Congenital Aortic Valve Malformation Research Articles

Identification of congenital aortic valve malformations in juvenile natriuretic peptide receptor 2-deficient mice using high-frequency ultrasound.

Mouse models of congenital aortic valve malformations are useful for studying disease pathobiology, but most models have incomplete penetrance [e.g., ∼2 to 77% prevalence of bicuspid aortic valves (BAVs) across multiple models]. For longitudinal studies of pathologies associated with BAVs and other congenital valve malformations, which manifest over months in mice, it is operationally inefficient, economically burdensome, and ethically challenging to enroll large numbers of mice in studies without first identifying those with valvular abnormalities. To address this need, we established and validated a novel in vivo high-frequency (30 MHz) ultrasound imaging protocol capable of detecting aortic valvular malformations in juvenile mice. Fifty natriuretic peptide receptor 2 heterozygous mice on a low-density lipoprotein receptor-deficient background (Npr2+/-;Ldlr-/-; 32 males and 18 females) were imaged at 4 and 8 wk of age. Fourteen percent of the Npr2+/-;Ldlr-/- mice exhibited features associated with aortic valve malformations, including 1) abnormal transaortic flow patterns on color Doppler (recirculation and regurgitation), 2) peak systolic flow velocities distal to the aortic valves reaching or surpassing ∼1,250 mm/s by pulsed-wave Doppler, and 3) putative fusion of cusps along commissures and abnormal movement elucidated by two-dimensional (2-D) imaging with ultrahigh temporal resolution. Valves with these features were confirmed by ex vivo gross anatomy and histological visualization to have thickened cusps, partial fusions, or Sievers type-0 bicuspid valves. This ultrasound imaging protocol will enable efficient, cost effective, and humane implementation of studies of congenital aortic valvular abnormalities and associated pathologies in a wide range of mouse models.NEW & NOTEWORTHY We developed a high-frequency ultrasound imaging protocol for diagnosing congenital aortic valve structural abnormalities in 4-wk-old mice. Our protocol defines specific criteria to distinguish mice with abnormal aortic valves from those with normal tricuspid valves using color Doppler, pulsed-wave Doppler, and two-dimensional (2-D) imaging with ultrahigh temporal resolution. This approach enables early identification of valvular abnormalities for efficient and ethical experimental design of longitudinal studies of congenital valve diseases and associated pathologies in mice.

An 18-year evolution of congenital heart disease in China: An echocardiographic database-based study

ObjectiveData on the evolution of congenital heart disease (CHD) in China remain scarce. Based on a Chinese echocardiography database, we analyzed the observed rate (OR) and spectrum changes of CHD over the past 18 years with a focus on the congenital aortic valve malformation (CAVM) and Adult CHD (ACHD). Methods and resultsThe transthoracic echocardiographic data of 682,565 records from 2003 to 2020 were retrospectively reviewed at Fujian Medical University Union Hospital, China. A total of 37,200 CHD cases were recruited in this study. Over the three periods (from 2003 to 2008, 2009–2014, to 2015–2020), the OR of Total CHD decreased (106.72, 90.64, and 67.43 per 1000 cases, respectively); the proportion of Simple CHD to Total CHD increased (80.96%, 83.41%, and 87.97%, respectively), with a decrease in the proportion of Complex CHD (18.11%, 15.51%, and 10.42%, respectively) (p < 0.05 for all). The proportion of ACHD increased in most types of CHD [Total CHD: 25.79%, 27.84%, and 31.43%; CAVM: 69.02%, 73.42%, and 78.16%; CAVM with aortic stenosis (AS): 67.42%, 70.73%, and 79.25%; respectively, p < 0.05 for all], with a much higher proportion in both CAVM and CAVM with AS than in the other CHD types. The proportion of CHD patients receiving intervention increased over the designated periods. ConclusionsThis study depicts the longitudinal changes of CHD in the Chinese population with a single-center echocardiographic data, revealing an increased proportion of Simple CHD, ACHD (including CAVM and CAVM with AS), and a decreased OR of Total CHD and proportion of Complex CHD.

Surgical treatment of aortic paravalvular abscess by infective endocarditis

To summarize the clinical features, pathology and surgical treatment experiences in the patients with aortic paravalvular abscess by infective endocarditis. The study consisted of a retrospective analysis of 29 cases with aortic paravalvular abscess by infective endocarditis underwent surgical treatment between January 2001 and June 2013. Among the 29 patients, 22 were male and 7 were female, and the mean age was (37 ± 16) years (range from 11 to 63 years). The primary cardiac disease was congenital aortic valve malformation in 16 patients. There were 15 patients with a history of severe heart failure. Of 29 cases, 8 abscess cavities, 13 pseudoaneurysms and 6 fistulas were found, and complete aortoventricular discontinuity was present in 5 patients with serious infections. Of them, the abscess was above the annulus in 14 patients and below the annulus in 10 patients, and simultaneously involved the annulus above and below in 5 patients. 19 patients were culture positive either positive preoperative blood cultures or positive cultures of surgical specimens, including 9 patients with Staphylococcus infection. The paravalvular defect was repaired by patch in 19 cases, and by local closure in 10 cases. The valvular annulus was reconstructed simultaneously in 16 patients. Aortic valve replacement was performed in 26 patients, and Bentall procedure in 2 patients, including 23 with prosthetic mechanical valve and 5 with biological valve. Of the total 29 patients, 28 patients were recovered, and 1 patient was died of sepsis. During 3 months to 13 years postoperative follow-up (average 4.5 years), one was died of non-cardiac cause, and no patient had recurrent endocarditis and paravalvular leakage. Aortic paravalvular abscess by infective endocarditis is not uncommon, prone to heart failure. According to the different pathological manifestations, the appropriate surgical approach and strategy can achieve satisfactory outcomes.

Identification of Reference Genes for Quantitative RT-PCR in Ascending Aortic Aneurysms

Hypertension and congenital aortic valve malformations are frequent causes of ascending aortic aneurysms. The molecular mechanisms of aneurysm formation under these circumstances are not well understood. Reference genes for gene activity studies in aortic tissue that are not influenced by aortic valve morphology and its hemodynamic consequences, aortic dilatation, hypertension, or antihypertensive medication are not available so far. This study determines genes in ascending aortic tissue that are independent of these parameters. Tissue specimens from dilated and undilated ascending aortas were obtained from 60 patients (age ≤70 years) with different morphologies of the aortic valve (tricuspid undilated n = 24, dilated n = 11; bicuspid undilated n = 6, dilated n = 15; unicuspid dilated n = 4). Of the studied individuals, 36 had hypertension, and 31 received ACE inhibitors or AT1 receptor antagonists. The specimens were obtained intraoperatively from the wall of the ascending aorta. We analyzed the expression levels of 32 candidate reference genes by quantitative RT-PCR (RT-qPCR). Differential expression levels were assessed by parametric statistics. The expression analysis of these 32 genes by RT-qPCR showed that EIF2B1, ELF1, and PPIA remained constant in their expression levels in the different specimen groups, thus being insensitive to aortic valve morphology, aortic dilatation, hypertension, and medication with ACE inhibitors or AT1 receptor antagonists. Unlike many other commonly used reference genes, the genes EIF2B1, ELF1, and PPIA are neither confounded by aortic comorbidities nor by antihypertensive medication and therefore are most suitable for gene expression analysis of ascending aortic tissue.

Ascending Aortic Wall Cohesion: Comparison of Bicuspid and Tricuspid Valves

Objectives. Bicuspid aortic valve (AV) represents the most common form of congenital AV malformation, which is frequently associated with pathologies of the ascending aorta. We compared the mechanical properties of the aortic wall between patients with bicuspid and tricuspid AV using a new custom-made device mimicking transversal aortic wall shear stress. Methods. Between 03/2010 and 07/2011, 190 consecutive patients undergoing open aortic valve replacement at our institution were prospectively enrolled, presenting either with a bicuspid (group 1, n = 44) or a tricuspid (group 2, n = 146) AV. Aortic wall specimen were examined with the “dissectometer” resulting in nine specific aortic-wall parameters derived from tensile strength curves (TSC). Results. Patients with a bicuspid AV showed significantly more calcified valves (43.2% versus 15.8%, P < 0.001), and a significantly thinner aortic wall (2.04 ± 0.42 mm versus 2.24 ± 0.41 mm, P = 0.008). Transesophageal echocardiography diameters (annulus, aortic sinuses, and sinotubular junction) were significantly larger in the bicuspid group (P = 0.003, P = 0.02, P = 0.01). We found no difference in the aortic wall cohesion between both groups as revealed by shear stress testing (P = 0.72, P = 0.40, P = 0.41). Conclusion. We observed no differences of TSC in patients presenting with tricuspid or bicuspid AVs. These results may allow us to assume that the morphology of the AV and the pathology of the ascending aorta are independent.

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

Mechanisms underlying aortic dilatation in congenital aortic valve malformation.

The high incidence of aortic disease in subjects with congenital aortic valve malformations suggests a causative relationship between these 2 conditions. The histological observation in aortic dilatation/aneurysm/dissection is Erdheim cystic medial necrosis (CMN), a noninflammatory loss of smooth muscle cells (SMCs), fragmentation of elastic fibers, and mucoid degeneration. To examine whether apoptosis is 1 of the mechanisms underlying CMN and aortic medial layer SMC loss, ascending aortic wall specimens from 32 patients were collected at cardiothoracic surgery and examined by histochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling. From echocardiography results, 4 groups of patients were identified: bicuspid valve carriers with (bi/dil) or without (bi/0) aortic dilatation and tricuspid valve carriers with (tri/dil) or without (tri/0) aortic dilatation. Massive focal apoptosis was observed in the medial layers of bi/dil (mean apoptotic index [mAI], 8.1+/-6.0) and tri/dil (mAI, 8.1+/-8.3) compared with tri/0 (mAI, 0.9+/-1.2; P=0.0079 and P=0.037). In bi/0 (mAI, 9.1+/-5.7) compared with tri/0 (mAI, 0.9+/-1.2), rates of medial SMC apoptosis were increased (P=0.0025). Bi/dil (mean age, 40. 6+/-15.7 years) were significantly younger than tri/dil (mean age, 56.4+/-12.8 years) undergoing the same operation (P=0.0123). Premature medial layer SMC apoptosis could be part of a genetic program underlying aortic disease in patients with aortic valve malformations.

261 Smooth muscle cell apoptosis is one of the key mechanisms underlying aortic dilatation in congenital aortic valve malformations

261 Smooth muscle cell apoptosis is one of the key mechanisms underlying aortic dilatation in congenital aortic valve malformations

Dissection of the aorta associated with congenital malformation of the aortic valve

The association of congenital aortic valve malformation and aortic dissection is analyzed. Over a 30 year period, 186 patients with non-iatrogenic aortic dissection were studied at necropsy. The aortic valve was tricuspid in 170 (91.4%), bicuspid in 14 (7.5%) and unicuspid in 2 (1.1%). Among the 16 patients with aortic dissection and a congenitally malformed valve, the age at death ranged from 17 to 82 years (mean 52) and 13 (81%) were men. The entrance tear of the aortic dissection was located in the ascending aorta in all 16 patients with a malformed valve but in only 68% of those with a tricuspid aortic valve. The aortic valve was stenotic in 6 of the 16 patients with a congenitally malformed valve. Fatal rupture of the false channel occurred after acute ascending aortic dissection in each of the 11 patients (none with healed dissection) who did not have operative therapy for the dissection. Two of the 16 patients with a malformed valve compared with no patient with a tricuspid aortic valve had aortic isthmic coarctation. Histologic sections of aorta from 10 patients disclosed severe degeneration of the elastic fibers of the media in 9 patients. Thus, a congenitally malformed aortic valve appears to be present at least 5 times more frequently in adults with than in those without aortic dissection, and in our patients the entrance tear was always in the ascending aorta, which usually had severe loss of elastic fibers in its media.