209 INTRODUCTION The development of transgenic and gene-targeting technologies that enable experimental manipulation of the mouse genome have yielded important new insights into the molecular mechanisms and patho- physiology of numerous human diseases. Mouse models of hypertrophic and dilated cardiomyopathy offer unique advantages in the study of the patho- physiology of heart failure compared with larger ani- mal models.The abilities to express transgenes in a tissue-specific, temporally regulated manner and to target genes for inactivation allow detailed studies of the influence of single genes on the progression and severity of cardiac disease.Transgenic and knockout mice have a short gestational period of 3 weeks and reach adulthood in 8 weeks, which allows assess- ment of therapeutic interventions on the natural his- tory of heart failure over a relatively short period of time. Furthermore, recent advances in mouse genet- ics allow the possibility of screening randomly muta- genized populations in search of novel genes in- volved in cardiac function and development. We have recently used a transgenic approach to develop a mouse model of idiopathic dilated car- diomyopathy that resembles many of the anatomic, physiologic, and clinical features of human dilated cardiomyopathy. 1 These mice express a dominant negative mutant form of the CREB transcription fac- tor (CREB A133 ) under the control of the cardiac spe- cific α–major histocompatibility complex promoter. Between 4 and 20 weeks of age, 4-chamber cardiac dilatation develops in the CREB A133 mice and, as noted in preliminary observations, a significant re- duction is demonstrated in both systolic and diastolic left ventricular (LV) performance. Until recently, the usefulness of mouse models of heart failure has been limited by the inability to accu- rately and precisely assess cardiovascular physiology in vivo.This situation has changed in the last 5 years with the development of high-frequency, high-reso- lution echocardiographic transducers and catheter- The Left Ventricular Stress-Velocity Relation in Transgenic Mice Expressing a Dominant Negative CREB Transgene in the Heart Richard C. Fentzke, BS, Claudia E. Korcarz, DVM, Sanjeev G. Shroff, PhD, Hua Lin, MD, Jeffrey M. Leiden, MD, PhD, and Roberto M. Lang, MD, Chicago, Illinois; Pittsburgh, Pennsylvania; and Boston, Massachusetts From the Department of Medicine, University of Chicago (R.C.F., C.E.K., R.M.L.); the Department of Bioengineering, University of Pittsburgh (S.G.S.); and the Harvard School of Public Health/ Harvard Medical School, Brigham and Women’s Hospital, Boston, Mass (H.L., J.M.L.). This work was supported in part by a grant (HL54592) from the NHLBI to J.M.L. Reprint requests: Roberto M. Lang, MD, University of Chicago Medical Center, 5841 S. Maryland Avenue, MC 5084, Chicago, IL 60637 (E-mail: rlang@medicine.bsd.uchicago.edu). Copyright © 2001 by the American Society of Echocardiography. 0894-7317/2001/$35.00 + 0 27/1/111473 doi:10.1067/mje.2001.111473 Objective: CREB A133 transgenic mice that express a dominant negative CREB transcription factor in car- diomyocytes develop a dilated cardiomyopathy that is anatomically, physiologically, and clinically simi- lar to human idiopathic dilated cardiomyopathy. The goals of this study were to quantitate left ventricular (LV) contractility and measure cardiac reserve in CREB A133 mice by using the relation of end-systolic wall stress to the velocity of fiber shortening. Methods: A total of 37 adult CD-1 mice (including both nontransgenic and CREB A133 transgenic mice) were studied with simultaneously acquired high-fidelity instantaneous aortic pressures and 2-dimensionally targeted M-mode echocardiograms. Results: CREB A133 mice displayed significantly lower values of LV fiber shortening velocities over a wide range of afterloads, and they displayed smaller do- butamine-induced shifts from baseline contractility relations. Counterbalancing effects of differences in LV geometry and aortic pressures resulted in com- parable levels of LV wall stress during ejection in both groups. Conclusion: These results demonstrate directly that CREB A133 mice display reduced LV contractility at baseline and decreased cardiac reserve. (J Am Soc Echocardiogr 2001;14:209-18.)