Po-02-151 increased ventricular arrhythmias in a mouse model of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy. The disease is characterized by a high incidence of sudden cardiac death (SCD) at young ages, in which ventricular arrhythmias are the major cause of SCD. However, the intimate mechanisms are not completely understood. We aimed to investigate the susceptibility to ventricular arrhythmias and the arrhythmic substrate in an early stage of HCM in a genetic mouse model of the disease. We used a humanized HCM mouse model carrying a mutation in the cardiac troponin I (cTnIGly146, heterozygous). Male FVB/N mice served as controls. At the age of five months, mice were assessed by echocardiogram, in vivo electrophysiological studies (invasive programmed electrical stimulation), ex vivo by whole-heart high-resolution optical mapping, and histology (picrosirius red). Echocardiographic studies at 5 months revealed no signs of cardiac hypertrophy or systolic dysfunction. The lack of hypertrophy was further confirmed by no changes in the absolute (5%, p = 0.47) and normalized heart weights (3%, p = 0.66). On the other hand, cTnIGly146 mice had already evident increased lung weight compared to controls (+21%, p = 0.01). Surface ECG studies revealed decreased QRS complex duration (-27%, p = 0.02) and QTc interval (-20%, p = 0.01) in cTnIGly146 compared to controls. Moreover, cTnIGly146 mice presented higher inducibility of ventricular tachycardia (5 out of 8; p = 0.03) compared to controls (0 out of 6). Optical mapping studies revealed slower conduction velocity (-20%, p = 0.01) in cTnIGly146 compared to controls. Increased ventricular fibrosis by histology was seen (156%, p = 0.004). Our results show that ventricular fibrosis developed before overt cardiac hypertrophy in HCM, may lead to abnormal impulse propagation favoring re-entry ventricular arrhythmias.