Transthoracic echocardiography in models of cardiac disease in the mouse.

BACKGROUND Transthoracic echocardiography (M-mode and Doppler) offers a noninvasive approach for in vivo evaluation of the mouse heart. The present study examines its usefulness for assessing the morphological/functional phenotype of the left ventricle (LV) in several transgenic and surgical murine models of cardiac disease. METHODS AND RESULTS Observations were made in 83 intact, anesthetized mice. In mice with a surgical arteriovenous fistula, volume overload and LV dilation were detected. In normal mice, echocardiographic indexes of increased contractility (dobutamine) were confirmed by LV dP/dtmax. In transgenic mice with overexpression of the beta 2-adrenergic receptor, heart rate and mean velocity of circumferential fiber shortening were increased, indicating enhanced contractility. In colony screening of transgenic mice overexpressing the H-ras gene, 45% had increased LV wall thickness (> 0.9 mm), and those showing a striking increase were selected for breeding. In mice with LV hypertrophy (aortic constriction) and normal mice, the actual LV mass determined by echocardiography correlated well (r = .93), and 95% confidence limits were determined. The maximum intraobserver and interobserver coefficients of variation for M-mode data were 0.03 +/- 0.29 mm (+/- 2 SD), < 10% for LV internal dimensions but 27% to 30% for wall thickness. CONCLUSIONS These studies provide the first application of transthoracic echocardiography for morphological/functional characterization of the cardiac phenotype in transgenic and surgical murine models, including (1) high reliability for detecting LV chamber dilation and function; (2) reliability (and its limits) for determining abnormal LV wall thickness and LV mass; (3) identification of marked, sometimes asymmetrical, hypertrophy in a transgenic model of hypertrophic cardiomyopathy; and (4) usefulness for transgenic colony screening to identify markedly abnormal phenotypes.

[1]  J. Ross,et al.  Application of end-systolic pressure-volume and pressure-wall thickness relations in conscious dogs. , 1987, Journal of the American College of Cardiology.

[2]  J. Ross,et al.  Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Lefkowitz,et al.  Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. , 1994, Science.

[4]  J Ross,et al.  Influence of the Force–Frequency Relation on Left Ventricular Function During Exercise in Conscious Dogs , 1992, Circulation.

[5]  R. Walsh,et al.  In vivo echocardiographic detection of enhanced left ventricular function in gene-targeted mice with phospholamban deficiency. , 1995, Circulation research.

[6]  A. DeMaria,et al.  Recommendations Regarding Quantitation in M-Mode Echocardiography: Results of a Survey of Echocardiographic Measurements , 1978, Circulation.

[7]  J. Ross,et al.  Effects of changes in preload, afterload and inotropic state on ejection and isovolumic phase measures of contractility in the conscious dog. , 1975, The American journal of cardiology.

[8]  THOMAS RYAN,et al.  Annular Array Technology: Application to Cardiac Imaging , 1987 .

[9]  W J Manning,et al.  In vivo assessment of LV mass in mice using high-frequency cardiac ultrasound: necropsy validation. , 1994, The American journal of physiology.

[10]  Ha Won Kim,et al.  Mouse phospholamban gene expression during development in vivo and in vitro. , 1992, Circulation research.

[11]  J. Ross,et al.  Nature of Enhanced Performance of the Dilated Left Ventricle in the Dog during Chronic Volume Overloading , 1972, Circulation research.

[12]  J. Gardin,et al.  Echocardiographic assessment of left ventricular mass and systolic function in mice. , 1995, Circulation research.

[13]  J.W. Hunt,et al.  An Annular Array System for High Resolution Breast Echography , 1982 .

[14]  L Masotti,et al.  Two-dimensional echocardiographic imaging: in vitro comparison of conventional and dynamically focused annular array transducers. , 1987, Ultrasound in medicine & biology.

[15]  D. Altman,et al.  STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT , 1986, The Lancet.

[16]  J Ross,et al.  Molecular and physiological alterations in murine ventricular dysfunction. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Doetschman,et al.  Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. , 1994, Circulation research.

[18]  J. Ross,et al.  Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[19]  K. Chien,et al.  Ventricular Expression of a MLC-2v-ras Fusion Gene Induces Cardiac Hypertrophy and Selective Diastolic Dysfunction in Transgenic Mice (*) , 1995, The Journal of Biological Chemistry.

[20]  R. Kloner,et al.  Echocardiographic and cardiac Doppler assessment of mice. , 1995, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[21]  S. Bishop,et al.  The c-myc proto-oncogene regulates cardiac development in transgenic mice , 1990, Molecular and cellular biology.

[22]  K. Chien,et al.  In vivo murine cardiac hypertrophy : a novel model to identify genetic signaling mechanisms that activate an adaptive physiological response , 1993 .