Comprehensive Approach to Congenital Heart Defects

Review Article

Authors:

Huliyurdurga Srinivasa Setty Natraj Setty, Shivanand Sanganna Gouda Patil, Raghu Thagachagere Ramegowda, Vijaykumar, Iswarappa Balekundre Vijayalakshmi, Cholenahalli Nanjappa ManjunathDepartment of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, INDIA.

Abstract

Congenital heart defects (CHD) are cardiovascular malformations that generally occur due to aberrant development of a normal structure in the fetus, or failure of such a structure to progress beyond an early stage of embryonic or fetal development. Malformations are due to complex multi-factorial genetic and environmental causes. Congenital heart defects, in a definition proposed by Mitchell et al, is a gross structural abnormality of the heart or intrathoracic great vessels that are actually or potentially of functional significance. A comprehensive approach to every aspect of CHD, covering from embryology, fetal malformations, pathology, clinical approach, investigations, interventions to the surgery is very essential to reduce the morbidity and mortality in children with CHD.

Key words: Congenital malformation, Great vessels, Fetus, ASD,VSD,TOF.

Submission Date: 17-11-2016 | Review completed: 24-01-2017 | Accepted Date: 07-02-2017.

DOI: 10.5530/jcdr.2017.1.1


INTRODUCTION

Congenital heart defects (CHD) are the commonest of all congenital lesions and the most common type of heart defects among children.1Schoen FJ. “The Heart” Kumar V et al. 6th ed. Robins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Company. 1999;543-600. These defects generally result from the aberrant development of a normal structure in fetus or failure of progress beyond the early stage of embryonic or early fetal development. Cardiac mal-development early in the embryo leads to significant morbidity and mortality. The CHD as defined by Mitchell et al is a gross structural abnormality of the heart or intra thoracic great vessels that are actually significance.2Mitchell SC et al. “Congenital heart disease in 56,109 births” Incidence and natural history. Circulation. 1971; 43(3):323-32. The estimated prevalence of CHD is 8 to 10 per 1000 live births, with a higher rate of stillbirth, spontaneous abortion, and prematurity.3Fyler DC et al. “Report of the New England Regional Infant Cardiac Program”. Pediatrics. 1980;65(2):375-461. The relative frequency of the most common lesions varies with different reports but nine common lesions form 80% of congenital heart defects.4Jackson M et al. “Epidemiology of congenital heart disease in Merseyside–1979 to 1988”. Cardiol Young. 1996:6(4):272-80. Recent advances in diagnosis and surgical treatment over the past 40 years have led to dramatic increases in survival for children with serious heart defects.

Etiopathogenesis

The etiological factor of most Congenital heart defects is unknown. In the present scenario, the complex genetics, and inheritance of CHD remains incompletely understood. In the past, the circumstances were even more worst because many children with CHD did not survive to reproductive age and fetal echocardiography was not available. In most of the cases, it is multi-factorial in origin and is a result of both genetic predisposition and environmental factors. Known genetic causes of heart disease includes inherited chromosomal abnormalities such as trisomy 21, 13, and 18, as well as a range of newly recognized genetic point mutations, point deletions and other genetic abnormalities as seen in syndromes such as CATCH 22, familial ASD with heart block, Alagille syndrome, Noonan syndrome, and many more. Known ante-natal environmental factors include maternal infections (Rubella), drugs (alcohol, hydantoin, lithium and thalidomide) and maternal illness (diabetes mellitus, phenylketonuria, and systemic lupus erythematosus).5Anderson RH et al . “Fetal circulation and circulatory changes at birth” Anderson RH et al eds. Paediatric Cardiology. Churchill Livingstone. 1987;2:109. High levels of stress were more likely to have high levels of a hormone called corticotrophin-releasing hormone (CRH) in their blood. Researchers have found a link between high levels of CRH and preterm labor or congenital heart defect in the baby. The researchers speculate that increased levels of stress-related hormones may affect both maternal blood pressure and fetal growth and development.6Artman M, et al. “Neonatal Cardiology”. The McGraw-Hill Companies Medical Publishing Division. 2002b. The fraction of cardiac malformations that support intrauterine circulation compromise the spectrum of congenital heart defect (CHD). The anatomic features of most CHD in humans have been carefully analyzed. Genetic alterations and null mutations have targeted the cardia and vascular system and established abnormalities in cardiovascular ontogeny as a primary cause of embryonic demise.7Sullivan ID: Prenatal diagnosis of structural heart disease: does it make a difference to survival. Heart. 2002:87:405-6. In recent years it has become evident, based on ultrasound and fetal echocardiographic studies that the incidence is considerably higher than that usually thought earlier. Prenatal ultrasound examination has documented not only congenital heart lesions but also cardiac arrhythmias and myocardial dysfunction as important causes of fetal morbidity and mortality. The cardiac anomalies and arrhythmias are the most common causes of non-immune hydropsfetalis. Thus, of all deaths related to a congenital heart defects, 50 percent occurred in six months, and 80 percent by 1 year of age. It is thus appropriate that attention should be focused on heart disease in the neonate.8Friedman WF, et al. “Congenital Heart Disease in Infancy and Childhood”, In Heart Disease A Textbook of Cardiovascular Medicine..6th ed. Ed By Braunwald et al. WB Saunders Company Philadelphia London New York StLouis Sydney Toronto. 2001:1505-91. The Table 1A lists the various genes implicated in CHD. The CHD caused by various disorders are listed in Table 1B. The classification of CHDs depending on the pathogenesis is given in Table 2.

Family History

A careful family history spanning at least three generations should be obtained during the evaluation of any child with CHD. The possibility of consanguinity should be investigated, as it is a clue for autosomal recessive inheritance and a recognized factor for increased risk of recurrence. The risk of recurrence increases if close relatives are also affected.15Bosi G et al “IMER Working Party”. Temporal variability in birth prevalence of congenital heart defects as recorded by a general birth defects registry. J Pediatr 2003;142:690-8. Relatives of patients with syndromic CHD should be carefully evaluated for minor manifestations of the disorder. It is especially important in those with mandolin syndromes that are known to have a high degree of variability of expression (e.g. Noonan syndrome, Kartagener syndrome, hypertelorism-hypospadias syndrome, and Waardenburg syndrome).16Stephensen SS et al “Congenital cardiac malformations” in Iceland from 1990 through 1999. Cardiol Young 2004;14:396-401.

Table 1A: Genes Implicated in the Etiology of Congenital Heart Defects9Genetic Causes of Syndromic and Non-Syndromic Congenital Heart Disease Akl C. Fahed and Georges M. Nemer Chapter 6 p:130-132
Table 1B: Genetic approach and Environmentally Induced Disorder with CHD10Noonan JA. “Association of congenital heart disease with syndromes or other defects”. Pediatric Clinical Am. 1878;25:797-816.

Clinical Presentation

Clinical manifestations of congenital heart defect vary according to the type and severity of the defect.10Noonan JA. “Association of congenital heart disease with syndromes or other defects”. Pediatric Clinical Am. 1878;25:797-816. In neonatal period the presenting feature of CHD is cyanosis, heart failure, failure to thrive, an abnormal clinical sign detected on routine examination.11Camm AJ et al. “Cardiovascular Disease”. Kumar P et al, 6th ed. Kumar & Clark Clinical Medicine. Edinburgh Elsevier Saunders. 2005;725-872. In infancy and childhood, the usual presenting features are cyanosis, digital clubbing, murmur, syncope, squatting episodes, heart failure, arrhythmia, failure to thrive.12Clark EB. “Mechanisms in the pathogenisis of congenital cardiac malformations”. In Pierpont ME et al “Genetics of cardiovascular disease”. Amsterdam et al. 1986;3-11. Cyanosis is an important clinical sign in the newborn. It is the primary symptom of the most common forms of the cyanotic congenital cardiac disease that present symptomatically in the newborn. If cyanosis due to congenital cardiac disease is not recognized the newborn may experience rapid and severe cardiovascular decompensation. If the newborn has an arterial oxygen saturation above 85%, cyanosis may be quite difficult to detect by visual inspection. Oxygen saturation should be measured by pulse oximetry. The Pulse oximetry should be performed on the right hand, which, in a normal aortic arch receives blood from the ascending aorta, and on either foot, which receives blood from the descending aorta. Different conditions are associated with different relationships in oxygen saturation between the upper and lower body and defining the relationship be very helpful in identifying the specific defect causing cyanosis.13Sastroasmoro S. Penatala ksanaan awal penyakit jantung bawaan sianotik. Dalam: Sastroasmorodan Madiyono B ed. Penatala ksanaan kedaruratankardiovas kularpadaanak Naskahleng kap Pendidikan Kedokteran BerkelanjutanIlmu Kesehatan Anak XX FKUI. Desember 1989.hal 1-20. A pulse oximetry screen is performed on an infant within the first 24 h of life, and can easily and quickly determine whether an infant has CCHD. This procedure was developed in the early 1970‘s, and is dependent on the different absorption spectrum that exists between oxygenated and deoxygenated hemoglobin.14sadeghian H and Savand-Rooni Z: Fetal heart echocardiography of twins, Echocardiographic Atlas of adults Congenital Heart Dieses 2015. Springer International Publishing. 461-463.2015.

Associated Extracardiac Anomalies

In most patients, CHD occurs as an isolated malformation, but approximately one-third have associated anomalies and 10 to 15 percent have specific dysmorphic syndromes. The reported incidence of associated extracardiac anomalies ranges from 7.7 to 45.0 per cent.5Anderson RH et al . “Fetal circulation and circulatory changes at birth” Anderson RH et al eds. Paediatric Cardiology. Churchill Livingstone. 1987;2:109.,6Artman M, et al. “Neonatal Cardiology”. The McGraw-Hill Companies Medical Publishing Division. 2002b.,17Wojtalik M et al. “Congenital heart defect with associated malformations in children”. J Pediatr Surg. 2005;40(11):1675-80. A prospective study of 1016 children with congenital heart defects identified 135 (13.3 per cent) who had recognized syndromes, embryopathies, or associations (Table 3).

Management

Prevention of Congenital heart defects

Primary prevention

Modification/abolishment of risk factors, e.g. a) Vaccines b) health promotion (via exercise) vitamins especially Folic acid to be started before conceiving.

Secondary Prevention

Recognition of subclinical disease and early treatment of initial clinical manifestations to prevent progression of disease.

Teritary Prevention

Limiting disability to the least possible and aiding the recovery from complications e.g. rehabilitation efforts.19Johnson K et al. “Recommendations to improve preconception health and health care” in the United States. MMWR Recomm Rep. 2006:1-23.

Initial Treatment

Initiation of medical therapy in a newborn with a critical congenital heart defect is necessary to prevent and/or reverse clinical deterioration and complications. The general approach should follow the usual guidelines for management of a critically ill or potentially critically ill newborn.20Lewis AB, et al. “Side effect of prostaglandin E1 in infants with critical congenital heart disease”. Circulation. 1981:64:893-8.

Table 2: Classification of CHD by Pathogenetic Mechanisms12Schoen FJ. “The Heart” Kumar V et al. 6th ed. Robins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Company. 1999;543-600.*

a. Oxygen

Supplemental oxygen is often administered to cyanotic newborn with known or suspected heart disease.20Lewis AB, et al. “Side effect of prostaglandin E1 in infants with critical congenital heart disease”. Circulation. 1981:64:893-8.

b. Mechanical ventilation

Mechanical ventilation of the newborn whose primary symptom is cyanosis is often unnecessary. In contrast, mechanical ventilation and sedation are often very beneficial to the newborn with decreased systemic perfusion.

c. Fluid

Careful attention to fluid status and urine output is essential when managing newborns with a critical congenital heart defect. In general, on the first day or two of life, a newborn with CHD, manifest the same fluid, glucose, and electrolyte requirements as infants without a congenital heart defect. Depending on the particular defect, however, fluid and electrolyte management may change dramatically in the neonatal period. Symptoms and signs of heart failure develop due to increasing pulmonary blood flow, reduced systemic output, and compensatory sodium and water retention. Free water restriction and diuretic therapy are indicated to reduce total body sodium and water.19Johnson K et al. “Recommendations to improve preconception health and health care” in the United States. MMWR Recomm Rep. 2006:1-23.

Table 3: Extracardiac malformations most frequently reported among patients with congenital heart diseases15Bosi G et al “IMER Working Party”. Temporal variability in birth prevalence of congenital heart defects as recorded by a general birth defects registry. J Pediatr 2003;142:690-8.18Miller A, et al. “Congenital heart defects and major structural noncardiac anomalies” Atlanta, Georgia, 1968 to 2005. J Pediatr. 2011;159(1):70-8.

Principles of Medical Management5,6,20

The essential care of the newborn with a critical heart defect is no different from that of a newborn with other medical conditions in that application of a few general principles will promote effective care and minimize the chance of iatrogenic misadventures. It is imperative that a concerted team approach involving neonatology, cardiology, nursing, surgery, and anesthesiology is utilized. Effective and ongoing communication is essential for optimizing care and providing a uniform approach to the management of these complex cases.

Timing of Surgery

In general, PGE1 should be administered to a cyanotic newborn with duct dependent condition along with another supportive measure. Surgery should be scheduled on a semi-elective basis after careful evaluation is complete. One exception is noteworthy: surgery is the only effective therapy for neonates with obstructed total anomalous pulmonary venous return and should be performed as soon as the diagnosis is established. Patients with d-transposition of the great arteries who have restrictive patent foramen ovale often need emergent balloon atrial septostomy because of profound hypoxemia. After successful septostomy these newborn are usually quite stable and corrective surgery should be delayed until any end-organic damage resolves. A newborn who present with congestive heart failure and shock because of left heart obstructive lesions (e.g., interrupted aortic arch) also can be stabilised by the administration of PGE1 and other supportive care. Surgery is done for more complex defects or when catheterization cannot correct the defect. But, in some defects might need a combination of surgery and catheterization. The kind of surgery will depend on what defect the child has. Some congenital heart defects can be completely repaired with one surgery. Defects that are more complex often require staged surgeries over time.21Freda DeKeyser, et al. “Psychoneuroimmunology in Critically Ill Patients”. American Association of critical care Nurses. 2004:121-6.

Types of surgical procedures (Congenital Defect Repair)

a. Palliative surgery

Palliative surgery refers to procedures where complete repair of the heart defect is not possible and blood flow is controlled either with a shunt or an artificial tube implanted in the heart or with only one ventricle of the heart.

b. Cardiac catheterization

Cardiac catheterization is a procedure in which a thin flexible tube called a catheter is passed into the cardia and its surrounding blood vessels. Cardiac catheterizations can be performed in 2 ways: 1. Diagnostic catheterization, 2. Interventional catheterization. The catheters are used for blood sampling, pressure measurements, dye injection (angiogram), and to repair specific areas of the heart and the surrounding blood vessels. The introduction of therapeutic interventions has made Pediatric Cardiology more attractive. The Pediatric Cardiologist does not have to depend on surgical colleagues for relieving obstructions like pulmonic stenosis, aortic stenosis, and coarctation of the aorta. They can dilate distally located peripheral pulmonic stenosis, which is not only difficult but at times impossible for a surgeon to reach. Atrial septal defect, patent ductus arteriosus, and some ventricular septal defects can be closed with various types of devices and operative surgeries,22Mavroudis C, Baker C. Patent ductus arteriosus ligation. Atlas of pediatric Cardiac Surgery. Springer. [London. 35-43.2015. Coil embolization of collaterals, pulmonary and coronary arteriovenous fistulae is being done routinely at many centers. Various catheter-based therapeutic interventions have revolutionized the management of Congenital Heart defects. The device closure of various defects gives complete cure to nearly 65% of simple Congenital Defect Repairs without a scar on the chest.23Vijayalakshmi IB. “Present scenario of device closure for congenital heart diseases”. J Indian Med Assoc. 2003;101(2):86-8. Review. Hydropsfetalis with pinpoint aortic stenosis can be literally saved from death. Interventions have threatened the supremacy of surgery and at times they are adjunct to surgery.

c. Arterial switch procedure

An arterial switch procedure can be an option for neonates who have defects known as transposition of the great arteries (TGA). With this defect, the positions of the vessels that take blood away from the heart to the lungs and the body are switched. An arterial switch procedure, usually performed within the first few weeks of life, is done to correct the blood flow. This open heart procedure involves “switching” the pulmonary artery and the aorta back to their normal positions and attaching the coronary arteries to the new aorta in the correct positions.24Choi BS et al. “Long-term outcomes after an arterial switch operation for simple complete transposition of the great arteries”. Korean Circ J. 2010;40(1):23-30.

d. Blalock-Taussig (BT) shunt

Blalock-Taussig shunts, or “BT Shunts,” are used for defects that affect the flow of blood from the right ventricle, through the pulmonary artery, and to the lungs. These include pulmonary atresia, pulmonary stenosis, tricuspid atresia, and tricuspid stenosis. Also called the blue baby operation, it is a palliative procedure since it doesn‘t correct the defect but helps to resolve symptoms until the child is older and/or the defect itself can be repaired.24Choi BS et al. “Long-term outcomes after an arterial switch operation for simple complete transposition of the great arteries”. Korean Circ J. 2010;40(1):23-30.

e. Norwood procedure

The Norwood Procedure is used for neonates with only one pumping chamber in their heart and other single ventricle defects. The Norwood can be done as part of a series of surgeries. It involves reconstructing the aorta using the pulmonary artery to allow the ventricle to easily pump blood out to the body. It also involves placing a BT Shunt to maintain blood flow to the lungs and inserting a Bi-Directional Glenn Shunt. The final step is the fenestrated Fontan.25Norwood WI et al. “Experience with operations for hypoplastic left heart syndrome”. J Thorac Cardiovasc Surg. 1981;82(4):511-9.

Pediatric Heart Transplantation

  • Heart transplantation has been used for the treatment of end-stage pediatric heart disease for nearly 4 decades, with the first infant heart transplantation performed in the late 1960s. The development of cyclosporine-based immune suppression regimens 20 years ago stimulated an increased application of heart transplantation in pediatric patients with intractable heart Failure.26Pennington DG, Sarafian J, Swartz M. Heart transplantation in children. J Heart Transplant. 1985;4:441-5. The Registry of the International Society for Heart and Lung Transplantation (ISHLT)27 recorded the occurrence of 41 pediatric heart transplantations. In 1995, the registry recorded 370 pediatric heart transplantations. At that time, consensus indications,28Mudge GH, Goldstein S, Addonizio LJ, Caplan A, Mancini D, Levine TB, et al. 24th Bethesda conference: cardiac transplantation: Task Force 3: recipient guidelines/prioritization. J Am Coll Cardiol. 1993;22:21-31. for heart transplantation for pediatric heart disease included the following.
  • Need for ongoing intravenous inotropic or mechanical circulatory support.
  • Complex congenital heart disease not amenable to conventional surgical repair or palliation or for which the surgical procedure carried a higher risk of mortality than transplantation.
  • Progressive deterioration of ventricular function or functional status despite optimal medical care with digitalis, diuretics, and angiotensin-converting enzyme (ACE) inhibitors.
  • Malignant arrhythmia or survival of cardiac arrest unresponsive to medical treatment, catheter ablation, or an automatic implantable defibrillator.
  • Progressive pulmonary hypertension that could preclude cardiac transplantation at a later date.
  • Growth failure secondary to severe congestive heart failure unresponsive to conventional medical treatment.
  • Unacceptably poor quality of life.29Indications for Heart Transplantation in Pediatric Heart Disease Charles E. Canter, MD, Chair; Robert E. Shaddy, MD; Daniel Bernstein, MD. Circulation. 2007;115:658-76.

CONCLUSION

Congenital Heart Defect is the biggest single cause of child mortality and early childhood hospitalization. The world has become small and all the advances in cardiology spread to the other parts of the world in no time. The pediatric cardiology discipline today takes care of pediatric cardiac patients from newborn (intrauterine) to grown-up congenital. The evolution of this subspecialty of cardiology is the result of years of perseverance, patience and passionate dedication of several genius minds as pioneers. But the cardiac catheterization laboratory has clearly transformed from a diagnostic facility to a place for providing definitive treatment to nearly 65% of simple CHDs without a scar on the chest. As enhanced medical interventions have significantly improved the survival rates for infants and children, there has been an increased focus on the quality of life of these individuals and their families. Recent developments in the field of Pediatric cardiac surgery and Pediatric Cardiology especially non-surgical transcatheter interventions have changed the pre-operative or pre-procedure diagnostic workup of the cardiac malformations. However, it should be clear that the physicians and surgeons looking after Pediatric Cardiac patients are complementing each other in the care and welfare of the sick babies and children and not competing with each other.

CONFLICT OF INTEREST

None

REFERENCES

1. Schoen FJ. “The Heart” Kumar V et al. 6th ed. Robins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Company. 1999;543-600.
2. Mitchell SC et al. “Congenital heart disease in 56,109 births” Incidence and natural history. Circulation. 1971; 43(3):323-32.
3. Fyler DC et al. “Report of the New England Regional Infant Cardiac Program”. Pediatrics. 1980;65(2):375-461.
4. Jackson M et al. “Epidemiology of congenital heart disease in Merseyside–1979 to 1988”. Cardiol Young. 1996:6(4):272-80.
5. Anderson RH et al . “Fetal circulation and circulatory changes at birth” Anderson RH et al eds. Paediatric Cardiology. Churchill Livingstone. 1987;2:109.
6. Artman M, et al. “Neonatal Cardiology”. The McGraw-Hill Companies Medical Publishing Division. 2002b.
7. Sullivan ID: Prenatal diagnosis of structural heart disease: does it make a difference to survival. Heart. 2002:87:405-6.
8. Friedman WF, et al. “Congenital Heart Disease in Infancy and Childhood”, In Heart Disease A Textbook of Cardiovascular Medicine..6th ed. Ed By Braunwald et al. WB Saunders Company Philadelphia London New York StLouis Sydney Toronto. 2001:1505-91.
9. Genetic Causes of Syndromic and Non-Syndromic Congenital Heart Disease Akl C. Fahed and Georges M. Nemer Chapter 6 p:130-132
10. Noonan JA. “Association of congenital heart disease with syndromes or other defects”. Pediatric Clinical Am. 1878;25:797-816.
11. Camm AJ et al. “Cardiovascular Disease”. Kumar P et al, 6th ed. Kumar & Clark Clinical Medicine. Edinburgh Elsevier Saunders. 2005;725-872.
12. Clark EB. “Mechanisms in the pathogenisis of congenital cardiac malformations”. In Pierpont ME et al “Genetics of cardiovascular disease”. Amsterdam et al. 1986;3-11.
13. Sastroasmoro S. Penatala ksanaan awal penyakit jantung bawaan sianotik. Dalam: Sastroasmorodan Madiyono B ed. Penatala ksanaan kedaruratankardiovas kularpadaanak Naskahleng kap Pendidikan Kedokteran BerkelanjutanIlmu Kesehatan Anak XX FKUI. Desember 1989.hal 1-20.
14. sadeghian H and Savand-Rooni Z: Fetal heart echocardiography of twins, Echocardiographic Atlas of adults Congenital Heart Dieses 2015. Springer International Publishing. 461-463.2015.
15. Bosi G et al “IMER Working Party”. Temporal variability in birth prevalence of congenital heart defects as recorded by a general birth defects registry. J Pediatr 2003;142:690-8.
16. Stephensen SS et al “Congenital cardiac malformations” in Iceland from 1990 through 1999. Cardiol Young 2004;14:396-401.
17. Wojtalik M et al. “Congenital heart defect with associated malformations in children”. J Pediatr Surg. 2005;40(11):1675-80.
18. Miller A, et al. “Congenital heart defects and major structural noncardiac anomalies” Atlanta, Georgia, 1968 to 2005. J Pediatr. 2011;159(1):70-8.
19. Johnson K et al. “Recommendations to improve preconception health and health care” in the United States. MMWR Recomm Rep. 2006:1-23.
20. Lewis AB, et al. “Side effect of prostaglandin E1 in infants with critical congenital heart disease”. Circulation. 1981:64:893-8.
21. Freda DeKeyser, et al. “Psychoneuroimmunology in Critically Ill Patients”. American Association of critical care Nurses. 2004:121-6.
22. Mavroudis C, Baker C. Patent ductus arteriosus ligation. Atlas of pediatric Cardiac Surgery. Springer. [London. 35-43.2015.
23. Vijayalakshmi IB. “Present scenario of device closure for congenital heart diseases”. J Indian Med Assoc. 2003;101(2):86-8. Review.
24. Choi BS et al. “Long-term outcomes after an arterial switch operation for simple complete transposition of the great arteries”. Korean Circ J. 2010;40(1):23-30.
25. Norwood WI et al. “Experience with operations for hypoplastic left heart syndrome”. J Thorac Cardiovasc Surg. 1981;82(4):511-9.
26. Pennington DG, Sarafian J, Swartz M. Heart transplantation in children. J Heart Transplant. 1985;4:441-5.
27. Boucek MM, Edwards LB, Keck BM, Trulock EP, Taylor DO, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: eighth official pediatric report-2005. J Heart Lung Transplant. 2005;24:968-82.
28. Mudge GH, Goldstein S, Addonizio LJ, Caplan A, Mancini D, Levine TB, et al. 24th Bethesda conference: cardiac transplantation: Task Force 3: recipient guidelines/prioritization. J Am Coll Cardiol. 1993;22:21-31.
29. Indications for Heart Transplantation in Pediatric Heart Disease Charles E. Canter, MD, Chair; Robert E. Shaddy, MD; Daniel Bernstein, MD. Circulation. 2007;115:658-76.
Biblio Doi: 
10.5530/jcdr.2017.1.1