Epidemiological studies, clinical observations and recent advances in molecular genetics are shedding increasing light on the genetic origin of congenital heart disease (CHD). Chromosomal anomalies, Mendelian syndromes or associations account for nearly 30% of all congenital cardiac malformations. These developmental anomalies may be part of well-defined syndromes due to chromosomal or submicroscopic genomic anomalies or may be non-syndromic as a consequence of still unidentified genes with sporadic occurrence in families. This paper summarizes the available findings from literature on the inference of genetics on cardiac development by classifying the congenital heart diseases as cono-truncal defects, atrio-ventricular canal and septal defects, right-sided obstruction and left-sided obstruction.

Cono-truncal defects represent an anatomically heterogeneous group of CHDs affecting the outflow tract of the ventricles and the arterial pole of the heart. The most common malformations of this group are tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus and interrupted aortic arch. These CHDs are associated with genetic syndromes in 25-40% of cases and even in non-syndromic forms show a high incidence of mono-genic abnormalities.

Atrio-ventricular canal is a complex malformation due to abnormal septation of the “crux cordis” resulting in ostium primum atrial septal defect, inlet ventricular septal defect and common atrio-ventricular valve. It is almost always associated with genetic syndromes, being non-syndromic in only 25% of cases. However, septal defects other than atrio-ventricular canal are rarely due to genetic syndromes, ranging from 3% to 25% of cases, yet with a high rate of segregation in some families.

Valvular or vascular-elicited right sided obstructions, are due to genetic syndromes in about 10% of cases and this association results in difficult treatment due to the ineffectiveness of any percutaneous treatment and extent of the lesions along the pulmonary trunk.

Among left heart obstructions, supra-valvular stenosis is a well-know malformation due to disruption of the elastin gene associated with Williams syndrome in many cases.

Conversely, aortic coarctation and other left-sided heart stenosis or hypoplastic malformation are often non-syndromic, being associated with genetic syndromes in less than 10% of cases.

In conclusion, improved molecular genetic technologies has led to the discovery of several causes of syndromic and non-syndromic CHDs. Nevertheless, much work remains in identifying in etiology of non-syndromic CHDs, since the number of genes known to be involved is still limited.

Heart failure is considered the end-stage phenotype of a variety of different basal cardiac defects, determined by several possible cellular regulation mechanisms. Complex and monogenic diseases can be the first manifestation of a developing phenotype leading to final heart failure. Hypertension, myocardial infarction and other forms of atherosclerotic cardiovascular disease can be precursors of heart failure; moreover, different types of cardiomyopathy can evolve to a heart failure phenotype. Recent advances in molecular biology and genetics have allowed for further comprehension of the basis of the development of cardiac diseases. Particularly, genetics of cardiomyopathies, although known since the early 1990s, studies are still in progress as an increasing number of genes (causing or predisposing to the disease) are discovered. Genetic studies in this field are now supported by new technical approaches (such as microarray chips) that increase the output results of the analysis allowing the evaluation of the entire genome in a single experiment and extending the research to new classes of biological molecules such as microRNA. Cellular mechanisms of impaired energetic metabolism, contractile force generation and propagation, ion channel exchanges and mitochondrial functioning are commonly recognized as the principal causes of the development of heart failure. Identifying which genetic cause has led to a specific phenotype is not only important to foresee the prognosis, but also to design a specific pharmacological therapy on the basis of the individual necessity (this approach is known as “pharmacogenetics” or “pharmacogenomics”). Other promising therapeutic innovations are found in stem cell therapy and different classes of cells have been tested for this purpose, but clinical application is, to date, still under investigation.

Pulmonary hypertension (PH) in children is a serious disease, characterized by an inauspicious prognosis. It is a complex disorder with various etiologies, including congenital heart diseases (CHDs), idiopathic and familial diseases (IPH), and connective tissue diseases (CTD). Half of these patients have associated congenital heart disease (50%), while idiopathic forms of PH accounts for 40% of cases. The pathogenesis of PH is multi-factorial. The increase of pulmonary vascular resistance is due to cellular and biochemical modifications that lead to endothelial dysfunction, vasoconstriction, arterial wall thickening and thrombosis: the first stimulus that leads to these modifications has not been understood yet, but several hypotheses support the importance of both genetic predisposition and risk factors. The pattern of inheritance in heritable PH was observed to be autosomal dominant with highly variable and incomplete expression and penetrance among families; the penetrance is estimated to be very low. BMPR2 (a member of TGF-β family) is the first candidate gene for heritable PH and sporadic PH: loss of function mutations in the gene encoding for this receptor could cause proliferation of vascular cells, but these mutations cannot be considered the only cause of the disease. Moreover, carriers for mutations in BMPR2 have 15% to 20% chance of developing PH in their lifetime, so a large part of “sporadic” cases could be unrecognized familial forms of pulmonary hypertension. Other genes, not actually known, could explain all cases of heritable PH in which no mutations in BMPR2 gene are detectable. CHD is the most common condition associated to PH. A high number of young patients have PH as part of a syndrome, and the most common example is Down syndrome. Among these patients who have a CHD, screening for PH and early correction of CHD could represent a tool to prevent PH development. It is now widely known that genetic variations may influence outcome and/or response to drugs in different patients. These differences exist both to drug effects and to toxicity of a specific treatment: genetic variants may influence the absorption, the metabolism and the physiologic effect of a drug. Pharmacogenomic studies have shown that genetic variants may account for differences in the pharmacokinetics and pharmacodynamics: these results lead to individual responses to drugs. In PH area, it is interesting to turn the attention to endothelin-1 (its plasma levels are increased in IPAH) and its receptors, ETA and ETB.

Echocardiography has a primary role in the diagnosis and management of congenital heart diseases. However conventional echocardiography has two major limitations in the evaluation of congenital heart diseases: quantification of both right and left ventricular function and morphological evaluation. The availability of a new high-frequency transthoracic pediatric three-dimensional probe the same size as a standard 2D echo-Doppler probe now makes 3D echocardiography available in for pediatric cardiology echo-lab. In pediatric cardiology 3D echo can be used for a more accurate evaluation of left or right ventricle mass and volume, or to improve anatomical definition either of simple and of complex congenital heart disease.

Strain and strain rate are very helpful tools to establish segmental myocardial contractility. In addition, strain and strain rate are less load dependent. In pediatric cardiology, many studies have demonstrated the impact of S and SR on the echocardiographic evaluation of CHD, helping in assessment of left and right ventricular function, in clinical management and in surgical planning.

Magnetic Resonance Imaging (MRI) has emerged as a valuable non-invasive diagnostic tool in congenital heart malformations providing anatomical and functional data regardless of patient’s size and quality of thoracic window. This technique is particularly indicated to avoid cardiac catheterization in post-surgical adult patients in whom the echocardiographic window is often poor. MRI is able to provide both accurate 3-dimensional images of the cardiovascular system as well as precisely quantify volumes and mass of the cardiac chambers and functional data of any single segment of the heart. MRI is now considered a Class I indication in pediatric or adult patients with congenital heart malformations. It is able to define morphological data of cardiac malformation and its functional consequences at the same time. This paper summarizes the most relevant technical aspects of MRI in congenital heart disease and reports on useful protocols to evaluate the most common malformations.

Thanks to significant advances in techniques and devices, trans-catheter treatment of congenital heart disease has taken important steps forward over the last decades. This paper summarizes the most relevant advances in percutaneous therapy of congenital heart malformations, highlighting the available procedures in 3 main groups: balloon dilatation and/or stenting of valves and vessels, device closure of intra-cardiac or extra-cardiac communications and pulmonary valve implantation.

1- Percutaneous treatment of valve stenosis can now be effective in a high percentage of cases either in newborns or in adult patients. Indeed, pulmonary or aortic valve dilation can be performed using one or two balloons with very good early and long-term results. Systemic or pulmonary vessel stenosis (either native or post-surgical) can be effectively treated by balloon angioplasty or stent implantation. High-pressure or cutting balloons are highly useful for native lesions, while the relief of post-surgical stenoses can be achieved by stent implantation. To date, the only significant limitation to this latter approach is the size of the patient in terms of potentiality of growth, although the use of bio-absorbable stents could overcome this drawback, allowing the treatment of even newborns or small infants. Native aortic coarctation can be effectively approached by balloon dilatation in newborns and infants, while stent implantation is suggested in patients older than 8 years of age. However, post-surgical re-coarctation can be successfully treated by balloon angioplasty (preferably in low-weight patients) or stent implantation.

2- Percutaneous closure of atrial septal defect and patent foramen ovale is possible in most patients using devices with different mechanism and physiology. This approach makes it possible to tailor the device to the defect anatomy and size. Early and longterm results of this technique are very satisfactory, with closure rate near to 100% and very low complications rate. Device closure of muscular ventricular septal defects is possible and safe also in low-weight infants, while the percutaneous approach to membranous ventricular septal defect should be indicated in patients older than 6 years due to high risk of heart block in younger patients. Patent ductus arteriosus can be safely approached by percutaneous techniques at any age, although this treatment is more challenging in patients weighting less than 5 kg. The most used device are detachable coils or Amplatzer Duct Occluder devices, with very high success rate and low complication rate.

3- The first percutaneous pulmonary valve replacement was performed almost 10 years ago by Bohnoeffer et al. Nowadays, this approach is widely used in patients older than 5 years and/or weighting more than 20 kg with pulmonary conduit stenosis and/or insufficiency. In these patients the Melody® valve can be effectively implanted with a high rate of success and anticipated good effectiveness over a mid-term follow-up.

Despite current trends toward primary repair, surgical systemic-to-pulmonary shunt is still an invaluable palliative option in some patients with congenital heart defects and duct-dependent pulmonary circulation. However, arterial duct stabilization with high-flexibility coronary stent could be an effective alternative in high-risk surgical candidates or whenever a short-term pulmonary blood flow support is anticipated. This paper highlights history, methods and results of this attractive mini-invasive palliative approach to cardiac malformation with duct-dependent pulmonary circulation. Based on ductal origin and morphology, stenting procedure can be perfomed from arterial or venous route. Following arterial duct angiographic imaging, the stabilizing stent is chosen to completely cover the entire ductal length and dilated slightly less than the proposed surgical shunt. Procedural failure mainly depends on ductal tortuosity and ranges around 10% of cases. Morbidity and mortality are 8-11% and less than 1%, respectively. Mid-term fate of the stented duct is spontaneous, slow and progressive closure within a few months. Compared to Blalock-Taussig shunt, stented duct result in similar but more uniform pulmonary artery growth over a mid-term follow-up.

In conclusion, arterial duct stenting is a technically feasible, safe and effective palliation in congenital heart disease with duct-dependent pulmonary circulation. It is advisable either in high-risk neonates or whenever a short-term pulmonary blood flow support is anticipated. The stented duct appears less durable than a conventional surgical shunt although it is highly effective in promoting a global and uniform pulmonary artery growth.

Hybrid therapy is an emerging field of cardiology in which the skills of surgeons and cardiologists (both interventional and imaging experts) are co-operatively combined during a procedure to improve patient outcome. A hybrid approach is defined as a combined intervention performed in a single setting or in a planned close sequential fashion. Hybrid therapies aim to “play to the strengths and minimize the weaknesses” of the different disciplines in order to tackle lesions otherwise inaccessible without a combined procedure or with suboptimal outcomes when tackled using a single approach. Inevitably this philosophy has been used to extend the boundaries of therapy in patients at or beyond the limits of traditional surgery or transcatheter treatment for example very small infants with hypoplastic heart syndrome and patients with large and potentially inaccessible muscular ventricular defects. Hybrid therapy has the potential to reduce patient morbidity and systemic stress and can offer a bridge to definitive treatment in vulnerable patients.

In addition to the more “traditional” and accepted hybrid treatments for hypoplastic left heart syndrome, ventricular septal defect closure and intra-operative stenting a number of other techniques have been described including intra-operative valvoplasty, coarctation stenting and atrial septal defect closure.

Ideally hybrid therapy requires a dedicated operating facility although many procedures can be adequately performed in ordinary catheter laboratories or operating suites with relatively minor modifications.

Given that the majority of hybrid techniques are novel the precise indications and limitations of procedures require further definition.