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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.

SYMPOSIUM: CARDIOVASCULAR

PAEDIATRICS AND CHILD HEALTH 23:2 47 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.paed.2012.08.005http://dx.doi.org/10.1016/j.paed.2012.08.005


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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.




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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




10/48

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




11/48

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


12/48

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




14/48

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

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