Bicuspid Aortic Valve and Endothelial Dysfunction: Current Evidence and Potential Therapeutic Targets

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).

Prevalence of Bicuspid Aortic Valve in Turner Syndrome Patients Receiving Cardiac MRI and CT: A Meta-Analysis

“…This meta-analysis suggests that BAV is the most common CHD affecting approximately one out of four TS females. Changes in ascending aortic blood flow characteristics due to valve malformations (e.g., BAV) are widely considered to be one of the causes of aortic dilation and aortic dissection [27]. Compared to healthy controls, Hope et al [28] were able to demonstrate that helical flow patterns which lead to increased wall stress can be observed during ascending aortic systole in patients with BAV.…”

NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease

“…These observations support that BAV-asociated CAVD has a developmental origin, and its postnatal stenotic progression by calcification is triggered by external stimuli as a second hit after the primary structural defect in utero ( 9 ). In support of this view of the pathogenesis of CAVD, the developmental defect of the aortic valve can cause abnormal flow dynamics and thereby predispose the valve to endothelial dysfunction and inflammatory activation, leading to earlier calcification in adulthood ( 9 , 15 – 18 ). Therefore, better understanding of molecular mechanisms regulating aortic valve development, as well as postnatal aortic valve homeostasis, is required for the development of new therapeutic strategies for CAVD.…”

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

“…Another important factor related to BAV aortopathy is nitric oxide (NO). The NO secreted by vascular endothelial cells promotes the dilation of blood vessels, and changes in its signaling or bioavailability can alter vascular homeostasis and thus, become an important modulator of the development of cardiovascular diseases such as aortic aneurysm [ 80 ]. According to this, the relationship between NO signaling and BAV aortopathy has been described.…”