Long-Term Effects of Renal Artery Denervation.

Background and Objectives: Renal artery denervation (RDN) procedure is a broadly discussed method in the treatment of resistant hypertension. Many studies report short-term (3-12 months) results for blood pressure and arterial stiffness. The primary endpoints were changes in 24 h mean systolic blood pressure (BP) and office systolic BP 48 months after RDN. The secondary endpoints were changes in aortic pulse wave velocity and impact of polypharmacy on these variables. Materials and Methods: Renal artery denervation was performed in 73 patients treated for resistant hypertension; 49 patients remained in final analysis. Patient examination was carried out before the procedure, and subsequently at 3, 6, 12, 24, and 48 months later. Patients' antihypertensive and overall medication regimens were carefully analysed. Results: Mean 24 h arterial blood pressure lowered and was sustained at lower levels for up to 48 months; median (interequartile range-IQR) from 158(23.5)/100(14.2) to 140(26.5)/86(16.2) mmHg. Mean reduction in 24 h ambulatory systolic BP was -11 ± 25 mmHg (95% CI, -20 to -2; p < 0.001), while office systolic BP reduced by -7 ± 23 mmHg (95%CI, -24 to -1; p < 0.02). A significant reduction in median aortic pulse wave velocity 12 months after the procedure (drop from baseline 11.2 [3.15] m/s (95%CI 6.1 to 16.2) to 9.8 [2.1] m/s (95%CI 6.1 to 13.7; p = 0.002)). After 48 months, there was no worsening compared to the baseline level of 10.3 [4.0] m/s (95% CI 6.9 to 17.8) (p > 0.05). The total mean number of antihypertensive drugs remained unchanged: 5.97(±1.1) vs. 5.24 (±1.45). A higher number of pills after 48 months was associated with higher aortic pulse wave velocity (1-5 pill group: 8.1 ± 1.6 m/s; 6-10 pill group: 10.9 ± 1.8 m/s; >11 pill group: 15.1 ± 2.6 m/s) (p = 0.003). Conclusions: Antihypertensive effect after renal denervation lasts up to 48 months with no worsening of arterial stiffness compared to baseline. In our study, polypharmacy was associated with increased arterial stiffness 48 months after the procedure.

Could careful patient selection for renal denervation warrant a positive effect on arterial stiffness and left ventricular mass reduction?

AIMS: After the sequence of Symplicity HTN trials, the impact of the procedure on lowering blood pressure (BP) and cardiovascular risk is still debatable. We present initial results of the multimodal pilot study that aimed at carefully selecting proper patients and investigating the effects of RASD on cardiac morphology and central haemodynamic parameters in 15 patients with resistant arterial hypertension prior and 6 months after RASD. METHODS AND RESULTS: The multimodal (applanation tonometry, echocardiography and cardiac magnetic resonance (CMR)) study findings have shown a significant BP decrease (190/112 ± 23/12 to 153/91 ± 18/11 mm Hg, P < 0.002), a decrease of the arterial markers (carotid-femoral pulse wave velocity decreased from 11.46 ± 2.92 m/s to 9.17 ± 2.28 m/s and the augmentation index decreased from 25.47 ± 10.55 to 21 ± 12.19, P < 0.006), a significant left ventricular mass index decrease by 10% both by echocardiography (140.83 ± 38.46 to 115.26 ± 25.37 g/m2, n = 14, P < 0.001) and CMR (108.32 ± 39.02 to 97.25 ± 30.06 g/m2, n = 15, P = 0.003). A significant decrease of CMR retrograde flow volume in the ascending aorta non-dependent on BP was also found. CONCLUSIONS: Our study is characterised by strict and extensive patient selection criteria for renal artery sympathetic denervation (RASD), which seem to warrant a positive effect of the procedure on BP, arterial stiffness and left ventricular mass 6 months after RASD, although it should be confirmed in larger controlled trials.

Renal Artery Denervation for the Management of Hypertension: Current Trends and Future Direction.

Renal artery denervation has re-emerged as a potential therapeutic option for patients with hypertension, especially those resistant to conventional pharmacotherapy. This comprehensive review explores the importance of careful patient selection, procedural techniques, clinical efficacy, safety considerations, and future directions of renal artery denervation in hypertension management. Drawing upon a wide range of available evidence, this review aims to provide a thorough understanding of the procedure and its role in contemporary hypertension treatment paradigms.

Catheter-based renal artery denervation: facts and expectations.

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.

Renal denervation prevents myocardial structural remodeling and arrhythmogenicity in a chronic kidney disease rabbit model.

BACKGROUND: The electrophysiological (EP) effects and safety of renal artery denervation (RDN) in chronic kidney disease (CKD) are unclear. OBJECTIVE: The purpose of this study was to investigate the arrhythmogenicity of RDN in a rabbit model of CKD. METHODS: Eighteen New Zealand white rabbits were randomized to control (n = 6), CKD (n = 6), and CKD-RDN (n = 6) groups. A 5/6 nephrectomy was selected for the CKD model. RDN was applied in the CKD-RDN group. All rabbits underwent cardiac EP studies for evaluation. Immunohistochemistry, myocardial fibrosis, and renal catecholamine levels were evaluated. RESULTS: The CKD group (34.8% ± 9.2%) had a significantly higher ventricular arrhythmia (VA) inducibility than the control (8.6% ± 3.8%; P <.01) and CKD-RDN (19.5% ± 6.3%; P = .01) groups. In the CKD-RDN group, ventricular fibrosis was significantly decreased compared to the CKD group (7.4% ± 2.0 % vs 10.4% ± 3.7%; P = .02). Sympathetic innervation in the CKD group was significantly increased compared to the control and CKD-RDN groups [left ventricle: 4.1 ± 1.8 vs 0.8 ± 0.5 (102 µm2/mm2), P <.01; 4.1 ± 1.8 vs 0.9± 0.6 (102 µm2/mm2), P <.01; right ventricle: 3.6 ± 1.0 vs 1.0 ± 0.4 (102 µm2/mm2), P <.01; 3.6 ± 1.0 vs 1.0 ± 0.5 (102 µm2/mm2), P <.01]. CONCLUSION: Neuromodulation by RDN demonstrated protective effects with less structural and electrical remodeling, leading to attenuated VAs. In a rabbit model of CKD, RDN plays a therapeutic role by lowering the risk of VA caused by autonomic dysfunction.

Insights on safety and efficacy of renal artery denervation for uncontrolled-resistant hypertension in a high risk population with chronic kidney disease: first Italian real-world experience.

AIMS: To evaluate the safety and efficacy of catheter-based radiofrequency renal sympathetic denervation (RSD) in a daily practice population of patients with uncontrolled resistant hypertension, on top of medical therapy. METHODS: Consecutive unselected patients with uncontrolled resistant hypertension undergoing RSD were enrolled. Office and ambulatory blood pressure (BP) measurements were collected at baseline and 3, 6 and 12 months after RSD. Efficacy was assessed even in patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2. Patients were defined as responders if systolic BP decreased by at least 5 mmHg at ambulatory BP or by 10 mmHg at office BP at their last follow-up visit. RESULTS: Forty patients with multiple comorbidities underwent RSD from 2012 to 2019. Baseline office and ambulatory BP was 159.0/84.9 ± 26.2/14.9 mmHg and 155.2/86.5 ± 20.9/14.0 mmHg, respectively. At 12-month follow up a significant reduction in office and ambulatory systolic BP, respectively by - 19.7 ± 27.1 mmHg and by - 13.9 ± 23.6 mmHg, was observed. BP reduction at 12-month follow-up among patients with eGFR < 45 mL/min was similar to that obtained in patients with higher eGFR. Twenty-nine patients (74.4%) were responders. Combined hypertension, higher ambulatory systolic BP and lower E/E' at baseline emerged as predictors of successful RSD at univariate analysis. No major complications were observed and renal function (was stable up to 12 months), even in patients with the lowest eGFR values at baseline. CONCLUSION: RSD is safe and feasible in patients with uncontrolled resistant hypertension on top of medical therapy, even in a high-risk CKD population with multiple comorbidities, with a significant reduction in systolic BP and a trend towards a reduction in diastolic BP lasting up to 12 months.

The NEW-HOPE study and emerging therapies for difficult-to-control and resistant hypertension.

Despite the availability of numerous approved antihypertensive drugs, difficult-to-control and resistant hypertension are persistent and are major risk factors for cardiovascular disease. Emerging and investigational treatments that are currently being explored to target hypertension include firibrastat, empagliflozin and interventional procedures, including improved approaches to renal artery denervation and a novel baroreceptor device implantation. Firibrastat is an investigational drug that specifically and selectively inhibits aminopeptidase A leading to decreased formation of angiotensin III in the brain, resulting in decreased blood pressure. Sodium-glucose cotransporter-2 inhibitors, such as empagliflozin used to treat type 2 diabetes, may be beneficial as antihypertensive agents. Empagliflozin in a recent study demonstrated significant reductions in high blood pressure in an African American population. Advances in renal artery denervation and an investigational baroreceptor device implantation also show promise as potential interventions in patients with difficult-to-control and resistant hypertension.

Transvascular Pacing of Aorticorenal Ganglia Provides a Testable Procedural Endpoint for Renal Artery Denervation.

OBJECTIVES: This study sought to develop a method to assess renal sympathetic nerve function through localization and pacing of aorticorenal ganglia (ARG). BACKGROUND: Transcatheter renal denervation procedures often fail to produce complete renal denervation because of the lack of a physiological procedural endpoint. METHODS: High-frequency pacing was performed in the inferior vena cava and aorta in sheep (n = 19) to identify ARG pace-capture sites. Group A (n = 5) underwent injection at the ARG pace-capture site for histological verification, group B (n = 6) underwent unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1 week post-procedure; and group C (n = 8) underwent ARG pacing before and 2 to 3 weeks after unilateral microwave renal denervation. RESULTS: ARG pace-capture responses were observed at paired discrete sites above the ipsilateral renal artery eliciting a change in mean arterial blood pressure of 22.2 (interquartile range [IQR]: 15.5 to 34.3 mm Hg; p < 0.001) with concurrent ipsilateral renal arterial vasoconstriction, change in main renal artery diameter of -0.42 mm (IQR: -0.64 to -0.24 mm; p < 0.0001), and without consistent contralateral renal vasoconstriction. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation led to significant ipsilateral renal denervation. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing-induced renal vasoconstriction and significant ipsilateral renal denervation. CONCLUSIONS: Transvascular ARG pace-capture is feasible and recognized by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing-induced vasoconstriction may indicate successful renal sympathetic denervation and serve as a physiological procedural endpoint to guide transcatheter renal denervation.

Resistant hypertension: Renal denervation or pharmacovigilance? Insights from a renal denervation screening program.

BACKGROUND: With emerging new therapeutic concepts including renal denervation (RDN), there is a renewed interest in resistant hypertension (ResH). Among patients suspected of having ResH, a definitive diagnosis needs to be established. OBJECTIVES: This study presents observations from a standardized single-center screening program for RDN candidates, including medical therapy modification and reassessment. MATERIAL AND METHODS: All patients referred to our center for RDN underwent a standardized screening protocol. Candidates were recruited from among patients receiving no less than 3 antihypertensive drugs, including diuretics with office blood pressure (BP) >140/90 mm Hg. The assessment included 2 measurements of BP and ambulatory BP monitoring (ABPM). If needed, pharmacotherapy was intensified and the diagnosis of ResH was reconfirmed after 6 weeks. If ResH was persistent, patients were hospitalized with repeated ABPM on day 4. Further, renal CT-angio was performed and a multidisciplinary team discussed the patients' suitability for RDN. RESULTS: A total of 87 patients with a ResH diagnosis were referred for RDN. Mean office BP was 159/92 (±7.0/6.5) mm Hg and mean ABPM was 154/90 (±9.0/4.8) mm Hg. The initial medication included angiotensin convertase inhibitors (ACE-I, 78%), angiotensin receptor blockers (12%), ß-blockers (85%), calcium channel blockers (36%), and diuretics (93%). During the 18 months of the RDN program, 5 patients underwent RDN and 2 further had ineligible renal anatomy. A new diagnosis of secondary hypertension was made in 21 patients. However, in 59 patients, BP control was achieved after optimization of medical therapy, with a mean ABPM of 124/74 mm Hg. The final treatment included ACE-I (100%), ß-blockers (92%), indapamide (94%), amlodipine (72%), and spironolactone (61%). Medication in most of these patients (88%) included single-pill triple combination (52.5%) or double combination (35.6%). CONCLUSIONS: Patients with elevated BP screened for RDN require a rigorous diagnostic workup. Up to 2/3 of patients can be managed with strict pharmacotherapy compliance and pharmaceutical intensification, including single-pill combinations and improved drug compliance. Hasty use of RDN may be a result of poor drug optimization and/or compliance. It does remain a viable treatment option in thoroughly vetted ResH patients.

Treating Hypertension Using Renal Artery Denervation: Problems and Progress.

Early reports of renal denervation as a therapy for hypertension generated intense interest in this approach to management of elevated blood pressures despite ongoing treatment. The publication of the large, sham-controlled randomized clinical trial of renal denervation, Symplicity HTN-3, failed to show superiority of renal denervation by radiofrequency energy ablation compared with a sham procedure similar to the procedure used for denervation but without the application of energy to the renal artery. This prompted consideration of confounding factors and rethinking about the protocol and the procedure itself. This review describes these confounders and the progress made to improve trial design in the field of renal artery denervation.

Individualised renal artery denervation improves blood pressure control in Kazakhstani patients with resistant hypertension.

BACKGROUND: The prevalence of hypertension in Kazakhstan is high, and the majority of patients are not adequately controlled. Treatment with renal artery denervation (RAD) could represent a useful therapeutic option for a subset of patients in Kazakhstan with resistant hypertension. AIM: To assess the impact of RAD in a cohort of patients from Kazakhstan with resistant hypertension. METHODS: Between March 2012 and December 2013, 63 patients underwent RAD at our tertiary care centre. Eligibility criteria were office blood pressure more than 160 mm Hg systolic (SBP) or more than 90 mm Hg diastolic (DBP) despite being treated with three or more antihypertensive medications, including a diuretic. Ambulatory blood pressure was measured at baseline and at month 12, and monitoring also included impact on insulin resistance and renal function. RESULTS: There were significant decreases of 25 ± 24 mm Hg for ambulatory SBP during the daytime and of 26 ± 23 mm Hg for ambulatory SBP during the nighttime (p < 0.0001). We observed significant decreases of 12 ± 14 mm Hg for ambula-tory daytime DBP and of 11 ± 14 mm Hg in ambulatory nighttime DBP (p < 0.0001). A decrease in creatinine clearance was observed from 100.2 ± 33.6 mL/min at baseline to 90.2 ± 22.8 mL/min at month 12 (p < 0.001). Homeostasis model assessment-insulin resistance (HOMA-IR) decreased from 3.0 ± 4.6 at baseline to 2.5 ± 3.7 at 12 months (p = 0.007). CONCLUSIONS: In this population RAD resulted in statistically and clinically significant blood pressure reduction at 12 months with minimal adverse events.

Denervação de artéria renal em paciente com hipertensão arterial refratária / Renal denervation in patient with refrataryarterial hypertension

Caso clínico de uma paciente com quadro de hipertensão arterial refratária, sendo inicialmente atribuída como etiologia a displasia de artéria renal. Os níveis pressóricos mantiveram elevados após a angioplastia de artéria renal, mantendo descontrole pressórico apesar do uso de 10 classes de anti-hipertensivos. Foi indicada a denervação de artéria renal e após tal, foi possível redução das medicações e êxito no controle de seus níveis tensionais. Destaca-se a importância do adequado diagnóstico de hipertensão arterial refratária, a exclusão de hipertensão secundária, somado à otimização terapêutica e indicação de procedimentos quando necessário, tendo como objetivo o melhor controle pressórico e consequente redução de lesões de órgãos-alvo e eventos cardiovasculares graves (AU).

It will be explained the patient clinical case of with refractory hypertension, which was initially attributed to renal artery dysplasia, but after the renal artery angioplasty, remained with high blood pressure levels despite adequate anti-hypertensive drugs administration. Renal denervation was indicated and after medications was reduced, with adequate blood pressure level control. It emphasizes the importance of secondary hypertension diagnosis, therapeutic optimization and specific therapies, if necessary, with the aim to take blood pressure control and the consequent reduction of target-organ damage and severe vascular events (AU).

Interventional Therapies for Resistant Hypertension: A Brief Update.

Resistant hypertension remains a clinical challenge with few management options beyond maximisation of medications. Catheter- based renal artery denervation (RDN) was proposed in 2009 as a possible therapy for resistant hypertension and early feasibility trials caused excitement among cardiologists and antihypertensive specialists, showing remarkable and sustained blood pressure reductions. In 2014, enthusiasm for RDN dampened following the SYMPLICITY 3 trial results, which showed no statistically significant difference in blood pressure between the intervention and control arms. However, hope remains for the improved management of resistant hypertension; procedural understanding, technological advancements and alternative targets - such as baroreceptor activation therapy and arteriovenous shunts - may aid the identification of those patients for whom specific interventional therapies will be effective.

Management of Renovascular Hypertension.

Renal artery stenosis is a potentially reversible cause of hypertension, and transcatheter techniques are essential to its treatment. Angioplasty remains a first-line treatment for stenosis secondary to fibromuscular dysplasia. Renal artery stenting is commonly used in atherosclerotic renal artery stenosis, although recent trials have cast doubts upon its efficacy. Renal denervation is a promising procedure for the treatment of resistant hypertension, and in the future, its indications may expand.

Surgical, interventional, and device innovations in the management of hypertension.

The prevalence of hypertension around the world has increased significantly with projections for an increasing major global burden of hypertension. Medication-resistant hypertension can be perplexing and frustrating. The existence of these difficult patients results in the need for additional approaches to treatment including surgery, percutaneous interventions, and device management. The sophistication of these techniques has progressed markedly and initial procedures such as classical sympathectomy and renal artery bypass are almost never performed. Newer techniques of angioplasty with stenting, renal artery denervation, and baroreflex activation therapy via electrical stimulation of the carotid baroreceptors are now in use with increasing evidence for significant benefit.

Resistant hypertension and renal sympathetic denervation--what does the future hold?

Hypertension is a major public health problem and despite adequate pharmacological treatment, blood pressure remains uncontrolled in a subset of patients with hypertension. Renal sympathetic denervation is a percutaneous catheter-based treatment for select patients with resistant hypertension. In this article, we discuss the development of this intervention, its role in patients with resistant hypertension and the need for guarded optimism in the future of device-directed renal sympathetic denervation.