Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well-established knowledge to new frontiers.

Congenital heart diseases (CHDs) and cardiovascular abnormalities are one of the pillars of clinical diagnosis of 22q11.2 deletion syndrome (22q11.2DS) and still represent the main cause of mortality in the affected children. In the past 30 years, much progress has been made in describing the anatomical patterns of CHD, in improving their diagnosis, medical treatment, and surgical procedures for these conditions, as well as in understanding the underlying genetic and developmental mechanisms. However, further studies are still needed to better determine the true prevalence of CHDs in 22q11.2DS, including data from prenatal studies and on the adult population, to further clarify the genetic mechanisms behind the high variability of phenotypic expression of 22q11.2DS, and to fully understand the mechanism responsible for the increased postoperative morbidity and for the premature death of these patients. Moreover, the increased life expectancy of persons with 22q11.2DS allowed the expansion of the adult population that poses new challenges for clinicians such as acquired cardiovascular problems and complexity related to multisystemic comorbidity. In this review, we provide a comprehensive review of the existing literature about 22q11.2DS in order to summarize the knowledge gained in the past years of clinical experience and research, as well as to identify the remaining gaps in comprehension of this syndrome and the possible future research directions.

Improved Outcomes in Patients with 22q11.2 Deletion Syndrome and Diagnosis of Interrupted Aortic Arch Prior to Birth Hospital Discharge, a Retrospective Study.

Interruption of the aortic arch (IAA) is a rare but life-threatening congenital heart defect if not corrected in the neonatal period. IAA type B is highly correlated with 22q11.2 deletion syndrome (22q11.2DS); approximately 50% of patients with IAA type B also have 22q11.2DS (Peyvandi et al.; Goldmuntz et al.). Early identification and repair of IAA can prevent severe morbidity and death. However, IAA is challenging to identify prenatally, or even in the neonatal period. In this study, we examined infants with IAA, diagnosed during pregnancy and prior to discharge (PPTD) from the birth hospital vs. those diagnosed following discharge (FD) from the newborn nursery. Our goals were to determine: (1) if early diagnosis improved outcomes; and (2) if patients with IAA and without 22q11.2DS had similar outcomes. In total, 135 patients with a diagnosis of 22q11.2DS and IAA were ascertained through the 22q and You Center at the Children's Hospital of Philadelphia (CHOP). The examined outcomes included: timing of diagnosis; age at diagnosis (days); hospital length of stay (LOS); duration of intensive care unit (ICU) stay; mechanical ventilation (days); duration of inotrope administration (days); year of surgical intervention; birth hospital trauma level; and overall morbidity. These outcomes were then compared with 40 CHOP patients with IAA but without 22q11.2DS. The results revealed that the PPTD neonates had fewer days of intubation, inotrope administration, and hospital LOS when compared to the FD group. The outcomes between deleted and non-deleted individuals with IAA differed significantly, in terms of the LOS (40 vs. 39 days) and time in ICU (28 vs. 24 days), respectively. These results support the early detection of 22q11.2DS via prenatal screening/diagnostics/newborn screening, as IAA can evade routine prenatal ultrasound and postnatal pulse oximetry. However, as previously reported in patients with 22q11.2DS and congenital heart disease (CHD), patients with 22q11.2DS tend to fare poorer compared to non-deleted neonates with IAA.

The impact of the maternal-foetal environment on outcomes of surgery for congenital heart disease in neonates.

OBJECTIVES: Pregnancies with congenital heart disease in the foetus have an increased prevalence of pre-eclampsia, small for gestational age and preterm birth, which are evidence of an impaired maternal-foetal environment (MFE). METHODS: The impact of an impaired MFE, defined as pre-eclampsia, small for gestational age or preterm birth, on outcomes after cardiac surgery was evaluated in neonates (n = 135) enrolled in a study evaluating exposure to environmental toxicants and neuro-developmental outcomes. RESULTS: The most common diagnoses were transposition of the great arteries (n = 47) and hypoplastic left heart syndrome (n = 43). Impaired MFE was present in 28 of 135 (21%) subjects, with small for gestational age present in 17 (61%) patients. The presence of an impaired MFE was similar for all diagnoses, except transposition of the great arteries (P < 0.006). Postoperative length of stay was shorter for subjects without an impaired MFE (14 vs 38 days, P < 0.001). Hospital mortality was not significantly different with or without impaired MFE (11.7% vs 2.8%, P = 0.104). However, for the entire cohort, survival at 36 months was greater for those without an impaired MFE (96% vs 68%, P = 0.001). For patients with hypoplastic left heart syndrome, survival was also greater for those without an impaired MFE (90% vs 43%, P = 0.007). CONCLUSIONS: An impaired MFE is common in pregnancies in which the foetus has congenital heart disease. After cardiac surgery in neonates, the presence of an impaired MFE was associated with lower survival at 36 months of age for the entire cohort and for the subgroup with hypoplastic left heart syndrome.

Effect of Fontan-Associated Morbidities on Survival With Intact Fontan Circulation.

Although survival after the Fontan operation has improved, little is known about the burden of major medical morbidities associated with the modern total cavopulmonary connection (TCPC). A total of 773 consecutive patients who underwent a first Fontan operation at our institution between 1992 and 2009 were retrospectively reviewed. All subjects underwent TCPC (53% lateral tunnel, 47% extracardiac conduit). Median length of follow-up was 5.3 years (interquartile range 1.4 to 11.2), and 30% had follow-up >10 years. Freedom from a composite medical morbidity outcome (protein-losing enteropathy, plastic bronchitis, serious thromboembolic event, or tachyarrhythmia) was 47% at 20 years (95% confidence interval [CI] 38 to 55). Independent risk factors for morbidity included pre-Fontan atrioventricular valve regurgitation (hazard ratio [HR] 1.7, 95% CI 1.2 to 2.4, p = 0.001), pleural drainage >14 days (HR 1.5, 95% CI 1.01 to 2.2, p = 0.04), and longer cross-clamp time (HR 1.2 per 10 minutes, 95% CI 1.06 to 1.3, p = 0.004) at the time of TCPC. Surgical era, Fontan type, and ventricular morphology were not associated with the composite outcome. Presence of Fontan-associated morbidity was associated with a 36-fold increase in the risk of subsequent Fontan takedown, heart transplantation, or death (95% CI 17 to 76, p <0.001). For patients without any component of the composite outcome, freedom from Fontan failure was 98% at 20 years (95% CI 96 to 99). Medical morbidities after TCPC are common and significantly reduce the longevity of the Fontan circulation. However, for those patients who remain free from the composite morbidity outcome, 20-year survival with intact Fontan circulation is encouraging.

Usefulness of left ventricular inflow index to predict successful biventricular repair in right-dominant unbalanced atrioventricular canal.

The outcome of biventricular (BV) repair for right-dominant unbalanced atrioventricular canal has remained poor, because it is difficult to predict left ventricular (LV) adequacy before surgery. Our aim was to determine whether preoperative echocardiographic parameters, specifically analysis of color inflow into the LV, would predict survival after BV repair in patients with right-dominant unbalanced atrioventricular canal. Subjects with right-dominant unbalanced atrioventricular canal diagnosed from 1994 to 2007 were included. The echocardiographic parameters were analyzed blinded to the palliation strategy and survival. The LV inflow index (LVII) was calculated as the secondary color inflow diameter indexed to the left atrioventricular valve (AVV) annulus diameter. Univariate analysis, survival analysis, and multivariate modeling with stepwise logistic regression were performed. Of the 45 subjects, 23 (51%) underwent single ventricle (SV) palliation and 22 (49%) underwent BV repair. Of the 23 who underwent SV palliation, 15 (65%) survived compared to 18 (82%) of 22 who underwent BV repair (p = 0.34). In the BV group, a greater LVII predicted survival (R2 = 0.46, p = 0.03). No subjects with a LVII <0.5 survived BV repair. Mortality in the BV group was associated with younger age at initial surgery (p <0.01) and abnormal left AVV morphology (p = 0.02). Of the BV subjects with a patent ductus arteriosus at the initial operation (n = 11), the nonsurvivors were more likely to have retrograde flow in the transverse arch (p <0.01). In the BV group, reoperation within 30 days of the initial repair was strongly associated with mortality (p <0.01). In conclusion, in cases of mild or moderate LV hypoplasia, a greater LVII predicted survival after BV repair in patients with right-dominant unbalanced atrioventricular canal. We propose incorporation of the LVII into the echocardiographic assessment of these patients.

Predictors of impaired neurodevelopmental outcomes at one year of age after infant cardiac surgery.

OBJECTIVE: For most newborns, congenital heart defects (CHD) appear to be isolated anomalies and the brain is presumed to have normal developmental potential. Most studies of neurodevelopmental outcomes have focused on operative management strategies. METHODS: Infants with complex CHD and no identified syndromes other than 22q11 microdeletions enrolled in a study of apolipoprotein E (APOE) polymorphisms and developmental outcome were evaluated at one year of age; including genetic evaluation and the Bayley Scales of Infant Development-II [mental (MDI) and psychomotor developmental indices (PDI)]. RESULTS: Five hundred and fifty infants enrolled and 359 (20 with 22q11) of 501 survivors (72%) returned. Mean MDI was 90+/-15 and PDI was 78+/-18. Genetic syndromes not identified at birth were confirmed in 28 (8.1%) and suspected in 51 (15.0%). By multivariable analysis, suspected/confirmed genetic syndromes and APOE varepsilon2 allele predicted lower MDI and PDI, all p<0.04. Lower birth weight (p<0.001) and preoperative intubation (p=0.012) predicted lower MDI. Higher hematocrit during the initial operation was associated with higher MDI (p=0.007). Longer postoperative length of stay was predictive of lower PDI (p=0.002). Additional operations with cardiopulmonary bypass were associated with lower MDI and PDI (both p<0.002), but use of deep hypothermic circulatory arrest was not. CONCLUSIONS: Patient factors (birth weight and preoperative status) are significant determinants of neurodevelopmental outcomes as opposed to operative management strategies. In this cohort, genetic syndromes unsuspected at birth were surprisingly common and correlate with poor neurodevelopmental outcomes. Without multiple congenital anomalies, syndromes may be missed in infancy. Genetic evaluation should be considered in all infants with CHD.

Hyperglycaemia after Stage I palliation does not adversely affect neurodevelopmental outcome at 1 year of age in patients with single-ventricle physiology.

OBJECTIVE: Hyperglycaemia has been associated with worse outcome following traumatic brain injury and cardiac surgery in adults. We have previously reported no relationship between early postoperative hyperglycaemia and worse neurodevelopmental outcome at 1 year following biventricular repair of congenital heart disease. It is not known if postoperative hyperglycaemia results in worse neurodevelopmental outcome after infant cardiac surgery for single-ventricle lesions. METHODS: Secondary analysis of postoperative glucose levels in infants <6 months of age undergoing Stage I palliation for various forms of single ventricle with arch obstruction. The patients were enrolled in a prospective study of genetic polymorphisms and neurodevelopmental outcomes assessed at 1 year of age with the Bayley Scales of Infant Development-II yielding two indices: mental developmental index (MDI) and psychomotor developmental index (PDI). RESULTS: Stage I palliation was performed on 162 infants with 13 hospital and 15 late deaths (17.3% 1-year mortality). Neurodevelopmental evaluation was performed in 89 of 134 (66.4%) survivors. Glucose levels at admission to the cardiac intensive care unit and during the first 48 postoperative hours were available for 85 of 89 (96%) patients. Mean admission glucose value was 274+/-91 mg dl(-1); the maximum was 291+/-90 mg dl(-1), with 69 of 85 (81%) patients having at least one glucose value >200 mg dl(-1). Only two patients had a value <50 mg dl(-1). Mean MDI and PDI scores were 88+/-16 and 71+/-18, respectively. There were no statistically significant correlations between initial, mean, minimum or maximum glucose measurements and MDI or PDI scores. Only delayed sternal closure resulted in a statistically significant relationship between initial, minimum and maximum glucose values within the context of a multivariate analysis of variance model. CONCLUSIONS: Hyperglycaemia following Stage I palliation in the neonatal period was not associated with lower MDI or PDI scores at 1 year of age.