Congenital anomalies occur in developing fetus. Congenital heart disease (CHD) is major congenital anomalies, which consists of heart defects present from the birth. CHD among all birth defects is the main cause of death in infancy. It is the structural abnormality of heart or great vessels, detected either at the time of birth or later in life. Globally, CHD constitutes the major cause of mortality among children, especially in developing countries.[3,4] It also accounts for more than 20% of infant's death prenatally.[5,6] The prevalence rate of CHD is estimated to be 8/1000 live births. The classification of CHD is of great complexity, generally classified as moderate, severe, and simple CHD. The estimated prevalence of moderate and severe CHD is more consistently assessed on 1.5/1000 live births in each group. The detection of cardiac defects by prenatal ultrasound and subsequent termination of pregnancy further affects the prevalence rate of CHD. Previous studies showed approximately 57-85% of severe lesions are detected before the end of pregnancy. Despite recent advances in the diagnosis and treatment, the incidences of congenital heart defects from various studies differ from about 4/1000 to 50/1000 live births.[4,5,6] The congenital heart defects can be life-threatening during early childhood, and infants born with this disorder are at much higher risk (∼12) of mortality especially in the 1st year of life. Newborns with congenital heart disorders are symptomatic and soon identified after birth and some cases of CHD remains undiagnosed until or unless the disease progresses to a severe stage. The severity and type of diseases depend on the signs and symptoms. High morbidity and mortality rate is associated with critical cardiac lesions in infants and the risk increases as diagnosis and treatment gets delayed. Therefore, the screening process is very important tool in diagnosing CHD. In developing countries, the echocardiographic screening may be difficult due to lack of availability of sonographers and echocardiographic machines. As a result, CHD in patients can be determined by physical examinations and clinical presentations such as cardiac arrhythmia, murmur, cyanosis, chest pain, and palpitation. Thousands of children die each year because of CHD, and millions more who survived are in urgent need of treatment. There is an urgent need of reducing the prevalence of this disease by knowing the real cause and developing prevention strategies and effective management.
Types of congenital heart defects
Some studies reports the birth prevalence of eight most common congenital heart defects subtypes, i.e. (a) ventricular septal defect (VSD), (b) atrial septal defect (ASD), (c) pulmonary stenosis (PS), (d) patent ductus arteriosus (PDA), (e) tetralogy of Fallot, (f) coarctation (Coarc), (g) transposition of great arteries (TGA), and (h) aortic stenosis (AoS) [Table 1].
The prevalence generally shows the probability of a person having a disease in a given population during a given time. It represents the disease incidences in a given population at a given time. The birth prevalence of CHD increased substantially from 0.6/1000 live births between the year 1930 and 1934; to 9.1/1000 live births after 1995. This increase was S-shaped overtime initially increase from 1930 to 1960, then by stabilization around 5.3/1000 live births from 1961 to 1975, then further increase in the year 1970, till 1995, and then stabilization in the last 15 years, around 9.1/1000 live births. The prevalence of CHD according to geographical location was found significantly different. The birth prevalence of total CHD was reported highest in Asia, i.e., 9.3/1000 lives births; and lowest in Africa, i.e., 1.9/1000 live births. The second highest birth prevalence of CHD was found in Europe, i.e., 8.2/1000 live births. The high-income countries have the highest prevalence of CHD (8.0/1000 live births) as compared to low-income countries. Globally, the prevalence of CHD ranges from 3.7 to 17.5/1000 live births accounting 30%–45% of all the birth defects. There are also some reported cases of the adult prevalence of CHD that can estimate the requirement of adult cardiological services. It is very difficult to diagnose the cases of CHD in adults. Some CHD patients have recovered spontaneously, the diagnosed cases of adults with CHD continue to rise, and now, it is higher than diagnosed pediatric CHD cases.
In vertebrates, the development of heart begins at embryonic day 15 which comprises of an organized series of morphological and molecular events including the following five primary steps.[16,17]
- Precardiac cells migration at the myocardial plate from the cardiac crescents assembly and primitive streak
- Formation of the primitive heart tube by cardiac crescents coalescence
- Alignment of cardiac chambers
- Heart chamber formation and septation
- Cardiac conduction system development and formation of the coronary vasculature.
Any alteration in the developmental processes of embryonic structure or failure of structure to develop during an early embryonic stage leads to congenital heart defects. It is an anatomical defect influencing the structure and function of the organ system. The etiology behind the abnormal heart development in babies remains unclear. Although substantial knowledge behind the cause of CHD has been made during the last decade. Genetic disorders may be associated with the congenital malformations, and also some malformations are consequences of environmental teratogens or diet. An alteration in the migration of the cells leads to disorder in the cardiac development. These findings together emphasize the multifactorial and complex etiology of the CHD. Additional research is needed to determine the etiology of CHD which will pave the way in understanding the preventive measures and therapeutic treatment by the health-care professionals as well as health officers. Table 2 represents the genetic disorders associated with the etiology of CHD and Table 3 shows the maternal factors causing CHD.
CHD is identified as intracardiac shunting lesions. In a normal cardiac physiology, there is complete separation of deoxygenated and oxygenated blood. These two circulations run in parallel, maintaining one-to-one volume relationship on the pulmonary and systemic region of circulation, each feeding the other. The deoxygenated blood returns to the right atrium (RA) and pumped to the lungs as pulmonary blood flow. After oxygenation, the blood returns from the pulmonary veins to the left atrium (LA) and is pumped to the aorta, i.e., cardiac output. “Shunt” refers to the abnormality in the flow of blood from one side of the circulation to the other side. In left-to-right shunt, the pulmonary venous blood (oxygenated) return directly to the lungs, instead of being pumped to the body. Similarly, in the right-to-left shunt, the systemic venous blood return (deoxygenated) bypass the lungs and return directly to the body without becoming oxygenated. Circulation in each shunt become less efficient and increases blood demand on the ventricles. In most of the cases, the severity of the symptoms determines the volume of shunted blood.
The normal aerobic respiration is maintained at cellular level, delivery of oxygen is performed in sufficient quantities to meet the metabolic demands of the body. In left-to-right shunt, the cardiac output volume gets reduced by the shunted volume amount. This causes a reduction in the delivery of oxygen to tissues.
In normal cardiac physiology, the hemoglobin, lung function, arterial blood oxygen content varies only to a certain extent when pulmonary oxygenation of alveoli changes. In right-to-left shunt, the systemic venous blood which is deoxygenated returns directly to the systemic circulation of the artery. This causes fall in the oxygen content of the systemic arterial blood in proportion with the systemic venous blood volume mixes with the normal venous return from the lungs. This reduction in the oxygen content even with the normal cardiac output, the delivery of oxygen to tissue falls and limits the muscle capacity.
Quantifying shunt volumes
The ratio of the total pulmonary blood flow to the total systemic blood flow is an important tool in quantifying the net shunt. The ratio 1:1 is normal and indicates no shunting situation. If the ratio is >1:1, it indicates that the pulmonary flow is greater than the systemic flow and it is called as net left-to-right shunt. If this ratio is lesser than 1:1, it indicates net right-to-left shunt. Both such shunting (bidirectional) may be present in the same patient. When the magnitude of left-to-right shunt equals right-to-left shunt, it is possible to have 1:1 ratio of total pulmonary volume and total systemic volume.
Ventricular septal defect
This defect is based on the complex development of the ventricular septum during embryogenesis, involving the fusion of distinct septal components. The site of fusion of all components resides behind the tricuspid valve septal leaflet and below the valve of the aorta of the left ventricle (LV) outflow tract. The VSD of endocardial cushion is associated with insufficiency of atrioventricular valve (AV) valve, aortic insufficiency associated outflow defects, and complicated physiological lesions. The pathophysiology of VSD and ASD differs depending on the differences in the hemodynamic effects of VSD and ASD. In VSD, the ventricular blood flow has two systolic pathways, i.e., usual outflow tract of ventricle and blood flow through the VSD to the outflow tract of the ventricle. The volume and direction of systolic blood flow across the VSD is determined by the ohm's law, i.e., by comparing the resistance of each pathway. For example, In patients having low resistance from the LV to the pulmonary artery compared with the resistance of low to the systemic circulation, leading to large left to right systolic flow across the defect. In case if the VSD is very small, then there will be high resistance at the defect limiting the shunt (left to right) with low pulmonary resistance. If resistance of pulmonary circulation is higher than the resistance of systemic circulation, there will be right-to-left shunt not depending on the defect size. Comparing the blood volume crossing a VSD in systole, the blood flow in diastole is very low. The flow across the VSD in a diastole is much similar to that of flow across the ASD in systole.[106,107]
Atrial septal defect
The atrial septal formation consists of the growth and partial reabsorption of tissue membrane septum primum and septum secundum, their fusion causes the formation of membranes forming endocardial cushions and the fetal sinus venosus reabsorbed into the structure and forms RA. During the embryonic development, if any error occurs in this developmental process will causes a defect in the wall separating the two atria called as ASD. The ASD includes ostium primum defect, i.e., deficiency of endocardial cushion tissue and ostium secundum defect, i.e., reabsorption of septum primum in excess and the sinus venous defect, i.e., error in introduction of sinus venous chamber into RA. In the pathophysiology of ASD is multifactorial and complex and the flow across the defects occur in both the systole and diastole. In isometric strain, transient right-to-left shunt occurs are common. During diastole, the bulk flow of the shunt occurs. During this phase, the blood flow occurs in each atrium through two alternate pathways, i.e., one following the normal pathway through AV to the ventricle passes through the ASD and fills the opposite ventricle. The difference in the compliance and capacity of the two ventricles determines the flow across the ASD. In normal patient, the pumping of the LV to the systemic circulation possess larger workload than the right ventricle (RV), pumping toward the lungs. Hypertrophy of the LV occurs, showing its work level whereas the RV myocardium remains thin. Thick-walled LV contracts to accept additional volume less readily when compared with thinner RV. This result in the favoring of left-to-right shunt by difference in compliance of chambers in ASD patients because blood fills more compliantly in the RV from the LA easily. Congenital obstruction in the pulmonary arteries or veins resulting from parenchymal disease or primary hypertension of lungs causes hypertrophy of RV and increases RV after load. Left-to-right shunting is minimal in ASD, showing little overall difference between the two ventricles.[108,109]
PS can be of two types, i.e., valvular and subvalvular or supravalvular. The most common form is valvular stenosis. In valvular PS, there is a narrow central opening (dome like) in the pulmonary valve, rudimentary raphes can be observed. Dysplastic valve with myxomatous thickened leaflets is present less often. PS can also be associated with other congenital heart defects such as ASD and TGA. The subvalvular PS, also called as infundibular or subinfundibular PS. Infundibular PS can be seen as a part of teratology of Fallot, while isolated infundibular PS is rare. Hypertrophy of secondary infundibular PS occurs because of circular muscular structure of the right ventricular outflow tract. Obstruction in RV outflow occurs because due to RV hypertrophy. Subinfundibular PS also called double chambered RV RV cavity has two parts low pressure outlet part and high pressure inlet part. Local hypertrophy may develop because of high velocity jet of a small VSD which is directed at the opposite wall of RV. The supravalvular PS associated with other cardiac disorders or extracardiac abnormality. It can be isolated and described in syndromes such as Noonan, Williams–Beuren, and Alagille syndrome. This stenosis located in the pulmonary trunk, pulmonary branches, or bifurcation.
Patent ductus arteriosus
During pregnancy, in fetus the ductus allows blood flow from RV to bypass the lungs (nonfunctional) and through the descending aorta, return to the placenta. After 72 h of birth, the ductus gets closed in maximum newborns by the arteriolar smooth muscle contraction, mechanism stimulated by increase in level of the postnatal systemic oxygen. PDA is a condition in which the lumen of the ductus is not closed and there are arterial connections between pulmonary and systemic circulation. In VSD physiology, the PDA size is resistor in the circuit, and determines the volume of flow. With large PDA in VSD patients, the left ventricular end-diastolic volumes (preload) increases and allow the stroke volume supply to both normal cardiac output and left-to-right shunt. The pressure in the LA rises and congestion of pulmonary veins occur. With large defect of PDA, the diastolic flow “runoff” results in impairment of coronary and splanchnic perfusion.
Tetralogy of Fallot
It is a complex heart defect having following four components: (a) PS, i.e., the valve between the RV and lungs become narrow; (b) hypertrophy of RV, i.e., lower chamber of the heart become enlarged; (c) VSD; and (d) overriding aorta, i.e., enlarged aorta located over a VSD. The combination of all these defects causes poor oxygen blood supply delivery to the body, which causes cyanosis in babies (due to poor oxygen supply babies have blue skin color).
There are two theories known in the causation of Coarc (a) ductus tissue theory, i.e., constriction of aberrant ductal tissue postnatally, (b) hemodynamic theory, i.e., alterations in the flow of blood (intrauterine) through aortic arch. Deformity occurs in ductus arteriosus with descending aorta called aortic isthmus; Coarc is characterized by narrowing of the left subclavian artery (distal) or proximal aorta.
- Localized stenosis: In the posterior wall of the aorta, a shelf-like infolding occurs into the aortic lumen, distal or proximal to the ductus arteriosus
- Long hypoplastic segment: hypoplasia, i.e., tubular occur in the aortic arch or the aorta which is distal to the left subclavian artery origin and ductus area
- Simple Coarc is the Coarc occur in the absence of lesions
- Complex Coarc involves cardiac and extracardiac lesions. Bicuspid aortic valve: 50%–60% suffer from this. VSD and ASD occur along with Coarc
- Coarc and complex CHD includes transposition of arteries, atrioventricular defect, hypoplastic left heart syndrome. Coarc can also be present with other types of left heart obstruction, i.e., mitral stenosis, AoS. Noncardiac anomaly, i.e., intracranial aneurysm occur in 10% of patients.
In Coarc left ventricular hypertension (elevated systolic pressure) occur which is caused by increased resistance to LV outflow due to narrowing of aorta. The blood pressure of lower extremity is lower than the upper body blood pressure. Upper extremity hypertension occur.
Transposition of great arteries
It is the most common cyanotic lesion of the heart present in neonates by birth. Ventriculoarterial discordance is the hallmark of TGA in which the pulmonary artery (PA) arises from morphologic left LV and aorta arises from morphologic RV. The functioning of systemic and pulmonary circulations occurs in parallel rather than in series. The pulmonary venous blood, i.e. oxygenated returns to the LA and LV but again it is recirculated through the abnormal connection of the PA to the LV, to the pulmonary vascular bed. The systemic venous blood, i.e. deoxygenated returns to the RA and RV where it is pumped to the systemic circulation subsequently by passing through the lungs effectively. This parallel arrangement causes deficiency in oxygen supply to the tissues and increase in workload of the RV and LV. There are three common anatomic regions in TGA of mixing deoxygenated and oxygenated blood; they are patent foramen ovale or ASD and VSD, and PDA.
The progression of aortic valve occurs from sclerosis to stenosis, the LV combat chronic resistance to ejection of blood during systole. Higher systolic pressure generated by ventricle than the pressure opposite produced by calcified aortic valve. Increased resistance during systolic ejection is known as afterload. The left ventricular myocardial wall gets thickened to compensate raised afterload, the LV diameter maintains normal size. LV wall thickening is also called as concentric hypertrophies, which strengthens left ventricular systolic contraction and maintain proper stroke volume and cardiac output. The detrimental effect of high LV afterload includes decrease in the myocardial elasticity of LV and coronary blood flow and increases oxygen consumption, myocardial workload, and mortality. LV hypertrophy increases pressure during diastole and causing delay of the left ventricular untwisting as a result a forced atrial contraction is required for sufficient filling of the LV to maintain stroke volume and cardiac output. Late symptoms of LV hypertrophy include smaller LV chamber size decreases preload and aggravate systolic dysfunction.
Echocardiography of fetuses is an important tool in the diagnosis of CHD, which provide information and improvement in counseling of the parents, guide the patient about timing and location of delivery. It allows appropriate planning and consultation by the neonatologists and cardiologists. It also provides accurate diagnosis of fetal arrhythmias and its management. Transesophageal and transthoracic echocardiographies have improved its imaging quality. New techniques such as tissue strain analysis and Doppler imaging have been introduced.
Cardiovascular magnetic resonance imaging
For investigating the function and anatomy of adult CHD, cardiovascular magnetic resonance imaging (MRI) is an alternative, frequent, and complementary imaging modality. It has several advantages over other techniques as it does not require contrast reagent (iodinated) or ionizing radiations. Advances in its software and hardware (coil design, new pulse sequences, and faster gradients) provide accurate assessment of anatomy, function, and physiology.
Other imaging modalities
Computed tomography is another useful tool in assessing the cardiac and extra cardiac structure such as intracardiac anatomy, aortic dimensions, myocardial function, and coronary artery anatomy. Position emission tomography is a research tool in metabolic imaging, pathological and physiological processes. Fused hybrid coronary computed tomography angiography and positron emission tomography myocardial perfusion imaging provide additional benefit in the management of patients with anomalies of coronary artery and myocardial perfusions.
Brain natriuretic peptide (BNP), secreted by cardiac cells in response to ventricular wall pressure. Its vasodilatory and diuretic effect determines the effect of heart failure. BNP values are highly elevated in adults with complex CHD. Troponins are markers of myocardial damage; also identify myocardial infarction.
The late complications of CHD are heart failure, arrhythmias, pulmonary arterial hypertension, and endocarditis. Older CHD patients may develop acquired cardiovascular complications such as hypertension, diabetes, and hyperlipidemia. The treatment of CHD with drugs is mainly based on pathophysiological conditions or acquired heart disease. For example, the treatment of systemic right ventricular failure with digoxin recommended by the European Society of Cardiology 2010 guideline. Specific groups of population have been studied like study of beta blocking agents and angiotensin-converting enzyme or angiotensin receptors blockers in patients having systemic RV. For the treatment of pulmonary arterial hypertension, several trials have been done to evaluate the hemodynamic and clinical parameters, biomarkers, and lifestyle modifications. The drugs which are used in the treatment of pulmonary arterial hypertension are bosentan, sildenafil, prostacyclin, and riocugat. Other drugs used in CHD are rosuvastatin in the AoS progression, ramipril in RV function in Fallot, and losartan in Marfan syndrome. Additional trials and research is needed to develop evidence-based medicine as increased cost of the drugs, lack of funding, and increasing administrative burden have a negative impact on this evolution.
Surgery is the milestone treatment of CHD patients. Developments of catheter techniques such as percutaneous interventions have replaced the surgery. For example preferred treatment of ASD is percutaneous closure. In 1967, transcatheter closure of PDA was introduced. For the treatment of aortopulmonary collaterals, venous collaterals, and pulmonary arteriovenous fistulas, the transcatheter embolization is the preferred treatment replaces surgery.
Previously, patients with dilated aortic root were operated with total root replacement, but this type of surgery has bleeding and thromboembolism risks. Valve sparing root replacement reported excellent long and short term results. It offers freedom from risks of bleeding and thromboembolism. Nowadays, a more advanced approach has been used, i.e., a personalized aortic root support (external) with a mesh sleeve which reduces the formation of aneurysm in these patients. The word total correction or repaired in surgery appears to be a misconception as many late complications may occur which require reoperation.
Recent advancement in the treatment of congenital heart disease
There has been major advancement in the treatment of pediatric cardiac disorders. Interventional cardiology and catheterization have evolved as major technological achievement, during the last 10 years. Cardiac imaging modalities such as intracardiac echocardiography, transesophageal echocardiography (TEE), real-time 3-dimensional (3D), MRI, Echo Navigator and Vessel Navigator systems, and rotational angiography with holography, 3D roadmap, 3D printing. Due to such technological advancement, treatment of the many types of CHDs is possible in cardiac catheter laboratory. The treatment of lesions involving PS, acute postoperative stenosis, and obstructive surgical conduits can now be managed with a greater success rate as they are resistant to interventional therapies.
Hybrid procedures for the treatment of congenital heart disease
This procedure involves cooperation between interventions and surgeons to get better outcome of their individual approaches and minimize invasiveness.
Hybrid procedure for hypoplastic left heart syndrome
In 1993, first hybrid approach including stenting of the arterial duct percutaneously and surgical banding of the branch PA stenosis, for hypoplastic left heart syndrome was reported. Gissen group modified this method and achieves reduction in pressure of distal PA (<50%) of the systemic pressure and in systemic oxygen saturation (80%), which shows the cases of survival 82% through Stage II palliation. Columbus group further modified this method by performing PA stenting and banding of the arterial duct that showed the cases of 83% survival through Stage III palliation.
Hybrid procedure for ventricular septal defect closure
For the closure of muscular and membranous VSDs in infants the perventricular approach was used. The main advantage of this approach was direct access to the heart after surgical sternotomy for direct placement of closure device across VSDs. This procedure was conducted under the guidance of TEE, without the requirement for cardiopulmonary bypass or radiation.[125,126] Intraoperative stentings, hybrid pulmonic valve replacement, and hybrid fontan completion are the other hybrid procedures used.
Stem cell therapy has been extensively studied in the ischemic heart disease and cardiomyopathy dilation, both by experimental as well as clinical studies. Stem cell therapy is still at an early stage of development. A recent study shows that umbilical cord blood mononuclear cell transplantation preserves the functions of RVs, especially diastolic function in a model of the right ventricular volume overload. There are two major mechanisms to be considered in stem cell therapy, i.e., cardiomyocytes substitution and paracrine effects. Recently, paracrine effects are the most appropriate mechanism of action of stem cell therapy. Paracrine effects activation may leads to decreased apoptosis, increased angiogenesis, improved ventricular remodeling, and endogenous cardiac progenitor cell activation. Human embryonic stem cells, cardiac stem cells, and induced pluripotent stem cells are the cell types which are currently studied. Stem cell therapy is an important research topic that will also involve active investigation in CHD.
In the past 4–5 decades, the fate of babies with congenital heart defects has changed dramatically. Babies born with CHD are symptomatic and identified soon after birth and also some of the cases remain undiagnosed until the disease progresses to a severe conditions. Clinical manifestations determine the severity of the diseases. Owing to advances in diagnosis and surgical strategies, there are majority of patients with CHD. Advanced approaches in surgery have been used but the increase of late complications requires reoperations, device implantations and percutaneous interventions to reduce mortality. The landscape of congenital heart defects is an ongoing evolving research demanding efforts from all health-care professionals to give optimal care to these expanding, chronically ill CHD patients. Apart from the major advancement in the field of genetics, with regards to diagnosis that influences prognosis and genetic counseling, the majority of the etiology of CHD remains incompletely unknown. Several experimental and epidemiological studies will provide us important information related to the anatomy and physiology of CHD, identifying hypothesis related to its etiology.
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