Progressive atrioventricular conduction block in a mouse myotonic dystrophy model

Introduction: Myotonic dystrophy is caused by expansion of a CTG trinucleot ide repeat on human chromosome 19, and leads to progressive skeletal myopat hy and atrioventricular conduction disturbances. A murine model of myotonic dystrophy has been designed by targeted disruption of the myotonic dystrop hy protein kinase (DMPK) gene. The DMPK-deficient mice display abnormalitie s in A-V conduction characteristics, similar to the human cardiac phenotype . The purpose of this study was to determine whether age-related progressio n of A-V block occurs in a mouse model of DMPK-deficiency. Methods and Results: Surface ECGs and intracardiac electrophysiology (EP) s tudies were performed in 60 immature and 90 adult homozygous (DMPK-/-), het erozygous (DMPK+/-), and wild-type (WT) DMPK+/+ control mice. Complete stud ies were obtained on 141 of 150 mice. The RR, PR, QRS, and QT intervals wer e measured on ECG. Sinus node recovery time, AV refractory periods, paced A V Wenckebach and 2:1 block cycle lengths, atrial and ventricular effective refractory periods were compared between genotypes and age groups. There we re no differences in ECG intervals or EP findings in the young mutant mice, but progressive PR prolongation in older mice. The A-V conduction defects are also sensitive to DMPK gene dosage. Adult DMPK-/- mice develop 1 degree s, 2 degrees and 3 degrees A-V block, whereas DMPK+/- mice develop only 1 d egrees heart block. Conclusion: These data demonstrate that both age and DMPK dose are importan t factors regulating cardiac conduction in myotonic dystrophy. This mouse m odel of DM is remarkably similar to the human phenotype, with age-related p rogression in atrioventricular conduction defects.