**3. Pediatric cardiomyopathies**

**2. The cardiomyopathies**

292 Cardiomyopathies

also contribute to the development of the disease.

Cardiomyopathy is a chronic disease of the heart muscle (myocardium), in which the muscle is abnormally enlarged, thickened, and/or stiffened. The weakened heart muscle loses the ability to pump blood effectively, resulting in irregular heartbeats (arrhythmias) and possibly even heart failure. Cardiomyopathy, a disease of the heart muscle, primari‐ ly affects the left ventricle, which is the main pumping chamber of the heart. Usually, cardiomyopathy begins in the heart's lower chambers (the ventricles), but in severe cases can affect the upper chambers, or atria.The disease is often associated with inadequate heart pumping and other heart function abnormalities. Cardiomyopathy is not common but it can be severely disabling or fatal. Most people are only mildly affected by cardiomy‐ opathy and can lead relatively normal lives.However, people who have severe heart failure may need a heart transplant.Cardiomyopathy is a heart condition that not only affects middle-aged and elderly persons, but can also affect infants, children, and adolescents. Cardiomyopathy is classified as either "ischemic" or "nonischemic". All cases related to children and teenagers are considered "nonischemic" cardiomyopathy. Non-ischemic cardiomyopathy predominately involves the heart's abnormal structure and function. It does not involve the hardening of arteries on the heart surface typically associated with ischemic cardiomyopathy. Nonischemic cardiomyopathy can then be broken down into: 1) "primary cardiomyopathy" where the heart is predominately affected and the cause may be due to infectious agents or genetic disorders and 2) "secondary cardiomyopathy" where the heart is affected due to complications from another disease affecting the body (i.e. HIV, cancer, muscular dystrophy or cystic fibrosis).Cardiomyopathy is nondiscriminatory in that it can affect any adult or child at any stage of their life. It is not gender, geographic, race or age specific. It is a particularly rare disease when diagnosed in infants and young children. Cardiomyopathy continues to be the leading reason for heart transplants in children.Pediatric cardiomyopathy is a rare heart condition that affects infants and children. Specifically, cardiomyopathy means disease of the heart muscle (myocardium). Several different types of cardiomyopathy exist and the specific symptoms vary from case to case. In some cases, no symptoms may be present (asymptomatic); in many cases, cardiomyop‐ athy is a progressive condition that may result in an impaired ability of the heart to pump blood; fatigue; heart block; irregular heartbeats (tachycardia); and, potentially, heart failure and sudden cardiac death.There are numerous causes for a complex disease such as cardiomyopathy. For the majority of diagnosed children, the exact cause remains un‐ known (termed "idiopathic"). In some cases, it may be related to an inherited condition such as a family history of cardiomyopathy or a genetic disorder such as fatty acid oxidation, Barth syndrome, orNoonan syndrome. Cardiomyopathy can also be a conse‐ quence of another disease or toxin where other organs are affected. Possible causes include viral infections (Coxsackie B - CVB), auto-immune diseases during pregnancy, the buildup of proteins in the heart muscle (amyloidosis), and an excess of iron in the heart (hemochromatosis). Excessive use of alcohol, contact with certain toxins, complications from AIDS, and the use of some therapeutic drugs (i.e. doxorubicin) to treat cancer can Pediatric cardiomyopathy is a rare heart condition that affects infants and children.There is a vast amount of literature on adult cardiomyopathy but not all of the information is relevant to children diagnosed with the disease. Unfortunately, there has been little research and focus on pediatric cardiomyopathy over the years. Consequently, the causes are not well understood. Pediatric cardiomyopathy is more likely to be due to genetic factors while lifestyle or envi‐ ronmental factors play a greater role in adult cardiomyopathy.

In rare cases, pediatric cardiomyopathy may be a symptom of a larger genetic disorder that may not be immediately detected. For example, when an infant or young child is diagnosed with dilated cardiomyopathy, a rare genetic heart disease called Barth Syndrome or a mito‐ chondrial defect (i.e. Kearns-Sayre syndrome) may be the cause. Similarly, a child with severe hypertrophic cardiomyopathy may actually have Noonan Syndrome, Pompe disease (type II glycogen storage disease), a fatty acid oxidation disorder, or mitochondrial HCM. It is therefore important for any diagnosed child to be properly evaluated for other suspected genetic disorders. A thorough evaluation remains a complicated and expensive process due to the large number of rare genetic causes, the broad range of symptoms and the existence of many specialized biochemical, enzymatic and genetic tests. Verifying a diagnosis may require getting additional blood, urine or tissue tests and consulting other specialists such as a neurologist and geneticist.

Cardiomyopathy in children may also present differently from diagnosed teenagers or adult. It is considered unusual when an infant or a child is diagnosed with symptoms at such a young age. Typically, symptoms are not apparent until the late teens or adult years when most patients are diagnosed. With hypertrophic cardiomyopathy, the disease commonly develops in association with growth and is detected when a child progresses through puberty. Even in genetically affected family members, a child that carries the muted gene from birth may appear to have a normal heart and be asymptomatic until puberty.

A diagnosis at a young age usually, but not always, signifies a serious heart condition that requires aggressive treatment. The concern lies in the uncertainty of how the heart muscle will respond with each additional growth spurt. With some older children, the condition may stabilize over time with the aid of certain medications or surgery. In severe cases, small children may experience progressive symptoms quickly leading to heart failure. This presentation contrasts with most diagnosed adults who may only have minor symptoms without serious limitations or major problems for years.Aside from differences in the cause and manifestation, cardiomyopathy may also progress differently in children than adults. When children are diagnosed at an early age, the prognosis may be poor depending on the form of cardiomyop‐ athy and the stage of the disease. For example, dilated cardiomyopathy can progress quite rapidly when diagnosed in young children. Up to 40% of diagnosed children with dilated cardiomyopathy fail medical management within the first year of diagnosis and of those that survive many have permanently impaired heart function. Children diagnosed with hypertro‐ phic cardiomyopathy seem to fare better but the outcome is highly variable.Mortality and heart transplant rates of childhood cardiomyopathies are much higher than in adults due to the rarity and uncertainty of the disease. Less than optimal outcomes may be attributed to the more fragile state of infants and young children or it may be a function of the disease's advanced progression associated with another genetic disorder. Another unfortunate reason is that cardiomyopathy is not usually detected until the end stage when obvious symptoms of heart failure are apparent. Cardiomyopathy can be easily missed in routine check-ups when there are no obvious symptoms (i.e heart murmur) or when there is no reason for diagnostic testing (i.e. no family history of the disease).

According to the Pediatric Cardiomyopathy Registry, cardiomyopathies can be grouped into

Pediatric Cardiomyopathies http://dx.doi.org/10.5772/55820 295

This a leading cause in children with cardiomyopathy and is more commonly associated with DCM. It is caused by viral infections that cause the body's immune system to malfunction damaging/inflaming the heart muscle tissue while attacking the invading virus. At this point, it is unknown whether certain children have a certain genetic makeup that may make them

Isolated familial cardiomyopathy is considered when the child does not show features of metabolic or muscular disorders, and there is a known family history of cardiomyopathy. In affected families with HCM, ARVD, DCM, and RM, the condition is predominately inherited in an autosomal dominant manner where an affected parent has a 50% chance of passing the defective gene to his/her offspring. In rare cases, ARVC, DCM and HCM can be inherited through autosomal recessive or maternal transmission where unaffected parent(s) have a 25%

Although the genetic defect is the same in all members of an individual family, there are variable outcomes and severity of the disease in different family members. The disease's manifestation can range from minimal abnormality and no symptoms to severe complications within the same family. In some families it may appear that the mutated gene skips a generation but in reality the defective gene may not have expressed itself fully in a particular family

Neuromuscular diseases associated with cardiomyopathy include those that affect the nerve or skeletal muscles. These include muscular dystrophies (i.e. Duchenne and Becker), congen‐ ital myopathies, metabolic myopathies, and ataxias (i.e. Friedreich Ataxia). Common symp‐ toms are decreased muscle tone, weakness beginning after infancy, loss of motor control, decreased muscle relaxation and decreased muscle bulk. Almost all of the neuromuscular

five categories based on the specific genetic cause of the disease:

**•** neuromuscular disorders associated with cardiomyopathy (22%),

**•** malformation syndromes associated with cardiomyopathy (10%).

**•** myocarditis and other viral infections (27%),

**•** familial inherited cardiomyopathies (24%),

**3.2. Myocarditis and other viral infections**

more susceptible to contracting myocarditis.

chance of an affected child with each pregnancy.

member, and therefore echocardiograms may appear normal.

diseases associated with cardiomyopathy have a genetic basis.

*3.3.1. Neuromuscular disorders associated with cardiomyopathy*

**3.3. Familial inherited cardiomyopathies**

**•** metabolic disorders (16%),

#### **3.1. What causes cardiomyopathy?**

Although pediatric cardiomyopathy is one of the leading causes of cardiac death in children, an explanation for why it occurs remains unknown. Most cases are familial conditions that are genetically transmitted, but the disease can also be acquired during childhood. The most common cause for acquired cardiomyopathy is myocarditis, a viral infection that weakens the heart muscle. Other causes for acquired cardiomyopathy include: 1) cardiovascular conditions (i.e. Kawasaki disease, congenital heart defect, hypertension, cardiac transplantation or surgery), 2) infectious or inflammatory diseases, 3) immunologic diseases (i.e. HIV), 4) obesity or dietary deficiencies, 5) toxin reactions (i.e. drug, alcohol, radiation exposure), 6) connective tissue and autoimmune diseases, 7) endocrine diseases and 8) pregnancy related complica‐ tions. Persistent rhythm problems or problems of the coronary arteries, either congenital or acquired, can also lead to a weakening of the heart.

It is being increasingly recognized that certain genetic mutations are the primary cause for pediatric cardiomyopathy. Mutations are defects in the DNA spiral, the protein structure of many genes. The abnormalities in DNA involve a displacement in the sequence of one or more of the amino acids that make up a gene protein. The disease is either inherited through one parent who is a carrier (autosomal dominant transmission with a 50% chance of recurrence) or through both parents who each contribute a defective gene (autosomal recessive transmis‐ sion with a 25% chance of recurrence). Cardiomyopathy can also be inherited by maternal transmission (X-linked). Research continues to focus on identifying the specific genes that cause cardiomyopathy and better understanding how these genetic abnormalities contribute to the disease. However, it is a complex process with multiple diverse genes producing extremely variable outcomes. Many children with hypertrophic cardiomyopathy (50-60%) and to a lesser degree with dilated cardiomyopathy (20-30%) have a family history of the disease. Recent advancements in genetic research show that hypertrophic cardiomyopathy involves defects in the sarcomere genes and can be inherited in an autosomal dominant manner. Dilated cardiomyopathy involves defects in the cytoskeleton genes and can be inherited autosomal dominant, autosomal recessive or X-linked. In some cases, cardiomyopathy can be related to another inherited metabolic or congenital muscle disorder such as Noonan syndrome, Pompe disease, fatty acid oxidation defect or Barth syndrome. Most often, symptoms of these disorders present early in life.Although there is a long list of possible causes for cardiomyop‐ athy, few of them are directly treatable and most therapy is aimed at treating the secondary effects on the heart.

According to the Pediatric Cardiomyopathy Registry, cardiomyopathies can be grouped into five categories based on the specific genetic cause of the disease:


rarity and uncertainty of the disease. Less than optimal outcomes may be attributed to the more fragile state of infants and young children or it may be a function of the disease's advanced progression associated with another genetic disorder. Another unfortunate reason is that cardiomyopathy is not usually detected until the end stage when obvious symptoms of heart failure are apparent. Cardiomyopathy can be easily missed in routine check-ups when there are no obvious symptoms (i.e heart murmur) or when there is no reason for diagnostic

Although pediatric cardiomyopathy is one of the leading causes of cardiac death in children, an explanation for why it occurs remains unknown. Most cases are familial conditions that are genetically transmitted, but the disease can also be acquired during childhood. The most common cause for acquired cardiomyopathy is myocarditis, a viral infection that weakens the heart muscle. Other causes for acquired cardiomyopathy include: 1) cardiovascular conditions (i.e. Kawasaki disease, congenital heart defect, hypertension, cardiac transplantation or surgery), 2) infectious or inflammatory diseases, 3) immunologic diseases (i.e. HIV), 4) obesity or dietary deficiencies, 5) toxin reactions (i.e. drug, alcohol, radiation exposure), 6) connective tissue and autoimmune diseases, 7) endocrine diseases and 8) pregnancy related complica‐ tions. Persistent rhythm problems or problems of the coronary arteries, either congenital or

It is being increasingly recognized that certain genetic mutations are the primary cause for pediatric cardiomyopathy. Mutations are defects in the DNA spiral, the protein structure of many genes. The abnormalities in DNA involve a displacement in the sequence of one or more of the amino acids that make up a gene protein. The disease is either inherited through one parent who is a carrier (autosomal dominant transmission with a 50% chance of recurrence) or through both parents who each contribute a defective gene (autosomal recessive transmis‐ sion with a 25% chance of recurrence). Cardiomyopathy can also be inherited by maternal transmission (X-linked). Research continues to focus on identifying the specific genes that cause cardiomyopathy and better understanding how these genetic abnormalities contribute to the disease. However, it is a complex process with multiple diverse genes producing extremely variable outcomes. Many children with hypertrophic cardiomyopathy (50-60%) and to a lesser degree with dilated cardiomyopathy (20-30%) have a family history of the disease. Recent advancements in genetic research show that hypertrophic cardiomyopathy involves defects in the sarcomere genes and can be inherited in an autosomal dominant manner. Dilated cardiomyopathy involves defects in the cytoskeleton genes and can be inherited autosomal dominant, autosomal recessive or X-linked. In some cases, cardiomyopathy can be related to another inherited metabolic or congenital muscle disorder such as Noonan syndrome, Pompe disease, fatty acid oxidation defect or Barth syndrome. Most often, symptoms of these disorders present early in life.Although there is a long list of possible causes for cardiomyop‐ athy, few of them are directly treatable and most therapy is aimed at treating the secondary

testing (i.e. no family history of the disease).

acquired, can also lead to a weakening of the heart.

**3.1. What causes cardiomyopathy?**

294 Cardiomyopathies

effects on the heart.

**•** malformation syndromes associated with cardiomyopathy (10%).

#### **3.2. Myocarditis and other viral infections**

This a leading cause in children with cardiomyopathy and is more commonly associated with DCM. It is caused by viral infections that cause the body's immune system to malfunction damaging/inflaming the heart muscle tissue while attacking the invading virus. At this point, it is unknown whether certain children have a certain genetic makeup that may make them more susceptible to contracting myocarditis.

#### **3.3. Familial inherited cardiomyopathies**

Isolated familial cardiomyopathy is considered when the child does not show features of metabolic or muscular disorders, and there is a known family history of cardiomyopathy. In affected families with HCM, ARVD, DCM, and RM, the condition is predominately inherited in an autosomal dominant manner where an affected parent has a 50% chance of passing the defective gene to his/her offspring. In rare cases, ARVC, DCM and HCM can be inherited through autosomal recessive or maternal transmission where unaffected parent(s) have a 25% chance of an affected child with each pregnancy.

Although the genetic defect is the same in all members of an individual family, there are variable outcomes and severity of the disease in different family members. The disease's manifestation can range from minimal abnormality and no symptoms to severe complications within the same family. In some families it may appear that the mutated gene skips a generation but in reality the defective gene may not have expressed itself fully in a particular family member, and therefore echocardiograms may appear normal.

#### *3.3.1. Neuromuscular disorders associated with cardiomyopathy*

Neuromuscular diseases associated with cardiomyopathy include those that affect the nerve or skeletal muscles. These include muscular dystrophies (i.e. Duchenne and Becker), congen‐ ital myopathies, metabolic myopathies, and ataxias (i.e. Friedreich Ataxia). Common symp‐ toms are decreased muscle tone, weakness beginning after infancy, loss of motor control, decreased muscle relaxation and decreased muscle bulk. Almost all of the neuromuscular diseases associated with cardiomyopathy have a genetic basis.

#### *3.3.2. Metabolic disorders*

Inborn errors of metabolism consist of numerous infiltrative storage diseases, abnormal energy production, biochemical deficiencies and disorders related to toxic substances accumulating in the heart. This category also includes mitochondrial abnormalities (i.e. MELAS, MERRF, respiratory chain diseases, mitochondrial myopathies), fatty acid oxidation defects (carnitine deficiency, VCHAD, LCHAD, LCAD, MCAD), Pompe disease and Barth syndrome. When the demand for energy exceeds what the body can supply (i.e. during illness, physical stress or decreased oral intake), patients with impaired energy metabolism are unable to maintain their body's biochemical stability. This may lead to low blood sugar, excessive acidity in the blood and/or high ammonia levels that put additional strain on the heart.Metabolic disorders are inherited by autosomal recessive transmission (each parent contributes a defective gene) or Xlinked transmission (mother contributes defective gene). Usually patients appear to be physically normal in early childhood but as the body's energy production continues to be impaired, toxic substances may accumulate throughout the body leading to multiple organ failure. Common symptoms include muscle weakness, decreased muscle tone, growth retardation, developmental delays, failure to thrive, constant vomiting and lethargy. In critical states, the child may exhibit stroke like symptoms, seizures, have low blood sugar, and be unable to use the body's fuel correctly.

With each type of cardiomyopathy, symptoms and reactions to pharmaceutical or surgical

Pediatric Cardiomyopathies http://dx.doi.org/10.5772/55820 297

Dilated or congestive cardiomyopathy (DCM) is diagnosed when the heart is enlarged (dilated) and the pumping chambers contract poorly (usually left side worse than right). A diagram and echocardiogram comparing a normal heart and a heart with DCM (fig. 15)

**Figure 15.** A normal heart is shown on the left compared to a heart with dilated cardiomyopathy on the right.

This condition is the most common form of cardiomyopathy and accounts for approximately 55–60% of all childhood cardiomyopathies. It can have both genetic and infectious/environ‐ mental causes.It is more commonly diagnosed in younger children with the average age at diagnosis being 2 years. Dilated cardiomyopathy can be familial (genetic), and it is estimated that 20–30% of children with DCM have a relative with the disease, although they may not

Dilated cardiomyopathy can appear along a spectrum of no symptoms, subtle symptoms or, in the more severe cases, congestive heart failure (CHF), which occurs when the heart is unable to pump blood well enough to meet the body tissue needs for oxygen and nutrients.When only subtle symptoms exist, infants and young children are sometimes diagnosed with a viral upper respiratory tract infection or recurrent "pneumonia" without realizing that a heart problem is the basis for these symptoms. Older children and adolescents are less likely to be diagnosed with viral syndromes and more likely to present with decreased exercise capacity or easy fatigability. With CHF, babies and young children will usually have more noticeable clinical changes such as irritability, failure to thrive (poor gain weight), increased sweating especially with activities, pale color, faster breathing and/or wheezing. In older children, congestive heart failure can manifest as difficulty breathing and/or coughing, pale color, decreased urine output

therapies may vary widely among patients.

have been diagnosed or have symptoms.

**4.1. Signs and symptoms of DCM**

**4. Dilated cardiomyopathy**

In contrast, patients with storage diseases such as Pompe, Cori, and Andersen disease cannot break down glycogen, the storage form of sugar. These syndromes are characterized by problems with growth, brain dysfunction, decreased muscle tone, muscle weakness, and symptoms of heart failure.

#### *3.3.3. Malformation syndromes associated with cardiomyopathy*

Malformation syndromes are characterized by minor and major physical abnormalities with distinctive facial features. It is caused by genetic mutations through autosomal dominant, autosomal recessive, or X-linked recessive inheritance. It can also be cause by a chromosomal defect where a specific chromosome is deleted or duplicated. Noonan syndrome is the most common form associated with pediatric cardiomyopathy. Common symptoms include short stature, webbed neck, wide set eyes, low set ears and extra skin folds.

#### **3.4. Forms of cardiomyopathy**

There are four main types of nonischemic cardiomyopathy that are recognized by the World Health Organization: dilated (DCM), hypertrophic (HCM), restrictive (RCM) and arrhythmo‐ genic right ventricular (ARVC). Each form is determined by the nature of muscle damage. With some patients, cardiomyopathy may be classified as more than one type or may change from one type to another over time. According to the pediatric cardiomyopathy survey, dilated cardiomyopathy is the most common (58%), followed by hypertrophic cardiomyopathy (30%) and a few cases of restrictive cardiomyopathy (5%) and arrhythmogenic right ventricular cardiomyopathy (5%). Although not formally categorized by the World Health Organization, left ventricular non-compaction cardiomyopathy (LVNC) is increasingly being recognized. With each type of cardiomyopathy, symptoms and reactions to pharmaceutical or surgical therapies may vary widely among patients.
