Mucopolysaccharidosis I (MPS I, alpha-l-iduronidase deficiency disease) is a heritable lysosomal storage disorder involving multiple organs, including the heart. Malfunction of the heart is also a major manifestation in the mouse model of MPS I, progressing in severity from 6 to 10 months (of a 1 year life span). In comparisons of MPS I with wild-type mice, the heart was found enlarged, with thickened septal and posterior walls, primarily because of infiltration of the muscle by storage-laden cells. Heart valves were enlarged and misshapen, and contained large numbers of highly vacuolated interstitial cells. The thickened aortic wall contained vacuolated smooth muscle cells and interrupted elastic fibers. Hemodynamic measurements and echocardiography revealed reduced left ventricular function as well as mitral and aortic regurgitation. But despite these abnormalities, free-roaming MPS I mice implanted with radio telemetry devices showed surprisingly normal heart rate and blood pressure, though their electrocardiograms were abnormal. An incidental finding of the telemetry studies was a disturbed circadian rhythm in the MPS I mice. Restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in normalization of left ventricular function as well as loss of storage vacuoles in myocytes and endothelial cells, though not in valvular interstitial cells. This study demonstrates the usefulness of the mouse model for in-depth studies of the cardiovascular component of MPS I.