Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy

Atsushi Sanbe, Jeanne James, Volkan Tuzcu, Selman Nas, Lisa Martin, James Gulick, Hanna Osinska, Sadayappan Sakthivel, Raisa Klevitsky, Kenneth S. Ginsburg, Donald M. Bers, Bruce Zinman, Edward G. Lakatta, Jeffrey Robbins

Research output: Contribution to journalArticle

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. Methods and Results - Cardiac troponin I (cTnI) mutations can cause familial hypertrophic cardiomyopathy. An inhibitory domain mutation, arginine146→glycine (cTnI146Gly), was modeled with the use of transgenic expression in the rabbit ventricle. cTnI146Gly levels >40% of total cTnI were perinatally lethal, whereas replacement levels of 15% to 25% were well tolerated. cTnI146Gly expression led to a leftward shift in the force-pCa2+ curves with cardiomyocyte disarray, fibrosis, and altered connexin43 organization. In isolated cTnI146Gly 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 QTmax 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 cTnI146Gly 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.

Original languageEnglish (US)
Pages (from-to)2330-2338
Number of pages9
JournalCirculation
Volume111
Issue number18
DOIs
StatePublished - May 10 2005
Externally publishedYes

Keywords

  • Cardiovascular diseases
  • Heart diseases
  • Hypertrophy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Sanbe, A., James, J., Tuzcu, V., Nas, S., Martin, L., Gulick, J., Osinska, H., Sakthivel, S., Klevitsky, R., Ginsburg, K. S., Bers, D. M., Zinman, B., Lakatta, E. G., & Robbins, J. (2005). Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy. Circulation, 111(18), 2330-2338. https://doi.org/10.1161/01.CIR.0000164234.24957.75