Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

Abstract

Bicuspid aortic valve (BAV) associated with aortopathy is the most common congenital heart disease in the general population. Far from being a simple harmless valve malformation, it can be a complex and heterogeneous disease and a source of chronic and acute pathology (early valvular disease, aneurysm, dissection). In the previous years, intense research has been carried out to find out and understand its mechanisms, but the pathophysiology of the disease is still not fully understood and many questions remain open. Recent studies have discovered several genetic mutations involved in the development of valvular and aortic malformations, but still cannot explain more than 5–10% of cases. Other studies have also focused on molecular alterations and cellular processes (TGF-β pathway, microRNAs, degradation of the extracellular matrix, metalloproteinases, etc.), being a field in constant search and development, looking for a therapeutic target to prevent the development of the disease. Increased knowledge about this multifaceted disorder, derived from both basic and clinical research, may influence the diagnosis, follow-up, prognosis, and therapies of affected patients in the near future. This review focuses on the latest and outstanding developments on the molecular and genetic investigations of the bicuspid aortopathy.

Hyperechoic mass of the right ventricle in adults: A rare presentation of an intracardiac teratoma

“…BAV is considered an autosomal dominant disorder with a low penetrance and variable expressivity for which NOTCH1 is the main associated gene. In addition, members of the GATA family of the zinc finger superfamily of transcriptions factors are also related to BAV 7 . Patients with mature teratomas often test negative for an increase in the short arm of chromosome 12, a major genetic aberration in germ cell tumors associated with malignant potential.…”

Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

“…In addition to eNOS uncoupling, several more pathways, such as mechanical stress [ 34 , 37 ], transforming growth factor beta 1 (TGF-β1) stimulation [ 36 ], and S-glutathionylation protein are involved in NO impaired production [ 59 ]. BAV aortopathy studies on OS reiterate the role of NO in endothelial homeostasis [ 60 , 61 , 62 ].…”

“…Under hypercholesterolemia and oxidative stress, endothelial valvular cells secrete Wnt3 that binds to receptors LRP5 and Frizzled on the VIC surface [ 34 , 58 , 82 ], further inducing the RUNX2 expression via the Wnt pathway [ 7 ]. The Notch signaling pathway, consisting of four receptors (Notch1/2/3/4), ligands, Jagged-1/2, and delta-like proteins (DLL1/3/4), is a physiological neutralizer of the Wnt pathway, upholding indirect regulatory effects on RUNX2 [ 20 ], being in close conjunction with NF-κB and TLR4 activation in calcific areas of aortic leaflets [ 60 , 82 ].…”

Novel Targets for Old and Diseased Hearts

“…Finally, the review by Junco-Vincente and co-workers provides an update on the latest developments on the genetic and molecular determinants involved in the pathogenesis of bicuspid aortic valve (BAV) and its associated aortopathy [ 3 ]. At present, there are no validated biomarkers to be used in the management of patients affected by bicuspid aortopathy, while they would be extremely relevant to decide about the optimal timing for surgical replacement, monitor disease progression and assess patient’s risk profile and prognosis.…”

“…While the disease is currently diagnosed at a later stage, when the aortic structure is already compromised, early diagnosis could allow implementing targeted therapies and prevent disease progression. The review offers some perspective on some molecular targets that could be exploited therapeutically to prevent disease progression, including Neurogenic locus notch homolog protein 1 (NOTCH1) and Protein kinase B (AKT) signaling pathways [ 3 ]. Yet, to what extent these interventions could lead to a real improvement in the management of these patients remains to be established.…”