Circulation Research. 2004
Published online before print October 21, 2004, doi: 10.1161/01.RES.0000148664.33695.2a
Published online before print October 21, 2004, doi: 10.1161/01.RES.0000148664.33695.2a
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Submitted on May 3, 2004
Revised on October 11, 2004
Accepted on October 14, 2004
Modulation of Cardiac Gap Junction Expression and Arrhythmic Susceptibility
Stephan B. Danik ;
From the The Leon H. Charney Division of Cardiology (S.B.D., F.L., J.Z., G.E.M., G.I.F., D.E.G.), New York University School of Medicine, New York; and Division of Cardiology (H.J.S.), Brigham and Women’s Hospital, Boston, Mass.
* To whom correspondence should be addressed. E-mail: david.gutstein{at}med.nyu.edu.
Connexin43 (Cx43), the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction, and its absence in the mouse heart results in sudden arrhythmic death. The mechanisms linking reduced Cx43 abundance in the heart and inducibility of malignant ventricular arrhythmias have yet to be established. In this report, we investigate arrhythmic susceptibility in a murine model genetically engineered to express progressively decreasing levels of Cx43. Progressively older cardiac-restricted Cx43 conditional knockout (CKO) mice were selectively bred to produce a heart-specific Cx43-deficient subline ("O-CKO" mice) in which the loss of Cx43 in the heart occurs more gradually. O-CKO mice lived significantly longer than the initial series of CKO mice but still died suddenly and prematurely. At 25 days of age, cardiac Cx43 protein levels decreased to 59% of control values (P<0.01), but conduction velocity was not significantly decreased and no O-CKO mice were inducible into sustained ventricular tachyarrhythmias. By 45 days of age, cardiac Cx43 abundance had decreased in a heterogeneous fashion to 18% of control levels, conduction velocity had slowed to half of that observed in control hearts, and 80% of O-CKO mice were inducible into lethal tachyarrhythmias. Enhanced susceptibility to induced arrhythmias was not associated with altered invasive hemodynamic measurements or changes in ventricular effective refractory period. Thus, moderately severe reductions in Cx43 abundance are associated with slowing of impulse propagation and a dramatic increase in the susceptibility to inducible ventricular arrhythmias.
Key words: connexin43 • arrhythmia • electrophysiology • heart • mice
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