Submitted on December 20, 2007
Revised on March 21, 2008
Accepted on April 9, 2008
Impaired Relaxation Is the Main Manifestation in Transgenic Mice Expressing a Restrictive Cardiomyopathy Mutation, R193H, in Cardiac TnI
Jianfeng Du1, Jing Liu1, Han-Zhong Feng, M. Moazzem Houssain2, Nariman Gobara1, Chi Zhang, Yuejin Li1, Pierre-Yves Jean-Charles1, J.-P. Jin2, and Xu-Pei Huang1*
1 Florida Atlantic University
2 Northwestern University
* To whom correspondence should be addressed. E-mail: xhuang{at}fau.edu.
Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cTnI R192H mutation in the heart (cTnI193His mice). The objective of this study was to assess the cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored on cTnI193His mice and wild type littermates for a period of 12 months. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with a high-resolution echocardiography by a reversed E/A ratio, increased deceleration time (DT), and prolonged isovolumetric relaxation time (IVRT). At age of 12 months, cardiac output (CO) in cTnI193His mice was significantly declined and some TG mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve the CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the C-terminal domain of cTnI in the diastolic function of cardiac muscle.
