congenital heart defect congenital heart defect a congenital heart defect (chd), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. a congenital heart defect is classed as a cardiovascular disease. signs and symptoms depend on the specific type of defect. symptoms can vary from none to life-threatening. when present, symptoms are variable and may include rapid breathing, bluish skin (cyanosis), poor weight gain, and feeling tired. chd does not cause chest pain. most congenital heart defects are not associated with other diseases. a complication of chd is heart failure. congenital heart defectother namescongenital heart anomaly, congenital heart diseasethe normal structure of the heart (left) in comparison to two common locations for a ventricular septal defect (right), the most common form of congenital heart defectspecialtycardiologysymptomsrapid breathing, bluish skin, poor weight gain, feeling tiredcomplicationsheart failuretypescyanotic heart defects, non-cyanotic heart defectscausesoften unknownrisk factorsrubella infection during pregnancy, alcohol or tobacco, parents being closely related, poor nutritional status, taking antidepressant during pregnancy or obesity in the mothertreatmentnone, catheter based procedures, heart surgery, heart transplantationprognosisgenerally good (with treatment)frequency48.9 million (2015)deaths303,300 (2015) congenital heart defects are the most common birth defect. in 2015, they were present in 48.9 million people globally. they affect between 4 and 75 per 1,000 live births, depending upon how they are diagnosed. in about 6 to 19 per 1,000 they cause a moderate to severe degree of problems. congenital heart defects are the leading cause of birth defect-related deaths: in 2015, they resulted in 303,300 deaths, down from 366,000 deaths in 1990. the cause of a congenital heart defect is often unknown. risk factors include certain infections during pregnancy such as rubella, use of certain medications or drugs such as alcohol or tobacco, parents being closely related, or poor nutritional status or obesity in the mother. having a parent with a congenital heart defect is also a risk factor. a number of genetic conditions are associated with heart defects, including down syndrome, turner syndrome, and marfan syndrome. congenital heart defects are divided into two main groups: cyanotic heart defects and non-cyanotic heart defects, depending on whether the child has the potential to turn bluish in color. the defects may involve the interior walls of the heart, the heart valves, or the large blood vessels that lead to and from the heart. congenital heart defects are partly preventable through rubella vaccination, the adding of iodine to salt, and the adding of folic acid to certain food products. some defects do not need treatment. others may be effectively treated with catheter based procedures or heart surgery. occasionally a number of operations may be needed, or a heart transplant may be required. with appropriate treatment, outcomes are generally good, even with complex problems. signs and symptoms digital clubbing with cyanotic nail beds in an adult with tetralogy of fallot signs and symptoms are related to type and severity of the heart defect. symptoms frequently present early in life, but it is possible for some chds to go undetected throughout life. some children have no signs while others may exhibit shortness of breath, cyanosis, fainting, heart murmur, under-development of limbs and muscles, poor feeding or growth, or respiratory infections. congenital heart defects cause abnormal heart structure resulting in production of certain sounds called heart murmur. these can sometimes be detected by auscultation; however, not all heart murmurs are caused by congenital heart defects. associated conditions congenital heart defects are associated with an increased incidence of seven other specific medical conditions, together being called the vacterl association: v — vertebral anomalies a — anal atresia c — cardiovascular anomalies t — tracheoesophageal fistula e — esophageal atresia r — renal (kidney) and/or radial anomalies l — limb defects ventricular septal defect (vsd), atrial septal defects, and tetralogy of fallot are the most common congenital heart defects seen in the vacterl association. less common defects in the association are truncus arteriosus and transposition of the great arteries. causes the cause of congenital heart disease may be genetic, environmental, or a combination of both. genetic genetic mutations, often sporadic, represent the largest known cause of congenital heart defects. they are described in the table below. genetic lesions attributable percent examples primary genetic testing method aneuploidies 5-8% survivable autosomal trisomies (chromosomes 13, 18, 21), chromosome x monosomy (turner syndrome) karyotyping copy number variants 10-12% 22q11.2 deletion/duplication (velocardiofacial/digeorge syndrome), 1q21.1 deletion/duplication, 8p23.1 deletion/duplication, 15q11.2 deletion (burnside-butler syndrome) array comparative genomic hybridization (also known as chromosomal microarray analysis) inherited protein-coding single nucleotide variant (snv) or small insertion/deletion (indel) 3-5% holt–oram syndrome, noonan syndrome, alagille syndrome gene panel de novo protein-coding snv or indel ~10% mutations in genes highly expressed during heart development whole exome sequencing molecular pathways the genes regulating the complex developmental sequence have only been partly elucidated. some genes are associated with specific defects. a number of genes have been associated with cardiac manifestations. mutations of a heart muscle protein, α-myosin heavy chain (myh6) are associated with atrial septal defects. several proteins that interact with myh6 are also associated with cardiac defects. the transcription factor gata4 forms a complex with the tbx5 which interacts with myh6. another factor, the homeobox (developmental) gene, nkx2-5 also interacts with myh6. mutations of all these proteins are associated with both atrial and ventricular septal defects; in addition, nkx2-5 is associated with defects in the electrical conduction of the heart and tbx5 is related to the holt–oram syndrome which includes electrical conduction defects and abnormalities of the upper limb. the wnt signaling co-factors bcl9, bcl9l and pygo might be part of these molecular pathways, as when their genes are mutated, this causes phenotypes similar to the features present in holt-oram syndrome. another t-box gene, tbx1, is involved in velo-cardio-facial syndrome digeorge syndrome, the most common deletion which has extensive symptoms including defects of the cardiac outflow tract including tetralogy of fallot. examples of gene products and associated features myh6gata4nkx2-5tbx5tbx1 locus14q11.2-q138p23.1-p225q3412q24.122q11.2 syndromeholt–oramdigeorge atrial septal defects✔✔✔✔ ventricular septal defects✔✔✔ electrical conduction abnormalities✔✔ outflow tract abnormalities✔ non-cardiac manifestationsupper limb abnormalitiessmall or absent thymus small or absent parathyroids facial abnormalities the notch signaling pathway, a regulatory mechanism for cell growth and differentiation, plays broad roles in several aspects of cardiac development. notch elements are involved in determination of the right and left sides of the body plan, so the directional folding of the heart tube can be impacted. notch signaling is involved early in the formation of the endocardial cushions and continues to be active as the develop into the septa and valves. it is also involved in the development of the ventricular wall and the connection of the outflow tract to the great vessels. mutations in the gene for one of the notch ligands, jagged1, are identified in the majority of examined cases of arteriohepatic dysplasia (alagille syndrome), characterized by defects of the great vessels (pulmonary artery stenosis), heart (tetralogy of fallot in 13% of cases), liver, eyes, face, and bones. though less than 1% of all cases, where no defects are found in the jagged1 gene, defects are found in notch2 gene. in 10% of cases, no mutation is found in either gene. for another member of the gene family, mutations in the notch1 gene are associated with bicuspid aortic valve, a valve with two leaflets instead of three. notch1 is also associated with calcification of the aortic valve, the third most common cause of heart disease in adults. mutations of a cell regulatory mechanism, the ras/mapk pathway are responsible for a variety of syndromes, including noonan syndrome, leopard syndrome, costello syndrome and cardiofaciocutaneous syndrome in which there is cardiac involvement. while the conditions listed are known genetic causes, there are likely many other genes which are more subtle. it is known that the risk for congenital heart defects is higher when there is a close relative with one. environmental known environmental factors include certain infections during pregnancy such as rubella, drugs (alcohol, hydantoin, lithium and thalidomide) and maternal illness (diabetes mellitus, phenylketonuria, and systemic lupus erythematosus). alcohol exposure in the father also appears to increase the risk of congenital heart defects. being overweight or obese increases the risk of congenital heart disease. additionally, as maternal obesity increases, the risk of heart defects also increases. a distinct physiological mechanism has not been identified to explain the link between maternal obesity and chd, but both pre-pregnancy folate deficiency and diabetes have been implicated in some studies. mechanism main article: heart development there is a complex sequence of events that result in a well formed heart at birth and disruption of any portion may result in a defect. the orderly timing of cell growth, cell migration, and programmed cell death ("apoptosis") has been studied extensively and the genes that control the process are being elucidated. around day 15 of development, the cells that will become the heart exist in two horseshoe shaped bands of the middle tissue layer (mesoderm), and some cells migrate from a portion of the outer layer (ectoderm), the neural crest, which is the source of a variety of cells found throughout the body. on day 19 of development, a pair of vascular elements, the "endocardial tubes", form. the tubes fuse when cells between then undergo programmed death and cells from the first heart field migrate to the tube, and form a ring of heart cells (myocytes) around it by day 21. on day 22, the heart begins to beat and by day 24, blood is circulating. at day 22, the circulatory system is bilaterally symmetrical with paired vessels on each side and the heart consisting of a simple tube located in the midline of the body layout. the portions that will become the atria and will be located closest to the head are the most distant from the head. from days 23 through 28, the heart tube folds and twists, with the future ventricles moving left of center (the ultimate location of the heart) and the atria moving towards the head. on day 28, areas of tissue in the heart tube begin to expand inwards; after about two weeks, these expansions, the membranous "septum primum" and the muscular "endocardial cushions", fuse to form the four chambers of the heart. a failure to fuse properly will result in a defect that may allow blood to leak between chambers. after this happens, cells that have migrated from the neural crest begin to divide the bulbus cordis, the main outflow tract is divided in two by the growth a spiraling septum, becoming the great vessels—the ascending segment of the aorta and the pulmonary trunk. if the separation is incomplete, the result is a "persistent truncus arteriosus". the vessels may be reversed ("transposition of the great vessels"). the two halves of the split tract must migrate into the correct positions over the appropriate ventricles. a failure may result in some blood flowing into the wrong vessel (e.g.overriding aorta). the four-chambered heart and the great vessels have features required for fetal growth. the lungs are unexpanded and cannot accommodate the full circulatory volume. two structures exist to shunt blood flow away from the lungs. cells in part of the septum primum die creating a hole while muscle cells, the "septum secundum", grow along the right atrial side the septum primum, except for one region, leaving a gap through which blood can pass from the right artium to the left atrium, the foramen ovale. a small vessel, the ductus arteriosus allows blood from the pulmonary artery to pass to the aorta. changes at birth the ductus arteriosus stays open because of circulating factors including prostaglandins. the foramen ovale stays open because of the flow of blood from the right atrium to the left atrium. as the lungs expand, blood flows easily through the lungs and the membranous portion of the foramen ovale (the septum primum) flops over the muscular portion (the septum secundum). if the closure is incomplete, the result is a patent foramen ovale. the two flaps may fuse, but many adults have a foramen ovale that stays closed only because of the pressure difference between the atria. theories rokitansky (1875) explained congenital heart defects as breaks in heart development at various ontogenesis stages. spitzer (1923) treats them as returns to one of the phylogenesis stages.