Myocardial Disorders in the NeonateManish Bansal, MD*

*Division of Pediatric Cardiology, University of Iowa Stead Family Children’s Hospital, Iowa City, IA

Education Gaps

1. Several physiologic changes take place in the myocardium after birth.

2. Knowledge about common primary myocardial disorders that present in

the neonatal period has been limited.

Abstract

Myocardial disorders in the neonate could be a significant cause of

morbidity and mortality. The neonatal myocardium is immature and

undergoes several changes after birth. These include changes in the size

of the myocardium, cellular transport of calcium, and utilization for fatty

acid and glucose metabolism. Neonatal myocardium relies heavily on

the heart rate to improve cardiac output. Myocardial disorders in the

neonate can be classified as primary and secondary. Primary myocardial

disorders have an inherent abnormality in the cardiac muscle and can be

further subclassified based on the morphology and presentation. These

include hypertrophic cardiomyopathy, dilated cardiomyopathy, and

restrictive cardiomyopathy. Secondary myocardial disorders are usually

caused by a systemic disorder that affects the cardiac muscle and

function. These include inborn errors of metabolism, neuromuscular

disorders, and mitochondrial disorders. The diagnosis and management

of cardiomyopathy is very specific to the type of cardiomyopathy or

underlying disorders. A team approach, including neonatology, genetics

and metabolism, and cardiology and cardiac transplantation, is essential

in managing these cases.

Objectives After completing this article, readers should be able to:

1. Describe myocardial physiology and adaptation in the neonatal period.

2. List the common primary myocardial disorders.

3. Recognize myocardial disorders secondary to other diseases.

AUTHOR DISCLOSURE Dr Bansal hasdisclosed no financial relationships relevant tothis article. This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.

ABBREVIATIONS

ARVC arrhythmogenic right ventricular

cardiomyopathy

DCM dilated cardiomyopathy

ECG electrocardiography

HCM hypertrophic cardiomyopathy

IEM inborn error of metabolism

LVOT left ventricular outflow tract

MRI magnetic resonance imaging

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INTRODUCTION

The neonatal myocardium differs from the adult myocar-

dium structurally as well as functionally. An understanding

of the newborn myocardium and its disorders is crucial in

the management of newborns. This review provides a

summary of the structural and functional differences in

the newborn myocardium and describes common myocar-

dial disorders encountered in the neonatal period.

POSTNATAL CHANGES

The newborn myocardium is disorganized in structure and

has a lower amount of contractile proteins than the adult

mature myocardium. The neonatal myocardium also has

decreased cellular transport. Both effects lead to a relatively

impaired myocardial function in the neonate. (1) However,

the role of the myocardium is similar in the neonate as in

the adult: to increase heart rate and/or inotropy to improve

cardiac output.

At birth, neonatal myocardial tissue responds to changes

in the circulation quite rapidly. Both left ventricular mass

and volume increase due to changes in the left and right

ventricular workloads. (2) As the pulmonary vascular resis-

tance drops, the right ventricular workload decreases and

the left ventricle becomes the dominant ventricle after birth.

(3) The number of myocytes increases initially in the first

few of weeks after birth, and is then followed by the increase

in cardiac mass, mostly as a result of hypertrophy of the

myocytes. (4)

After birth, the neonatal myocyte changes from a rela-

tively short and round shape into a longer and more slender

shape as it matures. (1) The amount of mitochondria in the

neonatal myocyte is localized centrally. With maturity, the

amount of mitochondria increases and thus, the mature

myocardium is able to use long-chain fatty acids rather than

carbohydrates as its energy source. (5) In contrast, immature

myocardium ismore dependent on extracellular calcium for

myocardial contraction. Because the neonate has a lower

amount of calcium channels compared with later in life, the

neonatal myocardium has less functional reserve. (6) The

fetal and neonatal myocardium also has a limited ability to

respond to an increased afterload, and ventricular compli-

ance is relatively decreased compared with the adult. Thus,

a newborn heart is stiffer and requires relatively small

volumes to achieve a desired filling pressure.

Myocardial disorders account for only approximately 1%

of childhood cardiac disease (7) and can be classified into 2

major groups based on the organ involvement. (8) Primary

cardiomyopathy solely affects the heart muscle and is

relatively infrequent. Secondary cardiomyopathies have

myocardial involvement as a part of a generalized systemic

disorder.

PRIMARY CARDIOMYOPATHY

The clinical disease process of primary cardiomyopathies

predominantly involves the myocardium. Primary cardio-

myopathy can be further divided into 3 groups: genetic,

mixed, and acquired (Table). Not all of these disorders

manifest in the neonatal period but most of them are

diagnosed in the neonatal period because of a family history

of a similar disorder. The types seen in the neonatal period

are usually the most severe.

TABLE. Causes of Primary Cardiomyopathy

1. Genetic

a. Hypertrophic cardiomyopathy

b. Arrhythmogenic right ventricular cardiomyopathy

c. Left ventricular noncompaction cardiomyopathy

d. Glycogen storage disorders

i. PRKAG2

ii. Danon cardiomyopathy

e. Conduction defects

f. Mitochondrial myopathies

g. Ion channel disorders

i. Long QT syndrome

ii. Brugada syndrome

iii. Short QT syndrome

iv. Catecholaminergic polymorphic ventricular tachycardia

v. Asian sudden unexplained nocturnal death syndrome

2. Mixed

a. Dilated cardiomyopathy

b. Restrictive cardiomyopathy

3. Acquired

a. Inflammatory (myocarditis)

b. Stress-provoked (“tako-tsubo”)

c. Peripartum

d. Tachycardia-induced

e. Infant of insulin-dependent diabetic mother

f. Ischemia/hypoxia

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GeneticHypertrophic Cardiomyopathy. Idiopathic hypertrophic car-

diomyopathy (HCM) is caused by mutations of the cardiac

contractile proteins, most commonly b-myosin heavy chain

and myosin-binding protein C. (8) In patients with HCM,

the cardiac mass and wall thickness are increased and

generally affect the left ventricle. A murmur is usually

the presenting feature. (9) Affected infants can have various

clinical findings, including marked congestive heart failure

and cardiomegaly on chest radiography. Electrocardiogra-

phy (ECG) shows left ventricular hypertrophy with ST-T

changes (Fig 1). Echocardiography (Fig 2) usually confirms

the diagnosis in the absence of other reasons for ventricular

hypertrophy such as maternal diabetes, steroid exposure, or

neonatal hypertension. Cardiac magnetic resonance imaging

(MRI) can demonstrate myocardial fibrosis and scarring.

The goal of management for patients with HCM is

symptomatic relief and prolonging survival. b-Blockers

are the most commonly used agents for the purpose of

decreasing gradients in acute settings. (10)(11) These agents

help to reduce left ventricular outflow gradients by decreasing

contractility, wall tension, and myocardial oxygen demand.

At the author’s institution, propranolol 2 mg/kg per day is

used in 3 divided doses. The dose can be titrated based

on symptoms, heart rate, blood pressure, and response. In

neonates with left ventricular outflow tract (LVOT) obstruc-

tion, caution is required when using vasodilators or positive

ionotropic agents because of the risk of increasing the LVOT

gradient. Diuretics are generally counterproductive as they

decrease the patient’s overall volume, and thus decrease the

ventricular cavity.

In general, the prognosis of neonatal HCM is poor,

especially if the neonate has congestive heart failure. (9)

Patients with inborn errors of metabolism (IEM) and mal-

formation syndrome usually have a poorer prognosis than

those with idiopathic infantile HCM, with mean 5-year

survival rates of 41%, 74%, and 82%, respectively. (12)

HCM secondary to disorders such as hypertension, steroid

use, and maternal diabetes have a very good prognosis, with

a reversal of the cardiomyopathy with conservative manage-

ment or treatment of the underlying disorder.

Arrhythmogenic Right Ventricular Cardiomyopathy.

This type usually involves the right ventricle with loss of

myocytes and fatty or fibroblast tissue replacement. Arrhyth-

mogenic right ventricular cardiomyopathy (ARVC) has a

broad clinical spectrum, but most patients present with

ventricular tachyarrhythmias. It rarely presents during

infancy. ARVC typically has an autosomal dominant pattern

of inheritance and the diagnosis is usually based on family

history, characteristic findings on ECG, and cardiac MRI.

Left Ventricle Noncompaction Cardiomyopathy. This

type is characterized by a spongy appearance of the left

ventricular myocardium on echocardiography (Fig 3). Non-

compaction usually involves the apical portion of the left

ventricle with deep intratrabecular recesses (Fig 3) commu-

nicating with the ventricular cavity; this results from an

Figure 1. Electrocardiogram showing left ventricular hypertrophy in a patient with hypertrophic cardiomyopathy.

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arrest in normal cardiac embryogenesis. (13) Left ventricle

noncompaction cardiomyopathy may be an isolated abnor-

mality or associated with other congenital heart diseases

such as LVOT abnormalities, Ebstein anomaly, and tetral-

ogy of Fallot. (14) The diagnosis is usually made with

2-dimensional echocardiography or cardiac MRI. Presenta-

tion in the neonatal period is usually associated with poor

prognosis, leading to death or a need for transplantation

early in life.

Conduction System Diseases. As depicted in the Table,

there are various conduction system abnormalities and ion

channel disorders that are classified as cardiomyopathies.

Although classified in this way, the myocardium is usually

normal in these disorders. These disorders are character-

ized by ECG changes and arrhythmias. Cardiac function

could be affected secondary to an arrhythmia. Several spe-

cific genes have been connected to these disorders.

MixedDilated Cardiomyopathy. Dilated cardiomyopathy (DCM) is

more common than HCM or restrictive cardiomyopathy.

(15) The prevalence is about 1 in 2,500 in the general

population and it is the most frequent cause of heart trans-

plantation. DCM can result from a primary abnormality

in the cardiac myocyte or can be secondary to a wide range

of other disorders such as myocarditis. Other secondary

causes include autoimmune and systemic disorders, pheo-

chromocytoma, neuromuscular disorders, and mitochon-

drial, endocrine, and nutritional disorders. About 20% to

35% of DCM cases are familial. (8) Inheritance is hetero-

geneous, with most cases being autosomal dominant.

Patients with DCM usually present at a later age and

rarely in the neonatal period. This disorder is characterized

by ventricular enlargement and decreased systolic function;

affected patients present with symptoms of low cardiac

output such as pallor, irritability, and diaphoresis. (7) Phys-

ical findings include tachypnea, tachycardia, narrow pulse

pressure, and hepatomegaly. ECG shows flattening of the T

wave with possible depression of the ST segments. Cardio-

megaly is evident on chest radiography. Echocardiography is

diagnostic. Cardiac MRI is often helpful in identifying

myocardial fibrosis and scarring but may be difficult to

interpret in neonates with increased heart rates. Manage-

ment includes treatment of heart failure. In contrast to

HCM, vasodilators, diuretics, and inotropes are useful in

the management of DCM. If management is unsuccessful,

patients can develop severe heart failure, arrhythmias, or

sudden death.

Restrictive Cardiomyopathy. This is an extremely rare

condition in which the ventricular cavities are small and

diastolic function is impaired, involving both but predom-

inantly the left ventricle. (7) The systolic function is normal,

at least initially. It is very rare in neonates. Affected neonates

present with signs and symptoms of congestive heart fail-

ure. ECG often shows conduction abnormalities and evi-

dence of ischemia at higher heart rates. Echocardiography

shows normal or small ventricles with dilation of both atria.

Restrictive cardiomyopathy should be differentiated from

constrictive pericarditis as affected patients could have

Figure 3. Echocardiogram of a neonate with left ventriclenoncompaction cardiomyopathy. Arrow shows the deep trabecularrecess.

Figure 2. Echocardiogram of a neonate showing left ventricularhypertrophy with more pronounced septal hypertrophy. LV¼leftventricle; RV¼right ventricle.

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similar presentations. The prognosis is poor. Survival with-

out transplantation was reported at 39% in 1 center with

children of all ages. (16)

Acquired CardiomyopathyMyocarditis. Myocarditis is the most common form of

acquired cardiomyopathy in neonates. It is caused by acute

or chronic inflammation of the myocardium as a result of

a wide variety of toxins or infections. The most common

infectious agent is viral (eg, Coxsackie virus, adenovirus,

parvovirus, human immunodeficiency virus). Other infec-

tious causes include bacterial, fungal, and parasitic. Most of

these infections are encountered outside the neonatal

period. Endocardial fibroelastosis is a type of cardiomyop-

athy that can be caused by an intrauterine infection with the

mumps virus. (17) The clinical presentation ofmyocarditis is

similar to that of dilated cardiomyopathy.

Maternal Diabetes. Infants of diabetic mothers may have

a transient hypertrophic cardiomyopathy with spontaneous

regression during the first 6 months of age when insulin levels

normalize. (18) It is a complication in 25% to 30% of infants

born to women with gestational or prepregnancy diabetes.

The ventricular septum is preferentially affected but both the

right and left ventricle free walls may also be involved. (19)

Ischemia/Hypoxia. Neonatal myocardial infarction is

rare, with a few case reports in the literature. (20)(21) Neo-

nates can have a good recovery with interventions such as

extracorporeal membrane oxygenation or catheter interven-

tions. (22)(23)

Birth asphyxia is associated with several cardiovascular

changes. Ongoing severe asphyxia is associated with signifi-

cantly reduced ventricular output and stroke volume. (24) The

cause of eventual myocardial dysfunction is multifactorial,

including low heart rate associated with asphyxia, acidosis,

and ischemic myocardial injury. (25)(26) Affected newborns

have an increased troponin level, which has been associated

with myocardial damage. (27) Clinical management of cardiac

dysfunction relies on maintaining adequate perfusion to or-

gans by maintaining blood pressure and cardiac contractility.

SECONDARY CARDIOMYOPATHY

Themyocardial involvement in these disorders is secondary

to various multisystem disorders. The frequency and severity

of the myocardial involvement varies significantly among

these diseases. Some of these disorders are very uncommon,

and even then the involvement might not be seen in the

neonatal period. IEMs are among the most common causes

of secondary cardiomyopathy.

Inborn Errors of MetabolismApproximately 5% to 26% of infants and children with

cardiomyopathy have an IEM. (28) In some cases, the car-

diomyopathy dominates the clinical presentation and is the

major cause of death. More than 40 disorders are known to

cause IEM cardiomyopathy, including fatty acid oxidation

defects, organic acidemias, amino acid disorders, glycogen

storage diseases, and congenital disorders of glycosylation

as well as peroxisomal, mitochondrial, and lysosomal stor-

age disorders. (29) Most of these present in infancy or early

childhood with multiorgan dysfunction. Many of these dis-

orders are treatable by targeting the underlying pathophys-

iology of the disease. Some of the cardiomyopathies could

also be reversed by treating the underlying disorder.

IEMs cause cardiomyopathy through various mecha-

nisms. (29) The first is deposition or infiltration of a sub-

strate within the myocyte. These deposits involve large

macromolecules such as triglycerides, glycogen, and lyso-

somal substrates. This has a mechanical effect on the

myocyte function. A second mechanism is impaired energy

production within the myocyte. These include oxidative

phosphorylation defects. A third mechanism is production

of toxic metabolites such as organic acidemias.

Each IEM is associated with a specific type of cardiomy-

opathy, usually DCM or HCM. Of the HCMs caused by

IEMs, 50% are due to glycogen storage diseases, of which

Pompe disease is the most common. (15) Infants with

Pompe disease present with hypotonia, muscle weakness,

an enlarged tongue, and congestive heart failure. ECG

shows tall QRS waves and short PR intervals. Chest radi-

ography demonstrates cardiomegaly while echocardiogra-

phy shows severe left ventricular hypertrophy with or

without LVOTobstruction. In the pediatric cardiomyopathy

registry, fatty acid oxidation defects and oxidative phosphor-

ylation defects comprise 25% of IEM-related cardiomyopa-

thies, with most leading to DCM.

Most cardiomyopathies caused by IEMs present during

infancy or early childhood. Cardiomyopathy may be the

dominant clinical presentation. An extensive evaluation often

reveals signs of multisystem involvement, including physical

findings (coarse facial features, cloudy corneas or cataracts,

and hepatosplenomegaly), neurologic abnormalities, skeletal

myopathy, and skeletal abnormalities. (29) Early diagnosis

is key to management of these disorders. Management is

aimed at correction of the underlying metabolic disorder.

Neuromuscular/Neurologic DisordersMany neuromuscular disorders can have associated cardio-

myopathies but it is unusual for cardiomyopathy to be the

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presenting symptom. (30) Duchenne and Becker muscu-

lar dystrophies are among the most common myopathies

associated with cardiomyopathy. The heart is usually

affected later in life and affected infants usually are

asymptomatic.

Myotonic dystrophy is the most common form of mus-

cular dystrophy. The clinical presentation depends on the

form of the disease: congenital, infantile, juvenile, or adult-

onset. The severity depends on the number of CTG repeats,

with the most severe disease developing in patients with

more than 1,000 repeats. (30) The congenital form presents

with decreased movements in fetal life, hypotonia, and

respiratory failure. Cardiac involvement appears in the

second decade of life. Cardiovascular symptoms in these

disorders are not overt because of the low level of physical

activity.

Mitochondrial DisordersMitochondrial disorders are a heterogeneous group of

multisystem diseases secondary to mutations in nuclear

or mitochondrial DNA. These can be diagnosed at any age

depending on the severity of the disease. Cardiac manifes-

tations could include HCM or DCM. (31) Cardiac involve-

ment is typical of certain abnormalities.

Kearns-Sayre syndrome is a mitochondrial myopathy

consisting of ptosis, ophthalmoplegia, and retinal pigmen-

tation; affected patients are predisposed to atrioventricular

conduction abnormalities.

Patients with myoclonic epilepsy with ragged red

fibers or mitochondrial encephalomyopathy with lactic

acidosis and strokelike episodes could develop HCM or

DCM.

The most common infantile mitochondrial disorder is

Leigh syndrome, a progressive neurodegenerative disorder.

(31) This syndrome is characterized by gliosis, demyelin-

ation, capillary necrosis, and necrosis in the brain. Cardiac

involvement could be in the form of HCM and conduction

defects such as Wolff-Parkinson-White syndrome.

Sengers syndrome presents with congenital cataracts,

HCM,mitochondrialmyopathy, and lactic acidosis. Affected

patients can present with a severe neonatal form that causes

infantile death or a more benign form with longer survival.

The cause of death is usually HCM.

Barth syndrome is an X-linked genetic disorder charac-

terized by cardiomyopathy, intermittent neutropenia, mus-

cular weakness, and 3-methyl-glutanic aciduria. It is caused

by mutation in the tafazzin (TAZ) gene. Affected patients

have a high mortality rate during infancy as a result of

cardiac dysfunction.

DIAGNOSIS AND MANAGEMENT

The evaluation of patients with a cardiomyopathy ismethod-

ical, and involves evaluation by multiple specialties includ-

ing neonatology, cardiology, metabolism, and genetics.

Psychological and family support should be available,

because quite often these patients have an underlying

systemic or genetic disorder that requires extensive coun-

seling and guidance. The cardiac transplant team should

be involved when providers suspect a possible cardiomyop-

athy. If relevant, a muscle or myocardial biopsy can help to

identify the underlying neuromuscular disorder. Manage-

ment of secondary cardiomyopathies often involves correc-

tion of the underlying metabolic or genetic disorders. The

role of immunoglobulin administration in neonatal myo-

carditis is uncertain. Cardiac failure is oftenmanaged symp-

tomatically with the use of diuretics, afterload-reducing

agents in infants with DCM, and b-blockers in patients

with HCM.

CONCLUSION

Myocardial disorders in the neonatal period are not uncom-

mon and may have a heterogeneous presentation. Patients

with a primary cardiomyopathy usually do not present

during the neonatal period. If symptoms are present, the

condition is usually associated with a poor prognosis.

Patients with a secondary cardiomyopathy may present in

the neonatal period, depending on the severity of the

underlying defect.

American Board of PediatricsNeonatal-Perinatal ContentSpecifications• Know the anatomy and pathophysiology (including genetics) ofan infant with a condition affecting myocardial performance.

• Recognize the clinical features in an infant with a conditionaffecting myocardial performance.

• Recognize the laboratory, imaging, and other diagnostic featuresof an infant with a condition affecting myocardialperformance.

• Formulate a differential diagnosis of an infant with a conditionaffecting myocardial performance.

• Know the evaluation and medical and/or surgical managementand associated potential complications or adverse effects of suchmanagement for an infant with a condition affecting myocardialperformance.

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Manish BansalMyocardial Disorders in the Neonate

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