The extent of the raphe in bicuspid aortic valves is associated with aortic regurgitation and aortic root dilatation.

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 < 0.001) and smaller diameters of the ascending aorta (33.7 vs. 37.8 mm, p < 0.001) and aortic arch (25.8 vs. 30.2 mm, p < 0.001) than patients with isolated BAV. 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.

Differential and linear insertion of atrioventricular valves: a useful tool?

OBJECTIVE: The differential insertion of the atrioventricular valves is the ultrasonographic representation of the more apical attachment of the tricuspid valve to the septum with respect to the mitral valve. A linear insertion is present when both valves form a linear continuum and has been suggested as a marker for atrioventricular septal defects (AVSDs). The objective of this study was to evaluate the anatomical substratum of differential and linear insertions of the atrioventricular valves in normal fetal hearts and fetal hearts with an AVSD. METHODS: The extent and position of the fibrous skeleton and attachment of the atrioventricular valves to the septum were studied in histological sections of 17 normal hearts and four hearts with an AVSD from 10 + 0 weeks' gestation to 3 days postpartum with various immunohistochemical tissue markers. In addition, spatiotemporal image correlation (STIC) volumes of 10 normal hearts and STIC volumes of eight hearts with an AVSD at 13 + 6 to 35 + 5 weeks' gestation were examined. RESULTS: The differential insertion of the atrioventricular valves was visible in normal hearts in the four-chamber plane immediately beneath the aorta, but nearer the diaphragm a linear insertion was found. In hearts with an AVSD, a linear appearance was observed in the four-chamber plane immediately beneath the aorta. Towards the diaphragm, however, first a differential insertion and, more caudally, a linear insertion was found. CONCLUSIONS: Both differential and linear insertions can be found in normal fetal hearts and fetal hearts with AVSD, depending on the plane in which the four-chamber view is visualized. Therefore, measurement of the differential insertion is likely to be useful only in experienced hands.

Expression of Id2 in the second heart field and cardiac defects in Id2 knock-out mice.

The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.

Maternal hyperhomocysteinaemia is a risk factor for congenital heart disease.

OBJECTIVE: To investigate the inter-relation between mother and infant homocysteine, folate and vitamin B12 status and the risk of a child with congenital heart disease (CHD). DESIGN: Case-control study. SETTING: Erasmus MC, University Medical Centre, Rotterdam, the Netherlands. POPULATION: Participants were 149 case-mothers and their children with CHD (n = 151) and 183 control-mothers with their children (n = 175). METHODS: Approximately 17 months after the index-pregnancy maternal fasting, children's random venous blood samples were drawn to measure plasma total homocysteine, serum and red blood cell (RBC) folate, and serum vitamin B12 concentrations. Data were compared between cases and controls using the Mann-Whitney U test. The biochemical parameters were dichotomised according to the cutoff value of the 10th percentile of vitamin concentrations and the 90th percentile of homocysteine concentrations based on control data. Risk estimates for the association between CHD and the biochemical parameters were estimated in a logistic regression model. MAIN OUTCOME MEASURES: Medians (minimum-maximum) and odds ratios (OR) (95% confidence intervals [CI]). RESULTS: The OR (95% CI) of having a child with CHD was 2.9 (1.4-6.0) for maternal hyperhomocysteinaemia (>14.3 micromol/l). This finding is substantiated by a significant concentration-dependent risk (Ptrend = 0.004). Hyperhomocysteinaemic case-mothers showed significantly lower serum folate and vitamin B12 concentrations than normohomocysteinaemic case-mothers. Serum and RBC folate concentrations were significantly higher in case-children than that in control-children. CONCLUSIONS: Maternal hyperhomocysteinaemia is associated with an increased risk of CHD, partially due to low folate and vitamin B12 status. The folate status of children warrants further investigation.

First-trimester fetuses with increased nuchal translucency do not show altered intracardiac flow velocities.

OBJECTIVE: To study intracardiac flow velocities in first-trimester fetuses with normal nuchal translucency thickness (NT) and those with increased NT. METHODS: Ultrasound examinations were performed in 85 normal fetuses and 45 fetuses with NT > 95(th) percentile. Follow-up was complete and postmortem examination was performed on terminated pregnancies. Flow velocities during the early (e-wave) and late (a-wave) peaks across the tricuspid and mitral valves were measured and compared, using multilevel analysis, between the fetuses with normal and those with increased NT. In the group with increased NT, fetuses with and without a heart defect irrespective of the karyotype were compared, and in this group, euploid and aneuploid fetuses were compared, irrespective of the presence of a heart defect. RESULTS: No difference in intracardiac flow velocities was found between fetuses with normal and those with increased NT. Within the group of fetuses with increased NT, there was no difference between the fetuses with and without a cardiac defect. However, comparison of aneuploid with euploid fetuses within the group with increased NT showed that both the e-wave and a-wave peaks were decreased significantly by 3.03 cm/s and 5.95 cm/s, respectively, across the tricuspid valve, and by 3.47 cm/s and 5.92 cm/s, respectively, across the mitral valve (P < 0.05). The most common cardiac malformations were septal defects. CONCLUSION: There is no difference in intracardiac blood flow velocities between normal fetuses and those with increased NT. This contradicts the theory that NT is caused by impaired atrial contraction or cardiac failure. In fetuses with increased NT, those with aneuploidy show a decreased e-wave and a-wave compared with euploid fetuses. This cannot, however, be explained by the presence of cardiac defects, because there is no difference between fetuses with and without a cardiac defect. Therefore, we hypothesize that the relationship between enlarged NT and cardiac defects can only be explained by a developmental process that coexists at this period of gestation and is linked to cardiovascular development.

Development of the coronary vasculature and its implications for coronary abnormalities in general and specifically in pulmonary atresia without ventricular septal defect.

AIM: Coronary vascular anomalies are an important factor in congenital heart disease in the neonate. However, our knowledge of the pathomorphogenesis is still defective. MATERIAL AND METHODS: (1) Study of coronary anomaly variations in congenital heart disease using specimens and (2) study of the role of epicardium-derived cells (EPDC) and neural crest cells in coronary vascular formation using quail-chicken chimeras. RESULTS: The clinical and pathological data revealed the existence of ventriculo-coronary arterial communications during fetal life before pulmonary atresia was established. This supported a primary coronary developmental anomaly as the origin of some cases of pulmonary atresia as opposed to other cases in which the pulmonary orifice atresia was the primary anomaly. Our experimental work showed the high relevance of the development of the epicardium and epicardium-derived cells for the formation of the coronary vasculature, and showed the coronary vascular ingrowth into the myocardium and subsequently into the aorta and the right atrium. The absence of epicardium-derived cells leads to embryonic death, while delayed outgrowth could result in the absence of the main coronary arteries to pinpoint orifice formation. In these cases, the circulation was maintained through ventriculo-coronary arterial communications. Neural crest cells were important for the patterning of the coronary vasculature. We have extended this knowledge to a number of other heart malformations. CONCLUSIONS: Coronary vascular anomalies are highly linked to the development of extracardiac contributors like the epicardium and the neural crest. A proper interaction between these cell types and the myocardium and aortic arterial wall are important for normal vascular development.

Cardiac malformations in first-trimester fetuses with increased nuchal translucency: ultrasound diagnosis and postmortem morphology.

OBJECTIVE: The aim of this study was to explore the diagnostic accuracy of first-trimester transvaginal echocardiography in fetuses with increased nuchal translucency (NT) thickness, by comparing the ultrasound diagnosis with the findings on postmortem examination or mid-gestational ultrasound and neonatal outcome. METHODS: Transvaginal echocardiography was performed in 45 fetuses with a NT > 95th centile. Karyotyping was performed in 43. In 20 of the 23 pregnancies in which termination of pregnancy was carried out, postmortem examination was performed to determine the presence and type of heart defect. Mid-gestational echocardiography was performed in ongoing pregnancies and neonatal follow-up information was obtained. Findings on first-trimester transvaginal echocardiography were compared to those of second-trimester echocardiography or the results of postmortem examination. The mean NT in the fetuses with and without heart defects was calculated. RESULTS: Of the 45 fetuses, heart malformations were suspected on first-trimester ultrasound in 10 (22%), of which eight (80%) were found to have a chromosomal abnormality. Postmortem examination showed minor additional findings in some cases and major discrepancies occurred in none. Septal defects were the most common defects in trisomic fetuses. In three fetuses with a 45 X karyotype, hypoplastic left heart syndrome was diagnosed. Heart defects were diagnosed in three euploid fetuses in which fetal demise occurred. The sensitivity and specificity for the detection of heart defects of transvaginal echocardiography were 88% and 97%, respectively. The mean NT in fetuses with a normal heart (4.3 mm) was significantly smaller than that of fetuses with heart defects (7.4 mm). CONCLUSION: Transvaginal echocardiography can be performed reliably in first-trimester fetuses with an increased NT. In this study, the proportion of chromosomally abnormal fetuses with a heart defect was not different from that found in newborns, except for cases of Turner syndrome. Fetal demise occurred in all three euploid fetuses with a heart malformation. The fetuses with a heart defect had a larger NT than did those without.

Congenital polyvalvular disease: a review.

This review outlines the morphologic and pathogenetic characteristics of congenital polyvalvular disease. Two cases are used for exemplification. The macroscopic and histologic features of the valves as well as associated cardiac lesions and clinical syndromes are described, followed by a discussion of morphogenesis of this disease.

Spin echo MRI in the evaluation of hearts with a double outlet right ventricle: usefulness and limitations.

The surgical approach to a double outlet right ventricle (DORV) is dependent on the spatial relationship of the semilunar valves, outflow tracts and ventricular septal defect (VSD). The purpose of the study was to assess the value of MRI for the evaluation of cardiovascular anatomy in patients before and after surgery for DORV. Spin echo MRI was performed in 12 patients with DORV (eight preoperative and four postoperative patients). Thin-section MRI was performed in three orthogonal planes and selected angulated views were obtained. Conventional imaging by color Doppler echocardiography and cine-angiocardiography and surgical findings, when present, served as the reference standards. The results found that the spatial relationship between semilunar valves and VSD was accurately assessed by MRI in eight out of eight preoperative patients. In the four postoperative cases MRI depicted the morphology of both outflow tracts and provided adequate information on their patency. Of the eight preoperative patients, five have undergone corrective surgery and the MRI findings were confirmed. MRI provided additional information to conventional imaging preoperatively in three cases in which the VSD opened into the outlet portion of the DORV, without there being a direct relation to a semilunar valve. In two preoperative cases in which the VSD was directly committed to the aorta, conventional imaging was conclusive. MRI was unable to depict aberrant chordae tendineae in four out of four cases. We conclude that MRI provides accurate additional anatomic information in patients with DORV, which is helpful in presurgical planning as well as during follow-up. Spin echo MRI does not visualize aberrant chordae tendineae.

Nasopharyngeal teratoma and mosaic tetrasomy 1q detected at amniocentesis. A case report and review of the literature.

The occurrence of nasopharyngeal teratomas (NPT) is an infrequent event and prenatal detection of such tumors is even rarer. We present a case report and review of the literature (N = 78 cases), in which we describe the cytogenetic, DNA, and pathological findings of a fetus with a mature NPT which was detected prenatally by ultrasound investigation following complaints of severe polyhydramnios by the mother.

CHARGE association-related ocular pathology in a newborn with partial trisomy 19q and partial monosomy 21q, from a maternal translocation (19;21) (q13.1;q22.3).

We report a novel case of partial trisomy 19q and concomitant partial monosomy 21q, segregated from a maternal translocation (19;21) (q13.1;q22.3), identified by spectral karyotyping. Clinical examination revealed dysmorphic features of the face and limbs, cleft palate, bilateral colobomas with associated bilateral colobomatous optic nerve cysts, hearing loss, and a cardiac anomaly. At autopsy, the dysmorphic features and cleft palate were confirmed. The ocular histopathology is described in detail and the cardiac anomaly was further specified. The combination of phenotype features is diagnostic of the CHARGE (coloboma, heart malformation, atresia choanae, retarded growth and development, and/or CNS anomalies, genital hypoplasia, ear anomalies and/or deafness) association. This case also has some phenotypic features in common with previous cases of partial trisomy 19q. The importance of a complete autopsy in cases with multiple congenital anomalies and/or genetic abnormalities is emphasized. This will allow optimal genetic counseling and contribute to our understanding of developmental biology.

Autologous pericardium for ventricular septal defect closure.

BACKGROUND AND AIMS OF THE STUDY: The use of living, untreated autologous pericardium for patch repair in the left ventricular outflow tract was considered attractive in children. METHODS: Ventricular septal defect (VSD) closure with an untreated autologous pericardial patch was performed in 102 children of mean age 13.4 months (range: 1 to 73 months). Postoperative transthoracic Doppler echocardiography was performed in all children at a mean of nine weeks (range: one day to 50 weeks) after surgery. One pericardial patch, which was explanted at autopsy two months after surgery, was studied microscopically. RESULTS: At short-term follow up, no or only minor residual VSD was found in 97 patients, moderate VSD in two and severe VSD in one patient. One patient was reoperated for residual VSD and an aneurysmic patch first diagnosed seven days after surgery. Two more patients showed ballooning of the patch without VSD after five and seven days respectively. All aneurysmic patches were attributed to intraoperative patch oversizing. Patch integrity was confirmed in all other patients. No inflammatory or degenerative changes were observed at microscopy, rather a remodeling response had caused the patch to thicken, indicating an adaptation of the living tissue. CONCLUSIONS: The untreated autologous pericardial patch has shown to be a safe alternative for VSD closure, provided that the patch is properly sized.

Severe cardiac defect in a patient with the OEIS complex.

The OEIS complex is an association of fetal malformations including omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects. We present a fetus with the OEIS complex in combination with a cardiac defect. Until now very few cases with this combination have been described.

Morphology of the pulmonary and aortic roots with regard to the pulmonary autograft procedure.

Aortic root replacement with the pulmonary autograft warrants a thorough histologic comparison of the morphologic characteristics of the pulmonary and aortic roots. For this purpose nine normal heart specimens (7 neonatal and 2 adult hearts) were studied. Histologic study confirmed the collagenous anulus in both roots to be a complex circular-shaped structure, intricately interposed between the elastic lamellae of the arterial wall and the ventricular structures of the heart. In this sinus the elastic lamellae of the arterial wall continue along the luminal side with collagen being situated at the outside. At the interleaflet triangle this relation is reversed. Surprisingly, islet of elastic fibers were found in the otherwise completely collagenous interleaflet triangles. The amount of elastic lamella distal to the commissures was in both arteries higher than that in the middle of the sinuses, with a preponderance in the aorta as compared with the pulmonary trunk. The pulmonary root anulus proximally inserts into the relatively thin right ventricular myocardium, whereas the aortic root anulus inserts into the thick left ventricular myocardium and several fibrous structures. The pulmonary root is hardly supported by the right ventricular myocardium, whereas the aortic root is supported by its wedged position between the left and right atrioventricular anuli and the bulging thick left ventricular myocardium. When the pulmonary autograft is used for aortic root replacement it should be inserted as proximally as possible to get the support of the fibrous structures of the left ventricular outflow tract and the surrounding ventricular and atrial myocardium.

Body wall defects in two sibs.

We describe 2 sibs, a male fetus with an unusual lumbar hernia and spina bifida occulta, and a female fetus with a median abdominoschisis. The first fetus had some signs of lumbocostovertebral syndrome (LCVS), which consists of a congenital lumbar hernia and associated abnormalities such as absent or hypoplastic ribs, hemivertebrae, and scoliosis. Abdominoschisis has not been described in LCVS, and the given abnormalities in the 2 sibs have not been published to date. One can hypothesize that vascular disruption of a somite or a group of somites may result in the described abdominal wall defects. We conclude that these abnormalities could be coincidental in the 2 sibs or could have a related, probably multifactorial, cause.

Anatomy of the proximal coronary arteries as a risk factor in primary repair of common arterial trunk.

The objective of this study was to investigate whether the proximal coronary arterial anatomy is a risk factor in surgical treatment of common arterial trunk, with special focus on the value of preoperative angiocardiography. A retrospective analysis was performed of all 22 patients who underwent primary surgical repair of the common arterial trunk, with a mean follow-up of 5.1 years. In 18 patients preoperative angiocardiography was performed. Anatomical features (angiocardiographical, surgical as well as post-mortem) of the proximal coronary arteries were investigated. With standard biplane angiocardiography single and dual coronary arterial systems could adequately be distinguished. However, the position of the coronary orifices in relation to the sinus of Valsalva could not adequately be identified. Three patients had coronary abnormalities without surgical consequences. In 2 cases the surgical approach had to be modified due to the coronary anatomy. Early mortality was 23% (5/22) and was correlated with worse functional class (p < 0.05) and earlier date of operation (p < 0.05). Late mortality was 5% (1/22). Five patients were reoperated, without mortality. Fourteen surviving patients are in functional class I, and 2 in class II. A further improvement of the surgical therapy of common arterial trunk might be provided by adequate appreciation of the proximal coronary arterial anatomy at surgery.

Common arterial trunk, uncommon coronary arterial anatomy.

Macroscopic investigation was done in 44 postmortem specimens of hearts with common arterial trunk. In 38 hearts, the normal distribution in left and right coronary arteries was found. Of the coronary orifices, five were pinpoint and three showed a double orifice. The left coronary orifice was positioned in the posterior part of the truncus (p < 0.0001); the right coronary orifice was positioned in the right anterior and lateral part (p < 0.0001). In 19 hearts, coronary orifices were found above sinus level, left coronary orifices more often than right coronary orifices (p < 0.001). In seven hearts, type I truncus was found, in seven type II truncus was found, in 17 the truncus was intermediate between types I and II, in two type III truncus was found. In 11 hearts, the pulmonary artery distribution could no longer be identified. The truncal valve was bicuspid in 11 hearts, tricuspid in 25 hearts, and quadricuspid in eight hearts. The truncal valve showed overriding of 5% to 100%. Malformations of the coronary arteries were found in 28 hearts (64%). In 27 hearts (61%), the coronary arterial anatomy might have had clinical consequences. In nine hearts, coronary arterial orifices were at risk in excision of the pulmonary arteries from the common arterial trunk. The role of the neural crest as an etiologic factor of coronary arterial malformations in common arterial trunk should be taken into account.

Morphogenetic considerations on congenital malformations of the outflow tract. Part 2: Complete transposition of the great arteries and double outlet right ventricle.

On the basis of our recent embryologic work concerning the separation process of the outflow tract, our study of the morphology of specimens from the Leiden Collection of malformed hearts, and in conjunction with our review of the literature, we have reconsidered the morphogenesis of complete transposition and double outlet right ventricle. In complete transposition, a mirror-image arrangement of the columns of the aorto-pulmonary septum could explain the discordant ventriculo-arterial connexion and might thus play a role in its development. Dedicating a cardinal role to the aorto-pulmonary septum in the morphogenesis of complete transposition does not, however, seem justified. Double outlet right ventricle is not an embryologic entity. From the stance of the embryologist, we prefer to consider double outlet right ventricle in terms of a feature that may occur in specimens related to hearts with either a concordant ventriculo-arterial connexion (such as tetralogy of Fallot, or the so-called Eisenmenger ventricular septal defect), or a discordant ventriculo-arterial connexion (complete transposition).

Morphogenetic considerations on congenital malformations of the outflow tract. Part 1: Common arterial trunk and tetralogy of Fallot.

On the basis of our recent embryologic work concerning the separation process of the outflow tract, together with our study of the morphology of specimens from the Leiden Collection of malformed hearts, we have reconsidered, in conjunction with the pertinent literature, the morphogenesis of common arterial trunk and tetralogy of Fallot. The constant characteristics of common arterial trunk, namely a common trunk, a common arterial orifice and a ventricular septal defect, can be explained simply by absence of the aorto-pulmonary septum, or its complete failure to contribute to the process of separation. The nature of the variable morphologic features, however, is not always clear. Presence of such variation is not contradictory to the explanation of the main characteristics in this malformation. Tetralogy of Fallot, in contrast, can be considered to result from anterior displacement of the columns of the aorto-pulmonary septum relative to the outlet segment and its proximal boundary, the primary fold. Our findings, and suggestions, diverge considerably from conventional theories concerning the morphogenesis of these malformations.

The outflow tract of the heart--embryologic and morphologic correlations.

The separation process of the heart by which two great arteries and two outflow tracts are formed, was studied microscopically in 20 human embryos, ranging from 6 to 28 mm crown-rump length and macroscopically in eight hearts, ranging from 28 weeks of gestation to 80 years of age. The proximal (primary fold) and distal (ventriculo-arterial junction) borderlines of the outlet segment of the embryonic heart are important landmarks in this process. The remarkable, curved and twisted configuration of the ventriculo-arterial junction implies that the position of the arterial orifices, as well as the relative dimensions of the corresponding outflow tracts, are, already in a very early stage, similar to those in the fully developed heart. It furthermore implies that the separation by the aorto-pulmonary septum starts at this level and immediately involves the outlet segment where the two columns of the aorto-pulmonary septum mobilize the myocardium to form the posterior wall of the right ventricular outflow tract, rather than a septum between both outflow tracts. These findings make the morphology of the outflow tract of the normal heart comprehensible from a developmental point of view and throw a new light upon the morphogenesis of outflow tract malformations.