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Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

ABSTRACT: Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture. Here we present the most comprehensive description of differentially expressed genes (DEGs) to date from the pathology of CoA, which were obtained using this model. Aortic samples (n=4/group) from the ascending aorta that experiences elevated blood pressure (BP) from induction of CoA, and restoration of normal BP after its correction, were analyzed by gene expression microarray, and enriched genes were converted to human orthologues. 51 DEGs with >6 fold-change (FC) were used to determine enriched Gene Ontology terms, altered pathways, and association with National Library of Medicine Medical Subject Headers (MeSH) IDs for HTN, cardiovascular disease (CVD) and CoA. The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID's for HTN and CVD, and individual genes were associated with the CoA MeSH ID. A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA.

SUBMITTER: LaDisa JF

PROVIDER: S-EPMC4514739 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

LaDisa John F JF Bozdag Serdar S Olson Jessica J Ramchandran Ramani R Kersten Judy R JR Eddinger Thomas J TJ

PloS one 20150724 7

Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an ...[more]

PMID: 26207811

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Project description:BackgroundIn aortic coarctation, current guidelines recommend reducing pressure gradients that exceed given thresholds. From a physiological standpoint this should ideally improve the energy expenditure of the heart and thus prevent long term organ damage.ObjectivesThe aim was to assess the effects of interventional treatment on external and internal heart power (EHP, IHP) in patients with aortic coarctation and to explore the correlation of these parameters to pressure gradients obtained from heart catheterization.MethodsIn a collective of 52 patients with aortic coarctation 25 patients received stenting and/or balloon angioplasty, and 20 patients underwent MRI before and after an interventional treatment procedure. EHP and IHP were computed based on catheterization and MRI measurements. Along with the power efficiency these were combined in a cardiac energy profile.ResultsBy intervention, the catheter gradient was significantly reduced from 21.8±9.4 to 6.2±6.1mmHg (p<0.001). IHP was significantly reduced after intervention, from 8.03±5.2 to 4.37±2.13W (p < 0.001). EHP was 1.1±0.3 W before and 1.0±0.3W after intervention, p = 0.044. In patients initially presenting with IHP above 5W intervention resulted in a significant reduction in IHP from 10.99±4.74 W to 4.94±2.45W (p<0.001), and a subsequent increase in power efficiency from 14 to 26% (p = 0.005). No significant changes in IHP, EHP or power efficiency were observed in patients initially presenting with IHP < 5W.ConclusionIt was demonstrated that interventional treatment of coarctation resulted in a decrease in IHP. Pressure gradients, as the most widespread clinical parameters in coarctation, did not show any correlation to changes in EHP or IHP. This raises the question of whether they should be the main focus in coarctation interventions. Only patients with high IHP of above 5W showed improvement in IHP and power efficiency after the treatment procedure.Trial registrationclinicaltrials.gov NCT02591940.

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Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

Publications

Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

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