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Patients with Down syndrome and congenital heart disease:
survival is improving but challenges remain
Konstantinos Dimopoulos MD, MSc, PhD 1,2,3 Aleksander Kempny MD 1,2,3
[1] Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton
Hospital, London, UK
[2] NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart
and Lung Institute, Imperial College London, UK
[3] National Heart and Lung Institute, Imperial College School of Medicine, London, UK
Correspondence to:
Dr Konstantinos Dimopoulos
Adult Congenital Heart Centre and Centre for Pulmonary Hypertension
Royal Brompton and Harefield NHS Foundation Trust
Sydney Street, SW3 6NP London, UK
Tel +44 207351 8362, Fax+44 207351 8629
E-mail: [email protected]
Abstract
Down syndrome (DS) is the most common chromosomal abnormality and a third of patients are born
with congenital heart disease (CHD). Unless treated early, post-tricuspid cardiac defects (e.g.
ventricular of atrioventricular septal defects or patent ductus arteriosus) can lead to the development
of pulmonary arterial hypertension (PAH) and Eisenmenger syndrome (i.e. severe PAH with reversal
of the shunt, causing cyanosis). PAH, and especially Eisenmenger syndrome, significantly affects
survival prospects and is associated with significant morbidity and a reduced quality of life.
Advances in the management of CHD have resulted in the vast majority of DS patients in developed
countries undergoing early repair of CHD. However, a sizeable population of DS patients with PAH
and Eisenmenger syndrome exists and their management poses significant challenges. Moreover, even
after timely repair of CHD, close surveillance is recommended in order to diagnose and manage longterm sequelae relating to the CHD or other comorbidities. High levels of expertise and a
multidisciplinary effort are required for improving the cardiovascular risk profile of DS patients and
optimising their outcome.
Key Words
Eisenmenger Syndrome
Six minute walk test
Oxygen saturation
Adult congenital heart disease
Outcome
Abbreviations list
CHD=Congenital heart disease
DS=Down syndrome
ES=Eisenmenger syndrome
PH=Pulmonary hypertension
PAH=Pulmonary arterial hypertension
Down’s syndrome (DS) is one of the most common chromosomal abnormalities. The incidence of DS
at birth in developed countries has remained relatively stable over the last 20 years, at approximately
1 per 1000 live births.1 DS is associated with a number of congenital defects but are also at increased
risk of conditions that may develop later in life and, thus, require multidisciplinary care and close
surveillance. Congenital heart disease (CHD) is present in 35-50% of patients and is
haemodynamically significant in two thirds.2,3 Early diagnosis and treatment in expert centres is
essential for improving short and long-term outcome and avoiding important complications, such as
the development of pulmonary arterial hypertension (PAH).
Pulmonary arterial hypertension related to congenital heart disease in Down syndrome
The CHD most commonly encountered in DS is atrioventricular septal defects, ventricular septal
defects and atrial septal defects.2 Large post-tricuspid defects allow significant left-right shunting after
birth and produce significant pressure and volume overload to the pulmonary circulation, which over
time can lead to the development of pulmonary vascular disease. Eisenmenger syndrome (ES) is at the
extreme of the spectrum of PAH related to congenital heart disease (PAH-CHD), with severe
pulmonary vascular disease, resulting in systemic levels of pulmonary vascular resistance and reversal
of the shunt causing central cyanosis. ES is a systemic condition, significantly affecting effort
tolerance and quality of life and, over time, resulting in multiorgan failure.4 Major recent advances in
management, including the use of targeted PAH therapies, have led to an improvement in the
functional capacity of ES patients and a likely improvement in outcome.5–7 Despite this, the mortality
of ES patients remains high and all efforts should be made early in life to repair the cardiac defect
early and avoid the development of PAH.8
Approximately, one third of adult ES patients have DS.6 Patients with DS are generally prone to
developing pulmonary vascular disease earlier in infancy compared to non-DS patients with similar
CHD, making timely diagnosis and early repair of the defect even more important.9 This should be
balanced against the risks relating to cardiac surgery and the presence of comorbidity. Non-cardiac
congenital abnormalities are present in 15% of newborns with DS, including abnormalities of the
nervous system, digestive, genito-urinary and respiratory systems with airway abnormalities,
including subglottic stenosis, laryngomalacia, tracheomalacia, tracheal bronchus, and bronchomalacia
and cervical spine instability which may complicate management in the post-natal period.2 However,
DS nowadays is not a risk factor for morbidity and mortality after surgical repair and has even been
associated with a lower risk of in-hospital death at the time of surgery compared to non-DS patients.10
In this edition of Heart, Körten et al. provide an important insight into the outcome of DS patients
born with CHD and demonstrate how dramatically the management of DS patients has changed over
the last few decades.11 The vast majority of DS patients with large post-tricuspid lesions nowadays
undergo surgical repair within the first 6, or even 3-4 months of life in some centres, and a very small
minority develop ES. This proactive approach has resulted in an almost ten-fold improvement in life
expectancy. These data are encouraging and are likely to reflect the experience in other developed
countries, despite some obvious limitations in the design of this study. For example, the total
population of DS patients analysed by Körten was 1549: assuming a conservative prevalence of CHD
in DS of 30%, the sample would have been drawn from a population of just over 5000 DS patients.
Wu and Morris estimated that, in 2011, there were 37090 DS patients alive in England and Wales
(total population of approximately 50 million).12 The population of Germany was 82 million in 2011,
hence one would expect a 10-fold higher number of DS patients in the German National Register for
Congenital Heart Defects. [9] This demonstrates the inherent limitations of voluntary registries of
CHD, especially when including patients who were born in previous decades and are likely to be
natural survivors (immortal time bias). As a result of systematic prenatal screening and termination of
pregnancy in many cases of DS encountered in utero, the number of DS infants who are born with
CHD has declined in recent years, and may explain why a database established in the last 2 decades
may underestimate the overall prevalence of DS.
The challenges of managing PAH-CHD in DS
While early repair of CHD is highly desirable, it does not completely abolish the risk of developing
PAH. The population of patients in whom PAH develops or persists after CHD repair has grown in
recent decades and has a worse prognosis compared to ES in adult cohorts. Moreover, long-term
sequelae and need for reoperation is not uncommon in patients with successful repair in infancy (e.g.
repair of atrioventricular valve regurgitation). Therefore, all DS patients diagnosed with CHD should
remain under regular follow-up at CHD centres with expertise in the diagnosis and management of
pulmonary hypertension (PH). Indeed, fundamental to the management of any PH is accurate
diagnostic classification and risk stratification, according to international guidelines.13 While PAHCHD belongs to group 1 (PAH) of the international classification, obesity, sleep apnoea and other
airways abnormalities may also contribute to the development of precapillary PH (Group 3). Obesity,
metabolic disorders, such as diabetes and left-sided residual cardiac lesions (e.g. left atrioventricular
valve regurgitation or left ventricular outflow tract obstruction) may cause post-capillary PH (Group
2). Finally, PH relating to abnormal myelopoiesis may belong to group 5 (multifactorial). Each PH
group is treated differently and, before treating DS patients with PAH therapies, efforts should be
made to exclude or treat concomitant causes of PH.
Once PAH is diagnosed, there are major challenges in managing this in DS patients, as evidence
specific to the DS population is lacking. In fact, only recently were DS patients included for the first
time in an on-going large PAH randomised controlled study, the Maestro trial (endothelin receptor
antagonist Macitentan in patients with Eisenmenger syndrome). Current recommendations are, thus,
based on evidence from the non-DS population, and may be difficult to implement to all DS patients.
For example, international PH guidelines recommend that the management and follow-up of PH
patients should be driven by a "multidimensional approach", risk-stratifying patients into a low,
intermediate and high risk of 1-year mortality based on a list of clinical variables aimed at identifying
deterioration and the adequacy of treatment. Implementation of this risk assessment can be
challenging in many DS patients, because of various degrees of learning disabilities, needlephobia,
and comorbidities (see Table 1). Symptoms displayed by DS patients, relating to PAH or its therapies,
vary depending on the degree of language and communication impairment and intellectual disability.
Compliance with monthly blood testing, exercise recommendations and dental hygiene can become
problematic. Decisions regarding the use of parenteral medication, transplantation and end-of life
management can be difficult. Assessing the psychological and quality of life impact of PAH on DS
patients and providing psychological support in a population prone to neurobehavioural and
psychiatric comorbidity requires expertise and a multidisciplinary approach. Good knowledge of the
processes of consent, assessment of mental capacity and deprivation of liberty legislation is
paramount when caring for patients with learning difficulties.
The long-term outcome of Down patients: metabolic profile and cardiovascular risk factors
Despite a significant improvement in survival after timely repair of CHD, Körten et al. report a 4-fold
increased mortality for DS patients compared to the general population. This is most likely related to
comorbidity relating to DS, as non-DS patients with timely and uncomplicated repair of
atrioventricular or ventricular septal defects or a patent ductus are expected to have a normal life
expectancy. As the DS population ages, acquired cardiovascular disease is likely to become more
prevalent and may be driven by known abnormalities in metabolic profile. Patients with DS are prone
to obesity, diabetes mellitus, hypothyroidism, obstructive sleep apnoea and have raised plasma lipid
concentration. Poor dietary habits and physically inactivity are not uncommon, while systemic
hypertension and smoking are less frequent compared to the non-DS population.14,15 Gene
overexpression resulting from trisomy 21 is said to partially protect DS patients from atherosclerosis,
due to decreased levels of homocysteine and increased resistance to serum lipid oxidation.16 However,
a recent cohort study showed that DS patients have 3-fold increased risk of stroke, even though there
was no clear increase in the risk of coronary artery disease, possibly thanks to the low number of
smokers .17
Conclusions
Western countries, like Germany, appear to have largely overcome the first hurdle of managing CHD
in DS, i.e. avoiding the development of pulmonary vascular disease and ES through early surgical
repair. Further challenges lie ahead and the challenge of optimising the management of CHD in
childhood and adult life for patients with DS remains. This can only be achieved with a
multidisciplinary approach and team effort, including patients, their families and carers, physicians
and healthcare workers of different expertise, and patient associations. Active screening for long-term
sequelae of CHD and other comorbidities is paramount, while promoting a healthy lifestyle and
proactive control of cardiovascular risk factors.
Disclosures
.Dr Dimopoulos has received unrestricted education grants and has acted as a consultant for Actelion,
GSK, Pfizer and Bayer. Dr Kempny was supported by the Deutsche Herzstiftung e.V
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Table 1
Determinants of prognosis
(estimated 1-year mortality, as
presented in the International
PH guidelines, Table 13)13
Clinical signs of right heart failure
WHO functional class
Aplicability to patients with Down syndrome

Applies to DS but:
o Signs of heart failure can be due to underlying residual
haemodynamic lesions, not just PAH
o Short wide neck and obesity and may make assessment of
JVP and hepatomegaly difficult


Ordinary activities differ from those of non-DS patients
DS patients may not be able to communicate the degree of
limitation of physical activity
They may be unable to describe symptoms, such as palpitations
They may be unable to distinguish between fatigue and dyspnoea


Progression of symptoms

It may be difficult to discern the rate of progression and severity of
symptoms, depending on intellectual capacity
Syncope



Syncope could be of non-cardiac origin (e.g. epilepsy)
Could be caused by other cardiac reasons (e.g. heart block)
Patients may not be able to describe prodromal symptoms (e.g.
palpitations, dizziness)
6-minute walk test


Known to be unreliable in the DS population
Depends on motivation and ability to follow instructions
Cardiopulmonary exercise testing




Depends on motivation and ability to follow instructions
Some patients find mask claustrophobic or difficult to breathe in
Requires careful interpetation in severely obese patients.
May be difficult or unreliable in patients with muscle-skeletal
abnormalities
Natriuretic peptide levels



Valuable in assessing progression of disease
May be influenced by other cardiac lesions
Serial testing may not be possible in severely needle-phobic
patients
Imaging
(echocardiography,
cardiac
magnetic
resonance
imaging): RA area, pericardial
effusion


Echocardiography is possible in most DS patients
Cardiac magnetic resonance may require sedation or general
anaesthesia (to be avoided in ES/PAH)
RA area may be increased due to atrioventricular valve
regurgitation
Pericardial effusion not uncommon in DS, often does not reflect
severe RV failure


Haemodynamics


Invasive catheterisation possible under local anaesthesia is some
DS patients, many require general anaesthesia (which carries risks
in PAH).
Low oxygen saturations may be related to non-PAH causes (e.g.
sleep apnoea or hypoventilation)

Raised RA pressure may be related to atrioventricular valve
regurgitation
Additional challenges in Down syndrome
Quality of life questionnaires


Needlephobia


Dental hygiene



Parenteral PAH therapies



Exercise





Psychological support



Ceiling of care discussions




May be difficult for some DS patients to understand and fill
accurately
Likely unreliable when filled in by carers
Severe in some DS patients, precluding the use of PAH therapies
that require monthly liver function monitoring
Difficult to monitor iron status, haemoglobin and platelet count,
renal and hepatic function, uric acid levels and natriuretic peptide
levels
Important for minimising the risk of infective endocarditis
Good hygiene may be difficult in patients with significant learning
difficulties
Dental tratment requires general anaesthesia in some DS patients:
involve experienced anaesthetists in PH centres
Intravenous therapies require significant training and complicance
for the medication to be safe
Inhaled therapies: 6-8 inhalations a day may be difficult for some
DS patients, technique is important.
Subcutaneous therapies can be painful
Most DS patients enjoy exercising
Important to find suitable exercise that patients can enjoy (e.g.
dancing or swimming)
Walking regularly is important, avoid wheelchair
Most will exercise to their own ability
Few may overexert: risk of syncope. Discuss with family/carers.
Neurobehavioral or psychiatric co-morbidity can affect up to a third
of patients
Wide range of disorders have been described in DS, including
anxiety, obsessive compulsive behaviour, chronic sleep difficulties,
hyperactive-type behaviours, autistic spectrum disorder, depression
and regression, with decline in cognitive and social skills.
If behaviour changes, rule out:
o progression of PAH or other cardiac condition
o thyroid dysfunction, obstructive sleep apnoea, chronic
inflammatory processes
o abuse, family issues
Ceiling of care and end of life discussions should be part of the
management of advanced PH
Do not resuscitate (DNR) orders are designed to prevent
unnecessary suffering close to the end of life
Learning difficulties are not a reason for setting a DNR order
Presume that all DS pts have capacity to make decisions, unless
proven otherwise (arrange formal assessment of capacity if in


doubt).18
Maximise the patient's capacity to make their own decisions
Discuss with the family and carers/support workers (best interest
meetings)18
DNR: do not resuscitate; DS: Down syndrome; JVP: jugular venous pressure; PAH: pulmonary
arterial hypertension; PH: pulmonary hypertension; RA: right atrium, RV: right ventricle; WHO:
World Health Organisation.