Surgery for Complex forms of Atrioventricular Septal Defect: Early Survival and Probability of Cure

Atrioventricular Septal Defects (AVSD) account for 7.4% of Congenital Heart Defects (CHD). They may occur in isolation, with a narrow spectrum of age at presentation and prognosis, or in association with other intracardiac malformations: here symptoms and needs for treatment vary considerably. Moreover, their frequent association with abnormal genetic disorders, such as Trisomy 21 or Heterotaxy, further complicates the task of surgical treatment. Analysing the data is seemingly complex: some associations are exceedingly rare, while in other more common morphologies, the approach is variable and controversial. Although results have greatly improved in the last decades, early and late survival remains suboptimal, sometimes poor. Early mortality greatly varies, along with complexity of pathophysiology and repair, from 5% to over 30%. The dilemma between high operative risk and palliation of the univentricular type is at times daunting. The possibility of surgical cure is discussed according to surgical options but the frequent need for reintervention makes hope elusive. Late survival greatly differs, from 45% to 80% at 5-year follow-up. It is hardly surprising, in the western type of society, that prenatal diagnosis should result in a high rate of termination of pregnancy. This holds particularly true when a chromosomal abnormality is also identified

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age.Methods: From the Italian LIPIGEN cohort, we selected 1188 (>= 18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation.Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives.Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age

Sindrome da delezione del cromosoma 22q11.2: valutazione della funzione cardiorespiratoria, delle patologie extracardiache e correlazioni genotipo-fenotipo

Background La sindrome da delezione del cromosoma 22q11.2 (22q11.2DS, OMIM 188400/192430) è la più comune sindrome da microdelezione cromosomica, con una prevalenza di circa 1:4000 nati vivi. Nonostante i progressi nella diagnosi e nel trattamento abbiano portato ad un miglioramento dell’aspettativa di vita e al raggiungimento dell’età adulta da parte di questi pazienti, i dati limitati che abbiamo a disposizione sulla popolazione adulta con 22q11.2DS hanno sottolineato un aumentato rischio di morte prematura per cause cardiovascolari (come la morte improvvisa o lo scompenso cardiaco), anche in assenza di cardiopatia congenita (CC). Lo scopo di questo studio è stato quello di valutare la funzione cardiaca e respiratoria a riposo e la tolleranza all'esercizio fisico in un gruppo di adolescenti e adulti con 22q11.2DS senza CC. Inoltre, sono state indagate le possibili correlazioni tra fenotipo cardiopolmonare, fenotipo extracardiaco e caratteristiche genetiche. Materiali e Metodi Sono stati arruolati 32 pazienti (20M,12F; età media 26.00 ± 8.08) con diagnosi di 22q11.2DS senza CC. Tutti i soggetti sono stati valutati da un team multidisciplinare per individuare le caratteristiche fenotipiche extracardiache, sono stati sottoposti a valutazione cardiologica completa con ECG, ecocardiografia transtoracica convenzionale e speckle tracking (STE), test di funzionalità respiratoria e test da sforzo cardiopolmonare. Sono stati raccolti i dati genetici dei pazienti sottoposti ad analisi array genomiche (CGH- e SNP-array), analizzando l’estensione e la localizzazione della delezione e l’eventuale presenza di microriarrangiamenti aggiuntivi, oltre alla microdelezione 22q11.2. E’ stata condotta un’analisi di correlazione genotipo-fenotipo tra gli aspetti funzionali cardiorespiratori, le anomalie extracardiache e l’assetto genetico. I risultati degli esami strumentali sono stati confrontati con un gruppo di controllo (GC) e i valori p≤0.05 sono stati considerati statisticamente significativi. Risultati I pazienti con 22q11.2DS hanno mostrato un aumento delle dimensioni del VS (IVSd p=0.005; LVIDd p=0.03; LVPWd p=0.05), della massa ventricolare sinistra indicizzata per l’altezza (LVMI g/m2,7 p<0.001) e del diametro del bulbo aortico (p<0.001) rispetto al GC. Nove pazienti (~28%) hanno mostrato una dilatazione lieve del bulbo aortico (Z-score 2-3) e 3 pazienti (~9%) una dilatazione moderata (Z-score 3,01-4). Il TDI ha rivelato una iniziale compromissione della funzione diastolica del VS e l’analisi STE ha identificato una riduzione dello “strain” miocardico longitudinale globale del VS (GLS Avg) nei pazienti affetti rispetto al GC (p<0.001). I valori di VO2max, FEV1% e FVC% sono risultati inferiori nei pazienti 22q11.2DS (p<0,001). La scoliosi, il BMI e lo stile di vita sedentario sembrano influenzare la funzione respiratoria. Nel gruppo 22q11.2DS, valori patologici di Z-score del bulbo aortico correlano significativamente con la presenza di patologie dell’apparato scheletrico/connettivo (p=0.04) e valori ridotti di GLS Avg del VS mostrano una relazione diretta con i disturbi GI (p=0.026). Sebbene, non sia emersa una correlazione significativa, circa il 67% dei pazienti con delezione “atipica” e distale presentava un GLS Avg del VS alterato. Tra i pazienti con alterazione del GLS Avg del VS, ~27% mostrava una delezione “atipica”, ~13% una delezione distale e ~7% presentava mutazioni genetiche aggiuntive, non correlate alla microdelezione 22q11.2. Conclusione I pazienti adolescenti/adulti 22q11.2DS senza CC, presentano segni iniziali di compromissione diastolica e sistolica del VS in fase subclinica, mantenendo una performance ventricolare complessivamente conservata e mostrano una dilatazione del bulbo aortico di grado lieve-moderato. Inoltre, è stata evidenziata una riduzione della funzionalità respiratoria e dell’efficienza cardiopolmonare. Pertanto, anche in assenza di CC, è opportuno che questi pazienti seguano un regolare follow-up cardiopolmonare fin dall’età pediatrica, per evidenziare potenziali comorbilità correlate, identificare l'insorgenza precoce di eventuali anomalie funzionali cardiorespiratorie e monitorare l’eventuale progressione di una dilatazione del bulbo aortico nel tempo. La stretta correlazione emersa tra alcune anomalie extracardiache e il fenotipo cardiorespiratorio può consentire una migliore stratificazione del rischio prognostico e prevenire possibile complicanze a lungo termine. Ulteriori studi di correlazione genotipo-fenotipo sono necessari per chiarire se la presenza di una delezione “atipica” e/o distale possa predisporre i pazienti con 22q11.2DS senza CC ad un maggior rischio di disfunzione miocardica ventricolare sinistra e quanto le eventuali mutazioni genomiche aggiuntive possano contribuire al fenotipo funzionale cardiopolmonare

Transpositions of the great arteries versus aortic dextropositions. A review of some embryogenetic and morphological aspects

This review examines and discusses the morphology and embryology of two main groups of conotruncal cardiac malformations: (a) transposition of the great arteries (complete transposition and incomplete/partial transposition namely double outlet right ventricle), and (b) aortic dextroposition defects (tetralogy of Fallot and Eisenmenger malformation). In both groups, persistent truncus arteriosus was included because maldevelopment of the neural crest cell supply to the outflow tract, contributing to the production of the persistent truncus arteriosus, is shared by both groups of malformations. The potentially important role of the proximal conal cushions in the rotatory sequence of the conotruncus is emphasized. Most importantly, this study emphasizes the differentiation between the double-outlet right ventricle, which is a partial or incomplete transposition of the great arteries, and the Eisenmenger malformation, which is an aortic dextroposition. Special emphasis is also given to the leftward shift of the conoventricular junction, which covers an important morphogenetic role in both aortic dextropositions and transposition defects as well as in normal development, and whose molecular genetic regulation seems to remain unclear at present. Emphasis is placed on the distinct and overlapping roles of Tbx1 and Pitx2 transcription factors in modulating the development of the cardiac outflow tract

Some Isolated Cardiac Malformations Can Be Related to Laterality Defects

Human beings are characterized by a left⁻right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left⁻right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left⁻right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects

Impact of genetic studies on comprehension and treatment of congenital heart disease

The great impact of genetic factors in the field of congenital heart disease (CHD) was highlighted about 30 years ago by the Baltimore-Washington Infant Study. Moreover, recent genetic studies have shown their importance not only in detecting the cause of some heart malformations, but also in improving their treatment and prognosis. Three fields may be recognized in which genetic studies have enhanced our knowledge and ability to care for children with CHD: • Reverse medicine includes genotype-phenotype correlations and the new diagnostic criteria to classify CHD. • Predictive medicine regards genotype-prognosis correlations to detect risk factors and to establish specific protocols and treatment. • Preventive medicine can help to prevent the defect or to reduce its severity and complications. This approach proved to be useful in CHD associated with genetic syndromes but it is also promising in isolated non-syndromic CHD

Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia with consequent immune deficiency, cardiac malformations, hypoparathyroidism, facial and palatine abnormalities, variable degrees of cognitive impairment and psychiatric disorders. The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction. Neuroinflammation in DGS individuals could be directly related to the development of the syndrome’s characteristic psychiatric and cognitive disorders. In patients with psychotic disorders, the most frequent psychiatric manifestation in DGS, Th-17, Th-1 and Th-2 cells are increased with consequent elevation of proinflammatory cytokine IL-6 and IL1β. In patients with anxiety disorders, both CD3 and CD4 are increased. Some patients with autism spectrum disorders (ASDs) have an augmented level of proinflammatory cytokines IL-12, IL-6 and IL-1β, while IFNγ and the anti-inflammatory cytokine IL-10 seem to be reduced. Other data proposed that altered synaptic plasticity could be directly involved in DGS cognitive disorders. In conclusion, the use of antioxidants for restoring mitochondrial functionality in DGS could be a useful tool to protect cortical connectivity and cognitive behavior

22q11.2 Deletion Syndrome: Impact of Genetics in the Treatment of Conotruncal Heart Defects

Congenital heart diseases represent one of the hallmarks of 22q11.2 deletion syndrome. In particular, conotruncal heart defects are the most frequent cardiac malformations and are often associated with other specific additional cardiovascular anomalies. These findings, together with extracardiac manifestations, may affect perioperative management and influence clinical and surgical outcome. Over the past decades, advances in genetic and clinical diagnosis and surgical treatment have led to increased survival of these patients and to progressive improvements in postoperative outcome. Several studies have investigated long-term follow-up and results of cardiac surgery in this syndrome. The aim of our review is to examine the current literature data regarding cardiac outcome and surgical prognosis of patients with 22q11.2 deletion syndrome. We thoroughly evaluate the most frequent conotruncal heart defects associated with this syndrome, such as tetralogy of Fallot, pulmonary atresia with major aortopulmonary collateral arteries, aortic arch interruption, and truncus arteriosus, highlighting the impact of genetic aspects, comorbidities, and anatomical features on cardiac surgical treatment