Abstract
Bicuspid aortic valve (BAV), the most frequent congenital heart malformation, is characterized by the presence of a two-leaflet aortic valve instead of a three-leaflet one. BAV disease progression is associated with valvular dysfunction (in the form of stenosis or regurgitation) and aortopathy, which can lead to aneurysm and aortic dissection. This morphological abnormality modifies valve dynamics and promotes eccentric blood flow, which gives rise to alterations of the flow pattern and wall shear stress (WSS) of the ascending aorta. Recently, evidence of endothelial dysfunction (ED) in BAV disease has emerged. Different studies have addressed a reduced endothelial functionality by analyzing various molecular biomarkers and cellular parameters in BAV patients. Some authors have found impaired functionality of circulating endothelial progenitors in these patients, associating it with valvular dysfunction and aortic dilation. Others focused on systemic endothelial function by measuring artery flow-mediated dilation (FMD), showing a reduced FMD in BAV individuals. Novel biomarkers like increased endothelial microparticles (EMP), which are related to ED, have also been discovered in BAV patients. Finally, latest studies indicate that in BAV, endothelial-to-mesenchymal transition (EndoMT) may also be de-regulated, which could be caused by genetic, hemodynamic alterations, or both. Different hypothesis about the pathology of ED in BAV are nowadays being debated. Some authors blamed this impaired functionality just on genetic abnormalities, which could lead to a pathological aorta. Nevertheless, thanks to the development of new and high-resolution imaging techniques like 4D flow MRI, hemodynamics has gained great attention. Based on latest studies, alterations in blood flow seem to cause proper modification of the endothelial cells (ECs) function and morphology. It also seems to be associated with aortic dilation and decreased vasodilators expression, like nitric oxide (NO). Although nowadays ED in BAV has been reported by many, it is not clear which its main cause may be. Comprehending the pathways that promote ED and its relevance in BAV could help further understand and maybe prevent the serious consequences of this disease. This review will discuss the ED present in BAV, focusing on the latest evidence, biomarkers for ED and potential therapeutic targets (Figure 1).
Highlights
Bicuspid aortic valve (BAV) disease is related to ascending aorta dilation (AD), that becomes very frequent and it appears at a much younger age than patients with a normal tricuspid aortic valve (TAV), which can lead to an increased risk of aneurysm formation and aortic dissection (Michelena et al, 2008, 2011; Tzemos et al, 2008, 2010; Alegret et al, 2013)
Higher levels of asymmetric dimethylarginine (ADMA)-inhibitor of endothelial nitric oxide synthase (eNOS) have been found in some BAV patients Higher concentrations of endothelial microparticles (EMP) has been associated with BAV and, aortic dilation Diverse micro RNAs (miRNAs) patterns have been identified to be related to endothelial dysfunction (ED) in BAV
Evidence of ED in BAV has surfaced in the latest years, showing a direct relation with BAV related aortopathies and worse prognosis of BAV
Summary
BAV DiseaseBicuspid aortic valve (BAV) is the most frequent cardiac congenital malformation, affecting 1–2% of population, with a higher prevalence in men (3:1; Tzemos et al, 2008; Alegret et al, 2013). Latest studies indicate that in BAV, endothelial-to-mesenchymal transition (EndoMT) may be de-regulated, which could be caused by genetic, hemodynamic alterations, or both. Alterations in blood flow seem to cause proper modification of the endothelial cells (ECs) function and morphology.
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