Autoantibodies Against Serotoninergic 5-HT₄ Receptor in Patients with Heart Failure

 

 Buy Article Permissions and Reprints

Abstract

Serotoninergic 5-HT₄ receptors have been detected in several tissues including the heart. An autoimmune mechanism may underline the pathogenesis of heart failure. The aim of this work was to look for autoantibodies to the 5-HT₄ receptor in patients with heart failure. We looked for the presence of autoantibodies against 5-HT₄ receptor as well as angiotensin II type (AT1), β₁-adrenoceptor, and muscarinic M2 receptors in the sera of 176 patients with heart failure (female: n=96, male: n=80) and in 108 controls (female: n=69; male: n=39). The prevalence of 5-HT₄ receptor autoantibodies was 18.8% (n=33) in the group of patients with heart failure and 4.6% (n=5) in the control group (p<0.002). The prevalence of autoantibodies against AT1 was 1.7 (n=3), β₁-adrenoreceptor 0.6 (n=1), and muscarinic-receptor M2 4.2 (n=5). Female patients with diabetes and heart failure had a positive trend (p=0.07) to the presence of 5-HT₄ receptor autoantibodies. In the group of female heart failure patients we found a significant correlation with the presence of coronary heart disease (p=0.05). The clinical relevance of 5-HT₄ receptor autoantibodies has to be further studied. The prevalence of 5-HT₄ receptor autoantibodies was highly significant in patients with chronic heart failure. It was also a significant correlation between these autoantibodies and the female subgroup with coronary heart disease. It is conceivable that the increased prevalence of autoantibodies against the 5-HT₄ receptor in patients with heart failure is more than just an epiphenomenon.

• References

• 1 Kaumann AJ, Levy FO. 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther 2006; 111: 674-706
  CrossrefPubMedGoogle Scholar
• 2 Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005; 112: 1825-1852
  CrossrefPubMedGoogle Scholar
• 3 Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999; 38: 1083-1152
  CrossrefPubMedGoogle Scholar
• 4 Ray AM, Kelsell RE, Houp JA, Kelly FM, Medhurst AD, Cox HM, Calver AR. Identification of a novel 5-HT₄ receptor splice variant (r5-HT_4c1) and preliminary characterisation of specific 5-HT_4a and 5-HT_4b receptor antibodies. Eur J Pharmacol 2009; 604: 1-11
  CrossrefPubMedGoogle Scholar
• 5 Langlois M, Fischmeister R. 5-HT₄ receptor ligands: applications and new prospects. J Med Chem 2003; 46: 319-344
  CrossrefPubMedGoogle Scholar
• 6 Bach T, Syversveen T, Kvingedal AM, Krobert KA, Brattelid T, Kaumann AJ, Levy FO. 5HT4_(a) and 5-HT4_(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle. Naunyn Schmiedebergs Arch Pharmacol 2001; 363: 146-160
  CrossrefPubMedGoogle Scholar
• 7 Brattelid T, Kvingedal AM, Krobert KA, Andressen KW, Bach T, Hystad ME, Kaumann AJ, Levy FO. Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT₄ receptor splice variant, 5-HT₄(i). Naunyn-Schmiedebergs Arch Pharmacol 2004; 369: 616-628
  PubMedGoogle Scholar
• 8 Coupar IM, Desmond PV, Irving HR. Human 5-HT₍₄₎ and 5-HT₍₇₎ receptor splice variants: Are they Important?. Curr Neuropharmacol 2007; 5: 224-231
  CrossrefPubMedGoogle Scholar
• 9 Bender E, Pindon A, van Oers I, Zhang YB, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W. Structure of the human serotonin 5-HT₄ receptor gene and cloning of a novel 5-HT₄ splice variant. J Neurochem 2000; 74: 478-489
  PubMedGoogle Scholar
• 10 Eftekhari P, Roegel JC, Lezoualc’h F, Fischmeister R, Imbs JL, Hoebeke J. Induction of neonatal lupus in pups of mice immunized with synthetic peptides derived from amino acid sequences of the serotoninergic 5-HT₄ receptor. Eur J Immunol 2001; 31: 573-579
  CrossrefPubMedGoogle Scholar
• 11 Baba A, Yoshikawa T, Chino M, Murayama A, Mitani K, Nakagawa S, Fujii I, Shimada M, Akaishi M, Iwanaga S, Asakura Y, Fukuda K, Mitamura H, Ogawa S. Keio Interhospital Cardiology Study (KICS) Group . Characterization of antimyocardial autoantibodies in Japanese patients with dilated cardiomyopathy. Jpn Circ J 2001; 65: 867-873
  CrossrefPubMedGoogle Scholar
• 12 Hussain RI, Qvigstad E, Birkeland JA, Eikemo H, Glende A, Sjaastad I, Skomedal T, Osnes JB, Levy FO, Krobert KA. Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation. Br J Pharmacol 2009; 156: 575-586
  CrossrefPubMedGoogle Scholar
• 13 Sallé L, Eftekhari P, Aupart M, Cosnay P, Hoebeke J, Argibay JA. Inhibitory activity of antibodies against the human atrial 5-HT₄ receptor. J Mol Cell Cardiol 2001; 33: 405-417
  CrossrefPubMedGoogle Scholar
• 14 Eftekhari P, Sallé L, Lezoualc’h F, Mialet J, Gastineau M, Briand JP, Isenberg DA, Fournié GJ, Argibay J, Fischmeister R, Muller S, Hoebeke J. Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT₄ serotoninergic receptor could explain neonatal lupus congenital heart block. Eur J Immunol 2000; 30: 2782-2790
  CrossrefPubMedGoogle Scholar
• 15 Dobrev D. 5-Hydroxytryptamine and atrial arrhythmogenesis: a “culprit mechanism” or bystander in patients with chronic atrial fibrillation?. J Mol Cell Cardiol 2007; 42: 51-53
  CrossrefPubMedGoogle Scholar
• 16 Brattelid T, Avigstad E, Lynham JA, Molennaar P, Aass H, Geiran O, Skomedal T, Osnes JB, Levy FO, Kaumann AJ. Functional serotonin 5-HT₄ receptors in porcine and human ventricular myocardium with increased 5-HT₄ mRNA in heart failure. Naunyn-Schmiedebergs Arch Pharmacol 2004; 370: 157-166
  PubMedGoogle Scholar
• 17 Qvigstad E, Brattelid T, Sjaastad I, Andressen KW, Krobert KA, Birkeland JA, Sejersted OM, Kaumann AJ, Skomedal T, Osnes JB, Levy FO. Appearance of a ventricular 5-HT₄ receptor-mediated inotropic response to serotonin in heart failure. Cardiovasc Res 2005; 65: 869-878
  CrossrefPubMedGoogle Scholar
• 18 Qvigstad E, Sjaastad I, Brattelid T, Nunn C, Swift F, Birkeland JA, Krobert KA, Andersen GO, Sejersted OM, Osnes JB, Levy FO, Skomedal T. Dual serotonergic regulation of ventricular contractile force through 5-HT_2A and 5-HT₄ receptors induced in the acute failing heart. Circ Res 2005; 97: 268-276
  CrossrefPubMedGoogle Scholar
• 19 Birkeland JA, Sjaastad I, Brattelid T, Qvigstad E, Moberg ER, Krobert KA, Bjornerheim R, Skomedal T, Sejersted OM, Osnes JB, Levy FO. Effects of treatment with a 5-HT₄ receptor antagonist in heart failure. Br J Pharmacol 2007; 150: 143-152
  CrossrefPubMedGoogle Scholar
• 20 Brattelid T, Qvigstad E, Birkeland JA, Swift F, Bekkevold SV, Krobert KA, Sejersted OM, Skomedal T, Osnes JB, Levy FO, Sjaastad I. Serotonin responsiveness through 5-HT_2A and 5-HT₄ receptors is differentially regulated in hypertrophic and failing rat cardiac ventricle. J Mol Cell Cardiol 2007; 43: 767-779
  CrossrefPubMedGoogle Scholar
• 21 Rahme MM, Cotter B, Leistad E, Wadhwa MK, Mohabir R, Ford AP, Eglen RM, Feld GK. Electrophysiological and antiarrhythmic effect of the atrial selective 5-HT₄ receptor antagonist RS-100302 in experimental atrial flutter and fibrillation. Circulation 1999; 100: 2010-2017
  CrossrefPubMedGoogle Scholar
• 22 Kamel R, Eftekhari P, Clancy R, Buyon JP, Hoebeke J. Autoantibodies against the serotoninergic 5-HT₄ receptor and congenital heart block: a reassessment. J Autoimmun 2005; 25: 72-76
  CrossrefPubMedGoogle Scholar
• 23 Trimpert C, Herda LR, Eckerle LG, Pohle S, Müller C, Landsberger M, Felix SB, Staudt A. Immunoadsorption in dilated cardiomyopathy: long-term reduction of cardiodepressant antibodies. Eur J Clin Invest 2010; 408: 685-691
  PubMedGoogle Scholar
• 24 Fukuda Y, Miyoshi S, Tanimoto K, Oota K, Fujikura K, Iwata M, Baba A, Hagiwara Y, Yoshikawa T, Mitamura H, Ogawa S. Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces early after depolarization and decreases in K-channel density in rabbits. J Am Coll Cardiol 2004; 43: 1090-1100
  CrossrefPubMedGoogle Scholar
• 25 McCombe PA, Greer JM, Mackay IR. Sexual dimorphism in autoimmune disease. Curr Mol Med 2009; 9: 1058-1079
  CrossrefPubMedGoogle Scholar
• 26 Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH. Estrogens and autoimmune diseases. Ann N Y Acad Sci 2006; 1089: 538-547
  CrossrefPubMedGoogle Scholar
• 27 Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nature Rev Drug Discov 2006; 5: 1425-1438
  PubMedGoogle Scholar