April 1, 2016

Schaeffer, Emily

Introduction:
Every parent has big dreams for their children, and look forward to the day they finally
hold them and look into their childs face. To discover that their child is not healthy is the last
thing any parent wants to hear. One of the defects that some parents face are ventricle septal
defects, which are a type of congenital heart defect, or CHD, that results in the failure to form a
complete wall between the left and right ventricle. Fortunately, the mortality rate associated with
ventricular septal defects has decreased over the last ten years, thanks to new and improving
pediatric surgical techniques (Zhang et al., 2015). However, as the mortality rates decrease, new
studies suggest that ventricular septal defects have long-term issues, even when the disease is
surgically corrected (Zhuang et al., 2013). Parents of children with these defects should be well
informed and encouraged to look out for the long-term effects associated with children who were
diagnosed with ventricular septal defect (Hovels-Gurich et al., 2008). Although many cases of
VSD have no long-term cardiac symptoms due to surgical or independent wall closure, the
presence of a ventricular septal defect results in lowered cognitive and learning abilities, as well
as decreased emotional control, in affected persons during their early childhood and adolescence
due to hypoxia during early development (Matos et al., 2013; Hovels-Gurich et al., 2008; Guan
et al., 2014; Guan et al., 2011; Spandou et al., 2005; and Heiberg et al., 2015).

Development of the heart and formation of ventricular septal defects:

When a normal heart is developing it begins as a wall of muscle with an empty cavity
(Anderson et al., 2013). The construction of chambers begins with endocardial cushions, which
grow together to separate the heart into the atria septa and ventricular septa (Anderson et al.,
2013). These will eventually become the atrium and ventricles as can be seen in figure 1

Schaeffer, Emily

(Anderson et al., 2013). During development of the

Figure 1: Fully developed human heart

(When your child has a ventricular septal
defect, fairview.org, March 1, 2016)

human heart there is a thick wall that grows in order

to create the left and right ventricles called the
ventricular septum (Anderson et al., 2013). During
the early stages of development there is a small
opening between the two ventricles called the
interventricular
septum, which typically will be closed at about
week seven in human development. (Anderson et
al., 2013). Once it is closed, the full wall, or ventricular septum, functions to separate the left and
right ventricles (Anderson et al., 2013).
During fetal development the heart has only one chamber, and the left and right chambers
form when a muscular wall develops between them (NIH, www.nlm.nih.gov, 2016).
Occasionally this wall does not fully develop,
leaving a space between the left and right
ventricle, known as ventricular septal defect,
which is represented by figure 2 (Chen et al.,
2011). The presence of this defect prevents blood
from flowing out through the heart and allows
Figure 2: Heart with a VSD

("Postinfarction Ventricular Septal

Rupture.", Fairview.org, March 1, 2016)

blood flow back into the lungs, according to the

National Institute of Health. In more severe

cases, this can cause fetal hypoxia, or a deprivation of oxygen to the brain, and hypoxemia, or
lowered oxygen to the blood (Hovels-Gurish et al. and NIH, www.nlm.nih.gov, 2016).

Schaeffer, Emily

Ventricular septal defects are among the most common kinds of congenital heart disease,
and are responsible for about 32% of all diagnosed congenital heart defects (Jin et al., 2012).
Some cases of ventricular septal defect are more severe and sometimes require surgical closure;
however, about 76% of ventricular septal defects will close spontaneously before the child turns
one (Frandsen et al., 2014). Even after birth, most cases of ventricular septal defect will close
naturally (Chen et al., 2011). If natural closure does not occur surgery may be required to close
the gap (Chen et al., 2011). The rate at which they close varies depending on the size and
location of the ventricular septal defect, it can take up to five years after the birth of the patient to
complete closure of their VSD (Jin et al., 2012). The criteria for surgery also varies based on the
size and location of the ventricular septal defect. (Chen et al., 2011).
Research on the long-term effects can be difficult, but lately animal studies regarding
ventricular sepal defects have helped pediatric researchers to study the effects of ventricular
septal defects (Moazzen et al., 2014). Fortunately, there is a significant similarity in the
development of the heart in mice and humans (Krishnan et al., 2014). Using EFIC and MRI
technology, which are machines that allow us to see images of the body noninvasively, to see
three dimensional pictures of the heart, scientists compared the development of different types of
congenital heart defects, including ventricular septal defects, in mice and humans and concluded
that the differences were minimal (Krishnon et al., 2014). This opened up many possibilities for
future research on these common heart defects found in humans (Krishnon et al., 2014).
Although there is no consensus of the causes of a VSD, there is a strong link between
diabetic mothers, which is solidified through the mouse experiment (Moazzen et al., 2014). A
mouse study involving the cardiac differences in healthy mother mice, and mother mice with
varying levels of blood sugar, 58.1% of the offspring of diabetic mothers had a congenital heart

Schaeffer, Emily

defect (Moazzen et al., 2014). Of those offspring with a congenital heart defect, 40.3 of them
were affected specifically with a ventricular septal defect (Moazzen et al., 2014). Although there
is little research on what causes the link between diabetic mothers and their offspring, most
scientists argue that it is likely oxidative stress causing the abnormalities in the developing heart
(Moazzen et al., 2014). Scientific efforts have been focused on finding treatments to reduce the
risk of congenital heart defects in the offspring of diabetic mother (Moazzen et al., 2014).

Hypoxia due to ventricular septal defects and its role in long-term cognitive impairments:
Cognitive defects in patients diagnosed with ventricular septal defects are commonly
understood to be a result of the hypoxia that affects the individual due to the defect in the heart
(Moazzen et al., 2014). Fetal hypoxia has been linked to the same long-term cognitive defects
that we see in children affected by ventricular septal defects (Spandou et al., 2015).
Neurocognitive exams of affected children are common in long-term follow ups to determine if
any damage that occurred during their brain development (Spandou et al., 2005). However, there
is evidence that damage due to neonatal hypoxia can be reduced (Spandou et al., 2005). In a rat
study scientists found that the presence of erythropoietin reduced the long term effects of rats
who experienced neonatal hypoxia (Spandou et al., 2005). The erythropoietin hormone is
secreted by the kidneys when the body is in low oxygen supply (Spandou et al., 2005). The
purpose of the hormone is to cause the bone marrow to create more red blood cells and therefore
increase the bodys ability to transfer oxygen throughout the body (Spandou et al., 2005). This
study gives hope that the long term effects of a ventricular septal defect due to neonatal hypoxia
can be prevented (Tomita et al., 2008 and Spandou et al., 2005).

Schaeffer, Emily

Patients with ventricular septal defect, and many other types of congenital heart defects,
experience hypoxia due to increased blood flow back into the lungs (Tomita et al., 2008). Recent
research would suggest that there is a link between ventricular septal defects and cognitive
defects in adolescents, including a positive correlation between size of ventricular septal defect
and severity of cognitive limitations (Hovels-Gurich et al., 2008). Although many cases of
ventricular septal defect, or VSD, will have no long-term cardiac symptoms, the presence of
VSD during fetal development may result in lowered cognitive abilities and emotional control of
the affected persons during their adolescence (NIH, www.nlm.nih.gov, 2016; Chen et al., 2011;
Jin et al., 2012). The human brain is highly metabolic and dependent upon the heart for delivery
of oxygen and nutrients (Matos et al., 2013). Children who experience heart defects are more
likely to experience a lack of oxygen to the brain tissues during neurodevelopment, which causes
impairments in learning, speech and motor function, and emotional development (Hovels-Gurich
et al., 2008).
One of the most common learning deficits we see in adolescents who were diagnosed
with a ventricular septal defect is attention deficit hyperactivity disorder, or ADHD (Matos et al.,
2013 and Guan et al., 2014). Interestingly, mild to sever hypoxia was found to provide similar
results in rats (Miguel et al., 2015). A rat study found that rats that were subject to neonatal
hypoxia experienced lowered ability to focus and complete tasks (Miguel et al., 2015). There was
also a positive correlation between the severity of the neonatal hypoxia and their ability to focus
and complete tasks (Miguel et al., 2015). Some brain damage was also associated (Miguel et al.,
2015). This study provides strong evidence to support that neonatal hypoxia due to a ventricular
septal defect can be linked to learning disabilities (Miguel et al., 2015).

Schaeffer, Emily

Controversy over long-term effects of ventricular septal defects:

Doctors disagree on whether small cases of ventricular septal defects require follow-up
appointments (Frandson et al., 2014 and Heiberg et al., 2015). In terms of cardiac performance,
evidence from Frandson et al. would argue that their data confirms that there is not need to
patients diagnosed with a ventricular septal defect to attend any follow up appointments after
closure (Frandson et al., 2014). However, compelling data they presented seems, the study also
chose not to consider patients with moderate or large ventricular septal defects, which would be
more likely to require medical care and follow up with a physician, and no patients whose
ventricular septal defect required surgical closure were considered in the study (Frandsen et al.,
2014). Although medical professionals continue to disagree, when hypoxia is caused from
neonatal brain damage long term evaluations and follows ups are conducted and the long term
effects from hypoxia caused from heart disease should be considered equally (Spandou et al.,
2005).

Evidence supporting the long-term cognitive, emotional, and physical effects of a VSD:
One of the ways that a diagnosis of a ventricular septal defect will affect patients long
term are limited speech and motor abilities (Hovels-Gurich et al., 2008). A clear division
between those with ventricular septal defects and their healthy peers begins to become clear as
early as the age of five (Hovels-Gurich et al., 2008). In a study where children between the ages
of five and seven were interviewed by speech and language therapists, scientists found that 25%
of children who were diagnosed with VSD were in need of speech therapy (Hovels- Gurich et al.,
2008). This is astonishing when compared to the the average percent of children who attend
speech therapy, which is around two percent (Hovels-Gurich et al., 2008). This study found a

Schaeffer, Emily

direct link between children who were affected with hypoxia during neurological development
due to a ventricular septal defects and an impairment of language and motor abilities due to the
inability of the affected heart to pump a sufficient amount oxygen rich blood to the developing
brain. (Hovels-Gurich et al., 2008).
The long term effects of ventricular septal defect; however, do not end at early childhood
with speech disabilities. Ventricular septal defects continue to affect patients into their
adolescence where students with ventricular septal defects are prone to learning disabilities and
autistic characteristics (Matos et al., 2013). One study found that children with ventricular septal
defects had higher dropout rates and lower scores on neurological tests than did those of their
healthy peers (Matos et al., 2013). However, although patients with VSD have lower scores than
healthy peers, they had more cognitive abilities than adolescents with cyanotic types of
congenital heart disease (Matos et al., 2013). Cyanotic heart disease is another kind of heart
disease which prevents oxygen from circulating the body correctly, they generally cause the
infant to be blue in color (Matos et al., 2013). The results of this study supports the argument that
children who have been diagnosed with a VSD do worse in school than their healthy peers
(Matos et al., 2013). Not surprisingly, the children who had cyanotic heart disease who
experienced even less oxygen to the brain during development reported even lower scores than
did children with a ventricular septal defects (Matos et al., 2013).
A diagnosis of ventricular septal defect may not only be a precursor to learning
disabilities and speech impairments. There is significant evidence to support the hypothesis that
adolescents with ventricular septal defects suffer from emotional and behavioral issues, including
mental health issues (Guan et al., 2014). In one study mental health exams of adolescents who
were diagnosed with a ventricular septal defect during infancy were more likely to suffer from

Schaeffer, Emily

depression, compulsion, social withdrawal, rule breaking behavior, and internalizing behavior
than healthy adolescents of the same age group (Guan et al., 2014). The gap between girls with
ventricular septal defects and the control group was substantially larger than the gap between the
boys (Guan et al., 2014). In contrast the gap between boys with ventricular septal defect and the
control groups was much larger than that of the girls (Guan et al., 2014). The study also broke
the adolescents into two groups: a surgical closure group and a transcatheter group, but found
that the emotional and behavioral tendencies found for the adolescents with ventricular septal
defects were the same regardless of the type of treatment (Guan et al., 2014).
There is significant evidence to suggest that school-aged patients whose families chose to
use surgical closure to treat their ventricular septal defect have reduced neurocognitive abilities
in comparison to children whose ventricular septal defect closed naturally (Guan et al., 2011).
The difference in neurocognition is hypothesized to be linked to the use of hypothermic
cardiopulmonary bypass, or CPB, which uses machinery to circulate oxygen through the body
while the patient is undergoing surgery (Guan et al., 2011). In a test where children under the age
of ten were tested, the data showed that children who underwent CPB during surgical closure had
significantly lower scores on cognitive exams (Guan et al., 2011). In auditory response tests the
surgery group took a longer time to respond to the stimulus, and also needed more aggressive
stimuli, or louder sound, to gain their attention (Guan et al., 2013). Interestingly, although there
was no significant difference in the IQs of the surgical and natural closure group, all children
diagnosed with ventricular septal defects scored lower on IQ tests than healthy children of the
same age group (Guan et al., 2013). The conclusion of this study was that children who were
diagnosed with ventricular septal defects had lower neurocognitive abilities and poorer
information processing skills than healthy peers. Unfortunately, it is not yet clear if the use of

Schaeffer, Emily

CPB during surgical closure of the ventricular septal defect is the cause of the more severe
cognitive defects, or whether the larger defects are the cause and happen to also require surgery,
or a combination of the two (Guan et al., 2013 and Chen et al., 2010). There is certainly research
that supports each argument (Guan et al., 2014 and Chen et al., 2010).
Although in terms of congenital heart defects ventricular septal defects are considered to
be the most common, data indicates that they are also one of the least harmful types of congenital
heart defects in terms of long term neurocognitive abilities (Matos et al., 2013). In a study that
included the results of cognitive tests of patients with both cyanotic types of congenital heart
defects and ventricular septal defects the patients with VSD scored higher on cognitive function
tests than did those with cyanotic types of congenital heart defects (Matos et al., 2013). Cyanotic
types of congenital heart defects differ in ventricular septal defects, as well as other types of noncyanotic defects, by the color of the skin, which turns blue with cyanotic defects from lack of
oxygen to the blood (NIH, www.nlm.nih.gov, 2016). This reflects the argument that there is a
correlation between size of the congenital heart defect and the level of cognitive function (Chen
et al., 2011 and Matos et al., 2013). Children who had a ventricular septal still scored worse than
their healthy peers (Matos et al., 2013). The overall results of the study concluded that the
hypothesis that adolescents with CHD have worse neurocognitive abilities than healthy peers, as
out CHD participants had a significantly poorer performance than the CG in almost every
dimension studied (Matos et al., 2013).
Not only does ventricular septal defect have long term effects on the neurocognitive
functions of those affected, but recent studies suggest that the presence of a ventricular septal
defect can actually impact the exercise capacity of adults and can morph over the patients
lifetime (Heiberg et al., 2015). This increases the concerns that the long term risk of long term

10

Schaeffer, Emily

pulmonary problems stemming from the presence of a VSD (Heiberg et al., 2015). New research
is suggesting that morbidity due to ventricular septal defects can come much later in life, and this
is an aspect of congenital heart defects that will need more attention in the future (Heiberg et al.,
2015). Research in the future should focus on how the ventricular septal defects may change over
time, and how these morphologies affect the affected person (Heiberg et al., 2015).

Conclusion:
It is clear that ventricular septal defects have many long term cognitive effects on
adolescent patients including emotional and mental health issues, learning disorders and trouble
in school, and speech and motor impairment (Guan et al., 2011; Guan et al., 2013; and Matos et
al., 2013). Scientists agree that these effects are caused due to the VSD causing hypoxia during
crucial times for the development of the brain (Spandou et al., 2005 and Hovels-Gurich et al.,
2007). There is also new evidence that a VSD can cause long term aerobic impairment and
possible late pulmonary issues or morbidity (Heiberg et al., 2015). Although physicians generally
do not indicate to their patients that the VSD needs any long term attention, recent data suggests
that more attention should be paid to the long term effects that one with a VSD might experience
( Heiberg et al., 2015 and Frandson et al., 2014).

Future research:
Future research should be conducted to pinpoint the causes of abnormalities in patients
with ventricular septal defects and establishing the morphology over time (Heilberg et al., 2015).
A forty-year study should be put into place following the patients over time and analyzing any
changes in the ventricular septal defects. The study should include patients with both small

11

Schaeffer, Emily

defects and those who underwent surgical closure of their VSD. This will give us more
information on how a VSD may change over a long period of time and how that will affect the
patient long-term

12

Schaeffer, Emily

Works Cited:
Anderson, R., Webb, S., Brown, N., Lamers, W., Moorman, A., 2003. Development of the heart
(2): separation of the atrium and ventricles. Education in Heart 89, 949-958.
Chen, H., Xu, Z., Wang, S., Shen, J., Zhang, Z., Hong, H., 2010. Eisenmenger Ventricular
Defect: Classification, Morphology, and Indications for Surgery
Springer 32, 17-23.
Frandsen, E., House, A., Xiao, Y., Danford, D., Kutty, S., 2014. Subspecialty surveillance of
long-term course of small and moderate muscular ventricular septal defect: heterogeneous
practices, low yeild. BMC Pediatrics 14, 282.
Guan, G., Liu, H., Wang, Y., Han, B., Jin, Y., 2013. Behavioral and emotional outcomes in
school-aged children after surgery or transcatheter closure treatment for ventricular septal
defect. Cambridge University Press 24, 910-917.
Guan, G.-T., Jin, Y.-P., Zheng, R.-P., Liu, F.-Q., Wang, Y.-L., 2011. Cognitive P300-evoked
potentials in school-age children after surgical or transcatheter intervention for ventricular
septal defect. Pediatrics International 53, 995-1001.
Heiberg, J., Redington, A., Hjortdal, V., 2015. Exercise capacity and cardiac function after
surgical closure of ventricular septal defect- Is there unrecognized long-term morbidity.
International Journal of Cardiology, 590-594.
Hovels-Gurich, H., Bauer, S., Schnitker, R., Hinckeldey, K., Messmer, B., Seghaye, M.-C.,
Huber, W., 2008. Long-term outcome of speech and language in children after corrective
surgery for cyanotic or acyanotic cardiac defects in infancy. Official Journal of the European
Paediatric Neurology Society 12, 378-386.
Jin, Y., Wang, A., Wang, Y., Wang, Y., Wang, W., Hou, X., 2012. Natural history of prenatal
ventricular septal defects and their association with foetal echocardiographic features.
Cardiology in the Young 22, 323-326.
Krishnan, A., Samtani, R., Dhanantwari, P., Lee, E., Yamada, S., Shiota, K., Donofrio, M.,
Leatherbury, L., Lo, C., 2014. A detailed comparison of mouse and human cardiac
development. Basic Science Investigation, 500-507.
Matos, S., Sarmento, S., Moreira, S., Pereira, M., Quintas, J., Peixolo, B., Areias, J., Areias, M.,
2013. Impact of Fetal Development on Neurocognative Performance of Adolescents with
Cyanotic and Acynotic Congenital Heart Disease. Congenit Heart Disease 9, 373-381.

13

Schaeffer, Emily

Miguel, P., Schuch, C., Rojas, J., Carletti, J., Deckmann, I., Martino, L., Pires, A., Bizarro, L.,
Pereira, L., 2015. Neonatal Hypoxia-Ischemia Induces Attention-Deficit Hyperactivity
Disorder-Like Behavior in Rats. American Psychological Association, 309-320.
Moazzen, H., Lu, X., Ma, N., Velenosi, T., Urquhart, B., Wisse, L., Groot, A., 2014. NAcetylcysteine prevents congenital heart defects induced by pregestational diabetes.
Cardiovascular Diabetology, 1-24.
"National Library of Medicine - National Institutes of Health." U.S National Library of
Medicine. U.S. National Library of Medicine, n.d. Web. 31 Mar. 2016.
"Postinfarction Ventricular Septal Rupture." : Overview, Pathophysiology, Epidemiology. N.p.,
n.d. Web. 01 Apr. 2016.
Spandou, E., Papadopoulou, Z., Soubasi, V., Karkavelas, G., Simeonidou, C., Pazaiti, A.,
Guiba-Tziampiri, O., 2005. Erythropoietin prevents long-term sensorimotor deficits and brain
injury following neonatal hypoxia-ischemia in rats. Brain Research, 22-30.
Tomita, H., Matsuoka, T., Uemura, S., 2008. Stenting of a Stenosed Major Aortopulmonary
Collateral Artery in a Baby With Pulmonary Atresia and a Ventricular Septal Defect: Rescue
From Critical Hypoxia in teh Immediate Postoperative Stage of Unifocalization Supported by
Extracorporeal Membrane Oxygenation. Catheterization and Cardiovascular Interventions 73,
109-112.
Zhang, S., Zhu, D., An, Q., Tang, H., Li, D., Lin, K., 2015. Minimally invasive perventricular
device closure of double committed sub arterial ventricular septal defects: single center longterm follow-up results. Journal of Cardiothoracic Surgery 10, 1-7.
Zhuang, Y., Young, Y.-h., Yao, J., Ji, L., Xu, D., 2013. Left Ventricular Rotation and Torsion in
Patients with Perimembranous Ventricular Septal Defect. Wiley, 362-369.

14