Author + information
- Received July 30, 2012
- Revision received September 10, 2012
- Accepted September 12, 2012
- Published online January 1, 2013.
- ↵⁎Reprint requests and correspondence:
Dr. Mehdi H. Shishehbor, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Mail Code J3-5, Cleveland, Ohio 44195
The treatment of resistant hypertension has undergone remarkable advancements in recent years. Endovascular radio frequency renal sympathetic denervation (RSD) has shown initial success in treating resistant hypertension by targeting the connection between the brain and renal sympathetic nerves. However, the encouraging results of first-generation RSD have been tempered by important procedural limitations and a need for long-term results of safety and efficacy. In an effort to build on early clinical success, several second-generation RSD technologies are now being developed that may improve procedural safety and efficacy. Preliminary evidence for some of the latest technologies is now available. In this review, we summarize the current evidence in support of RSD and consider unique features of several new technologies that are likely to refine the endovascular treatment of resistant hypertension.
Among the estimated 76 million Americans with hypertension, over one-half have inadequately controlled blood pressure (BP) (1). This looming problem persists despite national public health efforts promoting awareness and achieving improved treatment rates (1). Over the past decade, new therapeutic options for uncontrolled and resistant hypertension (RH) that target the autonomic nervous system have become the focus of considerable medical interest. Renal sympathetic denervation (RSD) has stood out as an intriguing and potentially viable treatment option for RH, as was expertly reviewed in a previous issue of JACC: Cardiovascular Interventions (2). However, important limitations with available RSD treatments have provided an opportunity for novel technologies to improve on already impressive BP-lowering results.
Here we briefly review the societal impact of RH, elaborate on the evolution of treatment favoring use of autonomic modulation for RH, and explore various endovascular strategies that may strengthen therapeutic options against RH.
Scope of Resistant Hypertension
Resistant hypertension is defined as persistent elevation of BP above goal despite concurrent use of 3 antihypertensive agents, each of unique class with a diuretic included among the treatment regimen, and with all drugs at target dose (3). Hypertension that is controlled to goal levels using 4 or more medications is also considered resistant to treatment (3). From the 2003 to 2008 National Health and Nutrition Examination survey cycles, 12.8% of the U.S. adult hypertensive population met the strict definition for RH (4).
Even though RH accounts for a minor proportion of the overall hypertensive population, it serves as an alarming marker of increasingly more difficult BP control (5). Among adult Americans taking at least 3 medications, the rate of uncontrolled hypertension has risen from 15.9% (1988 to 1994) to 28.0% (2005 to 2008) (6), mirroring the rising prevalence of obesity from 23% (1988 to 1994) to 34% (2007 to 2008) (7). As the epidemic of obesity and diabetes grows, the prevalence of RH, and its associated costs are sure to rise. Whereas cost-effectiveness and durability of new RH therapies has yet to be determined, the concept of successful BP reduction among high-risk populations has garnered considerable enthusiasm for patients and providers.
Splanchnicectomy and the Basis for Renal Sympathetic Denervation
The basis for targeting the autonomic nervous system to treat RH was established decades ago. In 1938, hypertension had a 25% prevalence among Americans and carried a clear association with cardiovascular disease (8). Treatment was limited to a small number of sedative and antihypertensive drugs and radical surgeries, such as nephrectomy and surgical lysis of the autonomic nerves. Thoracolumbar splanchnicectomy was introduced as a treatment for hypertension, a particularly invasive surgical procedure involving resection of splanchnic innervation to the kidneys (9). The benefits of splanchnicectomy were confirmed in a large nonrandomized clinical trial that spanned nearly a decade from 1938 to 1947. The dramatic results of surgery were clear; for those treated surgically (n = 1,266) versus those declined for surgery and treated medically (n = 467), 5-year mortality rates were 19% and 54%, respectively (9). Furthermore, the BP-lowering result after surgery was durable. After a successful operation, some patients enjoyed BP-lowering results that extended up to 10 years or more. Nevertheless, as medical treatments became increasingly available and effective, adverse surgical side effects and procedural risks relegated surgical splanchnicectomy out of favor.
Over the next 50 years, considerable research efforts contributed to a more refined understanding of the benefits of autonomic renal nerve modification. The kidneys are richly innervated with post-ganglionic sympathetic efferent fibers that associate with efferent and afferent renal arterioles, the juxtaglomerular apparatus, and the renal tubular system (10). Acute increase in efferent sympathetic nerve activity from the brain to the kidney results in renal vasoconstriction, renin release, and sodium retention (Fig. 1). When unchecked, excessive renal sympathetic efferent tone from the brain contributes to pathological hypertension through these mechanisms (Fig. 2) (11).
With recent advancements in technology, the concept of severing the brain-kidney connection to treat poorly controlled hypertension has undergone a revival. RSD targets the renal efferent and afferent sympathetic nerves, which lie in the adventitia of the arterial wall and are locally injured during the procedure, thereby reducing brain-kidney crosstalk and systolic BP. RSD has evolved into 3 unique strategies: radiofrequency ablation (RFA); ultrasonic ablation; and tissue-directed pharmacological ablation (Table 1). Most RSD technologies have been investigated among the RH population, although contemporary clinical studies have expanded application to a population with less-severe BP elevation that does not meet the strict definition of RH. Emerging preliminary results from small clinical trials provide encouraging signs that RSD for RH is rapidly advancing.
Radiofrequency Ablation Technology
The feasibility of RFA for the renal nerves using a standard electrophysiology catheter has been applied and proven successful (12). However, proprietary systems specifically designed for RSD are most likely to maximize patient comfort, procedural safety, and efficacy, if not at greater costs. Several variations of RFA technology designed for RSD are under clinical study or are in development.
Symplicity renal denervation system
The Symplicity catheter system (Medtronic Inc., Minneapolis, Minnesota) uses a novel percutaneous single-electrode RFA catheter inserted sequentially into each renal artery that delivers ablative energy to the endoluminal surface. The Symplicity catheter system received CE (Conformité Européene) Mark approval in Europe (2010), although it remains investigational in the United States. The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial is currently under way and will be pivotal for potential U.S. Food and Drug Administration approval of the device.
The SYMPLICITY HTN-1 (SYMPLICITY I: One-Year Results Following Sympathetic Renal Denervation in Refractory Hypertension) (13) and SYMPLICITY HTN-2 (Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension) (14) clinical trials evaluated the safety and effectiveness of RSD among an international cohort of patients with RH. The SYMPLICITY HTN-1 trial was a proof-of-principle, open-label, multicenter study of procedural safety and efficacy for RSD among patients with RH (13). The SYMPLICITY HTN-2 trial was a larger, randomized, efficacy study that built on the impressive results from SYMPLICITY HTN-1 (14). The results of these trials have been extensively reviewed elsewhere (2,15–18) and are summarized in Table 2. Important limitations of the Symplicity catheter system have provided opportunities for further improvement of RSD application. These opportunities now drive emerging technologies focused on advancing the application of RSD.
Limitations of the SYMPLICITY HTN-1 and HTN-2 trials
Although the Symplicity catheter system has proven itself as an acceptably safe and effective treatment for RH, several aspects of the RSD procedure are likely to undergo optimization in the near future. Reducing procedural duration and exposure to painful endovascular RFA is a priority. Smaller delivery systems might expand application to a broader spectrum of patients; currently, the Symplicity catheter is not recommended for renal arteries <4 mm in diameter or those with <20 mm of longitudinal endoluminal surface accessible for ablation. Mapping of pre- and post-procedural renal nerve activity may provide confirmation of procedural success, thereby enhancing effectiveness and durability of RSD.
Periprocedural sedation is required for diffuse, visceral, nonradiating abdominal pain during denervation. The Symplicity procedure involves a series of 2-min ablations along the endoluminal surface of the artery (19). The initial procedure time reported in the SYMPLICITY HTN-1 trial was estimated at 40 min, although as experience has grown, procedural time continues to shrink. Reducing procedural time and exposure to painful ablation has been an important advance in newer technologies.
The Symplicity catheter system requires femoral arterial access to place a guiding catheter in the renal arteries through which the Symplicity catheter is advanced. In the SYMPLICITY HTN-1 trial, a single patient suffered renal artery dissection due to manipulation of the guiding catheter. Another patient developed a femoral pseudoaneurysm. From the SYMPLICITY HTN-2 trial, procedure-related adverse events included a single femoral artery pseudoaneurysm. Radial arterial access has become increasing popular for endovascular procedures owing to reduced rates of vascular complications. Radial access RSD may also facilitate cannulation of the renal arteries and improve procedural safety. Further advancements that might eliminate the need for a guiding catheter, which can have more aggressive angulations than the treatment catheter itself, might reduce procedure-related renal artery dissection.
Other acute, procedural complications that have been reported include intraprocedural bradycardia requiring atropine and post-procedural hypotension. Whereas these dramatic consequences of RSD likely indicate the abrupt effect of the procedure, the ablation of renal nerves might be best tolerated with a graded, gradual ablative effect. New technologies that provide biochemical ablation might enable such a strategy.
The short-term BP-lowering results from SYMPLICITY HTN-1 and HTN-2 are encouraging, although further evidence is needed to confirm the durability and long-term effectiveness of RSD. Among a small cohort of nonrandomized patients in the original SYMPLICITY HTN-1 cohort, 2- and 3-year results suggest the technology offers durable BP-lowering. Mean reduction in office-based BP at 2 years (n = 18) was −32/−14 mm Hg (20) and at 3 years (n = 24) was −33/−19 mm Hg (21). Nevertheless, 13% of SYMPLICITY HTN-1 patients had systolic BP reductions <10 mm Hg and were deemed nonresponders (13). Similarly, 10% of intervention patients had no decline in systolic BP in the SYMPLICITY HTN-2 trial (14). The ability to measure procedural success, perhaps via renal nerve monitoring, might enable identification of nonresponders to RSD. Such an alert might enable additional treatment acutely, or suggest alternative modalities to treat RH. Treatment of RH is likely to be advanced by further research that elaborates on appropriate patient selection and post-procedural indicators of efficacy.
EnligHTN multielectrode renal denervation system
The multielectrode basket design of the EnligHTN catheter (St. Jude Medical Inc., St. Paul, Minnesota) allows for simultaneous energy delivery to 4 sites along the endoluminal surface of the artery, with a potential benefit of reducing renal denervation procedural time. Shorter treatment time offers less RFA time and thereby reduced procedural pain for the patient, a known and common side effect of RSD as described in the SYMPLICITY trials. The EnligHTN RFA catheter system recently received CE Mark approval (May 2012) on the basis of preliminary results of St. Jude's ongoing ARSENAL (Safety and Efficacy Study of Renal Artery Ablation in Resistant Hypertension Patients) trial. This prospective, open-label, feasibility study began enrolling in October 2011 at centers in Greece and Australia. Study completion is anticipated in March 2013 after enrollment and 6-month follow-up of 47 participants. Primary outcome measures are all adverse events and office-based BP. Exclusion criteria are similar to that of the SYMPLICITY trials. Preliminary results presented at the 2012 European Association for Percutaneous Cardiovascular Interventions (EuroPCR) meeting included 1-month mean office BP change of −28/−10 mm Hg from baseline, with 78% of patients having systolic BP reduction of >10 mm Hg (22). No serious complications were reported. Minor complications that were reported included procedure-related access site hematomas (n = 4), vasovagal responses with sheath removal (n = 3), and post-procedural bradycardia (n = 2).
Vessix V2 renal denervation system
The Vessix V2 renal denervation system (Vessix Vascular Inc., Laguna Hills, California) offers a unique, over-the-wire low-pressure balloon equipped with bipolar RFA electrodes attached to the balloon surface that is claimed to offer treatment times of 30 s. The balloon catheter also accommodates smaller arterial diameters (3.0 mm). The Vessix V2 balloon catheter system is currently being studied in the REDUCE-HTN (Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transluminal Angioplasty Catheter) study. REDUCE-HTN is an ongoing prospective, open-label, feasibility study that began enrollment in February 2012 throughout centers in Europe and Australia. Enrollment is estimated at 64 participants with study completion anticipated in August 2014. The primary outcome is acute procedural safety. Secondary efficacy outcomes of 6-month office-based and 24-h ambulatory BP assessment will also be performed. Preliminary results of REDUCE-HTN were presented at EuroPCR 2012. In 10 patients, the mean office-based BP was −30/−11 mm Hg below baseline BP (23).
OneShot renal denervation system
The RAPID (Rapid Renal Sympathetic Denervation for Resistant Hypertension) trial is a prospective, open-label, feasibility study that began enrollment in May 2012 throughout Europe and New Zealand. The OneShot catheter (Maya Medical Inc., Campbell, California) was unveiled at EuroPCR 2012 and uses an irrigated balloon catheter with a helical electrode on its surface, allowing a single-treatment approach. Estimated enrollment for the RAPID trial is 40 patients with systolic BP ≥160 mm Hg, although it requires a specific renal artery diameter of 4 to 7 mm and a segment amendable to ablate of >20 mm. The primary outcome is chronic procedural safety and office-based systolic BP reduction >10 mm Hg at 6 months compared with baseline. Study completion is anticipated December 2013. The OneShot technology received CE Mark approval in February 2012.
ThermoCool renal sympathetic denervation system
The Celsius ThermoCool RFA catheter system (Biosense Webster Inc., Diamond Bar, California) uses a saline-irrigated catheter to ablate the endoluminal surface of the renal artery. The SWAN HT (Renal Sympathetic Modification in Patients With Essential Hypertension) study is an ongoing, prospective, nonrandomized, open-label, safety and efficacy trial evaluating the ThermoCool catheter in patients with essential hypertension (≥140/90 mm Hg). The study began enrollment in August 2011, has an anticipated enrollment of 800 patients, and a study completion date of August 2016. Results of a small pilot study using the same catheter in 10 patients with uncontrolled hypertension was recently published, demonstrating improvement in blood pressure while reducing markers of sympathetic activity (24).
In a separate study, the Celsius ThermoCool RFA catheter and the Chilli II irrigated RFA catheter (Boston Scientific Inc., San Jose, California) are being evaluated in the long-term safety and efficacy SAVE (Impact of Renal Sympathetic Denervation on Chronic Hypertension) study. Enrollment began in May 2012. The study is planned to include 500 patients with BP ≥140/90 mm Hg with an anticipated study completion of December 2019. The primary outcome is change in ambulatory BP at 6 months, which is unique from many other renal denervation studies that use office-based measures. Secondary outcome measures are planned through 48 months and include office-based BP, renal artery blood flow and dimension, renal function, and difference in number of total antihypertensive medications.
Despite its limitations, RFA of the renal sympathetic nerves currently leads the available technologies for the endovascular treatment of RH. As alternatives to painful RFA, ultrasonic and tissue-directed pharmacological RSD have been introduced with early but intriguing BP-lowering results that deserve consideration.
Ultrasonic Ablation Technology
Ultrasound-based RFA may play a role in sympathetic denervation, offering a more targeted injury pattern to the renal sympathetic nerves contained within the adventitia of the renal artery. A number of companies are pursing ultrasound ablative technology with various invasive approaches as well as a unique noninvasive system.
PARADISE catheter system
The PARADISE (ReCor Percutaneous Renal Denervation System) catheter (ReCor Medical Inc., Ronkonkoma, New York) uses a 6-F ultrasonic balloon catheter and self-centering transducer that delivers a proprietary energy algorithm to circumferentially ablate the renal sympathetic nerves. The ultrasonic sound waves emitted from the central core of the balloon produce frictional heating of soft tissues outside of the artery while the fluid-filled balloon cools the endoluminal surface of the artery. The REALISE (Renal Denervation by Ultrasound Transcatheter Emission) study is a single-arm, open-label, first-in-man feasibility study of the PARADISE catheter in 20 RH patients with a primary outcome of acute procedural safety. Secondary outcomes include 12-month change ambulatory BP and 12-month change in baseline antihypertensive medication intake. Preliminary data from 15 patients was presented at EuroPCR 2012, demonstrating office-based BP was reduced by an average of −32/−16 mm Hg over a 3-month follow-up (25).
Therapeutic intravascular ultrasound catheter system
The therapeutic intravascular ultrasound (TIVUS) system was developed as a high-intensity, nonfocused catheter-based ablation system (Cardiosonic Ltd., Tel Aviv, Israel). The TIVUS catheter is delivered into the renal artery over a 0.014-inch guidewire via a 6-F flexible sheath. The RFA source does not contact the arterial wall, enabling remote thermal energy delivery to the adventitia while sparing the endoluminal surface. The technology offers self-regulating safety technology that monitors local tissue temperature that prevents overtreatment if blood temperature becomes elevated.
Ultrasound-based treatment for hypertension
Kona Medical Inc. (Bellevue, Washington) is developing a noninvasive technology using low-intensity focused ultrasound that avoids many of the challenges of invasive endovascular intervention. The system is integrated with an external imaging-modality that identifies and monitors the treatment areas while delivering low-intensity ultrasonic energy with an external ultrasound probe. This system is in the pre-clinical phase of development. Given a noninvasive approach, if the Kona system proves successful, it is sure to generate considerable medical interest.
Tissue-Directed Pharmacological Ablation Technology
An alternate approach to induce renal sympathetic nerve injury may be achieved through the delivery of neurotoxins. Vincristine is a vinca alkaloid antineoplastic drug mainly used to treat acute leukemia, lymphomas, and some sarcomas. Vincristine also exhibits neurotoxic properties that may make the drug suitable for RSD using microinfusion catheter technology (26). In a swine model, successful sympathetic renal denervation using vincristine and the Bullfrog microcatheter was presented at the 2011 meeting of Transcatheter Therapeutics in San Francisco (27).
Bullfrog microinfusion catheters
The Bullfrog microinfusion catheter (Mercator MedSystems Inc., San Leandro, California) was designed to inject therapeutic agents directly through the arterial wall and into the perivascular tissues. For renal denervation, the sympatholytic neurotoxin guanethidine has been studied for injection in the renal arteries. The U.S. Food and Drug Administration approved guanethidine in 1960 for the treatment of moderate-to-severe hypertension. When taken orally, guanethidine accumulates in low concentrations in the sympathetic nerves and reversibly interferes with the transmission of neural hormones, thereby decreasing BP. Given locally, guanethidine induces an autonomic denervation directly and through an immune-mediated pathway (28).
The Bullfrog catheter is equipped with a 130-μm microneedle and protective balloon system. The balloon catheter is guided and inflated at low expansion pressures (approximately 2 atm) within the renal artery to deploy the neurotoxin. As the balloon is inflated, the needle becomes unsheathed from the balloon and penetrates the vessel wall, allowing for perivascular delivery of the therapeutic agent. The Bullfrog catheter has U.S. Food and Drug Administration 510(k) clearance for medication delivery to the vessel wall and perivascular area.
Other Nonendovascular Autonomic Modulation Therapies
Baroreceptor activation therapy, spinal cord stimulation, and vagal-nerve stimulation represent novel and nonendovascular treatments against RH (29–31) and other sympathetically driven conditions, such as chronic heart failure, among others. Though beyond of the scope of this review, these nonendovascular therapies may complement or supplant some of the RSD therapies described herein. Because these non-RSD treatments generally require more invasive, elaborate procedures, the aforementioned percutaneous options may have more long-term appeal.
The results of SYMPLICITY HTN-3, ARSENAL, and other pivotal trials are sure to expand the possibilities for endovascular treatment of RH. Whereas emerging evidence from these small trials are encouraging, results from larger randomized clinical trials are needed to confirm procedural safety and durability before more widespread clinical application occurs. Those at high risk for RH-related cardiovascular complications are likely to gain the most from RSD, particularly if a positive impact on important clinical outcomes can be demonstrated. With further confirmatory evidence of procedural safety, patient selection, and therapeutic durability, RSD is sure to strengthen the treatment options for poorly controlled hypertension.
The authors wish to thank Mrs. Marion Tomasko for her artistic expertise and assistance in creating the illustrations.
Dr. Shishehbor is a consultant for Medtronic, Abbott Vascular, and BARD, but he receives no personal compensation for this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- blood pressure
- Conformité Européene
- European Association for Percutaneous Cardiovascular Interventions
- radiofrequency ablation
- resistant hypertension
- renal sympathetic denervation
- Received July 30, 2012.
- Revision received September 10, 2012.
- Accepted September 12, 2012.
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- Scope of Resistant Hypertension
- Splanchnicectomy and the Basis for Renal Sympathetic Denervation
- Radiofrequency Ablation Technology
- Ultrasonic Ablation Technology
- Tissue-Directed Pharmacological Ablation Technology
- Other Nonendovascular Autonomic Modulation Therapies