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Background Mechanical support using a left ventricular assist device (LVAD) can lead to functional recovery of the myocardium in patients with end-stage heart failure (HF). Molecular remodeling, cytoskeletal disruption, and apoptosis activation are associated with abnormal gene expression in the failing ventricular myocardium of HF subjects and can normalize in response to medium- and long-term mechanical unloading in adults. However, there is little knowledge of the changes in gene expression after short-term mechanical support in children with HF. Methods We evaluated left ventricular biopsies from 4 children with HF. The children had implantation of a continuous- or a pulsatile-flow LVAD for 8 to 16 days before undergoing heart transplantation. At the time of LVAD insertion and removal, we performed quantitative real-time polymerase chain reaction (QPCR) to study the expression of 326 genes encoding for structural, transcriptional, and signaling pathways proteins, and immunoblot analysis on dystrophin and apoptotic factors. Results Short-term LVAD therapy significantly decreased brain natriuretic peptide (BNP) levels from pre-LVAD (3,584.5 ± 378.3 pg/ml [95% CI]) to post-LVAD (447.5 ± 52.7 pg/ml [95% CI]) in 2 patients in whom comparative BNP measurements were available. In addition, short-term LVAD therapy reduced HF and apoptosis markers, whereas it upregulated structural proteins, including dystrophin, as well as pro-hypertrophic and pro-inotropic markers. Furthermore, LVAD therapy normalized expression of genes involved in calcium homeostasis, cell growth, and differentiation. Conclusions Our pilot study suggests that even short-term LVAD therapy in children with severe HF can reverse molecular remodeling. This favorable effect should be taken into consideration in eligible children with significant ventricular dysfunction.