title: Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Transgenic and gene-targeted models have focused on the mouse. Fundamental differences between the mouse and human exist in Ca2+ handling during contraction/relaxation and in alterations in Ca2+ flux during heart failure, with the rabbit more accurately reflecting the human system.
  
  
  RESULTS
  Cardiac troponin I (cTnI) mutations can cause familial hypertrophic cardiomyopathy. An inhibitory domain mutation, arginine146-->glycine (cTnI(146Gly)), was modeled with the use of transgenic expression in the rabbit ventricle. cTnI(146Gly) levels >40% of total cTnI were perinatally lethal, whereas replacement levels of 15% to 25% were well tolerated. cTnI(146Gly) expression led to a leftward shift in the force-pCa2+ curves with cardiomyocyte disarray, fibrosis, and altered connexin43 organization. In isolated cTnI(146Gly) myocytes, twitch relaxation amplitudes were smaller than in normal cells, but [Ca]i transients and sarcoplasmic reticulum Ca2+ load were not different. Detrended fluctuation analysis of the QT(max) intervals was used to evaluate the cardiac repolarization phase and showed a significantly higher scaling exponent in the transgenic animals.
  
  
  CONCLUSIONS
  Expression of modest amounts of cTnI(146Gly) led to subtle defects without severely affecting cardiac function. Aberrant connexin organization, subtle morphological deficits, and an altered fractal pattern of the repolarization phase of transgenic rabbits, in the absence of entropy or other ECG abnormalities, may indicate an early developing pathology before the onset of more obvious repolarization abnormalities or major alterations in cardiac mechanics.
authors.affiliation: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Jeanne
authors.initials: J
authors.lastname: James
authors.forename: Volkan
authors.initials: V
authors.lastname: Tuzcu
authors.forename: Selman
authors.initials: S
authors.lastname: Nas
authors.forename: Lisa
authors.initials: L
authors.lastname: Martin
authors.forename: James
authors.initials: J
authors.lastname: Gulick
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Sadayappan
authors.initials: S
authors.lastname: Sakthivel
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ginsburg
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Bruce
authors.initials: B
authors.lastname: Zinman
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D005355:Fibrosis; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000473:pathology; D010641:Phenotype; D011817:Rabbits; D019076:Transgenes; D019210:Troponin I / Q000235:genetics*
chemical_list: D018031:Connexin 43; D019210:Troponin I; D002118:Calcium