Histological examination of renal nerve distribution, density, and function in humans.

BACKGROUND: Renal denervation is optimised when guided by knowledge of nerve distribution. AIMS: We aimed to assess sympathetic nerve distribution along the renal arteries, especially in post-bifurcation vessel segments. METHODS: Renal arteries and surrounding tissue from 10 body donors were collected and examined histologically. Immunohistochemical staining was used to analyse nerve distribution and to identify afferent and efferent sympathetic nerves. RESULTS: A total of 6,781 nerves surrounding 18 renal arteries were evaluated. The mean lumen-nerve distance of the left renal artery (2.32±1.95 mm) was slightly greater than the right (2.29±2.03 mm; p=0.161); this varied across the arteries' courses: 3.7±2.3 mm in proximal segments, 2.5±2.0 mm in middle segments, 1.9±1.6 mm in distal prebifurcation segments and 1.3±1.0 mm in post-bifurcation segments (p<0.001). The number of nerves per quadrant was highest in the proximal segments (13.7±18.6), followed by the middle (9.7±7.9), distal prebifurcation (8.0±7.6), and distal post-bifurcation (4.3±4.0) segments (p<0.001). Circumferentially, the number of nerves was highest in the superior (7.8±9.4) and the ventral (7.6±13.1) quadrants (p=0.638). The mean tyrosine hydroxylase (TH) to calcitonin gene-related peptide (CGRP) ratio increased from proximal (37.5±33.5) to distal (72.0±7.2 in the post-bifurcation segments; p<0.001). Thirty-eight neuroganglia were identified along 14 (78%) renal arteries. CONCLUSIONS: Nerves converge to the renal arteries' lumen in the distal segments and along branches, resulting in the lowest number of nerves per quadrant and the shortest lumen-nerve distance in the distal post-bifurcation segments. Efferent nerves occur predominantly, and the ratio of efferent to afferent nerves continues to increase in the vessels' course.

Renal nerve stimulation identifies renal innervation and optimizes the strategy for renal denervation in canine.

BACKGROUND: Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. METHODS: The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. RESULTS: The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). CONCLUSIONS: RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN.

Translational value of preclinical models for renal denervation: a histological comparison of human versus porcine renal nerve anatomy.

BACKGROUND: Preclinical models have provided key insights into the response of local tissues to radiofrequency (RF) renal denervation (RDN) that is unobtainable from human studies. However, the anatomic translatability of these models to the procedure in humans is incompletely understood.  Aims: We aimed to compare the renal arterial anatomy in normotensive pigs treated with RF-RDN to that of human cadavers to evaluate the suitability of normotensive pigs for determining the safety of RF-RDN. METHODS: Histopathologic analyses were performed on RF-treated renal arteries in a porcine model and untreated control renal arteries. Similar analyses were performed on untreated renal arteries from human cadavers.  Results: In both human and porcine renal arteries, the median number of nerves was lower in the more distal sections (the numbers in the proximal, middle, distal, 1st bifurcation, and 2nd bifurcation sections were 65, 58, 47, 22.5, and 14.7 in humans, respectively, and 39, 26, 29, 16.5, and 9.3 in the porcine models, respectively). Renal nerves were common in the regions between arteries and adjacent veins, but only 3% and 13% of the renal nerves in humans and pigs, respectively, were located behind the renal vein. The semiquantitative score of RF-induced renal arterial nerve necrosis was significantly greater at 7 days than 28 days (0.98 vs 0.75; p=0.01), and injury to surrounding organs was rarely observed. CONCLUSIONS: The distribution of nerve tissue and the relative distribution of extravascular anatomic structures along the renal artery was similar between humans and pigs, which validates the translational value of the normotensive porcine model for RDN.

Histological evidence supporting the durability of successful radiofrequency renal denervation in a normotensive porcine model.

BACKGROUND: Sustained blood pressure reductions after radiofrequency (RF) renal denervation (RDN) have been reported to 3 years in patients with uncontrolled hypertension. However, mechanistic data to support procedural durability are lacking. We aimed to quantify the long-term nerve anatomic and functional effects of RF RDN in a preclinical model. METHODS: Bilateral RF RDN was performed in 20 normotensive swine. Renal tissue samples were obtained in the RDN-treated groups at 7 ( n  = 6), 28 ( n  = 6), and 180 days ( n  = 8) postprocedure for quantification of cortical norepinephrine (NE) levels and renal cortical axon density. Tissue fibrosis, necrosis and downstream nerve fiber atrophy (axonal loss) were also scored for each sample. Three additional untreated groups ( n  = 6, n  = 6 and n  = 8, respectively) served as control. RESULTS: Pathologic nerve changes were characterized by necrosis in the ablated region at 7 days that partially resolved by 28 days and fully resolved at 180 days. Axonal loss was apparent within and downstream to the ablation regions and was evident at 7, 28 and 180 days in the main vessel and branch vessels. Consequently, renal cortical axon density and corresponding cortical NE levels were significantly reduced at 7 days in the RDN vs. control group and remained suppressed at 180 days. CONCLUSIONS: Reductions in renal NE, cortical axon density and downstream axonal loss caused by axonal destruction persisted through 180 days post-RDN in a normotensive swine model. These results suggest functional nerve regrowth after RF RDN is unlikely and support published clinical evidence that the procedure results in durable blood pressure reduction.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction in isolated renal artery.

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) repressively regulates protein translation through phosphorylating eEF2. We previously showed that expression and activity of eEF2K are increased in isolated mesenteric arteries from spontaneously hypertensive rats (SHR) contributing to development of essential hypertension. Furthermore, we have recently shown that 7-Amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide (A484954), a selective eEF2K inhibitor, induces endothelium-dependent relaxation in isolated mesenteric arteries from SHR inducing an antihypertensive effect. In order to test the hypothesis that inhibition of eEF2K activity induces vasodilatation by suppressing sympathetic nerve activity, we examined the effects of A484954 on perivascular sympathetic nerve stimulation-induced contraction in isolated renal artery from normotensive and hypertensive rats. Electrodes were placed near the isolated renal arteries that were applied with transmural nerve stimulation (TNS). Then, contraction of the arteries was isometrically measured. A484954 inhibited TNS-induced contraction. The A484954-mediated inhibition of TNS-induced contraction was significantly prevented by NG-nitro-L-arginine methyl ester. In SHR isolated renal artery, TNS-induced contraction was enhanced compared with normotensive Wistar rats. Furthermore, A484954-mediated inhibition of TNS-induced contraction in SHR was enhanced compared with Wistar rats. In conclusion, this study demonstrates for the first time that A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction at least in part perhaps through nitric oxide (NO) release from NO-operating nerve.

Time, Temperature, Power, and Impedance Considerations for Radiofrequency Catheter Renal Denervation.

Radio frequency (RF) based percutaneous catheter renal denervation systems offer an additional clinical tool, along with lifestyle modification and drug therapy, to address the global epidemic of uncontrolled hypertension. The most widely applied RF system has been designed to optimize both procedural and safety and efficacy. Lesion size, shape, and depth result from a complex interaction of device design, anatomy, and tissue electrical conduction properties. Power control algorithms must be carefully designed, incorporating feedback to maximize nerve destruction while minimizing collateral damage. Physical and numerical modelling as well as analysis of sensor feedback provide insight into design performance that cannot be derived from clinical trials. This review is focused on key design and performance aspects of the most widely applied renal denervation system meant to optimize safety and efficacy of the procedure.

Renal artery denervation prevents ventricular arrhythmias in long QT rabbit models.

Long QT syndrome (LQTS) is commonly presented with life-threatening ventricular arrhythmias (VA). Renal artery denervation (RDN) is an alternative antiadrenergic treatment that attenuates sympathetic activity. We aimed to evaluate the efficacy of RDN on preventing VAs in LQTS rabbits induced by drugs. The subtypes of LQTS were induced by infusion of HMR-1556 for LQTS type 1 (LQT1), erythromycin for LQTS type 2 (LQT2), and veratridine for LQTS type 3 (LQT3). Forty-four rabbits were randomized into the LQT1, LQT2, LQT3, LQT1-RDN, LQT2-RDN, and LQT3-RDN groups. All rabbits underwent cardiac electrophysiology studies. The QTc interval of the LQT2-RDN group was significantly shorter than those in the LQT2 group (650.08 ± 472.67 vs. 401.78 ± 42.91 ms, p = 0.011). The QTc interval of the LQT3-RDN group was significantly shorter than those in the LQT3 group (372.00 ± 22.41 vs. 335.70 ± 28.21 ms, p = 0.035). The VA inducibility in all subtypes of the LQT-RDN groups was significantly lower than those in the LQT-RDN groups, respectively (LQT1: 9.00 ± 3.30 vs. 47.44 ± 4.21%, p < 0.001; LQT2: 11.43 ± 6.37 vs. 45.38 ± 5.29%, p = 0.026; LQT3: 10.00 ± 6.32 vs. 32.40 ± 7.19%, p = 0.006). This study demonstrated the neuromodulation of RDN leading to electrical remodeling and reduced VA inducibility of the ventricular substrate in LQT models.

Mapping Renal Innervations by Renal Nerve Stimulation and Characterizations of Blood Pressure Response Patterns.

Increased sympathetic nervous activity is one of main contributors to pathogenesis and progression of hypertension. Renal denervation (RDN) has been demonstrated as a potential therapy for treatment of hypertension; however, lack of indicators of intra-/post-procedure results in inconsistent clinical outcomes. Renal nerve stimulation (RNS), a simple and promising method, could evoke elevated blood pressure as an intraoperative indicator for RDN. But related researches on patterns of blood pressure responses to RNS are still incomplete. To investigate and categorize the phenotypes of blood pressure response to RNS and heart rate alteration before and after RNS, 24 Chinese Kunming dogs were used to perform RNS from bifurcation to ostium of renal arteries after angiography, and a total of 483 stimulated sites were complete. We identified five different patterns of blood pressure response to RNS in 483 stimulated sites, (1) continuous ascending and finally keeping steady above baseline (26.9%), (2) declining and then rising over baseline (11.8%), (3) declining and then rising but below baseline (14.5%), (4) fluctuating in the vicinity of baseline (39.5%), and (5) continuous declining and finally keeping steady below baseline (7.2%), and found no difference in RR intervals among five blood pressure responses before and after renal nerve stimulation. Renal nerve stimulation could elicit different patterns of blood pressure response, which could potentially assist in distinguishing sympathetic-excitatory sites and sympathetic-inhibitory sites from mixed nerve components, which might help to improve the efficacy of RDN.

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).

Technical advance in silico and in vitro development of a new bipolar radiofrequency ablation device for renal denervation.

BACKGROUND: Renal denervation with radiofrequency ablation has become an accepted treatment for drug-resistant hypertension. However, there is a continuing need to develop new catheters for high-accuracy, targeted ablation. We therefore developed a radiofrequency bipolar electrode for controlled, targeted ablation through Joule heating induction between 60 and 100 °C. The bipolar design can easily be assembled into a basket catheter for deployment inside the renal artery. METHODS: Finite element modeling was used to determine the optimum catheter design to deliver a minimum ablation zone of 4 mm (W) × 10 mm (L) × 4 mm (H) within 60 s with a 500 kHz, 60 Vp-p signal, and 3 W maximum. The in silico model was validated with in vitro experiments using a thermochromic phantom tissue prepared with polyacrylamide gel and a thermochromic ink additive that permanently changes from pink to magenta when heated over 60 °C. RESULTS: The in vitro ablation zone closely matched the size and shape of the simulated area. The new electrode design directs the current density towards the artery walls and tissue, reducing unwanted blood temperature increases by focusing energy on the ablation zone. In contrast, the basket catheter design does not block renal flow during renal denervation. CONCLUSIONS: This computational model of radiofrequency ablation can be used to estimate renal artery ablation zones for highly targeted renal denervation in patients with resistant hypertension. Furthermore, this innovative catheter has short ablation times and is one of the lowest power requirements of existing designs to perform the ablation.

Renal Denervation by Noninvasive Stereotactic Radiotherapy Induces Persistent Reduction of Sympathetic Activity in a Hypertensive Swine Model.

Background We have previously reported the feasibility of noninvasive stereotactic body radiotherapy (SBRT) as a novel approach for renal denervation. Methods and Results Herein, from a translational point of view, we assessed the antihypertensive effect and chronological evolution of SBRT-induced renal nerve injury within 6 months in a hypertensive swine model. Hypertension was induced in swine by subcutaneous implantation of deoxycorticosterone acetate pellets in combination with a high-salt diet. A single dose of 25 Gy with SBRT was delivered for renal denervation in 9 swine within 3.4±1.0 minutes. Blood pressure levels at baseline and 1 and 6 months post-SBRT were comparable to control (n=5), whereas renal norepinephrine was significantly lower at 6 months (P<0.05). Abdominal computed tomography, performed before euthanasia and renal function assessment, remained normal. Standard semiquantitative histological assessment showed that compared with control (1.4±0.4), renal nerve injury was greater at 1 month post-SBRT (2.3±0.3) and peaked at 6 months post-SBRT (3.2±0.8) (P<0.05), along with a higher proportion of active caspase-3-positive nerves (P<0.05). Moreover, SBRT resulted in continuous dysfunction of renal sympathetic nerves and low level of nerve regeneration in 6 months by immunohistochemistry analysis. Conclusions SBRT delivering 25 Gy for renal denervation was safe and related to sustained reduction of sympathetic activity by aggravating nerve damage and inhibiting nerve regeneration up to 6 months; however, its translation to clinical trial should be cautious because of the negative blood pressure response in the deoxycorticosterone acetate-salt hypertensive swine model.

Renal denervation in a patient with a highly tortuous renal artery using a guide extension catheter: a case report.

BACKGROUND: Catheter-based renal denervation (RDN) has been introduced to treat resistant hypertension. Although the technology of RDN has been largely improved, denervation of tortuous renal arteries remains challenging. CASE PRESENTATION: This is a case report of a 49-year-old man with drug resistant hypertension. The patient was selected for RDN after ruling out possible causes of secondary hypertension. Computed tomography angiography showed a highly tortuous left renal artery. An Iberis multielectrode ablation catheter failed to reach the target vessel with a regular guiding catheter. A 5-French extension catheter was introduced into the proximal segment of the main left renal artery to provide extra support force, which enabled successful ablation of the highly tortuous left renal artery. His ambulatory blood pressure was significantly decreased at 1 month follow-up. CONCLUSIONS: It is feasible and effective to use a guide extension catheter for denervation of highly tortuous renal arteries. The present study provides a useful method to ablate tortuous and angled renal arteries and branches.

Effect of renal denervation on long-term outcomes in patients with resistant hypertension.

Increasing studies strongly prove that renal denervation, a minimally invasive surgery, is a promising new non-drug treatment method that can effectively control blood pressure in patients with resistant hypertension, but the evaluation of the long-term blood pressure control effect of renal denervation for resistant hypertension is still lacking. Here, we critically review current long-term follow-up data about the use of renal denervation for RH to comprehensively evaluate the effectiveness of renal denervation for RH, and to provide practical guidance for practitioners who are establishing a renal denervation service. Limited by the current research, many problems need to be solved before renal denervation is applied to RH. In addition, ambulatory blood pressure should be the first choice for the evaluation of blood pressure. Finally, the continuous antihypertensive effect of renal denervation in different renal denervation systems also needs to be strictly compared.

Renal Denervation in Hypertension.

The column in this issue is supplied by Drs. Benjamin Lee, MD, and Usman Ansari, DO. Dr. Lee is an assistant professor of clinical medicine at the Houston Methodist Institute for Academic Medicine and Weill Cornell Medical College. After earning his medical degree at Harvard Medical School, Dr. Lee completed a residency in internal medicine and a nephrology fellowship at the University of California San Francisco (UCSF) while simultaneously obtaining a master of advanced study in clinical research from the UCSF departments of Epidemiology and Biostatistics. He maintains his clinical practice with the Houston Kidney Consultants. Dr. Ansari earned a Doctor of Osteopathy from Touro University College of Osteopathic Medicine in California and is completing his internal medicine residency at Houston Methodist.

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.

BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.

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.

Impact of Renal Pelvic Denervation on Systemic Hemodynamics and Neurohumoral Changes in a Porcine Model.

INTRODUCTION: The blood pressure (BP) response to arterial renal denervation (RDN) is variable. METHODS: This study examined the effectiveness of renal pelvic denervation (RPD) on BP, heart rate (HR), norepinephrine (NE), and histopathology in 42 swine. NE levels were measured immediately, 7, 14, 30, and 90 days after RPD. Intra-arterial BP and HR were measured throughout RPD and after 14 days in 5 swine. RESULTS: During the procedure, RPD immediately reduced systolic BP (-20.6 ± 18.3 mm Hg), diastolic BP (-6.0 ± 8.3 mm Hg), and HR (-5.4 ± 5.6 bpm), which remained decreased at follow-up. The porcine kidneys had a mean NE reduction of 76% directly post procedure and 60% after 7 days, 64% after 14 days, 57% after 30 days, and 65% after 90 days. Histopathological examination confirmed nerve ablation. CONCLUSIONS: These preliminary findings suggest that the renal pelvis nerve ablation is an encouraging target for RDN. Clinical trials are required to test the feasibility of RPD in human hypertension.

Changes in Plasma Renin Activity After Renal Artery Sympathetic Denervation.

BACKGROUND: The renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP. OBJECTIVES: The purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN. METHODS: Analyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus <0.65 ng/ml/h (n = 116). Follow-up treatment differences between RDN and sham control groups were adjusted for baseline values using multivariable linear regression models. RESULTS: Baseline PRA was similar between RDN and control groups (1.0 ± 1.1 ng/ml/h vs. 1.1 ± 1.1 ng/ml/h; p = 0.37). Change in PRA at 3 months from baseline was significantly greater for RDN compared with control subjects (-0.2 ± 1.0 ng/ml/h; p = 0.019 vs. 0.1 ± 0.9 ng/ml/h; p = 0.14), p = 0.001 for RDN versus control subjects, and similar differences were seen for aldosterone: RDN compared with control subjects (-1.2 ± 6.4 ng/dl; p = 0.04 vs. 0.4 ± 5.4 ng/dl; p = 0.40), p = 0.011. Treatment differences at 3 months in 24-h and office systolic blood pressure (SBP) for RDN versus control patients were significantly greater for patients with baseline PRA ≥0.65 ng/ml/h versus <0.65 ng/ml/h, despite similar baseline BP. Differences in office SBP changes according to baseline PRA were also observed earlier at 2 weeks post-RDN. CONCLUSIONS: Plasma renin activity and aldosterone levels for RDN patients were significantly reduced at 3 months when compared with baseline as well as when compared with sham control. Higher baseline PRA levels were associated with a significantly greater reduction in office and 24-h SBP. (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study; NCT02439749).

Renal Sympathetic Denervation in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Arterial hypertension is the most common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and mediates adverse hemodynamics through related aortic stiffness and increased pulsatile load. We aimed to investigate the clinical and hemodynamic implications of renal sympathetic denervation (RDN) in patients with HFpEF and uncontrolled arterial hypertension. METHODS: Patients undergoing RDN between 2011 and 2018 in a single-center were retrospectively analyzed and classified as HFpEF (n=99) or no HF (n=65). Stroke volume index and aortic distensibility were measured through cardiac magnetic resonance imaging, and left ventricular (LV) systolic and diastolic properties were assessed echocardiographically. RESULTS: At baseline, patients with HFpEF had higher stroke volume index (median 40 [interquartile range, 33-48] versus 33 [26-40] mL/m2, P=0.002), pulse pressure (69 [63-77] versus 61 [55-67] mm Hg, P<0.001), but lower LV-VPES100mm Hg (18 [10-28] versus 24 [15-40] mL, P=0.007) and aortic distensibility (1.5 [1.1-2.6] versus 2.7 [1.1-3.5] 10-3 mm Hg-1, P=0.013) as compared to no-HF patients. Systolic blood pressure decreased comparable in patients with HFpEF and no-HF patients following RDN (-9 [-16 to -2], P<0.001). After RDN stroke volume index (-3 [-9 to +3] mL/m2, P=0.011) decreased and aortic distensibility (0.2 [-0.1 to +1.1] 10-3 mm Hg-1, P=0.007) and systolic stiffness (P<0.001) increased in HFpEF patients. LV diastolic stiffness and LV filling pressures as well as NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased after RDN in patients with HFpEF (P=0.032, P=0.043, and P<0.001, respectively). CONCLUSIONS: Patients with HFpEF undergoing RDN showed increased stroke volume index, vascular, and LV stiffness as compared to no-HF patients. Following RDN those hemodynamic alterations and reduced systolic and diastolic LV stiffness were partly normalized, implying RDN might be a potential therapeutic strategy for arterial hypertension and HFpEF.