present. This strongly suggests that the human transplanted kidney remains functionally denervated.
The renal nerves are the communication link between the central nervous system and the kidney. In response to multiple peripheral and central inputs, efferent renal sympathetic nerve activity is altered so as to convey information to the major structural and functional components of the kidney, the vessels, glomeruli, and tubules, each of which is innervated. At the level of each of these individual components, information transfer occurs via interaction of the neurotransmitter released at the sympathetic nerve terminal-neuroeffector junction with specific postjunctional receptors coupled to defined intracellular signaling and effector systems. In response to normal physiological stimuli, changes in efferent renal sympathetic nerve activity contribute importantly to homeostatic regulation of renal blood flow, glomerular filtration rate, renal tubular epithelial cell solute and water transport, and hormonal release. Afferent input from sensory receptors located in the kidney participates in this reflex control system via renorenal reflexes that enable total renal function to be self-regulated and balanced between the two kidneys. In pathophysiological conditions, abnormal regulation of efferent renal sympathetic nerve activity contributes significantly to the associated abnormalities of renal function which, in turn, are of importance in the pathogenesis of the disease.
Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR).
To develop an equation to predict GFR from serum creatinine concentration and other factors.
Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease.
1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample.
The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample.
To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively.
The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder.
Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure.
In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals.
The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.
Over 11 million Americans have both diabetes and hypertension-comorbid diseases that strongly predispose people to both renal as well as cardiovascular (CV) injury. Hypertension substantially contributes to CV morbidity and mortality in people with diabetes. Diabetes is the most common cause of end-stage renal disease in the United States. Furthermore, hypertension and diabetes are particularly prevalent in certain populations, such as African-Americans and Native Americans. Since the 1994 Working Group Report on Hypertension and Diabetes, a large body of clinical trial data has affirmed the original blood pressure goal of less than 130/85 mmHg recommended to preserve renal function and reduce CV events in people with hypertension and diabetes. Data that are more recent have emerged, however, to support an even lower diastolic blood pressure goal, ie, 80 mmHg, in order to optimally preserve renal function and reduce CV events in people with diabetic nephropathy. A review of clinical trials indicates that more than 65% of people with diabetes and hypertension will require two or more different antihypertensive medications to achieve the new suggested target blood pressure of 130/80 mmHg. The purpose of this report is to update the previous recommendations with a focus on level of blood pressure control, proteinuria reduction, and therapeutic approaches to achieve these goals. We provide an evidence-based approach, integrating data from the major clinical trials that were designed as randomized prospective, long-term studies that had as a primary endpoint either progression of diabetic nephropathy or reduction in CV events. This report also addresses socioeconomic and cultural barriers that hinder achievement of blood pressure goals. Lastly, the report discusses approaches to resolve cultural barriers, both physician- and patient-derived, that interfere with achievement of lower blood pressure goals.
Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure.
We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Phi, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean+/-SEM. MSNA was significantly elevated in hemodialysis patients (43+/-4 bursts/min), RTX-CSA (44+/-5 bursts/min), RTX-FK (34+/-3 bursts/min), and RTX-Phi (44+/-5 bursts/min) as compared with CON (21+/-3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20+/-3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44+/-6 versus 43+/-5 bursts/min, P=NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney.
Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.
Levels of hypertension treatment and control have been noted to vary between Europe and North America, although direct comparisons with similar methods have not been undertaken. In this study, we sought to estimate the relative impact of hypertension treatment strategies in Germany, Sweden, England, Spain, Italy, Canada, and the United States by using sample surveys conducted in the 1990s. Hypertension was defined as a blood pressure of 160/95 mm Hg or 140/90 mm Hg, plus persons taking antihypertensive medication. "Controlled hypertension" was defined as a blood pressure less than threshold among persons taking antihypertensive medications. Among persons 35 to 64 years, 66% of hypertensives in the United States had their blood pressure controlled at 160/95 mm Hg, compared with 49% in Canada and 23% to 38% in Europe. Similar discrepancies were apparent at the 140/90 mm Hg threshold, at which 29% of hypertensives in the United States, 17% in Canada, and </=10% in European countries had their blood pressure controlled. At the 140/90 mm Hg cutpoint, two thirds to three quarters of the hypertensives in Canada and Europe were untreated compared with slightly less than half in the United States. Although guidelines vary among countries, resulting in different case definitions, this does not account entirely for the varying success of different national control efforts. Low treatment and control rates in Europe, combined with a higher prevalence of hypertension, could contribute to a higher burden of cardiovascular disease risk attributable to elevated blood pressure compared with that in North America.
The effect of supradiaphragmatic splanchnicectomy on the blood pressure of 294 hypertensive patients followed for 10 to 18 months after surgery is compared with the effects of nonspecific medical management in a control group of 79 patients similarly studied. The data are presented in simple graphic form. It is concluded that 29 per cent of the hypertensive patients had reductions in blood pressure outside the range of spontaneous variation, that the vascular complications of hypertension decreased the likelihood of a good result, and that extension of the sympathetic ganglionectomy upward appeared to increase the frequency of good results without requiring a two-stage operation or producing significant postoperative orthostatic hypotension.
The John Paul II Hospital
- Thomas Zeller
- Bad Herz-Zentrum Bad Krozingen
- Krozingen
- Jerzy Germany
- Krzysztof Sadowski
- Bartus
Thomas Zeller (Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany),
Jerzy Sadowski and Krzysztof Bartus (The John Paul II Hospital,
Jagiellonian University, Krakow, Poland), and Paul A Sobotka,
Craig A Straley, and Neil C Barman (Ardian, Mountain View, CA, USA).
Handbook of hypertension: hypertension research in the twentieth century
- M Esler
Esler M. Looking at the sympathetic nervous system as a primary
source. In: Zanchetti A, Robertson JIS, Birkenhager WH, eds.
Handbook of hypertension: hypertension research in the twentieth
century. Amsterdam: Elsevier, 2004: 81-103.
Eff ects of renal sympathetic denervation on noradrenaline spillover and systemic blood pressure in patients with resistant hypertension
- M P Schlaich
- H Krum
- R Whitbourn
Schlaich MP, Krum H, Whitbourn R, et al. Eff ects of renal
sympathetic denervation on noradrenaline spillover and systemic
blood pressure in patients with resistant hypertension.
J Hypertens 2009; 27 (suppl 4): 154.
A novel catheter based approach to denervate the human kidney reduces blood pressure and muscle sympathetic nerve activity in a patient with end stage renal disease and hypertension
- M Schlaich
- H Krum
- T Walton
Schlaich M, Krum H, Walton T, et al. A novel catheter based
approach to denervate the human kidney reduces blood pressure
and muscle sympathetic nerve activity in a patient with end stage
renal disease and hypertension. J Hypertens 2009; 27 (suppl 4): S437.