This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 110/22/3444    most recent 01.CIR.0000148178.19465.11v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kittleson, M. M. Articles by Hare, J. M. Search for Related Content PubMed PubMed Citation Articles by Kittleson, M. M. Articles by Hare, J. M. Related Collections Chronic ischemic heart disease Congestive

(Circulation. 2004;110:3444-3451.)
© 2004 American Heart Association, Inc.

Heart Failure

Identification of a Gene Expression Profile That Differentiates Between Ischemic and Nonischemic Cardiomyopathy

Michelle M. Kittleson, MD; Shui Q. Ye, MD, PhD; Rafael A. Irizarry, PhD; Khalid M. Minhas, MD; Gina Edness, RN; John V. Conte, MD; Giovanni Parmigiani, PhD; Leslie W. Miller, MD; Yingjie Chen, MD, PhD; Jennifer L. Hall, PhD; Joe G.N. Garcia, MD; Joshua M. Hare, MD

From Departments of Medicine, Division of Cardiology (M.M.K., K.M.M., G.E., J.M.H.) and Pulmonary and Critical Care Medicine (S.Q.Y., J.G.N.G.), Department of Surgery, Cardiothoracic Division (J.V.C.), Johns Hopkins University School of Medicine and the HOPGENE Applied Genomics in Cardiopulmonary Disease (M.M.K., S.Q.Y., K.M.M., G.E., J.G.N.G., J.M.H.), Baltimore, Md; Department of Biostatistics (R.A.I., G.P.), Johns Hopkins University School of Public Health, Baltimore, Md; and Department of Medicine (L.W.M., Y.C., J.L.H.), University of Minnesota, Minneapolis, Minn.

Correspondence to Joshua M. Hare, MD, Ross 1059, 720 Rutland Ave, Baltimore, MD 21205. E-mail jhare{at}mail.jhmi.edu

Received June 1, 2004; revision received September 15, 2004; accepted September 29, 2004.

Background— Gene expression profiling refines diagnostic and prognostic assessment in oncology but has not yet been applied to myocardial diseases. We hypothesized that gene expression differentiates ischemic and nonischemic cardiomyopathy, demonstrating that gene expression profiling by clinical parameters is feasible in cardiology.

Methods and Results— Affymetrix U133A microarrays of 48 myocardial samples from Johns Hopkins Hospital (JHH) and the University of Minnesota (UM) obtained (1) at transplantation or left ventricular assist device (LVAD) placement (end-stage; n=25), (2) after LVAD support (post-LVAD; n=16), and (3) from newly diagnosed patients (biopsy; n=7) were analyzed with prediction analysis of microarrays. A training set was used to develop the profile and test sets to validate the accuracy of the profile. An etiology prediction profile developed in end-stage JHH samples was tested in independent samples from both JHH and UM with 100% sensitivity and 100% specificity in end-stage samples and 33% sensitivity and 100% specificity in both post-LVAD and biopsy samples. The overall sensitivity was 89% (95% CI 75% to 100%), and specificity was 89% (95% CI 60% to 100%) over 210 random partitions of end-stage samples into training and test sets. Age, gender, and hemodynamic differences did not affect the profile’s accuracy in stratified analyses. Select gene expression was confirmed with quantitative polymerase chain reaction.

Conclusions— Gene expression profiling accurately predicts cardiomyopathy etiology, is generalizable to samples from separate institutions, is specific to disease stage, and is unaffected by differences in clinical characteristics. This strongly supports ongoing efforts to incorporate expression profiling-based biomarkers in determining prognosis and response to therapy in heart failure.

Key Words: heart failure • genetics • cardiomyopathy

This article has been cited by other articles:

				G. W. Dorn II and S. J. Matkovich Put Your Chips on Transcriptomics Circulation, July 15, 2008; 118(3): 216 - 218. [Full Text] [PDF]

				B. Heidecker, E. K. Kasper, I. S. Wittstein, H. C. Champion, E. Breton, S. D. Russell, M. M. Kittleson, K. L. Baughman, and J. M. Hare Transcriptomic Biomarkers for Individual Risk Assessment in New-Onset Heart Failure Circulation, July 15, 2008; 118(3): 238 - 246. [Abstract] [Full Text] [PDF]

				R. Kuner, A. S. Barth, M. Ruschhaupt, A. Buness, L. Zwermann, E. Kreuzer, G. Steinbeck, A. Poustka, H. Sultmann, and M. Nabauer Genomic analysis reveals poor separation of human cardiomyopathies of ischemic and nonischemic etiologies Physiol Genomics, June 10, 2008; 34(1): 88 - 94. [Abstract] [Full Text] [PDF]

				T. A. Bullard, T. L. Protack, F. Aguilar, S. Bagwe, H. T. Massey, and B. C. Blaxall Identification of Nogo as a novel indicator of heart failure Physiol Genomics, January 17, 2008; 32(2): 182 - 189. [Abstract] [Full Text] [PDF]

				T. P. Cappola Molecular Remodeling in Human Heart Failure J. Am. Coll. Cardiol., January 15, 2008; 51(2): 137 - 138. [Full Text] [PDF]

				S. Ikeda, S. W. Kong, J. Lu, E. Bisping, H. Zhang, P. D. Allen, T. R. Golub, B. Pieske, and W. T. Pu Altered microRNA expression in human heart disease Physiol Genomics, November 14, 2007; 31(3): 367 - 373. [Abstract] [Full Text] [PDF]

				G. Kitsios and E. Zintzaras Genetic Variation associated with Ischemic Heart Failure: A HuGE Review and Meta-Analysis Am. J. Epidemiol., September 15, 2007; 166(6): 619 - 633. [Abstract] [Full Text] [PDF]

				H. Ashrafian and H. Watkins Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications: Cardiomyopathies: Therapeutics Based on Molecular Phenotype J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1251 - 1264. [Abstract] [Full Text] [PDF]

				G. S. Ginsburg, D. Seo, and C. Frazier Microarrays Coming of Age in Cardiovascular Medicine: Standards, Predictions, and Biology J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1618 - 1620. [Full Text] [PDF]

				M. P. Donahue, D. A. Marchuk, and H. A. Rockman Redefining Heart Failure: The Utility of Genomics J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1289 - 1298. [Abstract] [Full Text] [PDF]

				D. Seo, G. S. Ginsburg, and P. J. Goldschmidt-Clermont Gene Expression Analysis of Cardiovascular Diseases: Novel Insights Into Biology and Clinical Applications J. Am. Coll. Cardiol., July 18, 2006; 48(2): 227 - 235. [Abstract] [Full Text] [PDF]

				A. S. Barth and J. M. Hare The Potential for the Transcriptome to Serve as a Clinical Biomarker for Cardiovascular Diseases Circ. Res., June 23, 2006; 98(12): 1459 - 1461. [Full Text] [PDF]

				W.H. W. Tang and G. S. Francis The Year in Heart Failure J. Am. Coll. Cardiol., December 6, 2005; 46(11): 2125 - 2133. [Full Text] [PDF]

				M. M. Kittleson, K. M. Minhas, R. A. Irizarry, S. Q. Ye, G. Edness, E. Breton, J. V. Conte, G. Tomaselli, J. G. N. Garcia, and J. M. Hare Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure Physiol Genomics, May 11, 2005; 21(3): 299 - 307. [Abstract] [Full Text] [PDF]