Titin is a recently discovered protein that extends in the sarcomere from the Z-line to the M-line and that forms, in addition to thin and thick filaments, the third myofilament of the cardiac sarcomere. The segment of the molecule that is found in the I-band behaves elastically when sarcomere length is changed. The PI's laboratory has shown that extension of this elastic segment underlies the majority of the passive force developed by cardiac myocytes when stretched beyond their slack length. The work has also indicated that, over a considerable part of the physiological sarcomere-length range, titin-based passive force is an important contributor to the diastolic wall stress of rat myocardium. Furthermore, in rat cardiac myocytes titin also develops restoring force when sarcomeres shorten to below the slack length, indicating that titin may be able to contribute to the elastic diastolic recoil of the heart that aids in ventricular filling. Titin's importance in determining the compliance of the heart is also suggested by studies that have reported reduced expression of titin in patients with dilated cardlomyopathy. However, no systematic study has been carried out on the relation between the properties of titin (the amount of titin and its elasticity) and the altered compliance of cardiac muscle during heart disease. Altered compliance of the heart may result not only from titin, but also from changes in the cytoskeleton, as well as changes in the extracellular matrix (collagen). The investigators' aim is to study each of these components in the normal heart and in the diseased heart. They will first focus on dilated cardiomyopathy (DCM) using the turkey model of DCM. The investigators' preliminary work has revealed that, relative to the normal heart, the left ventricle of the DCM heart functions at much shorter sarcomere lengths, and that diastolic wall stress of the DCM heart increases more steeply with sarcomere length. These and other findings support the need to dissect the molecular origin of the diastolic properties of normal and DCM hearts. To study whether the findings can be extrapolated to other species, the canine heart will also be studied, both from normal animals and animals with DCM produced by rapid pacing. Finally, the investigators propose to study the role of titin in the altered ventricular compliance in human patients with DCM. A multi-faceted approach will be taken with mechanical, immuno-electron microscopical, and biochemical techniques at the molecular, cellular, multi-cellular and isolated heart level.
Showing the most recent 10 out of 59 publications
