Baroreflex sensitivity in patients with chronic heart failure: the clinical significance and impact of therapy


Cite item

Full Text

Abstract

The review deals with the baroreflex regulation of circulation in chronic heart failure (CHF). The pathophysiological aspects of development of dysfunction of the baroreflex clinically estimated from its sensitivity are presented; the clinical value of this indicator is discussed in relation to the etiology of the underlying disease and clinicohemodynamic status. Data on the impact of some components of current therapy for CHF and nondrug treatments on the values of baroreflex sensitivity are shown.

About the authors

Mikhail Viktorovich Nepoklonov

Email: lesstalkmorerock@mail.ru

Anatoliy Nikolaevich Rogoza

Andrey Aleksandrovich Skvortsov

Shurat Bodzievna Gorieva

Sergey Nikolaevich Tereshchenko

M V Nepoklonov

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

A N Rogoza

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

A A Skvortsov

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

Sh B Goriyeva

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

S N Tereshchenko

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

Russian Cardiology Research-and-Production Complex, Russian Agency for Medical Technologies

References

  1. Eckberg D. L., Sleight P. Human baroreflexes in health and disease. Oxford: Clarendon Press; 1992.
  2. Grassi G., Seravalle G., Cattaneo B. M. et al. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 1995; 92: 3206-3211.
  3. Fergusson D. W., Berg W. J., Sanders J. S. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. J. Am. Coll. Cardiol. 1990; 16: 1125-1134.
  4. Guzzetti S., Cogliati C., Turiel M. et al. Sympathetic predominance in the progression of chronic heart failure. Eur. Heart J. 1995; 16: 1100-1107.
  5. Eaton G. M., Cody R. J., Nunziata E., Binkley P. F. Early left ventricular dysfunction elicits activation of sympathetic drive and attenuation of parasympathetic tone in the paced model of congestive heart failure. Circulation 1995; 92: 555-561.
  6. Kinugawa T., Dibner-Dunlap M. E. Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure. Am. J. Physiol. 1995; 268: R317-R323.
  7. Portar T. R., Eckberg D. L., Fritsch J. M. et al. Autonomic pathophysiology in heart failure patients. J. Clin. Invest. 1990; 85: 1362-1371.
  8. Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension 1994; 24: 571-575.
  9. Monahan K. D., Urs A. et al. Aldosterone impairs baroreflex sensitivity in healthy adults. Am. J. Physiol. Heart Circ. Physiol. 2007; 292: H190-H197.
  10. Wang W., Jwo-Sheng C., Zucker I. H. Carotid sinus baroreceptor sensitivity in experimental heart failure. Circulation 1990; 81: 1959-1966.
  11. Monahan K. D., Tanaka H., Dinenno F. A. et al. Central arterial compliance is associated with age- and habitual exercise-related differences in cardiovagal baroreflex sensitivity. Circulation 2001; 104: 1627-1632.
  12. Francis G. S., Benedict C., Johnstone D. E. et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990; 82: 1724-1729.
  13. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J. Am. Coll. Cardiol. 1992; 20: 248-254.
  14. Floras J. S. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J. Am. Coll. Cardiol. 1993; 22(Suppl. A): 72A-84A.
  15. Cohn J. N., Levine T. B., Olivari M. T. et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 1984; 311: 819-823.
  16. Mancia G., Seravalle G., Giannattasio C. et al. Reflex cardiovascular control in congestive heart failure. Am. J. Cardiol. 1992; 69: 17G-23G.
  17. Schwartz P. J., Billman G. E., Stone H. L. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with a healed myocardial infarction. Circulation 1984; 69: 780-790.
  18. Mortara A., La Rovere M. T., Pinna G. D. et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 1997; 96: 3450-3458.
  19. Marin-Neto J. A., Pintya A. O., Gallo Jьnior L., Maciel B. C. Abnormal baroreflex control of heart rate in decompensated congestive heart failure and reversal after compensation. Am. J. Cardiol. 1991; 67(7): 604.
  20. La Rovere M. T., Bigger J. T. Jr., Marcus F. I. et al. for the ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Baroreflex sensitivity and heart rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478-484.
  21. De Ferrari G. M., Sanzo A., Bertoletti A. et al. Baroreflex sensitivity predicts longterm cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function. J. Am. Coll. Cardiol. 2007; 50(24): 2285-2290.
  22. Grimm W., Glaveris C., Hoffmann J. et al. Noninvasive risk stratification in idiopathic dilated cardiomyopathy: and first results of the Marburg Cardiomyopathy Study. Pace 1998; 21(II): 2551-2556.
  23. Grassi G., Seravalle G., Quarti-Trevano F., Dell'Oro R. Left ventricular dysfunction sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009; 53: 205-209.
  24. Grassi G., Cattaneo B. M., Seravalle G. et al. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension 1998; 31: 68-72.
  25. Grassi G., Bolla G. B., Seravalle G. et al. Comparison between reproducibility and sensitivity of muscle sympathetic nerve traffic and plasma noradrenaline in man. Clin. Sci. 1997; 92: 285-289.
  26. Milan A., Caserta M. A., Del Colle S. et al. Baroreflex sensitivity correlates with left ventricular morphology and diastolic function in essential hypertension. J. Hypertension 2007; 25(8): 1655-1664.
  27. Schillaci G., Pasqualini L., Verdecchia P. et al. Prognostic significance of left ventricular diastolic dysfunction in essential hypertension. J. Am. Coll. Cardiol. 2002; 39: 2005-2011.
  28. Grassi G. Role of the sympathetic nervous system in human hypertension. J. Hypertens. 1998; 16: 1979-1987.
  29. Eleuteri E., Lanfranchi P., Scapellato F. et al. Restrictive left ventricular filling pattern as a strong predictor of depressed baroreflex sensitivity in heart failure. Ital. Heart J. 2001; 2(5): 344-348.
  30. Likoff M. J., Chandler S. L., Kay H. R. Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am. J. Cardiol. 1987; 59: 634-638.
  31. La Rovere M. T., Specchia G., Mortara A., Schwartz P. J. Baroreflex sensitivity, clinical correlates, and cardiovascular mortality among patients with a first myocardial infarction. A prospective study. Circulation 1988; 78: 816-824.
  32. Rovere M. T., Mortara A., Specchia G., Schwartz P. J. Myocardial infarction and baroreflex sensitivity. Clinical studies. G. Ital. Cardiol. 1992; 22: 639-645.
  33. Osterziel K. J., Hanlein D., Willenbrock R. et al. Baroreflex sensitivity and cardiovascular mortality in patients with mild to moderate heart failure. Br. Heart J. 1995; 73: 517.
  34. Moss A. J., Hall W. J., Cannom D. S. et al. Multicenter Automatic Defibrillator Implantation Trial Investigators. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N. Engl. J. Med. 1996; 335: 1933-1940.
  35. Buxton A. E., Lee K. L., Di Carlo L. et al. Multicenter Unsustained Tachycardia Trial Investigators. Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. N. Engl. J. Med. 2000; 342: 1937-1945.
  36. Moss A. J., Zareba W., Hall W. J. et al. Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N. Engl. J. Med. 2002; 346: 877-883.
  37. Bardy G. H., Lee K. L., Mark D. B. et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 2005; 352: 225-237.
  38. Buxton A. E. Should everyone with an ejection fraction less than or equal to 30% receive an implantable cardioverter-defibrillator? Not everyone with an ejection fraction < or = 30% should receive an implantable cardioverter-defibrillator. Circulation 2005; 111: 2537-2549.
  39. Anderson K. P., Freedman R. A., Maron J. W. Sudden death in idiopathic dilated cardiomyopathy. Ann. Intern. Med. 1987; 107: 104-106.
  40. Bigger J. T. Why patients with congestive heart failure die. Arrhythmias and sudden cardiac death. Circulation 1987; 75(Suppl. IV): IV-28-IV-35.
  41. Schwartz P. J., La Rovere M. T., Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation 1992; 85(Suppl. I): I-77-I-91.
  42. La Rovere M. T., Pinna G. D., Hohnloser S. H. et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation 2001; 103: 2072-2077.
  43. Ishise H., Asanoi H., Ishizaka S. et al. Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure. J. Appl. Physiol. 1998; 84: 1234-1241.
  44. Binkley P. F., Haas G. S., Starling R. C. et al. Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure. J. Am. Coll. Cardiol. 1993; 21: 655-661.
  45. Kamen P. W., Krum H., Tonkin A. M. Low dose but not high dose captopril increases parasympathetic activity in patients with heart failure. J. Cardiovasc. Pharmacol. 1997; 30: 7-11.
  46. Osterziel K. J., Dietz R. Improvement of vagal tone by ACE inhibitors: a mechanism of cardioprotection in patients with mild to moderate heart failure. J. Cardiovasc. Pharmacol. 1996; 27: S25-S30.
  47. Grassi G., Cattaneo B. M., Seravalle G. et al. Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure. Circulation 1997; 96: 1173-1179.
  48. Dibner-Dunlap M. E., Smith M. L., Kinugawa T., Thames M. D. Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure. J. Am. Coll. Cardiol. 1996; 27: 358-364.
  49. Lewis G. P., Reit E. The action of angiotensin and bradykinin on the superior cervical ganglion of the cat. J. Physiol. (Lond.) 1965; 179: 538-553.
  50. Shimamoto K., Matsuki T., Iimura O. Angiotensin converting enzyme inhibitors and the kallikrein-kinin system. J. Cardiovasc. Pharmacol. 1995; 15(Suppl. 6): S91-S98.
  51. Grassi G., Giannattasio C., Failla M. et al. Sympathetic modulation of radial artery compliance in congestive heart failure. Hypertension 1995; 26: 348-354.
  52. Binkley P. F., Nunziata E., Haas G. J. et al. Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure. Am. Heart J. 2000; 140(1): 34-42.
  53. Guo G. B., Abboud F. M. Angiotensin II attenuates baroreflex control of heart rate and sympathetic activity. Am. J. Physiol. 1984; 246: H80-H89.
  54. Mancia G., Mark A. L. Arterial baroreflex in humans. In: Shepherd J. T., Abboud F. M., eds. Handbook of physiology. Sect. 2: The cardiovascular system. Bethesda, Md: American Physiological Society; 1983. 755-793.
  55. Pickering T. G., Gribbin B., Petersen E. S. et al. Effects of autonomic blockade on the baroreflexes in man at rest and during exercise. Circ. Res. 1972; 30: 175-185.
  56. Eckberg D. L., Abboud F. M., Mark A. L. Modulation of carotid baroreflex responsiveness in man: effects of posture and propanolol. J. Appl. Physiol. 1976; 41: 383-3787.
  57. Pitzalis M. V., Mastropasqua F., Massari F. et al. Beta-blocker effects on respiratory sinus arrhythmia and baroreflex gain in normal subjects. Chest 1998; 114: 185-191.
  58. Floras J. S., Jones J. V., Hassan M. O., Sleight P. Effects of acute and chronic beta-adrenoceptor blockade on baroreflex sensitivity in humans. J. Auton. Nerv. Syst. 1988; 25: 87-94.
  59. Parati G., Mutti E., Frattola A. et al. Beta-adrenergic blocking treatmant and 24-h baroreflex sensitivity in essential hypertensive patients. Hypertension 1994; 23: 992-996.
  60. Lechat P., Packer M., Chalon S. et al. Clinical effects of beta-adrenergic blockade in chronic heart failure. A meta-analysis of double blind, placebo-controlled, randomized trials. Circulation 1998; 98: 1184-1191.
  61. Frishman W. H. Carvedilol. N. Engl. J. Med. 1998; 339: 1759-1765.
  62. Kubo T., Parker J. D., Azevedo E. R. et al. Vagal heart rate responses to chronic beta-blockade in human heart failure relate to cardiac norepinephrine spillover. Eur. J. Heart Fail. 2005; 7: 878-881.
  63. Xu X. L., Zang W. J., Lu J. et al. Effects of carvedilol on M2 receptors and cholinesterase-positive nerves in adriamycininduced rat failing heart. Auton. Neurosci. 2006; 130: 6-16.
  64. Keeley E. C., Page R. L., Lange R. A. et al. Influence of metoprolol on heart rate variability in survivors of remote myocardial infarction. Am. J. Cardiol. 1996; 77: 557-560.
  65. Sanderson J. E., Yeung L. Y., Chan S. et al. Effect of beta-blockade on baroreceptor and autonomic function in heart failure. Clin. Sci. 1999; 96: 137-146.
  66. Mortara A., La Rovere M. T. Nonselective beta-adrenergic blocking agent, carvedilol, improves arterial baroflex gain and heart rate variability in patients with stable chronic heart failure. J. Am. Coll. Cardiol. 2000; 36: 1612-1618.
  67. Vaile J. C., Chowdhary S., Osman F. et al. Effects of angiotensin II (ATII) receptor blockade on cardiac vagal control in heart failure. Clin. Sci. 2001; 101(6): 559-566.
  68. Hikosaka M., Yuasa F., Yuyama R. et al. Candesartan and arterial baroreflex sensitivity and sympathetic nerve activity in patients with mild heart failure. J. Cardiovasc. Pharmacol. 2002; 40(6): 875-880.
  69. Thames M. D., Waickman L. A., Abboud F. M. Sensitization of cardiac receptors (vagal afferents) by intracoronary acetyltrophanthidin. Am. J. Physiol. 1980; 239: H628-H635.
  70. Quest J. A., Gillis R. A. Effect of digitalis on carotid sinus baroreceptor activity. Circ. Res. 1974; 35: 247-255.
  71. Zucker I. H., Peterson T. V., Gilmore J. P. Ouabain increases left atrial stretch receptor discharge in the dog. J. Pharmacol. Exp. Ther. 1980; 212: 320-324.
  72. Thames M. D. Acetylstrophanthidin-induced reflex inhibition of canine renal sympathetic nerve activity mediated by cardiac receptors with vagal afferents. Circ. Res. 1979; 44: 8-15.
  73. Krum H., Bigger J. T., Goldsmith R. L., Packer M. Effect of long-term dioxin therapy on autonomic function in patients with chronic heart failure. J. Am. Coll. Cardiol. 1995; 25: 289-294.
  74. Feancis J., Weiss R. M., Shun-Guang Wei et al. Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure. Am. J. Physiol. Heart Circ. Physiol. 2001; 281: H2241-H2251.
  75. Monahan K. D., Urs A. et al. Aldosterone impairs baroreflex sensitivity in healthy adults. Am. J. Physiol. Heart Circ. Physiol. 2007; 292: H190-H197.
  76. Gentlesk P. J., Wiley T., Taylor A. J. A prospective evaluation of the effect of simvastatin on heart rate variability in non-ischemic cardiomyopathy. Am. Heart J. 2005; 150: 478-483.
  77. Hamaad A., Sosin M., Lip G. Y., MacFadyen R. J. Short-term adjuvant atorvastatin improves frequency domain induces of heart rate variability in stable systolic heart failure. Cardiovasc. Drugs Ther. 2005; 19: 183-187.
  78. Kurian K. C., Rai P., Sankaran S. et al. The effect of statins in heart failure: beyond its cholesterol-lowering effect. J. Card. Fail. 2006; 12: 473-478.
  79. Christensen J. H. n-3 fatty acids and the risk of sudden cardiac death: emphasis on heart rate variability. Dan. Med. Bull. 2003; 50: 347-367.
  80. Geelen A., Zock P. L., Swenne C. A. et al. Effect of n-3 fatty acids on heart rate variability and baroreflex sensitivity in middle-aged subjects. Am. Heart J. 2003; 146: E4.
  81. Pliquett R. U., Cornish K. G., Peuler J. D., Zucker I. H. Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation 2003; 107: 2493-2498.
  82. Lie Gao, Wei Wang, Yu-Long Li et al. Simvastatin therapy normalizes sympathetic neural control in experimental heart failure roles of angiotensin II type 1 receptors and NAD(P)H oxidase. Circulation 2005; 112: 1763-1770.
  83. Wassmann S., Laufs U., Baumer A. T. et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin ATI receptor expression and Rac 1 GTPase. Mol. Pharmacol. 2001; 59: 646-654.
  84. Driscoll G., Green D., Taylor R. R. Simvastatin, improves endothelial function within 1 month. Circulation 1997; 95: 1126-1131.
  85. Pieker L. E., Corti R., Binggeli C. et al. Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans. J. Am. Coll. Cardiol. 2000; 36: 213-218.
  86. Marchioli R., Barzi F., Bomba E. et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction. Time-Course Analysis of the Results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002; 105: 1897.
  87. Radaelli A., Cazzaniga M., Viola A. et al. Enhanced baroreceptor control of the cardiovascular system by polyunsaturated fatty acids in heart failure patients. J. Am. Coll. Cardiol. 2006; 48: 1600-1606.
  88. Giannattasio C., Failla M., Stella M. L. et al. Alterations of radial artery compliance in patients with congestive heart failure. Am. J. Cardiol. 1995; 76: 381-385.
  89. Leaf A., Kang J. X., Xiao Y. F. et al. Functional and electrophysiologic effects of polyunsaturated fatty acids on excitable tissues: heart and brain. Prostaglandins Leukot. Essent. Fatty Acids 1999; 60: 307-312.
  90. Sola S., Mir M. Q., Lerakis S. et al. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J. Am. Coll. Cardiol. 2006; 47: 332-337.
  91. La Rovere M. T., Pinna G. D., Maestri R. et al. Short term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation 2003; 107: 565-570.
  92. Elkayam U., Amin J., Mehra A. et al. A prospective, randomized, double blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990; 82: 1954-1961.
  93. Packer M., O'Connor C. M., Ghali J. K. et al. Effect of amlodipine on morbidity and mortality in severe congestive heart failure. N. Engl. J. Med. 1996; 335: 1107-1114.
  94. Packer M. Treatment of chronic heart failure. Lancet 1992; 340: 92-95.
  95. Grassi G., Spaziani D., Seravalle G. et al. Effects of amlodipine on sympathetic nerve traffic and baroreflex control of circulation in heart failure. Hypertension 1999; 33: 671-675.
  96. Hamdan M. H., Zagrodzky J. D., Joglar J. A. et al. Biventricular pacing decreases sympathetic activity compared with right ventricular pacing in patients with depressed ejection fraction. Circulation 2000; 102: 1027-1032.
  97. Najem B., Unger P., Preumont N. et al. Sympathetic control after cardiac resynchronization therapy: responders versus nonresponders. A. J. Physiol. Heart Circ. Physiol. 2006; 291: H2647-H2652.
  98. Gademan M. G., van Bommel R. J., Ypenburg C. et al. Biventricular pacing in chronic heart failure acutely facilitates the arterial baroreflex. Am. J. Physiol. Heart Circ. Physiol. 2008; 295: H755-H760.
  99. Piepoli M. F., Villani G. Q., Corra U. et al. Time course of effects of cardiac resynchronization therapy in chronic heart failure: benefits in patients with preserved exercise capacity. Pacing Clin. Electrophysiol. 2008; 31: 701-708.
  100. Tjen A. L. S., Pan H. L., Longhurst J. C. Endogenous bradykinin activates ischaemically sensitive cardiac visceral afferents through kinin B2 receptors in cats. J. Physiol. (Lond.) 1998; 510: 633-641.
  101. Waggoner A. D., Faddis M. N., Gleva M. J. et al. Cardiac resynchronization therapy acutely improves diastolic function. J. Am. Soc. Echocardiogr. 2005; 18: 216-220.
  102. Gao L., Schultz H. D., Patel K. P. et al. Augmented input from cardiac sympathetic afferents inhibits baroreflex in rats with heart failure. Hypertension 2005; 45: 1173-1181.
  103. Ruttanaumpawan P., Gilman M. P., Usui K. et al. Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea. J. Hypertens. 2008; 26(6): 1163-1168.

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2010 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
 

Address of the Editorial Office:

  • Novij Zykovskij proezd, 3, 40, Moscow, 125167

Correspondence address:

  • Alabyan Street, 13/1, Moscow, 127055, Russian Federation

Managing Editor:

  • Tel.: +7 (926) 905-41-26
  • E-mail: e.gorbacheva@ter-arkhiv.ru

 

© 2018-2021 "Consilium Medicum" Publishing house


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies