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Abstract

Hypertension (HTN) is one of the most significant medical problems affecting society today. The estimated 76 million Americans with hypertension represent a significant public health problem, contributing to cardiac, vascular, renal, and neurovascular morbidity and mortality. HTN is the most common indication for lifelong pharmacologic treatment, mainly because of the incontrovertible reductions in cardiovascular events with blood pressure (BP) reduction and control. However, despite the availability and potency of multiple different antihypertensive drugs, up to half of American patients have BPs above the recommended target. Given the overwhelming evidence of both the cost to society of HTN and the benefits that are accrued from improved BP control, alternatives or adjuncts to current management options have been sought to aid in treatment of these patients. Over the past few years, a device-based approach involving modulation of the autonomic nervous system, termed renal denervation, has evolved to meet this challenge. With early trials showing startlingly good results, with few side effects, multiple devices were fast-tracked to clinical trials and hence to the market. However, larger trials have shone an unfavorable light on the field, with concerns about the short- and long-term effectiveness, diverting attention back to operational and procedural details. Despite this, image-guided manipulation of the sympathetic nervous system to treat HTN remains a fertile area of laboratory and clinical research.

Keywords

hospital/clinical laboratory management systems engineering clinical automation

Introduction

Hypertension (HTN) is one of the most significant medical problems affecting society today, with an estimated 76 million Americans suffering from HTN. This represents a huge public health problem, contributing to extensive cardiac, vascular, renal, and neurovascular morbidity and mortality.^1,2 Furthermore, the cardiovascular mortality risk rises linearly as blood pressure (BP) rises, roughly doubling for every 20-mm Hg systolic and 10-mm Hg diastolic pressure rise above 115/75 mm Hg.³ A systematic review of reported studies has shown that a 10-mm Hg reduction in systolic BP and 5-mm Hg reduction in diastolic blood pressure results in 20% reduction in coronary heart disease, a 32% reduction in stroke, and a 24% reduction in heart failure.⁴ This, added to the generally asymptomatic nature of HTN with diagnostic and therapeutic challenges, has led to estimates of economic burden in the United States of $73.4 billion.⁵

HTN is the most common indication for lifelong pharmacologic treatment, mainly because of the incontrovertible reductions in cardiovascular events with BP reduction and control. However, despite the availability and potency of multiple different antihypertensive drugs, up to half of American patients have BPs above the recommended target for their demographic.⁶ In such circumstances, appropriate management, including dietary modification, lifestyle measures, compliance programs, and rationalization and optimization of pharmacologic therapies, should be performed. However, despite this, there will remain a certain percentage of patients who have persistently elevated BP, a condition termed resistant hypertension (RH).

RH is a specific clinical entity that is defined as persistent elevation in BP above the targeted goal (above 140/90 mm Hg [130/80 in diabetics or in patients with chronic renal disease]), despite concurrent compliant use of three different antihypertensive agents, at least one of which must be a diuretic.⁷ HTN that is controlled using four or more agents is also considered RH. The prevalence of RH varies according to population characteristics, but in the United States as a whole, up to 12.8% of all hypertensives meet the strict criteria for RH.⁸ Furthermore, as the rate of obesity increases (currently representing 34% of the population),⁹ the prevalence of RH is expected to concomitantly increase.¹⁰

Given the overwhelming evidence of both the cost to society of HTN and the benefits that are accrued from improved BP control, alternatives or adjuncts to current management options have been sought to aid in treatment of these patients. Over the past few years, a device-based approach involving modulation of the autonomic nervous system, termed renal denervation, has evolved to meet this challenge.

Renal Denervation as Therapy for Hypertension

The sympathetic autonomic nervous system modulates cardiovascular physiology via a complex system of central and peripheral neuroendocrine pathways that link the brain, heart, endothelium, nervous system, and kidneys. The efferent sympathetic innervation of the kidneys passes from both contra- and ipsilateral ganglia in postganglionic fibers from the sympathetic chain and ganglia to the adventitial surface of the renal arteries. Stimulation of these nerves contributes to elevating systemic blood pressure by two main mechanisms: stimulating alpha-adrenergic receptors eliciting direct vasoconstriction and, more potently, stimulating beta-adrenergic receptors of the juxtaglomerular apparatus leading to sodium retention, decreasing renal blood flow and activating the renin-angiotensin-aldosterone system with a subsequent increase in the concentration of the vasoconstrictor angiotensin II.^11,12 The afferent renal sympathetic nerves also contribute to systemic BP largely through the action of stretch- and chemoreceptors in the kidney, by modulating central sympathetic nervous system activity.

The sympathetic nervous system is not just a physiologic responder but has also been proven to be an active participant in the pathogenesis of HTN. Recently, markers of sympathetic activity such as plasma norepinephrine, norepinephrine spillover, and the mean frequency of single units of efferent sympathetic nerve activity (s-MSNA) have been shown to be increased in essential HTN and indeed to increase with increasing BP and worsening HTN.¹³ However, the aim of treating HTN by targeting the renal autonomic nervous system is not new. Indeed, up until the advent of oral antihypertensive agents, surgical denervation of the kidney by means of a thoracolumbar splanchnicectomy (“Smithwick procedure”) was performed in large numbers in specialty centers.¹⁴ This yielded a durable improvement in both BP control and mortality but faded from use in the 1960s with pharmacotherapy use due to the high morbidity of the procedure with long-term orthostatic events, sexual dysfunction, and sphincter incontinence.¹⁵

With advances in knowledge about the brain-heart-kidney axis, coming largely from the electrophysiology cardiology community,¹⁶ and in endovascular and energy deposition technologies, the theory of local denervation of renal neural supply has undergone a revival. Causing permanent disruption of the sympathetic nerves running in the adventitia of the renal arteries using nonoperative therapies has become the goal of many groups, with most energies being directed into one of three different strategies: catheter-directed radiofrequency ablation (RFA), ultrasonic ablation, and locally delivered pharmacologic ablation.¹⁷ To date, most clinical trialing and study have been performed into catheter-directed RFA, using platforms such as the Symplicity single-electrode RFA catheter (Medtronic, Minneapolis, MN), the EnligHTN multielectrode RFA catheter (St. Jude, St. Paul, MN), or the Thermocool irrigated RFA catheter (Biosense Webster, Diamond Bar, CA), or CE (Conformité Européenne) marked devices such as the Vessix balloon-mounted platform (Boston Scientific, Natick, MA), the Oneshot multielectrode catheter (Covidien, Dublin, Ireland), or the Iberis (Terumo, Tokyo, Japan). However, ultrasound ablation, such as with the Paradise ultrasonic balloon catheter (ReCor Medical, Ronkonkoma, NY) in the REALISE Trial,¹⁸ and pharmacologic agents, such as the Bullfrog microneedle-equipped balloon catheter (Mercator Medsystems, San Leandro, CA), are either in development or recruiting in trials.

Renal Denervation: Patient Selection, Technical Considerations, and Potential Complications

Patient selection should involve a multidisciplinary team that includes a specialist in the management of HTN and an interventionist skilled in endovascular renal arterial procedures, and it begins with the accurate diagnosis of HTN. This is a complex and controversial field with much debate as to the relative merits and accuracy of different modalities for BP measurement, such as office-based versus ambulatory, intermittent (i.e., several measurements taken at temporally discrete intervals and subsequently averaged) versus continuous, and invasive versus noninvasive methods. Although 24-h ambulatory BP monitoring is now usually required for diagnosis and monitoring in trials, most of the currently published data use office-based noninvasive BP measurement.^19,20 Once HTN has been diagnosed, as >140/90 mm Hg in nondiabetic populations, a diagnosis of RH is confirmed with exclusion of secondary HTN, reinforcement of treatment (increase of the dose of antihypertensive agents up to the maximum tolerated dose, choice of another diuretic, etc.), normalization of salt intake, and dietary/exercise modification.

Once RH has been diagnosed, renal anatomy and function must be evaluated. The 2012 expert consensus on renal denervation from the French Society of Hypertension, French Society of Cardiology, Working Group on Atheroma, Interventional Cardiology, and French Society of Radiology²¹ advised an estimated glomerular filtration rate (GFR) >45 mL/min/1.73 m² and the presence of two functioning kidneys ≥90 mm in the greatest dimension and favorable renal arterial anatomy (i.e., diameter >4 mm on both sides with an ostial trunk to first major branch length of ≥20 mm). Current contraindications include fibromuscular dysplasia and previous renal artery angioplasty or stenting, although case reports of use in stented arteries exist.²² Typically, renal arterial anatomy has been evaluated in the preprocedure screening phase with either contrast-enhanced computed tomography angiography (CTA) or contrast-enhanced magnetic resonance angiography (MRA), although less frequent use of Doppler ultrasound with subsequent catheter angiography has been described. A classification system to identify renal arterial anatomy suitable for RDN (renal denervation) has been proposed,²³ although there is increasing published experience of use of RDN in single or multiple renal arteries outside of established anatomical norms.^23–25

The procedure is performed in an angiography suite with an operator experienced in renal arterial procedures. Typically, at least conscious sedation is required as the short ablation cycles usually produce severe pain, exactly matching the time of ablation, which may be either visceral or somatic in sensation.²⁶ Technical specifics of the procure vary from vendor to vendor, but as currently performed, catheter-based RFA renal denervation commences with unilateral transfemoral arterial access with subsequent canulation of the renal artery with a dedicated catheter connected to a low-energy radiofrequency generator. Slow intra-arterial administration of 0.2 mg nifedipine for spasm prophylaxis (alternatively, use 100–200 µg nitroglycerine) and 2000 IU heparin for thrombosis prophylaxis may be given according to operator preference. The catheter then delivers RFA pulses at short (e.g., 2-min) intervals in a helical pattern to obtain a circumferential ablation of the adventitial renal nerves. The procedure is repeated on the contralateral renal artery.

Renovascular complications range from vasospasm, which is generally mild and does not lead to interruption of the intervention, to dissection. In case of severe spasm with stenosis, the only effective treatment is interruption of the intervention on the effected side. This occurred once in 53 patients in a recently published series.²⁶ Dissection is a feared complication requiring access to, and operator experience with, suitable angioplasty balloons and stents. There was a single renal artery dissection in the 153 patients of the Symplicity HTN-I pilot trial but none in the 106 patients in the Symplicity HTN-II trial. It should be noted that early experience was with a larger 8-Fr system that has subsequently been decreased to 5 or 6 Fr with later generation devices. Access site complications are similar to that for common femoral access procedures in general.

Renal denervation is typically performed as a day case with postprocedure care as for other renal arterial interventions. The patient should be confined to bed rest as a function of the use of a closure device, sedation status, and institutional policy after intra-arterial interventions. There is no need for immediate imaging except where there is intense and acute back pain, which should mandate repeat examination of the patient because this could reflect a local arterial or kidney complication. Patients may be discharged on antiplatelet therapy, as per the discretion of the operator, and follow-up renal function (creatinine/GFR) at 6, 12, 24, and 36 months. Antihypertensive medications are initially continued as BP response is delayed, and current evidence suggests that it reaches its peak at 3 months.¹⁹

Current State of Evidence for Catheter-Based Renal Denervation in Resistant Hypertension

Catheter-based renal denervation by RFA has been demonstrated in preclinical swine studies to cause a comparable reduction in sympathetic activity to direct surgical sympathectomy,²⁷ without significant smooth muscle hyperplasia or renal arterial thrombosis or stenosis. Early human clinical evaluation also mechanistically correlated denervation with reduced norepinephrine spillover, decreased renin activity, and increased renal plasma flow.²⁸ The first human study of catheter-based renal denervation for RH was published as a proof-of-principle cohort study (Symplicity HTN-1) by Krum et al.²⁰ in 2009, with demonstration of a significant and sustained BP reduction in 45 patients up to 1 year.

Encouraging results from these early studies led to enrollment into a larger, open-label, randomized efficacy study based in Europe and Australia (Symplicity HTN-2).¹⁹ The complete and complex details of this important trial are beyond the scope of this study, but in patients with severe RH (systolic BP >160 mm Hg despite three antihypertensives), those randomized to catheter-directed RFA renal denervation had a >30/10-mm Hg drop in BP at 6 months, as opposed to no change in the control/standard treatment group. The result was durable to 12 months, with mean office systolic blood pressure (SBP)/diastolic blood pressure (DBP) decreases of −28/10 mm Hg. Similar positive results with the EnlighHTN RFA catheter were presented with the 6-month data of the ARSENAL trial at the American Heart Association meeting in November 2012, with 76% of patients attaining at least a 10-mm Hg reduction in SBP, and 33.3% had <140 mm Hg SBP without significant vascular complication. A recent systematic review of published data that pooled two randomized controlled studies and 10 observational studies determined that there was a reduction in mean SBP and DBP at 6 months of −28.9 mm Hg and −11.0 mm Hg, respectively, compared with control medically treated patients, as well as a reduction in mean SBP and DBP at 6 months of −25.0 mm Hg and −10.0 mm Hg, respectively, compared with pre-RDN values.²⁹ When added to the possibility of reducing the lifelong polypharmacy associated with RH, the potential for a single device-based therapy to significantly reduce long-term costs is obvious, although the degree of benefit would naturally depend on the efficacy and durability of any RDN procedure.³⁰

While these results are impressive and encouraging, the entire field was thrown into turmoil by the publication of the Symplicity HTN-3 trial,³¹ a prospective, randomized, masked-procedure, single-blind trial, the results of which were published in the New England Journal of Medicine in March 2014. This pivotal study met its primary safety end point, with a rate of major adverse events of 1.4%, but did not meet its primary (office SBP change) or secondary efficacy end points (comparison of SBP change). These discouraging results immediately put a halt to multiple other device-based HTN therapy trials. Despite this, there has been considerable editorial criticism of the Symplicity HTN-3 trial, some of which has been focused on the study populations and whether post hoc analysis to identify susceptible cohorts may be of benefit,³² some of which has been focused on the fall in ambulatory BP in the sham cohort and whether this relates to a significant Hawthorne or placebo effect, and considerable focus on the preprocedural blood pressure medication stabilization regimens.³³ Furthermore, the relative inexperience of operators in the study, with a mean of three procedures performed, may have had a role in the inadvertent “underdenervation” of patients in the treatment arm, with a recent subanalysis demonstrating that only 25% of patients received four-quadrant ablation in at least one renal artery.³¹

While the validity of extending these results to larger and more diverse populations has been questioned, there is no doubt that extensive research is required before the momentum previously behind renal denervation is regained.³⁴ To this end, there have been several studies either commenced or planned, with the specific intention of addressing the concerns raised in Symplicity HTN-3. Funded by Medtronic, the Spyral HTN-ON trial will include approximately 100 patients with uncontrolled HTN but in the moderate- to high-risk HTN group, rather than the severe treatment-resistant population seen in Symplicity HTN-3. This study will enroll patients with ongoing drug antihypertensive therapy, while its closely aligned but separate study, the Spyral HTN-OFF trial, is designed to isolate the effects of RDN on blood pressure control. The Reduce HTN trial, using the Boston Scientific Vessix platform, enrolled a total of 146 patients in 23 centers in Europe, Australia, and New Zealand. While the interim data have been promising, the full publication is eagerly awaited and will function as a comparison to the uninspiring results of the Symplicity HTN-3 trial.

Future Directions

As the field of neuromodulation expands, renal denervation for other disease entities such as heart failure,³⁵ sleep apnea,³⁶ arrhythmia,³⁷ or diabetes³⁸ has pushed the development of new collaborations with groups not usually involved in endovascular therapeutics. As this happens, care must be taken to make sure that this new and exciting but potentially dangerous and costly treatment modality is incorporated into evidence-based treatment protocols and performed safely by physicians with the appropriate training, skill set, and experience^11,39,40 as part of a multidisciplinary team. Hence, referral of patients with RD to centers with experience of renal denervation from participation in established clinical trials is encouraged.

In conclusion, HTN contributes greatly to the burden of cardiac, vascular, neurologic, and renal disease endemic in society. The potential for a treatment strategy that not only improves outcomes but is not dependent on lifelong polypharmacy is enormous. While the results of pivotal trials such as Symplicity HTN-3 have slowed development in this field, ongoing technologic innovations and improvement are sure to expand the demand for this procedure. To ensure best results, renal denervation requires optimization of each step in the innovation chain and remains a fertile area for laboratory and clinical research.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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