Myocardial impulse propagation depends on intercellular current transfer at gap junctions. Atrial and ventricular myocytes express different combinations of multiple gap junction channel proteins (connexins) and are interconnected by markedly different spatial distributions of gap junctions. It is likely, therefore, that specific connexin phenotypes are important determinants of the disparate conduction properties of atrial and ventricular muscle and that derangements in intercellular coupling contribute to arrhythmogenesis. However, these hypotheses have never been tested directly nor are the specific functional roles of individual connexins known. We have recently discovered that mice heterozygous for a null mutation in the gene encoding Cx43, the principle cardiac connexin (Cx43 plus/minus mice), exhibit significant slowing of ventricular conduction but no atrial conduction defect. Accordingly, this grant is focused on the functional roles of Cx43 in Cx43 deficient mice, the first genetic model of which we are aware of abnormal cardiac conduction. We will test the hypotheses that: 1) deficient expression of Cx43 in Cx43 plus/minus and minus/minus mice does not cause changes in myocardial tissue structure or in the overall tissue content of Cx45 and Cx40 (to be tested in Specific Aim 1); 2) Cx43 functions as the predominant intercellular low resistance pathway in ventricular muscle (which expresses Cx43 and Cx45) but not in atrial muscle (which expresses Cx43, Cx45 and Cx40) (to be tested in Specific Aim 2); 3) uncoupling of ventricular myocytes in Cx43 minus/minus and plus/minus mice due to diminished Cx43 expression enhances the anisotropy of conduction velocity, sustains slow conduction in response to depression of active membrane properties, and enhances heterogeneity in action potential duration in response to changes in refractoriness (effects which would be expected to promote arrhythmogenesis) (to be tested in Specific Aim 3); and 4) diminishing coupling per se is proarrhythmic when ischemic injury occurs in a regional (i.e., spatially heterogenous) pattern (to be tested in Specific Aim 4). To test these hypotheses, we will analyze Cx43 deficient mice using multiple morphometric, molecular and electrophysiological approaches. We will measure gap junctional conductances and single channel properties directly in atrial and ventricular cell pairs, and characterize impulse propagation in patterned arrays of neonatal Cx43 plus/plus, plus/minus, and minus/minus myocytes in vitro with multisite, high resolution optical mapping and transmembrane recordings. We will also characterize conduction and arrhythmogenesis induced by ischemia in intact hearts from Cx43 plus/minus and plus/plus mice. The results of the proposed research will provide new insights into the roles of a specific relevant gene product in cardiac electrophysiology and will delineate the biological functions served by individual connexins in atrial and ventricular myocytes.
| Saffitz, Jeffrey E (2017) Molecular mechanisms in the pathogenesis of arrhythmogenic cardiomyopathy. Cardiovasc Pathol 28:51-58 |
| Beauchamp, Philippe; Desplantez, Thomas; McCain, Megan L et al. (2012) Electrical coupling and propagation in engineered ventricular myocardium with heterogeneous expression of connexin43. Circ Res 110:1445-53 |
| Beauchamp, Philippe; Yamada, Kathryn A; Baertschi, Alex J et al. (2006) Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circ Res 99:1216-24 |
| Gard, Joseph J; Yamada, Kiyomi; Green, Karen G et al. (2005) Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. Cardiovasc Res 67:539-47 |
| Betsuyaku, Tetsuo; Kanno, Shigeto; Lerner, Deborah L et al. (2004) Spontaneous and inducible ventricular arrhythmias after myocardial infarction in mice. Cardiovasc Pathol 13:156-64 |
| Yamada, Kathryn A; Kanter, Evelyn M; Green, Karen G et al. (2004) Transmural distribution of connexins in rodent hearts. J Cardiovasc Electrophysiol 15:710-5 |
| Kaplan, Starr R; Gard, Joseph J; Carvajal-Huerta, Luis et al. (2004) Structural and molecular pathology of the heart in Carvajal syndrome. Cardiovasc Pathol 13:26-32 |
| Beauchamp, Philippe; Choby, Cecile; Desplantez, Thomas et al. (2004) Electrical propagation in synthetic ventricular myocyte strands from germline connexin43 knockout mice. Circ Res 95:170-8 |
| Kanno, Shigeto; Kovacs, Attila; Yamada, Kathryn A et al. (2003) Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice. J Am Coll Cardiol 41:681-6 |
| Yamada, Kathryn A; Rogers, Joseph G; Sundset, Rune et al. (2003) Up-regulation of connexin45 in heart failure. J Cardiovasc Electrophysiol 14:1205-12 |
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