Background Homozygous mutant mice expressing a truncated form of myosin-binding protein C (MyBP-C^t/t) develop severe dilated cardiomyopathy, whereas the heterozygous mutation (MyBP-C^t/+) causes mild hypertrophic cardiomyopathy. Adult male MyBP-C^t/t and MyBP-C^t/+ 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/+, 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 variability and ambient arrhythmia activity were assessed with telemetric ECG monitors. Quantitative histological characterization was performed on serial sections of excised hearts. MyBP-C^t/t and MyBP-C^t/+ mice have normal ECG intervals and sinus node, atrial, and ventricular conduction and refractoriness. 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/+ mice (20%) and 0 of 17 wild-type controls (P<0.001). Ventricular ectopy was present only in MyBP-C^t/t mice during ambulatory ECG recordings. There were no differences in heart rate variability parameters. Interstitial fibrosis correlated with genotype but did not predict arrhythmia susceptibility within the MyBP-C^t/t group.

Conclusions MyBP-C^t/t mice, despite prominent histopathology and ventricular dysfunction, exhibit normal conduction and refractoriness, yet are vulnerable to ventricular arrhythmias. Somatic influences between genetically identical mutant mice most likely account for variability in arrhythmia susceptibility. A sarcomeric protein gene mutation leads to a dilated cardiomyopathy and ventricular arrhythmia vulnerability phenotype.