Crossed pulmonary arteries: An underestimated cardiovascular variant with a strong association with genetic syndromes-A report of 74 cases with systematic review of the literature.

Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11.2DS). We evaluated the correlation between CPAs and genetic diseases, in order to better define the characteristics of this variant, considered a rare anatomic pattern. An in-depth analysis of CPAs genotype-phenotype correlations was performed via a literature review. We detected 74 CPAs patients through echocardiography. Of these 74 patients, 35.1% of patients showed additional intracardiac malformations, while 29.7% showed extracardiac vascular anomalies, of which 16.2% were associated with intracardiac defects and 13.5% were not. In all, 62.2% of patients were diagnosed with genetic diseases and 52.2% of them were 22q11.2DS patients. In conclusions, CPAs represent a cardiovascular variant, which is detectable in nonsyndromic individuals, but especially in various genetic syndromes and in particular in 22q11.2DS patients. Data on the real prevalence of this morphology is lacking in literature. Knowledge of this anatomic variant is useful to interpret the unusual course of the pulmonary branches and is helpful information before cardiovascular surgical correction. Moreover, due to the strong association of CPAs with some genetic syndromes, the identification of this anatomic pattern can indicate the utility of a genetic assessment of these patients.

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.

Cardiac function in adolescents and young adults with 22q11.2 deletion syndrome without congenital heart disease.

BACKGROUND: Diagnosis and treatment of 22q11.2 deletion syndrome (22q11.2DS) have led to improved life expectancy and achievement of adulthood. Limited data on long-term outcomes reported an increased risk of premature death for cardiovascular causes, even without congenital heart disease (CHD). The aim of this study was to assess the cardiac function in adolescents and young adults with 22q11.2DS without CHDs. METHODS: A total of 32 patients (20M, 12F; mean age 26.00 ± 8.08 years) and a healthy control group underwent transthoracic echocardiography, including Tissue Doppler Imaging (TDI) and 2-dimensional Speckle Tracking Echocardiography (2D-STE). RESULTS: Compared to controls, 22q11.2DS patients showed a significant increase of the left ventricle (LV) diastolic and systolic diameters (p = 0.029 and p = 0.035 respectively), interventricular septum thickness (p = 0.005), LV mass index (p < 0.001) and aortic root size (p < 0.001). 2D-STE analysis revealed a significant reduction of LV global longitudinal strain (p < 0.001) in 22q11.2DS than controls. Moreover, several LV diastolic parameters were significantly different between groups. CONCLUSIONS: Our results suggest that an echocardiographic follow-up in 22q11.2DS patients without CHDs can help to identify subclinical impairment of the LV and evaluate a potential progression of aortic root dilation over time, improving outcomes, reducing long-term complications and allowing for a better prognosis.

Clinical Risk Factors for Aortic Root Dilation in Patients with 22q11.2 Deletion Syndrome: A Longitudinal Single-Center Study.

BACKGROUND: Aortic root dilation (ARD) has been described in 22q11.2DS, even without congenital heart disease (CHD). However, the clinical implications and longitudinal course are unclear. In this study, we evaluated aortic root (AR) dimensions in 22q112.DS adolescents/adults without major intracardiac CHDs, analyzed the progression over time and investigated correlations with extracardiac comorbidities. METHODS: AR dimensions were evaluated in 74 patients, measuring the sinus of Valsalva (VS) and proximal ascending aorta (AA), using Z-score to define mild, moderate and severe degrees. Changes in AR dimensions during longitudinal echocardiographic follow-up were investigated. Phenotypic characteristics have been collected. RESULTS: Twenty-four patients (32.4%) showed ARD in terms of VS Z-score (2.43; IQR 2.08-3.01), eight (33.3%) of a moderate/severe degree. Thirteen (54.2%) had concomitant AAD (Z-score 2.34; IQR 1.60-2.85). The risk of ARD was significantly directly related to skeletal/connective tissue disorders (OR 12.82, 95% CI 1.43-115.31; p = 0.023) and inversely related to BMI (OR 0.86, 95% CI 0.77-0.97; p = 0.011). A significant increase in AR diameter's absolute value (p = 0.001) over time has been detected. CONCLUSION: Isolated ARD is common in 22q11.2DS. Although some clinical risk factors have been identified, pathogenetic mechanisms and risk of complications are undefined. Regular cardiac evaluations should be part of the 22q11.2DS follow-up, and also in non-CHDs patients, to improve long-term outcome.

Focus on Cardiologic Findings in 30 Children With PANS/PANDAS: An Italian Single-Center Observational Study.

Objective: Cardiac involvement in PANS has not been clarified relying on the scientific literature available until today. It is known that streptococcal infections play a role in the etiology of a great number of diseases including Sydenham chorea and rheumatic fever, among others. Based on the suspected pathogenesis of PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) reported in the medical literature, we decided to investigate the cardiologic involvement in children with a recent PANS/PANDAS diagnosis. Methods: The study population satisfies PANS (1) and PANDAS (2) criteria of diagnoses. Cardiologic assessment was performed through clinical examination, electrocardiography, and echocardiography. Results: In the selected pediatric population, a significant number of children presented mitral valve involvement, systolic murmurs and electrocardiographic abnormalities. High ASLOT levels did not seem to be associated to a cardiac involvement. Conclusions: Often PANS is difficult to diagnose because it is little known by physicians and most of the cardiologic findings described in this study are common among the healthy pediatric population. Also, ASLOT levels seems not to be predictive of cardiac involvement. Furthermore, the existence of PANDAS as a clinical entity is associated with a group of anti-neuronal autoantibodies found in Sydenham chorea is still controversial. We recommend a complete cardiologic evaluation in those children who meet the PANS/PANDAS diagnostic criteria.

Left pulmonary artery in 22q11.2 deletion syndrome. Echocardiographic evaluation in patients without cardiac defects and role of Tbx1 in mice.

INTRODUCTION AND HYPOTHESIS: Patients with 22q11 deletion syndrome (22q11.2DS) present, in about 75% of cases, typical patterns of cardiac defects, with a particular involvement on the ventricular outflow tract and great arteries. However, in this genetic condition the dimensions of the pulmonary arteries (PAs) never were specifically evaluated. We measured both PAs diameter in patients with 22q11.2DS without cardiac defects, comparing these data to a normal control group. Moreover, we measured the PAs diameter in Tbx1 mutant mice. Finally, a cell fate mapping in Tbx1 mutants was used to study the expression of this gene in the morphogenesis of PAs. METHODS: We evaluated 58 patients with 22q11.2DS without cardiac defects. The control group consisted of 54 healthy subjects, matched for age and sex. All cases underwent a complete transthoracic echocardiography. Moreover, we crossed Tbx1+/- mice and harvested fetuses. We examined the cardiovascular phenotype of 8 wild type (WT), 37 heterozygous (Tbx1+/-) and 6 null fetuses (Tbx1-/-). Finally, we crossed Tbx1Cre/+mice with R26RmT-mG Cre reporter mice to study Tbx1 expression in the pulmonary arteries. RESULTS: The echocardiographic study showed that the mean of the LPA/RPA ratio in 22q11.2DS was smaller (0.80 ± 0.12) than in controls (0.97 ± 0.08; p < 0.0001). Mouse studies resulted in similar data as the size of LPA and RPA was not significantly different in WT embryos, but in Tbx1+/- and Tbx1-/- embryos the LPA was significantly smaller than the RPA in both mutants (P = 0.0016 and 0.0043, respectively). We found that Tbx1 is expressed near the origin of the PAs and in their adventitia. CONCLUSIONS: Children with 22q11.2DS without cardiac defects show smaller LPA compared with healthy subjects. Mouse studies suggest that this anomaly is due to haploinsufficiency of Tbx1. These data may be useful in the clinical management of children with 22q11.2DS and should guide further experimental studies as to the mechanisms underlying PAs development.

Paroxysmal reciprocating supraventricular tachycardia in infants: electrophysiologically guided medical treatment and long-term evolution of the re-entry circuit.

AIMS: The aim of this study is to evaluate the long-term prognosis in infants affected by paroxysmal reciprocating supraventricular tachycardia (SVT), to identify predictors of SVT disappearance, and to assess the efficacy of electrophysiologically guided drug therapy in preventing recurrences. METHODS AND RESULTS: A six step regimen of oral therapy was used in 55 infants with SVT: (i) propafenone (P); (ii) flecainide (F); (iii) flecainide plus propranolol (FP); (iv) amiodarone (A); (v) amiodarone plus propranolol (AP); (vi) amiodarone plus flecainide plus propranolol (AFP). If one step was not successful, the patient was passed on to the next treatment step and so on. Transesophageal atrial pacing (TAP) was used to evaluate treatment efficacy and the evolution of SVT at the end of the first, second, and third year. Propafenone was successful in 32.7% of the patients, F in 14.5%, FP in 23.6%, A alone in 5.4%, and AP in 18.1%; only 7.2% reached step 6. At month 12, after therapy wash out, SVT recurred spontaneously in 2 patients (3.6%) and remained inducible in 25 (45.5%). Inducibility was significantly higher in patients treated with A. At 24 months, SVT was inducible or spontaneous in 86% of the cases and at 36 months in 87%. There were no recurrences using the treatment confirmed by TAP. No further predictor of SVT inducibility was identified. CONCLUSION: Supraventricular tachycardia disappeared in approximately 50% of the patients during the first year of life and in another 20% thereafter. The necessity for A treatment is the only predictor of persistence of the re-entry circuit during the first year of life. Transesophageal atrial pacing is useful in guiding the medical treatment.

Conotruncal heart defects: impact of genetic syndromes on immediate operative mortality.

BACKGROUND: The surgical outcome of conotruncal heart defects in patients with genetic syndromes has been poorly studied. The aim of this prospective 5-year multicenter study was to elucidate the post-surgical death rate of children with conotruncal heart defects in relation to the presence of associated genetic syndromes. METHODS: Two institutions enrolled 350 consecutive inpatients with conotruncal heart defects, aged between 1 day and 60 months, who were submitted to surgery; all patients were evaluated by a clinical geneticist and had a standard metaphase chromosome analysis and a fluorescent in situ hybridization study searching for deletion of chromosome 22q11 (del22q11). RESULTS: No genetic syndrome was diagnosed in 289 patients; among the other 61 patients, 27 had DiGeorge velocardiofacial syndrome (del22q11), 16 patients had Down syndrome, and 18 presented with other genetic syndromes. The overall post-surgical death rate was higher in syndromic patients (18%) than in non-syndromic ones (10.7%) with a relative risk of 1.9 (p = 0.06). However, children with del22q11 showed a higher risk for surgical mortality (25.9 vs 10.7%; relative risk 2.4, p = 0.03). Del22q11 was identified as a risk factor for immediate surgical mortality in patients with pulmonary atresia and ventricular septal defect and in patients with interrupted aortic arch. CONCLUSIONS: Down syndrome is not a risk factor for surgery in children with conotruncal heart defects. The presence of a del22q11 may influence the surgical results in children with pulmonary atresia and ventricular septal defect and in those with interrupted aortic arch. Patients with genetic syndromes other than del22q11 and Down syndrome have a higher surgical mortality compared to that observed in non-syndromic patients. These data may be useful for preoperative counseling and for the elaboration of specific protocols of perioperative treatment.

[Transposition of great arteries. Understanding its pathogenesis]. / Trasposizione delle grandi arterie. Qualche spiraglio nell'inquadramento patogenetico.

Transposition of the great arteries (TGA) is a frequent and severe cardiac defect. In patients with this malformation, diagnostic and surgical results and the long-term prognosis significantly improved in the last years. From the embryological point of view there are two main theories: 1) the anomalous infundibular rotation, and 2) the anomaly of the aortico-pulmonary septum. Both of them still present important limits. Moreover, TGA is difficult to reproduce by animal experiments, but interesting data, using retinoid acid in pregnant rats, are nowadays available, as well as there are interesting data from the epidemiologic studies on human teratologic agents. TGA is rarely associated with genetic syndromes and with additional extracardiac anomalies. A few cases are in relation with DiGeorge syndrome with deletion of chromosome 22q11. On the contrary TGA is significantly prevalent, in association with other cardiac and extracardiac anomalies, in children with lateralization defects, heterotaxy and asplenia syndrome (right isomerism). However in patients with heterotaxy and polysplenia syndrome (left isomerism) TGA is significantly more rare. In mice with mutation of Smad2 and NODAL, two genes involved in the lateralization process, some cases of TGA, with or without right isomerism of the lungs, were reported. Moreover, in families with heterotaxy some cases with congenitally corrected TGA were reported and a new gene associated with heterotaxy, CRYPTIC, can present mutations in patients with "isolated" TGA. A recent study on familiar recurrence of TGA shows in the same family some cases of TGA and of corrected TGA so that a monogenic inheritance (autosomic dominant or recessive) with variable phenotypic expression can be suggested. The normal righthand spiralization of the heart is genetically determined in cases of situs solitus and d-loop of the ventricles. This pattern is not present in cases of TGA presenting a parallel position of the great arteries. On the basis of these observations and according to new epidemiologic and genetic data some cases of TGA should be classified in the group of the anomalies of lateralization and ventricular loop. The mystery is still present but perhaps some gleams of light are appearing.

Genetic syndromes and outcome after surgical correction of tetralogy of Fallot.

BACKGROUND: Genetic syndromes occur in 20% of patients with tetralogy of Fallot (TOF). The impact of genetic syndromes on surgical repair of TOF in infancy is still under investigation. METHODS: This retrospective study reviews the outcome of 306 consecutive patients (median age, 5.1 months) who underwent primary (266) or staged (40) repair of TOF between 1994 and 2004. Total follow-up was 1,188 patient-years (mean, 57 months). RESULTS: Genetic syndromes were documented in 85 patients (27.8%), including 22q11 deletion (27), trisomy 21 (13), vertebral, anal, cardiac, tracheoesophageal, renal, and limb abnormalities (VACTERL, 12), and others (33). Hypoplastic pulmonary arteries (PA) were more common in syndromic (19/85 = 22.3%) than nonsyndromic TOF (20/221 = 9.04%) (p < 0.001). Primary repair was performed in 82.4% syndromic and 88.7% nonsyndromic TOF (p = not significant [NS]). Ten-year actuarial survival was 94.1 +/- 2.3% in nonsyndromic and 84.3 +/-4.2% in syndromic TOF (p < 0.001). Ten-year survival was 96.3 +/- 3.6% for del22q11, 100% for trisomy 21, 63.6 +/- 14.5% for VACTERL, and 78.5 +/- 7.3% for patients with other syndromes (p = 0.022). Survival in syndromic TOF with normal PA anatomy was 89.6 +/- 4.2% for primary repair and 85.7 +/- 12.8% for staged repair (p = NS); freedom from reoperation after complete repair was 74.4 +/- 6.4% for primary correction and 56.3 +/- 11.9% for staged repair (p = 0.04). Cox proportional hazard identified the presence of genetic syndrome (p = 0.011) and central PA hypoplasia (p = 0.002) as independent predictors of mortality. CONCLUSIONS: Pulmonary arborization defects and genetic syndromes other than del22q11 or trisomy 21, are associated with worse outcome after correction of TOF. Primary TOF repair in syndromic patients with normal PA anatomy is a valid surgical strategy, with no additional risk for mortality and higher freedom from reintervention.