Ventricular arrhythmia vulnerability in cardiomyopathic mice with homozygous mutant myosin-binding protein C gene

Background-Homozygous mutant mice expressing a truncated form of myosin-bin ding, protein C (MyBP-C-t/t) develop severe dilated cardiomyopathy, whereas the heterozygous mutation (MyBP-C1/+) causes mild hypertrophic cardiomyopa thy. Adult male MyBP-C-t/t and MyBP-Ct/+ mice were evaluated for arrhythmia vulnerability with an in vivo electrophysiology study. Methods and Results-Surface ECGs were obtained for heart rate, rhythm, and conduction intervals. Atrial, atrioventricular, and ventricular conduction parameters and refractoriness were assessed in 22 MyBP-C-t/t, 10 MyBP-C-t/t , and 17 wild-type MyBP-C+/+ mice with endocardial pacing and intracardiac electrogram recording. Arrhythmia induction was attempted with standardized programmed stimulation at baseline and with isoproterenol. Heart rate vari ability and ambient arrhythmia activity were assessed with telemetric ECG m onitors. Quantitative histological characterization was performed on serial sections of excised hearts. MyBP-C-t/t and MyBP-Ct/+ mice have normal ECG intervals and sinus node, atrial, and ventricular conduction and refractori ness. Ventricular tachycardia was reproducibly inducible in 14 of 22 MyBP-C -t/t mice (64%) during programmed stimulation, compared with 2 of 10 MyBP-C -t/t mice (20%) and 0 of 17 wild-type controls (P <0.001). Ventricular ecto py was present only in MyBP-C-t/t mice during ambulatory ECG recordings. Th ere were no differences in heart rate variability parameters. Interstitial fibrosis correlated with genotype but did not predict arrhythmia susceptibi lity within the MyBP-C-t/t group. Conclusions-MyBP-C-t/t mice, despite prominent histopathology and ventricul ar dysfunction, exhibit normal conduction and refractoriness, yet are vulne rable to ventricular arrhythmias. Somatic influences between genetically id entical mutant mice most likely account for variability in arrhythmia susce ptibility. A sarcomeric protein gene mutation leads to a dilated cardiomyop athy and ventricular arrhythmia vulnerability phenotype.