Abstract
ObjectivesTo investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling.BackgroundInformation is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices.MethodsWe measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3–12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient “Super-Responder” (S-R) subset of A-S).ResultsFor 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a β1-adrenergic receptor gene network including enhanced Ca2+ signaling.ConclusionsTwo-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information.
Highlights
Heart failure is a consequence of structural and functional impairments of ventricular myocardium that reduce the ability of the heart to adequately supply blood to the body [1]
Two-platform concordant change in candidate gene expression is associated with left ventricular (LV) biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information
The current method of classifying heart failure is by whether left ventricular ejection fraction (LVEF) is reduced (“HFrEF”) or relatively preserved (“HFpEF), which generally subdivides heart failure into respective categories that respond to multiple types of drug or device therapies vs. those that do not [2]
Summary
Heart failure is a consequence of structural and functional impairments of ventricular myocardium that reduce the ability of the heart to adequately supply blood to the body [1]. In HFrEF we have attempted to identify abnormal gene expression profiles at the mRNA [6,7,8] or miRNA [9] level by producing therapeutic interventional reversal of the structural and functional abnormalities in HFrEF ventricles, and identifying ventricular septal endomyocardial biopsy gene expression changes associated with dynamic left ventricular reverse remodeling. Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices
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