Electrical Carotid Baroreceptor Stimulation in Resistant Hypertension
2010; Lippincott Williams & Wilkins; Volume: 55; Issue: 3 Linguagem: Inglês
10.1161/hypertensionaha.109.147306
ISSN1524-4563
AutoresGiuseppe Mancia, Gianfranco Parati, Alberto Zanchetti,
Tópico(s)Cardiovascular Health and Disease Prevention
ResumoHomeHypertensionVol. 55, No. 3Electrical Carotid Baroreceptor Stimulation in Resistant Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBElectrical Carotid Baroreceptor Stimulation in Resistant Hypertension Giuseppe Mancia, Gianfranco Parati and Alberto Zanchetti Giuseppe ManciaGiuseppe Mancia From the Department of Clinical Medicine and Prevention (G.M., G.P.), University of Milan-Bicocca, Milan, Italy; Department of Cardiology (G.P., A.Z.), Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy. , Gianfranco ParatiGianfranco Parati From the Department of Clinical Medicine and Prevention (G.M., G.P.), University of Milan-Bicocca, Milan, Italy; Department of Cardiology (G.P., A.Z.), Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy. and Alberto ZanchettiAlberto Zanchetti From the Department of Clinical Medicine and Prevention (G.M., G.P.), University of Milan-Bicocca, Milan, Italy; Department of Cardiology (G.P., A.Z.), Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy. Originally published25 Jan 2010https://doi.org/10.1161/HYPERTENSIONAHA.109.147306Hypertension. 2010;55:607–609Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 25, 2010: Previous Version 1 Resistant hypertension, as identified when administration of a thiazide diuretic plus ≥2 other antihypertensive drugs, all at full doses, fails to control an elevated blood pressure, is by no means a minor clinical problem. According to recent publications,1 the number of individuals falling into this category is ≈15% to 20% of the overall hypertensive population. Given the high prevalence of hypertension, this translates into a figure of several million patients per major country and of more than a hundred million patients worldwide.Several therapeutic approaches have been proposed to enhance the size of blood pressure reduction in resistant hypertension and possibly to achieve, in a noticeable fraction, blood pressure control. One approach is to add to the existing multidrug regimen an antialdosterone agent,2 thereby more effectively blocking the sodium-retaining properties of this hormone, the release of which escapes to a significant degree the effect of the blockers of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists) presently available.3 Another approach is to complement the usual multipharmacological treatment strategy with the vasodilator influence of the antagonists of endothelin receptors, which, indeed, seems capable of adding a further blood pressure reduction to any previous therapeutic effect.4A third approach is to resort to invasive procedures that can reduce the pressor or increase the depressor influences that physiologically modulate blood pressure. The invasiveness of this approach is ethically justified by the very high cardiovascular risk that characterizes the resistant hypertension condition.5 A reduction of the pressor influences can be obtained by denervating the kidneys through a radiofrequency generator positioned in the renal arteries through a percutaneously inserted catheter,6 because afferent fibers originating in the kidney exert sympathoexcitatory effects that can increase blood pressure,7 and removal of efferent sympathetic influences lowers overall total body norepinephrine spillover6 and reduces vasoconstriction in a region that accounts for a considerable proportion of systemic vascular resistance. An enhancement of the depressor influences can be obtained via the sympathoinhibitory effects of continuous "field" electric stimulation of the carotid baroreceptors via devices permanently placed around the carotid bifurcations.8 For either approach, the pathophysiological rationale is made even more compelling by the evidence that sympathetic activity increases progressively with the increase in the severity of hypertension9 and that a sympathoexcitatory state is especially pronounced in individuals in whom blood pressure control is particularly difficult, such as in isolated systolic hypertension,10 and in hypertension associated with obesity,11 particularly when obesity is accompanied by obstructive sleep apnea.12 Furthermore, use of electric baroreceptor stimulation is supported by the evidence that, in hypertension, the baroreflex undergoes a "resetting" that avoids baroreceptor saturation, thus preserving the reflex ability to cause vasodilatation and decrease blood pressure in response to an increase in its activity. This can be appreciated in the Figure, left panel, which shows the pressor and depressor responses (intra-arterial blood pressure measurements) to carotid baroreceptor deactivation and stimulation, respectively, obtained via the neck chamber technique in normotensive, moderate, and severe hypertensive patients.13 It can be further appreciated in the Figure, middle panel, which shows the sympathetic responses (microneurography) to arterial baroreceptor deactivation and stimulation obtained, in the same 3 conditions, by reducing and increasing blood pressure with vasoactive drug infusions.9Download figureDownload PowerPointFigure. Left, Progressive reductions and increases in mean arterial pressure (MAP; intra-arterial measurements) in response to progressive increases and reductions in carotid transmural pressure (CTP) obtained via a neck chamber device. The central and right panels show the reductions and increases in muscle sympathetic nerve activity (MSNA) and heart rate (HR) in response to increases and reductions in MAP obtained via infusion of phenylephrine and nitroprussiate. Data refer to mean regression line or mean values (±SE) from normotensive subjects (N), moderate essential hypertensive subjects (MH), and severe essential hypertensive subjects (SH). Data are from References 10 and 13 by permission (modified).Evidence that field electric stimulation of carotid baroreceptors can lower blood pressure on a chronic basis has been provided in dogs,14 and observations are available that a blood pressure reduction can also be obtained in resistant hypertensive patients after a use that spans over several months.15 This background information is expanded by the data reported in the article by Heusser et al16 published in this issue of Hypertension. Several findings of this article deserve to be emphasized. First, continuous electric stimulation of carotid baroreceptors over several months was accompanied by a reduction in 24-hour mean blood pressure. This expands on previous data regarding the persistent effectiveness of this stimulation procedure, the failure of which was responsible for the abandonment of this approach decades ago when it was first used for the treatment of resistant hypertension or intractable angina.17 It also provides evidence of a chronic depressor response on a variable such as daily life blood pressure that has special importance for patient prognosis.18 The size of the reduction (−10/−6 mm Hg systolic/diastolic blood pressure) was only apparently small if one considers that treatment-induced changes in 24-hour mean blood pressure are normally much smaller than the corresponding changes in clinic blood pressure.19 Second, the chronic blood pressure effect was related to the acute blood pressure fall obtained by electrical baroreceptor stimulation at a much earlier time, which gives hope that one might predict the long-term success of the procedure by earlier laboratory testing. Third, repeated acute stimulations, delivered 1 month after implantation of the devices, caused a clear-cut blood pressure reduction, as well as a marked inhibition of the outgoing sympathetic activity, as directly quantified in a peroneal nerve by microneurography. This is a relevant result because it shows that the surgical procedure by which the stimulating device is bilaterally implanted does not impair, through scarring, inflammation, or direct baroreceptor damage, the ability of the reflex to exert its sympathetic and vasomotor modulation. Additional support for this conclusion comes from the data provided by the sequence technique that, 1 month after the device implantation, the baroreflex was capable of modulating heart rate in response to spontaneous blood pressure changes, thereby subserving its role as a blood pressure stabilizer.The study of Heusser et al16 has 2 additional intriguing results, as well as some limitations. It is intriguing that, although significant, the relationship between the reduction in blood pressure and the reduction in sympathetic activity induced by acute baroreceptor stimulation showed a relatively low correlation coefficient (r2=0.42; P<0.05). This might mean that the sympathetic activity recorded in the peroneal nerve does not precisely represent the overall sympathetic influences of the baroreceptors. It may also mean, however, that nonsympathetic influences are involved in the blood pressure reduction. What these influences could be, however, it is not easy to imagine, because acute baroreceptor stimulation was associated with only a modest bradycardia and no significant changes in the spectral indices of heart rate variability, suggesting that a reduction in cardiac output was unlikely. There was, on the other hand, a significant, albeit not marked, reduction in plasma renin concentration, which is compatible with the possibility that a deactivation of the renin-angiotensin system plays a role. It is also intriguing that the baroreceptor stimulation had a much greater effect on sympathetic drive than on cardiac functions. As discussed by the authors,16 this may reflect an impairment of the baroreflex ability to modulate cardiac vagal, although not sympathetic, control. Indeed, this is supported by studies in experimental and human hypertension. Compared with Wistar Kyoto rats, in spontaneously hypertensive rats, an increase in blood pressure induced by infusion of norepinephrine was found to cause an equally marked sympathetic inhibition but a much smaller bradycardia.20 Similarly, compared with normotensive subjects, in moderate and severe essential hypertensive patients, increases and reductions in blood pressure induced by infusion of, respectively, vasopressor and vasodepressor drugs were found to be accompanied by progressively smaller changes in heart rate, whereas the changes in sympathetic activity were superimposable in the 3 conditions9 (Figure, middle and right panels). Incidentally, the reduced cardiac response to baroreflex stimulation is clinically advantageous, because a reduced cardiac output (eg, what happens with β-blockers) is associated with adverse effects, such as fatigue and limited exercise tolerance.21The limitations of the study by Heusser et al16 concern its small size and the timing of the acute baroreflex testing. Because the study included only 12 patients, generalization of the results to the effect of electrical baroreceptor stimulation in the large number of individuals with resistant hypertension is difficult. This is even more the case because the characteristics of the patients with resistant hypertension are extremely heterogeneous and, within the small group of patients included in the study, the responses to baroreceptor stimulation were so different as to range from a marked reduction to an increase in blood pressure and sympathetic activity. Furthermore, because the baroreflex was not tested immediately after implantation of the stimulating devices, the study lacks a "control" response and, thus, cannot exclude that, although qualitatively preserved, the baroreflex function was somewhat quantitatively altered by the surgical procedure. Finally, because the baroreflex was not acutely tested after the electric stimulus had been applied for months, the study cannot provide information on whether a prolonged intense stimulation may not ultimately result in, via receptor desensitization, alterations in the central integrating processes and/or reduced responsiveness of efferent neurons or effectors in deterioration and loss of its homeostatic role. It will be important to obtain this information in future studies that quantify the responses to acute baroreceptor stimulation before and at various times during the chronic stimulation procedure.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Giuseppe Mancia, Clinica Medica, Università Milano-Bicocca, Ospedale San Gerardo, via Pergolesi 33, 20052 Monza, Italy. E-mail [email protected] References 1 Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol. 2008; 52: 1749–1757.CrossrefMedlineGoogle Scholar2 Chapman N, Dobson J, Wilson S, Dahlöf B, Sever PS, Wedel H, Poulter NR; for the Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007; 49: 839–845.LinkGoogle Scholar3 Gumieniak O, Williams GH. Mineralocorticoid receptor antagonists and hypertension: is there a rationale? Curr Hypertens Rep. 2004; 6: 279–287.CrossrefMedlineGoogle Scholar4 Weber MA, Black H, Bakris G, Krum H, Linas S, Weiss R, Linseman JV, Wiens BL, Warren MS, Lindholm LH. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomized double-blind placebo-controlled trial. Lancet. 2009; 374: 1423–1431.CrossrefMedlineGoogle Scholar5 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germanò G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A. 2007 Guidelines for the Management of Arterial Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007; 25: 1105–1187.CrossrefMedlineGoogle Scholar6 Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009; 373: 1275–1281.CrossrefMedlineGoogle Scholar7 Calaresu FR, Stella A, Zanchetti A. Haemodynamic responses and renin release during stimulation of afferent renal nerves in the cat. J Physiol. 1976; 255: 687–700.CrossrefMedlineGoogle Scholar8 Mohaupt MG, Schmidli J, Luft FC. Management of uncontrollable hypertension with a carotid sinus stimulation device. Hypertension. 2007; 50: 825–828.LinkGoogle Scholar9 Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998; 31: 68–72.CrossrefMedlineGoogle Scholar10 Grassi G, Seravalle G, Bertinieri G, Turri C, Dell'Oro L, Stella ML, Mancia G. Sympathetic and reflex alterations in systo-diastolic and systolic hypertension in the elderly. J Hypertens. 2000; 18: 587–593.CrossrefMedlineGoogle Scholar11 Grassi G, Seravalle G, Dell'Oro R, Turri C, Bolla GB, Mancia G. Adrenergic and reflex abnormalities and obesity-related hypertension. Hypertension. 2000; 36: 538–542.CrossrefMedlineGoogle Scholar12 Grassi G, Facchini A, Quarti Trevano F, Dell'Oro R, Arenare F, Tana F, Bolla GB, Monzani A, Robuschi M, Mancia G. Obstructive sleep apnea- dependent and – independent adrenergic activation in obesity. Hypertension. 2005; 46: 321–325.LinkGoogle Scholar13 Mancia G, Ludbrook J, Ferrari AU, Gregoriani L, Zanchetti A. Baroreceptor reflexes in human hypertension. Circ Res. 1978; 43: 170–177.CrossrefMedlineGoogle Scholar14 Lohmeier TE, Irwin ED, Rossing MA, Serdar DJ, Kieval RS. Prolonged activation of the baroreflex produces sustained hypotension. Hypertension. 2004; 43: 306–311.LinkGoogle Scholar15 Scheffers IJ, Kroon AA, Tordoir JH, de Leeuw PW. Rheos Baroreflex Hypertension Therapy System to treat resistant hypertension. Expert Rev Med Devices. 2008; 5: 33–39.CrossrefMedlineGoogle Scholar16 Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, Peters T, Sweep FCGJ, Haller H, Pichlmaier AM, Luft FC, Jordan J. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010; 55: 619–626.LinkGoogle Scholar17 Brest AN, Wiener L, Bachrach B. Bilateral carotid sinus nerve stimulation in the treatment of hypertension. Am J Cardiol. 1972; 29: 821–825.CrossrefMedlineGoogle Scholar18 Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population. follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) Study. Circulation. 2005; 111: 1777–1783.LinkGoogle Scholar19 Mancia G, Parati G. Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: a meta-analysis. J Hypertens. 2004; 22: 435–444.CrossrefMedlineGoogle Scholar20 Ricksten SE, Thoren P. Reflex control of sympathetic nerve activity and heart rate from arterial baroreceptors in conscious spontaneous hypertensive rats. Cli Sci (Lond). 1981; 61: 169s–172s.CrossrefMedlineGoogle Scholar21 Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. β-Blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002; 288: 351–357.CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zucker I, Xia Z and Wang H (2023) Potential Neuromodulation of the Cardio-Renal Syndrome, Journal of Clinical Medicine, 10.3390/jcm12030803, 12:3, (803) Shanks J, de Morais S, Gao L, Zucker I and Wang H (2019) TRPV1 (Transient Receptor Potential Vanilloid 1) Cardiac Spinal Afferents Contribute to Hypertension in Spontaneous Hypertensive Rat, Hypertension, 74:4, (910-920), Online publication date: 1-Oct-2019. Cao Q, Zhang J, Yu Q, Wang J, Dai M, Zhang Y, Luo Q and Bao M (2019) Carotid baroreceptor stimulation in obese rats affects white and brown adipose tissues differently in metabolic protection, Journal of Lipid Research, 10.1194/jlr.M091256, 60:7, (1212-1224), Online publication date: 1-Jul-2019. Sata Y, Kawada T, Shimizu S, Kamiya A, Akiyama T and Sugimachi M (2015) Predominant Role of Neural Arc in Sympathetic Baroreflex Resetting of Spontaneously Hypertensive Rats, Circulation Journal, 10.1253/circj.CJ-14-1013, 79:3, (592-599), . Kouchaki Z, Georgakopoulos D, Butlin M and Avolio A (2014) Field stimulation of the carotid baroreceptor complex does not compromise baroreceptor function in spontaneously hypertensive rats 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 10.1109/EMBC.2014.6944240, 978-1-4244-7929-0, (2944-2945) Veglio F, Grassi G, Mancia G and Volpe M (2013) Clinical Management of Resistant Hypertension, High Blood Pressure & Cardiovascular Prevention, 10.1007/s40292-013-0022-3, 20:4, (251-256), Online publication date: 1-Dec-2013. Campese V (2013) Interventional hypertension, Journal of Hypertension, 10.1097/HJH.0b013e328364d3f1, 31:11, (2118-2122), Online publication date: 1-Nov-2013. Pathak A, Labrunee M, Vaccaro A, Della Rosa F, Guiraud T, Pavy Le Traon A, Galinier M and Senard J (2013) L'activation du baroréflexe par stimulation implantable du sinus carotidien dans le traitement de l'hypertension artérielle résistante, Archives des Maladies du Coeur et des Vaisseaux - Pratique, 10.1016/S1261-694X(13)70557-1, 2013:222, (22-26), Online publication date: 1-Nov-2013. Menne J, Jordan J, Linnenweber-Held S and Haller H (2012) Resistant hypertension: baroreflex stimulation as a new tool, Nephrology Dialysis Transplantation, 10.1093/ndt/gfs504, 28:2, (288-295), Online publication date: 1-Feb-2013., Online publication date: 1-Feb-2013. Volpe M and Tocci G (2013) Involvement of Health Professionals: From the General Practitioner to the Hypertension Specialist and the Hypertension Center Resistant Hypertension, 10.1007/978-88-470-5415-8_16, (181-191), . (2012) CardioPulse Articles, European Heart Journal, 10.1093/eurheartj/ehs296, 33:20, (2503-2509), Online publication date: 1-Oct-2012., Online publication date: 1-Oct-2012. Doumas M, Faselis C, Tsioufis C and Papademetriou V (2012) Carotid Baroreceptor Activation for the Treatment of Resistant Hypertension and Heart Failure, Current Hypertension Reports, 10.1007/s11906-012-0258-7, 14:3, (238-246), Online publication date: 1-Jun-2012. Parati G and Esler M (2012) The human sympathetic nervous system: its relevance in hypertension and heart failure, European Heart Journal, 10.1093/eurheartj/ehs041, 33:9, (1058-1066), Online publication date: 1-May-2012. Martin E and Victor R (2010) Premise, Promise, and Potential Limitations of Invasive Devices to Treat Hypertension, Current Cardiology Reports, 10.1007/s11886-010-0156-z, 13:1, (86-92), Online publication date: 1-Feb-2011. Jordan J and Grassi G (2010) Belly fat and resistant hypertension, Journal of Hypertension, 10.1097/HJH.0b013e328339b8d9, 28:6, (1131-1133), Online publication date: 1-Jun-2010. March 2010Vol 55, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.109.147306PMID: 20100993 Originally publishedJanuary 25, 2010 PDF download Advertisement SubjectsHypertensionTreatment
Referência(s)