Materiały źródłowe

• #1 Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: Key Points

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2023/07/27/15/17/mechanisms-of-aortic-dilatation

  BAV is the most common congenital heart anomaly, with a prevalence of 0.7-1.4% in the general population (2-3:1 male predominance). Patients with BAV are at risk for dilation of all aortic segments from the root to the mid-aortic arch. The age-adjusted risk of aortic aneurysm is 80 times higher in BAV patients than in the general population, and the age-adjusted risk of aortic dissection is 8.4 times higher. […] The two major etiologies of aortic dilation in BAV are: 1) genetically mediated intrinsic alterations of the aortic wall, and 2) altered blood flow dynamics related to valve dysfunction and aortic stiffness. Variants in genes such as NOTCH1 have been associated with BAV, but these account for only a small proportion of familial and sporadic BAV cases. Therefore, genetic testing in not recommended for most patients with BAV, though it is reasonable in patients

• #2 Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity – Martín – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/13433/html

  Bicuspid aortic valve (BAV) or bicuspid aortopathy is the most common congenital heart disease. […] Pathology of BAV is still not well known and many questions are unresolved. […] Different phenotypes related to valve morphology have been described, also distinct genetics alterations are widely accepted and the pathogenesis of associated aortic dilatation is not completely clear. […] The relevance of BAV aortopathy is clear and it is well known that these patients have an increased risk of dissection however the pathogenesis of this aortic disease is still a matter of debate and genetic and hemodynamic factors have been proposed. […] There is a feared risk of a progressive aortic dilatation associated to BAV. […] In comparison with three-leaflet aortic valves, BAVs present an increased risk of thoracic aortic aneurysm (TAA) and dissection (TAAD).

• #3 Normal and abnormal development of the aortic valve and ascending aortic wall: a comprehensive overview of the embryology and pathology of the bicuspid aortic valve – Grewal- Annals of Cardiothoracic Surgery

  https://www.annalscts.com/article/view/16943/html

  A bicuspid aortic valve (BAV) is the most prevalent congenital cardiac anomaly, in which the valve has only two leaflets, instead of the normal three. Patients with a BAV have an increased risk of aneurysm formation and the development of an aortic dissection. Vascular smooth muscle cells in both the non- and dilated aortic wall are characterized by a maturation defect in all BAV patients, as compared to patients with a tricuspid aortic valve, which can contribute to inherent developmental susceptibility. […] Although the risk for aortopathy is significant, not all BAV patients experience (acute) aortic complications in their lifespan, highlighting the complexity of the pathogenetic process. Recent studies have focused on the embryonic development of semilunar valves and the ascending aortic wall. Their findings highlight that a defect in the embryogenesis could not only explain the development of a malformed aortic valve but also the increased risk for ascending aorta and arch pathology. This review presents an overview of the normal and abnormal development of the aortic valve and the aortic wall: a common defect in early embryogenesis causes the development of a BAV and associated aortopathy.

• #4

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  Bicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of longterm morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. […] In particular, for CAVD in BAV, it is uncertain whether abnormalities noted in clinically removed BAV tissues are primary or secondary, and what are the key differences that account for the accelerated and nearly ubiquitous formation of CAVD in the context of BAV.

• #5 Bicuspid Aortic Valve: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/893523-overview

  Bicuspid aortic valve is a common congenital anomaly but does not cause functional problems unless aortic valve stenosis, aortic valve regurgitation, aortic root dilatation, or dissection or infective endocarditis occurs. […] Bicuspid aortic valve is often observed with other left-sided obstructive lesions such as coarctation of the aorta or interrupted aortic arch, suggesting a common developmental mechanism. […] Abnormalities in this area lead to the development of a bicuspid valve, often through incomplete separation (or fusion) of valve tissue. […] Valve morphology may be predictive of problems of stenosis, insufficiency, or both. Fusion along the right or left leaflets is less commonly associated with stenosis or insufficiency in children. […] This arrangement is much more common in patients with coarctation of the aorta, whose valves function adequately.

• #6 Is there a genetic basis to the different morphological subtypes of bicuspid aortic valve?

  https://atm.amegroups.org/article/view/23076/html

  Moreover, GATA6 haploinsufficiency also leads to an abnormal apoptosis and thus abnormal valve remodeling. […] Variants with GATA5 and GATA6 have been observed in patients with BAV and indirectly provide a link to BAV formation. […] This highly supports the idea of distinct genetic differences among the morphological subtypes of BAV possibly leading to variations in the developmental pathway of aortic valve formation. […] In order to comprehend these differences, we need to understand the embryogenesis of BAV and its morphological subtypes. […] Some recently published studies in mice and Syrian hamster also suggested that BAV with RN cusp fusion results from defective development of the outflow tract cushions, while BAV with RL cusp fusion possibly results from abnormal septation of proximal outflow tract region.

• #7 A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice | eLife

  https://elifesciences.org/articles/34110

  The pathogenesis of stenotic, dysplastic or bicuspid arterial valves remains obscure, although fusion of adjacent leaflets in fetal life, resulting in the presence of a raphe, is presumed to cause many cases of BAV. […] We have shown that the formation of the arterial valves, whilst encompassing some processes that are similar to the atrioventricular valves, is uniquely different, by virtue of the large influx of NCC and the dominant role played by the SHF. […] The central four valve leaflets, formed as the outflow tract septates, are filled by NCC and SHF cells secondarily derived through endocardium and transformed into valve interstitial cell precursors by EndMT. […] In contrast, the intercalated valve structures are not cardiac jelly-derived endocardial cushions, but instead differentiate directly from (Mef2c-AHF-Cre+;Tnnt2-Cre+) SHF-derived outflow wall.

• #8 Normal and abnormal development of the aortic valve and ascending aortic wall: a comprehensive overview of the embryology and pathology of the bicuspid aortic valve – Grewal- Annals of Cardiothoracic Surgery

  https://www.annalscts.com/article/view/16943/html

  Considering the clinical implications, comprehension of the development of the ascending aorta and both normal and abnormal aortic valves is mandatory. […] Based on the current developmental knowledge, we propose a unified hypothesis that the increased vulnerability for aortic complications in BAV can be explained by a defect in the early development of the aortic valve and ascending aortic wall. […] The embryonic origin of the semilunar valves is closely related to the development of the ascending aorta. Hence, distortion of the early developmental pathways could not only lead to a BAV, but also the associated aortopathy. […] The aforementioned studies, which have dealt with the embryonic development of an aortic valve and the aortic vascular smooth muscle cells, have taught us that there are many similarities in the normal as well as the abnormal development. Common developmental defects in the progenitor cells might therefore be responsible for both a BAV and the associated aortopathy.

• #9

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  In nonmineralised BAV leaflets from newborn infants, the trilaminar architecture and compartmentalisation of valve interstitial cells (VICs) is lost and there is increased volume of proteoglycans (PG), glycosaminoglycans (GAG) and extracellular matrix (ECM). Disorganised ECM in BAV may have an important impact on the development of CAVD later in life as increased PG/GAG content is a notable feature of CAVD. […] In BAV, the density of inflammatory cells is higher when compared to TAV. Studies indicate that chronic inflammation of the aortic valve is one important process involved in the ectopic mineralisation of valvular tissue. […] The morphology of the BAV increases the mechanical stress in the valve tissue and alters blood flow patterns. In addition, it is possible that the genetic variants that cause BAV formation in utero may contribute to increased mineralisation due to defective cell differentiation.

• #10 The surgical implications of bicuspid aortopathy – Limmer- Annals of Cardiothoracic Surgery

  https://www.annalscts.com/article/view/1405/html

  Aortic dilatation in the setting of BAV represents a particularly interesting combination of known potential pathogenetic mechanism, and lends itself to significant ongoing debate. […] There is substantial evidence for a primary aortopathy independent of hemodynamic stresses playing at least some role. […] Interestingly, valve morphology appears to be associated with variable aortic phenotypes. […] While the genetic elements that contribute to BAV are not fully known, familial clustering has been reported by numerous investigators and is well accepted. […] As we look at genetic causes of aortopathy, comparison of tissues from patients with BAV to tissues collected from patients with other heritable forms of thoracic aortic aneurysms further support the theory of an underlying development defect as the cause of aortopathy.

• #11

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  Familial clustering of BAV and left ventricular OFT malformations has been associated with NOTCH1 receptor mutations. The Notch signalling pathway is involved in formation of the OFT and in endocardial-mesenchymal transition (EndMT), both of which are important in development of the aortic and pulmonary valves. […] Hence, it is possible that complex interplay between GATA5, eNOS, Notch and Wnt/Lrp5 may promote early mineralisation of the aortic valve in BAV. These data suggest defective cellular differentiation in BAV that likely predisposes to mineralisation. Further investigations are needed to document the role of these pathways and how they may intersect with mechanical signals in promoting mineralisation of BAV.

• #12 Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment

  https://www.mdpi.com/2077-0383/13/17/4970

  Bicuspid Aortic Valve is defined by the presence of two functional commissures between the cusps with less than three zones of parallel placement in between. […] The purpose of this review is the concise evaluation of BAV with a focus on current approaches in surgical and interventional management. […] There are multiple methods of inheritance described, such as autosomal dominant, X-linked, and familial modes. Mutations in NOTCH1 (which correlate with de-suppression and calcium deposition in BAV) and GATA5 (which correlate with aortopathy) have been identified. […] The notable heterogeneity poses a challenge for researchers who try to identify genetic variations that lead to BAV or predict BAV-associated complications. […] In comparison to tricuspid valves, BAV has different localization and increased calcification of the aortic valve.

• #13 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  Recently, the molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2). […] Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor- B (RANK). […] The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology. […] Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells).

• #14 Is there a genetic basis to the different morphological subtypes of bicuspid aortic valve?

  https://atm.amegroups.org/article/view/23076/html

  Bicuspid aortic valve (BAV) is one of the most common congenital heart defects leading to a significant global financial health burden as a result of its complications. […] Even though the impacts of BAV are far and wide spread and despite decades of research and investigation, we still lack a clear understanding of the genetic and molecular pathophysiology of BAV. […] The study by Gharibeh et al. describes the role of GATA6 in regulation of aortic valve remodeling as a novel cellular and molecular mechanism underlying BAV. […] GATA6 haploinsufficiency leads to reduced levels of tissue inhibitor of metalloproteinase 1 (TIMP1), fibrillin 1 (FBN1), and Versican (VCAN), which play an important role in the integrity of extracellular matrix and could be a potential pathophysiological mechanism of abnormal valvulogenesis in BAV.

• #15 The hereditary basis of bicuspid aortic valve disease: a role for scre | AGG

  https://www.dovepress.com/the-hereditary-basis-of-bicuspid-aortic-valve-disease-a-role-for-scree-peer-reviewed-fulltext-article-AGG

  Mechanistically, GATA5 was found to regulate important pathways associated with endocardial cushion differentiation such as NOS3, NOTCH, BMP4, and TBX20. […] A genetic analysis in 100 BAV cases identified four rare nonsynonymous GATA5 variants (Gln3Arg, Ser19Trp, Tyr142His, and Gly166Ser) in GATA5 transactivational domain, pointing out a possible role for GATA5 in the pathogenesis of BAV. […] Even though no human mutations linked to BAV in genes other than NOTCH1 and GATA5 were reported, potential candidate genes that could underlie the formation of BAV were discovered by examination of the AoVs of genetically engineered mice. […] These results indicate an important role of ALK2 in AoV development and suggest that its absence can lead to AoV diseases. […] Given the established familial contribution to BAV, the use of next-generation technologies such as whole exome sequencing (WES) and whole genome sequencing should be considered. […] Therefore, it is important to accelerate the search for new causative genes that will allow for genetic screening as well as a better understanding of the molecular basis of BAV formation and degeneration.

• #16 Aortic root aortopathy in bicuspid aortic valve associated with high genetic risk | BMC Cardiovascular Disorders | Full Text

  https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-021-02215-y

  The aortic valve and ascending aorta share some common embryological origin. It is reasonable to hypothesize that rare variants of BAV associated genes are likely to be risk factors predisposing to BAV aortopathy, especially in the aortic root. […] The rare variant was identified as the independent risk factor of root dilatation. […] Our results presented a broad genetic spectrum in BAV patients. The rare variants of BAV genes contribute the most to the root phenotype among BAV patients. […] The root type aortopathy was strongly associated with the rare variants of BAV genes. […] The pathogenic variants in TGFBR1, TGFBR2, FLNA, and FBN1 are responsible for the aortic root dilatation. Indeed, it is a compelling finding that the pathogenic variants accounted for 57.1% of root phenotype in this consecutive BAV cohort.

• #17 The hereditary basis of bicuspid aortic valve disease: a role for scre | AGG

  https://www.dovepress.com/the-hereditary-basis-of-bicuspid-aortic-valve-disease-a-role-for-scree-peer-reviewed-fulltext-article-AGG

  Mechanistically, GATA5 was found to regulate important pathways associated with endocardial cushion differentiation such as NOS3, NOTCH, BMP4, and TBX20. […] A genetic analysis in 100 BAV cases identified four rare nonsynonymous GATA5 variants (Gln3Arg, Ser19Trp, Tyr142His, and Gly166Ser) in GATA5 transactivational domain, pointing out a possible role for GATA5 in the pathogenesis of BAV. […] Even though no human mutations linked to BAV in genes other than NOTCH1 and GATA5 were reported, potential candidate genes that could underlie the formation of BAV were discovered by examination of the AoVs of genetically engineered mice. […] These results indicate an important role of ALK2 in AoV development and suggest that its absence can lead to AoV diseases. […] Given the established familial contribution to BAV, the use of next-generation technologies such as whole exome sequencing (WES) and whole genome sequencing should be considered. […] Therefore, it is important to accelerate the search for new causative genes that will allow for genetic screening as well as a better understanding of the molecular basis of BAV formation and degeneration.

• #18 Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5622294/

  Bicuspid aortic valve (BAV) is the most common congenital valvular defect and is associated with ascending aortic dilation (AAD) in a quarter of patients. AAD has been ascribed both to the hemodynamic consequences of normally functioning and abnormal BAV morphology, and to the effect of rare and common genetic variation upon function of the ascending aortic media. AAD manifests in two overall and sometimes overlapping phenotypes: that of aortic root aneurysm, similar to the AAD of Marfan syndrome; and that of tubular AAD, similar to the AAD seen with tricuspid aortic valves (TAVs). […] Both reduced levels of normally functioning transcriptional proteins and structurally abnormal proteins have been observed in aneurysmal aortic media. We provide evidence that aortic root AAD has a stronger genetic etiology, sometimes related to identified common non-coding fibrillin-1 (FBN1) variants and other aortic wall protein variants in patients with BAV. In patients with BAV having tubular AAD, we propose a stronger hemodynamic influence, but with pathology still based on a functional deficit of the aortic media, of genetic or epigenetic etiology. […] The pathogenesis of AAD likely involves both structural coding variants and non-coding variants, and thus far has not been related to identified genetic etiologies of BAV, notably, variants in NOTCH1 and GATA4.

• #19 Etiology of bicuspid aortic valve disease: Focus on hemodynamics

  https://www.wjgnet.com/1949-8462/full/v6/i12/1227.htm

  The less popular hemodynamic theory considers the mechanical stresses produced by the abnormal valve anatomy as the driving factor of secondary valvulopathy and aortopathy. […] Evidence for this mechano-etiology is supported by the apparent correlation between the eccentric BAV orifice jet, the presentation of aortic dilation in wall regions subjected to wall shear stress overload and the preferential formation of calcific nodules on the fused BAV leaflet, which experiences a higher degree of wall shear stress abnormality relative to the non-fused leaflet. […] Collectively, those observations support a hemodynamic etiology by which the abnormal mechanical stresses experienced by BAV leaflets and BAV ascending aortas could trigger molecular pathways leading to the progressive calcification of the leaflets and the weakening of the aortic wall.

• #20 The surgical implications of bicuspid aortopathy – Limmer- Annals of Cardiothoracic Surgery

  https://www.annalscts.com/article/view/1405/html

  What then is the role of the MMPs? Patterns of expression and levels of activity of MMPs may provide insights into the etiology of aortic tissue weakness. […] The regional tissue properties are not limited to MMP activity alone in providing additional support for a hemodynamic mechanism underlying BAV aortopathy. […] Even here we can find evidence of a hemodynamic component. […] Importantly, even the functionally normal BAV exhibits eccentric and turbulent flow past the valve as well as abnormal flow patterns in the ascending aorta with increased levels of wall stress compared to tricuspid valves. […] Therefore, abnormally accelerated and deflected flow through the aortic valve may be responsible for the increased aortic wall stress identified in these patients and lead to flow induced elevations of MMPs, vascular remodeling and aortic aneurysm.

• #21 Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: Key Points

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2023/07/27/15/17/mechanisms-of-aortic-dilatation

  BAV-associated flow disturbances may result in increased wall shear stress, which is associated with aortic wall elastic fiber thinning and extracellular matrix dysregulation. Patients with the right-noncoronary fusion (RN) phenotype have more severe flow alterations than those with the right-left fusion (RL) phenotype. In BAV with aortic stenosis, wall shear stress tends to be asymmetric, and aortic wall fiber thinning is most pronounced in regions where the jet impacts the wall. Conversely, in BAV with aortic regurgitation, the increase in regional wall shear stress is more homogeneous and correlates positively with stroke volume. The authors suggest that 4D flow CMR at BAV diagnosis may help identify patients at risk of progressive aortic dilation, so that they may be followed more closely.

• #22 Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: Key Points

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2023/07/27/15/17/mechanisms-of-aortic-dilatation

  BAV-associated flow disturbances may result in increased wall shear stress, which is associated with aortic wall elastic fiber thinning and extracellular matrix dysregulation. Patients with the right-noncoronary fusion (RN) phenotype have more severe flow alterations than those with the right-left fusion (RL) phenotype. In BAV with aortic stenosis, wall shear stress tends to be asymmetric, and aortic wall fiber thinning is most pronounced in regions where the jet impacts the wall. Conversely, in BAV with aortic regurgitation, the increase in regional wall shear stress is more homogeneous and correlates positively with stroke volume. The authors suggest that 4D flow CMR at BAV diagnosis may help identify patients at risk of progressive aortic dilation, so that they may be followed more closely.

• #23 Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity – Martín – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/13433/html

  Although the most commonly dilated segment in BAV patients is the tubular ascending aorta, in up to 25% of its dilated aortas is the aortic root the one affected, with sinus of Valsalva dilatation. […] The prevalence of aortic dilatation increases with age. […] In summary, there is an aortopathy associated to BAV, presenting as an aortic dilatation in which the whole aorta may be affected. […] There are two different theories to explain the both pathogenesis and perpetuation of aortic dilatation in BAV. […] Aortopathy is thought to be secondary to the eccentric and turbulent flow through the BAV that produces an abnormal hemodynamic stress on the aortic wall. […] This supports the hemodynamic etiopathogenic mechanism, but also substantiates that even an apparently normal BAV in echocardiogram is, in fact, intrinsically dysfunctional.

• #24 Etiology of bicuspid aortic valve disease: Focus on hemodynamics

  https://www.wjgnet.com/1949-8462/full/v6/i12/1227.htm

  The hemodynamic theory postulates that the abnormal BAV anatomy subjects the valve leaflets and the ascending aortic wall to local stress overloads, which can be sensed by specific receptors in the tissue endothelium and then transduced into different pathological responses that would lead ultimately to the formation of calcific nodules on the leaflets or the progressive degeneration of the aortic media. […] The current evidence in support of the hemodynamic theory has been provided by short-term ex vivo studies and small-scale clinical investigations.

• #25 Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment

  https://www.mdpi.com/2077-0383/13/17/4970

  The asymmetrical motion and higher commissural height increase the shear stress through the valve and lead to an accelerated calcification process starting from an early age. […] Another consequence of shear stress is the dilatation of the aortic root and ascending aorta. […] The reported incidence of aortic root dilatation in BAV patients is in the range of 20–84%. […] Genetic factors as well as hemodynamic theory have been proposed as factors playing a role in the development of valvulopathy and aortopathy in BAV and also intense exercise is believed to negatively impact the hemodynamic parameters and accelerate the dilatation of the aorta, making athletes with BAV at higher risk for dissection. […] Aortic root dilatation may be connected by histologic changes, previously named as cystic necrosis of the tunica media, as a result from aberrant regulatory pathways of the vascular smooth muscle cells within the tunica media.

• #26 Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment

  https://www.mdpi.com/2077-0383/13/17/4970

  The asymmetrical motion and higher commissural height increase the shear stress through the valve and lead to an accelerated calcification process starting from an early age. […] Another consequence of shear stress is the dilatation of the aortic root and ascending aorta. […] The reported incidence of aortic root dilatation in BAV patients is in the range of 20–84%. […] Genetic factors as well as hemodynamic theory have been proposed as factors playing a role in the development of valvulopathy and aortopathy in BAV and also intense exercise is believed to negatively impact the hemodynamic parameters and accelerate the dilatation of the aorta, making athletes with BAV at higher risk for dissection. […] Aortic root dilatation may be connected by histologic changes, previously named as cystic necrosis of the tunica media, as a result from aberrant regulatory pathways of the vascular smooth muscle cells within the tunica media.

• #27

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  In nonmineralised BAV leaflets from newborn infants, the trilaminar architecture and compartmentalisation of valve interstitial cells (VICs) is lost and there is increased volume of proteoglycans (PG), glycosaminoglycans (GAG) and extracellular matrix (ECM). Disorganised ECM in BAV may have an important impact on the development of CAVD later in life as increased PG/GAG content is a notable feature of CAVD. […] In BAV, the density of inflammatory cells is higher when compared to TAV. Studies indicate that chronic inflammation of the aortic valve is one important process involved in the ectopic mineralisation of valvular tissue. […] The morphology of the BAV increases the mechanical stress in the valve tissue and alters blood flow patterns. In addition, it is possible that the genetic variants that cause BAV formation in utero may contribute to increased mineralisation due to defective cell differentiation.

• #28 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  Recently, the molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2). […] Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor- B (RANK). […] The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology. […] Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells).

• #29 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The novel pathway could be targeted to prevent or reverse aortic valve calcification in humans. […] Researchers have recently described a novel nitric oxide-mediated mechanism in calcific aortic valve disease that involves the ubiqutin-proteasome pathway, and its modulation in animal models was shown to cause aortic valve calcification. […] The pathway could potentially be modulated to prevent or treat calcific aortic valve disease, an increasingly prevalent disease among the growing aging population that individuals born with a bicuspid aortic valve are predisposed to developing as adults. […] “The proposed mechanisms are initiated by injury of the endothelial cells lining the aortic valve leaflets that ultimately drives a gene expression program within the valve cells leading to calcification,” says Dr. Garg.

• #30 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The team used mass spectrometry to identify which proteins were S-nitrosylated in aortic valve cells after nitric oxide exposure. Ubiquitin-specific processing was the most enriched pathway, and one ubiquitin-specific processing protease, USP9X, caught their interest because it had previously been connected to NOTCH signaling. […] This is the first time the ubiquitin-proteasome pathway has been linked to calcific aortic valve disease. Importantly, this pathway is targetable; studies of cancer patients are already testing drug targets in this pathway, which with further investigation may ultimately be applicable in calcific aortic valve disease.

• #31 Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis | Open Heart

  https://openheart.bmj.com/content/10/1/e002244

  Knowledge of this active pathophysiology has the potential to change the paradigm of AS management as pathway biomarkers and advanced imaging techniques aim to identify early signs of significant disease and Lp(a) lowering treatments have the potential to slow progression. […] On a cellular level, CAS progression can be divided into two phases: initiation and propagation. The initiation stage is analogous to that found in atherosclerosis. Initial endothelial insult results in the infiltration of low-density lipoproteins (LDLs) and Lp(a) into the valve, depositing within the fibrosa. […] Following this, reactive oxygen species modify the lipids into oxidised LDLs (OxLDLs). OxLDLs stimulate the extravasation of monocytes into the valve interstitium which consequently differentiate into macrophages. At this stage, the inflammatory cascade initiates; macrophages capture the OxLDLs to form foam cells, enhancing the influx of immune cells through a greater expression of adhesion molecules E-selectin and intercellular adhesion molecule 1, thus perpetuating the cycle.

• #32 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  Recently, the molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2). […] Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor- B (RANK). […] The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology. […] Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells).

• #33 Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment

  https://www.mdpi.com/2077-0383/13/17/4970

  The asymmetrical motion and higher commissural height increase the shear stress through the valve and lead to an accelerated calcification process starting from an early age. […] Another consequence of shear stress is the dilatation of the aortic root and ascending aorta. […] The reported incidence of aortic root dilatation in BAV patients is in the range of 20–84%. […] Genetic factors as well as hemodynamic theory have been proposed as factors playing a role in the development of valvulopathy and aortopathy in BAV and also intense exercise is believed to negatively impact the hemodynamic parameters and accelerate the dilatation of the aorta, making athletes with BAV at higher risk for dissection. […] Aortic root dilatation may be connected by histologic changes, previously named as cystic necrosis of the tunica media, as a result from aberrant regulatory pathways of the vascular smooth muscle cells within the tunica media.

• #34 Bicuspid aortic valve

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-13/Bicuspid-aortic-valve

  Bicuspid aortic valve may be complicated with aortic valve stenosis and/or regurgitation in addition to risk of endocarditis. […] The BAV is composed of not three aortic normal leaflets – as in the normal tricuspid valve – but two abnormal leaflets, usually unequal in size, possibly resulting from inadequate fibrillin-1 production during valvulogenesis. […] Various aetiologies have been suggested to explain the mechanism of aortic regurgitation in BAV, including cusp prolapse, endocarditis, dilated aortic root, and myxoid degeneration of the valve. […] The mechanism of aortopathy is explained by genetic theory (aortic root fragility and elastic fragmentation due to inherited developmental defect) and hemodynamic theory (abnormal stress on aortic root due to turbulent flow through BAV). […] Recent data suggest that BAV increases the risk of aortic dissection nine-fold over that in the general population. […] It is worth noting that aortic root dilatation is an important predictor of dissection and rupture in BAV-associated aneurysms, even if the aortic valve is functioning normally.

• #35 Prognosis of Unrepaired Ascending Aorta after the Surgical Replacement of Bicuspid Aortic Valves

  https://www.jchestsurg.org/journal/view.html?doi=10.5090/jcs.23.007

  The abnormal hemodynamics of BAV have emerged as a potential alternative or coincident etiology. Of note, the primary author of a previous report suggesting a genetic etiology for BAV now has a contradicting opinion favoring a hemodynamic etiology. Den Reijer et al. reported significant correlations between the blood flow jet angle, representing a quantitative measurement of misdirected blood flow, and the ascending aorta dimensions at the levels of the sinuses of Valsalva, sinotubular junction, and the tubular part of the ascending aorta, which were evaluated using 3-dimensional velocity-encoded cardiac magnetic resonance imaging. The significant positive correlation revealed that larger angles of misdirected flow at the aortic axis caused greater aortic dimensions and more severe aortic dilatation. In flow loop experiments with phantom models of the aorta, excised BAVs were shown to be associated with abnormal flow patterns and turbulence toward the right anterolateral wall (i.e., convexity) of the aorta. This implies that BAV with good valvular function and without AS or AR can cause abnormal hemodynamic effects in asymmetric aortic dilatation. These effects can cause various types of ascending aortic dilatation, including the aortic root type, due to differences in the spatial relationship of BAV. […] These findings promote the hemodynamic theory of BAV aortopathy and imply that subsequent dilatation of the ascending aorta will cease after AVR.

• #36 Bicuspid Aortic Valve-Associated Aortic Dilatation　― What Is the Mechanism of Bicuspid Aortopathy? ―

  https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_CJ-18-0844/_html/-char/en

  Bicuspid aortic valve (BAV) is the most common congenital heart defect, occurring in 0.5-2.0% of the general population. A broad spectrum of complications associated with BAV has been described, including aortic valve stenosis (AS) and/or regurgitation, infectious endocarditis, and ascending aortic complications, called bicuspid aortopathy. […] The previously reported pathophysiological and histological features of BAV-associated aortic dilatation are cystic medial necrosis, abnormal processing of the extracellular matrix protein fibrillin 1 by vascular smooth muscle cells (VSMCs), increase in the release of matrix metalloproteinases (MMPs), increased apoptosis of VSMCs, and abnormality in the medial layer probably because of the disrupted collagen and elastin. […] Despite the controversy regarding aortic dilatation representing a genetic preposition vs. being the result of abnormal hemodynamics, there is enough evidence to consider both as culprits in the origin of aortic dilatation in BAV.

• #37 Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment

  https://www.mdpi.com/2077-0383/13/17/4970

  The type of BAV also impacts the dilatation of the aorta: type 1 includes a dilatation of the tubular ascending aorta (especially along the length of its curvature), accompanied by varying degrees of aortic root dilatation. […] Therefore, it is recommended that patients with BAV undergo full echocardiographic evaluation of the aortic valve, where the BAV motif and the function of the aortic valve and the aorta will be determined to avoid missing the diagnosis of aortic root dilatation. […] The future of BAV management lies in a multidisciplinary approach that integrates genetic research, advanced imaging, dedicated devices, improved surgical techniques, AI-driven simulations, and novel therapeutic strategies.

• #38

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  Bicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of longterm morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. […] In particular, for CAVD in BAV, it is uncertain whether abnormalities noted in clinically removed BAV tissues are primary or secondary, and what are the key differences that account for the accelerated and nearly ubiquitous formation of CAVD in the context of BAV.

• #39

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  In nonmineralised BAV leaflets from newborn infants, the trilaminar architecture and compartmentalisation of valve interstitial cells (VICs) is lost and there is increased volume of proteoglycans (PG), glycosaminoglycans (GAG) and extracellular matrix (ECM). Disorganised ECM in BAV may have an important impact on the development of CAVD later in life as increased PG/GAG content is a notable feature of CAVD. […] In BAV, the density of inflammatory cells is higher when compared to TAV. Studies indicate that chronic inflammation of the aortic valve is one important process involved in the ectopic mineralisation of valvular tissue. […] The morphology of the BAV increases the mechanical stress in the valve tissue and alters blood flow patterns. In addition, it is possible that the genetic variants that cause BAV formation in utero may contribute to increased mineralisation due to defective cell differentiation.

• #40

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4939890/

  In nonmineralised BAV leaflets from newborn infants, the trilaminar architecture and compartmentalisation of valve interstitial cells (VICs) is lost and there is increased volume of proteoglycans (PG), glycosaminoglycans (GAG) and extracellular matrix (ECM). Disorganised ECM in BAV may have an important impact on the development of CAVD later in life as increased PG/GAG content is a notable feature of CAVD. […] In BAV, the density of inflammatory cells is higher when compared to TAV. Studies indicate that chronic inflammation of the aortic valve is one important process involved in the ectopic mineralisation of valvular tissue. […] The morphology of the BAV increases the mechanical stress in the valve tissue and alters blood flow patterns. In addition, it is possible that the genetic variants that cause BAV formation in utero may contribute to increased mineralisation due to defective cell differentiation.

• #41 Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5622294/

  Bicuspid aortic valve (BAV) is the most common congenital valvular defect and is associated with ascending aortic dilation (AAD) in a quarter of patients. AAD has been ascribed both to the hemodynamic consequences of normally functioning and abnormal BAV morphology, and to the effect of rare and common genetic variation upon function of the ascending aortic media. AAD manifests in two overall and sometimes overlapping phenotypes: that of aortic root aneurysm, similar to the AAD of Marfan syndrome; and that of tubular AAD, similar to the AAD seen with tricuspid aortic valves (TAVs). […] Both reduced levels of normally functioning transcriptional proteins and structurally abnormal proteins have been observed in aneurysmal aortic media. We provide evidence that aortic root AAD has a stronger genetic etiology, sometimes related to identified common non-coding fibrillin-1 (FBN1) variants and other aortic wall protein variants in patients with BAV. In patients with BAV having tubular AAD, we propose a stronger hemodynamic influence, but with pathology still based on a functional deficit of the aortic media, of genetic or epigenetic etiology. […] The pathogenesis of AAD likely involves both structural coding variants and non-coding variants, and thus far has not been related to identified genetic etiologies of BAV, notably, variants in NOTCH1 and GATA4.

• #42 Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5622294/

  Bicuspid aortic valve (BAV) is the most common congenital valvular defect and is associated with ascending aortic dilation (AAD) in a quarter of patients. AAD has been ascribed both to the hemodynamic consequences of normally functioning and abnormal BAV morphology, and to the effect of rare and common genetic variation upon function of the ascending aortic media. AAD manifests in two overall and sometimes overlapping phenotypes: that of aortic root aneurysm, similar to the AAD of Marfan syndrome; and that of tubular AAD, similar to the AAD seen with tricuspid aortic valves (TAVs). […] Both reduced levels of normally functioning transcriptional proteins and structurally abnormal proteins have been observed in aneurysmal aortic media. We provide evidence that aortic root AAD has a stronger genetic etiology, sometimes related to identified common non-coding fibrillin-1 (FBN1) variants and other aortic wall protein variants in patients with BAV. In patients with BAV having tubular AAD, we propose a stronger hemodynamic influence, but with pathology still based on a functional deficit of the aortic media, of genetic or epigenetic etiology. […] The pathogenesis of AAD likely involves both structural coding variants and non-coding variants, and thus far has not been related to identified genetic etiologies of BAV, notably, variants in NOTCH1 and GATA4.

• #43 Bicuspid Aortic Valve-Associated Aortic Dilatation　― What Is the Mechanism of Bicuspid Aortopathy? ―

  https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_CJ-18-0844/_html/-char/en

  Molecular, cellular and hemodynamic mechanisms of BAV-associated aortic dilatation are shown in the Figure, using the authors imagination based on previous papers and the present study. […] In summary, bicuspid aortopathy is a multifaceted heterogeneous disease with at least genetic and hemodynamic factors contributing.

• #44

  https://www.cnic.es/en/noticias/circulation-research-cnic-researchers-identify-new-signaling-mechanism-implicated

  These genes form part of a signaling mechanism that is possibly altered in patients with a bicuspid aortic valve (BAV), a prevalent condition that compromises cardiovascular health […] The research team has demonstrated the essential role of genes encoding components of the NOTCH signaling pathway in the development of the heart valves […] Using genetically modified mouse strains, the research team showed that the NOTCH signaling pathway plays an essential role throughout the process of heart valve formation. NOTCH is required for the formation of the primitive valves that function during fetal development and later for the acquisition of the definitive form of the mature valves. The study identifies a new NOTCH-regulated molecular mechanism that controls proliferation during late valve development. The research team, led by Jos Luis de la Pompa, showed that this control is inactivated by alterations to genes encoding NOTCH pathway components. The resulting excessive growth results in the fusion of the original 3 valves into 2, producing a bicuspid aortic valve instead of the normal tricuspid valve. […] The research findings could have important clinical implications in relation to both early genetic diagnosis and the classification of patients with heart valve malformations, and could contribute to the eventual development of therapies aimed at controlling excessive valve growth.

• #45 A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice | eLife

  https://elifesciences.org/articles/34110

  Ultimately, however, they appear indistinguishable from the valve leaflets derived from the main outflow cushions. […] Our data strongly argue against trans-differentiation as a mechanism for formation of the ICVS as although the Tnnt2-Cre+ cells activated the cTnT promoter, we never saw co-expression of cardiomyocyte markers in the forming ICVS. […] Notch signalling has been shown to be important for the differentiation of cardiac progenitor cells, with its down-regulation crucial for differentiation to cardiomyocytes and for activation of Sox9 in cartilage precursors. […] Our analyses extend these data to show that a discrete pulmonary ICVS is never formed in the Tbx1-/- and highlights similarities in the ICVS phenotype between these and the Vangl2;Isl1-Cre mutants.

• #46 Is there a genetic basis to the different morphological subtypes of bicuspid aortic valve?

  https://atm.amegroups.org/article/view/23076/html

  Bicuspid aortic valve (BAV) is one of the most common congenital heart defects leading to a significant global financial health burden as a result of its complications. […] Even though the impacts of BAV are far and wide spread and despite decades of research and investigation, we still lack a clear understanding of the genetic and molecular pathophysiology of BAV. […] The study by Gharibeh et al. describes the role of GATA6 in regulation of aortic valve remodeling as a novel cellular and molecular mechanism underlying BAV. […] GATA6 haploinsufficiency leads to reduced levels of tissue inhibitor of metalloproteinase 1 (TIMP1), fibrillin 1 (FBN1), and Versican (VCAN), which play an important role in the integrity of extracellular matrix and could be a potential pathophysiological mechanism of abnormal valvulogenesis in BAV.

• #47 Prognosis of Unrepaired Ascending Aorta after the Surgical Replacement of Bicuspid Aortic Valves

  https://www.jchestsurg.org/journal/view.html?doi=10.5090/jcs.23.007

  The abnormal hemodynamics of BAV have emerged as a potential alternative or coincident etiology. Of note, the primary author of a previous report suggesting a genetic etiology for BAV now has a contradicting opinion favoring a hemodynamic etiology. Den Reijer et al. reported significant correlations between the blood flow jet angle, representing a quantitative measurement of misdirected blood flow, and the ascending aorta dimensions at the levels of the sinuses of Valsalva, sinotubular junction, and the tubular part of the ascending aorta, which were evaluated using 3-dimensional velocity-encoded cardiac magnetic resonance imaging. The significant positive correlation revealed that larger angles of misdirected flow at the aortic axis caused greater aortic dimensions and more severe aortic dilatation. In flow loop experiments with phantom models of the aorta, excised BAVs were shown to be associated with abnormal flow patterns and turbulence toward the right anterolateral wall (i.e., convexity) of the aorta. This implies that BAV with good valvular function and without AS or AR can cause abnormal hemodynamic effects in asymmetric aortic dilatation. These effects can cause various types of ascending aortic dilatation, including the aortic root type, due to differences in the spatial relationship of BAV. […] These findings promote the hemodynamic theory of BAV aortopathy and imply that subsequent dilatation of the ascending aorta will cease after AVR.

• #48 Analysis of Serum Metabolites to Diagnose Bicuspid Aortic Valve | Scientific Reports

  https://www.nature.com/articles/srep37023

  The results of the study suggested that a predominant majority of the identified metabolites showing statistically significant concentration differences between the patient group and the control group were mainly clustered in several key pathways, including those associated with fatty acid metabolism, adenosine triphosphate (ATP) degradation, purine metabolism and endocannabinoid biosynthesis. […] The pathways related to purine metabolism and fatty acid biosynthesis were directly identified as those that might have been perturbed by the development of BAV. […] In addition, two single nucleotide polymorphisms (SNP), rs10827283 and rs1562861, were suggested to have the highest correlation with the observed metabolic perturbations in BAV patients. […] The main limitation of the current study lies in the relative small sample size.

• #49 Analysis of Serum Metabolites to Diagnose Bicuspid Aortic Valve | Scientific Reports

  https://www.nature.com/articles/srep37023

  The results of the study suggested that a predominant majority of the identified metabolites showing statistically significant concentration differences between the patient group and the control group were mainly clustered in several key pathways, including those associated with fatty acid metabolism, adenosine triphosphate (ATP) degradation, purine metabolism and endocannabinoid biosynthesis. […] The pathways related to purine metabolism and fatty acid biosynthesis were directly identified as those that might have been perturbed by the development of BAV. […] In addition, two single nucleotide polymorphisms (SNP), rs10827283 and rs1562861, were suggested to have the highest correlation with the observed metabolic perturbations in BAV patients. […] The main limitation of the current study lies in the relative small sample size.

• #50 Analysis of Serum Metabolites to Diagnose Bicuspid Aortic Valve | Scientific Reports

  https://www.nature.com/articles/srep37023

  Nevertheless, our serum-based diagnostic method is particularly suitable for use in community clinics and other medical institutes with inadequate equipment and funding, thanks to the easy availability of blood samples and the relatively low capital requirement for the analysis of small-molecule metabolites.

• #51 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The novel pathway could be targeted to prevent or reverse aortic valve calcification in humans. […] Researchers have recently described a novel nitric oxide-mediated mechanism in calcific aortic valve disease that involves the ubiqutin-proteasome pathway, and its modulation in animal models was shown to cause aortic valve calcification. […] The pathway could potentially be modulated to prevent or treat calcific aortic valve disease, an increasingly prevalent disease among the growing aging population that individuals born with a bicuspid aortic valve are predisposed to developing as adults. […] “The proposed mechanisms are initiated by injury of the endothelial cells lining the aortic valve leaflets that ultimately drives a gene expression program within the valve cells leading to calcification,” says Dr. Garg.

• #52 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The team used mass spectrometry to identify which proteins were S-nitrosylated in aortic valve cells after nitric oxide exposure. Ubiquitin-specific processing was the most enriched pathway, and one ubiquitin-specific processing protease, USP9X, caught their interest because it had previously been connected to NOTCH signaling. […] This is the first time the ubiquitin-proteasome pathway has been linked to calcific aortic valve disease. Importantly, this pathway is targetable; studies of cancer patients are already testing drug targets in this pathway, which with further investigation may ultimately be applicable in calcific aortic valve disease.

• #53 Elucidating the pathogenesis underlying bicuspid aortic valve disease using new disease models | Scholarly Publications

  https://scholarlypublications.universiteitleiden.nl/handle/1887/3249566

  A bicuspid aortic valve (BAV) is a congenital heart defect in which the heart valve between the left ventricle and the aorta consists of two valve flaps instead of the normal three (tricuspid aortic valve TAV). […] The aim of the research described in this thesis is to study the pathogenesis of aortic valve calcification and aortic dilatation in BAV patients with a focus on the role of endothelial cells in these processes. […] With the research described in this thesis, we have shown that endothelial cells from BAV patients respond differently than cells from people with a TAV. […] In addition, the endothelial cell activation in the vascular wall of BAV patients is different and dependent on the blood flow.

• #54 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  Recently, the molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2). […] Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor- B (RANK). […] The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology. […] Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells).

• #55 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The novel pathway could be targeted to prevent or reverse aortic valve calcification in humans. […] Researchers have recently described a novel nitric oxide-mediated mechanism in calcific aortic valve disease that involves the ubiqutin-proteasome pathway, and its modulation in animal models was shown to cause aortic valve calcification. […] The pathway could potentially be modulated to prevent or treat calcific aortic valve disease, an increasingly prevalent disease among the growing aging population that individuals born with a bicuspid aortic valve are predisposed to developing as adults. […] “The proposed mechanisms are initiated by injury of the endothelial cells lining the aortic valve leaflets that ultimately drives a gene expression program within the valve cells leading to calcification,” says Dr. Garg.

• #56 6.4: Bicuspid Aortic valve – Medicine LibreTexts

  https://med.libretexts.org/Bookshelves/Medicine/Textbook_of_Cardiology/06%3A_Valvular_Disease/6.04%3A_Bicuspid_Aortic_valve

  The abnormal shear stress leads to valve calcification and further aortic root dilation has been reported. […] The most common complication is aortic stenosis, caused by premature fibrosis, stiffening, and calcium deposition. […] A more rare complication of bicuspid aortic valve disease is aortic regurgitation.

• #57 Bicuspid aortic valve

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-13/Bicuspid-aortic-valve

  Bicuspid aortic valve may be complicated with aortic valve stenosis and/or regurgitation in addition to risk of endocarditis. […] The BAV is composed of not three aortic normal leaflets – as in the normal tricuspid valve – but two abnormal leaflets, usually unequal in size, possibly resulting from inadequate fibrillin-1 production during valvulogenesis. […] Various aetiologies have been suggested to explain the mechanism of aortic regurgitation in BAV, including cusp prolapse, endocarditis, dilated aortic root, and myxoid degeneration of the valve. […] The mechanism of aortopathy is explained by genetic theory (aortic root fragility and elastic fragmentation due to inherited developmental defect) and hemodynamic theory (abnormal stress on aortic root due to turbulent flow through BAV). […] Recent data suggest that BAV increases the risk of aortic dissection nine-fold over that in the general population. […] It is worth noting that aortic root dilatation is an important predictor of dissection and rupture in BAV-associated aneurysms, even if the aortic valve is functioning normally.

• #58 Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: Key Points

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2023/07/27/15/17/mechanisms-of-aortic-dilatation

  BAV is the most common congenital heart anomaly, with a prevalence of 0.7-1.4% in the general population (2-3:1 male predominance). Patients with BAV are at risk for dilation of all aortic segments from the root to the mid-aortic arch. The age-adjusted risk of aortic aneurysm is 80 times higher in BAV patients than in the general population, and the age-adjusted risk of aortic dissection is 8.4 times higher. […] The two major etiologies of aortic dilation in BAV are: 1) genetically mediated intrinsic alterations of the aortic wall, and 2) altered blood flow dynamics related to valve dysfunction and aortic stiffness. Variants in genes such as NOTCH1 have been associated with BAV, but these account for only a small proportion of familial and sporadic BAV cases. Therefore, genetic testing in not recommended for most patients with BAV, though it is reasonable in patients

• #59 Bicuspid Aortic Valve: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/893523-overview

  Fusion along the right and noncoronary leaflets is more frequently associated with pathologic changes of stenosis or insufficiency in the pediatric population. […] The changes are similar to those in atherosclerotic coronary arteries. […] The bicuspid valve may also be completely competent, producing no regurgitant flow. However, redundancy and prolapse of cusp tissue can lead to valve regurgitation. […] Complications arise in as many as one third of patients over their lifetimes; this disorder, therefore, deserves close attention and medical follow-up.

• #60 6.4: Bicuspid Aortic valve – Medicine LibreTexts

  https://med.libretexts.org/Bookshelves/Medicine/Textbook_of_Cardiology/06%3A_Valvular_Disease/6.04%3A_Bicuspid_Aortic_valve

  Bicuspid Aortic valve disease affects as many as 1-2% of the population, and is the most frequent congenital cardiovascular malformation in humans. […] Understanding of the pathogenesis of aortic valve malformation remains incomplete. […] Bicuspid aortic valve disease results from abnormal cusp formation during valvulogenesis, but coexisting genetic abnormalities of the aorta and proximal coronary vasculature are often present. […] During valvulogenesis, adjacent cusps of the bicuspid valve fuse to form a single aberrant cusp. […] This fusion results in large leaflet, yet smaller than 2 normal cusps, with most often a central raphe or ridge. […] Fusion of the right coronary and noncoronary cusps is associated with cuspal pathology. […] Fusion of the right and left coronary cusps is associated with coarctation of the aorta.

• #61 Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: Key Points

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2023/07/27/15/17/mechanisms-of-aortic-dilatation

  BAV-associated flow disturbances may result in increased wall shear stress, which is associated with aortic wall elastic fiber thinning and extracellular matrix dysregulation. Patients with the right-noncoronary fusion (RN) phenotype have more severe flow alterations than those with the right-left fusion (RL) phenotype. In BAV with aortic stenosis, wall shear stress tends to be asymmetric, and aortic wall fiber thinning is most pronounced in regions where the jet impacts the wall. Conversely, in BAV with aortic regurgitation, the increase in regional wall shear stress is more homogeneous and correlates positively with stroke volume. The authors suggest that 4D flow CMR at BAV diagnosis may help identify patients at risk of progressive aortic dilation, so that they may be followed more closely.

• #62 Genetics of Bicuspid Aortic Valve and Calcific Aortic Valve Disease | IntechOpen

  https://www.intechopen.com/chapters/45202

  Aortic valve malformation is a spectrum including Bicuspid Aortic Valve. […] Calcific Aortic Valve Disease is a growing public health problem. […] Bicuspid Aortic Valve is an independent risk factor for Calcific Aortic Valve Disease. […] Careful clinical phenotyping is critical for research, especially genetic discovery. […] The genetic basis of BAV and CAVD. […] BAV has a strong genetic basis, but the precise causes remain unknown. […] BAV is a congenital malformation, a defect in cardiac development. […] Genetic factors contributing to CAVD are numerous and relatively small. […] CAVD is a latent phenotype, an injury or defect in valve maintenance. […] Complex inheritance is characterized by a liability threshold. […] Developmental signaling pathways identify basic regulatory factors in valvulogenesis.

• #63 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The team used mass spectrometry to identify which proteins were S-nitrosylated in aortic valve cells after nitric oxide exposure. Ubiquitin-specific processing was the most enriched pathway, and one ubiquitin-specific processing protease, USP9X, caught their interest because it had previously been connected to NOTCH signaling. […] This is the first time the ubiquitin-proteasome pathway has been linked to calcific aortic valve disease. Importantly, this pathway is targetable; studies of cancer patients are already testing drug targets in this pathway, which with further investigation may ultimately be applicable in calcific aortic valve disease.

• #64 Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: Key Points

  https://www.acc.org/Latest-in-Cardiology/ten-points-to-remember/2023/07/27/15/17/mechanisms-of-aortic-dilatation

  BAV-associated flow disturbances may result in increased wall shear stress, which is associated with aortic wall elastic fiber thinning and extracellular matrix dysregulation. Patients with the right-noncoronary fusion (RN) phenotype have more severe flow alterations than those with the right-left fusion (RL) phenotype. In BAV with aortic stenosis, wall shear stress tends to be asymmetric, and aortic wall fiber thinning is most pronounced in regions where the jet impacts the wall. Conversely, in BAV with aortic regurgitation, the increase in regional wall shear stress is more homogeneous and correlates positively with stroke volume. The authors suggest that 4D flow CMR at BAV diagnosis may help identify patients at risk of progressive aortic dilation, so that they may be followed more closely.

• #65 The hereditary basis of bicuspid aortic valve disease: a role for scre | AGG

  https://www.dovepress.com/the-hereditary-basis-of-bicuspid-aortic-valve-disease-a-role-for-scree-peer-reviewed-fulltext-article-AGG

  Mechanistically, GATA5 was found to regulate important pathways associated with endocardial cushion differentiation such as NOS3, NOTCH, BMP4, and TBX20. […] A genetic analysis in 100 BAV cases identified four rare nonsynonymous GATA5 variants (Gln3Arg, Ser19Trp, Tyr142His, and Gly166Ser) in GATA5 transactivational domain, pointing out a possible role for GATA5 in the pathogenesis of BAV. […] Even though no human mutations linked to BAV in genes other than NOTCH1 and GATA5 were reported, potential candidate genes that could underlie the formation of BAV were discovered by examination of the AoVs of genetically engineered mice. […] These results indicate an important role of ALK2 in AoV development and suggest that its absence can lead to AoV diseases. […] Given the established familial contribution to BAV, the use of next-generation technologies such as whole exome sequencing (WES) and whole genome sequencing should be considered. […] Therefore, it is important to accelerate the search for new causative genes that will allow for genetic screening as well as a better understanding of the molecular basis of BAV formation and degeneration.

• #66 Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment

  https://www.mdpi.com/2077-0383/13/17/4970

  The type of BAV also impacts the dilatation of the aorta: type 1 includes a dilatation of the tubular ascending aorta (especially along the length of its curvature), accompanied by varying degrees of aortic root dilatation. […] Therefore, it is recommended that patients with BAV undergo full echocardiographic evaluation of the aortic valve, where the BAV motif and the function of the aortic valve and the aorta will be determined to avoid missing the diagnosis of aortic root dilatation. […] The future of BAV management lies in a multidisciplinary approach that integrates genetic research, advanced imaging, dedicated devices, improved surgical techniques, AI-driven simulations, and novel therapeutic strategies.

• #67 Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity – Martín – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/13433/html

  Nowadays, NOTCH1 remains the only proven candidate gene and has been associated with both familial and sporadic BAV. […] Multiple other common genetic variants may act as modifier genes in the pathogenesis of BAV aortopathy, contributing to the variability of clinical phenotypes. […] Different mechanisms are proposed: on the one hand, genetic predisposition and on the other, local stress in the valve tissue secondary to the bicuspid morphology which alters blood flow; both can contribute to the early mineralisation of the leaflets. […] Further researches with multidisciplinary approaches are necessary in order to know more and better this complex entity and all over the place, in order to stop progression of the disease in early stages.

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