VSDs

Cardiogenesis: Ventricular Septal Defects

Introduction
Congenital heart defects (CHDs) are the most common type of birth defect and have been seen to occur, on average, in around 1% of live births(15). The incidence is 10 times higher in stillborns and they are one of the main causes of death within the first year of life(4,69). Ventricular septal defects (VSDs) are a class of defect characterised by the presence of a hole within the interventricular septum (IVS). Perforations in this septum allows for the communication between the two ventricles of the heart resulting in complications. VSDs are said to account for up to 50% of all detected CHDs and can occur as isolated defects as well as in more complex CHDs such as tetralogy of Fallot(4,10). I hope to explain the processes that might lead to problems within the ventricular septum as well as explore the prevalence of VSDs and their clinical presentations.
Cardiogenesis
Cardiogenesis is the process in which the heart is formed in the embryo [Figure 1]. Recent breakthroughs in technology and molecular biology have greatly advanced the understanding of this process(7). Cardiogenesis is seen to start at gastrulation, in the third week post-fertilisation(11). Up to this point nutrition can be provided to the developing embryo by diffusion alone, however as the embryo grows it needs to develop a circulatory system to supply its metabolic demands(6). For this reason, the heart is the first organ to form within the human embryo(9).
Figure 1 A) The migration of progenitor cells out of the primitive streak (PS) into the cardiogenic regions. B) Formation of the cardiac crescent. C) Cardiac tube formation after fusion of the cardiac crescent. D) Looping of the heart tube and formation of the primitive right & left atriums. E) Completed looping. F) Septation completed.
[Image from Buckingham et al. (12)]
DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD
It is now known that two separate mesodermal regions known as the primary and secondary heart field give rise to cells that form the heart(12,13). Cell tracings have shown how different cell populations produce different parts of the heart [Figure 2](12).
Figure 2 Colour-coded cell population tracing, showing how different cell populations form different components of the heart.
[Image from Buckingham et al. (12)]
Cardiac progenitors are found in the epiblast lateral to the primitive streak [Figure 1a] (12). During gastrulation, these cells migrate through the primitive streak, to the splanchnic layer of the lateral plate mesoderm(6). They form two columns of cells either side of the midline and then extend to each other to form a horseshoe of epithelium, superior to the neural folds, known as the cardiaccrescent [Figure 1b & Figure 3](6,11,14). This collection of cells is called the primary heart field (PHF) and produces most of the cells needed for heart formation. It was thought that between days 16-18 the PHF differentiated into concentric horseshoe-shaped fields responsible for different regions of the heart, however these cells have been traced back prior to their migration through the primitive streak, where they have been shown to have already somewhat differentiated [Figure 2a]. Within the PHF, lateral to medial, these cell populations will later form: the atria, left ventricle and the majority of the right ventricle [Figure 3] (6). Their maturation is caused by local pharyngeal endoderm and results in the formation of cardiac myoblasts and blood islands, which will later, via vasculogenesis, form blood vessels and blood cells. The rest of the heart structures are derived from the secondary heart field (SHF), which arises during between day 20 and 21. The structures, which have their cellular origins in the SHF, include the conus cordis, truncus arteriosis and part of the right ventricle. The cells that form the SHF originate ventral to the posterior pharynx in splanchnic mesoderm (6). These cells migrate through the primitive streak and find themselves medial to the PHF(7,11). Like the PHF the SHF also forms concentric horseshoe shapes that give rise to the structures previously described [Figure 3]. The SHF allows for the elongation of the outflow tract, and is controlled by neural crest cells(6). The formation of the SHF occurs alongside the development of laterality (or sidedness) within the embryo causing cells within the SHF to form heart structures contralateral to their origin, helping to explain the spiral nature of the outflow tracts relative to their associated ventricles. Disruption of the laterality pathway in the embryo can cause CHDs(6).
Figure 3 The arrangement of the progenitor heart cells in the splanchnic layer of lateral plate mesoderm after gastrulation. The blue represents cells from the PHF that give rise to the: atrium, left ventri cle and part of the right ventricle (not coloured). The red represents cells from the SHF that arrange themselves concentrically to form the rest of the right ventricle, the conus cordis and the truncus arteriosus.
[Image from Langmans Medical Embryology (6)]
The maturation of the blood islands of cardiac progenitors causes the heart fields (PHF & SHF) to unite into their horseshoe shape. This structure of migrated and differentiating cardiac cells is collectively known as the cardiogenic region and is tubular. These tubes have an inner epithelium and surrounding myoblasts(13). The PHF is currently thought to act as a scaffold for the SHF to build upon(10).
Cardiac Tube Formation

The position of the cardiogenic region is initially found anterior to both the oropharyngeal membrane and neural plate. The development of the CNS causes cephalic folding of the embryo, moving the cardiogenic region into the neck and then back into thorax [Figure 4] (6). During cardiac tube development, growth is through cell differentiation and not proliferation(15).
Figure 4 Diagrams show the movement of the heart relative to the CNS. A) 18 days. B) 20 days. C) 21 days. D) 22 days.
[Image from Lan gmans Medical Embryology (6)]
At the same time as cephalic folding the embryo folds laterally, bringing the distal parts of the heart tubes together allowing them to merge into one primitive heart tube [Figure 1c & Figure 5c]. The most caudal ends of the tube remain divided making the tube resemble an inverted Y, the branches of which represent the atriums, the apex; the ventricle and the shaft; the outflow tract [Figure 1c] (11). The heart tube is now polarized, with a caudal and cranial end. The cranial end is known as the outflow tract, as here blood exits the heart, whilst the caudal area is the inflow tract, where venous blood enters the tubular heart.
Figure 5 Transverse sections showing lateral folding and formation of the single heart tube. A) 17 days. B) 18 days. C) 22 days.
The heart is held in place by dorsal mesocardium, which soon degrades leaving the heart tube suspended within the pericardial cavity by its inflow and outflow tracts(6). The myocardium secretes an extracellular matrix known as cardiac jelly which allows for communication with the epithelial layer(7,9). Mesothelial cells from the septum transversum and from the outflow tract form the proepicardium and the epicardium on the hearts surface. This extra layer of cells means the heart tube is now formed of three layers; the epicardium, myocardium (myoblast derived) and the endocardium (the endothelial layer).
Looping
During day 23 to 28 the heart tube undergoes a process known as looping, whereby the heart tube changes change. Neural crest cells which later septate the outflow tract, secrete fibroblast growth factors, which lengthen the heart tube at its cranial end. Myocardial hypertrophy of the central and cranial regions of the tube produces the ventricles and parts of the heart associated with the outflow tract(6). The primitive pericardial cavity provides limited space and continual differential growth of the outflow tract result in displacement of the tube. The cephalic part of the heart tube bends anteriorly, inferiorly and to the right, whilst the atrial part of the tube moves posteriorly, superiorly and to the left(11). Without the lengthening of the outflow defects such as VSDs can arise. During the process of looping the heart tube undergoes characterisation allowing for different parts of the tube to be identified [Figure 6](11,16).
Figure 6 Visualisation of cardiac loop formation and developing heart regions . A) 22 days. B) 23 days. C) 24 days.
The bulbus cordis is found at the cranial of the tube and can be divided into thirds. The distal third is the truncus arteriosus that will form the aorta and pulmonary artery. The middle third will form the conus cordis, which forms the ventricular outflow tracts, and the wider proximal third forms the trabeculated part of the right ventricle. The bulbus cordis meets the common ventricle at the narrow bulboventricular junction known as the primary interventricular foramen(6,13). It is marked exteriorly as the bulboventricular sulcus. After looping is complete trabeculations form distal and proximal to the primary
DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD 5
interventricular foramen in the common ventricle and the proximal third of the bulbus cordis, forming the primitive left and right ventricle. SHF cells invade the outflow tract during looping to elongate the tract(7,11,12). The primitive left ventricle connects to the common atrium, which was formed during looping from two distinct atria that used to lie external to the pericardial cavity [Figure 6]. The atrioventricular junction is narrow and is known as the atrioventricular canal. The bulboventricular flange causes that the atrioventricular canal to primarily communicate with the primitive left ventricle. Growth of the common atrium laterally causes the conus cordis to move to a more medial position [Figure 7].
Figure 7 Left : Frontal section of at 30 days, showing blood flow and the presence of the bulboventricular flange. Right : Similar image but taken further back, within a mouse embryo.
[ Left Image: from Langmans Medical Embryology (6)] [ Right Image: Moorman et al. (11)]
Septation
Septation of the heart occurs between the 27th and 37th day of embryo development. Septum formation can result from direct or indirect tissue growth, both of which are required for ventricular septation. Figure 8b shows a form of septation that is caused directly by tissue growth. Here regions opposing each other, known as endocardial cushions, undergo localised growth across a lumen. When they meet, they fuse together forming a septum. This process is involved in the formation of the membranous ventricular septum. Endocardial conditions are also involved in the growth of the atrial septum, atrioventricular canals and valves and the outflow tract. It is easy to see how membranous VSDs may be involved in a more complex cardiac abnormality.
Figure 8d-f show the development of a septum produced from indirect growth. Here an area of tissue, which isnt growing, folds in on itself as a result of the fast growth of surrounding tissue(18). The septum formed doesnt divide the lumen fully.
Figure 8 Different forms of septation.

Atrial Septum Formation The septation of the common atrium starts at the end of the fourth week when a crest grows into the lumen to form the septum primum. The apexes extend to endocardial cushions in the atrioventricular canal. The superior and inferior cushions grow to close the gap between them and the septum, known as ostium primum. Apoptosis forms perforations in the septum primum which coalescence to form ostium secundum, a hole in the septum, allowin continuation between the primitive atriums. Dilation of the right atrium forms the septum secundum, which is also crescent shape. This septum projects and overlaps the ostium secundum forming foramen ovale. The remaining superior part of the septum primum becomes the valve of the oval foramen. Todo photo FIGURE Ventricular Septum Formation The high frequency of VSDs is assumed to be related to the complex processes that occur to form the ventricular septum(17). Therefore the process of septation and those leading up to it could be responsible for defect formation. The IVS is believed to have mesenchymal and muscular components(10). At day 27 two endocardial cushions form on the anterior and posterior rim of the atrioventricular canal(6,18). By day 35 the bulboventricular flange becomes too small to prevent communication between the atrioventricular canal and the right
primitive ventricle. The endocardial cushions meet and fuse by this time and form a left and right atrioventricular orifice. During the forth week the two primitive ventricles expand due to the external growth of the myocardium and the trabeculation of the internal surfaces. The myocardial growth of the ventricles is thought to cause indirect septation [Figure 8d-f]. Fast growth causes part of the myocardium to fold in on itself and fuse forming the muscular IVS. Incomplete fusing of the external myocardium results in the formation of a cleft. This septum projects up from the apex of the heart towards the fused endocardial cushions that formed the atrioventricular orifices. The space between the muscular portion and fused cushions forms the interventricular foramen, which allows blood to communicate between the two ventricles(6,14). However some consider another theory whereby the muscular septum forms from a cluster of cells, the primitive interventricular septum, which actively expands towards the atrioventricular canal (Figure 8c)(10). The mesenchymal element results from the fusion of the conotruncal and atrioventricular cushion(10). In fifth week, two endocardial cushions form in the truncus; the right superior (RSTS) and left inferior (LITS) truncus swellings or ridges. The RSTS grows distally and leftward whilst the LITS grows distally and towards the right(6,14). Both truncus ridges spiral around each other as they descend. They fuse to form the aorticopulmonary septum to divide the truncus arteriosus into the aortic and pulmonary trunk tracts(18,19). A similar process occurs within the conus cordis. Two endocardial cushions; right posterior and left anterior, form and unite together to form a small septum that merges with the aorticopulmonary septum, to form the conotruncal septum, and with the ventricular septum. This results in the division of the outflow tracts into right and left. The conus septum fills part of the interventricular foramen, but not fully(18). The anterior atrioventricular orifice endocardial cushion grows over the muscular portion of the IVS to close the remainder of the interventricular foramen making contact between the muscular interventricular septum and the conus septum, completing the IVS(6). Complete closure of the interventricular foramen results in the formation of the membranous part of the IVS.
The atrioventricular cushions are endocardium derived mesenchymal cells whilst the outflow ridges are composed of neural crest cell derived mesenchymal cells.
Figure 8 The spiralling nature of the conotruncal septum and its fusion with the interventricular septum .
[Image from Lan gmans Medical Em bryology(6)]
Its important to note that the neural crest cells that control the growth of the SHF and that lengthen the outflow tract; migrate here to form endocardial cushions responsible for the aorticopulmonary and conus septums(6,19). VSDs can occur when there is a deficiency of the septum components or misalignment of the septums(20).
IVS Structure & VSD Classification

The IVS is divided into four regions defined by landmarks within the right ventricle. The right ventricle is characterised by the presence of prominent trabeculae carneae. The septomarginal trabecula is the most prominent of these meaty ridges and contains the moderator band, an important feature of the conductive system of the heart. The septomarginal trabecula extends from the apex of the heart and divides into two branches. The septal , or posterior, branch projects to the membranous component of the IVS. This landmark is used to identify the right ventricle in medical imaging, irrespective to the location and orientation of the heart.
VSDs are classified to allow for better treatment and to distinguish the wide variety of defects that can occur within the IVS. The classification of VSDs is complex and many schemes exist for their identification. On a basic level all forms of classification take into account the anatomical location of the defect, how many defects exist and the average size of the abnormality. VSDs can easily be divided into muscular and membranous defects according to which part of the septum is affected from its embryological origin. Membranous defects have been to seen to represent 45% of such defects with 55% being muscular abnormalities, although some reports show muscular defects representing up to 80% of VSDs, which is largely dependent on the sensitivity of diagnosis(6,21).
Figure 9 Types and locations of VSDs.

[Image from Sommer et al. (17)]
Muscular Septum
The muscular septum is divided into three regions: the inlet, trabecular and outlet septum [Figure 10](20,22). These fan out from the membranous septum in a triangular fashion (Fig 1.2). Muscular VSDs can involve any of these three regions of the IVS and have no membranous component, so have a purely muscular rim(20). Muscular defects account up to 55% of all VSDs(21,23,24). Its important to note that the term muscular defect can refer to a trabecular VSD.
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Figure 10 The division of muscular and membranous portions of the IVS relative to each other.
[Image from Soto et al. (22)]
Inlet Septum This part of the septum is smooth and stretches between the tricuspid atrioventricular valves septal attachment to the distal attachment for the valves chordal apparatus. It is found inferior and posterior to the membranous region of the IVS. Defects in the inlet septum are called inlet VSDs and represent only 5% of VSDs(23). Such defects can include faults within the atrioventricular canal that result in malformation of the inlet septum(22). They are typically found to exist in the posterior IVS under the level of the tricuspid atrioventricular valve as an isolated VSD. Trabecular Septum The trabecular septum forms the largest division of the IVS. It divides the large trabeculations in the right ventricle from the smaller ones in the left ventricle. This region of the septum stretches from the membranous septum to the apex of the heart as well as to the outlet septum. Defects in this part of the muscular septum represent 20% of all VSDs(22,23). A true trabecular, or muscular defect, is surrounded entirely by muscle(22). Due to the size of this region, defects here are further classified by their anatomical position in the IVS relative to structures within the right atrium. Anterior trabecular VSDs are found anterior to the septal band, whilst midmuscular VSDs are seen posterior to it. Apical defects are seen inferior to the moderator band and posterior defects are seen below the septal cusp of the tricuspid valve(25). The most common site of defects in the trabecular region towards the apex of the heart, or within the anterior or central portions of the trabecular region(23). Muscular VSDs often involve multiple defects within the muscular portion of the IVS(23). The trabeculated surface of the right ventricle makes it extremely hard to identify each and every defect. A complex trabecular VSD where multiple defects exist is known as Swiss-cheese Septum, which refers to multiple defects
within the muscular portion of the IVS(26). A single defect in the left ventricle may have many openings when viewed from the right ventricle. Outlet Septum The outlet septum is similar to the inlet septum in that it is smooth. Within the right ventricle it is separated from the trabecular septum by the septal band. It divides the outflow tracts, being more extensive on the right side of the heart where it borders papillary muscles, semilunar values and the membranous septum. Defects within this part of the muscular septum represent 5% of all VSDs(23). They typically occur above the septomarginal trabecula and below the pulmonary valve. They usually present as an isolated defect. As defects can present in numerous locations in the outlet septums, VSDs are classed as occurring in the infundibular, supracristal, conoventricular, conal and subpulmonary septums, as well as the parietal band.
Membranous Septum
The membranous septum makes up the smallest component of the IVS, however defects involving the membranous septum are the most common. The membranous septum is found inferior to the right non-coronary cusps of the aortic valve and between the inlet and outlet septum. It can be subdivided into the pars atrioventricularis and pars interventricularis relative to the anterior and septal leaflets of the tricuspid valve(22). Membranous septum defects are classed by how localised the defect is. Purely membranous defects occur solely within the membranous septum of the heart. They are enclosed by fibrous tissue on all sides and dont involve the surrounding muscular regions(22). Infracristal VSDs occur beneath the supraventricular crest; a muscular ridge that separates the conus arteriosus and the right ventricle. Perimembranous defects involve the membranous region of the septal wall and extend to one of the neighbouring muscular regions. The names perimembranous inlet, perimembranous outlet and perimembranous muscular (trabecular) help identify which muscular portions of the septum are affected [Figure 11](22). They typically occur in upper fibrous regions of the septum, beneath the septal cusp of the tricuspid atrioventricular valve or inside the left ventricles outflow tract, below the aortic valve. They are the most reported VSD; representing up to 80% of cases and typically occur as an isolated defect(23,27).
12
Figure 11 Images show the placement of potential VSDs and show the types of membranous defects.
[Images modified from Soto et al. (22)]
AV Septum
The tricuspid and bicuspid atrioventricular valves lie at different levels within the heart. This allows part of the right atrium and left ventricle to lie directly adjacent to each other. The wall that separates these two diagonal chambers is known as the atrioventricular (AV) septum. It is partly muscular and partly membranous. Perforations here are known as atrioventricular defects.
Size
VSDs are sized as very small, small, medium or large relative to the aortic valve diameter(23). VSDs equal to the aortic annulus are large, those equal to the radius are moderate and those smaller to it are small(23).
Epidemiology
Incidence and birth prevalence refer to the number of new cases a year relative to a number of live births (LB), whereas prevalence relates to the number of existing cases relative to a portion of the healthy population. CHDs are the most common birth defect and are one of the main causes of death within the first year of life(15,7). Currently over 1.35 million babies are born each year with a cardiac defect(2,4). The incidence of CHDs has been considered to be 8 per 1000 LB (2,4,20). However reports range significantly from 4 to 50 per 1000 LB(2,4,5,28). More recent data is now suggesting a higher average incidence rate of 9-13 per 1000 LB(2,29). Variation is seen between studies undertaken at different times and between geographical locations, suggests numerous factors are responsible for the precipitation of such congenital abnormalities. VSDs are the most common congenital heart defect occurring in 50% of cases, however value also ranges, 0.3 to 53.2 per 1000 LB, between populations and studies [Figure 16](4,24,28,30). Isolated defects are the most common and occur at 6 per 1000 LB [Figure 16](31). The true incidence of VSDs is thought to be 2.62 per 1000 LB (95% CI 2.59-2.65)(2,4,32).
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Figure 16 The incidence of VSDs and the proportion within the CHD population ranges between countries as shown.
[Image from Bernier et al. (4)]
It has been shown that the apparent birth prevalence of CHD has increased dramatically over time [Figure 12]. Meta-analysis has shown that from 19301934 the average incidence of CHD was found to be 0.6 per 1000 live births (95% CI 0.4-0.8), however since 1995 the average incidence was reported as 9.1 per 1000 live births (95% CI 9.0-9.2) (2). Prior to 1985 VSDs were seen to represent over 40% of all CHDs in 3 out of 20 studies. However after this date VSDs represented over 40% of all CHDs in 20 out of 34 studies(32).
Figure 12 Time course of reported total congenital heart disease (CHD) birth prevalence from 1930 until 2010. The blue line shows the time trend, and the square represent the calculated birth prevalence values for each time period (2)
[Image from van der Linde et al. (2)]
CHD & VSD incidence is also seen to vary between countries. Asia tends to have the highest birth prevalence of CHDs, at 9.3 per 1000 LB, and Africa having the lowest, at 1.9 per 1000 LB (2,3). The incidence of CHDs in the United States is 4DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD 14
10 per 1000 live births, but most reports are seen to focus around 8 per 1000 live births(3). A clear value for the birth prevalence of CHD in Europe hasnt been determined. A study (2000-2005) saw the average estimated incidence of CHD as 6.4 per 1000(4). In 2011 an incidence of 8.2 per 1000(2) was reported and more recently a value of 6.9 per 1000 live births(3).
FIGURE TODO Different healthcare systems could also affect a defects incidence rates in similar countries like American and England. Countries with private medical insurance may have a reduced number of reported CHDs and small VSDs might be treated by GPs rather than in centralised hospitals where figures are collected from(28). Alternatively these differences could be a result of assimilated migrant populations within these countries. For example Asian immigrants would raise the incidence rate and African immigrants would lower the birth prevalence values due to their reported differences in incidence and potential genetic factors involved. In America, severe CHDs were seen in 1.3 per 1000 births with 1.04 per 1000 needing surgery(4). It is estimated that a quarter of infants born with any CHD in the United States will require invasive treatment before they have their first birthday(3).
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High-income countries are seen to have a significantly higher incidence of CHDs, but data for low-income countries has yet to be determined [Figure 13]. The high birth prevalence of CHD in Asia (9.3 per 1000 live births) and countries such as Iran and India could be as a result of high consanguinity. There is a significantly higher risk of having a CHD is you have consanguineous parents, which points towards a genetic component(2,33).
Figure 13 Incidence of CHD by World Bank Income Groups
[Image from Bernier et al.(4)]
Breakthroughs in medicine over the past century and improvements in access to healthcare have increased the proportion of live birth rates. The medical profession and general public now better understand nutrition, which is important for the developing foetus. Mothers and newborn children are also vaccinated against more diseases, and medications now exist to treat a lot of infections and problems that would have led to infant death. Improvements in obstetrics and neonatal care have also directly impacted on live birth rates. Babies with CHDs are now more likely to survive that they were to in the past due to improvements in paediatric anaesthesia and cardiothoracic surgery(2). Similarly improvements in technology and knowledge have allowed for better diagnostics and surgical intervention(2). The invention and mainstreaming of Doppler echocardiology in the 1970s has allowed for more diagnoses to be made. Prior to this only large abnormalities could be easily identified, but nowadays Doppler echocardiology allows asymptomatic and smaller lesions to be easily
detected, including small VSDs (4,30,34). Incidence reports rely upon diagnosis, which in the past required cardiac catheterisation, which doctors were reluctant to perform to diagnose a mild defect(28). It has been proven that the routine use of Doppler echocardiology has led to an increase in the number of diagnoses of smaller defects, which otherwise wouldnt have been detected(30,32,34,35). This has made it hard to compare VSD prevalence between populations, and its better to compare perimembranous VSD prevalence(21). CHD incidence is largely dependent on the number of small VSDs and trivial lesions included within a study, however it has been posed that these small muscular defects may be a normal protracted process(21,28). It is expected that the use of foetal echocardiology will decrease the incidence of CHDs by increasing termination rates in high income countries whilst low income countries are likely to see a rise in CHD incidence as screening and healthcare improve(36). Despite better diagnostics; over 35% of CHD diagnoses are made after the first year of life, during which time some shunt lesions, that would have been present at birth, would have spontaneously closed, affecting incidence valuations (5,21,37). Therefore it is likely that figures reported from high-income countries may actually still be lower than true values. Complex VSD & CHD pathologies are more readily identifiable; therefore differences in diagnostic capabilities are unlikely to have any effect on the birth prevalence of complex abnormalities. This is proved by the stable incidence rates of complex CHDs. This suggests that the increase in birth prevalence of other CHDs such as VSDs is likely to be methodological; as logical result of an increased ability to detect and hence diagnose smaller abnormalities leading to an apparent increased birth prevalence and improved survival [Figure 14](2,28).
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Figure 14 The history of incidence of CHDs (1945-2010). The incidence of complex CHDs is stable, however the increases in isolated defects such as VSDs and ASDs could be attributed to better diagnostics leading to the detection of asymptomatic defects that previously wouldnt have been reported. AoS = aortic senosis; ASD = atrial septal defect; Coarc = coarctation; PDA = paten ductus arteriosus; PS = pulmonary stenosis; TGA = transposition of the great arteries; TOF = tetralogy of Fallot; VSD = ventricular septal defect. (2)
[Image from van der Linde et al. (2)]
This explainable increase in birth prevalence of CHD is attributable to an improvement in healthcare over time. This can be extrapolated to explain why higher income countries have a higher reported incidence of CHD than lower income and developing countries. For example; healthcare systems in less economically developed countries may resemble the healthcare system of a now developed country, but 50 years ago. Therefore it could be predicated that in these countries fewer CHD infants survive birth or die shortly after, due to their untreated abnormality, and that mild cases arent diagnosable and therefore such countries report a much lower birth incidence than the true value. However the true incidence of VSDs may have also changed over time and the factors described may not be entirely responsible for the increase in birth prevalence. Increased survival and birth rates of premature infants, particularly in high income countries, has raised the number of babies born with underdeveloped hearts, resulting in an increase in the birth prevalence of CHDs, especially VSDs, explaining some attributable increase in CHD incidence(38,39). Higher average maternal ages, particularly in more developed countries with higher average incomes, have resulted in higher instances of congenital abnormalities(40). Mothers over 35 years old are 20% more likely to have a
child with a CHD, particularly with isolated defects(41). The correlation between maternal age and VSDs has been shown to be statistically significant, with younger mothers (20-24 years) being at a lower risk and older mothers (>=35 years) being at a higher one [Figure 15] (41). Maternal obesity is now considered a risk factor too(42). Maternal Age 20-24 years 30-34 years 0.89 1.02 (0.80-1.00) (0.92-1.14) 0.78 0.86 (0.61-0.99) (0.68-1.09) 0.83 1.03 (0.70-0.99) (0.881-1.19)
VSDs Membranous VSDs Muscular VSDs
<20 years 0.91 (0.80-1.05) 0.81 (0.60-1.11) 0.82 (0.65-1.03)
>=35 years 1.20 (1.06-1.36) 1.21 (0.93-1.58) 1.11 (0.94-1.32)
Figure 15 - Values represent adjusted prevalence ratios. Maternal reference group was age 25 29 years). Confidence Intervals are bracketed. Bold items have a P value that is statistically significant.
[Data from Miller et al. (41)]
Pathophysiology and Clinical Presentation

Nowadays each class of VSD is considered to be its own pathology. Subarterial VSDs have been linked to ecto-mesenchymal tissue migration, so errors controlling this process are likely to result in this sort of defect. Perimembranous defects may be resultant of problems in intra-cardiac blood flow during development, resulting in failure of fusing of the septums(43). Muscular defects are thought to be caused by growth failure of the primitive interventricular septum or as a result of cell death in trabeculation(10,31). Inlet defects have been attributed to failed fusion of the atrioventricular cushions, and outlet defects to failure of the outlet cushions(10). VSDs are congenital diseases, meaning there are genetic and environmental factors. Only 15% of congenital cardiac abnormalities have a known cause(44). Different VSDs have different risk factors and population statistics, for example; outlet VSDs represent 5% of CHDs in the United States but 30% in Japan. VSDs are considered to be multifactorial diseases(31).
Genetics
VSD reports show a paternal recurrence risk of 2% and a maternal one of 6-10%. The incidence of other CHDs is also higher where parents have an isolated VSD(24). Higher consanguinity rates have been linked to CHD prevalence too(33). However discordance of VSDs is high, even in monozygotic twins(31,43). Although genes appear to play a considerable role patterns of Mendelian inheritance is rare(45). Gene NKX2.5 CHD TOF, ASD, DORV, VSD, HLHS, CoA, IAA, TGA, Ebstein
GATA4 CITED2 TBX TBX1
ASD, AVSD, VSD, TOF, HRHS, PAPVC VSD, ASD ASD, VSD, AVSD VSD, IAA, PAVSD
Figure 18 Genes afilliated to different CHDs. CHD, congenital heart defects; TOF, tetralogy of Fallot; ASD, atrial septal defect; DORV, double outlet right ventricle; VSD, ventricular septal defect ; HLHS, hypoplastic left heart syndrome; CoA, coarctation of aorta; IAA, interrupted aortic arch; TGA, transposition of great arteries; AVSD, atrioventricular septal defect; HRHS, hypoplastic right heart syndrome; PAPVC, partial anomalous pulmonary venous connection; PAVSD, pulmonary atresia with ventricular septal defect; (7)
[Data from Kodo et al. (7)]
NKX2.5 is known as the master gene in cardiogenesis(11,46). However recent data has heavily implicated TBX5, GATA4, and other NKX genes including; NKX2.3, NKX2.6, nkx2.7, nkx8 and nkx2.10(46). NKX2 genes code for DNAbinding transcription factors, with a binding site of 5T(C/T)AAGTG, which form dimmers to function(46). Hetrodimers can occur with other NK2 proteins as well as with GATA4 and Tbx5. These complexes act to promote genes, such as the ANF gene and alpha cardiac actin, and inhibit transcription of others such as catenin. The effect seen differs according to the hetrodimer used. (46) GATA4 and TBX5 are needed for normal cardiac septation. Mutations and polymorphisms in TBX5 cause Holt-Oram syndrome, where VSDs are a symptom. GATA factors have been found to be important in cardiac specification(15). GATA4 mutations have been affiliated to some cases of VSDs(10). The close association between NKX2.5, TBX5 and GATA4 suggests transcriptional activation may be responsible for their activity in septal defects(24). Morpholino knockdown of these genes suggests some overlap in their function and that NKX2.5 isnt critical for cardiac progenitor specification, but plays a redundant role with nkx2.7 to elongate the heart tube and control chamber size. NKX2 genes are conserved within other vertebrates, however this doesnt mean that their function is conserved, for example NKX2.3 is only expressed in the heart of the frog and chicken. Therefore in vivo studies may not truly reflect human development(46). NKX25 is considered important for normal cardiac morphological and physiological development in humans. Mutations in GATA4, NKX2.5, TBX5 and TBX20 are seen in septal defects(13,45). Mendelian genetics are observed where there are autosomal dominant mutations in GATA4, which produce septal defects(13).
Environmental Factors
It has been estimated that only 8-12% of CHDs are due to environmental factors, however other studies have reported higher values; up to 30%(4,47,48). Maternal pregestational diabetes is a risk factor for all CHDs, including VSDs, whilst alcohol consumption has been associated only with muscular defects only(8,31). Maternal phenylketonuria is affiliated with a 6-fold increase for
CHDs. Infections such as rubella, influenza and febrile illness increase the risk of VSDs. Some therapeutic drugs (such as ACE inhibitors), vitamin A supplements and marijuana-use are also risk factors for VSDs, with paternal marijuana use causing a 5% risk for isolated membranous defects(2,8,48). Ionizing radiation exposure didnt affect CHD birth prevalence, and data regarding the use of hard drugs and smoking is insufficient for calculating risk, however paternal cocaine use has a 5% risk for membranous VSDs(8). Organic solvents, such as phthalates, have also been associated with isolated membranous VSDs. Pesticide exposure is affiliated with a 5% risk(44,48). Hair dye use has a 3% risk for multiple membranous VSDs(48). The recent rise in birth prevalence could be associated with occupational exposure, as more mothers work during pregnancy. Children of fathers under the age of 20 were also found to be at double the risk of VSDs. Evidence is mounting that folic acid may hold some protective value against all CHDs(42). Good diabetic maintenance and rubella vaccination may also provide some protection, as well as avoidance of certain drugs(8,42). Accurate data on parental teratogen exposures has held back developments for reducing environmental exposures to prevent VSDs, primarily because these studies show large parental recall bias(9). The sensitive period for maternal exposure is believed to be from 3 months pre-fertilisation and weeks 2-7 of gestation. This time includes gastrulation which is a sensitive period for teratogen exposure(9). Maternal Illness Phenylketonuria Febrile Illness Influenza Ibruprofen Marijuana Maternal Rubella Organic Solvents Relative Risk >6 1.8 2.0 1.9 1.9 Data Unavailable Data Unavailable
Figure 17 - Maternal exposures that may increase the risk of VSDs in unborn children
[Data from Jenkins et al. (8)]
Either way its clear that genetics and environmental factors are important in this pathology, suggesting an epigenetic importance(10).
Physiology & Shunting

A VSD allows for communication between the two ventricles causing oxygenated blood in the left ventricle to mix with the deoxygenated blood of the right ventricle. The systemic and pulmonary circulations are no longer distinct and blood can be exchanged. The resistance of both pulmonary and systemic circulatory beds and the size of the defect dictate the direction and volume of exchanged blood according to Darcys law(10,49). This typically results in blood passing from the left ventricle, at high pressure, to the right ventricle, which has
a lower pressure, creating a left-right shunt (LR-shunt). A large VSD is nonrestrictive, as it offers no resistance between the left ventricle and pulmonary artery allowing a large LR-shunt(23). A small VSD offers high resistance so not much blood is communicated, despite the large differential pressure between systemic and pulmonary circulations(17). Shunting produces symptoms, not the VSD alone. A LR-shunt redirects oxygenated blood back into the pulmonary circuit ergo cardiac output (systemic circulatory volume) is reduced and the volume of blood within the pulmonary circulation increases. Thus pulmonary venous return to the left side of the heart increases. The increased load on the left ventricle causes its dilation and hypertrophy(10,23). The increased volume of the left ventricle doesnt result in a raised cardiac output, due to shunting of the blood back to the right side of the heart. The hypertrophy of the left ventricle raises end-diastolic pressure that results in a raised pulmonary venous pressure, which raises pulmonary capillary pressure, causing pulmonary hypertension. This can result in pulmonary oedema as fluid is pushed out of the capillaries into the interstitium(31). Pulmonary vascular disease can develop as a result of a VSD, resulting in irreversible pulmonary hypertension(50). This ultimately causes right ventricular hypertrophy and dilation, which can lead to the formation of a double chambered right ventricle(10). The pathophysiology and hence symptoms mimic congestive heart failure. Hypertrophy of the ventricles can be detected on an ECG(10,23). Eisenmengers syndrome results from long-term LR-shunting. The irreversibly high pressure of the pulmonary circuit results in a reversal of the shunt, causing right-left shunting.
Presentation
Examination, ECG, Doppler echocardiology, MRI and chest x-rays are important tools needed for diagnosing a VSD. Diagnosis tends to be made by Doppler echocardiology which is the gold standard due to its ability to determine the size and location of the defect and other relevant physiological information(28). Anatomically only the size of the VSD is relevant in determining the magnitude and direction of the shunt, not the location of the defect(10,24). This dictates the presentation. Due to screening a large number of isolated defects are detected within the first few weeks of life [Figure 19]. Perimembranous VSDs 17 (25%) 10 (15%) 37 (55%) 3 (5%) Muscular VSDs 38 (39%) 10 (10%) 27 (27%) 24 (24%)
< 1 week 1 week 1 month 1 month 1 year >1 year

[Data from Garne et al. (21)]
Figure 19 Time of diagnosis of isolated VSDs.
22
In an early neonate a large VSD may be asymptomatic due to the naturally high pulmonary vascular resistance(24). Two months following birth this falls, decreasing the difference in systemic and pulmonary vascular bed resistances, allowing shunting to occur, producing signs and symptoms(51). This fall in pulmonary vascular bed resistance occurs quicker in premature infants and slower in Down syndrome babies(24). Moderate and large defects may only produce a murmur by week-6 when tachypnea, poor weight gain and other symptoms will be already present (23). Large VSDs typically come to medical attention within six months of birth due to the extent of symptoms, however sometimes a delay in the fall of pulmonary vascular resistance results in a later presentation. Murmurs Isolated VSDs are suspected primarily on the hearing of a holosystolic or pansystolic murmur(10,21). The grade of the murmur is dependant on the magnitude of shunting, the velocity of the flow determines its pitch and the location of the murmur is dependant on the location of the defect(10,24). Small and moderate defects are therefore often the highest and loudest, and may have a thrill, whilst large VSDs are quiet, low and lack a thrill(23,24). Muscular defects can be heard on the lower left sternal border with variations in volume due to the defects change in size during systole(10,24). Infundibular defects can be heard at the top of the sternal border and perimembranous defects are identifiable by a systolic click. Most small VSDs are detected by the 2-week examination, even though most patients are asymptomatic, when a loud high-pitch grade 3, murmur is heard(23,31). If unheard the defect tends to be found by the 8th week. S2 remains split and a holosystolic murmur is heard on the lower left border of the sternum(31). Large defects have un-localised holosystolic murmurs that dont change throughout the cardiac cycle, as systole doesnt cause closure of the defect. They also have a diastolic rumble, heard at the apex, due to increased mitral flow when the pulmonary to systemic ration (Qp:Qs) is greater than 2:1 (10,31). A diastolic murmur indicates aortic insufficiency and a supracristal defect(31). Adults may have dyspnoea due to atrial fibrillation(20). Eisenmengers syndrome patients often have no murmur but have a large pulmonary component of the second heart sound. Increased ventricular loading can cause the apex of the heart to shift laterally(10,24). Eisenmengers syndrome patients will only have tachypnea and cyanosis during exercise(31). Signs & Symptoms The majority of perimembranous VSDs are diagnosed within one year of age, whilst nearly a quarter of all muscular VSDs are reported after one year. However most VSDs detected during the first week of life are muscular. A fifth of perimembranous VSDs are closed surgically, whilst its uncommon for isolated muscular defects to warrant repair(21).
23
Larger defects will cause signs of heart failure such as tachypnea, tachycardia, cardiomegaly and hepatomegaly. Larger VSDs cause left ventricle hypertrophy, which make it ineffective at delivering blood to the systemic circulation. The low level of oxygenated blood and cardiac output triggers compensatory mechanisms. Raised sympathetic tone from an increase in circulating catecholamines results in excessive sweating, pallor and tachycardia. Typically this is reported during feeding when a higher cardiac output is required. This is not too dissimilar to exercise intolerance in an adult with congestive heart failure. The reninangiotensin system is also upregulated due to apparent low blood volume causing increase in salt and water retention. Therefore patients have decreased urination and heightened thirst(49). Tachypnea causes pulmonary congestion resulting in recurrent respiratory infections(23). Rapid breathing and tachycardia raises the basal metabolic demand of the infant leading to poor weight gain, reported as a failure to thrive(31,52). Eisenmengers syndrome patient have central cyanosis, blood desaturation, chest pain and dyspnoea (24). These symptoms appear with exercise. Syncope and hemoptysis may also occur(31). Typically isolated VSDs dont result in cyanosis at rest or during exercise. These symptoms are a direct result from right-left shunting. They also have clubbing of the nail bed. Peripheral oedema indicates right sided heart failure(20). VSD patients may have cognitive problems too. However this is mostly affiliated with membranous defects(21).
Treatment
Patients with small defects may receive prophylactic antibiotics to prevent infective endocarditis as well as dental hygiene educations and checkups(10,23). Symptomatic infants with moderate and large VSDs may receive diuretics to decrease the load on the heart, medications to reduce afterload and increased calorific feedings to improve weight gain(31). Inotropic agents are only used if medications arent adequately effective(31). Perimembranous and trabecular defects are seen to get smaller in time or spontaneously close due to muscular occlusion or hypertrophy, unlike inlet and outlet VSDs which tend to require surgical repair(23,24,31). Indications for surgery include pulmonary vascular disease and shunting measured as Qp:Qs of 1.5:1-2:1(23,24). Large defects are repaired in the first year of life and smaller ones within the second. Sternotomy and cardiopulmonary bypass can be performed on an infant over 2kg, allowing for the defect is repaired through the atrioventricular or semilunar valves, via suturing or by patching over the defect(10,23). Operative and postoperative mortality is low(53). Catheterization-placed devices can now close some VSDs in patients that require minimal invasive techniques due to complications such as irreversible
pulmonary hypertension. This is commonly seen in adults who didnt receive surgical treatment in their youth(23,24).
Outlook
Children who have VSDs that spontaneously close or that are closed by surgical intervention have an average life expectancy with risks of infective endocarditis and arrhythmia(38). Patients tend to have normal lives once treated, although this may vary in childhood years(10). Due to the genetic involvement there is a paternal recurrence risk of 2% and a maternal recurrence risk of 6-10%(24). CHD mortality has decreased, for all age groups, over time, but there is still a risk of early mortality(38). All Patients Children (Age <18) Adults (Age 18-64) AMR p value AMR p value AMR p value (95% CI) (95% CI) (95% CI) VSD 0.40 <0.001 0.28 <0.001 0.54 0.01 (0.28-0.59) (0.13-0.60) (0.34-0.87)
Figure 20 - Adjusted Mortality Ratio (AMR) and 95% Confidence Intervals (CI) of VSD patients in 2000-2005 relative to those in 1987 -1990.
[Data from Khairy et al.(37) ]
The location of a defect is important when thinking about future complications. For example a supracristal VSD near the aortic valve and right coronary cusp can cause aortic insufficiency due to valve leaflet prolapse, which occurs in 5% of VSD patients(10,23,24,31). Aortic regurgitation may also occur in such a case due to Venturi waves from the VSD current(10,20). Right ventricular outflow tract obstruction was found in 7% of cases resulting from muscle bundles due to ventricular hypertrophy(31). 85-90% of asymptomatic muscular defects close spontaneously within ten months of life(32). Closure after 4 years is uncommon(31). Breakthroughs in cardiac surgery, paediatric cardiovascular medicine and diagnostics have increased life expectancy and survival of children born with congenital heart abnormalities(2,4,5,37). This has led to most CHD patients surviving to adulthood(28,37,54). Adults with a CHD are classed as having grown-up congenital heart disease (GUCH)(2). Not all GUCH patients require access to specialised care, but the majority do(54). GUCH patients are more likely to have a child with a CHD(5). Growing GUCH populations are likely to cause an increase in CHD birth prevalence and hence increase GUCH populations further. There are now more GUCH patients than CHD children(20). The prevalence of GUCH is also dependent on geography and ranges from study to study, potentially because the incidence of CHD varies too(5). It was estimated that in the year 2000, 800,000 adults in the United States were living with a congenital heart defect (1 per 150 adults) (3). On average GUCH prevalence is estimated at 3000-4000 per million adults(5,38). GUCH patients require longterm expert medical care which is expensive(55). The population of GUCH patients is growing due to the increased birth prevalence of CHDs and the heightened survival rates of CHD patients. CHD is now a major public health
issue(2). As life expectancy for patients with more complex CHDs increases so too are the numbers of complex GUCH patients, who predominantly are female(29,38). GUCH patients show abnormal conduction and diminished contractility, resultant of the same genetics responsible for the septal or cardiac defect, for example NKX2.5 mutants have smaller atrioventricular nodes than their counterparts. These defects present themselves later in life when the heart ages(13).
Discussion
Ventricular septal defects are the most common class of CHD. Only recently has it come to light how the interventricular septum forms and how its different components come about. The complex processes involved in human cardiogenesis are poorly understood, in terms of genetics, despite the creation of numerous animal models. Due to better embryological understanding membranous and muscular VSDs are now seen as epidemiologically different diseases. Risk factors are yet to be fully quantified for causing all defects although evidence is now emerging. Treatment of VSDs is significantly improved, with better diagnostics, treatment and awareness within the medical field. The future is likely to see better genetic and risk factor evaluations and hence a better quality of life for VSD patients.
References
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26. Mac L, Dervanian P, Le Bret E, Folliguet TA, Lambert V, Losay J, et al. Swiss cheese septal defects: surgical closure using a single patch with intermediate fixings. Ann. Thorac. Surg. 1999 Jun;67(6):17541758; discussion 17581759. 27. Perimembranous Ventricular Septal Defect. 2012 Jun 17 [cited 2013 Apr 5]; Available from: http://emedicine.medscape.com/article/899999-overview 28. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J. Am. Coll. Cardiol. 2002 Jun 19;39(12):1890900. 29. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital Heart Disease in the General Population Changing Prevalence and Age Distribution. Circulation. 2007 Jan 16;115(2):16372. 30. Chang J-K, Jien W-Y, Chen H-L, Hsieh K-S. Color Doppler Echocardiographic Study on the Incidence and Natural History of Early-Infancy Muscular Ventricular Septal Defect. Pediatrics & Neonatology. 2011 Oct;52(5):25660. 31. Ramaswamy P, Srinivasan K. Ventricular Septal Defects. Berger S, editor. Medscape Reference [Internet]. 2011 Nov 1 [cited 2013 Apr 6]; Available from: http://emedicine.medscape.com/article/892980-overview 32. Roguin N, Du ZD, Barak M, Nasser N, Hershkowitz S, Milgram E. High prevalence of muscular ventricular septal defect in neonates. J. Am. Coll. Cardiol. 1995 Nov 15;26(6):15458. 33. Naderi S. Congenital abnormalities in newborns of consanguineous and nonconsanguineous parents. Obstet Gynecol. 1979 Feb;53(2):1959. 34. Edler I, Lindstrm K. The history of echocardiography. Ultrasound Med Biol. 2004 Dec;30(12):1565644. 35. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J. Pediatr. 2008 Dec;153(6):80713. 36. Germanakis I, Sifakis S. The impact of fetal echocardiography on the prevalence of liveborn congenital heart disease. Pediatr Cardiol. 2006 Aug;27(4):46572. 37. Wren C, OSullivan JJ. Survival with congenital heart disease and need for follow up in adult life. Heart. 2001 Apr;85(4):43843. 38. Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M, Pilote L, Marelli AJ. Changing mortality in congenital heart disease. J. Am. Coll. Cardiol. 2010 Sep 28;56(14):114957. 39. Tanner K, Sabrine N, Wren C. Cardiovascular malformations among preterm infants. Pediatrics. 2005 Dec;116(6):e833838. 40. Baird PA, Sadovnick AD, Yee IM. Maternal age and birth defects: a population study. Lancet. 1991 Mar 2;337(8740):52730. 41. Miller A, Riehle-Colarusso T, Siffel C, Fras JL, Correa A. Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States. Am. J. Med. Genet. A. 2011 Sep;155A(9):213745. 42. Dolk H, Loane M, Garne E. Congenital Heart Defects in Europe Prevalence and Perinatal Mortality, 2000 to 2005. Circulation. 2011 Mar 1;123(8):8419. 43. Sands A, Casey F, Craig B, Dornan J, Rogers J, Mulholland H. Incidence and risk factors for ventricular septal defect in low risk neonates. Arch Dis Child Fetal Neonatal Ed. 1999 Jul;81(1):F61F63.
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Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiac Tube Formation

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Figure 8 Different forms of septation.

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

IVS Structure & VSD Classification

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Figure 9 Types and locations of VSDs.

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

[Image from Bernier et al.(4)]

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

VSDs Membranous VSDs Muscular VSDs

<20 years 0.91 (0.80-1.05) 0.81 (0.60-1.11) 0.82 (0.65-1.03)

>=35 years 1.20 (1.06-1.36) 1.21 (0.93-1.58) 1.11 (0.94-1.32)

Pathophysiology and Clinical Presentation

Cardiogenesis: Ventricular Septal Defects

GATA4 CITED2 TBX TBX1

Cardiogenesis: Ventricular Septal Defects

Physiology & Shunting

Cardiogenesis: Ventricular Septal Defects

< 1 week 1 week 1 month 1 month 1 year >1 year

Figure 19 Time of diagnosis of isolated VSDs.

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

Cardiogenesis: Ventricular Septal Defects

DAVID GEE (1107552) | MBBS 2 | SSC | CARDIOGENESIS: VSD

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