Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy

• Published in: Circulation (New York, N.Y.) Vol. 111; no. 18; pp. 2330 - 2338
• Main Authors: SANBE, Atsushi, JAMES, Jeanne, BERS, Donald M, ZINMAN, Bruce, LAKATTA, Edward G, ROBBINS, Jeffrey, TUZCU, Volkan, NAS, Selman, MARTIN, Lisa, GULICK, James, OSINSKA, Hanna, SAKTHIVEL, Sadayappan, KLEVITSKY, Raisa, GINSBURG, Kenneth S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 10.05.2005
• Subjects: Animals; Animals, Genetically Modified; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Calcium - metabolism; Cardiology. Vascular system; Cardiomegaly; Cardiomyopathy, Hypertrophic, Familial - genetics; Cardiomyopathy, Hypertrophic, Familial - pathology; Cardiomyopathy, Hypertrophic, Familial - physiopathology; Cardiovascular system; Connexin 43 - metabolism; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Electrocardiography; Fibrosis; Fundamental and applied biological sciences. Psychology; Heart Function Tests; Heart Ventricles - metabolism; Humans; Medical sciences; Mutation, Missense; Myocytes, Cardiac - pathology; Pharmacology. Drug treatments; Phenotype; Rabbits; Transgenes; Troponin I - genetics; Vasodilator agents. Cerebral vasodilators; Vertebrates: cardiovascular system; Human; hypertrophy; Rabbit; Cardiovascular disease; cardiovascular diseases; Lagomorpha; Myocardial disease; Vertebrata; Troponin; Mammalia; Animal; Heart disease; heart diseases; Hypertrophic cardiomyopathy
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000164234.24957.75

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. 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. 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.