Dataset Information

Aortic Stenosis: Changing Disease Concepts.

ABSTRACT: Aortic stenosis (AS) occurs in almost 10% of adults over age 80 years with a mortality about 50% at 2 years unless outflow obstruction is relieved by aortic valve replacement (AVR). Development of AS is associated with anatomic, clinical and genetic risk factors including a bicuspid valve in 50%; clinical factors that include older age, hypertension, smoking, diabetes and elevated serum lipoprotein(a) [Lp(a)] levels; and genetic factors such as a polymorphism in the Lp(a) locus. Early stages of AS are characterized by focal areas of leaflet thickening and calcification. The rate of hemodynamic progression is variable but eventual severe AS is inevitable once even mild valve obstruction is present. There is no specific medical therapy to prevent leaflet calcification. Basic principles of medical therapy for asymptomatic AS are patient education, periodic echocardiographic and clinical monitoring, standard cardiac risk factor evaluation and modification and treatment of hypertension or other comorbid conditions. When severe AS is present, a careful evaluation for symptoms is needed, often with an exercise test to document symptom status and cardiac reserve. In symptomatic patients with severe AS, AVR improves survival and relieves symptoms. In asymptomatic patients with severe AS, AVR also is appropriate if ejection fraction is < 50%, disease progression is rapid or AS is very severe (aortic velocity > 5 m/s). The choice of surgical or transcatheter AVR depends on the estimated surgical risk plus other factors such as frailty, other organ system disease and procedural specific impediments.

SUBMITTER: Rashedi N

PROVIDER: S-EPMC4486179 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Aortic Stenosis: Changing Disease Concepts.

Rashedi Nina N Otto Catherine M CM

Journal of cardiovascular ultrasound 20150626 2

Aortic stenosis (AS) occurs in almost 10% of adults over age 80 years with a mortality about 50% at 2 years unless outflow obstruction is relieved by aortic valve replacement (AVR). Development of AS is associated with anatomic, clinical and genetic risk factors including a bicuspid valve in 50%; clinical factors that include older age, hypertension, smoking, diabetes and elevated serum lipoprotein(a) [Lp(a)] levels; and genetic factors such as a polymorphism in the Lp(a) locus. Early stages of ...[more]

PMID: 26140146

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Project description:BackgroundBicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities.MethodsWe performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography.ResultsGenome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models.ConclusionsThese data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.

Dataset Information

Aortic Stenosis: Changing Disease Concepts.

Publications

Aortic Stenosis: Changing Disease Concepts.

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