Endovascular Therapy for Treatment of Resistant Hypertension: Emerging Controversies and Technical Evolution

Abstract

Report of the first successful transluminal application of radiofrequency energy to ablate sympathetic renal nerves in patients with treatment-resistant hypertension and the subsequent Symplicity HTN-1 publication demonstrating the safe and sustained reduction in systolic blood pressure in a 45 patient cohort through 6-month has stirred considerable interest in this novel therapy among patients, health practitioners, and interventionalists. Subsequent reports in relatively small cohorts of treatment-resistant hypertension have detailed a variety of “collateral benefits” including improved glucose control and symptoms of obstructive sleep apnea, reduction in dyspnea, regression of left ventricular hypertrophy, and cardiac dysthymias resulting from ablation of renal sympathetic nerves. However, despite these encouraging early observations, recent reports in larger patient cohorts have suggested higher than initially reported nonresponder rates, defined as the inability to achieve a SBP reduction of ≥10 mmHg, approaching 20% to 30% at 12 months, and focused attention on shortening total procedural ablation times, thereby reducing patient pain and procedural complexity. Industry has responded with rapid device iteration, applying different energy sources (i.e., nonfocused and focused ultrasound) and simpler catheter designs. Emerging evidence from small, uncontrolled trials continues to explore new potential applications (i.e., moderate treatment-resistant hypertension) while the US Symplicity HTN-3, a 550-patient randomized, sham-controlled trial will attempt to better define the safety and effectiveness of RDN in the treatment of TRH and associated hyper-adrenergic states.

VASCULAR DISEASE MANAGEMENT 2013:10(6):E103-E113

Key words: endovascular therapy, new techniques, renal artery intervention, new devices

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Resistant hypertension is a common, growing, and neglected clinical problem. An estimated 80 million Americans are diagnosed with hypertension¹ and more than half are inadequately controlled and meet JNC-7 and ESC goals for blood pressure control.^2,3 However, accurate assessments are lacking of the prevalence of TRH, defined as a SBP above target level, despite antihypertensive agents from different classes, including a diuretic.⁴ Estimates from the National Health and Nutrition Examination Survey and from large randomized clinical trials indicate that between 20% and 30% of hypertensive patients require at least 3 or more antihypertensive agents to achieve blood pressure targets, whereas recent data from a large Spanish registry suggests that treatment-resistant hypertension (TRH) is present in 12% of the treated hypertensive population.⁵ Failure to reach target blood pressure levels, despite therapeutic intervention, exposes patients to increased risks for major cardiovascular events which doubles each 20/10-mmHg elevation in blood pressure values above 150/75 mmHg. As such, developing new approaches to the current resistant hypertension management remains a priority.

Renal artery denervation (RDN), a new therapeutic option to address TRH, targets the autonomic nervous system at the level of the renal arteries and has generated considerable attention from the medical, industry, and investor communities. However, as new radiofrequency (RF) and non-RF technologies (i.e., focused and nonfocused ultrasound) are introduced into first-in-man trials and larger RF-treated registries with longer follow-up are reported, important questions have arisen regarding appropriate patient selection, the renal artery anatomic limitations of currently available RF technologies, and the true “nonresponder” rate and the appropriate timeframe for its definition. Additionally, as the use of RDN to treat lesser degrees of TRH is examined, concerns regarding its safety and its clinical and cost effectiveness will certainly arise. We review the societal impact of TRH,^1,6,7 evolving RDN technologies, and emerging controversies involving this exciting and novel technology.

The Sympathetic Nervous System and Blood Pressure Regulation

The contribution of sympathetic nervous system (SNS) hyperactivity to the development and progression to TRH and associated pathologies has been extensively investigated in numerous animal and human models⁸ and was recently capably reviewed.⁹ In general terms, renal sympathetic efferent nerve activity is involved in renal excretion, sodium retention, reduced renal blood flow, and cardiovascular and peripheral vascular effects (Figure 1). Renal sympathetic afferent nerves affect central nervous system drive; therefore, the inhibition of renal efferent and/or afferent nerves is a potential target for treatment for TRH and carries the promise that its control may result in a subsequent decline in associated cardiovascular morbidity and mortality.

Currently, there are two primary approaches under clinical investigation for the treatment of blood pressure via modulation of the SNS: (1) baroreceptor sensitization, in which the Rheos device (CVRx) is implanted as patch electrodes over the carotid sinuses and stimulated via an implanted generator so that the carotid sinus excitation results in enhanced afferent signaling of the cardiovascular control centers of the brain to reduce sympathetic outflow and blood pressure¹⁰ and (2) RDN, originally performed surgically using a variety of approaches in the 1930s to 1950s for treatment of severely hypertensive patients. However, the surgical procedure was abandoned due to unacceptable postoperative morbidity and mortality and complications including disabling orthostatic hypotension. To date, percutaneous transluminal RDN using a single monopolar electrode catheter (Symplicity, Medtronic) represents the vanguard of the RDN technique.^11,12

Kidneys are densely innervated by afferent sensory and efferent sympathetic fibers. The sensory efferent nerve activity directly influences sympathetic outflow to the kidney and other highly innervated organs, including the heart and blood vessels, by modulating the rostral anterolateral medulla and the posterior hypothalamic activity (Figure 1). 

In the kidney, these efferent and afferent sympathetic nerves interact to modulate renal blood flow and changes in blood pressure through activation of renal chemoreceptors. Ablation of renal sensory afferent nerves reduces blood pressure and ameliorates organ-specific damage caused by chronic sympathetic overactivity in various animal models. Afferent nerve activity cannot be quantified in humans, but there is strong evidence that it modulates a level of central sympathetic outflow, not only to the muscle vasculature (quantified by muscle sympathetic nerve activity (MSNA) assessed by microneurography), but also to other organs involved in the cardiovascular and metabolic control. Indeed, increased MSNA is an important negative prognosticator in various disease states, including hypertension, heart failure, metabolic syndromes, chronic renal failure, obstructive sleep apnea, and obesity.

Assessment of regional norepinephrine overflow from the kidney into the plasma has demonstrated that renal norepinephrine spillover rates are markedly elevated in patients with essential hypertension and are associated with hypertensive end organ damage, such as left ventricular hypertrophy (LVH), cardiorenal syndromes, and TRH.¹³ Post-ganglionic sympathetic efferent nerve fibers innervate all essential renal structures, including the renal vasculature, renal tubules, and juxtaglomerular apparatus. As such, renal sympathetic activity results in volume retention, sodium reabsorption, renal blood flow reduction, and renin-angiotensin-aldosterone system activation. Renal denervation, therefore, presents an obvious therapeutic target and a tool to restore sympathetic balance to an imbalanced system.

Blood pressure is a surrogate for hypertension as well as cardiovascular and renal disease and, while it is the de facto study endpoint in the Symplicity HTN-1 and Symplicity HTN-2 trials, blood pressure is both variable and dynamic. Blood pressure values are dependent on cardiac output, vascular capacitance, compliance, reflection, and resistance. The Symplicity HTN trials use office blood pressure (OBP) assessment as the “gold standard” to assess this surrogate. The studies also used 24-hour ambulatory blood pressure monitor (ABPM) as a secondary endpoint. ABPM is used both to exclude white coat hypertension syndrome¹⁴ and identify a patient cohort with severe TRH. While the mean OBP values are obtained from three assessments preformed in a meticulous and reproducible manner, these values, when compared to the 24-hour ABPM values will differ. The OBP and daytime ABPM values should be proportionate and directionally similar. Typically, OBP and daytime ABPM values should differ within the 95% confidence limits corresponding to 11 ± 4 mmHg.¹⁵

Symplicity HTN-1 and HTN-2 Trials 

Given this background, a novel catheter-based approach to selective human RDN was reintroduced into a proof-of-concept clinical trial in 2007 to test the endpoint hypothesis that RDN was safe and resulted in a >10 mmHg blood pressure reduction, as assessed by OBP, within 6 months.¹¹ This minimum OBP reduction of  >10 mmHg, which defined a patient as a “responder,” was selected with the understanding that lesser degrees of blood pressure reduction have been associated with a clinically relevant decrease in cardiovascular events.¹⁶ 

This percutaneous approach applies approximately 3 to 8 watts via a single monopolar platinum electrode (Symplicity Arch Catheter, Medtronic) to the renal intima at various circumferential points along the main renal artery. The initial report of the first 45 TRH patients in this registry documented a substantial 32/18 mmHg decline in blood pressure from a preprocedure mean blood pressure of 182/75 mmHg, while on an average of 5.2 antihypertensive medications. Furthermore, the study documented a significant improvement in 24-hour ABPM values and appeared to demonstrate safety without noninvasive assessment of renal artery injury through the 6-month primary endpoint. This first-generation Symplicity Arch Catheter was quickly iterated and replaced by the Symplicity Flex Catheter, which provided greater maneuverability, torqueability, and electrode contract with the renal intima.

Symplicity HTN-2, a prospective, randomized crossover design trial, assessed OBP 6 months post treatment and allowed subsequent treatment of the untreated control group, if the patient cohort continued to meet OBP entry criteria after 6 months.¹² The results of this therapy continue to be very positive, and recent 1-year follow-up of the all enrolled patients reported a sustained benefit in blood pressure improvement of -28 mmHg from baseline values.¹⁷ Notably, this substantial decline in blood pressure was not associated with a change in glomerular filtration rate (GFR) or a decrease in the number of blood pressure medications in 28% of patients. Finally, this trial noted a 12-month 28.7% nonresponder rate, and increase from the 16.8% nonresponder rate at 6 months. This increase in the nonresponder rate from the initially reported 10% nonresponder from Symplicity HTN-1 may be explained by the medication changes, which occurred during the course of the trial, by patient selection, or both.

While the Symplicity HTN-1 and HTN-2 trials documented significant SBP reductions in a highly selected patient cohort with severe TRH, the trials’ design and procedural technique highlighted several important limitations. First, the inclusion and exclusion criteria required patients to have a SBP of >160 mmHg, representing a higher degree of TRH than the generally accepted definition of TRH, >140 mmHg despite three anti-hypertensive medications of the three different classes, which included a diuretic.^2,3 In order to appropriately identify such TRH patients, serial OBP determinations were required over a 2-week observational run-in period during which no blood pressure medication changes were allowed and a 24-hour ABPM assessment was required prior to performing the procedure. These screening mechanisms resulted in a 19% clinical screen failure rate.  Additionally, the renal artery anatomic requirement for treatment, specifically a minimal main renal length prior to the first major bifurcations of 2 cm (allowing for a required number of ablation sites) and the exclusion of renal arteries <4 mm in diameter and accessory renal arteries, resulted in an additional anatomic screen failure rate of 16%. 

When combined with other exclusion criteria prior to randomization, the clinical and anatomic study entry requirements resulted in a 44% screen failure rate. Finally, the required 2-minute ablation treatment time per site, a potential of 24 minutes of total RF ablation time per patient, frequently resulted in significant patient visceral discomfort, requiring the use of intravenous analgesics for pain control.

“Nonresponders” to Renal Denervation 

Notably, as longer-term follow-up data from the Symplicity trials and clinical experience from single-center and registry experiences have been reported, the prespecified definition of lack of clinical effectiveness, “non-responders,” defined as a reduction in SBP of ≤10 mmHg at 6 months, has become a point of both interest and concern. The initial 6-month nonresponder rate in the Symplicity HTN-1 and HTN-2 trials, albeit small patient cohorts, was noted at 10% and 16.8%, respectively.^11,12 However, non-responder rates as high as 20% to 30% at 6 to 12 months have been reported in the Symplicity HTN-1 extended follow-up in a larger cohort (n=144).¹⁸ 

Of additional interest is the recently reported nonresponder rate in the treated control group from the Symplicity HTN-2 trial of 38%.¹⁷ However, it must be acknowledged that this treated control group was small (n=35) and patients were not required to re-enter the 2-week run-in observation period and 24-hour ABPM assessment, thereby introducing an element of uncertainty regarding a required stable medication regime. Nonetheless, concern regarding the true nonresponder rate from the Symplicity trials has been voiced, in addition to the question of whether and when retreatment should be considered, potentially with a non-RF technology.

It is important to note that blood pressure rarely changes immediately after RDN and often takes several months for maximal effect to be demonstrated. Additionally, an emerging class of “slow responders” has emerged; this may represent a cohort of patients that, due to intermediate levels of elevated vascular resistance, may require an additional time to fully realize a clinical response. 

At present, it is not possible to adequately define the reason for the emerging nonresponder rate, although as the results of the larger patient cohorts are reported, the previously noted 10% nonresponder rate actually may be higher. Furthermore, no reliable pretreatment clinical parameters have been identified that allow for the selection of TRH patients who will likely benefit from RDN.

Therefore, hypotheses as to the reason for the lack of a blood pressure reduction in certain TRH patients may include one or more factors:

1. A technical procedural failure, whereby the monopolar RF energy was not applied in sufficient amount or duration to the renal intima in order to sufficiently ablate renal nerves to achieve a reduction in blood pressure response. Recent evidence presented by Virmani using a perfusion fixed ex-vivo human renal cadaver model under physiologic pressure (80-100 mmHg) with 10% neutral buffer formalin perfusion with histologic sections taken deeper into the perirenal adventitia, suggested that a significant number of human sympathetic nerves, up to 20%, extend out into the renal adventitia between 4 mm and 6 mm.¹⁹ This is further than previously demonstrated in other nonperfused fixed cadaver renal models.²⁰ Additionally, nonobstructive renal atheroma was present in 50% of renal cadaver specimens; importantly, the presence of atheroma may dissipate heat generated from the RF electrode, thus reducing its penetration into the adventitia. Therefore, it can be hypothesized that application of a monopolar RF energy point source may be insufficient to reach a critical number of adventitial sympathetic nerves, too distant from the renal lumen, thereby resulting in an insufficient RDN and the resultant suboptimal clinical response. At present, this is only a hypothesis and will require further investigation.
2. Inappropriate patient selection whereby the patient’s underlying hypertension pathophysiology was not driven by sympathetic nerve overactivity as a contributor to the elevated blood pressure.
3. Despite a technical procedural success (i.e., successful anatomical denervation), the cardiovascular system, potentially due to the results of severe and protracted TRH, was unable to respond due to severely reduced vascular compliance.

RDN-Related Collateral Benefits

While the exact mechanism or mechanisms by which RDN results in blood pressure reductions are not fully understood, it is likely that a reduction of peripheral vascular resistance, positive vascular remodeling, and reduction in renin release and alteration in water and salt retention are mechanisms. Hypertension is frequently associated with metabolic alterations, such as overweight and obesity, impaired glucose metabolism, and insulin resistance. Sympathetic activation has been identified as an important contributor to this detrimental clinical scenario;²¹ as such, a reduction in sympathetic tone would be expected to improve glycemic control.²² 

In a small cohort substudy of the Symplicity HTN-2 trial, patients from both RDN (n=37) and control groups (n=13) underwent detailed evaluation of glucose metabolism, including fasting glucose, insulin, C-peptide, HbA1c values, and glucose levels during oral glucose tolerance test (OGTT) at baseline and at 1 and 3 months follow-up after bilateral renal RDN. 

In addition to the BP fall observed in the treatment group (-32/-12 mmHg) after 3 months,  fasting glucose,  insulin levels, and C-peptide levels were also significantly reduced after 3 months. It is hypothesized that the reduction of peripheral vascular resistance, the redistribution of visceral blood volume into the peripheral muscular, which metabolizes glucose more efficiently, may result in these observations of improved glucose metabolism.²³

Regression of Left Ventricular Hypertrophy

Additional factors that may translate into better outcomes after RDN include improvements in cardiac baroreflex sensitivity and a reduction in left ventricular (LV) mass from 184 to 169 grams at 12 months follow-up compared to baseline.²⁴ These initial findings have been confirmed in a larger cohort of 46 TRH patients who underwent RDN.²⁵ The authors demonstrated that RDN was not only associated with a substantial reduction in SBP and diastolic blood pressure (-22.5/-7.2 mmHg at 1 month and -27.8/-8.8 mmHg at 6 months, P<.001 at each time point), but also reduced mean interventricular septum thickness and LV mass index at 1 month and 6 months. Diastolic function was also improved as assessed by mitral valve lateral E/E' ratio, which decreased after RDN at 1 month and 6 months, indicating reduction of LV filling pressures. Isovolumic relaxation time, a surrogate for improved diastolic function, improved, whereas LV ejection fraction significantly increased after RDN. These improvements in LV function parameters were not observed in a matched group of 18 control patients. Interestingly, the beneficial effects appeared to be somewhat independent from BP effects, with LV hypertrophy being improved even in those patients who only had a minor or no blood pressure response. These data suggest that the effects of RDN may go beyond merely reducing blood pressure and may contribute to regression of hypertensive end-organ damage.

Chronic Kidney Disease

Recent observations document that RDN in TRH patients in stable renal function results in no untoward effects on renal hemodynamics, renal function, or urinary albumin excretion through 6-month follow-up.²⁶ However, the Symplicity HTN-I and HTN-2 studies excluded patients with substantial reduction in renal function (GFR<45 mL/min; KDOQI stage 3B). From animal and clinical studies, it is established that renal damage activates mechano- and chemoreceptors in the kidney. Through the activation of afferent sensory nerves, this increased sympathetic activity in the central and peripheral nervous systems leads to enhanced sympathetic transmitter release within target organs such as the heart, kidney, and vessels. 

It is assumed that activated afferent nerves originating from the kidney are the predominant underlying mechanism for the overactivity of the SNS in patients with renal damage.^27,28,29 Therefore, RDN may be expected to potentially normalize sympathetic nerve activity in this patient cohort. However, in situations with a low GFR, renal artery blood flow can be reduced. Because cooling of the Symplicity catheter platinum tip depends upon adequate renal artery blood flow, overheating may occur. An internal program algorithm that shuts off the RF energy to protect against thermal injury avoids overheating, but this may result in insufficient ablation of adventitial nerves.

As contrast media are administered during the procedure, patients with markedly reduced GFR may be particularly vulnerable to contrast-induced renal injury. The cholesterol emboli syndrome is also a potential risk in the presence of renal atherosclerosis³⁰ particularly in renal dialysis patients, in whom loss of residual renal function and diuresis may negatively impact quality of life and prognosis. Currently, RDN in chronic renal failure patients (GFR <45 mL/min) is recommended only within clinical trials.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) also may be linked to the consequences of elevated sympathetic tone. A recent observational, small, uncontrolled series of TRH patients with sleep studies pre- and post-RDN suggested that denervation and/or blood pressure reduction alone reduces the frequency of apneic-hypopneic episodes.³¹ 

The mechanism underpinning the relation to obstructive sleep apnea is unclear, but if small changes in circulating volume in hypertensive patients result in engorgement of soft neck tissues, then renal sympathetic denervation for the treatment of hypertension may result in volume shifts of engorged neck tissues into the periphery with recumbency. This might reduce the occurrence or severity of coexisting obstructive sleep apnea.³² Realizing that patients with OSA have elevated MSNA, which is reduced following adequate treatment of the airway obstruction, the suggestion that it is sympathetic system overactivity that underlies some of the obstruction bears further testing.

Moderate Treatment-Resistant Hypertension

Given the substantial evidence provided by 2-year follow-up from the Symplicity HTN-1 and HTN-2 trials, there is little uncertainty that a significant majority of appropriately selected TRH patients experience a substantial and durable reduction in BP. However, new strategies to reduce blood pressure control and reduce CV risk in less-severe forms of TRH are needed, as it is well established that irrespective of baseline blood pressure values, even modest BP reductions are associated with a significant reduction of CV morbidity and mortality.³³ In this regard, preliminary data from a small (n=20), single-center prospective analysis of RDN in moderate TRH (>140 and <160 mmHg on ≥3 antihypertensive medications), suggest a potential beneficial BP effect through 6-month follow-up.³⁴ Prospective multicenter pilot studies are currently ongoing in Europe to assess the potential effectiveness of RDN in moderate TRH using both OBP and 24-hour ABPM values at baseline and 6-month endpoints. These important studies will extend the evidence base of RDN beyond the rather limited cohort findings of the Symplicity HTN-1 and HTN-2 trials. Importantly, this moderate TRH cohort represents a substantial patient population, who may benefit from RDN. 

Beyond Symplicity

Despite the clinical success and excellent safety profile of the Symplicity catheter in TRH patients, a clear desire to reduce total ablation time per patient and thereby reduce patient pain, increase catheter ease of use, and reduce required French size has resulted in rapid catheter iterations. The most recently developed Symplicity Flex catheter requires a 2-minute ablation time at a minimum of 4 to 6 circumferentially placed sites per renal artery. A documented first-to-last ablation time of approximately 38 minutes was reported in the Symplicity HTN-2.¹²  To reduce the total ablation time and provide physicians with an over-the-wire catheter to promote ease of use, the Spyral catheter was recently introduced into clinical trials. This over-the-wire, four-monopolar electrode, 6F guide compatible catheter provides independent impedance readings and electrode activation of each electrode (Figure 2). 

Upon withdrawal of the 0.014˝ wire, the catheter assumes its spiral configuration, conforming to the renal artery anatomy and electrode contact with the renal intima. A 50-second simultaneous firing of the four electrodes is possible, and two separate ablation sites per renal artery are recommended. Whether the Spyral catheter will retain the clinical effectiveness established by the Symplicity Flex catheter, while promoting ease of use and reduced procedure times and patient pain, is currently being evaluated in clinical trials.

Other RF energy catheters are currently in clinical trials outside of the United States; their use in first-in-man clinical trials and preliminary data has been recently reviewed elsewhere³⁵ and are summarized in Table 1. These catheters include the multielectrode monopolar EnligHTN Renal Denervation System (St. Jude Medical), the monopolar electrode OneShot Renal Denervation Device (Covidien) and the bipolar Vessix Renal Denervation System (Boston Scientific). 

These RF-based technologies offer the application of RF energy to the renal intima in various confirmations with various treatment times using nonwire or over-the-wire systems. Additionally, it is unclear whether the application of monopolar (Symplicity, OneShot) vs bipolar (Vessix System) RF applications will prove an important clinical differentiator. RF energy is transmitted by direct tissue contact and application of a specific wattage for a specific duration to generate thermal injury resulting in renal nerve cell death. In the case of a monopolar system, one electrode is positioned against the renal intima and a grounding patch is positioned externally on the patient’s skin. During the application of wattage, RF energy passes from the energy-generating electrode to the externally positional electrode. 

A monopolar system has the theoretical disadvantage of a difficult-to-control lesion size and targeting.  Additionally, as RF energy passes through the patient between the internal electrode and external grounding pad, visceral pain results. Bipolar systems, as represented by the Vessix System, contain balloon-mounted electrodes separated by a short 1.6-mm distance. Once inflated, the balloon occludes the blood flow, and therefore no heat is lost to blood flow, resulting in shorter ablation times and, hence, less patient pain. Additionally, the occluding balloon allows delivery of very low power (0.5 to 2 watts per electrode), in contrast to mono-polar systems that require significant power (6 to 25 watts) in order to reach an effective temperature. 

Theoretically, a bipolar system allows for better control of lesion size, lesion homogeneity, and the potential for more exact lesion targeting. Whether these features will translate into safety and clinical effectiveness, similar to or superior to the monopolar systems and reduce visceral pain associated with the application of the RF energy, awaits larger clinical experience.

Ultrasonic Renal Nerve Ablation

Nonfocused ultrasound, when configured in specific parameters relating to power, intensity, and duration of energy application, generates vibrational heat,³⁶ resulting in renal nerve ablation in pre-clinical a porcine model.³⁷ Ultrasound has the potential theoretical advantages of ablating renal sympathetic nerves contained in the adventitia beyond those obtainable by the application of RF energy to the renal intima. The safety and effectiveness of nonfocused ultrasound-based technologies to reduce blood pressure in TRH patients is currently being evaluated in proof-of-concept trials. 

The PARADISE percutaneous RDN system catheter (ReCor Medical), an over-the-wire, 6 French based, self-centering ultrasound element that delivers a proprietary nonfocused ultrasonic energy algorithm circumferentially to the renal artery in single 30-second treatment at two locations in the renal artery, was recently introduced into clinical trials. 

This occlusion balloon-based system requires the infusion of a cooling saline solution through the inflated balloon catheter, which contains the ultrasound element, to prevent intimal injury. Importantly, this single balloon can accommodate renal arteries from 3 mm to 7 mm in diameter, allowing for the treatment of smaller accessory renal arteries (Table 1). Initial data from the Realise Trial, a single arm, open-labeled, first-in-man feasibility trial, which is ongoing in Europe, has established an average -32/-16 mmHg decline from baseline values at 6 months.

The therapeutic intravascular ultrasound catheter system (TIVUS; CardioSonic) is an ultrasound system that uses a 0.014˝-guidewire-based ultrasound catheter, which is distinct from nonfocused ultrasound. TIVUS delivers a proprietary algorithm of directed ultrasound energy via the renal lumen (Figure 3). 

Importantly, the ultrasound-generating element does not contact the renal intima and, as such, is cooled by the renal blood flow (Figure 4). The technology offers a self-regulating safety technology, which monitors local tissue temperature to prevent tissue overheating and provides the operator with an assessment of the distance from the transducer to the renal intima in order to permit precise positioning of the ultrasound element. The TIVUS I trial recently began first-in-man enrollment in Perth, Australia, with additional sites soon to be activated in Israel and Europe.

Conclusion

The results of several ongoing European and Australian first-in-man studies and large registries and the recently completed pivotal US Symplicity HTN-3 trial³⁸ will expand our knowledge and understanding of RDN in the treatment of TRH. Additionally, establishing the effectiveness of RDN in TRH patients with concomitant diabetes, obstructive sleep apnea, ventricular dysrhythmias, and non-TRH patients with congestive heart failure with preserved or reduced systolic function will strengthen the treatment options for these difficult patient populations at high risk for cardiovascular events.

Acknowledgments: We wish to acknowledge the contributions of Jeri Taapken and Elma Martinez in the preparation of this manuscript.

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Editor’s Note: Disclosure:  The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Rocha-Singh reports consultancy to Medtronic, Boston Scientific, CardioSonic, and CiBiem. 

 Manuscript received February 18, 2013; final version accepted April 18, 2013. 

Address for correspondence: Krishna J. Rocha-Singh, MD, Prairie Cardiovascular Consultants, 401 East Carpenter Street, Springfield, Illinois, 62702, USA. Email: ksingh@prairieheart.com