Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors.
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.


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.
Fabritz
Larissa
L
Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, University Hospital Münster, Muenster, Germany. fabritzl@uni-muenster.de
Kirchhof
Paulus
P
Fortmüller
Lisa
L
Auchampach
John A
JA
Baba
Hideo A
HA
Breithardt
Günter
G
Neumann
Joachim
J
Boknik
Peter
P
Schmitz
Wilhelm
W
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D001283:Atrioventricular Node / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D015870:Gene Expression; D006327:Heart Block / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010477:Perfusion; D043684:Receptor, Adenosine A3 / Q000235:genetics*; D012849:Sinoatrial Node / Q000503:physiopathology
D043684:Receptor, Adenosine A3