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Understanding and treatingheart failure in childrenNathalie Dedieu
Michael Burch
AbstractThe incidence of paediatric heart failure has increased as a result of
improvement in congenital heart surgery and heart failure therapy. It
seems therefore essential to understand the different mechanisms of
heart failure, identify the clinical signs as early as possible and under-
stand the rationale and treatment options.
Since some of these patients, especially those with cardiomyopathy,
are especially at risk of death or transplantation, it is extremely important
that they are referred to reference centres for management and that cardi-
ologists work closely with paediatricians at local hospitals. Hence the
need of providing a comprehensive framework for assessment and treat-
ment of paediatric heart failure.
Keywords heart failure; mechanisms; paediatrics; treatment
Introduction
Heart failure (HF) is a major healthcare problem in adults, yet
paediatric heart failure seems to have a low profile in public
health planning. While it is true that the number of affected
children is significantly less than adults the costs per patient
generated by admissions for HF in children are often substan-
tially higher. In addition, improvement in outcomes of congenitalheart surgery as well as improvement in HF therapies has led to
an increase in the number of patient with HF in childhood. In the
paediatric population the cause of HF is very rarely ischaemia
and instead is mainly related to complex congenital heart
diseases (CHD) and cardiomyopathies (CM).
Definition
Multiples definitions appear in the literature, Braunwalds is
perhaps the most widely used: HF is the pathophysiological state
in which an abnormality of cardiac function is responsible for the
failure of the heart to pump blood at a rate commensurate with
the requirements of the metabolizing tissues.
However among the paediatric community it is generally
acknowledged that Arnold Katz comes to a more precise appre-
ciation of HF describing its clinical manifestation and underlying
cellular mechanisms HF is a clinical syndrome in which heart
disease reduces cardiac output, increases venous pressures, and
is accompanied by molecular abnormalities that cause progres-
sive deterioration of the failing heart and premature myocardial
cell death.
Incidence
The incidence of HF in children varies between series. In
epidemiological European studies, children with heart failurerepresent 10e33% of all cardiac admissions with slightly more
than half of the HF admissions corresponding to children with
CHD.
HF associated with CHD has increased due to the improve-
ment of surgical outcomes and improved survival of complex
congenital heart malformation and it now represents around
20% of patients. In this group HF can present as the first mani-
festation of the disease (critical outflow tract obstruction, hypo-
plastic left heart syndrome), transiently after surgical correction
following cardiopulmonary bypass or may develop and appear
later in life as a late consequence of the surgical repair or palli-
ation (Tetralogy of Fallot, univentricular circulation). Neverthe-
less the incidence of HF among children with CHD is less than
25%.
According to several studies published in the last decade, CM
occurs in only 0.87e1.13 per 100,000 with a higher incidence of
new diagnosis in the first year of life. In this group over 50% of
children who develop HF have dilated CM, with a much lower
incidence of other aetiologies. 65e80% of children with CM will
develop HF being the leading cause of HF in children with
structurally normal heart. In the dilated CM subgroup, 83% of
the patients will receive heart failure therapy and only around
53% of them will be alive or free from transplant at 5 years post
diagnosis.
Pathophysiology
The symptoms are the expression of a complexinteraction between
circulatory, neurohormonal and molecular abnormalities.
The decrease in cardiac output induces the activation of
several mechanisms in order to compensate.
The activation of the sympathetic system, through increase of
heart rate and myocardial contractility as well as peripheral
vasoconstriction, tries to maintain adequate output through
inotropic and chronotropic support. However chronic activation
also induces activation of the renineangiotensinealdosterone
system and leads to increased venous and arterial tone, increased
noradrenaline concentration and progressive oedema. All this
induces an increase in the oxygen consumption. Furthermore it isassociated with myocyte apoptosis and hypertrophy as well as
focal myocardial necrosis. In the long run, the myocardiums
ability to respond to continuous high catecholamine level is
altered by a down regulation of beta receptors and reduction of
parasympathetic tone which induces abnormal autonomic
modulation of the sinus node and decrease in heart rate
variability.
The activation of the renineangiotensinealdosterone system
also results in vasoconstriction, an increase in circulating blood
volume with subsequent fluid retention. Added to its vasocon-
striction effect angiotensin II induces release of noradrenaline
that inhibits vagal tone and promotes aldosterone secretion with
Nathalie Dedieu MSc is SpR in Paediatric Cardiology at Great Ormond
Street Hospital, London, UK.
Michael Burch MD is Clinical Lead of Cardiology and Paediatric Trans-
plantation and Consultant Paediatric Cardiologist at Great Ormond
Street Hospital, London, UK.
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the consequent increased excretion of potassium and water and
sodium retention. It stimulates collagen production and
myocardial fibrosis.
In chronic HF vasopressin levels increase contributing also to
the development of hyponatraemia. Endothelins are also
increased and have a potent vasoconstrictor and sodium-retain-
ing effect. Cardiac secretion of natriuretic peptides rises in
response to ventricular volume and pressure overload and act asa physiological antagonist of the renineangiotensinealdosterone
system.
Although these neurohormonal mechanisms are designed to
provide cardiac support in response to acute physiological stress
in general they have a deleterious effect when they become
chronic.
Aetiology
HF can result from cardiac malformations or happen in a struc-
turally normal heart. Although this is a conventional classifica-
tion, it seems more appropriate to classify HF depending on the
primary underlying mechanism leading to the symptoms
(Figure 1).
Decreased ventricular contractility
This may be the consequence of an infection as in myocarditis, of
an iatrogenic cause as a consequence of treatment e.g. with
anthracyclines or as part of the clinical features in neurodegen-
erative or metabolic disorders (mitochondrial disease, hypothy-
roidism, vitamin D deficiency). In these patients the heart
progressively dilates and systolic function declines with, in
advanced phases of the disease, associated alteration of diastolic
function.
Ischaemia
Although cardiac ischaemia is relatively infrequent in children, it
generally appears as consequence of congenital coronaries
abnormalities or as a complication following surgical interven-tion for congenital heart disease involving coronaries arteries
such as arterial switch or Ross procedure. Acquired coronary
disease in children is typically from Kawasaki disease.
Increased preload
One of the most common causes of HF due to increase preload is
left to right shunts at ventricular level. Ventricular septal defect
or patent ductus arteriosus are associated with left ventricle
overload as well as increased pulmonary blood flow as soon as
the pulmonary vascular resistance has decreased. The increased
venous return then induces left atrium dilation. High filling
pressure and volume overload lead to myocyte stretching and
ultimately decreased myocardial contractility.The arteriovenous malformations cause HF throughout the
same mechanism as left to right shunt ultimately increases filling
pressure and volume loads the ventricle. In cases of valvular
incompetency, the regurgitant volume through the valve also
causes volume overload.
HF due to right heart volume loading is less frequent as the
right ventricle is significantly more compliant. It generally
happens after a long history of significantly increased volume
loading, as in the presence of a large atrial septal defect, anom-
alous systemic venous return or when there is significant
pulmonary valve regurgitation e.g. in some cases of Tetralogy of
Fallot repair.
Sepsis, is often associated with an initial increase in cardiacoutput and loading of both ventricles due to the secretion of
vasoactives peptides and a decrease in the systemic resistance.
Eventually tissue perfusion decreases producing lactic acid.
Vascular permeability increases causing fluid retention, and this
added to the tissue damage is negatively inotropic and increases
oxygen consumption.
Excessive afterload
Chronic outflow tract obstructive lesions, especially left heart
obstructive lesions such as aortic stenosis or coarctation of the
aorta induce excessive afterload and increase end-diastolic
pressure which then leads to inadequate coronary perfusion and
subendocardial ischaemia. Ultimately that causes cardiachypertrophy and ventricular remodelling.
Distensibility disorders
Hypertrophic and restrictive cardiomyopathies are associated
with impairment of ventricular relaxation and altered compliance
of the ventricles. At higher filling pressures preload is decreased
as a consequence of decreased end-diastolic volume. Trans-
mission of higher end-diastolic pressure to the pulmonary
circulation then causes symptoms of HF. In advanced stages, the
ventricle becomes so stiff that the end-diastolic volume cannot be
normalized with elevated filling pressure. This ultimately results
in a fall in stroke volume and cardiac output.
Contractility disorder (systolic dysfunction)
Dilated cardiomyopathy(idiopathic, myocarditis, etc.)
Preload increase:
Ventricular dilatation
Left to right shunt intra o extracardiac
Afterload increase:
Ventricular hypertrophy
Aortic stenosis, coarctation of the aorta, pulmonary
stenosis, hypertension
Isquemic heart disease
Distensibility/elasticity disorder (diastolic dysfunction)
Disorder of the cardiac muscle
Primary: Hypertrophic cardiomyopathy, restrictivecardiomyopathy, graft rejection.
Secondary to endocrinologic, metabolic, neuromuscular
diseases, tumors and deposits
Pericardium disease
CHD post-op: TOF, fontan
Rhythm disorder
Taqui/bradi arrhythmia
Figure 1 Principal mechanisms of heart failure.
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Constrictive pericarditis causes HF via a similar mechanism:
as the pericardium constricts the heart, the preload is decreased
requiring higher filling pressures to be able to maintain ejected
volume.
Rhythm disturbance
Arrhythmias can induce HF as a result of an inadequate heart
rate, either increased or decreased, to meet the tissue metabolic
demand.
During tachycardia, diastolic filling time shortens and leads to
inadequate filling and decreased cardiac output.
During bradycardia the left ventricular filling volume
increases leading to ventricular dilatation.
Clinical manifestations
Clinical symptoms and signs are well described and generally well
recognized. They differ depending on the patient age. Typically
infants present with failure to thrive, feeding difficulties including
diaphoresis and respiratory distress when feeding, tachypnoea,
grunting and hepatomegaly. In older children, respiratory
distress, tachypnoea and hepatomegaly persist but are alsoassociated with oedema, jugular venous distension, exercise
intolerance, dizziness, abdominal pain, nauseas and vomiting.
In advanced stages, a third heart sound (gallop rhythm) may
appear, and a thermal gradient with cool extremities is frequent
(Figure 2).
Complementary studies
Echocardiography provides a detailed description of cardiac
function and anatomy, allowing assessment of cardiac structures
as well as function. The available echocardiographic tools for
functional assessment are mainly designed for the left ventricle
and difficult to apply to the right ventricle/single ventricle due to
the different shape and fibre orientation.
Magnetic resonance imaging provides more precise informa-tion in quantifying volumes and function being especially helpful
in situations where echocardiography is difficult to obtain
because of obesity/scoliosis/hyperinflation etc.
In adults, exercise testing gives valuable information
regarding risk stratification and stage of the disease and it is used
as a criterion for listing for transplantation. In children never-
theless the data vary with age and it can be difficult to link the
results to probable outcome, although a recent publication has
shown that a peak VO2 less than 62% was associated with worse
outcome (death or transplantation). Obviously, in infants and
small children this cannot be performed and therefore more
widely used data in small children are generally failure to thrive,
rhythm disturbance and symptoms of chronic HF unresponsive
to therapy.
Biomarkers
Recently a numbers of biomarkers have been used in HF
enabling early recognition, assessment of severity and in
Extrinsic bronchiolar
compression (wheeze)
~ Bronchiolitis (infant)
GALLOP
Systemic venous
congestion: CVP
RV failing LV failing
Retrograde effects
Anterograde effects
Pulmonary venous
congestion: PCP
Infant Hepatomegaly
Child
Hepatomegaly Oedemas, ascitis
JVP
Pleural effusion
Pulmonary flow cyanosis
LV filling LV failing
Infant Dyspnea, nasal flaring, recession grunting
Feeding difficulties, sweatiness with feeds
Bronchial secretions, atelectasis, recurrent
pulmonary infections
Child
Dyspnea, cough
Low cardiac output Impaired peripheric perfusion, HR
Glomerular filtration (UO)
Exercise intolerance, syncopes
Figure 2 Clinical signs of heart failure.
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prediction of outcome The most widely used is brain natriuretic
peptide (BNP) and other natriuretic peptides and derivatives are
also used, notably N-terminal pro BNP. But inflammatory
markers such as C-reactive protein and tumour necrosis factor
alpha are also associated with worse outcome in adults with
heart failure. BNP level more than 300 picograms/millilitre has
shown to be associated with death, transplantation and HF
admission and to have a stronger correlation with worseoutcome than echocardiography.
Treatment
Unfortunately the therapeutic options in paediatric HF are driven
by adult studies, mainly due to the strength of the large study
populations involved and the fact that the pharmaceutical
industry is reluctant to undertake trials in children.
While pharmacodynamics are often similar, the pharmacoki-
netics are often quite different and the aetiologies and mecha-
nisms of HF are also very different. As a result, there is in general
low level of evidence for the paediatric use of HF therapies and
most of them are unlicensed.
In the guidelines published by the International Society forHeart and Lung Transplantation, none of the recommendations is
based on level A and only seven are based in level B.
CM, especially dilated, is perhaps the easiest HF scenario to
extrapolate results from adults trials. The institution of the
therapeutic options follows similar rationale with the introduc-
tion of the medication based on echocardiographic findings and
development of symptoms.
In cases of CHD, the ultimate treatment will obviously be the
surgical correction of the defect when possible or a palliative
procedure.
When the defect results in volume overload, the aim of the HF
medication is generally to minimize symptoms and optimize
growth until the surgical correction is performed. Despite a lackof evidence, diuretics have been and are widely used in this
setting and constitute the pillars of the therapy.
In the presence of pressure overload, especially due to
obstructive lesions, the symptoms depend on the severity and
duration of the load and these resolve with the relief of the
obstruction.
In complex CHD, when ventricular dysfunction appears, the
initial strategy focuses on trying to indentify and then treat
residual lesions or rhythm disturbances that could potentially
improve the functional status. If the ventricular dysfunction
persists, HF therapies will then be introduced in accordance with
the symptoms and clinical situation.
In the presence of isolated diastolic dysfunction, the thera-peutic options remain limited to the judicious use of diuretics to
decrease pulmonary venous congestion but maintaining
adequate preload. In advances phases of the disease the systolic
function fails too and the patient may require inotropic or
mechanical support.
Angiotensin-converting enzyme inhibitors: ACEi
The use of ACEi in HF is well recognized and based on a large
number of studies. Although the majority of them in adults, some
evidence has been published from paediatric populations.
ACEi improve symptoms by decreasing systemic afterload.
They are used as first-line therapy in paediatric HF, often being
the first medication introduced when evidence of ventricular
dysfunction occurs, even in asymptomatic patients. A test dose
when initiating treatment with careful titration of the therapy as
well as close monitoring of electrolytes, renal function and blood
pressure minimize potential adverse effect and the medication is
generally well tolerated.
Angiotensin receptor blockers are rarely used in children but
may be helpful when ACEi therapy is complicated by a trouble-some cough and then they can be used to substitute for the ACEi.
Beta-blockers (BB)
Incomplete evidence exists related to the use of BB in children,
there has been a randomized study but it was limited by the
heterogeneity of the population and the small study size in
relation to adult studies.
Nevertheless they are generally used despite the lack of
published recommendations by most of the paediatric cardiac
centres.
Carvedilol is used in perhaps the most widely used in cases of
moderate to severe systolic dysfunction with careful and slow
titration of the dose. The medication is generally well tolerateduntil late phases of paediatric HF when it may require
discontinuation.
Diuretics
Diuretics are commonly used in paediatric HF. They should be
introduced in cases of symptomatic HF with clinical evidence of
volume overload. Furosemide is the most common and despite
no published evidence its benefits are well recognized. Never-
theless overuse can lead to serious electrolyte imbalances,
especially hyponatraemia and hypokalaemia, as well as ACEi and
BB intolerance. Adverse effects, especially associated with long
term and high doses, include dehydration, nephrocalcinosis,
electrolytes abnormalities and ototoxicity in intravenous use. If
possible, diuretics should be weaned as soon as clinical status
allows it.
Aldosterone antagonists
The most commonly used is spironolactone. Their use has
increased recently due to their antifibrotic and antiremodelling
effect on the myocardium. They act as potassium sparing agents
too and this can be helpful in combination with loop diuretics.
The electrolytes need to be carefully controlled particularly when
used with and ACEi. Spironolactone therapy can induce gynae-
comastia however eplerenone does not.
Digoxin
Historically digoxin has been widely used in HF, especially due toits modest inotropic properties. In the 1990s several studies
showed controversial results with subsequent significant
decrease in its use.
Currently utilization of digoxin varies between institution and
it is largely based on preferences rather than evidence. Recent
evidence shows that digoxin used carefully may improve the
outcome in adult heart failure, probably by lowering the heart
rate rather like ivabradine.
Anticoagulation
Is frequently used to reduce the risk of thromboembolic disease
in paediatric heart failure. Recommendations are consensus
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based instead of evidence based. Aspirin is often used in small
children and patients with moderate to severe systolic dysfunc-
tion and warfarin in advanced stages of HF or in patients with
restrictive CM.
Pacing and resynchronization
Resynchronization is now accepted in the adult HF guidelines as
part of the conventional treatment. Ensuring adequate electrical
activation results in improved mechanical function of the
myocardium and improved ventricular contraction. Suitable
patients are those with impaired left ventricular systolic function
and QRS duration more than 120 msec due to left bundle branch
block.
Suitable children are quite rare as QRS tends to be normal and
is most beneficial in congenital heart disease with heart block
and right ventricular pacing.
Mechanical circulatory support
Theuse of mechanical support forpatients in situationof end-stage
HF has been increasing in the last decade. Extracorporeal
membrane oxygenation (ECMO) is generally used in acutelydecompensatepatientsas bridgeto recovery or more commonly as
a bridge to transplant. More recently there has been a switch to
ventricular assist devices (VAD) as these allow longer support time
with fewer complications. According to a recent American study
about 45% bridged with ECMO survive to transplant and about
10% recover. Despite a wide range of VADs in the adult pop-
ulation, paediatrics patients, especially infants and young chil-
dren, arenow predominantly bridged with theBerlin Heart EXCOR
device. Unfortunately the organs donors are rare and patientsoften
have to remain on the device for many months. The Berlin Heart is
an external pneumatic device and is not suitable for destination
therapy, children are usually managed in hospital for the entire
duration of support. Unfortunately this mechanical support carriesa high risk of complications including bleeding, thromboembolic
events, and infection resulting in high morbidity and mortality.
Close monitoring is then required, and even if children on the
BerlinHeart areallowed to leave theward forshortamount of time
they remain inpatients for the length of the bridging.
If the use of VAD as destination therapy doesnt seem to be an
option in paediatrics, the use of VAD as a bridge to recovery is
developing. The Berlin Heart has been shown to support 70% of
patients to transplant with a rate of recovery without trans-
plantation of 7% and mortality around 23%.
Heart transplantation
In cases of intractable heart failure when no further medicaltherapy or surgical option is available, cardiac transplantation is
then the only possibility.
Although transplantation does not restore normal life expec-
tancy it is a highly effective treatment which allows the patient to
recover a good quality of life.
Overall survival according to the ISHLT registry is around
50% at 20 years, using recent paediatric data. Within the
paediatric group, patient with congenital heart disease have
slightly worse outcome and infants who have survived a year
after transplant have the best long-term survival.
Rejection and coronary allograft vasculopathy are the main
graft complications and problems related to immunosuppression
include, infections, lymphoproliferative disorders, renal impair-
ment and hypertension. Of note non-adherence to treatment in
teenagers represents a major challenge and risk for rejection.
The limited available organs along with the increase of chil-
dren surviving with congenital heart surgery and acute heart
failure presentations mean that unfortunately some patients still
die on the waiting list. This has led to the development of novel
strategies to increase potential number of transplants. ABOincompatible transplant in patients less than 2 years is now
a reality and organ donation after cardiac death (non-heart
beating donation) rather than respiratory death with a beating
heart in a brain dead donor is being developed. A
FURTHER READING
Almond CS, Singh TP, Gauvreau K, et al. Extracorporeal membrane
oxygenation for bridge to heart transplantation among children in the
United States: analysis of data from the Organ Procurement and
Transplant Network and Extracorporeal Life Support Organization
Registry. Circulation 2011 Jun 28; 123: 2975e84.
Alvarez JA, Orav EJ, Wilkinson JD, et al. Pediatric Cardiomyopathy RegistryInvestigators. Competing risks for death and cardiac transplantation in
children with dilated cardiomyopathy: results from the pediatric
cardiomyopathy registry. Circulation 2011 Aug 16; 124: 814e23. Epub
2011 Jul 25.
Andrews RE, Fenton MJ, Ridout DA, Burch M. New-onset heart failure due
to heart muscle disease in childhood: a prospective study in the
United kingdom and Ireland. Circulation 2008; 117: 79e84.
Imamura M, Dossey AM, Prodhan P, et al. Bridge to cardiac transplant in
children: Berlin Heart versus extracorporeal membrane oxygenation.
Ann Thorac Surg 2009 Jun; 87: 1894e901. discussion 1901.
Janousek J, Gebauer RA, Abdul-Khaliq H, et al. Working Group for Cardiac
Dysrhythmias and Electrophysiology of the Association for European
Paediatric Cardiology. Cardiac resynchronisation therapy in paediatricand congenital heart disease: differential effects in various anatomical
and functional substrates. Heart 2009 Jul; 95: 1165e71.
Kantor PF, Mertens LL. Heart failure in children part I. Eur J Pediatr2010;
169: 269e79.
Kasama S, Toyama T, Kumakura H, et al. Effect of spironolactone on
cardiac sympathetic nerve activity and left ventricular remodeling in
patients with dilated cardiomyopathy. J Am Coll Cardiol 2003; 41:
574e81.
Law YM, Hoyer AW, Reller MD, Silberbach M. Accuracy of plasma B-type
natriuretic peptide to diagnose significant cardiovascular disease in
children. J Am Coll Cardiol 2009; 54: 1467e75.
Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric
cardiomyopathy in two regions of the United States. N Engl J Med2003; 348: 1647e55.
Massin MM, Astadicko I, Dessy H. Epidemiology of heart failure in
a tertiary pediatric center. Clin Cardiol 2008; 31: 388e91.
Morales DL, Almond CS, Jaquiss RD, et al. Bridging children of all sizes to
cardiac transplantation: the initial multicenter North American expe-
rience with the Berlin Heart EXCOR ventricular assist device. J Heart
Lung Transplant 2011 Jan; 30: 1e8.
Nugent AW, Daubeney PE, Chondros P, et al. The epidemiology of child-
hood cardiomyopathy in Australia. N Engl J Med2003; 348: 1639e46.
Price JF, Thomas AK, Grenier M, et al. B-type natriuretic peptide predicts
adverse cardiovascular events in pediatric outpatients with chronic left
ventricular systolic dysfunction. Circulation 2006; 114: 1063e9.
SYMPOSIUM: CARDIOVASCULAR
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Ratnasamy C, Kinnamon DD, Lipshultz SE, Rusconi P. Associations
between neurohormonal and inflammatory activation and heart failure
in children. Am Heart J 2008; 155: 527e33.
Rosenthal D, Chrisant MR, Edens E, et al. International Society for Heart
and Lung Transplantation: practice guidelines for management of
heart failure in children. J Heart Lung Transplant 2004; 23: 1313e33.
Schneeweiss A. Cardiovascular drugs in children. II. Angiotensin-
converting enzyme inhibitors in pediatric patients. Pediatr Cardiol1990; 11: 199e207.
Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and
adolescents with heart failure: a randomized controlled trial. JAMA
2007; 298: 1171e9.
Practice points
C Understanding the different mechanisms of heart failure and
their physiopathology and recognizing clinical symptoms
C In cases of congenital heart disease surgery often resolves the
symptoms
C Lack of evidence based in pharmacological treatmentC Worse prognosis of dilated cardiomyopathy and restrictive
cardiomyopathy
C Heart transplantation is not a cure
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Physiology and treatment ofhypertensionShenal Thalgahagoda
Mohan Shenoy
AbstractChildhood hypertension (HT) is an increasing problem brought about by
the epidemic of obesity. This is particularly true in adolescents, where
currently Primary HT (PHT) is more common than secondary HT (SHT).
The pathophysiology of PHT is complex and involves the interplay of
genetic, congenital and environmental factors. It is important that every
child with HT has a thorough evaluation so that any secondary cause of
HT is identified and managed appropriately. There is increasing role for
ABPM in the diagnosis and management of HT. Non-pharmacological
therapy should be commenced on all children with hypertension and
also those with high normal BP. The decision to initiate antihypertensive
therapy should not be based on BP readings alone but should consider
the presence or absence of end organ damage and other risk factors
such as obesity, kidney disease and family history. Long term studies
detailing the outcome of childhood HT and treatment are lacking. Since
adult studies have demonstrated that treatment of hypertension leads
to improved cardiovascular outcomes, it is imperative that HT is promptly
diagnosed and appropriate treatment is commenced to prevent progres-
sion of end organ damage.
Keywords ABPM; children; hypertension; obesity; pathophysiology
Introduction
Hypertension (HT) in children and adolescents is an increasing
problem, primarily due to the emergence of the epidemic of
obesity. The prevalence of HT in childhood varies with the study
population and methods used to assess blood pressure (BP) but
a recent large study reported a rate of 3.6%. The identification of
the metabolic syndrome, of which HT is a part, and its entailing
risks of morbidity and mortality has led to a growing awareness
about HT in childhood. Indeed, strong evidence exists that
childhood HT is associated with HT in later life. HT is a well-
known risk factor for coronary artery disease in adults and it is
now well recognized that exposure to cardiovascular risk factors
early in life may induce changes in arteries that contribute to the
development of atherosclerosis. This increased awareness has
led to the formulation of new consensus statements and
guidelines about childhood HT and to the increased availability
of information on the efficacy and safety of antihypertensive
medications in childhood. Furthermore, the development of large
databases on normative BP levels throughout childhood has
improved the ability to identify children with HT and contributed
to the awareness.
Definition
In adults the definition of HT is based on observational data
linking BP to cardiovascular events such as myocardial infarction
and stroke. No such data is available for children. The definition
of paediatric HT, therefore, is based on the normal distribution of
BP in healthy children. Accordingly, HT is defined as an average
systolic BP (SBP) and or diastolic BP (DBP) equal to or above the
95th centile for age, sex and height. (See Table 1) Elevated BP
must be repeated on three separate occasions before a patient is
classified as hypertensive.
The term white coat HT is used when a patient has a BP
above the 95th centile in a clinical setting but below the 90th
centile outside a clinical setting. Masked HT is essentially the
opposite of this where the BP is above the 95th centile outside
a clinical setting but is below the 90th centile when checked in
clinic. Ambulatory BP monitoring (ABPM) is obviously required
to diagnose both these conditions.
Aetiology
The marked increase in the prevalence of obesity in childhood
and adolescence has led to an increase in the prevalence of
primary (also known as essential) HT (PHT), where no cause is
identified. Thirty to fifty percent of children in some recent
studies have a diagnosis of PHT. Studies have shown that up to
30% of obese children are hypertensive. This is especially seen in
adolescents where PHT is the commonest cause of elevated BP.Secondary hypertension (SHT) is still the more common
aetiology in younger children and this is mainly due to reno-
vascular pathology. The severity of HT helps distinguish
between PHT and SHT because patients with the former usually
have only mild elevation in BP amounting to stage 1 HT whereas
the latter is associated with a much higher elevation of BP. Table 2
gives a guide to the common aetiologies depending on age.
Monogenic forms of HT which present during childhood (e.g.
Liddle syndrome, Gordon syndrome and apparent mineralocor-
ticoid excess) are extremely rare and not discussed in detail in
this review. These disorders present with hypertension and
stimulate sodium reabsorption along the nephron. They are
usually associated with hypokalaemia and often metabolicalkalosis along with a low plasma renin.
Pathophysiology
BP is the product of cardiac output and peripheral vascular
resistance. It follows that an elevation in either cardiac output or
peripheral vascular resistance, or both, will contribute to an
elevated BP. Cardiac output in turn is determined by stroke
volume and heart rate. Peripheral resistance is determined by
smooth muscle containing small arteries and arterioles. A brief
look into the mechanisms controlling BP is fundamental to the
understanding of the pathophysiology.
Shenal Thalgahagoda MBBS DCH MD is a Fellow in Paediatric Nephrology
in the Department of Paediatric Nephrology, Royal Manchester
Childrens Hospital, Manchester, UK.
Mohan Shenoy MBBS MRCPCH is Consultant Paediatric Nephrologist in
the Department of Paediatric Nephrology, Royal Manchester Childrens
Hospital, Manchester, UK.
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Autonomic nervous system
The vasomotor centre in the brain stem receives continuous infor-
mation from baroreceptors situated in the carotid sinus and aortic
arch. A fall in BP leads to stimulation of the sympathetic nervous
system and release of the adrenal medullary hormones adrenaline
and noradrenaline. This leads to increasedcardiac contractility, and
hence cardiac output, and also increased peripheral vascular resis-tance, thereby maintaining BP. A rise in BP causes increased vagal
tone, leading to bradycardia and vasodilatation.
Renin e angiotensin system (RAS)
Renin is a protease released by the juxtaglomerular apparatus of
the kidney. It cleaves angiotensinogen to angiotensin I. Angio-
tensin I is converted to angiotensin II by angiotensin-converting
enzyme (ACE). Though the main source of renin is the kidney,
the RAS is widespread in the body. Diminished renal perfusion
pressure and reduced sodium concentration in distal renal
tubular fluid lead to release of renin and stimulation of the RAS.
Additionally, renin release is also stimulated by b- and decreased
by a-adrenoceptor stimulation. High angiotensin II concentra-tions suppress renin secretion via a negative feedback loop.
Angiotensin II, a potent vasoconstrictor, acts on specific angio-
tensin receptors, AT1 and AT2, leading to smooth muscle
contraction. It also stimulates the release of aldosterone, pros-
tacyclin and catecholamines. Aldosterone causes sodium and
water retention by acting on the distal convoluted tubules and
the cortical collecting ducts in the kidneys.
Endothelial factors
Endothelin 1 released by the vascular endothelium is a potent
vasoconstrictor. Thromboxane A2 is an eicosanoid that is also
a vasoconstrictor. Vasodilatation is mediated by nitric oxide and
prostacyclin. Indeed, in hypertensive patients, vascular endo-
thelial cell dysfunction may lead to diminished nitric oxide
release and uninhibited endothelin mediated vasoconstriction.
Primary HT
The pathophysiology of PHT is complex and somewhat poorly
understood. It is thought to be the result of the interplay of
multiple genetic, congenital and environmental factors. Hyper-
tensive patients have increased activity of the sympathetic
nervous system with increased release, of and increased sensi-
tivity to, catecholamines. This is associated with an enhanced
response to stressful stimuli.
Endothelial dysfunction has also been observed in patients
with HT. Elevated uric acid levels have been implicated as one of
the causes of this. Endothelial dysfunction involves impaired
nitric oxide synthesis leading to unopposed vasoconstriction.
Renal vasoconstriction caused endothelial dysfunction and
sympathetic over-activation leads to activation of the RAS.
Indeed it has been shown that the RAS is also active in areas
apart from the kidney.
The incidence of PHT in adolescence is higher in those with
a low birth weight or born prematurely. The possible reason for
this could be a lower nephron mass.
The pathogenesis of HT in the obese is complex. Hyper-
insulinaemia and hyperleptinaemia are thought to be involved.
Hyperinsulinaemia results from peripheral resistance to insulin
and is postulated to cause HT through abnormal sodium
handling by the kidney, increased peripheral vascular resistance
and increased activity of the sympathetic nervous system.
Hyperleptinaemia is a consequence of the increased mass of
adipose tissue in the obese and causes increased activation of the
sympathetic nervous system.
It has been proposed that renal afferent arteriolar vasocon-
striction that occurs through many of the mechanisms outlined
above causes renal ischaemia, which in turn leads to mild
tubular injury and inflammatory infiltrates in the form of T
lymphocytes and macrophages. This leads to further activation of
the RAS and sodium and water retention through aldosterone.
The ensuing rise in BP increases perfusion and negates the
ischaemia allowing salt handling to return to normal, albeit at
a higher BP. This gives rise to the so called salt insensitive HT
with a parallel shift to higher BP.
With time and continued renal vasoconstriction, vascular
smooth muscle hypertrophy and remodelling takes place which
leads to arteriolar luminal narrowing and persistent ischaemia
and inflammation, not relieved by a rise in BP. This gives rise to
salt sensitive HT with exaggerated elevation of BP in response to
salt.
Renal parenchymal and reno-vascular HT
Activation of the renineangiotensinealdosterone axis is pivotal
in renal HT. Though a grossly elevated renin level is seen mainly
Classification of hypertension in children andadolescents
Class SBP and/or DBP percentile
Normal < 90th centile
Prehypertension 90th centile to < 95th centile
120/80 mmHg even if below 90th centile
Stage 1 95th centile to 99th centile 5mmHg
Stage 2 >99th centile 5 mmHg
Table 1
Aetiology of hypertension depending on age
Age Aetiology
Neonatal
periodto 1 year
Renal artery stenosis, coarctation of the aorta,
autosomal recessive polycystic kidney disease,renal parenchymal disease
1e5 years Renal parenchymal disease; renal vascular
disease; endocrine causes; coarctation of the
aorta; primary hypertension
5e10 years Renal parenchymal disease; primary hypertension;
renal vascular disease; endocrine causes;
coarctation of the aorta
10e20 years Primary hypertension; renal parenchymal disease;
renal vascular disease; endocrine causes;
coarctation of the aorta
Table 2
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in renal artery stenosis, the level of renin is inappropriately
elevated in most patients with chronic kidney disease (CKD)
when considering their level of HT. The source of hyper-
reninaemia in these patients may be diminished perfusion in
areas of scars, cysts and inflammation.
Salt and water retention and consequent volume overload is
predominant in CKD patients with a diminished urine output.
Volume overload is also seen in patients with glomerulonephritisand oliguric acute kidney injury.
Over activity of the sympathetic nervous system has also been
shown to contribute to HT in CKD. Afferent impulses from the
diseased kidney and accumulation of leptin in CKD have been
postulated as possible causes.
Endothelial dysfunction with diminished nitric oxide medi-
ated vasodilatation may occur in CKD. Chronic hyperparathy-
roidism seen in CKD leads to accumulation of calcium in vascular
smooth muscle cells, enhancing sensitivity to calcium and cate-
cholamines, contributing to HT.
HT is associated with endocrinopathies like hyperthyroidism,
hyperparathyroidism, Cushing syndrome, Conn syndrome and
phaeochromocytoma. Hyperthyroidism causes elevated SBPthrough tachycardia. In hyperparathyroidism intracellular
increased calcium leads to increased vascular tone. The adreno-
cortical disorders act through mineralocorticoid secretion and
sodium and water retention. Phaeochromocytomas are catechol-
amine secreting tumours that cause HT through increasing cardiac
output and vascular tone via adrenaline and noradrenaline.
Measurement of BP
In accordance with current recommendations, BP should be
routinely measured in all children three years and above at every
visit. In younger children, BP should be measured in patients
with a history of prematurity, low birth weight and who haverequired intensive care in the neonatal period, patients with
cardiac disease, established renal disease, patients with condi-
tions associated with HT, elevated intracranial pressure and
patients on medication known to cause HT. Furthermore, to
diagnose a patient as hypertensive three measurements on
separate occasions are required.
Both oscillometric and auscultatory techniques can be used
for measurement. However, any reading found to be high on
oscillometry should be confirmed by auscultation. During BP
measurement choosing the correct cuff size is of utmost impor-
tance. This should be one where the inflatable bladder width is at
least 40% of the upper arm circumference at a point midway
between the olecranon and the acromion. The cuff bladder lengthshould cover 80e100% of the circumference of the arm. An
undersized cuff overestimates BP and, theoretically, an oversized
cuff underestimates it. If an appropriate cuff size is not available
however, the next larger size should be used.
Any BP measurement found to be elevated should be repeated
twice at the same clinic visit for confirmation. All measurements
should be compared with the BP tables published by the Task
Force for Blood Pressure in Children which include the 50th, 90th
and 95th percentile of BP for age, sex and height.
If the patient is found to be prehypertensive, BP measurement
should be repeated in six months. In stage one hypertension, BP
needs to be reassessed in 1e2 weeks. If there is a persistent
elevation on two further occasions, the patient needs to be
evaluated and further management planned. Those found to
have stage 2 HT need to be evaluated for aetiology and target
organ damage within one week or immediately if symptomatic.
Clinical features (see Table 3)
The history and examination in a hypertensive patient should be
focused to identify possible aetiology and to look for complica-
tions of the disease. An important point to reiterate here is that
the higher the degree of HT and the younger the patient the more
likely it is due to a secondary cause. It is only moderate to severe
or sustained HT that gives rise to symptoms. As such most
patients with PHT remain asymptomatic and are picked up
during routine examination.
In the current history, features of HT like headache, visual
disturbances, vertigo and epistaxis should be sought. Dyspnoea
on exertion, facial palsy and seizures would indicate target organ
involvement. Haematuria, oliguria, polyuria, nocturia, oedema,
fatigue and growth failure are all suggestive of a renal aetiology.
A past history of recurrent urinary tract infections or urinary
tract anomalies would suggest renal scarring, obstructive urop-
athy or reflux nephropathy as the cause. A history of low birth
weight and prematurity would be important as would neonatal
intensive care admission and umbilical arterial catheterization.
The patient with PHT often has a family history of HT,
hyperlipidaemia, diabetes mellitus, cardiovascular disease or
stroke. Hereditary renal diseases like polycystic kidney disease
Examination findings in patients with hypertension
Examination finding Possible aetiology or relevance
Height, weight and BMI Primary hypertension, chronickidney disease
Pallor Chronic kidney disease
Malar rash Systemic lupus erythematosus
Cafe-au-lait spots Neurofibromatosis type 1,
tuberous sclerosis
Dysmorphic features Bardet-Biedl, Turner syndrome,
William syndrome
Moon face, truncal obesity Cushing syndrome
Obesity- generalized Cushing syndrome
Acanthosis nigricans Metabolic syndrome/primary
hypertension
Hirsutism, acne Metabolic syndrome/primary
hypertension, polycystic ovarysyndrome, Cushing syndrome,
Short stature Chronic kidney disease
Osteodystrophy Chronic kidney disease
Tachycardia Hyperthyroidism, phaeochromocytoma
Cardiomegaly Coarctation of aorta
Radio-femoral delay End organ damage
Murmur Coarctation of aorta
Abdominal mass ADPKD/ARPKD, neuroblastoma,
obstructive uropathy
Abdominal bruit Renal artery stenosis
Table 3
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and endocrine diseases like pheochromocytoma, glucocorticoid-
remediable aldosteronism, multiple endocrine neoplasia type 2
and von HippeleLindau syndrome could present with a positive
family history as would syndromes like neurofibromatosis.
A drug history should include both prescription medication
(corticosteroids, cyclosporine etc.) and over the counter medi-
cation (decongestants, oral contraceptives etc.). Illicit drug use
should also be probed.
Diagnosis and evaluation
Investigation of the hypertensive patient should be targeted to
define aetiology, identify co-morbid conditions and ascertain the
presence of target organ damage. (see Table 4) Screening tests
should be performed in all children. Additional tests would
depend on the findings on history and examination, and the
results of the screening investigations. Left ventricular hyper-
trophy is the most important evidence of target organ damage.
Fundoscopic evidence of retinal vascular changes, urinary
microalbuminuria and carotid intimal thickening are other indi-
cators of target organ damage.
ABPM
There has been an increasing role for ABPM in the diagnosis,
evaluation and management of HT in children over the last
decade. It helps to diagnose previously unrecognized conditions
such as white coat and masked HT. The European Society for
Hypertension recommends performing an ABPM to confirm the
diagnosis of HT prior to instituting therapy and also in patients
with type 1 diabetes, CKD and kidney transplant who are known
to demonstrate abnormal circadian variability of BP. In patients
with CKD and following kidney transplantation, a reduced
nocturnal dipping or even reversal of nocturnal dipping withhigher nighttime BP compared to daytime BP is known to occur
and therefore, ABPM is indispensable in these situations. It is
also recommended in the evaluation of refractory HT, assess-
ment of BP control in those with organ damage and also in
patients with symptoms of hypotension.
Management
The management of the hypertensive child includes both non-
pharmacological and pharmacological methods. These should
be coupled with patient and parent education in order to achieve
sustained control of BP. The goals of therapy should be a BP
below the 95th age, sex and height specific percentile and belowthe 90th percentile for those with co-morbid conditions. For
patients with CKD stricter control of blood pressure has been
shown to be beneficial by the ESCAPE (the Effect of Strict Blood
Pressure Control and ACE Inhibition on Progression of Chronic
Renal Failure in Pediatric Patients) trial. Therefore, a BP below
the 75th percentile in children without proteinuria, and below
the 50th percentile in patients with proteinuria is recommended.
Non-pharmacological therapy
This takes the form of lifestyle modification and includes weight
reduction in the obese, increase in physical activity, reduction in
sedentary time, dietary changes, cessation of smoking and
reduction in alcohol consumption. For patients with preHT anduncomplicated stage 1 HT initial therapy should be solely non-
pharmacological. It must be stressed that non-pharmacological
strategies should be continued even after pharmacological
therapy has been initiated.
For the obese patient the recommended goals of weight reduc-
tion are based on body mass index (BMI). Those with a BMI
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for moderate to vigorous physical aerobic activity for 30e60 min,
3e5 days per week, and to avoid more than 2 h per day of
sedentary activity. There is no reason to restrict competitive
sports in hypertensive patients except in those with uncontrolled
stage 2 HT. Highly strenuous static exercise such as weight lift-
ing, however, may be limited, considering the associated massive
elevation in both SBP and DBP, though definite evidence is
lacking to support this recommendation.Dietary modification in the obese should include limiting
calorie intake by reducing fat and excess sugar in the diet. Salt
reduction is also recommended, though the benefits of this may
not be as significant as for adults considering that many children
have salt insensitive BP.
Pharmacological therapy
The decision to treat HT should not be based on levels of BP
alone. Indications to initiate antihypertensive medication in
children and adolescents include symptomatic HT, presence of
end-organ damage, SHT, stage 1 HT unresponsive to lifestyle
modification, and stage 2 HT. Other indications would be the
presence of multiple cardiovascular risk factors like diabetesmellitus, dyslipidemia or smoking, which increase cardiovas-
cular risk in an exponential manner. It must be remembered
that, unlike in adults, trials on the safety and efficacy of anti-
hypertensive medication in children are extremely limited. Their
long term effects on growth and development are unknown.
Therefore initiation of pharmacotherapy should only be made
when definitely indicated. It should be reiterated here that life-
style modification should continue following initiation of
pharmacotherapy.
Once the decision to treat has been made, a further, perhaps
more difficult, challenge arises as to which drug to choose as
first-line medication. There are very few randomized controlled
trials in children comparing different classes of antihypertensivemedication. Therefore, the choice of medication is left at the
discretion of the prescriber. Acceptable drug classes for use as
first-line medication in children include angiotensin-converting
enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB),
beta blockers, calcium channel blockers, and diuretics. Table 5
gives details on commonly used agents.
Antihypertensive medication should be prescribed such that
the child is initially started on the lowest recommended dose. If
BP does not decrease sufficiently after 4e8 weeks, the dose is
gradually increased until the desired BP goal is achieved. Once
the highest recommended dose is reached or if the child
experiences side effects before the BP is controlled, a second
drug from a different class should be added. The same prin-ciple is followed with the second drug prior to the addition of
a third.
Certain circumstances do exist however, where preference or
avoidance of a certain class of drug is indicated. In patients with
acute glomerulonephritis and volume overload a diuretic would
be the logical first choice, followed by vasodilatation with
a calcium channel blocker. ACE inhibitors and ARBs are the first
line in proteinuric CKD and diabetes mellitus due to their anti-
proteinuric effects. In non-proteinuric CKD as well, ACE inhibi-
tors and ARBs may be more beneficial as they have been shown
to prolong renal survival possibly through a combination of
lowering intra-glomerular pressure through selective dilatation of
the glomerular efferent arteriole, and anti-inflammatory and anti-
fibrotic effects. Combined alpha and beta blockade with phe-
noxybenzamine is required in phaeochromocytoma. ACE inhib-
itors remain first choice therapy in reno-vascular HT though they
are contraindicated in bilateral renal artery stenosis.
Non cardio-selective beta blockers are contraindicated in
asthma and heart failure. Beta blockers should be avoided in
insulin dependent diabetics. ACEi are generally avoided in the
first 3e6 months following kidney transplantation.
Resistant HT
This is defined as HT in which lifestyle modification measures
and prescription of at least three drugs, including a diuretic, in
adequate doses has failed to lower SBP and DBP to goal. This
almost invariably indicates SHT. Points to consider here are the
possibility of noncompliance, both to medication and diet,
continued intake of BP increasing substances and progressive
renal impairment with volume overload. The addition of vaso-
dilators like minoxidil should be considered at this juncture. For
the severely oliguric or anuric patient in end stage renal failure
on dialysis, a bilateral nephrectomy may be the only option to
control BP.
Commonly used antihypertensive agents
Drug Dose Frequency
ACE inhibitors
Captopril 0.1e0.3 mg/kg/dose
initially, max.6 mg/kg/day
2e3 times daily
Enalapril 0.1mg/kg/dose initially,
max 1mg/kg/day
1e
2 times daily
ARBs
Losartan 0.7e1.4 mg/kg/dose Once daily
Beta blockers
Propranalol 0.25e1mg/kg/dose,
max 5mg/kg daily
Once daily
Atenolol 0.5e2 mg/kg per day,
max 100mg daily
Calcium channel blockers
Nifedipine 0.2e0.3 mg/kg/dose,
max 3mg/kg/day
3e4 times daily
Amlodipine 0.1e0.2mg/kg/day
initially, max 10mg daily
Once daily
Diuretics
Frusemide 0.5e2.0 mg/kg/dose 2e4 times daily
Spironolactone 1 mg/kg/day 1e2 times daily
Alfa blockers
Prazosin 0.01e0.1 mg/kg/day 3 times dai ly
Doxazosin 0.5e4 mg/day,
max 16mg daily
Once daily
Vasodilators
Minoxidil 0.2 mg/kg/day,
max 1mg/kg/day
1e2 time daily
Hydralazine 0.1e0.5 mg/kg/day,
max 3mg/kg daily
4e6 times daily
Table 5
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Hypertensive emergencies
A hypertensive emergency is defined as severe HT complicated
by acute target organ dysfunction, namely hypertensive
encephalopathy and congestive cardiac failure. Severe HT
without target organ dysfunction is defined as hypertensive
urgency. Hypertensive emergencies should be treated in an
intensive care setting. The goal of management is the immediate
reduction in BP to reduce target organ damage, but not toorapidly so as to cause hypoperfusion of vital organs. The
recommendation is that 30% of the desired reduction in BP be
made in the first 8 h followed by a gradual reduction to normalcy
in the next 24e48 h. Intravenous labetalol is the recommended
drug of first choice. It is however contraindicated in asthma and
congestive cardiac failure. Intravenous sodium nitroprusside and
hydralazine are alternatives.
Prognosis: uncontrolled HT leads to significant alteration in the
end organ structure and function in children. Long term studies
detailing the outcome of childhood HT and treatment are lacking.
Since adult studies have demonstrated that treatment of hyper-
tension leads to improved cardiovascular outcomes, it is imper-ative that HT in children is promptly diagnosed and appropriate
treatment is commenced to prevent progression of end organ
damage. Apart from those individuals where life style changes
leads to normalization of BP and also those with HT due to
treatable conditions such phaeochromocytoma, treatment of HT
is likely to be lifelong. A
FURTHER READING
1 National High Blood Pressure Education Program Working Group on
High Blood Pressure in Children and Adolescents. The fourth report on
the diagnosis, evaluation, and treatment of high blood pressure in
children and adolescents. Pediatrics. 2004; 114: 555e76.
2 Wingen AM, Fabian-Bach C, Schaefer F, Mehls O. Randomised multi-
centre study of a low-protein diet on the progression of chronic renal
failure in children. Lancet 1997; 349: 1117e23.
3 Furth SL, Cole SR, Moxey-Mims M, et al. Design and methods of the
chronic kidney disease in children (CKiD) prospective cohort study.
Clin J Am Soc Nephrol 2006; 1: 1006e15.
4 Falkner B. Hypertension in children and adolescents: epidemiology
and natural history. Pediatr Nephrol 2010 July; 25: 1219e24.
5 Johnson RJ, Feig DI, Nakagawa T, Sanchez-Lozada LG, Rodriguez-
Iturbe B. Pathogenesis of essential hypertension: historical paradigms
and modern insights. J.Hypertens 2008 March; 28: 381e
91.6 Wuhl E, Mehls O, Schaefer F, ESCAPE Trial Group. Antihypertensive and
antiproteinuric efficacy of ramipril in children with chronic renal failure.
Kidney Int 2004; 66: 768e76.
7 ESCAPE Trial Group. Strict blood pressure control and progression of
renal failure in children. N Engl J Med 2009; 361: 1639e50.
8 Lurbe E, Cifkova R, Cruickshank JK, et al. Management of high blood
pressure in children and adolescents: recommendations of the Euro-
pean Society of Hypertension. J Hypertens 2009; 27: 1719e42.
9 Feig DI, Johnson RJ. Hyperuricaemia in childhood primary hyperten-
sion. Hypertension 2003 September; 42: 247e52.
10 Lurbe E, Redon J. The role of ambulatory blood pressure monitoring
in diagnosis of hypertension and evaluation of target organ damage.
In: Flynn JT, Ingelfinger JR, Portman RJ, eds. Pediatric hypertension.Humana Press, 2011; 517e528.
Practice points
C Hypertension is an increasing health problem in childhood,
particularly adolescence due to the epidemic of obesity
C Aims of the investigations are to define aetiology and to
assess the presence and severity of end organ damage
C There is an increasing role for ambulatory blood pressure
monitoring in the diagnosis and management of hypertension
C Non-pharmacological intervention in the form of life style
changes such as weight reduction and increasing physical
activity should be the initial therapy in all children with pre and
stage 1 hypertension
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Dilated cardiomyopathy inchildrenThomas G Day
Matthew Fenton
AbstractDilated cardiomyopathy (DCM) is the most common paediatric heart
muscle disease, and the most common indication for cardiac transplanta-
tion in this age group. In terms of aetiology, DCM is a heterogeneous
condition, with infectious, inflammatory, metabolic and genetic causes,
although the precise pathogenesis remains unknown in most patients.
Because some of the causes of DCM are potentially reversible, an exten-
sive panel of investigations should be performed at first presentation,
which we describe here. Treatment usually begins with pharmacological
therapy, including beta-blockers, ACE inhibitors, digoxin, and diuretics.
Cardiac transplantation and the recently introduced mechanical ventricular
assist devices are alternatives when medical management is not effective.
Keywords cardiomyopathy; heart failure; myocarditis; paediatrics;transplantation
Introduction
Dilated cardiomyopathy (DCM) is the most common form of
heart muscle disease in children. Rather than a single disease
entity, DCM can be viewed as a heterogeneous mix of conditions,
all of which share a common phenotype of left ventricular dila-
tation and systolic dysfunction, with or without right ventricular
involvement. DCM results in a substantial degree of morbidity
and mortality, and it is the commonest reason for paediatric
cardiac transplantation outside of infancy.
DCM is an uncommon condition, with an estimated annual
incidence rate of between 0.34 and 0.73 per 100,000 children. It
appears to be more common in boys than girls, probably due to
a subset of DCM caused by X-linked conditions such as the
muscular dystrophies. DCM is also more common in non-white
populations, and in younger age-groups (especially the under-
1s) although it can occur at any age including adolescence.
The most common presentation of DCM is with signs and
symptoms of overt cardiac failure. In infants, this will usually
manifest as feeding difficulties, whereas older children will
usually report a reduction in exercise tolerance, dyspnoea, or
oedema. As discussed below, the outcome can be poor but is
improving with increasing expertise in cardiac transplantation,
and exciting new developments such as ventricular assist devices.
Aetiology and investigations
Although the aetiology of the majority of DCM cases remains
unknown even after extensive investigation, it is important to
thoroughly exclude potentially reversible causes of the DCM
phenotype. Studies estimate that a definitive cause can be found
in around 30e40% of DCM cases. Table 1 outlines most of the
possible underlying aetiologies, with the remainder being clas-
sified as idiopathic DCM. This is a diagnosis of exclusion, and at
first presentation an extensive of panel of investigations should
be performed, with the aim of identifying the conditions outlined
below. The panel of investigations performed at our institution is
shown in Table 2.
Myocarditis
In patients with DCM of known cause, the most common
underlying pathogenesis is infectious myocarditis. In the devel-
oped world, viruses are the most common causative agents ofmyocarditis, particularly adenoviruses and enteroviruses such as
coxsackieviruses, parvovirus, and echovirus. Worldwide, the
most common pathogen is Chagas disease (Trypanosoma cruzi),
although bacterial and fungal forms have also been reported. The
pathogenic mechanism of viral myocarditis remains open to
debate, but possible theories include cardiac myocyte destruction
by circulating autoantibodies triggered by viral infection, or the
destruction of infected cardiac myocytes by circulating cytotoxic
lymphocytes, as well as direct viral-induced cell damage.
Myocarditis often presents a diagnostic dilemma to clinicians
as it is difficult to confirm with confidence. Some centres perform
endomyocardial biopsy looking for lymphocytic infiltration of the
myocardium and myocytolysis (the Dallas criteria for myocar-ditis). This approach has several limitations however: it exposes
the patient to the risks of a general anaesthesia often in the
context of cardiac failure, and is an invasive procedure involving
tissue collection from a ventricular wall that is likely to be thin.
In addition, at a histological level the inflammatory process is
often patchy, and so a seemingly normal area of tissue may be
unwittingly sampled. The current practice in UK cardiac centres
is to avoid biopsy for this indication, as it is felt the risk/benefit
ratio does not support it.
Our investigation panel includes non-specific inflammatory
markers, virology PCR and serology (Table 2). These, coupled
with the presence or absence of recent infectious symptoms will
aid the clinician in deciding whether an infectious aetiology islikely for an individual patient. This may have important impli-
cations for both treatment and prognosis, as outlined below.
Left ventricular non-compaction cardiomyopathy (LVNC)
LVNC has been defined by the American Heart Association as
a congenital cardiomyopathy characterized by a spongy appear-
ance to the left ventricle. The appearance is most notable
towards the lateral wall and apex of the left ventricle and is
believed to be related to in utero arrest of normal myocardial
compaction. LVNC commonly occurs in conjunction with other
cardiac structural disorders, mainly atrial and ventricular septal
defects. Multiple genetic mutations have been reported and
Thomas G Day MBChB MRes MRCPCH is Academic Clinical Fellow in the
Department of Cardiology, Great Ormond Street Hospital, London, UK.
Conflicts of interest: none declared.
Matthew Fenton MB BS BSc MRCPCH is Consultant Cardiologist in the
Department of Cardiology, Great Ormond Street Hospital, London, UK.
Conflicts of interest: none declared.
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crossover between genes causing dilated, hypertrophic and
restrictive cardiomyopathy is common. As a relatively newly
defined condition outcomes are being evaluated. In a recent
review from Zuckerman and colleagues of 50 patients from their
institution, 26 patients had either died or been transplanted
within a year from presentation. Patients who survive beyond
a year have significantly better outcome. Within our institution
a number of patients with LVNC have diastolic dysfunction and
the subsequent risk of developing raised pulmonary vascular
resistance, a pathophysiological process similar to restrictive
cardiomyopathy. This process requires careful monitoring as
a significant increase in pulmonary vascular resistance in the
absence of symptoms may make cardiac transplantation more
risky or even impossible.
Genetic and familial causes
There are over 40 genes that have been identified as having
a causative role in DCM. Around 30e40% of DCM cases are
considered familial, defined as at least one first-degree relative
having DCM or sudden cardiac death at a young age. The most
common inheritance mode is autosomal dominant, often with
incomplete penetrance, but X-linked, autosomal recessive, and
mitochondrial forms of DCM have all been described. The
identification of familial cases of DCM is important, as it allowsclose follow-up of potentially affected siblings and other family
members. It has been shown that seemingly unaffected relatives
can show echocardiographic changes before becoming symp-
tomatic, and also that circulating cardiac autoantibodies can
predict the development of disease in this population. Hence
therapeutic intervention before the development of clinically
apparent heart failure may often be possible.
Clearly if the causal mutation can be identified, the risk
assessment of family members will become far easier. Despite
the number of identified genetic defects increasing over the
years, routine genetic testing is not currently performed in the
paediatric clinic in index cases. Family screening with
Secondary causes of dilated cardiomyopathy
Infections
Viral
Bacterial
Fungal
Protozoan (Chagas,
toxoplasmosis)
Rickettsial (Rocky
Mountain spotted fever)
Spirochetal (Lyme disease)
Arrhythmias
Supraventricular tachycardia
(atrial flutter, ectopic atrial
tachycardia)
Ventricular tachycardia
Bradycardia
Endocrine
Hyper/hypothyroidism
Infant of a diabetic mother
Catecholamine excess
(phaeochromocytoma or
neuroblastoma)
Congenital adrenal hyperplasia
Storage disease
Glycogen storage diseases
Mucopolysaccaridoses
Sphingolipidoses
Nutritional deficiencies
Protein (kwashiorkor)
Thiamine (beriberi)
Vitamin E
Vitamin D
Selenium
Carnitine
Phosphate
Ischaemia
Hypoxia
Birth asphyxia
Drowning
Kawasaki disease
Coronary artery
malformation (ALCAPA)
Premature coronary
artery disease
Toxins
Anthracyclines
Radiation
Other chemotherapeutic
agents
Sulfonamide sensitivity
Penicillin sensitivity
Iron (haemochromatosis)
Copper (Wilsons disease)
Systemic disorders
Systemic lupus
erythematosus
Juvenile idiopathic
arthritis
Polyarteritis nodosa
Osteogenesis imperfect
Noonan syndrome
Peripartum
cardiomyopathy
Haemolytic uraemia
syndrome
Leukaemia
Amyloidosis
Sarcoidosis
Reye syndrome
From Dadlani GH, Harmon WG, Lipshultz SE. Dilated cardiomyopathy. In:
Chang AC, Towbin JA, eds. Heart failure in children and young adults. Phila-
delphia: Saunders Elsevier; 2006: 248e263.
Table 1
Investigation panel at first presentation of DCM
Echocardiogram
Electrocardiogram,
including 24-hour tape
Chest radiograph
Urine
Organic acids
Glycosaminoglycans
Bloods
Full blood count
Erythrocyte sedimentation rate
Vacuolated lymphocytes
Urea and electrolytes
Liver function tests
C-reactive protein
Brain natriuretic peptide
Blood group and save
Lactate
Ammonia
Cholesterol and triglycerides
Thyroid function tests
Thiamine
Selenium
Red blood cell transketolase
Carnitine
Acyl carnitine profile
Red cell folate
Transferrin
Mitochondrial DNA
Plasma amino acids
Antinuclear and anti-DNA antibodies
Viral PCR, IgM and IgI for enterovirus,
EpsteineBarr virus, adenovirus,
cytomegalovirus, parvovirus,
coxsackievirus, echovirus
Ionized calcium
Parathyroid hormone
Vitamin D
Table 2
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echocardiography and ECG are recommended when a new case
is identified within a family group. Several research projects are
ongoing attempting to characterize and identify defects but
clinically the information is useful from a screening perspective
and not important with respect to the management of patients.
The identification of an abnormal genotype in a patient with
a normal cardiac phenotype may have wide ranging implications
without necessarily being of any benefit to the individual.Genetic testing in families with an abnormal gene identified and
strongly linked to a cardiomyopathic disease may be useful in
identifying which patients need to continue with regular
screening. Guidelines suggest that first-degree relatives of
patients with idiopathic DCM are screened on a 2 yearly basis,
however if a gene is identified and not present it is reasonable not
to continue to follow that patient in the clinic.
Dilated cardiomyopathy with skeletal myopathy
X-linked disorders involving dystrophin gene mutations warrant
specific mention in the context of dilated cardiomyopathy,
Duchenne and Becker muscular dystrophies being the most
familiar. These disorders of both cardiac and skeletal musclepresent with progressive muscle weakness from early childhood
and have devastating effects on both quality and duration of life,
particularly in Duchenne where boys become non-ambulatory in
early adolescence and by the start of their third decade nearly all
the boys affected will have changes suggestive of dilated
cardiomyopathy. The histopathology suggests fibro-fatty changes
in the base and lateral aspects of the left ventricle which prog-
resses to involve the remainder of the myocardium. This leads to
significant ventricular dysfunction and eventually cardiac failure.
Cardiac deterioration is becoming an increasing problem for
patients and the clinicians caring for them. Patients are regularly
receiving pulsed steroids to ameliorate the abnormalities of
skeletal and respiratory muscle progression with good effect,meaning that as individuals survive longer morbidity form
cardiac deterioration later in life becomes more significant. From
a management perspective drugs for cardiac dysfunction, mainly
angiotensin-converting enzyme (ACE) inhibitors, have been used
to improve cardiac function once echocardiographic appearances
develop. The benefit of using prophylactic ACE inhibitors has
been controversial but using an ACE inhibitor to reduce left
ventricular wall stress when the safety profile of the drug is good
and the effects of the disease process so devastating does not
seem unreasonable. A multi-centre international trial, including
our own, is currently in the process of randomizing patients prior
to the onset of echocardiographic features of cardiomyopathy to
assess its benefit.Becker muscular dystrophy is a less severe form both from
a skeletal and cardiac perspective and in some cases skeletal
muscle function can be preserved enough to consider cardiac
transplantation if cardiac function should deteriorate. Cardiac
transplantation for boys with Duchenne muscular dystrophy is
not usually considered because of the co-morbidities involved.
X-linked cardiomyopathy is a lesser known dystrophin gene
mutation disorder with poor outcome. The dystrophin gene
mutation is isolated to the cardiac muscle and boys develop
progressive cardiac dysfunction and arrhythmia in adolescence
and young adulthood with death from cardiac failure unless
cardiac transplantation can be performed.
A number of other gene mutations can lead to a phenotype of
skeletal muscle weakness, cardiomyopathy and commonly
arrhythmia. Lamin A/C gene mutations lead to limb-girdle
muscular dystrophies and some EmeryeDreifuss muscular
dystrophies (as well as an emerin gene mutation) both involving
significant cardiomyopathy.
Metabolic causesInborn errors of metabolism (IEM) can lead to DCM, and this is
the underlying cause in around 4e16% of cases. These patients
present at an earlier age on average than idiopathic cases, often
in infancy. Among DCM cases caused by an IEM, oxidative
phosphorylation defects and systemic carnitine deficiency are the
most common underlying problems, accounting for 40% of
metabolic cases. An oxidative phosphorylation disease that often
features DCM is Barth syndrome, an X-linked disorder of lipid
metabolism. The mutation causing Barth syndrome results in an
abnormal form of cardiolipin, a lipid essential for normal mito-
chondrial metabolism. The syndrome can be identified by raised
levels 3-methylglutaconic acid in the urine, hence the urine
organic acid screen included in our investigation panel.Other metabolic syndromes that can result in DCM include
mucopolysaccharidosis type I (Hurler syndrome) and type VI
(MaroteauxeLamy syndrome), glycogen storage disorder type IV
(Anderson disease), long-chain 3-hydroxyacyl-CoA dehydroge-
nase deficiency, and mitochondrial disorders other than Barth
such as MERFF (myoclonic epilepsy with red-ragged fibres). Our
investigation panel is aimed at identifying as many of these
underlying defects as possible.
It is important to recognize when a DCM case has an under-
lying metabolic cause and whilst only a small number of child-
ren present with this type of cardiomyopathy treatment may
be possible, dramatically improving cardiac function. Barth
syndrome is a good example of the importance of early identifi-cation of IEM in cases of DCM, as the disease responds well to
medical management, and heart function often improves after
puberty. Many children with a metabolic aetiology to their
cardiomyopathy will present to the intensive care with a life
threatening condition usually as infants. They will have features
suggestive of poor energy metabolism, including failure to thrive
and severe acidosis sometimes out of context with the severity of
cardiac dysfunction. An important rare reversible cause of
cardiomyopathy in these patients may be identified by initial
cardiomyopathy screening investigations. Of particular impor-
tance are disorders leading to a primary carnitine deficiency.
Defects in the OCTN2 carnitine transporter gene leads to failure
of fatty acid transport across cellular membranes, resulting ina lack of substrate for cellular energy and accumulation of fat,
physically affecting the function of myocytes. This clearly has
important implications for decisions such as cardiac transplant.
Other causes and investigations
Vitamin D deficiency, as well other causes of hypocalcaemia
such as primary hypoparathyroidism, is a rare but important
cause of DCM. With the resurgence of clinically apparent rickets
in recent years, this cause is increasing in incidence, and is
particularly amenable to medical treatment. Indeed, vitamin D
supplementation in some patients has been shown to normalize
ventricular function, hence the early identification of deficiency
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is vital. Deficiencies in other micronutrients such as selenium
and thiamine can also result in a reduction in cardiac function,
therefore these are also included on our investigation panel.
Anaemia, whether caused by dietary insufficiency or inherited
haemoglobinopathies, can result in a high cardiac-output state.
In some circumstances this increase in myocardial workload can
result in DCM, and so simple tests such as a full blood count
should not be omitted.An electrocardiogram (ECG) should be performed on all patients
presenting with DCM. Resting ECG usually shows a sinus tachy-
cardia with possible signs of atrial enlargement and ventricular
hypertrophy. A 24-hour ECG recording should also be performed,
as arrhythmias may be a cause, as well as a consequence, of DCM.
Sustained disturbances of rhythm may result in alterations of flow
dynamics through the heart, resulting in ventricular dysfunction
and ultimately DCM. The alteration in cardiac morphology caused
by DCM can also result in secondary arrhythmias that may further
lower cardiac output. In either case, prompt identification may lead
to anti-arrhythmic therapy that may improve ventricular function.
A further use of ECG in DCM is in the identification of anomalous
origin of the left coronary artery from the pulmonary artery(ALCAPA), a rare condition that can often go unrecognized, even
until adulthood. In this condition, the myocardium perfused by the
left coronary artery becomes increasingly ischaemic with resulting
wall motion abnormalities and eventually global hypokinesia. An
ECG may show deep Q waves in lead I and wide Q waves in lead
AVL, so helping the diagnosis.
ALCAPA can also be diagnosed on echocardiography, an
investigation that is perhaps the most important in DCM patients.
Echocardiography forms the basis of the DCM diagnosis by
defining and quantifying the extent of left ventricular dilatation
and dysfunction. In addition, echocardiography allows the
exclusion of structural abnormalities that can lead to DCM and
are potentially correctable, such as ALCAPA, valve disease, andother congenital anomalies.
An array of other medical conditions can also lead to DCM.
Thyroid function tests should be performed as both hyper- and
hypothyroidism can lead to severe myocardial dysfunction.
Systemic autoimmune disease including rheumatoid arthritis and
systemic lupus erythematosus (SLE) can be associated with
cardiomyopathy, and we screen for these with serum autoanti-
bodies. Although unlikely in the paediatric setting, excess alcohol
and use of cocaine can both result in cardiomyopathy. There are
also iatrogenic causes of DCM, especially anthracycline-based
chemotherapy, and serial echocardiograms should be per-
formed on all children at risk.
Management
Medical therapy
Compared to the adult literature, studies on children with heart
failure of any cause are limited in both number and size, and
there are relatively little data on the effect of most medical
therapies on long-term outcomes such as mortality. Because o