Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy

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 (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.