title: Mixed messages: transcription patterns in failing and recovering human myocardium.
abstract: In previous studies, mechanical support of medically refractory hearts with a left ventricular assist device (LVAD) has induced regression of many morphological and functional abnormalities characteristic of failing human hearts. To identify transcriptional adaptations in failing and LVAD-supported hearts, we performed a comprehensive transcription analysis using the Affymetrix microarray platform and 199 human myocardial samples from nonfailing, failing, and LVAD-supported human hearts. We also used a novel analytical strategy that defines patterns of interest based on multiple intergroup comparisons. Although over 3088 transcripts exhibited significantly altered abundance in heart failure, most of these did not exhibit a consistent response to LVAD support based on our analysis. Of those 238 with a consistent response to LVAD support, more than 75% exhibited persistence or exacerbation of HF-associated transcriptional abnormalities whereas only 11%, 5%, and 2% exhibited partial recovery, normalization, and overcorrection responses, respectively. Even among genes implicated by previous reports of LVAD-associated myocardial improvements, partial or complete normalization of transcription did not predominate. The magnitude of differences in transcript abundance between nonfailing and failing hearts, and between failing an LVAD-supported hearts, tended to be low with changes greater than or equal to 2-fold infrequently observed. Our results indicate that morphological or functional myocardial improvements may occur without widespread normalization of pathological transcriptional patterns. These observations also suggest that many failure-associated transcriptional changes have only a limited role in regulating cardiac structure and function and may represent epiphenomena and/or nonspecific myocardial plasticity responses. Differences in mRNA localization, translation efficiency, and posttranslational protein modifications or interactions may be more pivotal in regulating myocardial structure and function.
authors.affiliation: Cardiovascular Research Center, Cardiovascular Research Institute, University of Pennsylvania School of Medicine, Temple University School of Medicine, Philadelphia, Pa 19104-6160, USA. kenb@mail.med.upenn.edu
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Sunil
authors.initials: S
authors.lastname: Matiwala
authors.forename: Carla
authors.initials: C
authors.lastname: Cornejo
authors.forename: Henrik
authors.initials: H
authors.lastname: Olsen
authors.forename: William A
authors.initials: WA
authors.lastname: Craven
authors.forename: Daniel
authors.initials: D
authors.lastname: Bednarik
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D003289:Convalescence; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery / Q000628:therapy; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000628:therapy
chemical_list: D012333:RNA, Messenger; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases