Bicuspid Aortic Valve and Associated Aortopathy: An Update

doi:10.1053/j.semtcvs.2014.01.004

Seminars in Thoracic and Cardiovascular Surgery

Volume 25, Issue 4, Winter 2013, Pages 310-316

https://doi.org/10.1053/j.semtcvs.2014.01.004 Get rights and content

Bicuspid aortic valve (BAV) is the most common form of congenital heart disease and most such patients develop cardiovascular complications over time. Recent studies have shed light on one of the most common of these complications, BAV-associated aortopathy. Two distinct BAV phenotypes have been identified, which may have different causes of their associated aortopathy. Increasing evidence suggests that the BAV stenosis phenotype is predominantly secondary to hemodynamic perturbances in transvalvular flow and is associated with a more benign long-term prognosis once the stenotic BAV is replaced. In contrast, the root phenotype—which is associated with aortic insufficiency—appears to have a genetic origin and may be associated with a higher risk of adverse aortic complications, irrespective of the extent of valvular disease. Such observations may have implications for patient decision making. Future studies should be performed so as to better define phenotypes and risk factors for BAV-associated aortopathy.

Section snippets

Epidemiology and Natural History of Bicuspid Aortic Valve

Bicuspid aortic valve (BAV) disease is known to be the most common congenital anomaly of the human heart.1, 2 Taking into account all complications associated with BAV disease, it accounts for more morbidity and mortality than that of all the other congenital cardiac lesions combined.³ A broad spectrum of complications associated with BAV has been described, including aortic valve stenosis (ie, the most common form of symptomatic BAV disease), aortic valve insufficiency, infective endocarditis,

Morphology of BAV—What is Important for Functional Analysis?

There are several morphologic aspects that predispose to specific functioning patterns of bicuspid valves. One structural feature that influences transvalvular flow characteristics is the cusp fusion pattern. The 2 most common patterns of cusp fusion in BAV disease are fusion of the left and right coronary cusps, which occurs in 70%-85% of cases, and fusion of the right and noncoronary cusp, which occurs in 15%-30% of patients with BAV (Fig. 1). There is sufficient evidence in the literature

Rheological Characteristics of Clinically “Normal” BAV: Evidence From Recent Studies

The asymmetric and dome-shaped opening of clinically “normal” aortic valves in patients with BAV has been demonstrated experimentally by Robicsek et al¹⁸ in their pioneering in vitro study. The resultant perturbations in transvalvular flow through the clinically “normal”—but morphologically stenotic—BAV orifice have been shown to be eccentric and directed toward the proximal aortic wall rather than toward the aortic lumen as in patients with normal tricuspid aortic valves (TAV). The effect of

BAV-Associated Aortopathy: Always the Same Disease?

Most of the literature on BAV disease considered proximal aortic involvement as a homogeneous clinical entity, which may lead one to conclude that more aggressive surgical treatment is justified. The controversy regarding optimal treatment of BAV-associated aortopathy was primarily triggered by inconsistency of published follow-up data on long-term outcomes after AVR in patients with BAV.²³ Such a high variability in the prevalence of late aortic events (ie, 5%-30% over a mean of 13 years) may

Interaction of Morphology, Function, and Disease Process: Future Directions in BAV Research

Despite the fact that progress has been made in understanding BAV disease and its associated aortopathy in the last decade, major questions remain to be answered. Although we are aware of 2 distinct phenotypes of BAV disease, we are unable to assign every single patient with BAV to one of these entities. Other questions to be answered include the following: (1) Why does the aorta never dilate in 20%-30% of patients with BAV? (2) What is the cutoff value of aortic diameter that may be left

Summary

BAV is a common congenital disorder and a significant proportion of such patients develop cardiovascular complications over time. Associated aortopathy is an important—but still poorly understood—lesion that is frequently found in patients with BAV. Two distinct clinical-pathologic BAV phenotypes can be identified. Patients presenting with BAV stenosis seem to have a more benign form of associated aortopathy, and aggressive management of the condition in such patients may not be justified. By

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Transcription factor Sp2 promotes TGFB-mediated interstitial cell osteogenic differentiation in bicuspid aortic valves through a SMAD-dependent pathway
2022, Experimental Cell Research
Citation Excerpt :
Bicuspid aortic valve (BAV) is the most common congenital heart disease, with a prevalence of approximately 0.5%–2% in the world population [1,2].
Calcification of the bicuspid aortic valve (BAV) involves differential expression of various RNA genes, which is achieved through complex regulatory networks that are controlled in part by transcription factors and microRNAs. We previously found that miR-195–5p regulates the osteogenic differentiation of valvular interstitial cells (VICs) by targeting the TGF-β pathway. However, the transcriptional regulation of miR-195–5p in calcified BAV patients is not yet clear. In this study, stenotic aortic valve tissues from patients with BAVs and tricuspid aortic valves (TAVs) were collected. Candidate transcription factors of miR-195–5p were predicted by bioinformatics analysis and tested in diseased valves and in male porcine VICs. SP2 gene expression and the corresponding protein levels in BAV were significantly lower than those in TAV, and a low SP2 expression level environment in VICs resulted in remarkable increases in RNA expression levels of RUNX2, BMP2, collagen 1, MMP2, and MMP9 and the corresponding proteins. ChIP assays revealed that SP2 directly bound to the transcription promoter region of miR-195–5p. Cotransfection of SP2 shRNA and a miR-195–5p mimic in porcine VICs demonstrated that SP2 repressed SMAD7 expression via miR-195–5p, while knockdown of SP2 increased the mRNA expression of SMAD7 and the corresponding protein and attenuated Smad 2/3 expression. Immunofluorescence staining of diseased valves confirmed that the functional proteins of osteogenesis differentiation, including RUNX2, BMP2, collagen 1, and osteocalcin, were overexpressed in BAVs. In Conclusion, the transcription factor Sp2 is expressed at low levels in VICs from BAV patients, which has a negative impact on miR-195–5p expression by binding its promoter region and partially promotes calcification through a SMAD-dependent pathway.
Re: “Bicuspid Aortic Valve Associated Aortopathy: A Primer for Cardiac Anaesthesiologists”
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Commentary: Pseudoaneurysm aortopathy after heart transplantation—A link too far?
2019, Journal of Thoracic and Cardiovascular Surgery
Bicuspid aortic valve, atherosclerosis and changes of lipid metabolism: Are there pathological molecular links?
2019, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
The molecular pathogenesis of aortic dilatation involves a series of complex biological and biophysical mechanisms. Extracellular matrix remodelling and degeneration are leading events in ascending aorta disease in BAV patients [33,34]. This event may be caused by altered structure and biosynthesis of collagen and, more specifically, by impaired collagen cross-linking, as a consequence, for example, of reduced expression of the PLOD1 gene, encoding for lysyl hydroxylase, and/or decreased activity of this enzyme [35].
Bicuspid aortic valve (BAV) is recognized as a syndrome including aortic valve diseases and aortic wall alterations, such as aortic dilatation, dissection and rupture, but also coronary atherosclerosis. The current evidence, although partially controversial, suggests that several molecular mechanisms promoting atherosclerosis are activated in BAV patients and are involved in the progression of the related diseases, from aortic stenosis to aortopathies, along with altered hemodynamics. Among these factors, dyslipidemia (i.e., high LDL cholesterol, high lipoprotein (a)) and the activation of specific pro-inflammatory pathways (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 inflammasome and Toll-like receptor 4) appear to play a pivotal role in the progression of BAV-associated diseases. The further elucidation of such molecular mechanisms may lead to a better and personalized prognosis and follow-up for BAV patients and suggest novel pharmacological approaches to prevent disease progression.
Aortic Valvuloplasty or Rootplasty for Aortic Regurgitation
2018, Seminars in Thoracic and Cardiovascular Surgery: Pediatric Cardiac Surgery Annual
Citation Excerpt :
Tricuspidization of the bicuspid aortic valve is indicated in cases where the valve opening is eccentric. It centralizes blood flow, thus minimizing turbulence and hemodynamic trauma to the reconstructed valve, and consequently prolongs the functional life of the repaired valve.9,19,28,29 However, it may increase the complexity of the repair and weakens the reconstruction because of increased suture line and use of excessive patch material.
At present, aortic valvuloplasty is considered an effective procedure for treatment of aortic regurgitation in pediatric patients. It has encouraging mid- and long-term results. The improved outcome is primarily related to better understanding of the functional anatomy of the normal valve and the different factors that alter it. It is also related to the realization that outcome after valvuloplasty is dependent on comprehensive repair of all of the involved components of the aortic root. Refinement in preoperative diagnosis has helped identify these abnormal components and focus the surgical approach on the needed reconstruction. Although the technical aspects of valvuloplasty are well defined, suboptimal long-term results still occur in some cases because the patch material used for valve repair can become fibrotic or calcified. This review summarizes the surgical approach to and the management of the different abnormal root components in pediatric patients with significant aortic valve regurgitation.
Congenital malformations (bicuspid, right aortic arch, coarctation)
2018, New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation
Congenital malformations of the aorta are a heterogenous group of conditions that arise due to either embryological or vessel wall architectural defects. These congenital aortic anomalies may be divided into three main groups. The most common group includes diseases that obstruct blood flow to the distal circulatory system and the classical representative of this category is aortic coarctation. The second category includes those diseases that obstruct either the trachea or the esophagus. Right aortic arch (RAA) is a representative of this category. A third category of congenital malformations of the aorta includes abnormalities of the mechanical composition of the aorta. Classically Marfan syndrome is representative of this category. However, bicuspid valve and its associated aortopathy also qualify for this category and will be the focus of this chapter along with aortic coarctation and RAA. Congenital malformations of the aorta carry a significant morbidity and mortality due to delayed diagnosis, missed diagnosis, or inadequate treatment. Newer developments in endovascular technology, improved understanding of the pathobiology, emerging imaging strategies, and evolving indications to treat may potentially reduce the morbidity and mortality associated with this heterogenous group of conditions and will be briefly reviewed in this chapter.

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^☆: Dr Borger reports receiving lecture fees from Edwards Lifesciences, St. Jude Medical, and Sorin. Dr Girdauskas has no commercial interests to disclose.

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State of the artBicuspid Aortic Valve and Associated Aortopathy: An Update☆

Section snippets

Epidemiology and Natural History of Bicuspid Aortic Valve

Morphology of BAV—What is Important for Functional Analysis?

Rheological Characteristics of Clinically “Normal” BAV: Evidence From Recent Studies

BAV-Associated Aortopathy: Always the Same Disease?

Interaction of Morphology, Function, and Disease Process: Future Directions in BAV Research

Summary

J Am Coll Cardiol

Am J Cardiol

Heart Lung Circ

Am Heart J

Am J Cardiol

J Am Coll Cardiol

Mayo Clin Proc

J Cardiovasc Magn Reson

Ann Thorac Surg

Ann Thorac Surg

J Am Coll Cardiol

Ann Thorac Surg

Mol Cell Proteomics

Ann Thorac Surg

The clinical importance of variations in the number of cusps forming the aortic and pulmonary valves

Q J Med

Bicuspid aortic valve: Clinical approach and scientific review of a common clinical entity

Expert Rev Cardiovasc Ther

Clinical significance of the bicuspid aortic valve

Heart

Pathogenesis of aortic stenosis and its relation to age

Br Heart J

Aortic valve morphology definition with transthoracic combined with transesophageal echocardiography in a population with high prevalence of bicuspid aortic valve

Int J Cardiovasc Imaging

State of the art
Bicuspid Aortic Valve and Associated Aortopathy: An Update☆