Many hearts in end-stage, chronic failure (CHF) retain the capacity to reverse abnormal expression of genes regulating myocyte calcium cycling when supported with a left ventricular assist device (LVAD). In the present study, we determined whether LVAD-induced upregulation of the gene encoding for the key calcium cycling protein sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a (SERCA2a) is influenced by the nature of underlying disease broadly characterized as ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. Data from Northern blot analysis of SERCA2a messenger (m)RNA within 84 heart samples (50 CHF [23 DCM and 27 ICM] and 34 CHF+LVAD [18 DCM and 16 ICM]) were used for characterizing gene expression. In addition, measurements of the force-frequency relationship (FFR), a reflection of in vivo SERCA2a function, were obtained in myocardial trabeculae isolated from 75 hearts (51 CHF [29 DCM and 22 ICM] and 24 CHF+LVAD [10 DCM and 14 ICM]). SERCA2a mRNA demonstrated upregulation after LVAD that was not influenced by ICM or DCM. However, only in DCM hearts was the proportion of trabeculae exhibiting a normal FFR increased after LVAD. Thus, although upregulated SERCA2a gene expression after LVAD support is independent of myopathic origin, normalization of myocardial FFR, an index of SERCA2a function, is not. These data provide new insight into the process of cardiac "reverse molecular remodeling," and underscore potential differences in the impact of disease processes on posttranscriptional events.