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A bicuspid aortic valve (BAV) is the most prevalent congenital cardiac deformity, which is associated with an increased risk to develop a thoracic aortic aneurysm and/or an aortic dissection as compared to persons with a tricuspid aortic valve. Due to the high prevalence of a BAV in the general population and the associated life-long increased risk for adverse vascular events, BAV disease places a considerable burden on the public health. The aim of the present review is to discuss the role of transforming growth factor beta (TGF-β) signaling in the development of the vascular wall and on how this complex signaling pathway may be involved in thoracic aortic aneurysm formation in tricuspid and BAV patients.

Patients with a bicuspid aortic valve have an extreme high risk to develop a thoracic aortic aneurysm and dissection (TAAD). TAADs form a leading cause of death worldwide, with the majority of deaths be-ing preventable if individuals at risk are identified and properly managed. Risk stratification for TAADs in bicuspidy is so far solely based on the aortic diameter. Exclusive use of aortic wall dimension, as in the current guidelines, is however not sufficient in selecting patients vulnerable for future aortic wall complications. Moreover, there are no effective medical treatments for TAADs to retain progressive aortic dilatation and thus prevent or delay aortic complications. Only surgical replacement of the aorta increases life expectancy in patients with a risk for a TAAD. Therefore, the next major challenge in the manage-ment of TAADs is the development of a personalized patient-tailored risk stratification for early detection of patients with an increased risk for TAADs, who will benefit from surgical resection of the aorta. Sev-eral signaling pathways have been studied in recent times to develop a patient specific risk stratification model. In this paper we discuss TGF-,B signaling and downstream signalers as potential markers for fu-ture aortic complications in bicuspid aortic valve patients.(c) 2022 Elsevier Inc. All rights reserved.

Background: A bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. The development of the aortic valve is closely related to the development of the ascending aorta, associated with structural differences in the bicuspid aorta. Here we describe the non-dilated ascending aortic wall in bicuspid aortic valve patients. Methods: BAV (n = 41) and tricuspid aortic valve (TAV) (n = 18) non-dilated ascending aortic wall samples were studied. We investigated the following features of the aortic wall: vessel wall thickness, endothelial cell morphology, atherosclerosis, and elastic lamellae organization. Medial pathologic features encompass-ing elastic fiber thinning, fragmentation and degeneration, overall medial degeneration, mucoid extracel-lular matrix accumulation, and smooth muscle cell nuclei loss were studied. Furthermore, we included apoptosis, periaortic inflammation, and the level of expression of differentiated vascular smooth muscle cells. Results: The non-dilated BAV ascending aortic wall is characterized by a significantly thinner intimal layer, without features of atherosclerosis ( P < .001). The medial layer is significantly thicker ( P < .001) with more mucoid extracellular matrix accumulation ( P < .001). All other medial pathologic features were more prominent in the TAV ( P < .001). The media has significantly less differentiated vascular smooth muscle cells ( P < .001) between the neatly regulated elastic lamellae which are thinner in the BAV as compared to the TAV ( P < .0 0 01). Conclusions: The BAV ascending aorta without dilatation is characterized by a differentiation def ect of vascular smooth muscle cells in the media and a significantly thinner intimal layer without overt patho-logic features.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Objective We aimed to analyze the association among flow patterns, gene expression, and histologic alterations of the proximal aorta in patients with aortic valve disease. Methods A total of 131 patients referred for aortic valve replacement were grouped by valve dysfunction (aortic stenosis vs aortic regurgitation) and valve morphology (bicuspid vs tricuspid). On the basis of magnetic resonance imaging, aortic tissue from outer and inner curvature was collected for gene expression and histologic analysis. To identify differences in aortic remodeling, age- and sex-adjusted data for inflammation (CCL2, VCAM1, inflammation and atherosclerosis) and medial degeneration (COL1A1, ELN, fibrosis, elastin fragmentation, and cystic medial necrosis) were compared. Results First, we compared all patients with aortic regurgitation (n = 64) and patients with aortic stenosis (n = 67). In patients with aortic regurgitation, COL1A1 expression and all histologic markers were significantly increased. With respect to aortic diameter, all subsequent analyses were refined by considering only individuals with aortic diameter 40 mm or greater. Second, patients with bicuspid aortic valve were compared, resulting in a similar aortic diameter. Although patients with aortic regurgitation were younger, no differences were found in gene expression or histologic level. Third, valve morphology was compared in patients with aortic regurgitation. Although aortic diameter was similar, patients with regurgitant bicuspid aortic valve were younger than patients with regurgitant tricuspid aortic valve. Inflammatory markers were similar, whereas markers for medial degeneration were increased in patients with regurgitant tricuspid aortic valve. Conclusions Our results indicate that the proximal aorta in patients with aortic regurgitation showed an increased inflammation and medial degeneration compared with patients with aortic stenosis. Refining both groups by valve morphology, in patients with bicuspid aortic valve, no difference except age was detected between aortic regurgitation and aortic stenosis. In patients with aortic regurgitation, tricuspid aortic valve revealed increased markers for medial degeneration but no differences regarding inflammatory markers.

Background: The outflow tract of crocodilians resembles that of birds and mammals as ventricular septation is complete. The arterial anatomy, however, presents with a pulmonary trunk originating from the right ventricular cavum, and two aortas originating from either the right or left ventricular cavity. Mixing of blood in crocodilians cannot occur at the ventricular level as in other reptiles but instead takes place at the aortic root level by a shunt, the foramen of Panizza, the opening of which is guarded by two facing semilunar leaflets of both bicuspid aortic valves. Methods: Developmental stages of Alligator mississipiensis, Crocodilus niloticus and Caiman latirostris were studied histologically. Results and Conclusions: The outflow tract septation complex can be divided into two components. The aorto-pulmonary septum divides the pulmonary trunk from both aortas, whereas the interaortic septum divides the systemic from the visceral aorta. Neural crest cells are most likely involved in the formation of both components. Remodeling of the endocardial cushions and both septa results in the formation of bicuspid valves in all three arterial trunks. The foramen of Panizza originates intracardially as a channel in the septal endocardial cushion.

Acute aortic dissection is a rare, but potentially life-threatening and time-critical condition that is frequently misdiagnosed. Therefore, its prompt and proper diagnosis is vital to increase a patient's chance of survival and to prevent grievous complications. Raising awareness and educating the general population and healthcare professionals about an aortic dissection is mandatory, for early diagnosis and improving the chances of survival.

Background Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, which is often complicated by aortic valve stenosis (AoS). In tricuspid aortic valve (TAV), AoS strongly associates with coronary artery disease (CAD) with common pathophysiological factors. Yet, it remains unclear whether AoS in patients with BAV is also associated with CAD. This study investigated the association between the aortic valve morphological features and the extent of CAD. Methods and Results A single‐center study was performed, including all patients who underwent an aortic valve replacement attributable to AoS between 2006 and 2019. Coronary sclerosis was graded on preoperative coronary angiographies using the coronary artery greater even than scoring method, which divides the coronaries in 28 segments and scores nonobstructive (20%–49% sclerosis) and obstructive coronary sclerosis (>49% sclerosis) in each segment. Multivariate analyses were performed, controlling for age, sex, and CAD risk factors. A total of 1296 patients (931 TAV and 365 BAV) were included, resulting in 548 matched patients. Patients with TAV exhibited more CAD risk factors (odds ratio [OR], 2.66; 95% CI, 1.79–3.96; P P P P Conclusions Patients with BAV who are undergoing surgery for AoS carry a lower cardiovascular risk profile, correlating with less coronary sclerosis and a lower incidence of concomitant coronary revascularization compared with patients with TAV.

(1) Background: The pathophysiologic basis of an acute type A aortic dissection (TAAD) is largely unknown. In an effort to evaluate vessel wall defects, we systematically studied aortic specimens in TAAD patients. (2) Methods: Ascending aortic wall specimens (n = 58, mean age 63 years) with TAAD were collected. Autopsy tissues (n = 17, mean age 63 years) served as controls. All sections were studied histopathologically. (3) Results: Pathomorphology in TAAD showed predominantly moderate elastic fiber fragmentation/loss, elastic fiber thinning, elastic fiber degeneration, mucoid extracellular matrix accumulation, smooth muscle cell nuclei loss, and overall medial degeneration. The control group showed significantly fewer signs of those histopathological features (none-mild, p = 0.00). It was concluded that the dissection plane consistently coincides with the vasa vasorum network, and that TAAD associates with a significantly thinner intimal layer p = 0.005). (4) Conclusions: On the basis of the systematic evaluation and the consistent presence of diffuse, pre-existing medial defects, we hypothesize that TAAD relates to a developmental defect of the ascending aorta and is caused by a triple-hit mechanism that involves (I) an intimal tear, and (II) a diseased media, which allows (III) propagation of the tear towards the plane of the vasa vasorum where the dissection further progresses.

Background: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in the tricuspid aortic valve (TAV) and the BAV populations as a reference for future studies on aortopathy and related syndromes. Methods: Non-dilated TAV and BAV ascending aortic wall samples were collected, including 60 TAV (embryonic&ndash, 70 years) and 32 BAV specimens (fetal&ndash, 72 years, categorized in eight age groups. Results: In TAV, intimal development starts in the neonatal phase. After birth, the thickness of the medial layer increases significantly by increase of elastic lamellae up to and including the &ldquo, young child&rdquo, phase stabilizing afterwards. The BAV shows already prenatal intimal thickening becoming significantly thinner after birth subsequently stabilizing. In BAV, increase in elastic lamellae is seen between the young child and the adolescent phases, stabilizing afterwards. Conclusions: Vascular development in TAV is described in three phases: maturation, stabilization, and degeneration. For BAV, the development can be described in two phases: maturation (already prenatally) and degeneration. After birth, the development of the aorta is characterized by degeneration, leading to weakening of the ascending aortic wall and increasing the risk of aortopathy.

Background: A bicuspid aortic valve (BAV) is the most common congenital cardiac malformation and is associated with ascending aortic dilation in 60%-80% of patients. In this study, we aimed to address the role of hemodynamic influences on the development of aortopathy in BAV patients.Patient and methods: BAV (n=36) and tricuspid aortic valve (TAV) patients (n=17) undergoing aortic valve replacement underwent preoperative flow magnetic resonance imaging (MRI) assessment to detect the area of maximal flow-induced stress in the proximal aorta. Based on these MRI data, paired ascending aortic wall samples [i.e., area of maximal jet impact (jet sample) and the opposite aortic wall (nonjet sample)] were collected during surgery. To study and describe the effects of jet stream on the complete vascular wall, a pathology score was developed based on the recently published aortic consensus paper statement on surgical pathology of the aorta using routine histologic stainings (resorcin fuchsin, hematoxylin-eosin, and Movat) and immunohistochemistry (alpha smooth muscle actin, smooth muscle 22 alpha, platelet endothelial cell adhesion molecule).Results: Comparing the jet and nonjet samples in both BAV and TAV, regions of maximal jet impact did not show any difference in the pathology score in the adventitia and the middle and outer media. In the jet samples, the inner media however showed loss of actin expression in both BAV (P

Background The clinical course of bicuspid aortic valves (BAVs) is variable. Data on predictors of aortopathy and valvular dysfunction mainly focus on valve morphology. Aim To determine whether the presence and extent of the raphe (fusion site of valve leaflets) is associated with the degree of aortopathy and valvular dysfunction in patients with isolated BAV and associated aortic coarctation (CoA). Methods Valve morphology and aortic dimensions of 255 BAV patients were evaluated retrospectively by echocardiography. Results BAVs with a complete raphe had a significantly higher prevalence of valve dysfunction (especially aortic regurgitation) than BAVs with incomplete raphes (82.9 vs. 66.7 %, p = 0.01). Type 1A BAVs (fusion of right and left coronary leaflets) and complete raphe had larger aortic sinus diameters compared with the rest of the population (37.74 vs. 36.01, p = 0.031). Patients with CoA and type 1A BAV had significantly less valve regurgitation (13.6 vs. 55.8 %, p p p Conclusions Type 1A BAV with complete raphe is associated with more aortic regurgitation and root dilatation. The majority of CoA patients have incomplete raphes, associated with smaller aortic root diameters and less valve regurgitation.

Patients with Marfan (MFS) syndrome and patients with a bicuspid aortic valve (BAV) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common as well as distinct pathways of clinical relevance, we compared the histopathological substrates of aortic pathology.Ascending aortic wall specimen were divided in five groups: BAV (n=36) and TAV (n=23) without and with dilation and non-dilated MFS (n=8). We performed routine histology to study aortic wall features based on the aortic consensus statement. Immunohistological markers for vascular smooth muscle cell (VSMC) maturation, and expression of fibrillin-1 were additionally investigated for the underlying pathogenesis.On basis of the routine histology the aorta in MFS was similar to the aorta in dilated TAVs (overall medial degeneration, elastic fiber fragmentation, loss and disorganization, , and VSMC nuclei loss). The other markers aided in clustering the MFS and BAV patients with a significantly lower fibrillin-1 expression as compared to the TAVs (p0.05), a lower level of differentiated VSMC markers (p0.05) and elastic fiber thinning.Pathogenesis of aortopathy in MFS overlaps with mechanisms seen in BAV and TAV, leading to a so called double hit hypothesis for aortic complications in MFS. The ascending aortic wall in MFS is immature with undifferentiated VSMCs and low levels of fibrillin-1. The immature media becomes even more vulnerable for aortopathy due to other degenerative features which develop probably as a direct consequence of the fibrillin-1 mutation.

Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expression of markers for vascular smooth muscle cell (VSMC) maturation, markers predictive for ascending aortic dilation in BAV, and expression of fibrillin-1 were investigated. Both MFS and BAV showed an altered distribution and decreased fibrillin-1 expression in the aorta and a significantly lower level of differentiated VSMC markers. Interestingly, markers predictive for aortic dilation in BAV were not expressed in the MFS aorta. The aorta in MFS was similar to the aorta in dilated TAV with regard to the presence of medial degeneration and apoptosis, while other markers for degeneration and aging like inflammation and progerin expression were low in MFS, comparable to BAV. Both MFS and BAV aortas have immature VSMCs, while MFS and TAV patients have a similar increased rate of medial degeneration. However, the mechanism leading to apoptosis is expected to be different, being fibrillin-1 mutation induced increased angiotensin-receptor-pathway signaling in MFS and cardiovascular aging and increased progerin in TAV. Our findings could explain why angiotensin inhibition is successful in MFS and less effective in TAV and BAV patients.

The ductus arteriosus (DA) is a fetal vessel bypassing the still nonfunctional lungs. Closure of the DA at birth is essential for the transition from a fetal to a neonatal circulation. This closing process begins with a physiological contraction followed by definitive anatomical closure. The latter process starts already before birth by development of intimal thickening followed after birth by degeneration of the inner media, including cytolytic necrosis and apoptosis. The DA will remain patent when there is insufficient maturation in prematurely born babies or when there is a structural abnormality as seen in persistent DA (PDA). The histological changes during normal DA closure resemble the features seen in the premature ageing vessels in children with the Hutchinson progeria syndrome. The latter syndrome is caused by a mutation in the lamin A/C gene resulting in accumulation of the progerin splice variant. We studied human DA biopsies from the fetal to the neonatal period to investigate whether lamin A/C and progerin might be involved in the DA closure process. The results show an increase in the intima and inner media of progerin in the normal neonatal DA, while expression of lamin A/C is diminished. In the non-closing aorta, the fetal DA and the PDA, no or hardly any progerin expression was found. We postulate that the lamin A/C to progerin balance is important during normal anatomical closure of the DA presenting a unique case of physiological premature vascular ageing.

OBJECTIVES: The clinical course of many patients with a bicuspid aortic valve (BAV) is complicated by ascending aortic dilatation. Currently, the indication for aortic surgery is solely based on the aortic diameter and subsequently only a small proportion of BAV patients undergoing valve surgery require concomitant ascending aortic replacement based on these recommendations. Unfortunately, a substantial number of BAV patients still develop aortic dilatation in the future and would potentially benefit from a more aggressive approach towards ascending aortic replacement. We, therefore, designed this study to identify molecular biological markers in the aortic wall predictive of aortopathy in BAV. METHODS: Ascending aortic wall specimen of BAV (n = 36) and tricuspid aortic valve (TAV) (n = 23), both without and with (>44 mm) dilatation were investigated histologically and immunohistochemically for the expression of markers for vascular remodelling [transforming growth factor (TGF)-β, phosphorylated Smad2, matrix metalloproteinase 9 (MMP9)], cellular differentiation [c-Kit, phosphorylated-c-Kit, hypoxia-inducable factor-1 alpha (HIF1α)] and haemodynamic influences on the aortic wall [endothelial nitric oxide (eNOS)]. RESULTS: All BAV patients showed significantly less inflammation (P < 0.001) and an altered intima/media ratio when compared with TAV patients. The expression of markers of a signalling pathway characteristic for cellular dedifferentiation, as exemplified by the marked expression of c-Kit, phosphorylated c-Kit and HIF1α; in the dilated BAV group was however completely comparable with only a subgroup of the non-dilated BAV (BAb), whereas the remainder of the non-dilated BAV group (BAa) was significantly distinct. This difference between the dilated BAV and BAa was further confirmed in the expression of TGF-β, phosphorylated Smad2, MMP9 and eNOS. Besides the expression pattern, similarity in the dilated BAV and BAb was also noted clinically in the most common variant of commissure position and conjoined raphe of the BAV. Based on these observations, we consider the BAb group a likely candidate for future dilatation as opposed to the BAa group. CONCLUSIONS: Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.

Objective Patients with a bicuspid aortic valve have increased susceptibility to the development of ascending aortic dilation and dissection compared with persons with a tricuspid valve. To unravel a possible different mechanism underlying dilation in bicuspidy and tricuspidy, a comparison of the structure of the aortic wall was made. Methods Ascending aortic wall biopsies were divided into 4 groups: bicuspid (n = 36) and tricuspid (n = 23) without and with dilation. The expression of vascular smooth muscle cell maturation markers including lamin A/C, which plays a pivotal role in smooth muscle cell differentiation, and its splicing variant progerin indicative of aging, were studied immunohistochemically. Attention was also paid to the inflammatory status. Results There is a significant difference in the structure and maturation of the aortic wall in bicuspidy, persisting in the dilated aortic wall, presenting with a thinner intima, lower expression of α smooth muscle actin, smooth muscle 22α, calponin, and almost absent expression of smoothelin. We show for the first time significantly lowered lamin A/C expression in bicuspidy. Progerin was found to be significantly increased in the media of the dilated wall in tricuspidy, also showing increased periaortic inflammation. Conclusions The structure of the nondilated and dilated aortic wall in bicuspidy and tricuspidy are intrinsically different, with the latter having more aspects of aging. In bicuspidy there is a defective smooth muscle cell differentiation possibly linked to lowered lamin A/C expression. Based on this vessel wall immaturity and increased susceptibility to dilation, different diagnostic and therapeutic approaches are warranted.

Dilation of the wall of the thoracic aorta can be found in patients with a tricuspid (TAV) as well as a bicuspid aortic valve (BAV) with and without a syndromic component. BAV is the most common congenital cardiovascular malformation, with a population prevalence of 0.5-2 %. The clinical course is often characterised by aneurysm formation and in some cases dissection. The non-dilated aortic wall is less well differentiated in all BAV as compared with TAV, thereby conferring inherent developmental susceptibility. Furthermore, a turbulent flow, caused by the inappropriate opening of the bicuspid valve, could accelerate the degenerative process in the aortic wall. However, not all patients with bicuspidy develop clinical complications during their life. We postulate that the increased vulnerability for aortic complications in a subset of patients with BAV is caused by a defect in the early development of the aorta and aortic valve. This review discusses histological and molecular genetic aspects of the normal and abnormal development of the aortic wall and semilunar valves. Aortopathy associated with BAV could be the result of a shared developmental defect during embryogenesis.