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.

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. Besides structural abnormalities of the vascular wall, a turbulent blood flow, caused by bicuspid valve geometry, could expedite the pathological process in the aortic wall, leading to aortopathy. 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.

The Leiden Convention coronary coding system: translation from the surgical to the universal view.

AIMS: The Leiden Convention coronary coding system structures the large variety of coronary anatomical patterns; isolated and in congenital heart disease. It is widely used by surgeons but not by cardiologists as the system uses a surgeons' cranial view. Since thoracic surgeons and cardiologists work closely together, a coronary coding system practical for both disciplines is mandatory. To this purpose, the 'surgical' coronary coding system was adapted to an 'imaging' system, extending its applicability to different cardiac imaging techniques. METHODS AND RESULTS: The physician takes place in the non-facing sinus of the aortic valve, oriented with the back towards the pulmonary valve, looking outward from the sinus. From this position, the right-hand sinus is sinus 1, and the left-hand sinus is sinus 2. Next, a clockwise rotation is adopted starting at sinus 1 and the encountered coronary branches described. Annotation of the normal anatomical pattern is 1R-2LCx, corresponding to the 'surgical' coding system. The 'imaging' coding system was made applicable for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), echocardiography, and coronary angiography, thus facilitating interdisciplinary use. To assess applicability in daily clinical practice, images from different imaging modalities were annotated by cardiologists and cardiology residents and results scored. The average score upon evaluation was 87.5%, with the highest scores for CT and MRI images (average 90%). CONCLUSION: The imaging Leiden Convention is a coronary coding system that unifies the annotation of coronary anatomy for thoracic surgeons, cardiologists, and radiologists. Validation of the coding system shows it can be easily and reliably applied in clinical practice.

Ventricular Septation and Outflow Tract Development in Crocodilians Result in Two Aortas with Bicuspid Semilunar Valves.

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.

Extent of Coronary Artery Disease in Patients With Stenotic Bicuspid Versus Tricuspid Aortic Valves.

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<0.001). Patients with BAV had lower coronary artery greater even than 20 (1.61±2.35 versus 3.60±2.79) and coronary artery greater even than 50 (1.24±2.43 versus 3.37±3.49) scores (P<0.001), even after correcting for CAD risk factors (P<0.001). Patients with TAV more often needed concomitant coronary revascularization (OR, 3.50; 95% CI, 2.42-5.06; P<0.001). 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.

A Systematic Histopathologic Evaluation of Type-A Aortic Dissections Implies a Uniform Multiple-Hit Causation.

(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.

Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy.

Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3-/- mice, a model with congenital BAV formation. A combination of histological examination and in vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3-/- mice. Moreover, cell lineage analysis and single-cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3-/- mice. Spontaneous aortic dissections were found in ascending aortas located at the sinotubular junction in ∼13% of Nos3-/- mice. Moreover, Nos3-/- mice were prone to developing aortic dilations in the proximal and distal ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3-/- mice, as well as incomplete coverage of the aortic inner media by neural crest cell (NCC)-derived VSMCs. VSMCs of Nos3-/- mice showed downregulation of 15 genes, of which seven were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that, in addition to congenital BAV formation, disrupted endothelial-mediated nitric oxide (NO) signalling in Nos3-/- mice also causes aortic dilation and dissection, as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta.

Transforming Growth Factor Beta3 is Required for Cardiovascular Development.

Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3-/- fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3-/- fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3-/- fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFß3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFß3 was required for collagen matrix reorganization. Biochemical studies indicated the 'paradoxically' increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFß3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFß signaling pathways.

Pulmonary ductal coarctation and left pulmonary artery interruption; pathology and role of neural crest and second heart field during development.

OBJECTIVES: In congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary ductal coarctation) or even interruption We investigated embryonic remodelling and pathogenesis of this area. MATERIAL AND METHODS: Normal development was studied in WntCre reporter mice (E10.0-12.5) for neural crest cells and Nkx2.5 immunostaining for second heart field cells. Data were compared to stage matched human embryos and a VEGF120/120 mutant mouse strain developing pulmonary atresia. RESULTS: Normal mouse and human embryos showed that the mid-pharyngeal endothelial plexus, connected side-ways to the 6th pharyngeal arch artery. The ventral segment formed the proximal pulmonary artery. The dorsal segment (future DA) was solely surrounded by neural crest cells. The ventral segment had a dual outer lining with neural crest and second heart field cells, while the distal pulmonary artery was covered by none of these cells. The asymmetric contribution of second heart field to the future pulmonary trunk on the left side of the aortic sac (so-called pulmonary push) was evident. The ventral segment became incorporated into the pulmonary trunk leading to a separate connection of the left and right pulmonary arteries. The VEGF120/120 embryos showed a stunted pulmonary push and a variety of vascular anomalies. SUMMARY: Side-way connection of the DA to the left pulmonary artery is a congenital anomaly. The primary problem is a stunted development of the pulmonary push leading to pulmonary stenosis/atresia and a subsequent lack of proper incorporation of the ventral segment into the aortic sac. Clinically, the aberrant smooth muscle tissue of the ductus arteriosus should be addressed to prohibit development of severe pulmonary ductal coarctation or even interruption of the left pulmonary artery.

Human epicardium-derived cells reinforce cardiac sympathetic innervation.

RATIONALE: After cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of epicardium causes epicardium-derived cells (EPDCs) to acquire a mesenchymal character, contributing to cardiac regeneration. Whether EPDCs also contribute to cardiac re/hyperinnervation, is unknown. AIM: To investigate whether mesenchymal EPDCs influence cardiac sympathetic innervation. METHODS AND RESULTS: Sympathetic ganglia were co-cultured with mesenchymal EPDCs and/or myocardium, and neurite outgrowth and sprouting density were assessed. Results showed a significant increase in neurite density and directional (i.e. towards myocardium) outgrowth when ganglia were co-cultured with a combination of EPDCs and myocardium, as compared to cultures with EPDCs or myocardium alone. In absence of myocardium, this outgrowth was not directional. Neurite differentiation of PC12 cells in conditioned medium confirmed these results via a paracrine effect, in accordance with expression of neurotrophic factors in myocardial explants co-cultured with EPDCs. Of interest, EPDCs increased the expression of nerve growth factor (NGF) in cultured, but not in fresh myocardium, possibly due to an "ischemic state" of cultured myocardium, supported by TUNEL and Hif1α expression. Cardiac tissues after myocardial infarction showed robust NGF expression in the infarcted, but not remote area. CONCLUSION: Neurite outgrowth and density increases significantly in the presence of EPDCs by a paracrine effect, indicating a new role for EPDCs in the occurrence of sympathetic re/hyperinnervation after cardiac damage.

The Development of the Ascending Aortic Wall in Tricuspid and Bicuspid Aortic Valve: A Process from Maturation to Degeneration.

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-70 years) and 32 BAV specimens (fetal-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 "young child" 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.

Development and evolution of the metazoan heart.

The mechanisms of the evolution and development of the heart in metazoans are highlighted, starting with the evolutionary origin of the contractile cell, supposedly the precursor of cardiomyocytes. The last eukaryotic common ancestor is likely a combination of several cellular organisms containing their specific metabolic pathways and genetic signaling networks. During evolution, these tool kits diversified. Shared parts of these conserved tool kits act in the development and functioning of pumping hearts and open or closed circulations in such diverse species as arthropods, mollusks, and chordates. The genetic tool kits became more complex by gene duplications, addition of epigenetic modifications, influence of environmental factors, incorporation of viral genomes, cardiac changes necessitated by air-breathing, and many others. We evaluate mechanisms involved in mollusks in the formation of three separate hearts and in arthropods in the formation of a tubular heart. A tubular heart is also present in embryonic stages of chordates, providing the septated four-chambered heart, in birds and mammals passing through stages with first and second heart fields. The four-chambered heart permits the formation of high-pressure systemic and low-pressure pulmonary circulation in birds and mammals, allowing for high metabolic rates and maintenance of body temperature. Crocodiles also have a (nearly) separated circulation, but their resting temperature conforms with the environment. We argue that endothermic ancestors lost the capacity to elevate their body temperature during evolution, resulting in ectothermic modern crocodilians. Finally, a clinically relevant paragraph reviews the occurrence of congenital cardiac malformations in humans as derailments of signaling pathways during embryonic development.

The role of hemodynamics in bicuspid aortopathy: a histopathologic study.

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<.0001) and the TAV (P=.0074), and the intimal thickness was significantly enlarged in both patient groups (BAV P=.0005, TAV P=.0041), which was not accompanied by loss of elastic lamellae or vascular smooth muscle cell nuclei. CONCLUSIONS: In our study population, we could not demonstrate a potential distinct role for hemodynamics in the development of aortopathy in BAV patients even if corrected for aortic diameter, raphe position, or whether the valve is stenotic or regurgitant. The intimal layer and inner media however showed alterations in all jet specimens.

Disruption of RHOA-ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node.

The RHOA-ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. The current study aims to detect functional AVN disorders after disturbing RHOA-ROCK signaling in chicken embryos. RHOA-ROCK signaling was inhibited chemically by using the Rho-kinase inhibitor compound Y-27632 in avian embryos (20 experimental and 29 control embryos). Morphological examination of control embryos show a myocardial sinus venosus to atrioventricular canal continuity, contributing to the transitional zone of the AVN. ROCK inhibited embryos revealed lateralization and diminished myocardial sinus venosus to atrioventricular canal continuity and at the severe end of the phenotype hypoplasia of the AVN region. Ex ovo micro-electrode recordings showed an AV conduction delay in all treated embryos as well as cases with first, second (Wenkebach and Mobitz type) and third-degree AV block which could be explained by the spectrum of severity of the morphological phenotype. Laser capture microdissection and subsequent qPCR of tissue collected from this region revealed disturbed expression of HCN1, ISL1, and SHOX2. We conclude that RHOA-ROCK signaling is essential for normal morphological development of the myocardial continuity between the sinus venosus and AVN, contributing to the transitional zone, and possibly the compact AVN region. Disturbing the RHOA-ROCK signaling pathway results in AV conduction disturbances including AV block. The RHOA-ROCK inhibition model can be used to further study the pathophysiology and therapeutic strategies for AV block. Anat Rec, 302:83-92, 2019. © 2018 Wiley Periodicals, Inc.

Hemodynamics in Cardiac Development.

The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development, the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological alterations of the heart after changing the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, which might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to abnormal development of the aortopulmonary septal complex and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including an extended review of the involved Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfß/Bmp/Smad networks.

Bicuspid aortic valve formation: Nos3 mutation leads to abnormal lineage patterning of neural crest cells and the second heart field.

The bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, belongs to the most prevalent congenital heart diseases in the world, occurring in 0.5-2% of the general population. We aimed to understand how changes in early cellular contributions result in BAV formation and impact cardiovascular outflow tract development. Detailed 3D reconstructions, immunohistochemistry and morphometrics determined that, during valvulogenesis, the non-coronary leaflet separates from the parietal outflow tract cushion instead of originating from an intercalated cushion. Nos3-/- mice develop a BAV without a raphe as a result of incomplete separation of the parietal outflow tract cushion into the right and non-coronary leaflet. Genetic lineage tracing of endothelial, second heart field and neural crest cells revealed altered deposition of neural crest cells and second heart field cells within the parietal outflow tract cushion of Nos3-/- embryos. The abnormal cell lineage distributions also affected the positioning of the aortic and pulmonary valves at the orifice level. The results demonstrate that the development of the right and non-coronary leaflets are closely related. A small deviation in the distribution of neural crest and second heart field populations affects normal valve formation and results in the predominant right-non-type BAV in Nos3-/- mice.

Coding of coronary arterial origin and branching in congenital heart disease: The modified Leiden Convention.

OBJECTIVES: Variations in coronary anatomy are common and may relate to the position of the coronary ostium relative to the aortic sinus, the angle of coronary take-off, or the course of the coronary arterial branches. Several classification systems have been proposed. However, they all lack a simple rationale that is applicable irrespective of the relative position of the great arteries, as well as in bicuspid aortic valves. We present a modification of a relatively simple system introduced in the early 1980s, designated the "Leiden Convention." METHODS: The first step of the Leiden Convention is that the clinician takes position in the nonfacing sinus of the aorta looking toward the pulmonary orifice. The right-hand facing sinus is sinus 1, and the left-hand facing sinus is sinus 2. The coronary branches arising from sinus 1 are annotated proceeding in a counterclockwise fashion toward sinus 2. "Usual" (normal) coronary anatomy would be 1R-2LCx. Given their clinical relevance, single sinus coronary arteries are discussed separately. RESULTS: This system was originally designed and highly applicable in hearts with an altered great artery relationship, such as in the variable and complicated patterns seen in transposition of the great arteries and double outlet right ventricle. The modified system also can be used in cases with normally related great arteries, cases with single sinus coronary arteries, and cases with bicuspid aortic valves. CONCLUSIONS: The modified Leiden Convention is not a strict classification but a simple coronary coding system that is broadly applicable.

Pathogenesis of aortic wall complications in Marfan syndrome.

BACKGROUND: 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. PATIENT AND METHODS: 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. RESULTS: 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 (p<0.05), a lower level of differentiated VSMC markers (p<0.05) and elastic fiber thinning. CONCLUSIONS: 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.

Pulmonary Valve Morphology in Patients with Bicuspid Aortic Valves.

The aortic and pulmonary valve share a common developmental origin from the embryonic arterial trunk. Bicuspid aortic valve is the most common congenital anomaly and can occur isolated as well as in association with other congenital heart disease (CHD). Data on pulmonary valve morphology in these cases are scarce. In this study, we aimed to determine pulmonary valve morphology in hearts with BAV associated with CHD. In 83 post-mortem heart specimens with BAV and associated CHD, pulmonary valve morphology was studied and related to BAV morphology. In 14/83 (17%) hearts, the pulmonary valve was affected, bicuspid in 8/83 (10%), dome-shaped in 3/83 (4%) and atretic in 3/83 (4%). In specimens with a bicuspid pulmonary valve, 5/8 (63%) had a strictly bicuspid aortic valve (without raphe), 2/3 hearts (67%) with dome-shaped pulmonary valves and 2/3 hearts (67%) with atretic pulmonary valves had BAV without raphe. Six out of eight (75%) specimens with a bicuspid pulmonary valve had a perimembranous ventricular septal defect (VSD). 4/8 (50%) specimens with a bicuspid pulmonary valve were associated with chromosomal abnormalities: 3 (38%) had trisomy 18 and 1 (13%) had trisomy 13. In BAV with associated CHD, abnormal pulmonary valve morphology was observed in 17% of the hearts. The majority of hearts with abnormal pulmonary valve morphology had a Type B bicuspid aortic valve (without raphe). Bilateral semilunar valvular disease is associated with Type B BAVs and in many cases related to chromosomal abnormalities. As this study was performed in post-mortem specimens with high frequency of associated CHD, caution is warranted with application of these results to the general BAV population.