Park's Pediatric Cardiology for Practitioners, 6th Ed.

Cardiovascular Involvement in Systemic Diseases

Many collagen, neuromuscular, endocrine, and other systemic diseases may have important cardiovascular manifestations. The involvement of the cardiovascular system usually becomes evident when the diagnosis of the primary disease is well established, but occasionally cardiac manifestations may precede evidence of the basic disease. Cardiac manifestations of selected systemic diseases are briefly described here.

Acute Glomerulonephritis

Clinically evident myocardial involvement is found in 30% to 40% of patients with acute poststreptococcal glomerulonephritis. Pulmonary edema, systemic venous congestion, and cardiomegaly also are common, resulting from salt and water retention. Systemic hypertension, sometimes appearing with hypertensive encephalopathy, is a frequent manifestation and may be responsible for signs of congestive heart failure (CHF) in some, but not all, patients. Although hypertension probably reflects fluid expansion (secondary to impaired salt and water excretion), peripheral resistance has been found to be elevated. Increased renin activity may be responsible for the latter. The acute phase generally resolves within 6 to 8 weeks.

Treatment is directed toward lowering blood pressure and inducing diuresis. Sodium restriction, diuresis usually with intravenous Lasix, and antihypertensive therapy with calcium channel antagonists, vasodilators, or angiotensin-converting enzyme (ACE) inhibitors are standard treatment.

DiGeorge Syndrome

The same syndrome has been described by different researchers in different areas of expertise. Angelo DiGeorge, an endocrinologist, reported DiGeorge syndrome in the 1960s, and Robert Shprintzen, PhD, a speech pathologist, reported velocardiofacial syndrome in the 1970s. A Japanese cardiologist group called it conotruncal anomaly face (CTAF) syndrome in 1978. These syndromes share a common genetic cause in most cases, a chromosome 22q11 deletion; therefore, the term “22q11 deletion syndrome” is currently used. The great majority of patients with these syndromes have serious congenital heart defects (CHDs).

DiGeorge syndrome occurs in both males and females. Clinical features in these syndromes include abnormal facies, CHDs, and absence or hypoplasia of the thymus (with congenital immune deficiency and increased susceptibility to infection) and parathyroid gland (with hypocalcemia). Clinical features of the syndrome are collectively grouped under the acronym of CATCH-22 (cardiac, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia resulting from 22q11 deletion).

Approximately 90% of patients have a deletion of the long arm of chromosome 22 (22q11.2) detectable with current cytogenetic and fluorescence in situ hybridization (FISH) techniques. In 90% of cases, the disorder occurs as the result of a new mutation. In 10%, the disorder is inherited from a parent in an autosomal dominant fashion. Rarely, the syndrome may be caused by other chromosomal abnormalities or maternal environmental factors (e.g., alcohol, retinoids).

Clinical Manifestations

1. Abnormal facies: Abnormal facies is characterized by hypertelorism; micrognathia; a short philtrum with a fish-mouth appearance; an antimongoloid slant; and telecanthus with short palpebral fissures and low-set ears, often with defective pinna.

2. Cardiac: Many patients (85%) have cardiac defects. The most common cardiac anomalies include tetralogy of Fallot (TOF) (25%); interrupted aortic arch (15%); ventricular septal defect (VSD), usually perimembranous (15%); persistent truncus arteriosus (9%); and isolated aortic arch anomalies (5%). Less common anomalies include pulmonary stenosis (PS), atrial septal defect (ASD), atrioventricular (AV) canal defect, and transposition of the great arteries.

3. Cleft: Anomalies in the palate are common (70%–80%), with speech and feeding disorders. The palatal abnormalities may be overt or submucosal cleft. Occasionally, a bilateral cleft lip and palate may be present. Velopharyngeal insufficiency with delayed and hypernasal speech may occur.

4. Metabolic: Hypocalcemia (observed in 60%) is caused by hypoparathyroidism.

5. Immunologic: Thymic hypoplasia or aplasia leads to a mild to moderate decrease in T-cell number. Occasionally, humoral deficits, including IgA deficiency, have been observed (≈10%).

6. Recurrent infections are common, an important cause of later mortality.

7. General: Short stature, mental retardation, and hypotonia in infancy are frequent. Occasionally, psychiatric disorders (e.g., schizophrenia and bipolar disorder) develop.

8. Lateral view of chest radiograph shows a defective thymic shadow.

9. Cytogenetic analysis detects only 20% of the deletion in the region. The deletion is best identified by FISH.

Management

1. Correction of cardiac malformation as discussed in other sections. Cardiac defects are major causes of early death.

2. Irradiated, cytomegalovirus-negative blood products must be administered because of the risk of graft-versus-host disease with nonirradiated products.

3. Monitoring of serum calcium levels and supplementation of calcium and vitamin D are important.

a. Calcium gluconate (Kalcinate), 500 to 750 mg/kg/day, orally (PO) four times a day (QID), QID or calcium carbonate (Oscal, Titralac, Oystercal, Caltrate), 112.5 to 162.5 mg/kg/day, given QID.

b. Ergocalciferol (vitamin D2), 25,000 to 2000,000 U PO every day.

4. Live vaccines are contraindicated in patients with DiGeorge syndrome and in household members because of the risk of shedding live organism.

5. Usual prophylactic regimen for T- and B-cell deficiency.

6. Early thymus transplantation may promote successful immune reconstitution.

Prognosis

The prognosis depends on cardiac and immune system disorders. The prognosis is poor with complex cyanotic heart defects, with a 1-month mortality rate of 55% and 6-month mortality rate of 86%.

Friedreich’s Ataxia

Friedreich’s ataxia is inherited as an autosomal recessive trait. The onset of ataxia usually occurs before age 10 years, and it progresses slowly, involving the lower extremities to a greater extent than the upper extremities. Explosive dysarthric speech and nystagmus are characteristic, but intelligence is preserved.

Echocardiographic studies reveal evidence of cardiomyopathy in approximately 30% of the cases. Concentric hypertrophy of the left ventricle (LV) with normal LV systolic function is the most common finding. In advanced stages, the LV enlarges, and the LV wall thickness decreases with decreasing fractional shortening, suggesting the presence of fibrosis in the myocardium (Weidemann et al, 2012). Diastolic dysfunction of the LV may be present. The thickness of the interventricular septum correlates well with LV mass determined by magnetic resonance imaging (MRI). Microscopically, diffuse interstitial fibrosis and fatty degeneration of the myocardium, with compensatory hypertrophy of the remaining cells, frequently are found. CHF is the terminal event with most patients dying before 40 years of age.

Cardiac symptoms (e.g., dyspnea, chest pain) are common. Because of physical disability, cardiac problems may not be recognized until arrhythmias or signs of CHF develop. Importantly, there appears to be no clear correlation between the severity of myocardial involvement and that of neurologic dysfunction. A systolic murmur may be audible at the upper left sternal border. Electrocardiographic (ECG) abnormalities are very common. The most common finding is the T-vector change in the limb leads or left precordial leads. Occasionally, left ventricular hypertrophy (LVH), right ventricular hypertrophy (RVH), abnormal Q waves, or short PR interval is found. Chest radiographs usually are normal.

Treatments are the same as those described under different types of cardiomyopathies.

Hyperthyroidism: Congenital and Acquired

The thyroid hormones increase oxygen consumption, stimulate protein synthesis and growth, and affect carbohydrates and lipid metabolism. On the cardiovascular system, the thyroid hormones (1) increase heart rate, cardiac contractility, and cardiac output; (2) increase systolic pressure and decrease diastolic pressure, with mean pressure unchanged; and (3) may increase myocardial sensitivity to catecholamines. Hyperthyroidism results from excess production of triiodothyronine (T3), thyroxine (T4), or both.

Congenital hyperthyroidism most often is caused by increased thyroid-stimulating immunoglobulin in infants of mothers who had Graves’ disease during pregnancy. A newborn infant with congenital hyperthyroidism often is premature and usually has a goiter. The baby appears anxious, restless, alert, and irritable. The eyes are widely open and appear exophthalmic.

Juvenile hyperthyroidism is believed to be caused by thyroid-stimulating antibodies and often is associated with lymphocytic thyroiditis and other autoimmune disorders. The incidence of juvenile hyperthyroidism peaks during adolescence, with girls affected more often than boys. These children become hyperactive, irritable, and excitable. The thyroid gland is enlarged.

Both congenital and acquired hyperthyroidism manifests with tachycardia, full and bounding pulses, and increased systolic and pulse pressures. A nonspecific systolic murmur may be audible. Bruits may be audible over the enlarged thyroid in children but not in newborns. In severely affected patients, cardiac enlargement and cardiac failure may develop, requiring prompt recognition and treatment.

Chest radiographs usually are normal but may show cardiomegaly and increased pulmonary vascularity, especially in the presence of heart failure. ECG abnormalities may include sinus tachycardia, peaked P waves, various arrhythmias (supraventricular tachycardia, junctional rhythm), complete heart block, RVH, LVH, or biventricular hypertrophy (but arrhythmias are rare in acquired (juvenile) hyperthyroidism. Echocardiographic studies reveal a hyperkinetic state with increased fractional shortening.

In severely affected patients, a β-adrenergic blocker, such as propranolol, is indicated to reduce the effect of catecholamines. It is interesting to note that some actions of T3 on the heart are similar to those of β-adrenergic stimulation and that essentially all beta-blockers can alleviate many of the symptoms of hyperthyroidism. The mechanism of the similarity between these two is unclear; it may involve increased beta-adrenergic receptor density or it may occur independently of β-adrenergic receptor stimulation. Treatment of hyperthyroidism consists of oral administration of antithyroid drugs, propylthiouracil, or methimazole (Tapazole). If CHF develops, treatment with anticongestive medications is indicated (see Chapter 27).

Hypothyroidism: Congenital and Acquired

Hypothyroidism results from deficient production of thyroid hormone or a defect in its receptor. The disorder may manifest from birth or may be acquired.

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FIGURE 23-1 Tracing from a 3-month-old infant with congenital hypothyroidism. Note low QRS voltages in the limb leads, relatively low T-wave amplitude, and dome-shaped T wave with an absent ST segment in V6.

Congenital hypothyroidism, formerly known as cretinism, most often is caused by a developmental defect of the thyroid gland. Hypothyroidism may not be apparent until 3 months of age. The typical picture includes a protuberant tongue, cool and mottled skin, subnormal temperature, carotenemia, and myxedema. Untreated children become mentally retarded and slow in physical development. In the congenital type, patent ductus arteriosus and pulmonary stenosis are frequently found.

The patient may have significant bradycardia, a weak arterial pulse, hypotension, and nonpitting facial and peripheral edema. ECG abnormalities occur in more than 90% of patients and consist of some or all of the following: (1) low QRS voltages, especially in the limb leads; (2) low T-wave amplitude, not affecting the T axis; (3) prolongation of PR and QT intervals; and (4) dome-shaped T wave with an absent ST segment (“mosque” sign) (Fig. 23-1). Echocardiographic studies may show cardiomegaly, pericardial effusion, hypertrophic cardiomyopathy, or asymmetric septal hypertrophy in addition to CHDs, if present. Sodium-l-thyroxine given orally is the treatment of choice.

Acquired (or juvenile) hypothyroidism most often results from lymphocytic thyroiditis (Hashimoto’s disease or autoimmune thyroiditis). Hypothyroidism may result from subtotal or complete thyroidectomy or from protracted ingestion of goitrogens, iodides, or cobalt medications. Rarely, amiodarone can cause hypothyroidism. Serum levels of thyroxine and triiodothyronine are low or borderline.

The heart rate is relatively slow, and the heart sounds may be soft. A weak arterial pulse and hypotension may be present. Myxedema may be present. There is an increased occurrence of hypercholesterolemia. Echocardiographic studies frequently show pericardial effusion and asymmetric septal hypertrophy. The ECG, chest radiograph, and echocardiographic findings of juvenile hypothyroidism are the same as for congenital hypothyroidism. Treatment of hypothyroidism corrects the lipid abnormalities.

Marfan’s Syndrome

Marfan’s syndrome is a generalized connective tissue disease with clinical features involving skeletal, cardiovascular, and ocular systems. It is inherited as an autosomal dominant pattern with variable expressivity.

Skeletal features include tall stature with long slim limbs, little subcutaneous fat and muscle hypotonia, arachnodactyly, joint laxity with scoliosis and kyphosis, pectus excavatum or carinatum, and narrow facies. Eye manifestations may include lens subluxation, increased axial global length, myopia, and retinal detachment.

Clinically evident cardiovascular involvement occurs in more than 50% of patients by the age of 21 years. Microscopic changes probably are present in almost all patients even during infancy and childhood. A wide spectrum of cardiovascular abnormalities is seen in Marfan’s syndrome

1. The common abnormalities include dilatation of the sinus of Valsalva, dilatation of the ascending aorta (with or without dissection or rupture), and aortic regurgitation (AR). Microscopic examination of the proximal aorta (and the proximal coronary arteries) reveals disruption of the elastic media, with fragmentation and disorganization of the elastic fibers. Large accumulations of dermatan sulfate, heparan sulfate, and chondroitin sulfate have been reported in the media of the aorta.

2. Mitral valve abnormalities are more common in children and young adults than aortic lesions. The mitral valve and left atrial (LA) endocardium often undergo a fibromyxoid degeneration, resulting in dilatation of the mitral valve annulus, mitral regurgitation (MR) and mitral valve prolapse (MVP).

3. Aneurysm of the pulmonary artery (PA) is less frequently seen.

4. Rarely, myocardial fibrosis and infarction, rupture of chordae tendineae, aneurysm of the abdominal aorta, and aneurysmal dilatation of the proximal coronary arteries have been reported.

Auscultatory findings of MR and MVP appear in more than 50% of patients (see Chapter 21). Rarely, the murmur of AR is audible. The S2 may be accentuated in many patients, especially in those with thin chest walls or dilated PAs. The ECG findings may include LVH; T-wave inversion in leads II, III, aVF, and left precordial leads; and first-degree AV block. Chest radiographs may show cardiomegaly, either generalized or involving only the LV and LA, or a prominence of the ascending aorta, aortic knob, or the main PA segment.

Echocardiographic studies show an increased dimension of the aortic root with or without AR and a “redundant” mitral valve or MVP with thickened valve leaflets and MR. Periodic examination of the aortic root dimension and the status of the MR and MVP are important. As to the diagnosis of MVP in children, however, the adult criteria of MVP are met infrequently, probably because MVP is a progressive disease, and a full manifestation of the disease does not occur until adulthood.

Early death in individuals with this syndrome is most commonly precipitated by aortic dissection, chronic AR, or severe MR. Early and improved surgery and the use of beta-blockers have significantly increased the life expectancy of these patients in recent years.

1. Beta-blockers (atenolol, propranolol) are effective in slowing the rate of aortic dilatation and reducing the development of aortic complications. Recently, enalapril was reported to reduce the rate of increase in the aortic root diameter (Yetman et al, 2005). Thus, beta-blockers or ACE inhibitors (or both) should be administered to children when the aortic root size exceeds the upper limit of normal for age.

2. Certain physical activities are discouraged to reduce the damage to the aortic root and regurgitant aortic and mitral valves. Exercises, such as weightlifting, rowing, push-ups, pull-ups, sit-ups, and hanging on a monkey bar, should be avoided.

3. Surgery should be considered when the diameter of the aortic root increases significantly. However, there is controversy as to what is considered significant enlargement of the aortic root to require surgery. Some centers recommend surgery when the aortic root diameter is greater than 3.5 cm (Kim et al, 2005), others recommend surgery when the aortic root equals approximately twice the average measurement for that age group, and still others recommend surgery when the diameter reaches near 6.5 cm (Gott et al, 1999). Recently, a maximum sinus dimension of 5 cm or a rapid increase in dimension (>1 cm/year) have been suggested as indications for surgery (Tweddell et al, 2012). Normal two-dimensional echocardiographic dimensions of the aortic root and the aorta are presented in Table D-3 in Appendix D.

4. Valve-sparing aortic root reconstruction appears to be preferable to composite graft surgery.

5. Cardiac failure caused by severe MR is treated with mitral valve repair or valve replacement.

6. Aortic root dilatation or aortic aneurysm may occur in other connective tissue diseases, and similar surgical procedures may become necessary. The conditions may include, in addition to Marfan’s syndrome, Ehlers-Danlos syndrome, Turner syndrome, Loeys-Dietz syndrome, and others. Dilatation of the ascending aorta or the aortic root can also occur after surgery for CHDs, such as aortic stenosis (AS), TOF, and truncus arteriosus.

Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are a diverse group of inherited metabolic disorders in which excessive amounts of glycosaminoglycans (previously called mucopolysaccharides) accumulate in various tissues, including the myocardium and coronary arteries. Stored glycosaminoglycans vary with different types and include chondroitin sulfate, heparan sulfate, keratan sulfate, dermatan sulfate, and hyaluronan. Hurler (type IH), Hunter (II), Scheie (IS), Sanfilippo (III), and Morquio (IV) are well-known eponyms. A wide variety of clinical manifestations occur, including growth and mental retardation, skeletal abnormalities, a clouded cornea, upper airway obstruction, and cardiac abnormalities. In most cases, the cause of death is cardiorespiratory failure secondary to cardiac involvement and upper airway obstruction.

Echocardiographic studies show involvement of mitral and aortic valves (most frequently valve regurgitation) in more than 50% of the cases; about 25% of the cases show cardiomyopathy. The prevalence of these abnormalities increases as the patient becomes older.

1. MR is present in approximately 30% of the patients. It is more frequent in types IH (38%) than other types (24% in type II and 20% in type III). Thickening of the mitral valve is common.

2. Aortic regurgitation is present in about 15% of the cases, often with thickening of the valve. It is more common in type II (56%) and type IV (24%).

3. Myocardial abnormalities, such as asymmetric septal hypertrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and endocardial thickening, are present in about 25% of the cases.

4. Occasionally, systemic hypertension is present.

5. Rarely, myocardial infarction can occur.

Heart murmur may represent cardiac valve involvement. Chest radiographs may show cardiomegaly in severe cases of valve regurgitation. The ECG may show a prolonged QT interval, RVH, LVH, or left atrial hypertrophy (LAH). Management depends on the abnormalities present.

Muscular Dystrophy

Duchenne’s muscular dystrophy is a sex-linked recessive disease. Involvement of the pelvic muscles leads to lordosis, a waddling gait, a protuberant abdomen, and difficulty rising. Becker’s muscular dystrophy is the same fundamental disease as Duchenne’s dystrophy, but it follows a milder and more protracted course.

Cardiac enlargement, with occasional endocardial thickening of the LV and LA, is found on gross examination. Fatty degeneration and lymphocytic infiltration are found on microscopic examination. Dystrophic changes in the papillary muscles may be evident, with MR or MVP.

Exertional dyspnea and tachypnea are common symptoms. The P2 may be loud if pulmonary hypertension is present. One may hear either a systolic ejection murmur at the base or a regurgitant apical systolic murmur of MR. CHF is an ominous terminal sign.

Electrocardiographic abnormalities occur in 90% of teenagers with Duchenne’s type, and RVH and right bundle branch block (RBBB) are the most common abnormalities. Deep Q waves frequently are seen in the left precordial leads. A short PR interval is occasionally seen. T-vector changes may be seen in the limb leads or left precordial leads.

Echocardiographic studies show significant cardiac involvement in the form of dilated cardiomyopathy in both Duchenne’s and Becker’s types of muscular dystrophies and manifests clinically during adolescence. In the early stages of the disease, only diastolic dysfunction (of reduced diastolic relaxation pattern) may be present. Systolic dysfunction appears later in the disease process. Echocardiographic features of MR or MVP may be seen.

Treatment is the same as that described for dilated cardiomyopathy (see Chapter 18). Recent reports suggest that a more aggressive treatment with ACE inhibitors (e.g., perindopril) appears to lead to improved LV function and possible delay of progression of the disease (Duboc et al, 2005). Although prospective treatment may be better, the treatment appears to improve LV function even if started after abnormal echocardiographic findings appear. Addition of carvedilol (0.5–1 mg/kg twice daily) to the standard treatment was shown to prevent dilatation of the ventricle over baseline and to increase fractional shortening (Kajimoto et al, 2006). Recently, Viollet et al (2012) reported that treatment with of an ACE inhibitor (lisinopril) with or without additional beta-blockers (metoprolol) in 42 patients significantly improved the myocardial function. Beta-blockers were added to the ACE inhibitor when average heart rate exceeded 100 beats/min on a 24-hr Holter monitoring.

Myotonic Dystrophy

Myotonic muscular dystrophy is the second most common muscular dystrophy. This disease is characterized by myotonia (increased muscular irritability and contractility with decreased power of relaxation) combined with muscular weakness. This autosomal dominant disease causes dysfunction in multiple organ systems, including the musculoskeletal, gastrointestinal, cardiovascular, endocrine, and immunologic systems.

In infancy, myotonic dystrophy presents with feeding difficulties. Later in life, developmental retardation, poor coordination, and muscle weakness are evident. During childhood, the trunk and proximal muscle groups are involved, and in late in life, the distal muscle groups and facial and neck muscles are involved. A “hatchet” face is characteristic with an open mouth, drooling, and lack of expression.

Cardiac abnormalities are frequent with involvement of the AV conduction and structural abnormalities. Fatty infiltration in the myocardium and fibrofatty degeneration in the sinus node and AV conduction system may be responsible for the manifestations.

1. The ECG may show first-degree AV block and intraventricular conduction delay. As the disease progresses, second-degree and complete heart block may develop. In addition, atrial fibrillation and flutter, abnormal Q waves, and ventricular arrhythmias may develop. Sudden death is frequent and attributable to conduction abnormalities or arrhythmias.

2. MVP may develop, usually by adulthood.

3. LV systolic dysfunction may appears with advancing age. Rarely, LVH, LA dilatation, and regional wall motion abnormalities are seen.

Patients with symptoms or evidence of dysrhythmias should be considered for pacemaker treatment. LV dysfunction, if present, should be treated.

Noonan Syndrome

Noonan syndrome, once referred to as “male Turner syndrome,” is an autosomal dominant genetic disorder, occurring in both males and females. It is associated with normal chromosomes. It was first described by Dr. Jacqueline A. Noonan, a pediatric cardiologist, in the early 1960s. Noonan sydrome occurs in about one in 1000 to 2500 live births.

The diagnosis of Noonan syndrome is suspected by distinctive facial features, short stature, chest deformity, and CHD (Romano et al, 2010).

1. The facial appearance is most characteristic in infancy and early to middle childhood. It includes a large head, wide-spaced eyes, prominent epicanthal folds, horizontal or down-slanting palpebral fissures, low-set ears, and a short and broad nose with a depressed root. The neck is short with excess skin (webbed neck) and a low posterior hairline (55%).

2. Cubitus valgus is found in more than half of the patients. Hyperextensibility is common.

3. A characteristic pectus deformity of the chest with pectus carinatum superiorly and pectus excavatum inferiorly is seen in many children with the syndrome. Scoliosis is reported in 10% to 15% of patients.

4. Although some clinical features are similar to Turner syndrome, patients with Noonan syndrome are often mentally retarded, and normal sexual maturation usually occurs, although it is delayed.

5. Cardiovascular abnormalities: More than 80% of patients with the syndrome have an abnormality of the cardiovascular system.

a. Pulmonary valve stenosis is the most common one. The valve may be dysplastic in 25% to 35% of the cases.

b. Secundum ASD is often associated with pulmonary valve stenosis.

c. Hypertrophic cardiomyopathy is present in approximately 20% of patients. The condition may resolve, become rapidly progressive, or remain stable.

6. Abnormal ECG findings are present in about 50% of patients with LAD, LVH, and abnormal Q waves.

Management

1. For significant PS, initial treatment is usually pulmonary balloon valvuloplasty, but it may be unsuccessful if the valve is dysplastic. With severe dysplasia, a pulmonary valvectomy or pulmonary homograft may be needed in childhood.

2. Patients with hypertrophic cardiomyopathy may require the use of beta-blockers or surgical myomectomy to reduce outflow obstruction.

3. Individuals without heart disease on their initial evaluation should be followed every 5 years because of the possible late appearance of cardiac problems.

4. Patients should be followed by endocrinologists for:

a. Possible growth failure, which may require growth hormone therapy

b. Thyroid hormone replacement for hypothyroidism

c. Possible pubertal induction with estrogen (for females) or testosterone (for males) for absence of breast development in girls by the age of 13 years or no testicular enlargement in boys by 14 years of age.

Rheumatoid Arthritis

Rheumatoid arthritis represents an autoimmune disease in which the synovium is the principal target of inappropriate immune attack. Autopsy cases may exhibit multiple hemorrhages on parietal and visceral pericardial surfaces with dense fibrous adhesion. The myocardium may be hypertrophied with infiltration of inflammatory cells, and irregular nodular thickening may be seen on cardiac valves.

In clinical settings, the following cardiac manifestations may occur.

1. Pericarditis is the most common finding, occurring in about 50% of cases. Chest pain and friction rub signify pericarditis. It is most frequent in systemic-onset juvenile rheumatoid arthritis (JRA), occasionally in patients with polyarticular-onset JRA and very rarely in pauciarticular-onset JRA. Small pericardial effusion occurs without symptoms, but large effusion may cause symptoms. Cardiac tamponade only rarely occurs.

2. Myocarditis occurs infrequently (1%–10%) in JRA but can lead to life-threatening CHF and arrhythmias.

3. Rarely, MR and AR with thickening of these valves occur.

4. Occasionally, LV systolic dysfunction (decreased ejection fraction and fractional shortening) with dilated LV occurs.

5. ECG abnormalities occur in 20% of cases, with the most common findings being nonspecific ST-T changes. Rarely, involvement of the conduction system with heart block can occur.

Asymptomatic and mild pericarditis may be treated with nonsteroidal antiinflammatory agents (e.g., naproxen 15 mg/kg/day in two divided doses). Symptomatic or severe pericarditis may require treatment with corticosteroids for 8 to 16 weeks. Prednisone 0.5 to 2 mg/kg/day for 1 week is gradually reduced by approximately 20%. Tamponade is treated with pericardiocentesis.

Sickle Cell Anemia

In sickle cell anemia, erythrocytes become rigid and “sickled,” leading to capillary occlusion and sickle cell “crisis.” The increased stroke volume of the heart compensates for anemia, and the heart gradually dilates and hypertrophies. Heart failure may be a late complication.

Most of the clinical manifestations reflect anemia. The arterial pulse is brisk, and the precordium is hyperactive. The diastolic pressure is low with a wide pulse pressure. An ejection systolic murmur usually is audible along the upper right and left sternal borders. Rarely, one may hear an apical rumble and a gallop rhythm. ECG abnormalities may include first-degree AV block, LVH, and nonspecific T-wave changes. Chest radiographs show generalized cardiomegaly in nearly all patients. Echocardiographic findings include increased LV dimension and vigorous LV contraction, but the ejection fraction and systolic time intervals are within normal limits.

Systemic Lupus Erythematosus

This chronic multisystem autoimmune disease can affect the cardiovascular system. The condition most commonly affects girls older than 8 years of age (78%), with a girl-to-boy ratio of 6.3:1.

The most common symptoms of lupus include constitutional complaints (fever, fatigue, anorexia, weight loss), joint pain and stiffness with or without swelling (commonly finger joints), skin rash (typical malar “butterfly” rash, seen only in 50%), and chest pain (from pleuritis or pericarditis). Evidence of renal involvement, hypertension, and Raynaud’s phenomenon are also frequent. Chorea may be the sole presenting manifestation, requiring differentiation from acute rheumatic fever.

A positive antinuclear antibody (ANA) test result is present in more than 95% of the cases, making it the most helpful initial screening test. However, a positive ANA test result is not diagnostic of the disease, particularly if the titer is low. A positive ANA test result is seen in other connective tissue diseases, such as JRA (but not in systemic-onset type), dermatomyositis, scleroderma, Sjögren’s syndrome, and mixed connective tissue disease) and in some healthy children and adults. If the ANA test result is positive, further screening by a rheumatologist should be carried out.

Cardiovascular manifestations occur in about 30% to 40% of patients with lupus erythematosus, a higher rate than with other connective tissue diseases. Pathologically, varying degrees of immune-mediated changes occur in all layers of the heart, including the pericardium (patchy infiltration of inflammatory cells, fibrous adhesion), myocardium (mild to moderate acute and chronic inflammatory foci, perivasculitis of intramural arteries, increased interstitial connective tissue, myocardial cell atrophy), and cardiac valves (classical verrucous Libman-Sacks lesions).

1. Pericarditis with pericardial effusion is the most common manifestation (≈25%) and is often asymptomatic. Tamponade is rare, and constrictive pericarditis is extremely rare.

2. Clinically evident myocarditis occurs in 2% to 25%, with resting tachycardia.

3. The classic verrucous endocarditis (Libman-Sacks) is found most commonly on the mitral valve, less commonly on the aortic valve, and only rarely on the tricuspid and pulmonary valves. Echocardiographic studies show irregular vegetations 2 to 4 mm in diameter on the valve or subvalvular apparatus (seen in ≈10%). Rarely, embolization of the vegetations can occur to a coronary or cerebral artery. Recent studies indicate that, instead of verrucous lesion, the mitral or aortic valve may exhibit diffuse thickening with or without regurgitation.

Anterior chest pain may occur with pericarditis. Apical systolic murmur of MR frequently is found, but pericardial friction rub rarely is audible. The ECG shows nonspecific ST-T changes, arrhythmias, or conduction disturbances. With pericarditis, T-wave inversion and ST segment elevation may develop.

If active valvulitis is suspected, corticosteroid therapy may be warranted. Anticoagulation therapy should also be considered.

Turner Syndrome

Turner syndrome occurs in about one of 2000 live female births. Standard karyotyping shows a missing X chromosome in more than 50% of the patients (45,X); others have a combination of monosomy X and normal cells (45,X/46,XX), called mosaic Turner syndrome.

Diagnosis of Turner syndrome is suspected at birth by a characteristic edema of the dorsa of the hands and feet and loose skin folds at the nape of the neck. Clinical manifestations in childhood include webbing of the neck, a broad chest with wide-spaced nipples, cubitus valgus, and small stature. Cardiac abnormalities are found in about 35% of patients with Turner syndrome.

Important cardiac abnormalities are as follows:

1. Bicuspid aortic valve (BAV), coarctation of the aorta (COA), and aortic wall abnormalities (ascending aortic dilatation, aneurysm formation, and aortic dissection) are more commonly found in patients with webbing of the neck. BAV may lead to clinically significant AS or AR.

2. Less common CV anomalies include the following.

a. Elongated transverse arch is present, which may be prone to dilatation and perhaps dissection).

b. Partial anomalous pulmonary venous return involving the left upper PV is found in 13%.

c. Persistent left SVC (13%).

3. The ECG may show right axis deviation, T-wave abnormalities, accelerated AV conduction, and QTc prolongation.

4. Two-dimensional echocardiography and color Doppler studies usually detect most cardiovascular abnormalities, but MRI should also be performed to evaluate other abnormalities when it can be done without sedation.

The following are suggested in the follow-ups according to the organ systems (Bondy, 2007).

1. Cardiac follow-up is required with attention to the following.

a. Monitoring blood pressure for hypertension. Hypertension is treated with beta-blockers.

b. Aortic dimension should be determined on a regular basis. If the aorta is enlarged, the patient should be treated with beta-blockers.

c. Also monitor for diabetes and dyslipidemia.

d. MRI may be advised to evaluate the aortic dimension every 5 to 10 years.

2. They should be followed by pediatric endocrinologists.

a. Growth hormone is indicated as early as possible and through puberty to attain normal adult height. Optimal age for starting growth hormone is not established, but it may be as early 9 months of age.

b. Puberty induction with estrogen therapy at around 12 years of age, if pubertal development is absent (although 30% will have spontaneous pubertal development). Spontaneous pregnancies occur in 2% to 5% of patients.

3. Cautions with regard to pregnancy:

a. Aortic dissection during pregnancy and the postpartum period is possible.

b. If pregnancy is being considered, cardiology evaluation with MRI of the aorta is indicated.

c. A history of surgically repaired cardiovascular defect, BAV, aortic dilatation, and systemic hypertension are relative contraindications of pregnancy.

4. Exercise: Regular moderate aerobic activity is emphasized. Highly competitive sports and very strenuous or isometric exercise are not recommended for patients with a dilated aortic root.

Williams Syndrome

Williams syndrome is a rare genetic condition, occurring in one per 7500 to 20,000 births; most cases are sporadic. It occurs with equal prevalence in males and females. A microdeletion in the chromosomal region 7q11.23 near the elastin gene (ELN) is identified in virtually all individuals with Williams syndrome. Elastin is a protein that allows blood vessels and other tissues in the body to stretch. Elastin arteriopathy is generalized, but it most commonly affects the ascending aorta and the pulmonary arteries.

Important cardiovascular pathology includes the following.

1. Supravalvular AS and pulmonary artery stenosis are the two most common defects, occurring singly or together, in 55% to 80% of the patients. Pulmonary artery stenosis has been reported in up to 83% of cases (in some reports).

2. Less common defects include COA, hypoplastic aortic arch, ASD, VSD, TOF, complete AV canal, and hypertrophic cardiomyopathy.

3. High pressure in the sinus of Valsalva may lead to coronary ostial narrowing and coronary artery stenosis and may result in an increased risk for sudden death.

4. There may also be renal artery stenosis with resulting hypertension.

Patients with Williams syndrome have multisystem manifestations, including cardiovascular disease, developmental delay, learning disability, mental retardation, hearing loss, severe dental disease, ocular problems, nephrolithiasis, and bowel and bladder diverticula.

1. Many children have history of failure to thrive, poor weight gain, colic, or delayed motor development during early life.

2. Most young children with the syndrome have similar characteristic features. These features include a small upturned nose, a long philtrum (upper lip length), wide mouth, full lips, a small chin, a stellate pattern in the iris (seen in 50%), and puffiness around the eyes. They have personality trait of being very friendly, trusting strangers, fearing loud sounds, and being interested in music. They are also hyperactive, inattentive, and easily distracted (attention deficit disorder). Other findings include a hoarse voice, joint hyperelasticity, contractures, kyphoscoliosis, and lordosis.

3. Cardiac examination may show systolic ejection murmur (arising from supravalvular AS or pulmonary artery stenosis).

4. Systemic hypertension may be present or develop in approximately 50% of the patients.

5. The ECG may show LVH in severe cases of supravalvular AS. BVH or RVH may be present with severe PA stenosis. Rarely, ST-T-wave abnormalities may be present.

6. Echocardiography may show most of the known cardiac abnormalities (as described earlier).

7. Renal ultrasonography may find anatomic abnormalities (found in 15%–20%) or nephrolithiasis (caused by hypercalcemia).

8. Hypercalcemia, which is noted in approximately 15% of infants with Williams syndrome, is frequently asymptomatic and resolves in the first few years of life but can be lifelong.

The diagnosis of the syndrome is suspected by facial characteristics and cardiac abnormalities (supravalvular AS or pulmonary artery stenosis). Most deletions are detected through FISH, not through standard karyotyping.

A less well-recognized fact is an increased chance of sudden death (Bird et al, 1996). It has been estimated that sudden death can occur in patients with Williams syndrome at a rate 25- to 100-fold higher than in age-matched control subjects. Deaths have been reported after the use of anesthesia or sedation or during invasive procedures (e.g., cardiac catheterization and heart surgery). Sudden deaths with no apparent instigating event have also been reported. Several factors have been cited as the potential causes of sudden death.

1. Severe supravalvular AS or severe pulmonary stenosis leading to ventricular hypertrophy and myocardial ischemia

2. Coronary artery stenosis secondary to exposure to a high systolic pressure in the sinus of Valsalva

3. Recently, prolongation of the QTc interval has been raised as a possibility. Collins et al (2010) have reported a much higher prevalence of prolonged QTc interval in patients with the syndrome. Prolonged QTc interval (≥460 ms) was found in 13.6% of the patients compared with 2.0% in control participants. Whereas JTc prolongation (>340 ms) was found in 11.7% in the patients, it was found in 1.8% in control participants. Thus, prolonged cardiac repolarization seen in this condition may be a cause of sudden death.

Management may include the following.

1. Hypercalcemia should be treated, if present. Patients should avoid taking extra calcium and vitamin D.

2. Annual cardiology evaluation is indicated with assessment of the cardiac conditions, measurement of blood pressure, and checking the QTc interval.

3. When planning a procedure, the patient’s history should be evaluated carefully for syncope, angina, fatigue or dyspnea, and hemodynamic instability during previous anesthesia or sedation.

4. Management of cardiac defects is described under specific defects; supravalvular AS in Chapter 13 and PA stenosis in Chapter 15.