Faculty Collaboration Database

Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors. Cardiovasc Res 2004 Jun 01;62(3):500-8

Date

05/26/2004

Pubmed ID

15158142

Pubmed Central ID

PMC3910327

DOI

10.1016/j.cardiores.2004.02.004

Scopus ID

2-s2.0-2442436385 (requires institutional sign-in at Scopus site)   46 Citations

Abstract

OBJECTIVE: An increased expression of adenosine receptors is a promising target for gene therapy aimed at protecting the myocardium against ischemic damage, but may alter cardiac electrophysiology. We therefore studied the effects of heart-directed overexpression of A(3) adenosine receptors (A(3)ARs) at different gene doses on sinus and atrio-ventricular (AV) nodal function in mice.

METHODS AND RESULTS: Mice with heart-specific overexpression of A(3)AR at high (A(3)(high)) or low (A(3)(low)) levels and their wild-type littermates were studied. Telemetric electrocardiogram (ECG) recordings in adult freely moving A(3)(high) mice showed profound sinus bradycardia resulting in either ventricular escape rhythms or an incessant bradycardia-tachycardia syndrome (minimal heart rate A(3)(high) 217+/-25*; WT 406+/-21 beats/min, all values as mean+/-S.E.M., n=7 per genotype, *p<0.05). Exercise attenuated bradycardia in A(3)(high) mice (maximal heart rate A(3)(high) 650+/-13*; WT 796+/-13 beats/min) and first-degree AV nodal block was present (PQ interval A(3)(high) 36+/-4*; WT 23+/-5 ms). Isolated hearts showed complete heart block (10/17 A(3)(high)* vs. 1/17 WT). Atrial bradycardia and AV block were already present 3 weeks after birth. Doppler echocardiography revealed atrial dysfunction and progressive atrial enlargement that was moderate at 3 and 8 weeks, and progressed at 12 and 21 weeks of age (all p<0.05 vs. WT). Atrial contractility and sarcoendoplasmic Ca(2+) ATPase (SERCA) 2a protein expression were reduced in isolated left A(3)(high) atria at the age of 14 weeks. Fibrosis was present in left A(3)(high) atria at 14 weeks, but not at 5 weeks of age. A(3)(low) mice had first-degree AV block without arrhythmias or structural changes.

CONCLUSIONS: Heart-directed overexpression of A(3)AR resulted in gene dose-dependent AV block and pronounced sinus nodal dysfunction in vivo. Profound bradycardia heralded atrial and ventricular dilatation, dysfunction, and fibrosis. In contrast to A(1) adenosine receptors (A(1)AR), the effects of A(3)AR overexpression were attenuated during exercise. This may have implications for the physiology of sinus nodal regulation and for therapeutic attempts to increase the expression of adenosine receptors.

Author List

Fabritz L, Kirchhof P, Fortmüller L, Auchampach JA, Baba HA, Breithardt G, Neumann J, Boknik P, Schmitz W

Author

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Arrhythmias, Cardiac
Atrioventricular Node
Cardiomyopathy, Dilated
Echocardiography, Doppler
Electrocardiography
Gene Expression
Heart Block
Mice
Mice, Transgenic
Perfusion
Receptor, Adenosine A3
Sinoatrial Node