Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI

1 Department of Biomedical Science and Center for Molecular Biology and Biotechnology, University of Miami Miller School of Medicine Boca Regional Campus, Florida Atlantic University, Boca Raton, Florida; and 2 Section of Molecular Cardiology, Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, Illinois Submitted 20 December 2007 ; accepted in final form 9 April 2008 Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI 193His mice). The objective of this study was to assess 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 in cTnI 193His mice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI 193His mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI 193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI 193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI 193His mice but did not improve CO. The cTnI 193His 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 COOH-terminal domain of cTnI in the diastolic function of cardiac muscle. troponin I; cardiac relaxation; Doppler echocardiography; working heart function Address for reprint requests and other correspondence: X. Huang, Dept. of Biomedical Science, Florida Atlantic Univ., 777 Glades Rd., Boca Raton, FL 33431 (e-mail: xhuang{at}fau.edu )