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1 Department of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA
* To whom correspondence should be addressed. E-mail: bache001{at}tc.umn.edu.
Chronic unloading of the failing heart with a left ventricular assist device (LVAD) can decrease cardiac mass and myocyte size and has the potential to improve contractile function. To study the effect of chronic ventricular unloading on myocardial gene expression, a microarray (U133A, Affymetrix) profiling gene expression was compared before and after LVAD support in 7 patients with idiopathic dilated cardiomyopathy and end-stage heart failure. On average, 1374±155 genes were reported as "increased" and 1629±45 as "decreased" after LVAD support. A total of 130 gene transcripts achieved the strict criteria for up-regulation and 49 gene transcripts for down-regulation after LVAD support. Up-regulated genes included a large proportion of transcription factors, genes related to cell growth/apoptosis/DNA repair, cell structure proteins, metabolism, and cell signaling/communication. LVAD support resulted in down-regulation of genes for a group of cytokines. To validate the array data, ten altered genes were confirmed by real-time RT-PCR. Further study showed that the phosphoinositide-3-kinase-forkhead protein pathway and proteins related to nitric oxide synthesis, including eNOS and dimethylarginine dimethylaminohydrolase isoform-1 (DDAH1, an enzyme regulating endogenous nitric oxide synthase activity), were significantly increased during the cardiac remodeling process. Increased eNOS and DDAH1 expression after LVAD support may contribute to improved endothelial function of the failing hearts.
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