Implantable Carotid Sinus Stimulator for the Treatment of Resistant Hypertension: Local Effects on Carotid Artery Morphology

Article Outline

• Abstract
• Introduction
• Methods
  • Animal Study
  • Rheos Feasibility Trial
  • Data Analysis
• Results
  • Ovine Implants
  • Histological Findings
  • Human Studies
• Discussion
• References
• Copyright

Background

The Rheos™ System is a chronically implanted carotid sinus baroreflex activating system with a pulse generator and bilateral perivascular carotid sinus leads (CSLs) that is being evaluated in prospective clinical trials for the treatment of drug-resistant hypertension. We evaluated carotid artery structural integrity after implantation of the CSLs.

Methods

To assess the effect of chronic CSL attachment, 29 CSLs were implanted on the common carotid arteries of eight sheep. The studies were terminated at 3 and 6 months postimplantation to assess anatomic and histologic changes. Additionally, 10 patients with resistant hypertension were enrolled in the Rheos Multicenter Feasibility Trial. Duplex ultrasound (DUS) was performed before device implantation and at 1 and 4 months postimplantation in this patient cohort. An independent core laboratory assessed all DUSs.

Results

Ovine carotid angiography revealed no significant stenoses, while anatomic and histologic evaluations demonstrated electrode encapsulation in a thin layer of connective tissue with no evidence of stenosis, erosion, or inflammation. DUS evaluation revealed no significant increase in peak systolic velocities of the common and internal carotid arteries 1 and 4 months after initial implantation, indicating a lack of injury, remodeling, or stenosis.

Conclusion

The current data suggest that the CSLs used with the Rheos System are not associated with the development of carotid stenosis or injury. These short-term data support the concept of CSL placement and merit long-term investigation in a larger multicenter prospective trial.

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Introduction 

Hypertension, defined as a systolic blood pressure (SBP) >140 mm Hg and/or a diastolic blood pressure (DBP) >90 mm Hg, affects 31% of adults in the United States and is a major cause of cardiovascular morbidity and mortality.¹, ² The benefits of optimal hypertension management are well established. Chobanian et al.³ reported that for each increase in blood pressure of 20/10 mm Hg, above a base pressure of 117/75 mm Hg, the risk of cardiovascular death doubled. While effective treatment of hypertension reduces the incidence of myocardial infarction, congestive heart failure, and stroke by up to 50%, only 25-34% of individuals with hypertension in the United States have their blood pressure controlled to 140/90 mm Hg or below.¹, ⁴ Failure to control hypertension is multifactorial. Noncompliance with medical therapy is reported to account for up to 50% of cases,⁵, ⁶, ⁷ while as many as 30% of patients with hypertension cannot be controlled with medications and are considered “resistant” to treatment.⁸ Within this latter group, subsets of patients suffer with truly dangerous hypertension and remain at significant risk of cardiovascular disease, renal disease, and other sequelae. These patients would greatly benefit from innovative therapies for the management of hypertension.

A new device-based therapy has been developed that may assist in the treatment of patients with resistant hypertension and, if successful, may be applicable to a broader group of patients. This product, the Rheos™ Baroreflex Hypertension Therapy System (CVRx, Inc., Minneapolis, MN), is composed of an implanted pulse generator and electrodes which are affixed to the carotid sinus. Application of an electrical current activates the carotid baroreflex, inducing neurohumoral changes which produce sustained reductions in blood pressure.⁹, ¹⁰ As with any new therapy, its safety and effectiveness must be demonstrated. Early published data suggest that the Rheos System can significantly decrease the blood pressure of patients with resistant hypertension. Dose–response testing, performed the day after the implant procedure, revealed a linear relationship between the dose of therapy delivered and the degree of blood pressure reduction (r = 0.88), with the overall reduction in SBP averaging 41 mm Hg (mean fall from 180 to 139 mm Hg).¹¹ Therapy was initiated 1 month after implantation of the system, and patients were followed at monthly intervals. At 4 months, a significant mean reduction in SBP of 22 ± 21 mm Hg was noted by office blood pressure cuff measurements.¹² Uncertainties still exist regarding the short- and long-term local responses of the carotid vasculature and surrounding structures after electrical leads are secured to the vessels at the level of the carotid sinus. We reviewed the data from animal studies and the North American human feasibility trial (Rheos Trial) to analyze the effect of implanting carotid sinus electrodes on carotid artery morphology and function.

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Methods 

Animal Study 

To assess the effect of chronic carotid sinus lead (CSL) attachment to the carotid arteries, 29 CSLs were implanted in eight Suffolk crossbred sheep (85-120 kg with carotid artery diameters exceeding 8 mm as measured by preoperative duplex examinations). An ovine model was selected as the carotid arteries represent a relevant size for testing the safety of the human electrode in vivo. All aspects of the study were approved by the Animal Research Committee prior to initiation of the protocol. All animals were obtained from Food and Drug Administration (FDA)–approved vendors and maintained throughout the study in accordance with the regulations outlined in the U.S. Department of Agriculture's Animal Welfare Act (9 CFR, parts 1, 2 and 3) and the conditions specified in “The Guide for Care and Use of Laboratory Animals.”¹³

On the day of the implant procedure, the animals were anesthetized using isofluorane and oxygen, initially via nose cone, followed by endotracheal intubation with positive pressure ventilation. They underwent duplex ultrasound (DUS) examination (Aspen Ultrasound Imaging Equipment, Oceanside, CA; 7 MHz probe) to confirm that the carotid diameters exceeded 8 mm in diameter. The carotid arteries were exposed and the carotid sinus electrodes wrapped around the carotid artery. The stimulator is activated to identify the location with the highest sensitivity to the electrodes. Once this is determined, the electrodes are secured in place to the adventitial layer by placing three interrupted 6-0 Prolene sutures. While the final location of the electrodes is variable, the most common location is the junction of the distal common carotid artery (CCA) and proximal internal carotid artery (ICA) at the carotid bulb. Complete electrode lead bodies were implanted on each carotid artery. If the more distal carotid artery also met the size criteria, a second carotid sinus electrode was sutured to the carotid artery. Angiography was performed using right common femoral artery access. Hand injection was performed through a 6-French multiple-purpose catheter. Images were obtained in anteroposterior, anterior oblique, and lateral projections. Measurements were obtained using the known diameter of the catheter as a reference. Animals received care according to the standard operating procedures of the laboratory. Animals were followed for 3 (three animals) or 6 (five animals) months after the electrodes were implanted, at which time they were anesthetized for diagnostic angiography and necropsy. All necropsies were performed by a board-certified veterinary pathologist. Following en-bloc excision of the carotid vessels with implant and vagus nerve, the specimen was fixed with formalin. Transverse sections of 2-3 mm were obtained and the slides were stained with toluidine blue and basic fuchsin. All vessel sections were examined to determine vessel wall integrity, the presence or absence of erosion, vessel inflammation, endothelialization, presence of neointimal hyperplasia, presence and appearance of the inner connective tissue capsule, and the presence or absence of the external fibrous connective tissue capsule. If neointimal hyperplasia was present, the severity of the hyperplasia was assessed. Minimal was defined as two to three cell layers in thickness and of no clinical significance (not resulting in clinically significant stenosis).

Rheos Feasibility Trial 

The Rheos Feasibility Trial is a phase II multicenter trial approved by the FDA and each implanting center's institutional review board. All patients are under the care of internists, nephrologists, or cardiologists specializing in the treatment of hypertension. Eligibility is limited to patients with resistant hypertension, defined as SBP ≥160 mm Hg while receiving optimal therapy for 60 days prior to the implant procedure. Optimal therapy is defined as the maximal appropriate dose of at least three antihypertensive medications including a diuretic. Exclusion criteria included secondary causes of hypertension, baroreflex dysfunction, noncompliance with medical therapy for hypertension, significant carotid artery disease (>50% reduction in linear diameter or evidence of ulceration as determined by DUS), and prior cervical surgery or radiation therapy.¹¹ After selection for participation in the trial, the patients undergo implantation of the CVRx Rheos System as previously described by Illig et al.¹¹ In brief, the carotid bifurcations are exposed and the optimal location, as defined by the location producing the maximal hemodynamic response to acute baroreflex therapy, is determined. The electrodes are then sutured to the carotid bifurcation at this location. A pocket is fashioned in the subcutaneous tissues superficial to the right pectoralis muscle for placement of the implantable pulse generator. Tunnels are created between the cervical incisions and the implantable pulse generator pocket to allow connection of the carotid sinus electrodes to the implantable pulse generator and internalization of the entire system. The patients undergo routine postoperative care, continuing their stable antihypertensive regimens unless their treating physician deems changes necessary for patient safety. The implantable pulse generator is kept off for the first month to allow healing of the CSLs and pulse generator. The device is turned on during the 1-month visit, and office blood pressures as well as ambulatory blood pressures are obtained in all patients. Duplex examinations of the carotid arteries are obtained before implantation of the CSLs and at 1 and 4 months postoperatively. The duplex examinations are performed in accredited noninvasive vascular laboratories by certified technologists. All duplex studies are reviewed at the implanting center and by a core laboratory (Vascular Diagnostic Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA). The interpretations from the core laboratory were used in the subsequent analyses.

Data Analysis 

Data used in the duplex analysis were obtained from the core laboratory, which reviewed all duplex studies. Data were stored using commercially available computer spreadsheets. Comparisons were made for each arterial segment at the three time points using a one-way analysis of variance. Comparisons between the 1- and 4-month postoperative time points were made using a paired t-test. p < 0.05 was considered statistically significant. Unless otherwise specified, data are expressed as mean ± standard deviation (SD).

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Results 

Ovine Implants 

Eight Suffolk crossbred sheep underwent implantation of a total of 29 electrodes. Angiograms were available for review from the immediate implant procedure and the study end point when the animals were killed after 3 (n = 3) or 6 (n = 5) months. Anterior–posterior, oblique, and cross-table lateral images were reviewed for seven of the animals (2 at 3 months and 5 at 6 months). Two animals (one killed at 3 and one at 6 months) were noted to have six areas of <10% reduction in linear diameter of the carotid arteries on angiography. All cases were associated with the area of dissection with a gentle taper extending well beyond the electrode. In no case was there an area of localized narrowing limited to the arterial segment immediately beneath or adjacent to the electrode, and none of these mildly narrowed areas was demonstrated in all projections. This argues against a uniform concentric narrowing of the artery due to fibrotic scar tissue induced by the electrode but seems consistent with minor remodeling within the dissection field used to expose the artery for the implant procedure.

Histological Findings 

At necropsy, all implant sites identified on the carotid arteries were fully encapsulated and appeared normal. None of the 29 electrodes implanted during this study was associated with any evidence of infection. All implants were sutured securely in place around the carotid arteries and appeared normal. At the time of dissection, histological trimming, and processing, all carotid arteries appeared oval or round in transverse section. Vagus nerve segments adjacent to the electrode appeared normal. All electrode components were enveloped in a thin fibrous capsule, which was easily dissected from the lead body and external surface of the electrode. This included a capsule on the superficial aspect of the electrode (external capsule) and between the electrode and the adventitia (internal capsule). After removing the sutures securing the electrodes to the adventitia, the electrodes were easily removed from the external surface of the artery and associated internal capsule. Evidence of electrode damage (coil abnormalities or abrasion of the silicone backer) was not seen in any of the electrodes examined at the time of vessel dissection.

Microscopically, no erosion or inflammation of the carotid arteries at the site of the implant was observed. All vessels appeared completely endothelialized and of oval to round shape. Vessel integrity was maintained, and the wall of the vessel, as well as the periadventitial connective tissue, demonstrated a typical foreign body reaction but was otherwise free of inflammatory infiltrates. Minimal neointimal hyperplasia was seen in 32 of 54 (59%) sections from paraffin-embedded blocks from animals implanted for 3 months and 23 of 161 (14%) from paraffin-embedded tissues from animals implanted for 6 months. Neointimal hyperplasia was also found in sections of the carotid vessel that were proximal or distal to the implant that had no contact with the electrode. The neointimal hyperplasia was approximately two to three cell layers thick, was seen around portions of the luminal surface, and was considered clinically insignificant. Neointimal hyperplasia seen in longitudinal sections was not increased in thickness or prominence at the junction of the edge of the electrode implant site and the proximal or distal portion of the carotid artery in either the 3- or 6-month electrodes. The minimal neointimal hyperplasia was not considered to be device-related at either the 3- or 6-month time points.

The apposed silicone surfaces of the electrode were separated by a thin fibrous connective tissue ingrowth, and there was no evidence of abrasion of the electrode backer. Overall, the fibrous layer between the adventitia and the surrounding electrodes (internal capsule) was of a greater thickness in vessels explanted after the electrodes had been in place for 3 months than in specimens that had been implanted for 6 months. By 6 months postimplant, there was maturation of the collagenized fibrous connective tissue that comprised the internal capsule, and this connective tissue layer appeared thinner. The internal capsule was inspected from sections taken immediately beneath the coil portion of the CSL and the silicone backer between the coils. Both the 3- and 6-month electrode implants contained areas of granulomatous inflammation, which is typical of a foreign body reaction elicited by chronic implantation of a device within the body. There were no apparent differences in the thickness of the internal capsule or the inflammatory infiltrate on the external surface of the internal capsule between sections taken directly below the coils of the electrode or the silicone backer in either the 3- or 6-month implants. The granulomatous infiltrate and mononuclear cell inflammation of the external and internal capsules appeared more prominent in the 3-month electrodes than the 6-month electrodes. By 6 months, the normal inflammatory response to the electrode implant was subsiding and the implant site was stable.

Human Studies 

Ten patients with resistant hypertension were enrolled in the Rheos Feasibility Trial of baroreflex hypertension therapy (Table I).

Table I. Patient demographic data (n = 10)

Variable	Data
Sex	4 Female, 6 male
Race	4 Black, 6 white
Age (years, range)	50 ± 13 (33-71)
BMI (kg/m2, range)	34.3 ± 6.7 (29-51)
Office cuff BP (mm Hg)
SBP (range)	175 ± 22 (144-204)
DBP (range)	101 ± 22 (70-142)
Mean number of antihypertensive medications	6.2 ± 2.3 (3-9)

All patients underwent duplex examination on entry to the study as well as 1 and 4 months postoperatively. At each time point the proximal, mid-, and distal segments of the CCA and ICA were fully interrogated. After review by the core laboratory, the studies were deemed adequate for interpretation in 61 of 90 (68%) CCA segments on the left and right. For the ICA, 71 of 90 (79%) segments studied on the left and 70 of 90 (79%) on the right were deemed adequate for interpretation. The adequacy of the duplex studies for interpretation was similar between all three time points (entry to study, 1 month, and 4 months).

On entry to the study, the mean CCA peak systolic velocity (PSV) was 77.3 ± 15.4 cm/sec, while the mean ICA PSV was 69.3 ± 18.2 cm/sec; thus, all of the patients met the inclusion criteria for no stenosis producing a >50% reduction in linear diameter. Mean CCA and ICA PSVs were also measured at the 1- and 4-month duplex evaluations (Table II). There were no significant differences in the mean CCA and ICA PSVs when the preimplantation measurements were compared to the 1- and 4-month measurements.

Table II. PSV measurements

The core laboratory deemed that the duplex data provided adequate comparisons of PSV at the 1- and 4-month time points in 29 ICA segments. There were no significant differences in the PSV at any of the CCA or ICA segments when compared to the measurements at the 1- or 4-month follow-up study (Table III). The average change in ICA PSV between the 1- and 4-month time points was 6.57 ± 22.9 cm/sec (range –29 to + 92). This change did not reach statistical significance (p = 0.13). The difference in ICA PSV between the 1- and 4-month evaluations was positive in 16 segments and negative in 12, with no difference in one. Nineteen of these comparisons fell within the interobserver variability for DUS of 8–16 cm/sec as reported by Henry-Feugeas and colleagues,¹⁴ while nine segments in three patients demonstrated changes which exceeded 16 cm/sec. Two of these segments demonstrated a reduction in ICA PSV, –19 and –35 cm/sec, while seven segments demonstrated increases in ICA PSV (17, 18, 20, 24, 31, 40, and 92 cm/sec). Five of these seven arterial segments which had the greatest change were in a single patient who developed an infection requiring explant of the Rheos System. The entire system, both electrodes and implantable pulse generator, was subsequently removed. After healing was complete, follow-up ultrasound revealed no visible sign of stenosis, with velocities consistent with 0-15% reduction in linear diameter (personal communication from K. I.). If these are excluded, the difference between the 1- and 4-month time points fell beyond the expected interobserver variability in five of 24 ICA segments (increased by 18 and 50 cm/sec and reduced by 19, 19, and 21 cm/sec). The ICA/CCA ratio was 1.03 ± 0.33 cm/sec (range 0.644-2.08) at entry into the study compared to 1.07 ± 0.37 cm/sec (range 0.57-1.87) and 1.02 ± 0.39 cm/sec (range 0.68-2.12) at 1 and 4 months after implant, respectively (p > 0.05).

Table III. Differences in PSV (cm/sec), mean ± SD

At 4 months, the mean reduction in SBP was 21.6 ± 21.3 mm Hg (range –73 to +2) and the mean reduction in DBP was 17.3 ± 16.5 mm Hg (range –47 to +7). The average reduction in mean blood pressure was 18.7 ± 17.1 mm Hg (range –52 to +4).

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Discussion 

Hypertension is a major cause of cardiovascular morbidity and mortality in the United States. While noncompliance with medical therapy is reported to account for up to 50% of cases, as many as 30% of patients with hypertension cannot be controlled with medications and are considered “resistant” to treatment. The Rheos System is a new device-based therapy for the treatment of resistant hypertension. This system, composed of an implanted pulse generator and electrodes which are affixed to the carotid sinus, activates the carotid baroreflex by electrical stimulation, inducing neurohumoral changes which produce sustained reductions in blood pressure. As with any new therapy, the safety of the system, as well as its effectiveness, must be demonstrated.

The initial experience with the device, in the United States and Europe, suggests that it can be safely implanted and can significantly decrease blood pressure. Early experience with the device in the United States, published by Illig and collegues,¹¹ demonstrated no periprocedural complications associated with implantation. Dose–response testing performed during the initial hospitalization revealed consistent reductions in SBP of 41 mm Hg without significant bradycardia or other symptoms.¹¹ Tordoir and associates,¹⁵ discussing the European experience, reported no complications at the time of device implantation and significant decreases in SBP (28 ± 22 mm Hg) and DBP (16 ± 11 mm Hg) in the immediate postoperative period. More importantly, they found the response to be durable during the first 3 months of Rheos therapy.¹⁵ After 3 months of therapy, Bisognano and associates¹² found that the blood pressure reduction was durable, with decreases in SBP (22 mm Hg) and DBP (18 mm Hg). De Leeuw et al.¹⁶ published the experience of the Rheos DEBuT-HT trial in Europe and reported reductions of 24 and 12 mm Hg for SBP and DBP, respectively. Finally, de Leeuw and associates,¹⁷ reporting on the combined U.S. and European experience of the first 21 patients with 6 months of therapy, noted a stable response with reductions of 21 and 16 mm Hg for SBP and DBP, respectively. These trials suggest that implantation of the Rheos system can be performed safely and the perioperative effects on blood pressure are sustained during follow-up.

In addition to being effective, for a new therapy to be accepted, it must be demonstrated to be safe. In this analysis we found the Rheos system to be safe and free of deleterious long-term effects on the carotid arteries. The carotid sinus electrodes for the Rheos system were tested in a representative animal model with excellent results. The CSLs were completely encapsulated by a layer of collagenized fibrous connective tissue. The foreign body response to electrode implantation was subsiding by 6 months. All vagus nerve tissue, evaluated histologically, was free of any evidence of CSL-induced damage. There was no evidence of electrode-induced injury to the arteries, and vessel wall integrity was maintained. Minimal intimal hyperplasia was present in 25% of vessels. When present, it was seen uniformly throughout the arterial wall segments examined histologically, was not associated with arterial stenosis, and was not felt to be due to the presence of the CSLs. Finally, on angiography there was no evidence of electrode-induced alteration to the carotid arteries either at segments in contact with the electrode or at transition points at the edges of the electrodes. In summary, the animal studies revealed no evidence of infection, erosion, or inflammation of the CCA at the site of the implantion. Vessel integrity was maintained, and there were no concerning findings on gross or histologic examination. The electrodes were completely encapsulated and easily removed from the implantation site, suggesting that lead removal is unlikely to be associated with carotid artery injury during reexplorations.

Early clinical evaluation in humans also suggests that implantation of the CSLs at the carotid bifurcations of patients with absent or minimal carotid occlusive disease is not associated with the development of carotid stenoses in the vessels involved. This was determined by carotid duplex evaluations preoperatively and at 1 and 4 months postimplantation of the CSLs. In this patient population, there was no significant increase in PSVs or end-diastolic velocities of the ICS and CCA. To further characterize these patients, the ICA/CCA ratios were also analyzed. This ratio has been shown to be valid for predicting stenosis within the ICA, having particular utility when there are conditions in which the volume of blood flowing within the arteries varies. This ratio is included in an effort to remove any potential confounding effects of reduced blood pressure seen at the 4-month time point. We found no differences in the ICA/CCA ratios.

In summary, we have presented data from the first 10 patients enrolled in the phase II feasibility study of the Rheos system in resistant hypertension as well as preclinical animal studies. The blood pressure reduction seen in these patients was both clinically and statistically significant and is expected to reduce the risk of cardiovascular morbidity and mortality in the patient cohort. Additionally, histologic and angiographic data from large animal studies and duplex data from the phase II human feasibility study demonstrate that the system is well tolerated and does not produce local tissue changes which are expected to induce vessel wall injury. In the animal work implanted segments of the carotid arteries did not contain evidence of arterial wall erosion, thrombosis, or stenosis. Electrodes were completely encapsulated and easily removed from the implant site at the time of necropsy. Therefore, the presence of the electrode is not anticipated to increase the difficulty of reoperation beyond that typically seen for reoperative carotid procedures. Additionally, the duplex data demonstrate that the electrode does not induce local changes in the arteries that are associated with the development of stenosis in the early postoperative period. Taken together the histologic and angiographic findings from the preclinical work and the duplex studies from the clinical work support the safety of the Rheos carotid sinus electrodes used to deliver baroreflex hypertension therapy. Long-term clinical data are necessary to assure the continued inert nature of the CSLs implanted at the carotid bifurcation. Current data clearly support the progression to a larger multicenter trial for evaluation of the Rheos System.

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