Integrins link the extracellular matrix to the cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, and survival. Ablation of &bgr;1 integrin in all murine tissues results in peri-implantation embryonic lethality. To investigate the role of &bgr;1 integrin in the myocardium, we used Cre-LoxP technology to inactivate the &bgr;1 integrin gene exclusively in ventricular cardiac myocytes. Animals with homozygous ventricular myocyte &bgr;1 integrin gene excision were born in appropriate numbers and grew into adulthood. These animals had 18% of control levels of &bgr;1D integrin protein in the heart and displayed myocardial fibrosis. High-fidelity micromanometer-tipped catheterization of the intact 5-week-old &bgr;1 integrin knockout mice showed depressed left ventricular basal and dobutamine-stimulated contractility and relaxation (LV dP/dtmaxand LV dP/dtmin) as compared with control groups (n=8 to 10 of each,P<0.01). Hemodynamic loading imposed by 7 days of transverse aortic constriction showed that the &bgr;1 integrin knockout mice were intolerant of this stress as they had 53% survival versus 88% in controls (n=15 each). By 6 months of age, mice with depressed ventricular expression of &bgr;1 integrin developed a dilated cardiomyopathy that was not evident in any control animals and had patchy decrease in glucose metabolism as determined by positron emission tomography. Myocyte membrane integrity as determined via Evan’s blue dye staining was disrupted in the &bgr;1 integrin knockout mice. This model provides strong evidence for the importance of &bgr;1 integrin in cardiac form and function and indicates that integrins can be linked to development of cardiomyopathies.