A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice

Cardiac troponin I (cTnI) mutations have been linked to the development of restrictive cardiomyopathy (RCM) in human patients. We modeled one mutation in human cTnI C-terminus, arginine192 → histidine (R192H) by cardiac specific expression of the mutated protein (cTnI193His in mouse sequence) in transgenic mice. Heart tissue sections revealed neither significant hypertrophy nor ventricular dilation in cTnI193His mice. The main functional alteration detected in cTnI193His mice by ultrasound cardiac imaging examinations was impaired cardiac relaxation manifested by a decreased left ventricular end diastolic dimension (LVEDD) and an increased end diastolic dimension in both atria. The cardiac ejection fraction (EF) was not significant changed in 6- to 8-week-old cTnI193His mice, however, the EF was significantly decreased in cTnI193His mice at age of 11 months. These data indicate that individual genetic conditions and environmental factors participate together in the development of the cTnI mutation based-cardiac muscle disorders. This mouse model provides us with a tool to further investigate the pathophysiology and the development of RCM.