Gender-Specific Remodeling in Atrial Fibrillation?

Abstract

Background The authors wanted to investigate whether the remodeling process in AF regarding gap junction proteins, collagen I, and amyloid may be gender dependent in humans.

Methods In total, 123 patients with sinus rhythm (SR, n = 41) or atrial fibrillation (AF, n = 82) suffering from mitral valve disease undergoing cardiac surgery were included. Of the 123 patients, 66 patients (SR: n = 17, AF: n = 49) were investigated biochemically for the expression of the atrial gap junction proteins connexin40 (Cx40), connexin43 (Cx43) and collagen I and 57 patients (SR: n = 24; AF: n = 33) using histochemical methods for possible amyloid depositions.

Results AF led to increased levels of Cx40, Cx43, and collagen I protein. Regarding Cx40 this upregulation was significantly higher in female than in male patients. For AF-induced changes in collagen or Cx43, there were no significant gender-dependent differences. Amyloid depositions were found with increasing age, but were not significantly related to AF or gender.

Conclusions Remodeling in AF seems to be similar in men and women, with a tendency for women exhibiting somewhat stronger AF-induced changes in Cx40, which is probably a secondary effect because there is nothing known about hormone sensitivity of the Cx40 promoter, and a not significant tendency for higher Cx43 and collagen I.

Keywords

arrhythmia therapy - cardiac - histology - myocardial remodeling

• References

• 1 Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98 (10) 946-952
• 2 Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993; 22 (4) (Suppl A): 6A-13A
• 3 Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995; 155 (5) 469-473
• 4 Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002; 415 (6868) 219-226
• 5 Brundel BJJM, Henning RH, Kampinga HH, Van Gelder IC, Crijns HJGM. Molecular mechanisms of remodeling in human atrial fibrillation. Cardiovasc Res 2002; 54 (2) 315-324
• 6 Wetzel U, Boldt A, Lauschke J , et al. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 2005; 91 (2) 166-170
• 7 Dhein S. Role of connexins in atrial fibrillation. Adv Cardiol 2006; 42: 161-174
• 8 Dhein S, Rothe S, Busch A , et al. Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation. Br J Pharmacol 2011; 164 (2b) 607-616
• 9 Boldt A, Wetzel U, Lauschke J , et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart 2004; 90 (4) 400-405
• 10 Röcken C, Peters B, Juenemann G , et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation 2002; 106 (16) 2091-2097
• 11 Polontchouk L, Haefliger J-A, Ebelt B , et al. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol 2001; 38 (3) 883-891
• 12 Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 2002; 54 (2) 361-379
• 13 Yu W, Dahl G, Werner R. The connexin43 gene is responsive to oestrogen. Proc Biol Sci 1994; 255 (1343) 125-132
• 14 Grohé C, Kahlert S, Löbbert K , et al. Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett 1997; 416 (1) 107-112
• 15 Rosenkranz-Weiss P, Tomek RJ, Mathew J, Eghbali M. Gender-specific differences in expression of mRNAs for functional and structural proteins in rat ventricular myocardium. J Mol Cell Cardiol 1994; 26 (2) 261-270
• 16 Puchtler H, Waldrop FS, Meloan SN. A review of light, polarization and fluorescence microscopic methods for amyloid. Appl Pathol 1985; 3 (1–2) 5-17
• 17 Linhares VL, Almeida NA, Menezes DC , et al. Transcriptional regulation of the murine Connexin40 promoter by cardiac factors Nkx2-5, GATA4 and Tbx5. Cardiovasc Res 2004; 64 (3) 402-411
• 18 Seul KH, Tadros PN, Beyer EC. Mouse connexin40: gene structure and promoter analysis. Genomics 1997; 46 (1) 120-126
• 19 Teunissen BE, van Amersfoorth SC, Opthof T, Jongsma HJ, Bierhuizen MF. Sp1 and Sp3 activate the rat connexin40 proximal promoter. Biochem Biophys Res Commun 2002; 292 (1) 71-78
• 20 Dupays L, Mazurais D, Rücker-Martin C , et al. Genomic organization and alternative transcripts of the human Connexin40 gene. Gene 2003; 305 (1) 79-90
• 21 Dhein S, Duerrschmidt N, Scholl A , et al. A new role for extracellular Ca2+ in gap-junction remodeling: studies in humans and rats. Naunyn Schmiedebergs Arch Pharmacol 2008; 377 (2) 125-138
• 22 Yan H, Chen JZ, Zhu JH , et al. [Expression of connexin in atrium of patients with atrial fibrillation and its signal transduction pathway]. Zhonghua Yi Xue Za Zhi 2004; 84 (3) 209-213
• 23 Li DQ, Feng YB, Zhang HQ. [The relationship between gap junctional remodeling and atrial fibrillation in patients with rheumatic heart disease]. Zhonghua Yi Xue Za Zhi 2004; 84 (5) 384-386
• 24 Luo MH, Li YS, Yang KP. Fibrosis of collagen I and remodeling of connexin 43 in atrial myocardium of patients with atrial fibrillation. Cardiology 2007; 107 (4) 248-253
• 25 Huang XD, Sandusky GE, Zipes DP. Heterogeneous loss of connexin43 protein in ischemic dog hearts. J Cardiovasc Electrophysiol 1999; 10 (1) 79-91
• 26 Kaprielian RR, Gunning M, Dupont E , et al. Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation 1998; 97 (7) 651-660
• 27 Jozwiak J, Dhein S. Local effects and mechanisms of antiarrhythmic peptide AAP10 in acute regional myocardial ischemia: electrophysiological and molecular findings. Naunyn Schmiedebergs Arch Pharmacol 2008; 378 (5) 459-470
• 28 Girmatsion Z, Biliczki P, Bonauer A , et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 2009; 6 (12) 1802-1809
• 29 Wang Z, Lu Y, Yang B. MicroRNAs and atrial fibrillation: new fundamentals. Cardiovasc Res 2011; 89 (4) 710-721
• 30 Gramley F, Lorenzen J, Koellensperger E, Kettering K, Weiss C, Munzel T. Atrial fibrosis and atrial fibrillation: the role of the TGF-β1 signaling pathway. Int J Cardiol 2010; 143 (3) 405-413
• 31 Villar AV, Llano M, Cobo M , et al. Gender differences of echocardiographic and gene expression patterns in human pressure overload left ventricular hypertrophy. J Mol Cell Cardiol 2009; 46 (4) 526-535
• 32 Goette A, Röcken C. Atrial amyloidosis and atrial fibrillation: a gender-dependent “arrhythmogenic substrate”?. Eur Heart J 2004; 25 (14) 1185-1186
• 33 Ariyarajah V, Steiner I, Hájková P , et al. The association of atrial tachyarrhythmias with isolated atrial amyloid disease: preliminary observations in autopsied heart specimens. Cardiology 2009; 113 (2) 132-137
• 34 Steiner I, Hájková P. Patterns of isolated atrial amyloid: a study of 100 hearts on autopsy. Cardiovasc Pathol 2006; 15 (5) 287-290
• 35 Leone O, Boriani G, Chiappini B , et al. Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation. Eur Heart J 2004; 25: 1237-1241
• 36 Volgman AS, Manankil MF, Mookherjee D, Trohman RG. Women with atrial fibrillation: Greater risk, less attention. Gend Med 2009; 6 (3) 419-432
• 37 Friberg J, Scharling H, Gadsbøll N, Jensen GB. Sex-specific increase in the prevalence of atrial fibrillation (The Copenhagen City Heart Study). Am J Cardiol 2003; 92 (12) 1419-1423