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

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 (cTnI(193His) in mouse sequence) in transgenic mice. Heart tissue sections revealed neither significant hypertrophy nor ventricular dilation in cTnI(193His) mice. The main functional alteration detected in cTnI(193His) 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 cTnI(193His) mice, however, the EF was significantly decreased in cTnI(193His) 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.