Published online before print February 17, 2005, doi: 10.1161/01.RES.0000159390.03503.c3
© 2005 American Heart Association, Inc.
Clinical Research |
Mixed Messages
Transcription Patterns in Failing and Recovering Human Myocardium
From the Cardiovascular Research Center (K.B.M., S.M., C.C.), Temple University School of Medicine, Philadelphia, Pa; Artesian Therapeutics, Inc (H.O., D.B.), Gaithersburg, Md; and GeneLogic, Inc (W.A.C.), Berkeley, Calif.
Correspondence to Kenneth B. Margulies, MD, Associate Professor of Medicine, Cardiovascular Research Institute, University of Pennsylvania School of Medicine, 422 Curie Bvld, Philadelphia, PA 19104-6160. E-mail kenb{at}mail.med.upenn.edu
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.
Key Words: remodeling • genes • heart failure • recovery • circulatory assistance
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