[SCD-FORUM] 132E Atrial Standstill. Dr. Perez Riera to Zaklyazminskaya

[SCD Symposium]

Dear colleague Dr. Elena Zaklyazminskaya, M.D., Ph.D.from Moscow, Russia. Here Andrés Ricardo Pérez Riera answering from São Paulo Brazil. On the cellular level, AF leads to a strong shortening and an impaired rate adaptation of the AP as well as to changes in AP morphology. AF is associated with an altered gene expression of the L-type calcium channel  and of K+ channels (Ito, IK1 and IKACh). The molecular mechanisms of intra-atrial conduction slowing are less well understood; changes in the expression or distribution of gap junction proteins or a decrease of the fast Na+ inward channel  have been reported. A trigger of initiation for electrical remodeling is an overload of the cytoplasm with Ca2+ and a consecutive decrease of the systolic Ca2+ gradient, furthermore changes in calcium-handling proteins are detectable in AF. Gap junctions, assembled from connexins, form the cell-to-cell pathways  for propagation of the precisely orchestrated patterns of current flow that govern the regular rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are expressed in the heart; connexin43, connexin40 (Cx40) and connexin45 (Cx45) are found in distinctive combinations and relative quantities in different, functionally specialized subsets of cardiomyocyte. Gap junctional connexin proteins Cx40, Cx43  are a determinant of myocardial conduction and are implicated in the development of AF. An abnormal distribution of the gap junction occurs in chronic AF 1.  Alterations of gap junction organization and connexin expression are now well established as a consistent feature of human heart disease in which there is an arrhythmic tendency. These alterations may take the form of structural remodeling, involving disturbances in the distribution of gap junctions and/or alteration of the amount or type of connexins expressed 2. Downregulation of Cx40 and abnormal phosphorylation of Cx40 may result in abnormal cell-to-cell communication and alteration in the electrophysiologic properties of the atrium, leading to the initiation and/or perpetuation of AF. 
Two linked polymorphisms within regulatory regions of the gene for Cx40, at nucleotides -44 (G --> A) and +71 (A --> G) occur in about 7% of the general population. Cx40 is abundant in the atrium, and homozygosity for the linked polymorphisms combined with an SCN5A mutation appeared to be responsible for familial atrial standstill. The rare linked Cx40 polymorphisms are associated with enhanced coefficient of dispersion and thus with the substrate for reentry in AF. Reentry is promoted by spatial dispersion of refractoriness that can be expressed as a coefficient of dispersion3.
In neonatal hearts, the relative abundance of Cx43 and Cx40 is an important determinant of atrial impulse propagation through which dominance of Cx40 decreases and dominance of Cx43 increases local propagation velocity4. 
Wetzel et al. tested the hypothesis that AF is associated with changes in the expression of Cx40 and 43 in the left atrium with more pronounced changes in mitral valve disease than in lone AF. Protein concentrations of Cx40 and Cx43 were analyzed in left atrial tissue of patients undergoing cardiac surgery. One group of patients had lone AF (n = 41), one group had AF and mitral valve repair (n = 36), and one group in sinus rhythm served as controls (n = 15).  Western blot analysis of Cx 40 and Cx43 expression showed an increase of both gap junctional proteins (connexin 43 > connexin 40) in patients with AF of all forms compared with patients in sinus rhythm. Subgroup analysis showed increased concentrations of connexin 40 in lone AF and AF with mitral valve disease compared with sinus rhythm, whereas the same analysis for connexin 43 reached significance only in the mitral valve disease group. No differences in Cx40 and Cx43 expressions were detectable between lone AF and AF with mitral valve disease. Within the groups Cx40 and Cx43 expression did not differ between patients with paroxysmal AF and patients with chronic In this paper the authors concluded that AF can induce changes in the left atrium with increased connexin expression. Furthermore, no systematic differences between patients with paroxysmal and chronic AF were detected5.
In canine animal model enalapril suppressed atrial pacing-induced AF with tachycardia-mediated cardiomyopathy by suppressing interstitial fibrosis, Cx43 over-expression and conduction delay6;7
In the atria, features of gap organization and connexin expression have been implicated in the initiation of AF and, once the condition becomes chronic, gap junction alterations associated with remodelling may contribute to persistence of the condition. By correlating data from studies on the human patient with those from animal and cell models, alterations in gap junctions and connexins have emerged as important factors to be considered in understanding the pro-arrhythmic substrate found in a variety of forms of heart disease.
Atrial activation pattern during AF is related to connexin expression and this relationship is altered by AF-induced remodeling in the fibrillating atria of chronic AF. Intercellular coupling and pattern of atrial activation are interrelated, but only in conjunction with the remodeling of atrial electrophysiology that occurs in chronic AF8.
The cardiac gap-junction protein Cx40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. The two single nucleotide polymorphisms  in the promoter region of the Cx40 gene were significantly associated with AF. The Cx40 (-44A +71alleleG) haplotype was associated with a higher risk for AF. This haplotype also had significantly lower promoter activity in atrial myocytes9. 
References
1)       Nao T, Ohkusa T, Hisamatsu Y, et al. Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol. 2003; 91:678-683.
2)       Severs NJ, Coppen SR, Dupont E, et al. Gap junction alterations in human cardiac disease. Cardiovasc Res. 2004; 62:368-377.
3)       Hauer RN, Groenewegen WA, Firouzi M, et al. Cx40 polymorphism in human atrial fibrillation. Adv Cardiol. 2006;42:284-91
4)       Beauchamp P, Yamada KA, Baertschi AJ, et al. Relative Contributions of Connexins 40 and 43 to Atrial Impulse Propagation in Synthetic Strands of Neonatal and Fetal Murine Cardiomyocytes. Circ Res. 2006 Oct 19; [Epub ahead of print] 
5)       Wetzel U, Boldt A, Lauschke J, Weigl J,   et al. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart. 2005; 91:166-170.
6)       Sakabe M, Fujiki A, Nishida K, et al. Enalapril prevents perpetuation of atrial fibrillation by suppressing atrial fibrosis and over-expression of connexin43 in a canine model of atrial pacing-induced left ventricular dysfunction. J Cardiovasc Pharmacol. 2004; 43:851-859.
7)       Schultz R, Heusch G. Pathophysiology of atrial fibrillation: importance of the renin-angiotensin system] Dtsch Med Wochenschr. 2006;131:S95-98.
8)       Kanagaratnam P, Cherian A, Stanbridge RD, et al. Relationship between connexins and atrial activation during human atrial fibrillation. J Cardiovasc Electrophysiol. 2004;15:206-216., 
9)       Juabg JM, Chern YR, Tsai CT, The association of human connexin 40 genetic polymorphisms with atrial fibrillation. Int J Cardiol. 2006 Jun 27; [Epub ahead of print]

All the best

Andrés Ricardo Pérez Riera

Chief of Electro-Vectocardiology Sector of the Discipline of  Cardiology, 
ABC Faculty of Medicine (FMABC), Foundation of ABC (FUABC) - Santo André - 
Sao Paulo - Brazil. Rua Sebastiao Afonso  885 - Zip Code: 044417-100- Jardim 
Miriam   S.P  Brazil- Phone: 5504-6243  Fax: 5506-0398.