Aortic Valve Malformation Research Articles

Cleft-Like Formation of the Aortic Valve in an Adult Patient with a Single Coronary Artery

A 51-year-old woman was admitted to our hospital with heart failure due to aortic regurgitation. Examination showed severe aortic regurgitation mainly due to cleft-like deformity of the right coronary cusp and single coronary artery. Aortic valve replacement was performed, and the deformity was seen in all aortic cusps. Histological study showed elongation of the leaflets by myofibrotic and fibrotic hyperplasia without calcification and inflammation in the aortic valve. This deformity likely arose from an acquired modification of a congenitally malformed aortic valve.

Abstract P098: Inhibitory Role of Notch1 in Calcific Aortic Valve Disease Is Mediated by Sox9

Introduction: Aortic valve calcification is the most common form of valvular heart disease; however the mechanism(s) underlying calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. Objective: To investigate the molecular changes associated with the calcification of aortic valve that occurs with inhibition of Notch signaling. Methods and Results: The expression of Notch signaling pathway members was validated in the aortic valve cusps from adult mice, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1 signaling, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of many cartilage-specific genes that constitute the valve extracellular matrix (ECM). Analysis of these cartilage-specific genes demonstrated that several were transcriptional targets of Sox9, a master regulator of chondrogenesis, which has been previously shown to be essential for proper valve development and maintenance. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, utilizing transfection studies, addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. Conclusions: Loss of Notch signaling contributes to aortic valve calcification by a Sox9-dependent mechanism. Further elucidation of the Notch1-Sox9 molecular pathway and its role in the maintenance of the ECM will lead to an improved mechanistic understanding of aortic valve calcification and development of novel therapeutic strategies for CAVD.

Inhibitory role of Notch1 in calcific aortic valve disease.

Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.

Elastin Haploinsufficiency Results in Progressive Aortic Valve Malformation and Latent Valve Disease in a Mouse Model

Elastin is a ubiquitous extracellular matrix protein that is highly organized in heart valves and arteries. Because elastic fiber abnormalities are a central feature of degenerative valve disease, we hypothesized that elastin-insufficient mice would manifest viable heart valve disease. To analyze valve structure and function in elastin-insufficient mice (Eln(+/-)) at neonatal, juvenile, adult, and aged adult stages. At birth, histochemical analysis demonstrated normal extracellular matrix organization in contrast to the aorta. However, at juvenile and adult stages, thin elongated valves with extracellular matrix disorganization, including elastin fragment infiltration of the annulus, were observed. The valve phenotype worsened by the aged adult stage with overgrowth and proteoglycan replacement of the valve annulus. The progressive nature of elastin insufficiency was also shown by aortic mechanical testing that demonstrated incrementally abnormal tensile stiffness from juvenile to adult stages. Eln(+/-) mice demonstrated increased valve interstitial cell proliferation at the neonatal stage and varied valve interstitial cell activation at early and late stages. Gene expression profile analysis identified decreased transforming growth factor-beta-mediated fibrogenesis signaling in Eln(+/-) valve tissue. Juvenile Eln(+/-) mice demonstrated normal valve function, but progressive valve disease (predominantly aortic regurgitation) was identified in 17% of adult and 70% of aged adult Eln(+/-) mice by echocardiography. These results identify the Eln(+/-) mouse as a model of latent aortic valve disease and establish a role for elastin dysregulation in valve pathogenesis.

Aortopathy Is Prevalent in Relatives of Bicuspid Aortic Valve Patients

This study aimed to determine the prevalence of dilation and abnormal elastic properties of aortic root in first-degree relatives (FDRs) of bicuspid aortic valve (BAV) patients. Evidence indicates that BAV is a genetic disorder. Although FDRs of affected individuals have an increased prevalence of BAV, their risk of aortic root abnormalities is unknown. We studied dimensions as well as the elastic properties of the ascending aorta in 48 FDRs with morphologically normal tricuspid aortic valves, 54 BAV patients, and 45 control subjects using 2-dimensional echocardiography. The prevalence of aortic root dilation was 32% in FDRs and 53% in BAV patients, whereas all control subjects showed normal aortic dimensions (p < 0.001). The FDRs and BAVs had significantly lower aortic distensibility (1.7 +/- 1.4 x 10(-3) mm Hg and 1.4 +/- 2.0 x 10(-3) mm Hg vs. 2.5 +/- 1.6 x 10(-3) mm Hg, p < 0.001) and greater aortic stiffness index (26.7 +/- 25.8 and 55.9 +/- 76.8 vs. 18.7 +/- 40.1, p = 0.001) compared with control subjects. This difference remained significant in subjects without aortic root dilation or hypertension (p = 0.002 and p = 0.004, respectively). The aortic root is functionally abnormal and dilation is common (32%) in first-degree relatives of patients with BAV. Screening of FDRs by transthoracic 2-dimensional echocardiography should be considered for detection of aortic valve malformation and dilated ascending aorta.

Transesophageal Echocardiography of a Unicuspid Aortic Valve

Transesophageal Echocardiography of a Unicuspid Aortic Valve

Abstract 4278: Angiotensin II Receptor Antagonism and Transforming Growth Factor Beta and SMAD Signalling in Thoracic Aortic Aneurysm: Implications for Aneurysm Progression

Increased expression of transforming growth factor-beta (TGFβ) and Smad3 is associated with fibrosis and inflammatory cell infiltration in abdominal aortic aneurysm. In Smad3-null mice there is reduced extracellular matrix (ECM) deposition but enhanced neointimal hyperplasia in response to vascular injury suggesting a TGFβ/Smad3 role in ECM regulation and cell proliferation. In vitro studies show that exogenous TGFβ administration leads to phosphorylation and nuclear translocation of Smad3 while angiotensin II (AngII) induces fibrosis through TGFβ and Smad3 pathways. We investigated TGFβ/Smad3 signaling using immunohistochemical and cell culture studies in thoracic aortic aneurysm tissue derived from subjects with Marfan syndrome (MFS; 3M, 2F, 46±24yr, mean +/−SD) and bicuspid aortic valve malformation (BAV; (3M, 2F, 65±13yr) as well as normal aorta from organ donor subjects (3M, 2F 40±11yr). MFS and BAV tissue showed co-localisation of TGFβ1–3 and Smad3 in myofibroblasts, vascular smooth muscle cells (VSMCs) and chronic inflammatory cells in the subintimal layer and tunica media and in fibroblasts in tunica adventitia. In normal aortic wall there was minimal TGFβ and Smad3 staining. Cultured VSMCs (passage 1–5) from MFS and BAV showed nuclear Smad3 and strong cytoplasmic TGFβ1–3 expression in numerous vesicles and in areas of exocytosis and extracellular localisation. In control cells there was much weaker TGFβ1–3 staining compared to aneurysm derived cells. Smad3 staining in normal cells was located in the cytoplasm alone. Compared to normal tissue and cells AngII receptor type1 and 2 (ATR1 and 2) expression was increased in both aneurysm tissue and in cultured VSMCs derived from aneurysm. Cultured VSMCs were treated for 48h with the ATR1 antagonist losartan (10μM). This caused disappearance of TGFβ1–3 vesicle localisation and nuclear expression of Smad3. The findings of increased TGFβ1–3 and Smad3 expression in aneurysm tissue and cultured cells are consistent with aberrant TGFβ signalling and with activation of the Smad3 signalling pathway. Furthermore reduction in extracellular TGFβ and de-activation of Smad3 expression associated with losartan treatment supports a role for ATR1 antagonism in inhibition of aneurysm progression. Figure 1: Risk of IMH Conversion to Typical Dissection

Unicuspid Aortic Valve Disease: a Magnetic Resonance Imaging Study

Congenitally malformed aortic valves are a common finding in adults with aortic valve disease. Most of these patients have bicuspid aortic valve disease. Unicuspid aortic valve disease (UAV) is rare. The aim of our study was to describe valve morphology and the dimensions of the proximal aorta in a cohort of 12 patients with UAV in comparison to tricuspid aortic valve disease (TAV) using magnetic resonance imaging (MRI). MRI studies were performed on a 1.5 T scanner in a total of 288 consecutive patients with aortic valve disease. 12 aortic valves were retrospectively classified as UAV. Annulus areas and dimensions of the thoracic aorta were retrospectively compared to a cohort of 103 patients with TAV. In UAV, valve morphology was unicuspid unicommissural with a posterior commissure in all patients. Mean annulus areas and mean diameters of the ascending aorta were significantly greater in UAV compared to TAV (12.6 +/- 4.7 cm (2) vs. 8.7 +/- 2.3 cm (2), p < 0.01 and 4.6 +/- 0.7 cm vs. 3.6 +/- 0.5 cm, p < 0.0001, respectively), while no differences were observed in the mean diameters of the aortic arch (2.3 +/- 0.6 cm vs. 2.3 +/- 0.4 cm, p = 0.69). The diameters of the descending aorta were slightly smaller in UAV compared to TAV (2.2 +/- 0.5 cm vs. 2.6 +/- 0.3 cm, p < 0.05). In UAV, visualization of valve morphology by MRI is possible with good image quality. Valve morphology was classified as unicuspid unicommissural in all UAV patients. Dilatation of the proximal aorta > 4.5 cm is a frequent finding in UAV. Additional assessment of aortic dimensions is therefore recommended in patients with UAV.

Valve Structure and Survival in Quadragenarians Having Aortic Valve Replacement for Aortic Stenosis (±Aortic Regurgitation) With Versus Without Coronary Artery Bypass Grafting at a Single US Medical Center (1993 to 2005)

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in quadragenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed survival and valve structure in 48 adults (12 women), aged 40 to 49 years, having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 7 (15%) with and 41 (85%) without simultaneous CABG. Of the 48 quadragenarians, none died within 60 days of operation. Assessment of the relation between long-term survival and gender, aortic valve structure, preoperative severity of the AS, and concomitant CABG was not possible due to the low mortality. Four patients (9%) died >60 days after AVR: at 1.8, 6.3, 7.1, and 9.9 years, respectively. The aortic valve was congenitally unicuspid in 15 patients (31%), congenitally bicuspid in 32 (67%), and 3-cuspid in 1 (2%). In conclusion, of the 48 quadragenarians having AVR for AS, 47 (98%) had a congenitally malformed aortic valve, 60-day mortality was zero, and late mortality was low (8%).

Impact of Valvular Calcification on the Diagnostic Accuracy of Transesophageal Echocardiography for the Detection of Congenital Aortic Valve Malformation

Degeneration of congenital bicuspid or unicuspid aortic valves can progress more rapidly than that of tricuspid valves, and an early diagnosis significantly impacts decision making and outcome. We hypothesized that the extent of valvular calcification would negatively influence the diagnostic accuracy of multiplane transesophageal echocardiography (TEE) for the diagnosis of congenital aortic valve disease. TEE was performed in 57 patients undergoing aortic valve replacement surgery for aortic stenosis (n = 46), pure regurgitation (n = 9), or significant regurgitation with less than severe aortic stenosis (n = 2). The degree of aortic valve calcification and the number of valve cusps were determined at surgery. Surgical inspection confirmed 14 bicuspid and 43 tricuspid aortic valves. Sensitivity and specificity of TEE for the diagnosis of congenital aortic valve malformation was 93% (13/14) and 91% (39/43) (P = 0.0001), respectively. In patients with no or mild aortic valve calcification (n = 13), sensitivity and specificity of TEE for the diagnosis of congenitally malformed aortic valve was 100% (5/5) and 100% (8/8) (P = 0.001), respectively. In patients with moderate or marked aortic valve calcification (n = 44), sensitivity and specificity of TEE for the diagnosis of congenitally malformed aortic valve was 89% (8/9) and 89% (31/35) (P<0.0001), respectively. In this subgroup of 44 patients, there were four false-positive and one false-negative diagnoses due to valvular calcification. Although TEE is highly sensitive and specific for the detection of congenital aortic valve malformations, presence of moderate or marked calcification of the aortic valve may result in false positive and false negative diagnoses.

A classification system for the bicuspid aortic valve from 304 surgical specimens

In general, classification of a disease has proven to be advantageous for disease management. This may also be valid for the bicuspid aortic valve, because the term "bicuspid aortic valve" stands for a common congenital aortic valve malformation with heterogeneous morphologic phenotypes and function resulting in different treatment strategies. We attempted to establish a classification system based on a 5-year data collection of surgical specimens. Between 1999 and 2003 a precise description of valve pathology was obtained from operative reports of 304 patients with a diseased bicuspid aortic valve. Several different characteristics of bicuspid aortic valves were tested to generate a pithy and easily applicable classification system. Three characteristics for a systematic classification were found appropriate: (1) number of raphes, (2) spatial position of cusps or raphes, and (3) functional status of the valve. The first characteristic was found to be the most significant and therefore termed "type." Three major types were identified: type 0 (no raphe), type 1 (one raphe), and type 2 (two raphes), followed by two supplementary characteristics, spatial position and function. These characteristics served to classify and codify the bicuspid aortic valves into three categories. Most frequently, a bicuspid aortic valve with one raphe was identified (type 1, n = 269). This raphe was positioned between the left (L) and right (R) coronary sinuses in 216 (type 1, L/R) with a hemodynamic predominant stenosis (S) in 119 (type 1, L/R, S). Only 21 patients had a "purely" bicuspid aortic valve with no raphe (type 0). A classification system for the bicuspid aortic valve with one major category ("type") and two supplementary categories is presented. This classification, even if used in the major category (type) alone, might be advantageous to better define bicuspid aortic valve disease, facilitate scientific communication, and improve treatment.

Histopathological study of congenital aortic valve malformations in 32 children

The histopathological characteristics of congenital aortic valve malformations in children were investigated. All the native surgically excised aortic valves from 32 pediatric patients suffering from symptomatic aortic valve dysfunction due to congenital aortic valve malformations between January 2003 and December 2005 were studied macroscopically and microscopically. The patients' medical records were reviewed and the clinical information was extracted. The diagnosis was made by the clinical presentation, preoperative echocardiography, intraoperative examination, and postoperative histopathological study, excluding rheumatic or degenerative aortic valve diseases, infective endocarditis and primary connective tissue disorders, e.g. Marfan syndrome. Among 32 children with congenital aortic valve malformations, the age was ranged from six to 18 years, with a mean of 14.9 years, and there were 27 boys and five girls (male: female = 5.4:1). There were five cases of aortic stenosis (AS, 15.62%), 25 cases of aortic insufficiency (AI, 78.13%) and two cases of AS-AI (6.25%), without other valve diseases. Twenty cases still had other congenital heart diseases: ventricular septal defect (19 cases), patent ductus arteriosus (two cases), double-chambered right ventricle (one case), aneurysm of the right anterior aortic sinus of valsalva (three cases). Histopathological examination indicated that the cusps became thickening with unequal size, irregular shape (coiling and prolapse edge), enhanced hardness, and partly calcification. Microscopic investigation revealed the unsharp structure of valve tissue, fibrosis, myxomatous, reduced collagen fiber, rupture of elastic fibers, different degrees of infiltration of inflammatory cells, secondary calcareous and lipid deposit, and secondary fibrosis. Congenital aortic valve malformations in children involve males more than females, mostly associated with other congenital heart diseases. Aortic insufficiency is more common in children with congenital aortic valve malformations. Histopathologically, the leaflets of aortic valve are mainly myxomatous, thickening with unequal size, irregular shape (coiling and prolapse edge), reduced collagen fiber, rupture of elastic fibers, without small vessel proliferation and inflammatory cell infiltration, fibrosis and calcification rarely seen.

A Clinicopathological Study on Aortic Valves in Children

In order to investigate the clinicopathological characteristics of aortic valve disease in children, all the native surgically excised aortic valves obtained between January 2003 and December 2005 were studied macroscopically and microscopically. The patients’ medical records were reviewed and the clinical information was extracted. According to preoperative echocardiography, intraopera- tive assessment, and postoperative pathology, combined with clinical symptoms and signs, aortic valve diseases were divided into three categories: aortic stenosis (AS), aortic insufficiency (AI), and aortic stenosis with insufficiency (AS-AI). The etiology was determined according to the macro- scopic, microscopic and clinical findings. The results showed that among 70 aortic valves, patient age ranged from 6 to 18 years, with a mean of 15.4 years, and there were 56 boys and 14 girls (male: fe- male=4:1). Forty-four children only had pure aortic valve disease, and the other 26 children had aor- tic valve disease associated with other heart valve diseases. There were 5 cases of AS (7.14%), 60 cases of AI (85.71%) and 5 cases of AS-AI (7.14%). The causes were congenital aortic valve mal- formation (32 cases, 45.71%), rheumatic disease (28 cases, 40%), infective endocarditis (7 cases, 10%), Marfan syndrome (2 cases, 2.86%), and undetermined (1 case, 1.43%). It was concluded that the common causes of aortic valve disease in order of frequency in children were congenital aortic valve malformation, rheumatic disease, infective endocarditis, and Marfan syndrome. AI was more common in children with aortic valve disease. Compared with adult patients, congenital bicuspid aor- tic valve in children was often AI. Histologically, the leaflets of congenital bicuspid aortic valve were mainly myxomatous, fibrosis and calcification less seen. AI was frequently found in rheumatic dis- ease, mostly associated with other heart valve diseases. Macroscopic and microscopic examinations together with clinical information, echocardiographic findings a

Correlations with operative anatomy of real time three-dimensional echocardiographic imaging of congenital aortic valvar stenosis

To define the anatomic characteristics of the congenitally malformed and severely stenotic aortic valve using trans-thoracic real time three-dimensional echocardiography, and to compare and contrast this with the valvar morphology as seen at surgery. Prospective cross-sectional observational study. Tertiary centre for paediatric cardiology. All patients requiring aortic valvotomy between December 2003 and July 2004 were evaluated prior to surgery with three-dimensional echocardiography. Full volume loop images were acquired using the Phillips Sonos 7500 system. A single observer analysed the images using "Q lab 4.1" software. The details were then compared with operative findings. We identified 8 consecutive patients, with a median age of 16 weeks, ranging from 1 day to 11 years, with median weight of 7.22 kilograms, ranging from 2.78 to 22 kilograms. The measured diameter of the valvar orifice, and the number of leaflets identified, corresponded closely with surgical assessment. The sites of fusion of the leaflets were correctly identified by the echocardiographic imaging in all cases. Fusion between the right and non-coronary leaflets was identified in half the patients. Dysplasia was observed in 3 patients, with 1 patient having nodules and 2 shown to have excrescences. At surgery, nodules were excised, and excrescences were trimmed. The dysplastic changes correlated well with operative findings, though statistically not significant. We recommend trans-thoracic real time three-dimensional echocardiography for the assessment of the congenitally malformed aortic valve, particularly to identify sites of fusion between leaflets and to measure the orificial diameter. The definition of nodularity, and the prognosis of nodules based on the mode of intervention, will need a comparative study of patients submitted to balloon dilation as well as those undergoing surgical valvotomy.

Molecular genetics of aortic valve disease

Bicuspid aortic valve is the most common type of cardiac malformation and predisposes to aortic valve calcification, which is the third leading cause of heart disease in adults. These seemingly temporally disparate diseases have been described as having genetic influences but limited data exist on the precise genetic causes in humans. Several advances in the molecular genetics of aortic valve formation and calcification have recently been identified and are described here. A large family with autosomal-dominant aortic valve disease consisting of bicuspid aortic valve and aortic valve calcification was studied using genome-wide linkage analysis. This led to the identification of a nonsense mutation in NOTCH1 in affected individuals. This finding was supported by the discovery of a NOTCH1 frameshift mutation in an unrelated family with similar aortic valve disease, suggesting that NOTCH1 haploinsufficiency was a genetic cause of aortic valve malformations and calcification. The NOTCH signaling pathway was linked to a molecular pathway for aortic valve calcification, as NOTCH1 was found to repress activation of Runx2 - a transcription factor critical for osteoblast cell fate that is up-regulated in calcified human aortic valves. The recent genetic and biochemical findings provide novel insights into the molecular and genetic basis for aortic valve dysmorphogenesis and calcification. Future studies focusing on the identification of additional disease-causing and susceptibility genes will aid in the development of prevention strategies. Ultimately, it will be the careful dissection of these molecular pathways that will hopefully lead to novel therapeutic options.

Comparison of Valve Structure, Valve Weight, and Severity of the Valve Obstruction in 1849 Patients Having Isolated Aortic Valve Replacement for Aortic Valve Stenosis (With or Without Associated Aortic Regurgitation) Studied at 3 Different Medical Centers in 2 Different Time Periods

Aortic valve replacement (AVR) for patients with aortic stenosis (AS) has now been available for 45 years. During this period, indications for the procedure have changed. Operatively excised stenotic aortic valves (with or without associated aortic regurgitation and without associated mitral valve disease) from 3 different medical centers (National Institutes of Health, Georgetown University Medical Center, and Baylor University Medical Center) were examined during 2 different time periods by the same physician to compare aortic valve structure, valve weight, age at operation, preoperative transvalvular peak pressure gradient, calculated aortic valve area, and whether simultaneous coronary artery bypass grafting (CABG) was performed. Compared with the first 3 decades (1961-1990) of AVR, patients having this operation during the fourth and fifth decades (1991-2004) had a lower frequency of congenitally malformed aortic valves, a higher frequency of tricuspid aortic valves, an older age, valves of lighter weight and lower transvalvular peak pressure gradients, and more often simultaneous CABG. Although patients having isolated AVR for AS in the present and last decade were older than in the first 3 decades of valve replacement surgery, congenitally malformed aortic valves continue to be more common than tricuspid aortic valves, but the degree of AS and therefore, valve weight was significantly lower than in the earlier decades.

Can statin therapy alter the natural history of bicuspid aortic valves?

patients with bicuspid aortic valve (BAV) malformations, the most common congenital cardiac abnormality, are at significantly higher lifetime risk of developing aortic stenosis, aortic regurgitation, aortic root dilatation, infective endocarditis, aortic aneurysm, and aortic dissection.

The Bicuspid Aortic Valve

The population frequency of a bicuspid aortic valve is ≈0.9% to 1.36%,1–3 with a 2:1 male:female ratio. It is likely that the presence of a bicuspid aortic valve has a genetic basis, with the pattern of transmission in some families suggesting an autosomal dominant pattern of inheritance.4,5 Epidemiological data from the Baltimore-Washington Infant Study demonstrated the familial clustering of left heart obstructive lesions (including coarctation of the aorta, aortic valve stenosis, and hypoplastic left heart syndrome).6 More recently, the increased risk of identifying a bicuspid aortic valve in the parent or sibling of the proband with any form of left heart obstructive lesion was described.7 By inference, this also suggests the potential identification of a congenitally malformed aortic valve in the presence a family member with a more complex congenital heart lesion. In addition, a bicuspid aortic valve is present in >50% of patients with aortic coarctation8 and in 10% to 12% of women with Turner syndrome.9 The specific genetic locus and protein abnormality in patients with a bicuspid aortic valve have not yet been identified, however. See p 920 The tissue abnormality in patients with a bicuspid aortic valve is not confined to the valve leaflets; these patients are at increased risk of aortic aneurysm and dissection. At the tissue level, the aorta shows cystic medial necrosis, loss of elastic fibers, increased apoptosis, and altered smooth muscle cell alignment.10 When compared with patients with a trileaflet valve, patients with a bicuspid valve have larger aortic root dimensions and an increased rate of aortic dilation over time, with the degree of aortic dilation independent of valve hemodynamics.11,12 The risk of aortic dissection in patients with a bicuspid valve is 5 to 9 times higher than in the general population, although some investigators …

Structural alterations of the aorta in patients with bicuspid aortic valve malformations

Objectives: Tunica media is the largest layer that integrates and stabilizes the aortic wall. It consists besides elastin and collagen of smooth muscle cells (SMC). SMCs thought to initiate apoptosis in aneurysm formation of the aorta in patients with bicuspid aortic valve (BAV) and in Marfan syndrome (MS). However, a localisation in apoptosis signaling is unkown.

Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation

BackgroundPatients with bicuspid aortic valve malformations are at an increased risk of aortic dilatation, aneurysm formation, and dissection. Vascular tissues with deficient fibrillin-1 microfibrils release matrix metalloproteinases, enzymes that weaken the vessel wall by degrading elastic matrix components. In bicuspid aortic valve disease a deficiency of fibrillin-1 and increased matrix metalloproteinase matrix degradation might result in aortic degeneration and dilatation. MethodsSamples of the pulmonary artery and aorta were obtained from surgical patients with bicuspid aortic valves (n = 21) and tricuspid aortic valves (n = 16). ResultsFibrillin-1 content was reduced in bicuspid aortic valve aortas compared with that seen in tricuspid aortic valve aortas (P = .001), whereas the associated matrix components, elastin and collagen, were unchanged (P = .51 and P = .21). Reductions of aortic fibrillin-1 content were independent of valve function and patient age. Compared with tricuspid aortic valve aorta, matrix metalloproteinase 2 activity was increased more than 2-fold in bicuspid aortic valve aortas (P = .04) and correlated positively with aortic diameter (r = 0.74, P = .05). Matrix metalloproteinase 9 activity was not significantly different. Fibrillin-1 content was also reduced in the pulmonary arteries of patients with bicuspid aortic valves (P = .06), suggesting a systemic deficiency of fibrillin-1. Promatrix metalloproteinase 2 was increased (P = .04), reflecting an increased production of matrix metalloproteinase 2 in these fibrillin-1–deficient tissues, whereas active matrix metalloproteinase 2 and matrix metalloproteinase 9 species were unchanged, and correspondingly, the pulmonary arteries were not dilated. ConclusionsDeficient fibrillin-1 content in the vasculature of patients with bicuspid aortic valves might trigger matrix metalloproteinase production, leading to matrix disruption and dilatation. This process of vascular matrix remodeling in patients with bicuspid aortic valves offers novel therapeutic targets to prevent the aortic degeneration and dilatation characteristic of this disease.