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PULMONARY VASCULAR DISEASE: THE GLOBAL PERSPECTIVE
Pulmonary Hypertension Associated With
Congenital Heart Disease
Pulmonary Vascular Disease: The Global Perspective
Ian Adatia, MBChB; Shyam S. Kothari, MD; and Jeffrey A. Feinstein, MD
The incidence of congenital heart disease is approximately 8/1,000 live births and appears to be
constant around the world. The currently accepted paradigm for the development of pulmonary
vascular disease associated with congenital heart disease maintains that increased pulmonary
blood flow and pressure trigger unfavorable vascular remodeling. Endothelial cell dysfunction,
abnormal shear stress, circumferential wall stretch, and an imbalance in vasoactive mediators
conspire to promote vasoconstriction, inflammation, thrombosis, cell proliferation, impaired
apoptosis, and fibrosis. We estimate that worldwide 3 million children are at risk for the development of pulmonary vascular disease due to congenital heart disease. The majority of children at
risk globally will have a reparable heart defect, such as an isolated atrial septal or ventricular
septal defect or patent ductus arteriosus. Cardiac repair in the first 2 years of life would prevent
the development of Eisenmenger syndrome, the most advanced form of pulmonary vascular disease secondary to congenital heart disease. Worldwide, only a small fraction of those at risk are
offered surgical repair. Thus, access to timely medical care would eliminate the vast majority of
suffering, disability, and death from Eisenmenger syndrome. Globally, pulmonary vascular disease associated with congenital heart disease may be the most preventable cause of pulmonary
artery hypertension and related mortality and morbidity. CHEST 2010; 137(6)(Suppl):52S–61S
Abbreviations: ASD 5 atrial septal defect; IPAH 5 idiopathic pulmonary arterial hypertension; PDA 5 patent ductus
arteriosus; PVRI 5 pulmonary vascular resistance index; Rp:Rs 5 pulmonary vascular resistance to systemic vascular
resistance ratio; VSD 5 ventricular septal defect; WU 5 Wood units
vascular disease may complicate untreated
Pulmonary
congenital heart diseases as a result of increased
pulmonary artery pressure, blood flow, or both. Typical
lesions that predispose people to the development of
pulmonary vascular disease include ventricular septal
defect (VSD), patent ductus arteriosus (PDA), atrial
septal defect (ASD), as well as more complex forms
Manuscript received December 2, 2009; revision accepted February
13, 2010.
Affiliations: From the Stollery Children’s Hospital (Dr Adatia),
University of Alberta, Edmonton, AB, Canada; the All India Institute of Medical Sciences (Dr Kothari), New Delhi, India; and the
Lucile Packard Children’s Hospital (Dr Feinstein), Stanford University Medical Center, Palo Alto, CA.
Correspondence to: Ian Adatia, MBChB, Room 3A1.44, Walter
C McKenzie Health Sciences Center, 8440 112 St, Edmonton,
AB, T6G 3T7, Canada; e-mail: [email protected]
© 2010 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.09-2861
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of congenital heart disease without congenital or
acquired obstruction to pulmonary blood flow. There
is a paucity of data to estimate accurately the number
of children with congenital heart disease who have or
are at risk for developing pulmonary vascular disease.
We have estimated that worldwide about 600,000
babies are born annually with significant congenital
heart disease, and 50% or more will die of infection
and heart failure in infancy. Repair of simple congenital cardiac defects in infancy usually prevents the
development of pulmonary vascular disease. Therefore, pulmonary vascular disease associated with congenital heart disease is seen rarely in children in
countries with privileged referral patterns, timely
diagnosis, and surgical treatment. However, pulmonary vascular disease continues to be diagnosed in
adults with congenital heart disease. Globally (80% of
the population lives outside the developed countries), it is estimated that only 2% to 15% of patients
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with significant intracardiac or extracardiac shunt
lesions receive curative intervention. For example in
Papua New Guinea by the time surgical therapy is
offered 20% of a cohort of children will be inoperable
because of advanced pulmonary vascular disease.1 As
a result, primarily because of insufficient access to
specialist care, congenital heart disease is one of the
most common causes of pulmonary vascular disease.2
In European adults the prevalence of pulmonary vascular disease due to congenital heart disease, derived
from the French and Scottish registries, is estimated
to be between 1.6 and 12.5 cases per million adults,
with 25% to 50% of these patients suffering from
Eisenmenger syndrome with a reversed shunt.3
In this article, we discuss the pathophysiology of
pulmonary vascular disease associated with congenital heart disease and focus on the global perspective
and the interplay between environmental, genetic,
and socioeconomic factors. We present how geographic location, genetic makeup, and environmental
factors may conspire to affect and influence the phenotype of the disease.
It remains unequivocal that access to medical therapy is the single most important factor in the worldwide development of irreversible pulmonary vascular
disease secondary to congenital heart disease. The
stark reality is that developed regions account for
12% of the worldwide burden from all causes of death
and disability and yet account for 90% of health-care
expenditure worldwide.4 The inequality of access to
medical care exists not only as a northern vs southern
hemisphere divide or developed nation vs less developed but also as a result of economic disparity within
countries. There are disadvantaged communities, for
example indigenous peoples, within the developed
world who share a greater burden of disease risk.5,6
Inequitable situations exist within poorer countries
where expert medical therapy is available only to the
privileged or affluent sector. In India, of the 14 pediatric cardiac centers, only one is a government hospital; the rest are in the private sector where the price
of medical care is beyond the reach of most of the
population.7,8 The disease burden due to pulmonary
vascular disease from inadequate treatment of young
infants with congenital heart disease is, to a large
extent, avoidable. It shares similarities in global epidemiology with all illnesses for which poverty and
poor access to medical care are at the heart of the
matter. A huge population of children with simple
shunt lesions will die in childhood, adolescence, and
young adulthood after a life characterized by recurrent illness and growth failure. There is a stark contrast between the 85% of babies born with congenital
heart disease in the United States who are expected
to reach adulthood9 and the mortality rate of 11% for
all children , 5 years of age in Papua New Guinea.10
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It is sobering to remember that 10 million children
die each year from preventable illness, such as diarrhea and pneumonia (Fig 1).11 We are cognizant that
if access to clean water, good nutrition, and fundamental education for all children are a challenge
globally,11 the development of expensive infant cardiac
surgery programs will be neither a priority nor sustainable.8 The United Nations Children’s Fund report
in 2001 advised that timely intervention in the first
3 years of life is paramount in the approach to many
childhood diseases and disabilities. Congenital heart
disease should be included in this list if we are to prevent
the associated pulmonary vascular disease in later life.12
Classification of Pulmonary Hypertension
Pulmonary hypertension associated with congenital heart disease is classified in category 1, which
includes also pulmonary arterial hypertension due to
idiopathic (IPAH) and familial causes and related to
or associated with other diseases, including connective tissue disease and HIV infection.13 The rationale
for inclusion of pulmonary artery hypertension associated with congenital heart disease in category 1 is
the observation that the histology and endothelial cell
abnormalities of category 1 pulmonary arterial hypertensive diseases are indistinguishable from each
other. The plexiform lesion is the epitome of severe
disease in all category 1 diseases. There may be differences at cellular, genetic, and molecular levels
between disorders in category 1 that remain to be
elucidated. For instance, Lee et al14 have demonstrated that the plexiform lesions of patients with
familial pulmonary arterial hypertension contain
monoclonal proliferating endothelial cells in contrast
to the polyclonal endothelial cell proliferation in
secondary pulmonary hypertension due to congenital
cardiac shunts. Mutations in bone morphogenetic
receptor protein receptor type 2 are less common
in patients with pulmonary hypertensive congenital
heart disease than idiopathic pulmonary hypertension, but when present might have a profound impact
on outcome.15,16 In addition, any globally relevant
scheme of clinical classification cannot, and should
not, lose sight of the prevalence of the disease state
worldwide.17
The Global Incidence of Pulmonary
Vascular Disease Associated With
Congenital Heart Disease
Published reports estimate the incidence of congenital heart disease at eight to 12 per 1,000 live births.18,19
The incidence is similar in all countries and between
races. In addition, in school-aged children the prevalence
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Figure 1. The global distribution of deaths in childhood. Each dot represents 5,000 deaths. (Reprinted
with permission from Black et al.11)
of the common congenital heart diseases is similar
and also constant around the world. VSDs are the
most common lesions, followed by ASDs and PDAs.
These lesions affect the sexes equally and make up
about 60% of all heart defects encountered in schoolaged children around the world; they appear to have
remained constant over the last 30 years.1,7,19-41 The
prevalence of congenital heart disease in Québec,
Canada is 12/1,000 population. In less-privileged
countries the prevalence in school-aged children is
estimated at about 3/1,000 population.22,24,41 This suggests significant infant attrition and/or incomplete
case ascertainment. We calculate that there are
approximately 3.2 million children worldwide with an
isolated ASD, VSD, or PDA who if untreated and
surviving infancy would develop pulmonary vascular
disease and suffer the crippling morbidity of hypoxemia due to shunt reversal and a shortened life expectancy. In our estimate, we have made the following
assumptions: the distribution of the heart malformations is similar to Québec worldwide, and pulmonary
vascular disease develops in 10% of children with an
ASD, 20% with a VSD, and 20% with a PDA.
Standard recommendation for children with large
left-to-right shunts or evidence of an elevated pulmonary vascular resistance is operative closure of the
defect in the first 12 to 18 months of life. In patients
predisposed to pulmonary vascular disease, such as
trisomy 21, earlier repair by 6 months of age is recommended. Patients with truncus arteriosus or transposition of the great arteries with VSD are repaired
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within the first month of life. This strategy has been
effective at reducing the development of Eisenmenger syndrome or end-stage pulmonary vascular
disease. For instance, the 35- to 45-year survival in
Finland after surgical VSD closure is 79%, after PDA
ligation 88%, and after ASD closure 95%, in a country where 95% of the general population can expect
to live 45 years.42 In contrast, in Africa the mean age
of referral of those children who do see a pediatric
cardiologist is 17 months, and 5% to 10% of patients
have Eisenmenger syndrome at referral.23,27,43 In
Sudan, only 15% of children who need an operation
receive one. The outcome for those operated on is
extremely good.23,27 In Papua New Guinea, there is
21% mortality in those who need but do not receive
an operation and, one presumes, a high rate of Eisenmenger syndrome.1,44
In the northern hemisphere the prevalence of
Eisenmenger syndrome due to simple lesions has
decreased considerably. The Eisenmenger patient of
the future is likely to have complex cardiac lesions.
Yet in the developing world, where 80% of the world
population lives, the vast majority of patients now and
for the near future will have Eisenmenger syndrome
due to common and easily treated lesions. In North
America, the evaluation of a child with straightforward
cardiac lesions by cardiac catheterization to assess
if the pulmonary vascular resistance is low enough for
repair is performed only a handful of times per year,
yet remains a frequent occurrence in India and
accounts for between 5% to 25% of diagnostic cardiac
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catheterizations in selected pediatric cardiac units
(personal communication, Drs S. Shrivastava, J. M.
Tharakan, R. Krishnakumar, S. Maheswari).
Pathophysiology
The currently accepted paradigm for the development of pulmonary vascular disease associated with
congenital heart disease is that increased pulmonary
blood flow and pressure conspire to trigger unfavorable vascular remodeling. Endothelial cell dysfunction, abnormal shear stress, circumferential wall
stretch, and an imbalance in vasoactive mediators,
involving the prostacyclin, thromboxane, endothelin,
nitric oxide-cyclic guanosine monophosphate, transforming growth factor-b1, vascular endothelial growth
factor, and fibroblast growth factor-2 pathways, promote vasoconstriction, inflammation, thrombosis, cell
proliferation, impaired apoptosis, and fibrosis.45-58
Histologic Correlates
Heath and Edwards59 published the seminal work
in 1958 that described six grades of pulmonary vascular disease. Grade 1 is the mildest form, characterized
by medial hypertrophy, extension of smooth muscle
into normally nonmuscular arteries, and adventitial
thickening and fibrosis. Grades 4 to 6 represent severe
disease and are typified by the sequential appearance
of medial thinning, plexiform lesions, medial fibrosis,
and finally necrotizing arteritis.59 As mentioned previously, these changes seem to unify pulmonary vascular disease from various etiologies. However, the
Heath-Edwards classification is less useful to characterize the earliest changes frequently seen in infants
and children undergoing cardiac surgery. Therefore,
a morphometric approach was studied by Rabinovitch
et al,60,61 Haworth,62 and Haworth and Hislop.63 The
morphometric approach quantifies and grades from
A to C the degree of abnormal distal extension of smooth
muscle, the thickness of the medial hypertrophy, and
the density of small pulmonary arteries relative to the
number of alveoli. The results of the morphometric
analysis of lung biopsy specimens may be predictive
of late outcome, but lung biopsy is used rarely in the
routine assessment of operability. Nevertheless, the
morphometric approach has emphasized that young
age and preservation of small pulmonary arteries are
the best indicators of good pulmonary hemodynamics
postoperatively.60-63
Development and Reversibility of
Pulmonary Vascular Disease
Early in the disease, in children younger than about
2 years of age, the abnormal pulmonary vascular
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remodeling is generally reversible if the congenital
heart defect is repaired.61 However, not all lesions
have the same propensity to cause pulmonary vascular disease. For instance, pulmonary vascular disease
may be advanced at birth and persist despite neonatal
repair in patients with transposition of the great arteries, emphasizing the importance of prenatal conditions (eg, atrial septal or ductal restriction in utero)
and developmental pulmonary vascular influences.64-69
It is suggested that lesions with both a high flow and
high pressure develop pulmonary vascular changes
sooner and with more certainty than those with
increased flow alone. Yet, clinical observations suggest that even with high flow and pressure lesions
there is variability in the propensity to develop pulmonary vascular disease. Compare, for example, patients
with transposition of the great arteries and a VSD or
truncus arteriosus who develop severe pulmonary
vascular disease during the first year of life (and inevitably if unrepaired)70-74 with patients with an isolated
large VSD or PDA, the majority of whom may develop
pulmonary vascular disease over time but in whom it
is distinctly unusual to do so before 2 years of age.
There is also a subset of patients with a small shunt
from left to right who, nevertheless, develop pulmonary vascular disease of such severity that it is out of
keeping with the anatomic size of the defect. There
remains ongoing speculation as to whether those
patients with small ASDs and pulmonary hypertension have an additional predisposition, which, coupled with a small shunt, promotes the development
of pulmonary vascular disease, or whether they suffer
from IPAH with an irrelevant shunt.
On the one hand, few patients , 1 to 2 years old
have a severely elevated pulmonary vascular resistance
(pulmonary-to-systemic vascular resistance [Rp:Rs]
ratio of . 0.75). On the other hand, older patients with
severely elevated pulmonary vascular resistance index
(PVRI) are at risk for sustained pulmonary hypertension or a progressive increase in PVRI after repair.75
The exact level of PVRI that precludes safe closure of a defect is controversial and varies with each
lesion. In the first US Natural History Study, patients
with an Rp:Rs , 0.2 uniformly did well.76 Closure of
a VSD in the first 2 years of life, even when PVRI is
markedly elevated, usually results in normal or nearnormal pulmonary vascular resistance at follow-up.
The likelihood of favorable pulmonary vascular
remodeling is high if operation is performed in
the first year of life.61,77 Although an occasional
older child or adult with substantially elevated PVRI
has a marked decrease after repair, most patients
beyond the first few years of life with increased PVRI
preoperatively have the same or increased PVRI
postoperatively.75,78-85 Even if PVRI is normal at
rest after closure of a high-resistance VSD, it is well
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documented that abnormal responses to exercise
persist and the pulmonary vascular resistance not
only fails to decrease with exercise-induced flow but
increases.86,87 However, it is worth noting that many
of these studies predate improvements in preoperative treatments, cardiac surgical techniques, and
postoperative care, and more recent series may have
improved results.88 An elevated pulmonary vascular
resistance . 7 Wood units (WU)m2 and age . 5 years
were important risk factors for death on long-term
follow-up over 30 years.85 It is prudent to offer repair
of a VSD or PDA in the first 2 years of life. Pulmonary vascular disease is rare in children with ASDs,
and asymptomatic ASDs are usually closed between
3 and 5 years. Significantly increased pulmonary vascular resistance also increases the risk of mortality
immediately after operation because of right ventricular dysfunction compounded by pulmonary vascular
lability.89,90
For patients with high, but not systemic-level, pulmonary vascular resistance, we do not have a sufficiently sensitive and specific method for determining
who will respond favorably to operation. Wood,91 suggested 50 years ago that surgical repair is indicated
for those whose PVRI is not . 10 WUm2 and whose
pulmonary-to-systemic flow ratio is at least 2:1.
A contemporary approach to determining operative
suitability is to consider the reactivity of the pulmonary
circulation to vasodilators.92,93 Some patients with an
Rp:Rs between 0.2 and 0.5 may have progression of
pulmonary vascular disease on follow-up if they are
. 2 years old at repair,76 and general guidelines suggest that if pulmonary vascular resistance can be
decreased to 6 to 8 WUm2 and an Rp:Rs ratio , 0.3
that a good outcome after repair of VSD can be
expected. Thus, with rare exceptions end-stage pulmonary vascular disease is preventable by early intervention to repair congenital heart defects in the first
2 years of life.
Eisenmenger Syndrome
Eisenmenger syndrome is the name given to the most
severe spectrum of pulmonary vascular disease secondary to congenital shunt lesions. Although the disease
bears the name of Victor Eisenmenger,94 it was Paul
Wood91 who most elegantly characterized the disease
in a masterly account that remains germane today.
Wood defined Eisenmenger syndrome as pulmonary
hypertension at the systemic level, due to high PVRI
( . 800 dyne s/cm5 or 10 WUm2) with reversed
(ie, right-to-left) or bidirectional shunt.91 These patients
have severely remodeled pulmonary vasculature and
seldom respond to vasodilators with a large decline in
PVRI, especially if the shunting is purely right to
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left.91,95-97 In general at this stage closure of the
pulmonary-to-systemic connection is contraindicated
and associated with a worse outcome than the natural
history of Eisenmenger syndrome.91
Eisenmenger syndrome is a multisystem disorder
causing hemoptysis, cerebrovascular stroke, brain
abscesses, secondary erythrocytosis, coagulation abnormalities, cardiac arrhythmia, and sudden death. Many
patients with Eisenmenger syndrome can expect to
live longer than patients with IPAH because of preserved right ventricular function. The preservation of
right ventricular function is explained by the congenital adaptation of a right ventricle exposed to systemic
level of pressure since birth and the advantage of a
shunt that prevents right ventricular pressure from
reaching suprasystemic levels.98 For many years the
disease was regarded as a therapeutic orphan. However, the observation that even patients with established Eisenmenger syndrome have a small but
quantifiable degree of vasodilation in response to
inhaled nitric oxide97,99 and the recent emergence of
oral pulmonary hypertension-specific therapies has
raised awareness of the disease. Beneficial effects of
treatment with endothelin receptor antagonists, type
5 phosphodiesterase inhibitors, and prostacyclin analogs have been reported to improve symptoms in
patients with Eisenmenger syndrome.100,101 However,
until recently only type 5 phosphodiesterase inhibitors were available and affordable outside of Europe
and North America. Endothelin receptor antagonists
manufactured locally have just become available in
India. The benefits of drug therapy in established
Eisenmenger syndrome pale in comparison with the
advantage of early repair. Although there is a great
deal of interest in treating Eisenmenger syndrome
with pulmonary artery-specific therapy and reassessing operability,102 it is unclear whether any currently
available medical therapy can reverse the vascular
changes. Caution is required with this approach
because some patients . 2 years of age with an elevated pulmonary vascular resistance at repair may
have progression of the pulmonary vascular disease
with a worse outcome than children with IPAH.103
The Global Interplay of Congenital Heart
Disease and General Health of Children
It is unknown how other factors common in children with limited access to medical care might exacerbate the pulmonary vascular disease from congenital
heart disease. For instance, in of a group of children
evaluated in Africa, 53% were anemic, 47% underweight, and 33% marasmic compared with a control
group without congenital heart disease, of whom
none were marasmic and 14% were underweight.27
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TB is more than twice as common in patients with
congenital heart disease, especially lesions with an
increased pulmonary blood flow, and if treatment is
available, the major morbidity is delay of cardiac surgery.104 TB may also mask the signs of congenital heart
disease resulting in delayed referral for cardiac repair.105
HIV infection is endemic in sub-Saharan Africa.
Congenital heart disease affects 5% of children in
Uganda with HIV compared with 2% to 3% in developed countries.106 Pulmonary hypertension indistinguishable from IPAH complicates the course of
patients infected with HIV. In addition, infected children often have cor pulmonale.107 It is unknown how
concomitant HIV infection or other infections such
as malaria, which are more common in children with
congenital heart disease, will promote or potentiate
pulmonary vascular disease due to congenital heart
disease.108 Maternal health may also play a role in the
susceptibility to congenital heart disease. It is estimated that each year there are . 100,000 new cases
of congenital rubella syndrome.109 Up to 75% of those
affected will have congenital cardiovascular malformations (60% will have a PDA). Maternal rubella
infection can be almost eradicated by effective vaccination programs.109
Genetic Differences
The susceptibility of different genetic communities to certain types of congenital heart disease is well
documented. Total anomalous pulmonary venous
drainage occurs more frequently than expected in
aboriginal communities in Canada,110 subarterial VSDs
are more common in Asia, and Ebstein anomaly occurs
four times as often in Sudan.23 Conversely, coarctation
of the aorta and supravalvar aortic stenosis are rarely
seen in Taiwan.28
A permissive genetic trait may account for the variability in expression of different degrees of pulmonary
hypertension to similar stimuli. Du et al111 reported a
link between familial and acquired pulmonary hypertension, and molecular genetic contributions to
abnormal septation, PDA, and ASD continue to be
elucidated.112 It is unknown currently if pulmonary
vascular disease secondary to congenital heart disease
is influenced by specific genetic factors.
Environmental Factors
High altitude has profound and fascinating effects
on normal neonatal pulmonary vascular transition
that is related not only to altitude but also to ancestry.
Thus, ethnic groups with recent migration to high
altitude have lower oxygen saturations and higher
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pulmonary artery pressures than those with a long
ancestry of high-altitude living, such as native Tibetans
or Andean residents. In addition, the incidence of congenital heart disease increases at higher altitude, there
is delayed closure of the ductus arteriosus, and the
ductus is larger, with a higher pulmonary-to-systemic
blood flow ratio for any given pulmonary vascular resistance. Thus, operability assessment and management
decisions are different at high altitude.113-117
The Scope of Inequalities
The American College of Cardiology recommends
one pediatric cardiac program per 5 million people.
This level of primary care, let alone subspecialist care,
is not available in most countries. In Malawi, for
instance, a single cardiologist saw 4,000 new patients
in 5 years.118 In India, with a population of 1.2 billion,
there are 14 pediatric cardiac centers or one center
per 85 million people.7 Some countries with populations between 15 and 70 million have no access at all
to pediatric cardiac care.119 It should not be surprising, therefore, that an estimated 15 million children
die or are crippled annually by potentially treatable or
preventable cardiac diseases.
Extraordinary and innovative solutions have evolved
in response to the dearth of pediatric cardiac services.
In San Paulo, 800 congenital cardiac cases are operated on per year, and the operations are funded mostly
through social security provided by the government
rather than the private sector.120 Individual efforts to
train personnel in infant cardiac disease in Guatemala have yielded remarkable results.121 In Sudan,
the combined efforts of visiting and local surgical
teams yield a surgical mortality of only 8.3%.23 Teams
of pediatric cardiac specialists, often led by a cardiac
surgeon, visit countries and perform operations with
excellent short- and medium-term results.1,44,122
Summary
Pulmonary vascular disease secondary to congenital
heart disease is a preventable illness, especially if
repair is offered to children , 2 years of age. The collective efforts of many people and collaboration
between the worldwide medical communities will be
required to eradicate the suffering due to Eisenmenger
syndrome. The United Nations Children’s Fund,
reported in the State of the World’s Children that:
Attention to the youngest children is most needed where it
is most difficult to guarantee: in countries where the seemingly intractable grip of poverty, violence and devastating
epidemics seriously challenge parents’ hopes and dreams
for their children.12
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This is germane to all illness with origins in childhood. Globally, pulmonary vascular disease associated
with congenital heart disease may represent the most
preventable cause of pulmonary artery hypertension
and the morbid and fatal sequelae.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Adatia has been
a consultant to Pfizer and participated in a pediatric expert
panel to discuss Pfizer’s pediatric pulmonary arterial hypertension
program on November 6 and 7, 2009. Travel expenses from
Edmonton, Canada, to London, England, were paid by Pfizer and
a honorarium was paid to Dr Adatia. Dr Adatia was a member of
the GlaxoSmithKline National Advisory Board for Pulmonary
Arterial Hypertension on February 11, 2010. Travel expenses
from Edmonton, Canada, to Toronto, Canada, were paid by
GlaxoSmithKline and an honorarium was paid to Dr Adatia. Drs
Kothari and Feinstein have reported that no potential conflicts
exist with any companies/organizations whose products or services
may be discussed in this article.
References
1. Tefuarani N, Hawker R, Vince J, Sleigh A, Williams GM.
Surgical programme at Royal Alexandra Hospital, Sydney, for
Papua New Guinea children with congenital heart disease,
1978-1994. J Paediatr Child Health. 2002;38(2):178-182.
2. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular
disease in the developing world. Circulation. 2008;118(17):
1758-1766.
3. Galie N, Manes A, Palazzini M, et al. Management of pulmonary arterial hypertension associated with congenital
systemic-to-pulmonary shunts and Eisenmenger’s syndrome. Drugs. 2008;68(8):1049-1066.
4. Murray CJ, Lopez AD. Global mortality, disability, and the
contribution of risk factors: Global Burden of Disease Study.
Lancet. 1997;349(9063):1436-1442.
5. Gracey M, King M. Indigenous health part 1: determinants
and disease patterns. Lancet. 2009;374(9683):65-75.
6. King M, Smith A, Gracey M. Indigenous health part 2: the
underlying causes of the health gap. Lancet. 2009;374(9683):
76-85.
7. Saxena A. Congenital heart disease in India: a status report.
Indian J Pediatr. 2005;72(7):595-598.
8. Kumar RK, Shrivastava S. Paediatric heart care in India.
Heart. 2008;94(8):984-990.
9. Warnes CA, Liberthson R, Danielson GK, et al. Task force 1:
the changing profile of congenital heart disease in adult life.
J Am Coll Cardiol. 2001;37(5):1170-1175.
10. Bang AT, Bang RA; The SEARCH Team. Diagnosis of
causes of childhood deaths in developing countries by verbal autopsy: suggested criteria. Bull World Health Organ.
1992;70(4):499-507.
11. Black RE, Morris SS, Bryce J. Where and why are 10 million
children dying every year? Lancet. 2003;361(9376):2226-2234.
12. UNICEF. State of the world’s children. 2001. http://www.
unicef.org/sowc01/toc.htm. Accessed November 2009.
13. Simonneau G, Robbins IM, Beghetti M, et al. Updated
clinical classification of pulmonary hypertension. J Am Coll
Cardiol. 2009;54(1 suppl):S43-S54.
14. Lee S-D, Shroyer KR, Markham NE, Cool CD, Voelkel NF,
Tuder RM. Monoclonal endothelial cell proliferation is
present in primary but not secondary pulmonary hypertension. J Clin Invest. 1998;101(5):927-934.
58S
15. Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital
heart disease. Eur Respir J. 2004;24(3):371-374.
16. Harrison RE, Berger R, Haworth SG, et al. Transforming
growth factor-beta receptor mutations and pulmonary
arterial hypertension in childhood. Circulation. 2005;111(4):
435-441.
17. Kothari SS. Clinical classification of pulmonary arterial
hypertension. J Am Coll Cardiol. 2010;55(3):267.
18. 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;115(2):
163-172.
19. Hoffman JI. Incidence of congenital heart disease: I.
Postnatal incidence. Pediatr Cardiol. 1995;16(3):103-113.
20. Gupta B, Antia AU. Incidence of congenital heart disease in
Nigerian children. Br Heart J. 1967;29(6):906-909.
21. Ejim EC, Ike SO, Anisiuba BC, et al. Ventricular septal
defects at the University of Nigeria Teaching Hospital,
Enugu: a review of echocardiogram records. Trans R Soc
Trop Med Hyg. 2009;103(2):159-161.
22. Antia AU. Congenital heart disease in Nigeria. Clinical and
necropsy study of 260 cases. Arch Dis Child. 1974;49(1):
36-39.
23. Sulafa KM, Karani Z. Diagnosis, management and outcome of heart disease in Sudanese patients. East Afr Med J.
2007;84(9):434-440.
24. Caddell JL, Connor DH. Congenital heart disease in
Ugandan children. Br Heart J. 1966;28(6):766-767.
25. Marijon E, Tivane A, Voicu S, et al. Prevalence of congenital heart disease in schoolchildren of sub-Saharan Africa,
Mozambique. Int J Cardiol. 2006;113(3):440-441.
26. McLaren MJ, Lachman AS, Barlow JB. Prevalence of congenital heart disease in black schoolchildren of Soweto,
Johannesburg. Br Heart J. 1979;41(5):554-558.
27. el Hag AI. Pattern of congenital heart disease in Sudanese
children. East Afr Med J. 1994;71(9):580-586.
28. Shann MK. Congenital heart disease in Taiwan, Republic of
China. Circulation. 1969;39(2):251-258.
29. Shah GS, Singh MK, Pandey TR, et al. Incidence of congenital heart disease in tertiary care hospital. Kathmandu
Univ Med J (KUMJ). 2008;6(21):33-36.
30. Keith JD, Rose V, Collins G, Kidd BS. Ventricular septal
defect. Incidence, morbidity, and mortality in various age
groups. Br Heart J. 1971;33(suppl):81-87.
31. Hoffman JI, Kaplan S. The incidence of congenital heart
disease. J Am Coll Cardiol. 2002;39(12):1890-1900.
32. Muir CS. Incidence of congenital heart disease in Singapore.
Br Heart J. 1960;22:243-254.
33. Watler DC. Congenital heart disease in Jamaica. Observation on post mortem incidence, with a report of an
unusual case of cor triloculare biatriatum. West Indian Med J.
1960;9:194-200.
34. Bradlow BA, Zion MM, Fleishman SJ. Heart Disease in
Africa, with Particular Reference to Southern Africa. Am J
Cardiol. 1964;13:650-669.
35. Bannerman CH, Mahalu W. Congenital heart disease in
Zimbabwean children. Ann Trop Paediatr. 1998;18(1):5-12.
36. Jaiyesimi F, Ruberu DK, Misra VK. Pattern of congenital
heart disease in King Fahd Specialist Hospital, Buraidah.
Ann Saudi Med. 1993;13(5):407-411.
37. Alabdulgader AA. Congenital heart disease in 740 subjects:
epidemiological aspects. Ann Trop Paediatr. 2001;21(2):
111-118.
38. Akang EE, Osinusi KO, Pindiga HU, Okpala JU, Aghadiuno PU.
Congenital malformations: a review of 672 autopsies in
Ibadan, Nigeria. Pediatr Pathol. 1993;13(5):659-670.
Pulmonary Vascular Disease: The Global Perspective
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22086/ on 05/05/2017
39. Kokou O, Agbèrè AR, Balaka B, et al. The use of Doppler
echocardiography in the diagnosis of congenital heart disease in the Pediatric Department of CHU-Tokoin, at Lomé
(Togo)[In French]. Sante. 1996;6(3):161-164.
40. Asani MO, Sani MU, Karaye KM, Adeleke SI, Baba U.
Structural heart diseases in Nigerian children. Niger J Med.
2005;14(4):374-377.
41. Khalil SI, Gharieb K, El Haj M, Khalil M, Hakiem S.
Prevalence of congenital heart disease among schoolchildren of Sahafa Town, Sudan. East Mediterr Health J.
1997;3(1):24-28.
42. Nieminen HP, Jokinen EV, Sairanen HI. Late results of pediatric cardiac surgery in Finland: a population-based study
with 96% follow-up. Circulation. 2001;104(5):570-575.
43. Sani MU, Mukhtar-Yola M, Karaye KM. Spectrum of congenital heart disease in a tropical environment: an echocardiography study. J Natl Med Assoc. 2007;99(6):665-669.
44. Tefuarani N, Vince J, Hawker R, Sleigh A, Williams G. The
medium-to-long-term outcome of Papua New Guinean children after cardiac surgery. Ann Trop Paediatr. 2004;24(1):65-74.
45. Adatia I, Barrow SE, Stratton PD, Ritter JM, Haworth SG.
Effect of intracardiac repair on biosynthesis of thromboxane
A2 and prostacyclin in children with a left to right shunt.
Br Heart J. 1994;72(5):452-456.
46. Adatia I, Barrow SE, Stratton PD, Miall-Allen VM, Ritter JM,
Haworth SG. Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease. Circulation. 1993;88(5 Pt 1):2117-2122.
47. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased
plasma endothelin-1 in pulmonary hypertension: marker or
mediator of disease? Ann Intern Med. 1991;114(6):464-469.
48. Komai H, Adatia IT, Elliott MJ, de Leval MR, Haworth SG.
Increased plasma levels of endothelin-1 after cardiopulmonary bypass in patients with pulmonary hypertension
and congenital heart disease. J Thorac Cardiovasc Surg.
1993;106(3):473-478.
49. Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for
increased production of endothelin in pulmonary circulation. Circulation. 1991;84(6):2280-2285.
50. Botney MD. Role of hemodynamics in pulmonary vascular
remodeling: implications for primary pulmonary hypertension. Am J Respir Crit Care Med. 1999;159(2):361-364.
51. Rabinovitch M, Konstam MA, Gamble WJ, et al. Changes
in pulmonary blood flow affect vascular response to chronic
hypoxia in rats. Circ Res. 1983;52(4):432-441.
52. O’Blenes SB, Fischer S, McIntyre B, Keshavjee S,
Rabinovitch M. Hemodynamic unloading leads to regression
of pulmonary vascular disease in rats. J Thorac Cardiovasc
Surg. 2001;121(2):279-289.
53. Mata-Greenwood E, Meyrick B, Steinhorn RH, Fineman JR,
Black SM. Alterations in TGF-beta1 expression in lambs
with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2003;285(1):
L209-L221.
54. Mata-Greenwood E, Meyrick B, Soifer SJ, Fineman JR,
Black SM. Expression of VEGF and its receptors Flt-1 and
Flk-1/KDR is altered in lambs with increased pulmonary
blood flow and pulmonary hypertension. Am J Physiol Lung
Cell Mol Physiol. 2003;285(1):L222-L231.
55. Wedgwood S, Devol JM, Grobe A, et al. Fibroblast growth
factor-2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr
Res. 2007;61(1):32-36.
56. Lévy M, Maurey C, Celermajer DS, et al. Impaired apoptosis of pulmonary endothelial cells is associated with intimal
www.chestpubs.org
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
proliferation and irreversibility of pulmonary hypertension in congenital heart disease. J Am Coll Cardiol. 2007;
49(7):803-810.
Smadja DM, Gaussem P, Mauge L, et al. Circulating
endothelial cells: a new candidate biomarker of irreversible
pulmonary hypertension secondary to congenital heart disease. Circulation. 2009;119(3):374-381.
Diller GP, van Eijl S, Okonko DO, et al. Circulating
endothelial progenitor cells in patients with Eisenmenger
syndrome and idiopathic pulmonary arterial hypertension.
Circulation. 2008;117(23):3020-3030.
Heath D, Edwards JE. The pathology of hypertensive
pulmonary vascular disease. Circulation. 1958;18(4 pt 1):
533-547.
Rabinovitch M, Haworth SG, Castaneda AR, Nadas AS,
Reid LM. Lung biopsy in congenital heart disease: a
morphometric approach to pulmonary vascular disease.
Circulation. 1978;58(6):1107-1122.
Rabinovitch M, Keane JF, Norwood WI, Castaneda AR,
Reid L. Vascular structure in lung tissue obtained at biopsy
correlated with pulmonary hemodynamic findings after
repair of congenital heart defects. Circulation. 1984;69(4):
655-667.
Haworth SG. Pulmonary vascular disease in ventricular
septal defect: structural and functional correlations in lung
biopsies from 85 patients, with outcome of intracardiac repair.
J Pathol. 1987;152(3):157-168.
Haworth SG, Hislop AA. Pulmonary vascular development:
normal values of peripheral vascular structure. Am J Cardiol.
1983;52(5):578-583.
Sreeram N, Petros A, Peart I, Arnold R. Progressive pulmonary hypertension after the arterial switch procedure. Am J
Cardiol. 1994;73(8):620-621.
Kumar A, Taylor GP, Sandor GG, Patterson MW. Pulmonary
vascular disease in neonates with transposition of the
great arteries and intact ventricular septum. Br Heart J.
1993;69(5):442-445.
Maeno Y, Hornberger LK, Kamenir SA, et al. Prenatal features of restrictive foramen ovale and ductal constriction in
D-transposition of the great arteries. Circulation. 1999;
99(9):1209-1214.
Soongswang J, Adatia I, Newman C, Smallhorn JF, Williams
WG, Freedom RM. Mortality in potential arterial switch
candidates with transposition of the great arteries. J Am Coll
Cardiol. 1998;32(3):753-757.
Rudolph A. Congenital Diseases of the Heart: ClinicalPhysiological Considerations. Armonk, New York: Futura;
2001:703.
Rudolph AM. Aortopulmonary transposition in the fetus:
speculation on pathophysiology and therapy. Pediatr Res.
2007;61(3):375-380.
Haworth SG. Pulmonary vascular disease in different types
of congenital heart disease. Implications for interpretation of lung biopsy findings in early childhood. Br Heart J.
1984;52(5):557-571.
Clarkson PM, Neutze JM, Wardill JC, Barratt-Boyes BG.
The pulmonary vascular bed in patients with complete
transposition of the great arteries. Circulation. 1976;53(3):
539-543.
Lakier JB, Stanger P, Heymann MA, Hoffman JI, Rudolph
AM. Early onset of pulmonary vascular obstruction in
patients with aortopulmonary transposition and intact ventricular septum. Circulation. 1975;51(5):875-880.
Keane JF, Ellison RC, Rudd M, Nadas AS. Pulmonary
blood flow and left ventricular volumes in transposition of
the great arteries and intact ventricular septum. Br Heart J.
1973;35(5):521-526.
CHEST / 137 / 6 / JUNE, 2010 SUPPLEMENT
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22086/ on 05/05/2017
59S
74. Newfeld EA, Paul MH, Muster AJ, Idriss FS. Pulmonary
vascular disease in transposition of the great vessels and intact
ventricular septum. Circulation. 1979;59(3):525-530.
75. Kidd L, Rose V, Collins G, Keith J. The hemodynamics
in ventricular septal defect in childhood. Am Heart J.
1965;70(6):732-738.
76. Weidman W, Blount S, DuShane J, et al. Clinical course
in ventricular septal defect. Circulation. 1977;56(suppl l):
I56-I69.
77. Yeager SB, Freed MD, Keane JF, Norwood WI, Castaneda
AR. Primary surgical closure of ventricular septal defect in
the first year of life: results in 128 infants. J Am Coll Cardiol.
1984;3(5):1269-1276.
78. Clarkson PM, Frye RL, DuShane JW, Burchell HB, Wood EH,
Weidman WH. Prognosis for patients with ventricular septal
defect and severe pulmonary vascular obstructive disease.
Circulation. 1968;38(1):129-135.
79. Friedli B, Kidd BS, Mustard WT, Keith JD. Ventricular septal defect with increased pulmonary vascular resistance. Late
results of surgical closure. Am J Cardiol. 1974;33(3):403-409.
80. Cartmill TB, DuShane JW, McGoon DC, Kirklin JW. Results
of repair of ventricular septal defect. J Thorac Cardiovasc
Surg. 1966;52(4):486-501.
81. Castañeda AR, Zamora R, Nicoloff DM, Moller JH, Hunt CE,
Lucas RV. High-pressure, high-resistance ventricular septal defect. Surgical results of closure through right atrium.
Ann Thorac Surg. 1971;12(1):29-38.
82. Sigmann JM, Perry BL, Gehrendt DM, Stern AM, Kirsh MM,
Sloan HE. Ventricular septal defect: results after repair in
infancy. Am J Cardiol. 1977;39(1):66-71.
83. Hallidie-Smith KA, Hollman A, Cleland WP, Bentall HH,
Goodwin JF. Effects of surgical closure of ventricular septal defects upon pulmonary vascular disease. Br Heart J.
1969;31(2):246-260.
84. Keith J. Ventricular septal defect. In: Keith J, Vlad P, Rowe RD,
eds. Heart Disease in Infancy and Childhood. New York:
Macmillan Publishing Co; 1978:320-379.
85. Moller JH, Patton C, Varco RL, Lillehei CW. Late results
(30 to 35 years) after operative closure of isolated ventricular
septal defect from 1954 to 1960. Am J Cardiol. 1991;68(15):
1491-1497.
86. Hallidie-Smith KA, Wilson RS, Hart A, Zeidifard E.
Functional status of patients with large ventricular septal
defect and pulmonary vascular disease 6 to 16 years after
surgical closure of their defect in childhood. Br Heart J.
1977;39(10):1093-1101.
87. Kulik TJ, Bass JL, Fuhrman BP, Moller JH, Lock JE.
Exercise induced pulmonary vasoconstriction. Br Heart J.
1983;50(1):59-64.
88. Kannan BR, Sivasankaran S, Tharakan JA, et al. Long-term
outcome of patients operated for large ventricular septal defects with increased pulmonary vascular resistance.
Indian Heart J. 2003;55(2):161-166.
89. Hopkins RA, Bull C, Haworth SG, de Leval MR, Stark J.
Pulmonary hypertensive crises following surgery for congenital heart defects in young children. Eur J Cardiothorac
Surg. 1991;5(12):628-634.
90. Adatia I, Beghetti M. Early postoperative care of patients
with pulmonary hypertension associated with congenital
cardiac disease. Cardiol Young. 2009;19:315-319.
91. Wood P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. I. BMJ. 1958;2(5098):
701-709.
92. Neutze JM, Ishikawa T, Clarkson PM, Calder AL, BarrattBoyes BG, Kerr AR. Assessment and follow-up of patients
with ventricular septal defect and elevated pulmonary vascular resistance. Am J Cardiol. 1989;63(5):327-331.
60S
93. Balzer DT, Kort HW, Day RW, et al. Inhaled Nitric Oxide
as a Preoperative Test (INOP Test I): the INOP Test Study
Group. Circulation. 2002;106(12 suppl 1):I76-I81.
94. Eisenmenger V. Die angeborenes Defekt der Kammerschiedewand des Herzen. Z Klin Med. 1897:32(suppl)1-28.
95. Brammell HL, Vogel JHK, Pryor R, Blount SG Jr. The
Eisenmenger syndrome. A clinical and physiologic reappraisal. Am J Cardiol. 1971;28(6):679-692.
96. Post MC, Janssens S, Van de Werf F, Budts W. Responsiveness
to inhaled nitric oxide is a predictor for mid-term survival
in adult patients with congenital heart defects and pulmonary arterial hypertension. Eur Heart J. 2004;25(18):
1651-1656.
97. Adatia I, Perry S, Landzberg M, Moore P, Thompson JE,
Wessel DL. Inhaled nitric oxide and hemodynamic evaluation of patients with pulmonary hypertension before transplantation. J Am Coll Cardiol. 1995;25(7):1652-1664.
98. Hopkins WE, Ochoa LL, Richardson GW, Trulock EP.
Comparison of the hemodynamics and survival of adults with
severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant. 1996;15(1 pt 1):100-105.
99. Budts W, Van Pelt N, Gillyns H, Gewillig M, Van De Werf F,
Janssens S. Residual pulmonary vasoreactivity to inhaled nitric
oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome. Heart. 2001;86(5):553-558.
100. Gatzoulis MA, Beghetti M, Galiè N, et al; BREATHE-5
Investigators. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the
BREATHE-5 open-label extension study. Int J Cardiol. 2008;
127(1):27-32.
101. Galiè N, Beghetti M, Gatzoulis MA, et al; Bosentan
Randomized Trial of Endothelin Antagonist Therapy-5
(BREATHE-5) Investigators. Bosentan therapy in patients
with Eisenmenger syndrome: a multicenter, double-blind,
randomized, placebo-controlled study. Circulation. 2006;
114(1):48-54.
102. Dimopoulos K, Peset A, Gatzoulis MA. Evaluating operability in adults with congenital heart disease and the role of
pretreatment with targeted pulmonary arterial hypertension
therapy. Int J Cardiol. 2008;129(2):163-171.
103. Haworth SG, Hislop AA. Treatment and survival in children
with pulmonary arterial hypertension: the UK Pulmonary
Hypertension Service for Children 2001-2006. Heart. 2009;
95(4):312-317.
104. van der Merwe PL, Kalis N, Schaaf HS, Nel EH, Gie RP.
Risk of pulmonary tuberculosis in children with congenital
heart disease. Pediatr Cardiol. 1995;16(4):172-175.
105. Ifere OA, Aikhionbare HA, Yusuf U. Congenital heart disease masking pulmonary tuberculosis in children. East Afr
Med J. 1989;66(6):414-418.
106. Lubega S, Zirembuzi GW, Lwabi P. Heart disease among
children with HIV/AIDS attending the paediatric infectious disease clinic at Mulago Hospital. Afr Health Sci.
2005;5(3):219-226.
107. Bannerman C, Chitsike I. Cor pulmonale in children with
human immunodeficiency virus infection. Ann Trop Paediatr.
1995;15(2):129-134.
108. Okeniyi J, Kuti B. Cerebral malaria in children with cyanotic
heart diseases: the need for a closer look. Congenit Heart
Dis. 2008;3(1):73-76.
109. Oster ME, Riehle-Colarusso T, Correa A. An update on cardiovascular malformations in congenital rubella syndrome.
Birth Defects Res A Clin Mol Teratol. 2010;88(1):1-8.
110. McCrindle BW, Wood MM, Collins GF, Wheatley B, Rowe RD.
An increased incidence of total anomalous pulmonary venous
drainage among aboriginal Canadians. Can J Cardiol. 1996;
12(1):81-85.
Pulmonary Vascular Disease: The Global Perspective
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22086/ on 05/05/2017
111. Du L, Sullivan CC, Chu D, et al. Signaling molecules in
nonfamilial pulmonary hypertension. N Engl J Med. 2003;
348(6):500-509.
112. Vaughan CJ, Basson CT. Molecular determinants of atrial
and ventricular septal defects and patent ductus arteriosus.
Am J Med Genet C Semin Med Genet. 2001;97(4):304-309.
113. Chen QH, Wang XQ, Qi SG. Cross-sectional study of congenital heart disease among Tibetan children aged from 4
to 18 years at different altitudes in Qinghai Province. Chin
Med J (Engl). 2008;121(24):2469-2472.
114. Miao CY, Zuberbuhler JS, Zuberbuhler JR. Prevalence of
congenital cardiac anomalies at high altitude. J Am Coll
Cardiol. 1988;12(1):224-228.
115. Penaloza D, Arias-Stella J, Sime F, Recavarren S, Marticorena
E. The heart and pulmonary circulation in children at high
altitudes: physiological, anatomical, and clinical observations.
Pediatrics. 1964;34:568-582.
116. Sime F, Banchero N, Peñaloza D, Gamboa R, Cruz J,
Marticorena E. Pulmonary hypertension in children born
and living at high altitudes. Am J Cardiol. 1963;11:143-149.
www.chestpubs.org
117. Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic
mountain sickness. Circulation. 2007;115(9):1132-1146.
118. Soliman EZ, Juma H. Cardiac disease patterns in northern
Malawi: epidemiologic transition perspective. J Epidemiol.
2008;18(5):204-208.
119. Yacoub MH. Establishing pediatric cardiovascular services
in the developing world: a wake-up call. Circulation. 2007;
116(17):1876-1878.
120. Stolf NA. Congenital heart surgery in a developing country:
a few men for a great challenge. Circulation. 2007;116(17):
1874-1875.
121. Larrazabal LA, Jenkins KJ, Gauvreau K, et al. Improvement
in congenital heart surgery in a developing country:
the Guatemalan experience. Circulation. 2007;116(17):
1882-1887.
122. Novick WM, Sandoval N, Lazorhysynets VV, et al. Flap
valve double patch closure of ventricular septal defects in
children with increased pulmonary vascular resistance. Ann
Thorac Surg. 2005;79(1):21-28.
CHEST / 137 / 6 / JUNE, 2010 SUPPLEMENT
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22086/ on 05/05/2017
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