Dataset Information

Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress.

ABSTRACT: Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5). Local wall shear stress (WSS) and oscillatory shear indices (OSI) were calculated in three distinct regions of the LV - base, mid-ventricle (midV), and apex. In both the humans and pigs, WSS values were significantly lower in the apex and midV relative to the base. Additionally, both the apex and midV had greater oscillatory shear indices (OSI) than the base. To investigate regional phenotype, endocardial endothelial cells (EEC) were isolated from an additional 8 pigs and RNA sequencing was performed. A false discovery rate of 0.10 identified 1051 differentially expressed genes between the base and apex, and 321 between base and midV. Pathway analyses revealed apical upregulation of genes associated with translation initiation. Furthermore, tissue factor pathway inhibitor (TFPI; mean 50-fold) and prostacyclin synthase (PTGIS; 5-fold), genes prominently associated with antithrombotic protection, were consistently upregulated in LV apex. These spatio-temporal WSS values in defined regions of the left ventricle link local hemodynamics to regional heterogeneity in endocardial gene expression.

SUBMITTER: McCormick ME

PROVIDER: S-EPMC5513694 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress.

McCormick Margaret E ME Manduchi Elisabetta E Witschey Walter R T WRT Gorman Robert C RC Gorman Joseph H JH Jiang Yi-Zhou YZ Stoeckert Christian J CJ Barker Alex J AJ Yoon Samuel S Markl Michael M Davies Peter F PF

Journal of biomechanics 20161116

Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional ...[more]

PMID: 27916240

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Project description:BackgroundUnlike arteries, in which regionally distinct hemodynamics are associated with phenotypic heterogeneity, the relationships between endocardial endothelial cell phenotype and intraventricular flow remain largely unexplored. We investigated regional differences in left ventricular wall shear stress and their association with endocardial endothelial cell gene expression.Methods and resultsLocal wall shear stress was calculated from 4-dimensional flow magnetic resonance imaging in 3 distinct regions of human (n=8) and pig (n=5) left ventricle: base, adjacent to the outflow tract; midventricle; and apex. In both species, wall shear stress values were significantly lower in the apex and midventricle relative to the base; oscillatory shear index was elevated in the apex. RNA sequencing of the endocardial endothelial cell transcriptome in pig left ventricle (n=8) at a false discovery rate ≤10% identified 1051 genes differentially expressed between the base and the apex and 327 between the base and the midventricle; no differentially expressed genes were detected at this false discovery rate between the apex and the midventricle. Enrichment analyses identified apical upregulation of genes associated with translation initiation including mammalian target of rapamycin, and eukaryotic initiation factor 2 signaling. Genes of mitochondrial dysfunction and oxidative phosphorylation were also consistently upregulated in the left ventricular apex, as were tissue factor pathway inhibitor (mean 50-fold) and prostacyclin synthase (5-fold)-genes prominently associated with antithrombotic protection.ConclusionsWe report the first spatiotemporal measurements of wall shear stress within the left ventricle and linked regional hemodynamics to heterogeneity in ventricular endothelial gene expression, most notably to translation initiation and anticoagulation properties in the left ventricular apex, in which oscillatory shear index is increased and wall shear stress is decreased.

Project description:The bicuspid aortic valve (BAV) generates wall shear stress (WSS) abnormalities in the ascending aorta (AA) that may be responsible for the high prevalence of aortopathy in BAV patients. While previous studies have analyzed the magnitude and oscillatory characteristics of the total or streamwise WSS in BAV AAs, the assessment of the circumferential component is lacking despite its expected significance in this highly helical flow environment. This gap may have hampered the identification of a robust hemodynamic predictor of BAV aortopathy. The objective of this study was to perform a global and component-specific assessment of WSS magnitude, oscillatory and directional characteristics in BAV AAs. The WSS environments were computed in the proximal and middle convexity of tricuspid aortic valve (TAV) and BAV AAs using our previous valve-aorta fluid-structure interaction (FSI) models. Component-specific WSS characteristics were investigated in terms of temporal shear magnitude (TSM) and oscillatory shear index (OSI). WSS directionality was quantified in terms of mean WSS vector magnitude and angle, and angular dispersion index (Dα). Local WSS magnitude and multidirectionality were captured in a new shear magnitude and directionality index (SMDI) calculated as the product of the mean WSS magnitude and Dα. BAVs subjected the AA to circumferential TSM overloads (2.4-fold increase vs. TAV). TAV and BAV AAs exhibited a unidirectional circumferential WSS (OSI < 0.04) and an increasingly unidirectional longitudinal WSS between the proximal (OSI > 0.21) and middle (OSI < 0.07) sections. BAVs generated mean WSS vectors skewed toward the anterior wall and WSS angular distributions exhibiting decreased uniformity in the proximal AA (0.27-point increase in Dα vs. TAV). SMDI was elevated in all BAV AAs but peaked in the proximal LR-BAV AA (3.6-fold increase vs. TAV) and in the middle RN-BAV AA (1.6-fold increase vs. TAV). This analysis demonstrates the significance of the circumferential WSS component and the existence of substantial WSS directional abnormalities in BAV AAs. SMDI abnormality distributions in BAV AAs follow the morphotype-dependent occurrence of dilation in BAV AAs, suggesting the predictive potential of this metric for BAV aortopathy.

Dataset Information

Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress.

Publications

Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress.

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