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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2604    most recent 91506.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Du, J. Articles by Huang, X.-P. Search for Related Content PubMed PubMed Citation Articles by Du, J. Articles by Huang, X.-P.

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

¹Department 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 ²Section 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