Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI
Copyright policy )Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI
Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI193Hismice). 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 cTnI193Hismice 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 cTnI193Hismice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193Hison ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193Hismyocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193Hismice but did not improve CO. The cTnI193Hismice 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.
- Northwestern University United States
- Miami University United States
- Florida Atlantic University United States
Heart Failure, Cardiomyopathy, Restrictive, Cardiotonic Agents, Genotype, Troponin I, Age Factors, Mice, Transgenic, Myocardial Contraction, Echocardiography, Doppler, Mice, Phenotype, Diastole, Heart Rate, Dobutamine, Mutation, Disease Progression, Animals, Cardiac Output, Cell Size
Heart Failure, Cardiomyopathy, Restrictive, Cardiotonic Agents, Genotype, Troponin I, Age Factors, Mice, Transgenic, Myocardial Contraction, Echocardiography, Doppler, Mice, Phenotype, Diastole, Heart Rate, Dobutamine, Mutation, Disease Progression, Animals, Cardiac Output, Cell Size
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