Abstract
Despite a wide range of drug treatment for hypertension, resistant hypertension rates remain high. The Symplicity™ Renal Denervation System (Medtronic, Santa Rosa, CA), which creates renal nerve denervation, has shown initial success in lowering blood pressure among patients with resistant hypertension. Given the enormous market for this treatment approach, an estimated two dozen other companies are pursuing technologies with alternative approaches. Despite this fact, very little has been published on preclinical and clinical experience with these new devices. The current review summarizes the most prominent technologies in the pipeline and provides insight into the mechanism of action, preclinical, and clinical experience with these new devices.
1
Introduction
Despite major advances in drug therapies over time, hypertension remains an enormous public health problem second only to smoking. According to a recent report from the Centers for Disease Control and Prevention, one-third of US adults have hypertension . Data from the National Health and Nutrition Examination Surveys (NHANESs) have indicated decreased rates of patients considered uncontrolled (with or without antihypertensive medications) from 73.2% to 52.5% over the last two decades . However, a subgroup of patients with resistant hypertension still poses a substantial public health concern. Resistant hypertension is defined as blood pressure persistently above goal despite the use of antihypertensive medications from ≥ 3 drug classes . According to recent studies, 13%–24% of treated hypertensive patients are categorized as resistant and the prevalence of this subgroup appears to increase over time . A corroborating analysis from Europe shows similarly alarming rates of uncontrolled hypertension . These patients face worse cardiovascular outcomes and systemic hypertension-related complications, for which there is no viable treatment option.
A new percutaneous approach, based on the concept of an old surgical technique for sympathetic renal denervation (RDN), shows promising results in treating patients with resistant hypertension . Given the enormous market for this treatment approach and the rapidly compounded annual growth rate , an estimated two dozen companies are pursuing technologies to achieve RDN with equivalent or superior approaches. Despite this, very limited data have been published on preclinical and clinical experiences with these new devices, and the future of this field is controversial. We aimed to provide an overview of the field, to describe the preclinical and clinical experiences with the most prominent technologies in the pipeline, and to provide insights regarding the possible directions this field may be heading.
2
Theoretical basis for RDN in hypertension treatment
A large body of evidence has established the central role of the kidneys in hypertension, both as an affector and effector of the central sympathetic system . Renal efferent sympathetic activity initiates processes towards fluid retention, such as the release of renin and increased tubular sodium reabsorption . Moreover, afferent sympathetic activity increases central sympathetic drive, which plays a major role in sustaining hypertension . In fact, historic studies of surgical sympathectomy in patients with resistant hypertension or malignant hypertension uncontrolled by pharmacotherapy were shown to be effective in reducing blood pressure , albeit with severe side effects. Thus, with the introduction of more effective medications, this procedure was abandoned.
Renal sympathetic nerves run alongside the renal artery adventitia to enter the hilus of the kidney. Thereafter, they divide into smaller nerve bundles following the anatomic course of the renal blood vessels, penetrating the cortical and juxtamedullary areas inside the kidneys. Based on these anatomic features, it was postulated that creating local nerve injury along the renal arteries may achieve effective denervation.
2
Theoretical basis for RDN in hypertension treatment
A large body of evidence has established the central role of the kidneys in hypertension, both as an affector and effector of the central sympathetic system . Renal efferent sympathetic activity initiates processes towards fluid retention, such as the release of renin and increased tubular sodium reabsorption . Moreover, afferent sympathetic activity increases central sympathetic drive, which plays a major role in sustaining hypertension . In fact, historic studies of surgical sympathectomy in patients with resistant hypertension or malignant hypertension uncontrolled by pharmacotherapy were shown to be effective in reducing blood pressure , albeit with severe side effects. Thus, with the introduction of more effective medications, this procedure was abandoned.
Renal sympathetic nerves run alongside the renal artery adventitia to enter the hilus of the kidney. Thereafter, they divide into smaller nerve bundles following the anatomic course of the renal blood vessels, penetrating the cortical and juxtamedullary areas inside the kidneys. Based on these anatomic features, it was postulated that creating local nerve injury along the renal arteries may achieve effective denervation.
3
Approaches
A key issue in accomplishing effective RDN is to target the sympathetic nerve bundles lying in the adventitia of the renal arteries. Because the vast majority of devices currently under development are percutaneous, RDN is performed from within the vessel lumen. Thus, one of the most important features of such a device is the ability to minimize the damage to the renal artery wall. Conversely, the element responsible for inducing the actual nerve damage (e.g. heat, radiation, or drug) should be effective, localized, and should produce permanent nerve damage. Table 1 summarizes the principles that guide developers in designing a safe and effective device to induce RDN.
| • Minimally invasive device |
| • Maximum injury to renal nerves |
| • Permanent nerve destruction |
| • Predictability of injury pattern |
| • Ability to target the renal nerves |
| • Minimal injury to renal artery |
| • Minimal procedural pain |
| • Short procedure time |
An important feature yet to be addressed is targeting of the insult to the sympathetic nerves. Renal pre-ganglionic nerves run alongside the renal artery; however, there is patient-to-patient variability as to where the nerves are located. Utilizing advanced imaging technologies to identify the location of the nerve fibers in a specific patient could potentially improve procedural success rates.
4
Radio frequency-based renal denervation
Delivery of radio frequency (RF) energy to the renal artery wall induces controlled heat production. Once tissue temperatures exceed 50 °C, irreversible cellular damage and tissue death occur. As the renal nerves run alongside the renal artery, the heat plus local RF energy induces irreversible damage to adjacent nerve fibers. Devices utilizing RF energy for RDN are the most advanced in terms of development and regulatory status.
4.1
Symplicity™
The Symplicity™ Renal Denervation System (Medtronic, Santa Rosa, CA) is the first of multiple systems to utilize RF energy to create injury to the renal nerves. It is comprised of the Symplicity catheter and Symplicty RF generator (Medtronic, Santa Rosa, CA) and currently has CE approval. The system is still investigational in the US and is currently undergoing evaluation in the pivotal Symplicity HTN-3 study (ClinicalTrials.gov Identifier: NCT01418261).
The Symplicity catheter is delivered through a 6 F guiding catheter, is able to deliver a maximum energy of 8 W, and achieves temperatures of 40–75 °C. The catheter has ergonomic controls for rotation and articulation in order to orient the catheter tip for confident, atraumatic vessel wall contact ( Fig. 1 A ). The generator is fully automated and automatically switches off if the temperature reaches > 75 °C.
A typical procedure using the Symplicty system involves four treatments in each of the renal arteries, each of which in 90° rotation and in different locations along the renal artery in order to avoid circumferential arterial injury. The median procedure time is 38 min and typically requires administration of intravenous narcotics and sedatives to manage pain associated with the delivery of RF energy.
4.2
EnligHTN
The EnligHTN Renal Denervation System (St. Jude Medical, St. Paul, MN), which recently received CE approval, is another RF energy delivery system. This system includes the EnligHTN renal artery ablation catheter, comprised of a basket-like structure with four “arms”, each with built-in electrodes ( Fig. 1 B), which allow the performance of RDN from a single position in the renal artery and a radiofrequency ablation generator. The EnligHTN catheter is available in two sizes to accommodate renal artery sizes of 4–6 mm (small basket) and 5.5–8 mm (large basket), and is delivered to the renal arteries through an 8 F renal double curve-1 guiding catheter with the basket in a closed position. Once in the desired location within the renal artery, the basket is opened and delivers RF energy sequentially through the four electrodes by achieving definite contact of the electrodes with the vessel wall and a predictable ablation pattern. In most cases the system can then be closed, pulled back, rotated and expanded in a new location to deliver another set of lesions. This technique shortens the procedure time, decreases the need for contrast injection, and delivers lesions in a predictable way.
4.3
V 2
Vessix Vascular (Laguna Hills, CA) is developing the V 2 bipolar balloon catheter technology for the delivery of RF energy to the renal artery for RDN. This system is comprised of an over-the-wire inflatable balloon catheter with RF electrodes mounted on the balloon and a bipolar RF generator. The balloon catheter has built-in, 8 RF electrode pairs with a temperature sensor that monitors temperature continuously during energy delivery ( Fig. 1 C). This feature is important because during RF delivery the balloon is inflated and blood flow through the renal artery is occluded, thus the cooling effect of the flowing blood is absent. An additional important safety feature activates the system only if all electrodes have good apposition with the vessel wall and are able to deliver energy with all 8 electrodes simultaneously. The V 2 bipolar balloon catheter design is available in several sizes to accommodate treatment of renal arteries with diameters ranging from 3 to 7 mm and a treatment length of 21 mm.
4.4
OneShot
Maya Medical (Campbell, CA) is developing a balloon catheter-based approach for efficient delivery of RF energy. The RF electrode creates a helical shape along the balloon ( Fig. 1 D) that delivers the RF energy in a helical pattern along the vessel wall. Once positioned in the desired location within the renal artery, the balloon is inflated at low pressure to allow apposition of the RF electrode against the vessel wall, thus ensuring appropriate energy delivery.
5
Ultrasound energy-based renal denervation
Ultrasound energy consists of high-frequency sound waves emitted by a transducer within the catheter. This high energy can pass through surrounding fluids and can generate frictional heating in tissues resulting in a temperature increase that is sufficient to cause injury to the surrounding tissue, specifically the renal nerves. Based on these principles, several systems were developed and are currently being evaluated ( Table 2 ).
| Device | Company | CE mark | FDA approval | Clinical study |
|---|---|---|---|---|
| Radio frequency | ||||
| Simplicity | Medtronic | Yes | No | Symplicity HTN-3 ongoing |
| EnligHTN | St. Jude Medical | Yes | No | EnligHTN ongoing |
| V 2 | Vessix Vascular | No | No | REDUCE-HTN ongoing |
| OneShot | Maya Medical | No | No | |
| Ultrasound energy | ||||
| PARADISE | Recor Medical | Yes | No | REALISE ongoing |
| Kona Medical | No | No | ||
| β radiation | ||||
| Beta-cath | Novoste | No | No | |
| Drugs | ||||
| Vincristine | No | No | ||
| Guanetidine | No | No | ||
5.1
PARADISE
ReCor Medical’s (Ronkonkoma, NY) PARADISE™ Percutaneous Renal Denervation System is based on delivery of high ultrasonic energy to induce nerve tissue injury. The PARADISE system is composed of two components: a 6 F-compatible balloon catheter with a cylindrical ultrasound transducer that emits ultrasound energy circumferentially ( Fig. 2 A ) and a portable generator which controls automated balloon inflation and deflation, and energy delivery. Energy is delivered in 3 different locations along the artery with 50 s inflation and delivery of ultrasound energy at each site. This device received CE mark in February 2012.
