Downregulation of Immunodetectable Atrial Connexin4O in a Canine Model of Chronic Left Ventricular Myocardial Infarction: Implications to Atrial Fibrillation
Free accessResearch articleFirst published online June, 2002
Downregulation of Immunodetectable Atrial Connexin4O in a Canine Model of Chronic Left Ventricular Myocardial Infarction: Implications to Atrial Fibrillation
Background: The substrate(s) for atrial fibrillation associated with chronic left ventricular myocardial infarction remain poorly defined. Since atrial connexin40 has a rapid turnover rate and may cause atrial fibrillation, we hypothesized that chronic left ventricular myocardial infarction downregulates atrial Connexin40 and increases atrial fibrillation vulnerability.
Methods and Results: The left anterior descending coronary artery was occluded distal to the first diagonal branch in five dogs and studied 7 weeks later. Five dogs with no left anterior descending coronary artery occlusion served as control. Vulnerability to atrial fibrillation was tested by burst atrial stimulation (50 milliseconds for 3 seconds). Atrial fibrillation was induced in all myocardial infarction dogs, lasting from 20 seconds to several minutes. In contrast, only rapid repetitive activity and short-lasting atrial fibrillation (< 5 seconds) could be induced in control dogs. The mean refractory periods of epicardial RA and LA appendages were not significantly different in the two groups. Mean left ventricular myocardial infarction size was 17 ± 4% of the left ventricle. Histologic analyses showed no signs of atrial ischemic injury or interstitial fibrosis in either group. Atrial myocyte diameter measured at the level of the nuclei of longitudinally sectioned myocytes was not significantly different in the two groups (10.1 ± 1.2 pm vs. 10.2 ± 1.2 pm; P = 0.3). Atrial Connexin40 (both left and right atria) in the left ventricular myocardial infarction group was highly heterogeneous and had significantly smaller total area stained than in the control (0.48 ± 0.09% vs. 0.82 ± 0.13%; P < 0.01).
Conclusions: Chronic left ventricular myocardial infarction downregulates immunodetectable atrial Connexin40, a property that might contribute to the increased atrial fibrillation vulnerability in this model.
1. Li D, Fareh S, Leung TK, Nattel S.Promotion of atrial fibrillation by heart failure in dogs: Atrial remodeling of a different sort. Circulation100:87-95, 1999
2.
2. Thomas SA, Schuessler RB, Saffitz JE. Connexins, conduction, and atrial fibrillation. J Cardiovasc Electrophysiol9:608-611, 1998
3.
3. Saffitz JE, Laing JG, Yamada KA. Connexin expression and turnover: Implications for cardiac excitability. Circ Res86:723-728, 2000
4.
4. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res58:356-371, 1986
5.
5. Bastide B, Neyses L, Ganten D, Paul M, Willecke K, Traub O.Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions. Circ Res73:1138-1149, 1993
6.
6. Sepp R, Severs NJ, Gourdie RG. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart76:412-417, 1996
7.
7. Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation95:988-996, 1997
8.
8. 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. Circulation97:651-660, 1998
9.
9. Zhuang J, Yamada KA, Saffitz JE, Kleber AG. Pulsatile stretch remodels cell-to-cell communication in cultured myocytes. Circ Res87:316-322, 2000
10.
10. Saffitz JE, Kanter HL, Green KG, Tolley TK, Beyer EC.Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium. Circ Res. 74:1065-1070, 1994
11.
11. van der Velden HM, van Kempen MJ, Wijffels MC, et al. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol9:596-607, 1998
12.
12. Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B, Willecke K.Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. Circulation99:1508-1515, 1999
13.
13. Waldecker B.Atrial fibrillation in myocardial infarction complicated by heart failure: Cause or consequence?Eur Heart J20:710-712, 1999
14.
14. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C.The occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction. TRACE Study group. TRAndolapril Cardiac Evalution. Eur Heart J20:748-754, 1999
15.
15. Karagueuzian HS, Fenoglio JJ, Weiss MBJr, Wit AL. Protracted ventricular tachycardia induced by premature stimulation of the canine heart after coronary artery occlusion and reperfusion. Circ Res44:833-846, 1979
16.
16. Robinson G, Ellis IO, MacLennan KA. Immunocytochemistry. In Bancroft JD, Stevens A (eds): Theory and Practice of Histological Techniques. Churchill Livingstone, Edinburne London, Melbourne and New York, pp 413-436, 1990
17.
17. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation91:1588-1595, 1995
18.
18. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation92:1954-1968, 1995
19.
19. Elvan A, Huang XD, Pressler ML, Zipes DP. Radiofrequency catheter ablation of the atria eliminates pacinginduced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation96:1675-1685, 1997
20.
20. Lesh MD, Pring M, Spear JF. Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study. Circ Res65:1426-1440, 1989
21.
21. Fareh S, Villemaire C, Nattel S.Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation98:2202-2209, 1998
22.
22. van Rijen HV, van Kempen MJ, Postma S, Jongsma HJ. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine10:258-264, 1998
23.
23. Fernandez-Cobo M, Gingalewski C, Drujan D, De Maio A.Downregulation of connexin 43 gene expression in rat heart during inflammation. The role of tumour necrosis factor. Cytokine11:216-224, 1999
