Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling
Veli K. Topkara, Kari T. Chambers, Kai-Chien Yang, Huei-Ping Tzeng, Sarah Evans, Carla Weinheimer, Attila Kovacs, Jeffrey Robbins, Philip Barger, Douglas L. Mann
Veli K. Topkara, Kari T. Chambers, Kai-Chien Yang, Huei-Ping Tzeng, Sarah Evans, Carla Weinheimer, Attila Kovacs, Jeffrey Robbins, Philip Barger, Douglas L. Mann
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Research Article Cardiology

Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling

Abstract

To elucidate the mechanisms for reverse LV remodeling, we generated a conditional (doxycycline [dox] off) transgenic mouse tetracycline transactivating factor–TRAF2 (tTA-TRAF2) that develops a dilated heart failure (HF) phenotype upon expression of a proinflammatory transgene, TNF receptor–associated factor 2 (TRAF2), and complete normalization of LV structure and function when the transgene is suppressed. tTA-TRAF2 mice developed a significant increase in LV dimension with decreased contractile function, which was completely normalized in the tTA-TRAF2 mice fed dox for 4 weeks (tTA-TRAF2dox4W). Normalization of LV structure and function was accompanied by partial normalization (~60%) of gene expression associated with incident HF. Similar findings were observed in patients with dilated cardiomyopathy who underwent reverse LV remodeling following mechanical circulatory support. Persistence of the HF gene program was associated with an exaggerated hypertrophic response and increased mortality in tTA-TRAF2dox4W mice following transaortic constriction (TAC). These effects were no longer observed following TAC in tTA-TRAF2dox8W, wherein there was a more complete (88%) reversal of the incident HF genes. These results demonstrate that reverse LV remodeling is associated with improvements in cardiac myocyte biology; however, the persistence of the abnormal HF gene program may be maladaptive following perturbations in hemodynamic loading conditions.

Authors

Veli K. Topkara, Kari T. Chambers, Kai-Chien Yang, Huei-Ping Tzeng, Sarah Evans, Carla Weinheimer, Attila Kovacs, Jeffrey Robbins, Philip Barger, Douglas L. Mann

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Figure 9

Transcriptional profiling in nonfailing (NF) human hearts (n = 8) and paired failing human dilated cardiomyopathy (DCM) hearts (n = 8 pairs) before and after LVAD.

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Transcriptional profiling in nonfailing (NF) human hearts (n = 8) and pa...
(A) Venn diagram of normalized heart failure (HF) genes, persistently dysregulated HF genes, and new reverse remodeled genes (see text for details). (B) Unsupervised hierarchical clustering of changes in gene expression, and (C) principal component analysis (PCA) of changes in gene expression.(D) Number of persistently dysregulated and reversed HF cardiac myocyte genes. (E) Illustration of persistently dysregulated and reversed HF genes in gene modules relating to cardiac myocyte function (see text for details). The number of genes within each module is given in parenthesis. Red indicates increased gene expression; blue indicates decreased gene expression relative to LM; Rev, reversed HF genes; PD, persistently dysregulated HF genes. Analysis performed using Partek Genomics Suite. (F) Percentage of persistently dysregulated and reversed HF genes in functional cardiac myocyte gene modules after LVAD support. PC, principal component; PD, persistently dysregulated; Rev, reversed.