Pregnancy complications in singleton pregnancies with isolated fetal heart defects.

INTRODUCTION: As the prenatal detection rates of congenital heart defects (CHDs) increase, obstetricians are more frequently faced with pregnancies complicated by a fetal CHD. Congenital anomalies in general are associated with preterm birth and fetal demise. The aim of this study was to gain insight into the prevalence of preterm birth and fetal demise in singleton pregnancies with fetuses with isolated CHDs. MATERIAL AND METHODS: A geographical cohort study was performed in a large region in the Netherlands. Fetuses and infants from singleton pregnancies diagnosed with severe isolated CHD, born between 1 January 2002 and 1 January 2012, were included. All cases in the CHD cohort were assessed for preterm birth or fetal demise. The proportions of preterm birth and fetal demise were compared with those in a control group and odds ratios were calculated. RESULTS: The proportion of preterm births in the CHD cohort (n = 1013) was 9.1% (95% CI 7.3-10.9) compared with 5.6% (95% CI 5.4-5.8) in the control group, with an odds ratio of 1.7 (95% CI 1.4-2.1). The preterm birth started spontaneously in 49.5% and 38.4% were induced. In 15 cases fetal demise occurred (1.5%; 95% CI 0.8-2.2), compared with 0.7% (95% CI 0.6-0.8) in the control group, odds ratio 2.0 (95% CI 1.2-3.4). CONCLUSIONS: Higher rates of preterm birth and fetal demise occur in fetuses with isolated CHD compared with the general population. Prenatal specialists should be vigilant for signs of heart failure, premature closure of the foramen ovale or fetal distress in fetuses with isolated CHDs.

Chromosomal abnormalities and copy number variations in fetal left-sided congenital heart defects.

OBJECTIVES: To demonstrate the spectrum of copy number variants (CNVs) in fetuses with isolated left-sided congenital heart defects (CHDs), and analyse genetic content. METHODS: Between 2003 and 2012, 200 fetuses were identified with left-sided CHD. Exclusion criteria were chromosomal rearrangements, 22q11.2 microdeletion and/or extra-cardiac malformations (n = 64). We included cases with additional minor anomalies (n = 39), such as single umbilical artery. In 54 of 136 eligible cases, stored material was available for array analysis. CNVs were categorized as either (likely) benign, (likely) pathogenic or of unknown significance. RESULTS: In 18 of the 54 isolated left-sided CHDs we found 28 rare CNVs (prevalence 33%, average 1.6 CNV per person, size 10.6 kb-2.2 Mb). Our interpretation yielded clinically significant CNVs in two of 54 cases (4%) and variants of unknown significance in three other cases (6%). CONCLUSIONS: In left-sided CHDs that appear isolated, with normal chromosome analysis and 22q11.2 FISH analysis, array analysis detects clinically significant CNVs. When counselling parents of a fetus with a left-sided CHD it must be taken into consideration that aside from the cardiac characteristics, the presence of extra-cardiac malformations and chromosomal abnormalities influence the treatment plan and prognosis.

Volumetric Computed Tomography Angiography in the Evaluation of Mediastinal Fluid Collections following Congenital Cardiac Surgery.

We present 3 patients with 4 causes of mediastinal fluid collection after congenital cardiac surgery in this extended case report. Volumetric computed tomography played an essential role in diagnosing causes and extent, relevant to subsequent management. Recent advances in volumetric computed tomography allow fast and accurate imaging of cardiovascular and extravascular structures in children with acceptable radiation dose, providing a powerful imaging tool for the evaluation of complications after congenital cardiac surgery.

Mild residual pulmonary stenosis in tetralogy of fallot reduces risk of pulmonary valve replacement.

BACKGROUND: Current surgical strategies that aim at preventing pulmonary regurgitation in patients with corrected tetralogy of Fallot (cToF) may result in a certain grade of residual pulmonary stenosis (PS). The clinical implications of a postoperative residual PS in cToF patients remain unclear. Pulmonary valve replacement (PVR) is frequently needed during follow-up of cToF patients. The aim of the current study was to determine the role of residual PS in the need for PVR during follow-up in cToF patients. METHODS: cToF patients were included if clinical follow-up after primary surgical correction had taken place for a minimum of 5 years. Patient characteristics, surgical factors, and postoperative factors were reviewed, with a special focus on the transpulmonic systolic gradient. Cox proportional hazards regression analysis was performed to identify predictors of PVR. RESULTS: Of 171 cToF patients, 71 (41.5%) underwent PVR after 24.2 years (interquartile range, 16.8-31.6 years). Year of birth, older age at corrective operation, and patch use significantly predicted PVR during follow-up. By contrast, a mild residual PS in cToF patients (peak systolic gradient, 15-30 mm Hg) independently reduced the risk of PVR, as compared with patients without PS (hazard ratio, 0.47; p=0.02) and with moderate-to-severe PS (hazard ratio, 0.35; p=0.01). CONCLUSIONS: In addition to the known risks factors for PVR, a postoperative mild residual PS reduces the risk of PVR during follow-up of cToF patients. This finding provides clinical evidence for a conservative PS relief during correction of ToF.

Disturbed myocardial connexin 43 and N-cadherin expressions in hypoplastic left heart syndrome and borderline left ventricle.

OBJECTIVES: Borderline left ventricle is the left ventricular morphology at the favorable end of the hypoplastic left heart syndrome. In contrast to the severe end, it is suitable for biventricular repair. Wondering whether it is possible to identify cases suitable for biventricular repair from a developmental viewpoint, we investigated the myocardial histology of borderline and severely hypoplastic left ventricles. METHODS: Postmortem specimens of neonatal, unoperated human hearts with severe hypoplastic left heart syndrome and borderline left ventricle were compared with normal specimens and hearts from patients with transposition of the great arteries. After tissue sampling of the lateral walls of both ventricles, immunohistochemical and immunofluorescence stainings against cardiac troponin I, N-cadherin, and connexin 43, important for proper cardiac differentiation, were done. RESULTS: All severely hypoplastic left hearts (7/7) and most borderline left ventricle hearts (4/6) showed reduced sarcomeric expressions of troponin I in left and right ventricles. N-cadherin and connexin 43 expressions were reduced in intercalated disks. The remaining borderline left ventricle hearts (2/6) were histologically closer to control hearts. CONCLUSIONS: Four of 6 borderline left ventricle hearts showed myocardial histopathology similar to the severely hypoplastic left hearts. The remainder were similar to normal hearts. Our results and knowledge regarding the role of epicardial-derived cells in myocardial differentiation lead us to postulate that an abnormal epicardial-myocardial interaction could explain the observed histopathology. Defining the histopathologic severity with preoperative myocardial biopsy samples of hearts with borderline left ventricle might provide a diagnostic tool for preoperative decision making.

Long-term results of reoperation for left atrioventricular valve regurgitation after correction of atrioventricular septal defects.

BACKGROUND: Long-term results of reoperation for left atrioventricular valve regurgitation (LAVVR) after previous correction of atrioventricular septal defect (AVSD) are scarce. We evaluated long-term outcome of reoperation for LAVVR and identified risk factors for reoperation. METHODS: Between December 1976 and July 2006, 45 of 312 patients with correction of different AVSDs underwent reoperation for LAVVR. The cohort of 267 patients who did not need reoperation for LAVVR allowed for the identification of risk factors for reoperation and evaluation of overall survival after primary AVSD repair in a competing risk scenario. Clinical data were obtained by retrospective review. RESULTS: The left atrioventricular valve (LAVV) was repaired in 31 patients (68.9%) and replaced in 14 (31.1%). There were 3 in-hospital deaths (6.7%) and 2 late deaths (4.4%). Estimated overall survival was 88.1% at 15 years after the reoperation, and estimated incidence of death after reoperation in the total patient cohort was 2% at 15 years after the primary AVSD repair. Overall survival was significantly higher after LAVV repair than after replacement (p=0.010). Ten patients with LAVV repair required a second reoperation for LAVVR. At follow-up, survivors were in New York Heart Association functional class I (n=36) or II (n=4). Independent risk factors for first reoperation for LAVVR were associated cardiovascular anomalies (p<0.001), LAVV dysplasia (p<0.001), and nonclosure of the cleft (p=0.027). CONCLUSIONS: After previous correction of AVSD, LAVVR can usually be corrected by valve repair. A very dysplastic valve may necessitate replacement. Overall survival is higher after repair than after replacement. In general, overall survival of patients reoperated on for LAVVR is favorable. The overall mortality rate after primary repair of AVSD is explained only for a small part by mortality after reoperation for LAVVR.

The clinical spectrum of complete FBN1 allele deletions.

The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.

The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family.

Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation.

Long-term follow-up of arterial switch operation with an emphasis on function and dimensions of left ventricle and aorta.

OBJECTIVE: To analyze size and function of aortic root and left ventricle as well as quality of life in patients 20 years after arterial switch procedure. METHODS: Thirty-nine patients who underwent arterial switch operation between 1977 and 1989 were examined. Perioperative and follow-up data were analyzed. Evaluation included clinical assessment, ECG, echocardiography and quality of life questionnaire. RESULTS: Patients had simple transposition (24), transposition with ventricle septal defect (7), Taussig-Bing anomaly (4) or transposition with ventricle septal defect and aortic arch obstruction (4). Mean age at evaluation was 19.9+/-2.6 years. Seven patients required reintervention for pulmonary stenosis (4), coarctation (2) and subaortic stenosis, followed by valve replacement 10 years later (1). Arrhythmia occurred in four patients. Patients were in New York Heart Association functional class I (38) or II (1). Quality of life scores were comparable to normal controls except for the lower score in the domains of vitality, aggressive and depressive mood. Diameters of aortic annulus, sinus of Valsalva and sinotubular junction were 26.5+/-4.1, 36.5+/-5.6 and 29.2+/-6.6mm respectively. Sixty-five percent of sinus of Valsalva and 38% of sinotubular junction indexed to body surface area fall outside the 95% confidence interval. Aortic regurgitation was absent in 72%, mild in 13% and moderate in 15%. No patient had severe regurgitation. Patients without regurgitation had smaller diameters of annulus (p=0.005) and sinus of Valsalva (p=0.01). Left ventricular end-diastolic and end-systolic diameters were 51+/-7mm and 34+/-6mm respectively. Fractional shortening was 34+/-5%; no regional wall motion abnormalities were observed. CONCLUSIONS: Clinical outcome is good 20 years after arterial switch operation and aortic valve function remains preserved in most patients. However, aortic root dilatation is present in two thirds of patients emphasizing the need for careful follow-up.

Right ventricular outflow tract reconstruction with the bovine jugular vein graft: 5 years' experience with 133 patients.

BACKGROUND: We analyzed the results in two centers of using bovine jugular vein graft for right ventricular outflow tract reconstruction. METHODS: From April 1999 to July 2005, 133 children with a median age of 30.9 months (range, 4 days to 19 years) underwent graft implantation. Echocardiography was performed during follow-up and retrospectively reviewed. RESULTS: Nongraft-related early mortality occurred in 8 patients. Late mortality occurred in 11 patients, 2 late deaths were graft related (endocarditis). Median follow-up was 31.6 months (range, 1 to 73). Twelve patients received a new graft, because of endocarditis (3), distal pulmonary artery branch stenosis (4), graft obstruction caused by fibrosis (4), or thrombosis (1). Echocardiography Doppler studies showed good conduit function, with 92% of the patients having absent, trivial, or only mild valve regurgitation at last follow-up. A moderate degree of conduit stenosis due to external compression was observed in 2 patients. Twenty-five patients with otherwise intact conduits had hemodynamically significant distal stenosis. In most cases, the pulmonary branch stenosis was related to preoperative small pulmonary arteries and young age at operation. At 31.6 months, significant graft dilatation was observed in 4 grafts and was related to pulmonary artery branch obstruction or pulmonary hypertension. Calcification did not occur in 5 years time. Survival was 85.7%, freedom from conduit explantation was 91%, and freedom from intervention for pulmonary artery branch stenosis was 80% after 5 years. CONCLUSIONS: The bovine jugular vein graft is a valuable right ventricular outflow tract conduit, but younger age and small pulmonary arteries increase the risk of distal conduit stenosis.

Resynchronization therapy after congenital heart surgery to improve left ventricular function.

This report describes the mid-term beneficial hemodynamic effect of biventricular pacing in an infant with congestive heart failure after congenital heart surgery, due to resynchronization of the left and right ventricle, optimization of the AV delay, and (partial) correction of the LV dyssynchrony.