Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy

Hall, Jennifer L.; Birks, Emma J.; Grindle, Suzanne; Cullen, Martin E.; Barton, Paul J.R.; Rider, James E.; Lee, Sang-Jin; Harwalker, Subash; Mariash, Ami; Adhikari, Neeta; Charles, Nathan J.; Felkin, Leanne E.; Polster, Sean P.; George, Robert S.; Miller, Leslie W.; Yacoub, Magdi H.

doi:10.1093/eurheartj/ehl365

Cited by 107 publications

(83 citation statements)

References 33 publications

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“…Recently, Hall et al 69 performed a microarray analysis of 6 paired human heart samples before and after a novel combination therapy of LVAD and a selective β2 agonist, clenbuterol. They found a significant association between recovery and the integrin signaling pathway, and identified several novel targets that included EPAC2, a guanine nucleotide exchange factor that binds to cAMP.…”

Section: Changes In the Gene Expression In The Failing Myocardium Aftmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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Heart failure (HF) is a syndrome that involves multiple cellular mechanisms leading to a common phenotype of reduced ventricular contraction and cardiac chamber dilation. To clarify the mechanisms, a number of microarray analyses of the failing myocardium have been conducted. Gene expression profiles are usually compared between opposing pairs of samples, such as non-failing vs failing hearts, ischemic vs non-ischemic hearts, male vs female failing hearts or atria vs ventricles of failing hearts. Apart from these conventional methods, a different novel approach identified cardiac myosin light chain kinase (MLCK) as a HF-related gene by the comprehensive search for the genes that had an expression level that strongly correlated with the severity of HF; further investigations proved the important role of cardiac MLCK in HF. Moreover, a robust gene expression signature composed of 27 genes was revealed on analysis of 4 independent microarray data sets from the failing myocardium of dilated cardiomyopathy. The authors newly demonstrate 107 HF-related genes that were listed in 2 or more of 7 microarray data sets previously reported. Among these genes, many were observed to be involved in mitochondrial dysfunction and oxidative phosphorylation and 3 extracellular molecules, including periostin, pleiotrophin, and SERPINA3, which might become novel diagnostic and therapeutic targets for HF. These novel strategies warrant the new identification of specific genes that are linked to the pathophysiology of HF. (Circ J 2009; 73: 1568 -1576

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Section: Changes In the Gene Expression In The Failing Myocardium Aftmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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“…2, 3 The molecular and biochemical mechanisms potentially implicated in reverse remodeling after LVAD implant remain still incompletely understood. [4][5][6] Since an abnormal increase in metalloproteinases (MMP) activity and reduced expression of tissue inhibitors of MMP (TIMP) appear to be involved in the progression to overt HF, 7,8 the normalization of MMP/TIMP balance following LVAD implantation is considered one of the putative mechanisms of myocardial functional recovery. 4 Several studies have suggested that oxidative stress acts on MMP metabolism favoring progression of cardiac remodeling, 9, 10 by direct activation of the latent form of MMP, by CARUSO R et al…”

mentioning

confidence: 99%

Relationship Between Myocardial Redox State and Matrix Metalloproteinase Activity in Patients on Left Ventricular Assist Device Support

Caruso

Caselli

Boroni

et al. 2011

Circ J

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Background: Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). Methods and Results:During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-β1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-β1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities.Conclusions: LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD. (Circ J 2011; 75: 2387 - 2396

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“…47 This process has provided a unique opportunity to access myocardial tissue for gene expression analysis before and after reverse remodeling to identify mechanisms that are associated with improvement in left ventricular function with mechanical unloading. The reverse remodeling process appears to be associated with genes in the integrin pathway, 48 arginine metabolism, 49 and Wnt signaling, 50 whereas failure to recover function was associated with profibrotic genes such as TGFB1. 51 For patients with end-stage heart failure for whom left ventricular assist device support is not indicated or required, cardiac transplantation is sometimes an option.…”

Section: Musunuru Et Al Expressed Genome In Cardiovascular Diseases Amentioning

confidence: 99%

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

Musunuru¹,

Ingelsson²,

Fornage³

et al. 2017

Circ Cardiovasc Genet

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Abstract-There have been major advances in our knowledge of the contribution of DNA sequence variations to cardiovascular disease and stroke. However, the inner workings of the body reflect the complex interplay of factors beyond the DNA sequence, including epigenetic modifications, RNA transcripts, proteins, and metabolites, which together can be considered the "expressed genome." The emergence of high-throughput technologies, including epigenomics, transcriptomics, proteomics, and metabolomics, is now making it possible to address the contributions of the expressed genome to cardiovascular disorders. This statement describes how the expressed genome can currently and, in the future, potentially be used to diagnose diseases and to predict who will develop diseases such as coronary artery disease, stroke, heart failure, and arrhythmias. (Circ Cardiovasc Genet. 2017;10:e000037. DOI: 10.1161/HCG.0000000000000037.)Key Words: AHA Scientific Statements ◼ cardiovascular diseases ◼ DNA ◼ epigenomics ◼ genome ◼ metabolomics ◼ proteomics ◼ strokeThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on March 13, 2017, and the American Heart Association Executive Committee on April 17, 2017. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The American Heart Association requests that this document be cited as follows: Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the "Copyright Permissions Request Form" appears on the right side of the page. I n no small part as a result of the completion of the Human Genome Project, considerable effort has been invested over the past few decades in understanding the contribution of genetics to the risk of cardiovascular diseases and stroke. Genomewide association studies, candidate gene sequencing studies, a...

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Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy

Abstract: This data set represents the first description of signalling pathways associated with the functional recovery of end-stage human heart failure and the identification of new targets in the human heart that are modified by this combination therapy.

Cited by 107 publications

References 33 publications

Global Gene Expression Profiling in the Failing Myocardium

Global Gene Expression Profiling in the Failing Myocardium

Relationship Between Myocardial Redox State and Matrix Metalloproteinase Activity in Patients on Left Ventricular Assist Device Support

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

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