LETTERS TO THE EDITOR caution, noting that defects in calcium cycling might not represent a universal pathway for dilated cardiomyopathy. Their results clearly indicate that phospholamban gene ablation cannot rescue the dilated cardiomyopathy that accompanies tropomodulin over-expression, using several independent endpoints, including survival. The validity of their over-expressing tropomodulin mouse to human disease, however, is also an issue. Although one could argue that the MLP deficiency model reflects a subset of human disease that arises due to cytoskeletal mutations, the clinical relevance of the tropomodulin over-expression heart failure model to naturally occurring forms of human cardiomyopathy seems more tenuous. Most likely, the massive over-expression of tropomodulin produces cardiac injury and disruption of the stoichiometry that is required for normal sarcomeric assembly. Dilated cardiomyopathy results as a secondary effect, which, of course, would not be reflected in genetic or acquired human disease. Over 30 models of dilated cardiomyopathy have been reported through the cardiac over-expression of reporters (GFP)(ref. 10), signaling molecules, and channels to the amounts of alpha myosin heavy chain, raising the serious issue of the validity of any of these models to human disease11. Independent evidence has now confirmed and extended the results in the MLP model, documenting a critical role of calcium cycling defects in acquired forms of heart failure due to chronic pressure overload in normal animals12. Thus, calcium cycling defects may underlie some clinically relevant acquired forms of heart failure. Further work will be required to determine whether phospholamban inhibition will be beneficial after myocardial infarction, the most frequent etiology of human heart failure.