Summary
Despite a wide choice of effective antihypertensive treatments, blood pressure (BP) in roughly half of hypertensive subjects is not controlled. Resistant hypertension is defined as an uncontrolled BP despite optimal doses of three antihypertensive treatments, including a diuretic. After confirmation of resistant BP using home BP measurement or 24-hour ambulatory BP monitoring (ABPM), patients usually go through a work-up to rule out secondary hypertension. If secondary hypertension is ruled out, the recent European guidelines on hypertension consider baroreceptor stimulation or renal denervation to be possible options. The prevalence of resistant primary hypertension may reach up to 10% in specialized centres. The two proposed non-pharmacological therapeutic strategies have been developed recently to inhibit sympathetic overactivity in resistant hypertension. Among them, baroreceptor activation therapy (BAT) is an innovative approach that interferes with baroreflex function. The first-generation BAT device (Rheos ® ; CVRx, Inc., Minneapolis, MN, USA) demonstrated good efficacy in lowering office BP and ABPM, but had an insufficient safety profile due to complex surgery. The second-generation BAT device (Barostim neo ™ system; CVRx, Inc.) seems to share the same BP-lowering efficacy but has a better safety profile. We report the first French case of baroreceptor stimulation for hypertension using the Barostim neo ™ system. We also discuss the pathophysiological features of and current levels of evidence for this technique.
Résumé
Malgré la disponibilité de nombreuses classes d’anti-hypertenseurs, la moitié des patients hypertendus ne sont pas contrôlés. L’hypertension résistante se définit par une pression artérielle non contrôlée malgré l’utilisation de trois anti-hypertenseurs à doses optimales dont un diurétique. Après confirmation par auto-mesures ou holter tensionnel, les patients ayant une hypertension résistante doivent bénéficier d’un bilan complet à la recherche de formes secondaires. La prévalence de l’hypertension essentielle résistante est de l’ordre de 5 à 10 % dans les centres spécialisés. Les recommandations européennes proposent la stimulation des barorécepteurs ou la dénervation rénale en cas d’hypertension non contrôlées par les mesures pharmacologiques. Ces deux approches non pharmacologiques ont été développées récemment pour cibler l’hyperactivation du système nerveux sympathique dans l’hypertension artérielle résistante. La stimulation des barorécepteurs carotidiens est une approche innovante ciblant la régulation du baro-réflexe. La première génération de stimulateur des barorécepteurs (Rheos ® ; CVRx, Inc., Minneapolis, MN, États-Unis) a démontré une bonne efficacité en termes de baisse de pression artérielle, cependant les risques opératoires liés à la complexité de la procédure étaient importants. La seconde génération de stimulateur des barorécepteurs (le système Barostim neo ™ ; CVRx, Inc.) semble démontrer une efficacité similaire en termes de baisse de pression artérielle et un meilleur profil de sécurité en raison d’une procédure d’implantation plus simple. Nous présentons le premier cas français d’implantation d’un stimulateur des barorécepteurs avec le système Barostim neo ™. Nous décrivons également les aspects physiopathologiques et le niveau de preuve actuel de la technique.
Background
Despite a wide number of antihypertensive treatments, roughly half of hypertensive subjects are not controlled . The therapeutic strategy for managing resistant hypertension has been simplified recently in the latest French guidelines . Resistant hypertension is defined as an uncontrolled blood pressure (BP) despite optimal doses of three antihypertensive treatments, including a diuretic. Resistant office BP must be confirmed using home BP measurement or 24-hour ambulatory BP monitoring (ABPM). When resistant hypertension is confirmed, patients undergo a work-up to rule out secondary hypertension. This may leave up to 10% of true resistant primary hypertension in dedicated centers accustomed to the management of hypertension in France . These patients may be considered for a non-pharmacological approach (i.e. renal denervation). While this technique appeared very promising after the SYMPLICITY HTN-1 and HTN-2 trials, the publication of the SYMPLICITY HTN-3 trial has cast some doubt on its real efficacy . In addition, there are some limitations related to renal function (estimated glomerular filtration rate < 45 mL/min) and renal artery anatomy (length and diameter before bifurcation, accessory renal arteries) that preclude its use in every resistant patient. Thus, there is still room for other approaches in this currently unsettled field.
One alternative (or additional) approach could be baroreceptor stimulation – a novel technique targeting the baroreflex via stimulation of the carotid sinus wall . The recent European guidelines on hypertension made the following recommendations: to consider baroreceptor stimulation or renal denervation in case of ineffectiveness of drug treatment in patients with resistant hypertension (class IIb, level C) and, until more evidence is available on the long-term efficacy and safety of renal denervation and baroreceptor stimulation, to restrict these procedures to hypertension centers (class I, level C) .
We report here on the first French implantation of a baroreceptor stimulator for hypertension, and we discuss the pathophysiological features of and current levels of evidence for this technique.
Case report
A 74-year-old man was referred to our department for an arterial hypertension work-up. His medical history included peripheral artery disease (bypass graft and angioplasty), single-vessel coronary artery disease treated with a bare-metal stent on the left anterior descending artery, with a left ventricular ejection fraction (LVEF) of 55% and obstructive sleep apnea syndrome treated with continuous positive airways pressure. After withdrawal of antihypertensive treatment interfering with hormonal status, we ruled out secondary endocrine forms of hypertension (mainly primary aldosteronism, Cushing’s syndrome and pheochromocytoma). Duplex ultrasound did not demonstrate any significant renal artery stenosis. Target organ damage was observed at the level of the heart (left ventricular mass index 155 g/m 2 ), vessels (pulse wave velocity 16 m/s) and kidney (estimated glomerular filtration rate 49 mL/min and microalbuminuria 280 mg/24 hours). Antihypertensive treatment was gradually optimized and a low dose of spironolactone was not tolerated because of hyperkalemia. Finally, the patient received daily: indapamide 1.5 mg, amlodipine 10 mg, valsartan 160 mg, nebivolol 5 mg, rilmenidine 1 mg and prazosin 5 mg. ABPM was uncontrolled on supervised intake of drugs: 172/75 mmHg, 24 hours; 172/76 mmHg, daytime; and 172/72 mmHg, night-time (non-dipper status). Long-term non-compliance with antihypertensive treatment was unlikely using questionnaires and home BP measurement. The patient was first screened for renal denervation. A computed tomography scan demonstrated mild atherosclerotic stenosis of around 40% on both renal arteries and a right inferior accessory renal artery. Moreover, we observed an occlusion of the superficial right femoral artery and an occlusion of the left bypass. Renal denervation was not possible because of two exclusion criteria: renal artery atheroma and severe peripheral artery disease.
Carotid ultrasonography ruled out significant atherosclerosis (> 50% reduction in diameter). Baroreceptor stimulator implantation was indicated. Twenty-four hours before surgery, antihypertensive treatments that interfere with the sympathetic nervous system were withdrawn (angiotensin receptor blocker, diuretics and beta-blockers) and replaced with a continuous intravenous infusion of nicardipine. The level of the right carotid bifurcation was marked using ultrasound guidance. General analgesia was performed with specific drugs (etomidate, midazolam, fentanyl and rocuronium) known for their limited interaction with the sympathetic nervous system. A catheter was placed in the left radial artery for continuous BP monitoring. The implantation procedure consisted of a right carotid sinus exposure via a 4 cm incision ( Fig. 1 A ). The electrode was positioned around the bifurcation in the area of the carotid sinus ( Fig. 1 B). The electrode and lead were connected to the battery impulse generator and briefly activated with impulses of 3 V, 100 Hz and a pulse width of 480 micros, once blood pressure and heart rhythm were stable. The hemodynamic response was tested and the electrode was repositioned in different locations to identify the site of optimal response. A marked acute reduction in BP was observed from 171/64 to 119/45 mmHg ( Fig. 1 C). Once the optimal location was confirmed, the electrode was sutured in place; then, a subcutaneous pocket was made inferior to the right clavicle for the battery impulse generator (Barostim neo ™ system; CVRx, Inc.). The lead was advanced under the skin and connected to the battery ( Fig. 2 ). The battery impulse generator was sutured in place with a permanent suture, and the two incisions were closed in layers with absorbable sutures. All antihypertensive treatments were started 24 hours after surgery, and the patient was discharged from hospital on the third day after device implantation.
Baroreflex activation therapy (BAT) was initiated only 2 weeks after implantation. Programmed variables (pulse amplitude, pulse width and frequency) were titrated for optimal response over the first few months. Trained CVRx field staff performed device programming under the direction of the clinician. Prazosin was withdrawn after initiation of the therapy because of orthostatic hypotension. BAT was well tolerated, with only a transient episode of cough and hoarseness when a high intensity of stimulation was used. After 9 months of follow-up, we observed a reduction of 15 mmHg in SBP and a reduction of 8 mmHg in DBP on 24-hour ABPM (157/67 mmHg, 24 hours; 158/67 mmHg, daytime; and 155/66 mmHg, night-time), with five antihypertensive drugs: indapamide 1.5 mg; amlodipine 10 mg; valsartan 160 mg; nebivolol 5 mg; and rilmenidine 1 mg.
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