Dataset Information

GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

ABSTRACT: BACKGROUND:Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined. METHODS:Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells. RESULTS:Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice. CONCLUSIONS:The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.

SUBMITTER: Gharibeh L

PROVIDER: S-EPMC6151169 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

Gharibeh Lara L Komati Hiba H Bossé Yohan Y Boodhwani Munir M Heydarpour Mahyar M Fortier Megan M Hassanzadeh Romina R Ngu Janet J Mathieu Patrick P Body Simon S Nemer Mona M

Circulation 20180901 10

<h4>Background</h4>Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined.<h4>Methods</h4>Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium ...[more]

PMID: 29567669

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Project description:The immediate effect of aortic valve replacement (AVR) for aortic stenosis on perioperative myocardial function is unclear. Left ventricular (LV) function may be impaired by cardioplegia-induced myocardial arrest and ischemia-reperfusion injury, especially in patients with LV hypertrophy. Alternatively, LV function may improve when afterload is reduced after AVR. The right ventricle (RV), however, experiences cardioplegic arrest without benefiting from improved loading conditions. Which of these effects on myocardial function dominate in patients undergoing AVR for aortic stenosis has not been thoroughly explored. Our primary objective is thus to characterize the effect of intraoperative events on LV function during AVR using echocardiographic measures of myocardial deformation. Second, we evaluated RV function.In this supplementary analysis of 100 patients enrolled in a clinical trial (NCT01187329), 97 patients underwent AVR for aortic stenosis. Of these patients, 95 had a standardized intraoperative transesophageal echocardiographic examination of systolic and diastolic function performed before surgical incision and repeated after chest closure. Echocardiographic images were analyzed off-line for global longitudinal myocardial strain and strain rate using 2D speckle-tracking echocardiography. Myocardial deformation assessed at the beginning of surgery was compared with the end of surgery using paired t tests corrected for multiple comparisons.LV volumes and arterial blood pressure decreased, and heart rate increased at the end of surgery. Echocardiographic images were acceptable for analysis in 72 patients for LV strain, 67 for LV strain rate, and 54 for RV strain and strain rate. In 72 patients with LV strain images, 9 patients required epinephrine, 22 required norepinephrine, and 2 required both at the end of surgery. LV strain did not change at the end of surgery compared with the beginning of surgery (difference: 0.7 [97.6% confidence interval, -0.2 to 1.5]%; P = 0.07), whereas LV systolic strain rate improved (became more negative) (-0.3 [-0.4 to -0.2] s; P < 0.001). In contrast, RV systolic strain worsened (became less negative) at the end of surgery (difference: 4.6 [3.1 to 6.0]%; P < 0.001) although RV systolic strain rate was unchanged (0.0 [97.6% confidence interval, -0.1 to 0.1]; P = 0.83).LV function improved after replacement of a stenotic aortic valve demonstrated by improved longitudinal strain rate. In contrast, RV function, assessed by longitudinal strain, was reduced.

Dataset Information

GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

Publications

GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

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