Endovascular baroreflex amplification and the effect on sympathetic nerve activity in patients with resistant hypertension: A proof-of-principle study

Monique E A M van Kleef, Karsten Heusser, André Diedrich, P Liam Oey, Jens Tank, Jens Jordan, Peter J Blankestijn, Bryan Williams, Wilko Spiering, Monique E A M van Kleef, Karsten Heusser, André Diedrich, P Liam Oey, Jens Tank, Jens Jordan, Peter J Blankestijn, Bryan Williams, Wilko Spiering

Abstract

Background: First in human studies suggest that endovascular baroreflex amplification (EVBA) lowers blood pressure (BP). To explore potential mechanisms for BP reduction, this study examines the effects of EVBA on muscle sympathetic nerve activity (MSNA) and baroreceptor sensitivity (BRS).

Methods: In a single-center sub-study of the CALM-DIEM study (Controlling And Lowering blood pressure with the MobiusHD-Defining Efficacy Markers), 14 patients with resistant hypertension were treated with EVBA. Microneurography and non-invasive continuous BP measurements were performed at baseline and three months after MobiusHD implantation. The primary outcome was change in MSNA. Secondary outcomes were change in baroreflex sensitivity (BRS), cardiovascular responses to a sympathetic stimulus, BP, heart rate (HR) and heart rate variability (HRV).

Results: The primary endpoint was obtained in 10 of 14 patients enrolled in the sub-study. MSNA burst frequency and burst incidence decreased in 6 of 10 patients: mean change -4.1 bursts/min (95% confidence interval -12.2 to 4.0) and -3.8 bursts/100 heartbeats (-15.2 to 7.7). MSNA spike frequency and spike count decreased in 8 of 10 patients: mean change -2.8 spikes/sec (-7.3 to 1.8) and -3.0 spikes/heartbeat (-6.1 to 0.1). Change in MSNA and BP were not correlated. Office BP decreased by -14/-6 mmHg (-27 to -2/-15 to 3). We observed a trend towards decreased HR (-5 bpm, -10 to 1) and increased total power HRV (623 msec2, 78 to 1168). In contrast, BRS and cardiovascular responses remained unchanged after EVBA.

Conclusions: In this proof-of-principle study, EVBA did not significantly decrease MSNA in patients with resistant hypertension. EVBA did not impair baroreflex function.

Trial registration: Clinical trial registration at NCT02827032.

Conflict of interest statement

Monique E.A.M. van Kleef was indirectly paid from a research grant by Vascular Dynamics, Inc. Karsten Heusser, P. Liam Oey, Jens Tank, André Diedrich and Peter J. Blankestijn report no conflict of interest. Jens Jordan served as consultant for Novartis, Boehringer-Ingelheim, Sanofi, Orexigen, Riemser, Vivus, and is cofounder of Eternygen GmbH. Bryan Williams has received honoraria for consultancy from Vascular Dynamics Inc. W. Spiering is a consultant for Vascular Dynamics and has received a research grant from Vascular Dynamics. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow chart of the patients…
Fig 1. Flow chart of the patients screened, excluded, lost to follow-up and excluded from analysis of the primary endpoint.
SBP = systolic blood pressure, meds = antihypertensive medications, MSNA = muscle sympathetic nerve activity.
Fig 2. Individual MSNA changes and correlation…
Fig 2. Individual MSNA changes and correlation with change in BP.
Panel I: individual changes in burst frequency (Ia), burst incidence (Ib), mean beat-to-beat median spike frequency (Ic), and mean beat-to-beat spike count (Id). Panel II: correlation between change in office SBP and change in burst frequency (Ia), burst incidence (IIb), mean beat-to-beat median spike frequency (IIc), and mean beat-to-beat spike count (IId). Observations in the left lower quadrants of the plots support baroreflex-mediated BP reduction. SBP = systolic blood pressure, BF = burst frequency, BI = burst incidence, r = Pearson’s correlation coefficient, p = p-value.

References

    1. Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, et al.. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol. 2014;177(3):1020–5. doi: 10.1016/j.ijcard.2014.09.138
    1. Chapleau MW, Hajduczok G, Abboud FM. Peripheral and central mechanisms of baroreflex resetting. Clin Exp Pharmacol Physiol Suppl. 1989;15:31–43. doi: 10.1111/j.1440-1681.1989.tb02994.x
    1. Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, et al.. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010;55(3):619–26. doi: 10.1161/HYPERTENSIONAHA.109.140665
    1. Scheffers IJ, Kroon AA, Schmidli J, Jordan J, Tordoir JJ, Mohaupt MG, et al.. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol. 2010;56(15):1254–8. doi: 10.1016/j.jacc.2010.03.089
    1. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al.. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol. 2011;58(7):765–73. doi: 10.1016/j.jacc.2011.06.008
    1. Tordoir JH, Scheffers I, Schmidli J, Savolainen H, Liebeskind U, Hansky B, et al.. An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension. Eur J Vasc Endovasc Surg. 2007;33(4):414–21. doi: 10.1016/j.ejvs.2006.11.025
    1. Heusser K, Tank J, Brinkmann J, Menne J, Kaufeld J, Linnenweber-Held S, et al.. Acute Response to Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients With Resistant Arterial Hypertension. Hypertension. 2016;67(3):585–91. doi: 10.1161/HYPERTENSIONAHA.115.06486
    1. Spiering W, Williams B, Van der Heyden J, van Kleef M, Lo R, Versmissen J, et al.. Endovascular baroreflex amplification for resistant hypertension: a safety and proof-of-principle clinical study. Lancet. 2017;390(10113):2655–61. doi: 10.1016/S0140-6736(17)32337-1
    1. van Kleef M, Bates MC, Spiering W. Endovascular Baroreflex Amplification for Resistant Hypertension. Curr Hypertens Rep. 2018;20(5):46. doi: 10.1007/s11906-018-0840-8
    1. Ligtenberg G, Blankestijn PJ, Oey PL, Klein IH, Dijkhorst-Oei LT, Boomsma F, et al.. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med. 1999;340(17):1321–8. doi: 10.1056/NEJM199904293401704
    1. Vink EE, Verloop WL, Siddiqi L, van Schelven LJ, Liam Oey P, Blankestijn PJ. The effect of percutaneous renal denervation on muscle sympathetic nerve activity in hypertensive patients. Int J Cardiol. 2014;176(1):8–12. doi: 10.1016/j.ijcard.2014.06.021
    1. Diedrich A, Charoensuk W, Brychta RJ, Ertl AC, Shiavi R. Analysis of raw microneurographic recordings based on wavelet de-noising technique and classification algorithm: wavelet analysis in microneurography. IEEE Trans Biomed Eng. 2003;50(1):41–50. doi: 10.1109/TBME.2002.807323
    1. Brychta RJ, Shiavi R, Robertson D, Diedrich A. Spike detection in human muscle sympathetic nerve activity using the kurtosis of stationary wavelet transform coefficients. J Neurosci Methods. 2007;160(2):359–67. doi: 10.1016/j.jneumeth.2006.09.020
    1. Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G. Evaluation of baroreceptor reflex by blood pressure monitoring in unanesthetized cats. Am J Physiol. 1988;254(2 Pt 2):H377–83. doi: 10.1152/ajpheart.1988.254.2.H377
    1. Parati G, Di Rienzo M, Bertinieri G, Pomidossi G, Casadei R, Groppelli A, et al.. Evaluation of the baroreceptor-heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans. Hypertension. 1988;12(2):214–22. doi: 10.1161/01.hyp.12.2.214
    1. Westerhof BE, Gisolf J, Stok WJ, Wesseling KH, Karemaker JM. Time-domain cross-correlation baroreflex sensitivity: performance on the EUROBAVAR data set. J Hypertens. 2004;22(7):1371–80. doi: 10.1097/01.hjh.0000125439.28861.ed
    1. Kienbaum P, Karlssonn T, Sverrisdottir YB, Elam M, Wallin BG. Two sites for modulation of human sympathetic activity by arterial baroreceptors? J Physiol. 2001;531(Pt 3):861–9. doi: 10.1111/j.1469-7793.2001.0861h.x
    1. Hart EC, Joyner MJ, Wallin BG, Karlsson T, Curry TB, Charkoudian N. Baroreflex control of muscle sympathetic nerve activity: a nonpharmacological measure of baroreflex sensitivity. Am J Physiol Heart Circ Physiol. 2010;298(3):H816–22. doi: 10.1152/ajpheart.00924.2009
    1. Jacob G, Diedrich L, Sato K, Brychta RJ, Raj SR, Robertson D, et al.. Vagal and Sympathetic Function in Neuropathic Postural Tachycardia Syndrome. Hypertension. 2019;73(5):1087–96. doi: 10.1161/HYPERTENSIONAHA.118.11803
    1. Greaney JL, Matthews EL, Wenner MM. Sympathetic reactivity in young women with a family history of hypertension. Am J Physiol Heart Circ Physiol. 2015;308(8):H816–22. doi: 10.1152/ajpheart.00867.2014
    1. Jarvis SS, Okada Y, Levine BD, Fu Q. Central integration and neural control of blood pressure during the cold pressor test: a comparison between hydrochlorothiazide and aliskiren. Physiol Rep. 2015;3(9). doi: 10.14814/phy2.12502
    1. Victor RG, Leimbach WN Jr., Seals DR, Wallin BG, Mark AL. Effects of the cold pressor test on muscle sympathetic nerve activity in humans. Hypertension. 1987;9(5):429–36. doi: 10.1161/01.hyp.9.5.429
    1. Camm AJ, Malik M, Bigger JT, Breithardt G, Cerutti S, Cohen RJ, et al.. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17(3):354–81.
    1. Sundlof G, Wallin BG. The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol. 1977;272(2):383–97. doi: 10.1113/jphysiol.1977.sp012050
    1. Fagius J, Wallin BG. Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade. Clin Auton Res. 1993;3(3):201–5. doi: 10.1007/BF01826234
    1. Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116(6):976–90. doi: 10.1161/CIRCRESAHA.116.303604
    1. Hoogerwaard AF, de Jong MR, Adiyaman A, Smit JJJ, Delnoy PPHM, Heeg JE, et al.. Renal sympathetic denervation induces changes in heart rate variability and is associated with a lower sympathetic tone. Clin Res Cardiol. 2019;108(1):22–30. doi: 10.1007/s00392-018-1307-2
    1. Jordan J, Tank J, Hohenbleicher H, Toka H, Schroder C, Sharma AM, et al.. Heterogeneity of autonomic regulation in hypertension and neurovascular contact. J Hypertens. 2002;20(4):701–6. doi: 10.1097/00004872-200204000-00028

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다