Renal sympathetic nervous system and the effects of denervation on renal arteries

Resistant hypertension is associated with chronic activation of the sympathetic nervous system resulting in various comorbidities. The prevalence of resistant hypertension is often under estimated due to various reasons. Activation of sympathetic nervous system at the renal-as well as systemic-level contributes to the increased level of catecholamines and resulting increase in the blood pressure. This increased activity was demonstrated by increased muscle sympathetic nerve activity and renal and total body noradrenaline spillover. Apart from the hypertension, it is hypothesized to be associated with insulin resistance, congestive heart failure and obstructive sleep apnea. Renal denervation is a novel procedure where the sympathetic afferent and efferent activity is reduced by various techniques and has been used successfully to treat drug-resistant hypertension improvement of various metabolic derangements.Renal denervation has the unique advantage of offering the denervation at the renal level, thus mitigating the systemic side effects. Renal denervation can be done by various techniques including radiofrequency ablation, ultrasound guided ablation and chemical ablation. Various trials evaluated the role of renal denervation in the management of resistant hypertension and have found promising results. More studies are underway to evaluate the role of renal denervation in patients presenting with resistant hypertension in different scenarios. Appropriate patient selection might be the key in determining the effectiveness of the procedure.

Renal sympathetic denervation in therapy resistant hypertension-pathophysiological aspects and predictors for treatment success

Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheterinterventional renal sympathetic denervation(RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success.

Renal sympathetic denervation in resistant hypertension

Resistant hypertension remains a major clinical problem despite the available multidrug therapy.Over the next decades,its incidence will likely increase given that it is strongly associated with older age and obesity.Resistant hypertension patients have an increased cardiovascular risk,thus effective antihypertensive treatment will provide substantial health benefits.The crosstalk between sympathetic nervous system and kidneys plays a crucial role in hypertension.It influences several pathophysiological mechanisms such as the central sympathetic tone,the sodium balance and the systemic neurohumoral activation.In fact,studies using several animal models demonstrated that the renal denervation prevented and attenuated hypertension in multiple species.Large reductions in blood pressure were also observed in malignant hypertension patients submitted to sympathectomy surgeries.However,these approaches had an unacceptably high rates of periprocedural complications and disabling adverse events.Recently,an innovative non-pharmacological therapy that modulates sympathetic activation has been successfully developed.Renal sympathetic percutaneous denervation is an endovascular procedure that uses radiofrequency energy to destroy the autonomic renal nerves running inside the adventitia of renal arteries.This method represents a promising new approach to the strategy of inhibiting the sympathetic nervous system.The aim of this review is to examine the background knowledge that resulted in the development of this hypertension treatment and to critically appraise the available clinical evidence.

Effects of renal sympathetic denervation on cardiac systolic function after myocardial infarction in rats

This study investigated the therapeutic effects of renal denervation on cardiac systolic function after myocardial infarction （MI） in rats and the mechanism involved. Fifty male SD rats were randomly assigned to the sham group （n = 15）, the MI group （n = 20）, and the MI plus renal denervation group （n = 15）. MI was established through thoracotomic ligation of the anterior descending artery. Renal denervation was achieved by laparotomic stripping of the renal arterial adventitial sympathetic nerve, approximately 3 mm from the abdominal aorta. Left ventricular function and hemodynamics were measured several weeks following MI. The left ventricular systolic function of the MI group was significantly reduced and the systolic blood pressure （SBP） remarkably declined. In rats with MI treated with renal denervation, the left ventricular ejection fraction （EF）, fractional shortening （FS） and SBP markedly improved compared with the MI group. However, heart rate and fibrosis decreased significantly. These findings suggest that renal denervation has therapeutic effects on post-MI cardiac dysfunction. These effects are associated with increased left ventricular ejection fraction （LVEF） and SBP, as well as reduced heart rate and fibrosis. This may represent a new approach to the treatment of post-MI remodeling and subsequent heart failure.

Renal denervation as an option for the management of hypertension

Hypertension is a multifactorial condition which makes the development of treatment approaches difficult. The vast majority of patients are treated with lifestyle measures either alone or in combination with antihypertensive drugs, and this approach is largely successful in controlling blood pressure. However, for a subgroup of patients, control of blood pressure remains resistant to this approach and therefore the development of new strategies is im- perative. The sympathetic nervous system has been known to be implicated in hypertension for many decades, and evidence from studies in the past has revealed the benefit of reducing sympathetic nerve activity in the control of blood pressure albeit with severe side effects. Recent technological advances have allowed for specific targeting of the renal sympathetic nerves by catheter ablation. The Symplicity HTN-1 and HTN-2 trials have provided strong evidence for renal denervation giving rise to considerable blood pressure reductions in treatment-resistant hyper- tensives and, due to the high incidence of hypertension worldwide, this carries the promise of further reducing the global burden of hypertension and its attendant complications. Here we review the evidence for renal denervation in the management of hypertension.

Renal artery denervation suppresses intractable ventricular arrhythmia in patients with left heart thrombosis

Transcutaneous renal artery denervation （RND） has beeninitially developed for destruction of efferent nerve fireswith luminal delivery of radiofrequency or ultrasonic energyaiming blood pressure reduction in patients with refractoryhypertension. However, other positive results of RNDwere described afterwards, and they include suppression ofatrial fibrillation and ventricular tachycardia （VT） storm.

Chemical renal artery denervation with appropriate phenol in spontaneously hypertensive rats

Objective To explore the effectiveness of renal denervation (RDN) on blood pressure with the appropriate dosage of phenol/ethanol solution in spontaneously hypertensive rats (SHRs). Methods RDN was performed on the bilateral renal artery. Forty SHRs were divided into four groups according on the dosage of phenol (10% phenol in absolute ethanol): sham group, 0.5 mL phenol group, 1 mL phenol group and 1.5 mL phenol group (n = 10 in each group). Blood pressure was measured by tail-cuff plethysmography. Plasma creatinine was determined four weeks after the treatment. The kidneys and renal arteries were collected and processed for histological examination. Results A sustained decrease in systolic blood pressure (SBP) was only observed after the application of 1 mL phenol for four weeks, while SBP was lowered during the first week after RDN and increased in the following three weeks in the 0.5 mL and 1.5 mL phenol groups compared with the sham group. Renal norepinephrine (NE) was significantly decreased four weeks after RDN in the 1 mL and 1.5 mL phenol group compared with the sham group, but not in the 0.5 ml group. RDN with 1 mL phenol obviously reduced glomerular fibrosis. Histopathological analysis showed that tyrosine hydroxylase immunoreactivity was lower in the 1 mL and 1.5 mL phenol groups compared with the sham group. Moderate renal artery damage occurred in the 1.5 mL phenol group. Conclusion Chemical denervation with 1 ml phenol (10% phenol in absolute ethanol) effectively and safely damaged peripheral renal sympathetic nerves and contributed to the sustained reduction of blood pressure in SHRs.

The Effect of Renal Sympathetic Denervation (RSD) in Atrial Fibrillation (AF) Inducibility

Objective: The purpose of this study is to investigate the effects of renal sympathetic nerve stimulation (RSN-S) and ablation (RSN-A) on atrial effective refractory period (ERP) and AF in normal canine heart. Atrial Fibrillation (AF) is a complex disease and one of the most frequent arrhythmias, especially in elderly patients. Multiple mechanisms are involved including interaction between the autonomic nervous system (ANS), electrophysiological properties of the atria, and vulnerability for AF. Cardiac overload increases the incidence of AF. In lone AF the triggers are in the pulmonary veins. AF caused by underlying disease has different mechanism. Atrial fibrillation (AF) is associated with activity of renin-angiotensin-aldosterone system (RAAS). Reduction in renal nor-adrenaline spillover could be achieved after renal sympathetic denervation (RSD). Methods: 1) Establish of atrial fibrillation model;2) Ventricular rate analysis of AF;3) Statistical analysis. Results: 1) The establishment of atrial fibrillation model;2) Inducibility and duration of AF;3) The changes of AERP dispersion. Conclusion: Left RSN-S shortened left atrial ERP, increased ERP dispersion, but did not change right atrial ERP. Bilateral RSN-A produced significant prolongation in both atrial ERP, but did not affect ERP dispersion. The on time of RD effect is at 4 hrs after RD procedure and the RD effect on AF will last for 20 hrs after RD procedure.

Renal Denervation:Past,Present,and Future

Over the past decade,percutaneous renal denervation has been vigorously investigated as a treatment for resistant hypertension.The SYMPLICITY radiofrequency catheter system(Medtronic CardioVascular Inc.,Santa Rosa,CA,USA)is the most tested device in clinical trials.After the positive results of small phase I and II clinical trials,SYMPLICITY HTN-3(a phase III,multi-center,blinded,sham-controlled randomized clinical trial)was completed in 2014,but did not show signifi cant blood pressure lowering effect with renal denervation compared to medical therapy and caused the investigators and industry to revisit both the basic science elements of renal denervation as well as the design of related clinical trials.This review summarizes the SYMPLICITY trials,analyzes the SYMPLICITY HTN-3 data,and provides insights gained from this trial in the design of the most recent clinical trial,the SPYRAL HTN Global clinical trial.Other than hypertension,the role of renal denervation in the management of other disease processes such as systolic and diastolic heart failure,metabolic syndrome,arrhythmia,and obstructive sleep apnea with the common pathophysiologic pathway of sympathetic overactivity is also discussed.

Comparison of a 5 F Microtube-Irrigated Ablation Catheter and a General Ablation Catheter in the Treatment of Resistant Hypertension with Renal Denervation

Objective:To assess the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with resistant hypertension using a 5 F microtube-irrigated ablation catheter.Methods:Sixty patients with resistant hypertension were divided into two groups:a microtube-irrigated ablation catheter group and a general ablation catheter group.We conducted 12-month follow-up of all patients and recorded clinical blood pressure,ambulatory blood pressure,medication use,and biochemistry test results in both groups at the baseline and at the 12-month follow-up.Results:All patients underwent renal denervation.At the 6-month follow-up,ambulatory blood pressure in the mi-crotube-irrigated ablation catheter group was signifi cantly lower than in the general ablation catheter group(systolic blood pressure 142.0±14.4 mmHg vs.150.8±17.9 mmHg,P=0.04;diastolic blood pressure 81.2±7.0 mmHg vs.87.6±8.0 mmHg,P=0.002).At the 12-month follow-up,the between-group difference in ambulatory blood pressure was not statistically signifi cant.At the 12-month follow-up,the number of antihypertensive drugs and diuretics used in the microtube-irrigated ablation catheter group was less than in the general ablation catheter group(P=0.043).There was no statistical difference between the two groups in the results of biochemistry tests and echocardiography.Conclusion:The microtube-irrigated ablation catheter is more effective in treating hypertension than the general ablation catheter at the 6-month follow up and thus fewer antihypertensive drugs were used in the microtube-irrigated ablation catheter group than in the general ablation catheter group.

Main Renal Artery Plus Branch Ablation in the Treatment of Resistant Hypertension with Renal Denervation

Objective:To study the safety and effi cacy of denervation of renal artery branches in the treatment of resistant hy-pertension.Methods:Sixty patients with resistant hypertension were enrolled.The patients were randomly assigned to the main renal artery plus branch ablation group or the main renal artery ablation group.The clinical data and operation-related parameters,including number of ablation points,temperature,and average energy,were recorded.Ambulatory blood pressure was taken for all patients at the baseline and at 6 months after treatment.Offi ce blood pressure was recorded before treatment and after treatment every 3 months for 2 years.Results:Sixty patients with resistant hypertension were enrolled in this study.There were 30 patients in each group.Angiography was performed after ablation.No renal artery complications,such as stenosis and dissection,occurred in the two groups.There was no signifi cant difference in age,sex,BMI,comorbid disease,and medication between the two groups(P>0.05).The number of ablation points for the main renal artery plus branch ablation group was greater than that for the main renal artery ablation group.The offi ce blood pressure and 24-hour blood pressure were signifi cantly lower 6 months after treatment than before treatment in both groups(P<0.05).Offi ce blood pressure in the main renal artery plus branch ablation group was lower than that in the main renal artery ablation group during the 3-12-month follow-up period,with a statistical difference.However,as the follow-up time increased,the difference disappeared.Conclusion:The results of this study show that main renal artery plus branch ablation is a safe interventional method,but there was no obvious advantage on long-term follow-up compared with only main renal artery ablation.

Catheter-based renal sympathetic nerve denervation on hypertension management outcomes

BACKGROUND Renal sympathetic denervation(RSD)provides a minimally invasive interventional treatment modality for patients with resistant hypertension.However,the post-operative outcomes remain a key area of investigation since its earliest clinical trials.AIM To evaluate patient outcomes after RSD intervention among peer-reviewed patient cases.METHODS A systematic review of literature on MEDLINE,Google Scholar,and the Cochrane Database of Systematic Reviews for RSD case studies to assess post-operative hypertension readings and medical management.RESULTS Among 51 RSD cases,the post-operative RSD patients report an apparent reduction with a mean number of 3.1 antihypertensive medications.The mean systolic arterial blood pressure 1 year following RSD was 136.0 mmHg(95%CI:118.7-153.3).CONCLUSION The apparent improvements in office systolic blood pressure after 12 month postoperative RSD can support the therapeutic potential of this intervention for blood pressure reduction.Additional studies which utilized a uniform methodology for blood pressure measurement can further support the findings of this systematic review.

Computed tomography-guided chemical renal sympathetic nerve modulation in the treatment of resistant hypertension: A case report

BACKGROUND Resistant hypertension(RH)has always been a difficult problem in clinical diagnosis and treatment.At present,there is no recognized safe and effective minimally invasive treatment.CASE SUMMARY An 80-year-old woman was admitted to hospital due to trigeminal neuralgia(TN).The patient had a history of RH for more than 10 years and her blood pressure(BP)was not well-controlled.Before the treatment for TN,we decided to perform chemical renal sympathetic denervation with ethanol in the Pain Department of our hospital.One year after the operation,she stopped taking antihypertensive drugs,and her BP was satisfactorily controlled within 4 years after surgery.CONCLUSION Computed tomography-guided chemical renal sympathetic modulation may be a feasible method for the treatment of RH.

经皮去肾神经术:最新证据与患者筛选

尽管有许多药物和非药物治疗可降低血压,但难治性高血压仍是一个重要的健康问题。经皮去肾神经术(RDN)已成为有发展前景、临床证据最多的用于改善血压、提高血压控制率的器械治疗方法。现总结目前RDN治疗高血压的机制,同时总结关于RDN的多项随机假手术对照的临床研究和优化患者选择。

肾动脉去交感神经消融术在高血压治疗中的评价

全球约有12.8亿的高血压患者,在成年人口中约1/3患有高血压,目前我国30~79岁人群中高血压的患病人数为2.57亿^([1])。《中国心血管健康与疾病报告2021》指出,我国25~45岁居民血压正常高值的检出粗率已经高达42.9%~45.5%^([2])。近年多项研究证实,进一步将目标血压降至130/80mm Hg,可以使患者进一步获益。然而,与之形成鲜明对比的是,全球平均高血压控制率仅在13.8%,我国高血压控制率约在16.8%。因此,进一步丰富降压药物与手段,优化血管管理策略,是目前的临床需求。高血压治疗长期以来是“二驾马车”,即生活方式干预和药物治疗,但研究发现,我国高血压药物治疗的依从性一直不容乐观,仅44.8%的高血压患者能坚持每月就诊1次,63.9%能在家中自测血压,而50%在1年内停用降压药物,12.4%每周漏服降压药物≥1次。

中国自主研发去肾神经术器械治疗高血压临床试验数据的特色

经皮去肾神经术(RDN)是继治疗性生活方式改善以及药物治疗之外的第三种降压手段。目前,国内已经完成了三项RDN临床研究,Iberis-HTN研究、Netrod-HTN研究以及SMART研究。三项研究均入选了未控制的高血压人群,进行射频RDN治疗,分别采用6个月时的24小时动态血压、诊室收缩压和复合终点(包括诊室收缩压达标率<140 mmHg)以及抗高血压药负荷指数作为重要终点。初步证明了中国人进行RDN治疗的有效性和安全性。三项研究也显示了中国特色。在器械设计方面,无论是Iberis多电极肾动脉射频消融导管具有经桡动脉路径行RDN的功能,还是SyMapCath TM导管具备肾神经标测/选择性消融的特点以及Netrod网状多电极肾动脉射频消融导管都与国外设计有所不同。国内临床研究设计所提出的药物负荷指数方法也逐渐被认可。期待进一步开展RDN的基础、临床研究,促进高血压以及相关疾病的治疗。

当前不同去肾神经术的特点和存在的问题

多个国家临床指南和专家共识均指出,经导管肾动脉消融去肾神经术(RDN)治疗高血压是除了改善生活方式和药物治疗以外第三种抗高血压治疗方法。射频、超声、乙醇等多种不同方式的RDN器械被研发并开展了系列临床研究。现将详细分析这些不同RDN消融技术的基本特性、临床研究结果及存在的问题和争议,并对未来的发展方向进行探讨。

肾神经消融术治疗高血压的病理生理学基础和临床研究进展

高血压是严重危害人类健康的慢性心血管疾病,尽管有多种治疗药物,但大多数患者的血压仍未达到指南推荐的理想水平。交感神经过度激活在高血压发病中起重要作用,肾动脉交感神经消融术通过使用导管消融技术去除肾神经包括肾交感传出神经和传入神经,从而降低交感神经活动,成为高血压重要的补充和非药物治疗方法,特别是用于顽固性高血压的治疗。临床研究显示了肾动脉交感神经消融术的安全性和有效性,可以降低顽固性高血压患者的动脉血压、改善高血压预后。

经皮去肾神经术治疗高血压的临床获益:证据和争议

高血压是全球心血管疾病发病率和死亡率增加重要的可改变的危险因素之一。尽管目前有多种药物治疗和非药物治疗方法,高血压的控制率仍较低。经皮去肾神经术是一种微创介入手术,其作为一种新兴的高血压治疗方法备受关注,十余年来开展了一系列的临床研究。现总结当前经皮去肾神经术治疗高血压临床获益的证据和争议,旨在指导临床实践并推动相关研究的进展。

肾动脉与高血压

针对肾动脉与高血压的研究已有近百年历史。在肾血管性高血压领域,既往多项随机对照研究提示介入治疗并未在药物治疗基础上给患者提供进一步获益,但功能学评估及新型影像学方法有望进行更精准的患者筛选与个体化治疗评估。围绕肾动脉开展的去肾神经术这一新技术在经历了一波三折的循证研究历程后,即将进入中国临床应用。全面回顾以往研究、客观正确认识新技术的两面性,是其良性发展的有力保证。不仅如此,更多新的高血压介入诊疗技术仍在研究,围绕肾动脉的相关新技术仍将在高血压的精准诊断和治疗中发挥不可替代的作用,并造福广大患者。