The MLP Family of Cytoskeletal Z Disc Proteins and Dilated Cardiomyopathy: A Stress Pathway Model for Heart Failure Progression

Heart failure is a major cause of human morbidity andmortality, predicted to reach epidemic proportions in theearly period of the 21st century. This growing incidencereflects our current lack of understanding of the fundamental pathways that drive the progressive dilation of thecardiac chamber and the associated decreases in cardiaccontractility that accompany the diverse environmentalstimuli that can trigger the disease, including post-infarction injury, side effects of chemotherapeutic agents, viralinfection, and chronic exposure to volume and pressureoverload. In short, the disease is complex, the pathologicstimuli are diverse, genetic susceptibility is varied, andthe mechanisms that lead to progression are unclear.However, an integrative approach, employing insightsfrom genetic-based studies in mouse and humans, in vivosomatic gene transfer studies, bioinformatics, and computational biology (Chien 2000), is beginning to providenew insights into the disease process and suggesting newtherapeutic targets and strategies for intervening in thedisease. Recent studies are beginning to apply these toolsto clinical studies, representing a major scientific andtranslational opportunity in this post-genome era...