Echocardiography in Pediatric and Adult Congenital Heart Disease, 2nd Ed.

25. Systemic Diseases

Several systemic diseases can directly or indirectly affect the function and geometry of the heart. Here, we discuss the cardiac implications of the systemic diseases listed below and suggest an approach to cardiac imaging for each.

1.Rheumatic fever

2.Kawasaki disease

3.Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis)

4.Human immunodeficiency virus infection

5.Metabolic syndrome

6.Cardiac diseases in cancer patients

7.Myocarditis

8.Sickle cell disease

9.Chronic kidney disease

RHEUMATIC FEVER

Rheumatic fever (RF) is an inflammatory disease caused by autoantibodies generated in response to group A β-hemolytic streptococcal infection. These antibodies cross-react with various cardiac structures—predominantly valves—resulting in their dysfunction.

Rheumatic fever is prevalent in developing countries and, in fact, most valve procedures performed in developing countries are to treat rheumatic mitral disease. Rheumatic fever is rarely encountered in developed countries, where the diagnosis is usually limited to immigrants and travelers from developing countries. Prompt diagnosis and treatment of Streptococcal pharyngitis has reduced the incidence of RF in the U.S. to less than 1%.

The diagnosis of RF is based on a combination of major and minor clinical criteria called the modified Jones criteria (Table 25.1). Carditis is one of the major criteria and can occur in up to 50% of affected patients. Carditis can involve the endocardium, myocardium, and pericardium to a variable degree, although valvulitis is clinically the most important problem. The mitral and aortic valves are involved more often than the right-sided valves. The aortic valve is rarely involved without coexisting mitral valvulitis. Acute valvulitis manifests as regurgitation, but with recovery, the regurgitation may lessen. Scarring of affected valves may lead to stenosis as a delayed complication. Myocarditis and pericarditis are not often seen and are almost nonexistent in the absence of valvulitis.

Goals of Imaging

The foremost objective of echocardiographic imaging is to diagnose carditis because it is a major diagnostic criterion for RF. Echocardiography further helps to define the presence, severity, and progression of abnormalities of valvar and myocardial structure and function. The mitral valve is usually the first valve to be affected (in 60% to 70% of cases); the aortic valve is the second (in 25% of cases); and the tricuspid valve is involved in only about 10% of cases.

During imaging, detailed information should be collected on valvar structure and function, particularly of the mitral and aortic valves. Myocardial dysfunction in acute RF can be caused by myocarditis or by acute valvar insufficiency. Pericardial effusion can usually be seen when myocarditis is present.

Rheumatic Mitral Valve Disease

During the acute phase of RF, the primary echocardiographic findings are chordal lengthening and annular dilation, which lead to poor coaptation of the mitral valve leaflets and thus regurgitation (Table 25.2). Mitral valve prolapse, especially of the anterior mitral leaflet, can be seen on two-dimensional echocardiography (Fig. 25.1, Videos 25.1–25.4). Acute valvar regurgitation can also lead to dilation of the left atrium and left ventricle, which can also be detected by two-dimensional echocardiography.

Doppler echocardiography can measure valvar regurgitation and so can be used to assess the progression of the disease. It can also provide the hemodynamic data critical to planning interventions. Color Doppler echocardiography can detect degrees of regurgitation that cannot be auscultated. It can also measure the size and duration of the regurgitant jet, providing a rough estimate of the degree of regurgitation. The effective regurgitant orifice, volume, and fraction can be calculated with the proximal isovelocity surface area (PISA).

Regurgitant volume can also be calculated with a continuity equation if there is no aortic valve disease. The stroke volume, calculated by the aortic valve time-velocity index (TVI), is the same as the effective forward volume across the mitral valve. The actual forward volume across the mitral valve can be calculated by the TVI. The difference between the actual and the effective volumes across the mitral valve is the regurgitant volume. The regurgitant fraction is the regurgitant volume divided by the total forward volume across the mitral valve.

Interrogating the mitral valve medial and lateral annuli with tissue Doppler echocardiography can help detect occult systolic and diastolic myocardial dysfunction. Clinically important mitral valve disease affects the left atrial size, pulmonary venous Doppler pattern, and right ventricular pressure. The pulmonary venous Doppler pattern can help estimate mitral regurgitation. Diastolic velocity decreases as the severity of mitral regurgitation increases, and flow in the pulmonary veins reverses in systole when regurgitation is severe. In addition to myocarditis, acute valvar insufficiency can also lead to myocardial dysfunction from RF. The presence of pericardial effusion should also be assessed.

The goals of imaging in acute rheumatic mitral valve disease are summarized in Table 25.2.

In the chronic phase of rheumatic mitral valve disease, chronic fibrosis and scarring reverse the changes that occurred in the acute phase (Table 25.3). The chordae begin to shorten and the mitral valve annulus becomes tighter. Ideally, this process will stop when the valve is close to normal in structure and function. Clinically, the patient becomes asymptomatic, and there may be no signs of disease on auscultation. More often, the fibrosis continues to progress, and the mitral valve becomes stenotic. The chordae become thick and shorten, and the valve annulus becomes smaller. The valve leaflets thicken and their mobility is reduced. The valve commissures may fuse, further limiting leaflet mobility and markedly decreasing the size of the effective mitral orifice. With these changes, the shape of the mitral valve changes from a saddle-like (normal) to a funnel-like “fish-mouth” configuration (Fig. 25.2, Videos. 25.5–25.7).

About half the patients with marked rheumatic mitral stenosis continue to have substantial mitral regurgitation as a result of the restrictive movement and persistent coaptation gap between the valve leaflets. In adults, scarred mitral valves may become calcified. The anatomy and mobility of the mitral valve can be assessed with two-dimensional echocardiography. The valve orifice can be traced by planimetry in a parasternal short-axis view to show the mitral valve en face. Three-dimensional echocardiography can be useful in understanding the structural deformity of the mitral valve. The anterior leaflet of the mitral valve can assume a characteristic “hockey-stick” appearance when its mobility is somewhat preserved but the commissures are fused, creating a “doming” of the mitral valve.

In contrast to other chronic inflammatory diseases, such as rheumatoid arthritis or systemic lupus erythematosus, the entire valve is diffusely involved in rheumatic endocarditis. Calcification of the valve in chronic rheumatic disease starts from the edges of the leaflets and progresses toward the annulus. As the stenosis progresses, left atrial pressure continues to rise. Left atrial hypertension can be evident by increased left atrial size and an abnormal pulmonary venous Doppler pattern. Progressive left atrial dilation increases the risk of atrial arrhythmias and intracardiac thrombi, which must be sought during an echocardiographic study. In pure mitral stenosis, the size of the left ventricle can be normal. However, because many patients have both mitral stenosis and regurgitation, the left ventricle may still be dilated. To confirm this dilation, the ventricular dimensions and function should be assessed.

The goals of imaging in chronic rheumatic mitral valve disease are summarized in Table 25.3.

Rheumatic Aortic Valve Disease

The aortic valve is involved in about 25% of the cases of rheumatic carditis, but it is rarely involved in the absence of mitral valve disease. In the acute phase, just as in rheumatic mitral valve disease, the predominant finding is regurgitation. The aortic valve cusps should be assessed carefully to detect any prolapse. In diastole, the regurgitant jet from the aortic valve can reach the anterior mitral leaflet, making it flutter, an effect that can be seen by two-dimensional and M-mode echocardiography. Severely elevated left ventricular diastolic pressure may close the mitral valve prematurely.

The left ventricle is typically dilated and its function may be impaired. Severe acute regurgitation of the aortic valve imposes a great volume load on the left ventricle and can hinder its function. Increased left atrial volume in the absence of mitral valve disease can be the result of increased left ventricular diastolic pressure. Color Doppler echocardiographic interrogation of the aortic valve is key to diagnosing mild regurgitation (Fig. 25.3, Video 25.8). The origin, size, and direction of the regurgitant jet must be assessed by multiple views. Pressure half-time and the proximal isovelocity surface area can estimate this regurgitation more accurately. Marked reversal in diastolic flow in the descending and abdominal aorta, as apparent on Doppler interrogation, correlates with marked aortic valve regurgitation.

FIGURE 25.1. Images of acute rheumatic mitral valve disease. A: Parasternal long-axis view in systole with zoomed image showing mild prolapse of the anterior mitral leaflet. B: Parasternal long-axis view in systole with zoomed image showing mitral regurgitation with a posteriorly directed jet caused by a prolapsing anterior leaflet. C: Parasternal short-axis view in systole with an en face perspective of the mitral valve showing mitral regurgitation. D: Apical four-chamber view in systole showing eccentric mitral regurgitation jet.

FIGURE 25.2. Images of chronic rheumatic mitral valve disease. A: Parasternal long-axis view in systole showing the typical “hockey-stick” appearance of the anterior mitral leaflet caused by restricted mobility of the leaflet edge. B: Parasternal long-axis view in systole showing marked mitral regurgitation. C: Parasternal short-axis view in diastole with an en face perspective of the mitral valve showing restricted opening of the leaflets with a greatly reduced effective orifice.

The goals of imaging in acute rheumatic aortic valve disease are summarized in Table 25.4.

In chronic rheumatic aortic valve disease, fibrosis of the valve cusps leads to progressive stenosis. In addition, the fibrosis also causes the valve cusps to shorten and retract, leading to concomitant regurgitation. The commissures may fuse, limiting the excursion of cusps and resulting in a small effective orifice (Fig. 25.4, Videos 25.9–25.12). Planimetry by two-dimensional and three-dimensional echocardiography can determine the effective valve area. The effective valve area can also be determined by the continuity equation using the left ventricular outflow tract and the aortic valve TVI. Doppler interrogation provides critical hemodynamic information. Mean and maximum pressure gradients can be calculated by continuous-wave Doppler interrogation across the aortic valve. The severity of aortic stenosis can be underestimated when ventricular function is impaired. The TVI ratios of the left ventricular outflow tract and the aortic valve can help reveal this underestimated severity from decreased ventricular function.

FIGURE 25.3. Image of acute rheumatic aortic valve disease. Parasternal long-axis view in diastole showing mild aortic regurgitation.

The goals of imaging in chronic rheumatic aortic valve disease are summarized in Table 25.5.

KAWASAKI DISEASE

Kawasaki disease (KD) is an acute vasculitis syndrome of childhood that affects the coronary arteries. Its cause is unknown. It is more prevalent in Americans of Asian and Pacific Island descent, in which the incidence is about 30 per 100,000 children up to age 5 years. About 80% of affected children receiving medical care are under 5 years of age, and their median age is 2 years.

The diagnosis is based on clinical criteria (Table 25.6). Characteristic signs include fever for 5 days, cracked lips, bilateral conjunctivitis, “strawberry tongue” (glossitis), cervical lymphadenopathy, and desquamation of the hands and feet. Other clinical features include sterile pyuria, anterior uveitis, perianal erythema, edema and erythema of the hands and feet, gallbladder hydrops, hepatitis, and irritability. The disease is characterized by inflammation of the mid-sized arteries throughout the body, which results in various clinical features. However, the long-term sequelae stem from the involvement of the coronary arteries. Young infants and children older than 8 years have the highest rate of coronary artery involvement.

Cardiovascular pathology in KD progresses in four stages. In the first, acute phase, which occurs at about the first 10 days of illness, there is diffuse microvascular angiitis with endarteritis and perivasculitis of the major coronary arteries. These conditions can result in pericarditis, valvulitis, and endocarditis. More often, myocarditis is seen at this stage, which may involve the intracardiac conduction system. Stage 2, the subacute phase, lasts until the third or fourth week of illness and is characterized by a panvasculitis of the major coronary arteries, which results in aneurysm and thrombus formation. Myocarditis, endocarditis, and pericarditis can still be present in this stage. Stage 3 is also subacute and lasts from the fourth to the fifth week of illness. In this stage, microvascular angiitis resolves and the coronary arteries granulate, which causes intimal thickening. The fourth and late phase lasts 40 days to 4 years and is characterized by fibrosis and scarring of the coronary arteries and myocardium. Thrombosed vessels recanalize during this stage.

Goals of Imaging

Imaging is not a component of the diagnostic criteria for KD. The role of imaging in KD is primarily prognostic. However, according to the 2011 American Academy of Pediatrics statement for KD, it can also help in establishing the diagnosis in cases of incomplete KD, where all the required diagnostic criteria are not met. In this situation, a positive echocardiogram establishes the diagnosis.

The goals of imaging in Kawasaki disease are summarized in Table 25.7.

Given the pathophysiology of KD, the American Heart Association recommends that every child in whom KD is diagnosed be evaluated by echocardiography at the time of diagnosis, 2 weeks after diagnosis, and again 6 to 8 weeks after diagnosis. Furthermore, children with coronary artery disease should be assessed annually. For long-term follow-up, the American Heart Association recommendations include invasive and noninvasive assessment of ventricular function, coronary abnormalities, and perfusion studies based on the risk levels defined below.

■Risk level I. No coronary artery abnormality: no diagnostic imaging.

■Risk level II. Transient coronary artery ectasia resolving in 6 to 8 weeks: no diagnostic imaging.

■Risk level III. One small-to-medium-size coronary artery aneurysm: a yearly echocardiogram and electrocardiogram and a biennial stress test or perfusion imaging study. Angiography is indicated only if noninvasive imaging suggests ischemia.

■Risk level IV: One or more large or giant coronary artery aneurysms without obstruction: semi-annual echocardiograms and electrocardiograms and an annual stress test or perfusion imaging study. Angiography is recommended 6 to 12 months after diagnosis or sooner if clinically indicated. Repeat angiography is recommended if noninvasive tests suggest ischemia.

■Risk level V. Coronary artery obstruction: semiannual echocardiograms and electrocardiograms, an annual stress test or perfusion imaging study, and angiography to address therapeutic options.

FIGURE 25.4. Images of chronic rheumatic aortic valve disease. A: Parasternal short-axis view in systole with an en face perspective of the aortic valve showing the restricted opening of the leaflets with a greatly reduced effective orifice. B: Parasternal short-axis view of the aortic valve in diastole showing the central regurgitation jet. C: Parasternal long-axis view in systole showing the dome of the aortic valve leaflets created by restricted mobility. The left atrium is severely dilated as a result of concomitant severe mitral stenosis. D: Parasternal long-axis view in systole showing a wide regurgitant jet across the aortic valve, indicating substantial regurgitation. The effective orifice of the mitral valve is extremely reduced as a result of coexisting mitral stenosis. The left atrium is enlarged, and the anterior mitral leaflet has the “hockey-stick” appearance.

During the acute phase, the initial echocardiogram usually shows only a few subtle findings with respect to coronary artery disease. Increased perivascular brightness and mild coronary ectasia may indicate vasculitis. More important findings during the acute phase are the presence of pericardial effusion secondary to pericarditis, reduced ventricular function secondary to myocarditis, and new valvar (most likely mitral) regurgitation secondary to valvulitis.

Baseline ventricular function should be measured with several methods so that follow-up imaging can detect even small changes. Assessing regional wall motion abnormalities with deformation imaging may be useful. In the subacute and late phases, the goals of imaging are primarily to detect coronary abnormalities or reduced ventricular function with regional wall motion abnormalities. The proximal portion of the coronary arteries can be visualized easily in most patients. However, assessing coronary arteries in patients with KD is not limited to the proximal coronary arteries; the distal coronary arteries must also be interrogated with specific views, as explained in the next section.

The internal diameter of the coronary arteries should be compared to normative data. In normal individuals, the internal diameter of the coronary arteries should be less than 3 mm in children less than 5 years old, and less than 4 mm in children older than 5 years. Diffuse dilation of a coronary artery more than these limits, without aneurysm, is “coronary ectasia” (Fig. 25.5). Segmental dilation or narrowing along the length of a vessel is important. An internal diameter of a segment that measures 1.5 times that of the adjacent segment is considered to be abnormal.

Coronary aneurysms should be described by their number, shape, size, and location. The shape of the aneurysms can be described as either fusiform or saccular (Fig. 25.6).Multiple aneurysms in a coronary artery can give a “beads-on-string” appearance. The aneurysms can be classified as small (<5 mm in internal diameter), medium (5 to 8 mm in internal diameter), or giant (>8 mm in internal diameter).

Children with a diagnosis of KD but without coronary abnormalities (risk level I) are still considered high-risk for early onset of adult coronary artery disease. The 2011 National Heart, Lung, and Blood Institute Guidelines categorize children with KD as high-risk for early coronary artery disease and recommend lower cut-off values for body mass index, blood pressure, and lipid levels to trigger early interventions.

Imaging Coronary Arteries by Echocardiography

Echocardiographic assessment of coronary arteries is important in diagnosing and following patients with KD. The highest quality coronary artery images should be obtained. A high-frequency transducer should be used with the highest feasible frequency. In general, slightly reducing the two-dimensional gain and compression (dynamic range) will improve visualizing the coronary arteries. In most pediatric echocardiograms, imaging the origin and proximal portions of the coronary arteries is adequate. However, in children with KD, every effort should be made to visualize the length of each of the three major coronary arteries.

FIGURE 25.5. Kawasaki disease. Ectasia of the right coronary artery segment.

FIGURE 25.6. Kawasaki disease. Yellow arrow: saccular aneurysm of the right coronary artery. Red arrow: giant, fusiform aneurysm of the left coronary artery.

FIGURE 25.7. Kawasaki disease. The parasternal short-axis view is optimal to start imaging the coronary arteries. RCA, origin of the right coronary artery; LCA, origin of the left coronary artery.

The proximal left coronary artery is best visualized in the parasternal short-axis view. The bifurcation of the left coronary artery into the left anterior descending and circumflex arteries is best visualized by rotating the transducer clockwise to the 3 o’clock position (Fig. 25.7, Video 25.13). Tilting the transducer toward the left shoulder can better show the length of the left anterior descending coronary artery (Fig. 25.8, Video 25.14). Pointing the transducer downward will show the circumflex coronary artery better (Fig. 25.9). A high, left parasternal window can sometimes be useful in imaging the left coronary artery (Fig. 25.10, Video 25.15). The distal left anterior descending coronary artery can be better seen in the parasternal long-axis view by angling the transducer toward the left shoulder to visualize the anterior interventricular groove. A similar view of the distal left anterior descending coronary artery can be obtained through a subcostal window in the coronal plane. To visualize the length of the left circumflex coronary artery, anterior angulation in the apical view can be helpful.

FIGURE 25.8. Kawasaki disease. Counterclockwise rotation of the transducer with tilting toward the left shoulder shows the length of left anterior descending coronary artery (LAD) in the anterior interventricular groove. The LAD is ectatic with a distal fusiform aneurysm. Ao, aorta.

FIGURE 25.9. Kawasaki disease. Clockwise rotation of the transducer with downward tilting shows the left circumflex coronary artery (LCx). Ao, aorta.

The parasternal short-axis view is also optimal to image the right coronary artery (Fig. 25.7, Video 25.13), although better images of its origin can sometimes be obtained by rotating the transducer counterclockwise toward 12 o’clock. However, the length of the artery is better seen with the transducer at 3 o’clock. The parasternal long-axis view can be helpful in identifying a high origin of the right coronary artery. As in visualizing the left circumflex coronary artery, the right coronary artery can also be seen in the apical view with anterior angulation of the transducer. Posterior angulation of the transducer in the apical view can show the posterior descending coronary artery. The subcostal sagittal view, obtained by angling the transducer toward the right atrioventricular groove, can show the entire length of the right coronary artery. The subcostal coronal view with anterior angulation can show the right coronary artery in the anterior atrioventricular groove (Fig. 25.11, Videos 25.16).

FIGURE 25.10. Kawasaki disease. The high left parasternal window can be used to see the left coronary artery by tilting the transducer below the pulmonary artery. Note the fusiform aneurysm of the left anterior descending coronary artery (LAD).

AUTOIMMUNE DISEASES

Autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, stem from antibodies formed against various cell components (cell membrane, cytoplasm, and nucleus). These diseases involve several organs, but late mortality is primarily from cardiovascular causes. These diseases affect the cardiovascular system in several ways, but the major targets are the pericardium, myocardium, cardiac valves, conduction system, coronary arteries, and pulmonary and systemic vasculature.

Pericardial Involvement

The most common cardiac effect of rheumatoid arthritis and systemic lupus erythematosus is pericardial effusion (Fig. 25.12, Videos 25.17–25.19). From one-third to one-half of these patients may have pericardial disease, which may or may not manifest clinically. When clinically manifest, the usual symptom is chest pain. Cardiac tamponade is rare; however, pericardial fluid rich in inflammatory products can cause constrictive pericarditis. The degree of effusion usually correlates with the degree of immunosuppression. Therefore, pericardial effusion is commonly seen at presentation or during exacerbation.

FIGURE 25.11. Kawasaki disease. An aneurysm of the right coronary artery (RCA) seen from a subcostal coronal view tilted anteriorly toward the anterior atrioventricular groove.

Myocardial and Coronary Artery Involvement

Myocardial involvement can be multifactorial. Chronic inflammation, drug toxicity, coronary vasculitis, and premature coronary artery disease can all contribute to myocardial damage. Chronic inflammation in the myocardium continues to destroy cardiomyocytes and results in fibrosis and scarring, which can be detected by abnormal, delayed myocardial hyperenhancement on cardiac magnetic resonance imaging (Fig. 25.13). Continued scarring and destruction of cardiomyocytes eventually leads to dilated cardiomyopathy.

Myocarditis is usually subclinical and occurs in up to 10% of patients with lupus. It usually manifests as reduced ventricular function. Some transient myocardial thickening or increased echogenicity of the left ventricular walls from interstitial edema may be notable. Diastolic ventricular dysfunction is common and related to the duration of the disease. Therefore, ventricular systolic and diastolic function should always be assessed quantitatively in these patients, especially with tissue Doppler echocardiography.

FIGURE 25.12. Pericardial effusion in systemic lupus erythematosus. A: Parasternal subcostal view. B: Parasternal short-axis view. C: Apical four-chamber view.

FIGURE 25.13. Myocarditis in systemic lupus erythematosus. Magnetic resonance imaging reveals subepicardial to transmural, focal, abnormal delayed myocardial hyperenhancement at the mid-ventricular inferior segment (yellow arrows) of the left ventricle.

The chronic inflammatory nature of these diseases puts these patients at higher risk for early coronary artery disease. The 2011 National Heart, Lung, and Blood Institute Guidelines place children with chronic inflammatory diseases in the moderate-risk category for the early development of coronary artery disease as adults. Regional wall motion abnormalities can be useful in detecting advanced coronary artery involvement and can be measured by deformation imaging with strain and strain-rate analysis. Regional wall motion abnormalities can also be caused by localized vasculitis of the coronary arteries or myocarditis.

Valvar Involvement

Any cardiac valve can degenerate in these chronic inflammatory diseases. Non-bacterial thrombotic (Libman-Sacks) endocarditis (or “marantic endocarditis,” meaning endocarditis in a wasting state) can be present in systemic lupus erythematosus. These nonspecific vegetations are sterile but can embolize. They are also present in many other hypercoagulable states and cancers. On echocardiography, they appear along the lines of valvar closure and may have a smooth or “warty” look (a “verrucous” appearance). As in rheumatic endocarditis, these vegetations have a predilection to form on the mitral and aortic valves, but the right-sided valves can still be involved. The posterior leaflet of the mitral valve is a common site for these vegetations (Fig. 25.14, Videos 25.20–25.22). Verrucous vegetations can sometimes be seen in mural endocarditis. These vegetations rarely cause valvular stenosis and are more likely to distort the valves, resulting in regurgitation. Mitral or aortic regurgitation can be seen in 20% to 60% of adults with lupus. In rheumatoid arthritis, the primary valvar involvement is degeneration of the mitral and aortic valves, which begins in the core of the leaflets, creating rheumatoid nodules.

Pulmonary Vascular Involvement

Up to one-third of patients with systemic autoimmune diseases can have pulmonary hypertension, even in the absence of obvious cardiac or pulmonary disease. Estimating right ventricular pressure by tricuspid regurgitation is extremely important to estimate pulmonary artery pressure. Assessing right ventricular function and size is also critical in long-standing pulmonary hypertension. Right atrial enlargement or a dilated inferior vena cava may also indicate increased end-diastolic pressure of the right ventricle secondary to prolonged pressure overload.

FIGURE 25.14. Nonbacterial thrombotic (Libman-Sacks) endocarditis in systemic lupus erythematosus. Transesophageal echocardiographs of the mitral valve in three different patients showing small nodular masses on the posterior leaflet of the mitral valve (yellow arrowheads) at mid-esophageal four-chamber views (A and B) and left ventricular inflow–outflow view (C).

Systemic Vascular Involvement

Systemic hypertension, which is common in patients with chronic systemic autoimmune diseases, is usually caused by vasculitis and renal disease. In addition, chronic inflammatory mediators in the circulation also contribute to the early development of atherosclerosis. The secondary effects of systemic hypertension, such as left ventricular hypertrophy, should be assessed by echocardiography over several months, and the left ventricular mass should be calculated, primarily for prognostic purposes and to assess blood pressure control.

The goals of imaging in chronic systemic autoimmune diseases are summarized in Table 25.8.

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus is a disease resulting from the transplacental passage of maternal autoantibodies in infants born to mothers who have systemic chronic inflammatory diseases (such as systemic lupus erythematosus, rheumatoid arthritis, or Sjögren’s syndrome). This disease primarily involves the heart, liver, and skin. In the heart, the conduction system is the primary target of these antibodies. Congenital heart block occurs in 15% to 30% of infants born with neonatal lupus erythematosus. For this reason, fetal echocardiography is indicated in mothers with systemic lupus erythematosus (Fig. 25.15). Fetal rhythm should be assessed in detail in such cases. If a complete heart block is not present, the mechanical PR interval should be monitored to detect first-degree heart block in utero. The mechanical PR interval is the time from the start of atrial contraction to the start of ventricular contraction.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION

As in other systemic illnesses, human immunodeficiency virus (HIV) infection affects the cardiovascular system in several ways. In addition, antiretroviral therapies may also have long-term adverse cardiovascular effects. These effects are more important in children because many are exposed to these medications, even in utero. Exposure to highly active antiretroviral therapy (HAART) is a risk factor for metabolic abnormalities and accelerated coronary artery disease. Patients can have cardiac disorders related to other opportunistic infections and tumors as well. The major cardiovascular components involved include the pericardium, myocardium, cardiac valves, coronary arteries, and pulmonary vasculature.

FIGURE 25.15. Fetal echocardiogram showing complete heart block. Simultaneous Doppler interrogation of the left ventricle reveals different inflow and outflow rates of the atrium (red) and ventricle (yellow). The ventricular rate is 40 beats/min and the atrial rate is 140 beats/min.

Pericardial Involvement

The pericardium is a common target for HIV-related inflammation. The most common cause of pericardial effusion in HIV-infected patients is idiopathic. Bacterial, fungal, and other opportunistic infections are the second most common causes of pericarditis. Kaposi’s sarcoma and lymphomas can also cause pericardial effusion.

Clinically, pericardial disease may be silent or can present with shortness of breath or chest pain. Echocardiography can detect pericardial effusion in about a third of HIV-infected patients. Large pericardial effusions with cardiac tamponade are possible, especially with Mycobacterium infection. The presence of a pericardial effusion is considered a poor prognostic factor in patients with HIV infection.

Myocardial Involvement

In HIV-infected patients, the myocardium can be affected in several ways, especially by myocarditis, cardiomyopathy, and coronary artery disease. Focal myocarditis is identified at autopsy in up to half of HIV-infected patients. However, most of these patients are clinically asymptomatic. Myocarditis can be caused by opportunistic infections, but in up to 80% of cases, the cause is uncertain and may be a part of generalized inflammation. Myocarditis should be suspected from echocardiographic evidence of acutely reduced ventricular function. Chronic myocardial damage from ongoing myocarditis, accelerated coronary artery disease, cachexia, and drug toxicity can all contribute to the development of dilated cardiomyopathy. Every echocardiographic study should assess systolic and diastolic ventricular function in detail.

Coronary Artery Involvement

Children infected with HIV are at higher risk for early coronary artery disease. The 2011 National Heart, Lung, and Blood Institute Guidelines categorize patients with HIV infection in the moderate-risk group for the early development of coronary artery disease. Measuring ventricular systolic and diastolic function is important. Regional wall motion abnormalities should be assessed for accelerated coronary artery disease. Deformation imaging can measure regional wall motion abnormalities and can also detect subtle changes in systolic function.

Valvar Involvement

Nonbacterial thrombotic (marantic) endocarditis, similar to that in systemic lupus erythematosus, can develop during chronic inflammation in HIV infection. However, infective endocarditis is also common, especially in intravenous drug abusers.

Pulmonary Vascular Involvement

Pulmonary hypertension is most commonly idiopathic in these patients. Repeated pneumonias and pulmonary scarring can also lead to pulmonary hypertension. Diffuse pulmonary microemboli and pulmonary veno-occlusive disease can also occur. Right heart failure secondary to severe pulmonary hypertension is possible. Right ventricular function should be assessed with modalities such as tissue Doppler echocardiography and tricuspid annular plane systolic excursion. Right ventricular systolic pressure should be estimated by tricuspid regurgitation mapping.

Large-Vessel Arteriopathy

Arteriopathy of the aorta and pulmonary arteries consists of medial hypertrophy and chronic inflammation. Large-vessel arteriopathy is associated with increased left ventricular mass as well. Medial hypertrophy and chronic inflammation can cause areas of discrete or diffuse stenosis in the blood vessels.

Cardiac Tumors

Kaposi’s sarcoma and non-Hodgkin lymphoma are malignancies that may primarily involve the myocardium or pericardium. Pericardial effusion is usually the first sign of these malignancies, which can form obstructive intracavitary masses. However, more commonly, these tumors are diffusely infiltrative and may or may not be seen on echocardiography.

Echocardiographic imaging in patients with HIV infection is targeted principally to assess systolic and diastolic ventricular function and to rule out pericardial effusion.

The goals of comprehensive echocardiographic assessment are summarized in Table 25.9.

METABOLIC SYNDROME

Obesity causes structural and functional changes in the heart. It also increases the cardiometabolic risk and predisposes to early coronary artery disease. Obesity is an independent risk factor for heart failure in adults. This risk is incremental and increases directly with higher body mass index. The duration of morbid obesity is one of the strongest predictors of heart failure in adults. Type 2 diabetes mellitus, which is also a component of the metabolic syndrome, also causes structural and functional changes in the heart.

Structural Changes

Geometric changes in the heart associated with obesity include increased left and right ventricular mass and volume. Echocardiography can detect these changes long before symptomatic heart failure ensues. Left ventricular dilation, increased left ventricular mass, and left ventricular regional wall hypertrophy in obese adults have been described in several studies. Increased left ventricular mass may be the earliest and most important structural change that can be measured in children by echocardiography.

If obese children also have diabetes mellitus, left ventricular hypertrophy may be exaggerated. Hypertrophy of the left ventricle in obesity is eccentric, unlike that in hypertensive individuals, who usually have concentric patterns. Left atrial enlargement can also be seen in obese individuals and is most likely caused by impaired left ventricular diastolic function. The amount of epicardial adipose tissue increases around the coronary arteries and at the apex of the heart and can be detected by magnetic resonance imaging. There is no standard method to quantify epicardial adipose tissue.

Functional Changes

Although systolic left ventricular dysfunction is rare in children with the metabolic syndrome, diastolic dysfunction is quite common and may be the earliest manifestation of obesity-related cardiomyopathy. Increased left ventricular mass, by itself, can cause abnormal diastolic function, which, in turn, can cause left atrial enlargement. Abnormal blood flow across the mitral valve as detected by Doppler echocardiography can also indicate left ventricular diastolic dysfunction. Abnormalities in the tissue Doppler pattern can be seen in poorly controlled type 2 diabetes mellitus, which may or may not be reversible with good glycemic control. Many patients with abnormal Doppler patterns at rest may show left ventricular diastolic dysfunction with exercise. Systolic function is initially increased in obese individuals, but it declines over time. Right heart failure secondary to obstructive sleep apnea can also occur.

Goals of Imaging

The goals of imaging in the metabolic syndrome are to identify possible structural and functional changes (Table 25.10). However, echocardiographic imaging can be challenging in obese individuals as a result of poor acoustic windows. M-mode and two-dimensional measurements of the left ventricle are important. The thicknesses of the left ventricular free wall and the septal wall should also be measured. Left atrial volume should be measured to identify left ventricular diastolic dysfunction. Spectral Doppler and tissue Doppler imaging are crucial in identifying ventricular systolic and diastolic dysfunction. Early changes in left ventricular myocardial function may be detected with deformation imaging in obese individuals, even when two-dimensional echocardiography shows a normal left ventricular ejection fraction.

CARDIAC DISEASES IN CANCER PATIENTS

The prevalence of cardiotoxicity is increasing in cancer survivors because they are living longer. Early detection of cardiotoxicity in patients being treated for cancer is critical for their long-term survival. Serial echocardiographic examinations are the mainstay of detecting these adverse effects on the heart. These examinations are useful in diagnosing ventricular dysfunction and pericardial and valvar heart diseases.

Heart disease develops in cancer patients in several ways. The cancer and its cachexia by themselves can adversely affect the heart. Chemotherapy and radiotherapy can also have detrimental cardiac effects. In addition, cancer patients are also at risk of opportunistic infections secondary to immunosuppression. The primary targets of these effects in the cardiovascular system are the myocardium, pericardium, cardiac valves, coronary arteries, conduction tissue, and the pulmonary and systemic vasculature. In addition, cardiac compression from mediastinal tumors and metastasis of distant tumors is also possible.

Myocardial Involvement

Myocardial damage in cancer may be acute or chronic. After exposure to cardiotoxic chemotherapeutic agents, ventricular systolic function can quickly deteriorate. For this reason, most cardiotoxic chemotherapeutic protocols include echocardiographic surveillance. However, the predictive value of subclinical ventricular dysfunction during acute cancer therapy in children in terms of using those values to adjust chemotherapy to improve overall quality of life and survival free of both cancer and heart disease is unknown. Long-term follow-up is becoming more important with improved survival. Repeated cardiotoxic insults from the cancer, cachexia, chemotherapeutic agents, and radiation culminate in the progressive loss of cardiomyocytes, which are replaced by fibrous tissue.

The adverse effects of mediastinal radiation are caused primarily by the formation of oxygen free radicals, which initiate a diffuse inflammatory response in various mediastinal tissues, followed by diffuse fibrosis in all these tissues. Increased myocardial fibrosis may manifest as impaired diastolic function and may eventually lead to restrictive cardiomyopathy. Strain and strain-rate analysis by spectral tracking, along with tissue velocity imaging, may be useful in diagnosing subtle changes in ventricular function but its predictive value for disease free outcomes is unknown.

Pericardial Involvement

The acute cardiotoxic effects of chemotherapy and radiation may be associated with acute pericarditis. Pericardial effusion, which may or may not be clinically symptomatic, can be diagnosed with echocardiography. A small amount of pericardial effusion is common in patients undergoing cancer treatment. This effusion rarely progresses to tamponade. The long-term effect of mediastinal radiation is increased fibrosis in the mediastinum, including an increase in the thickness of the pericardium and constrictive pericarditis.

The echocardiographic diagnosis of increased pericardial thickness is extremely challenging, and computed tomography and magnetic resonance imaging may be more useful (Fig. 25.16). However, echocardiographic imaging can be useful in diagnosing constrictive pericarditis.

Valvar and Endocardial Involvement

Generalized mediastinal fibrosis also involves the cardiac valves and the mural endocardium. Endocardial fibrosis may lead to restrictive cardiomyopathy. Valvar tissue, primarily in the aortic and mitral valves, degenerates in long-term cancer survivors. The typical degenerative process of the valve apparatus usually starts from the annulus and progresses toward the leaflet tips (Fig. 25.17, Videos 25.23 and 25.24). Valvar sclerosis, fibrosis, and calcification can also occur in adult survivors.

Secondary Involvement of the Heart

Large mediastinal tumors can compress the cardiac chambers and major blood vessels (Fig. 25.18, Videos 25.25 and 25.26), although metastasis to the heart is rare. Tumors from other organs, such as kidney, can extend directly into the heart.

Goals of Imaging

Echocardiography is the imaging modality of choice in cancer patients for surveillance of cardiotoxic effects (Table 25.11). However, sometimes advanced imaging modalities, such as computed tomography or magnetic resonance imaging, may be needed. Even when echocardiography is unable to confirm a diagnosis, it may raise suspicion for pathology.

FIGURE 25.16. Pericardial thickening after mediastinal irradiation. Magnetic resonance imaging showing abnormal delayed myocardial hyperenhancement in the pericardium, which is thickened circumferentially and can be seen in all the slices (yellow arrowheads).

MYOCARDITIS

Myocarditis is inflammation of cardiac muscle that can be acute or chronic. Viral infections are the most common cause of acute myocarditis. Autoimmune disorders and toxins (drugs, venoms, etc.) can also cause myocarditis. The range of clinical presentation varies from no symptoms to sudden death with evidence of myocarditis on autopsy. Most children presenting to the hospital with a diagnosis of acute myocarditis have signs and symptoms of heart failure. Fulminant myocarditis is a more sudden presentation with severe hemodynamic compromise. The initial cardiomyocyte death occurs from the direct effect of viral infection. This is followed by activation of an innate immune response, which causes further myocardial damage. In the third phase, viral-specific immune responses create antibodies that may continue to damage the myocardium leading to a dilated cardiomyopathy in a genetically predisposed individual. The involvement of the myocardium is patchy and does not follow any specific pattern. Myocardial damage results in contractile dysfunction. The ventricles may be dilated. Papillary muscle dysfunction can cause mitral valve regurgitation. Pericardial effusion may be present.

FIGURE 25.17. Radiation-induced valve disease. A: Parasternal long-axis view showing thickening and calcification of the mitral valve annulus. Radiation-induced valve disease typically starts from the annulus and then extends toward the leaflet tips. B: The same view with color Doppler echocardiography showing marked regurgitation.

FIGURE 25.18. Mediastinal tumor compressing the right ventricular outflow tract. Parasternal short-axis views: A: Mediastinal mass (yellow arrowheads) compressing the right ventricular outflow tract. B: Color Doppler echocardiography interrogation shows the accelerated flow in the right ventricular outflow tract caused by outside compression.

Goals of Imaging

Endomyocardial biopsy is generally considered the gold standard for the diagnosis. However, the role of biopsy has been questioned for several reasons. First, it does not alter the clinical outcome. Biopsy-proven myocarditis follows the same clinical course and outcome as clinically diagnosed pediatric myocarditis without a biopsy; both having a different course than children with dilated cardiomyopathy (Foerster et al.). Second, the patchy involvement of the myocardium leads to false-negative tests, which result in low sensitivity of endomyocardial biopsy. These patchy infiltrates can be seen on cardiac magnetic resonance imaging as abnormal enhancement on delayed images. Echocardiography helps in narrowing the diagnosis by excluding anatomic defects such as coronary anomalies. In acute myocarditis, the left ventricular diastolic dimensions are increased, whereas these are normal in fulminant myocarditis. Similarly, septal thickness is normal in acute and increased in fulminant myocarditis. Periodic assessment of ventricular function and diastolic dimensions has prognostic value as well.

The goals of imaging in myocarditis are summarized in Table 25.12.

SICKLE CELL DISEASE

Sickle cell disease is a familial disorder, characterized by abnormal hemoglobin. It is the most common inherited blood disorder in the US involving more than 70,000 individuals. It occurs in 1 in every 500 African-Americans. Abnormal “sickling” of hemoglobin S leads to vaso-occlusive phenomena and hemolysis. Clinical manifestations vary among the genotypes: sickle cell anemia (HbSS – most severe), combined heterozygosity for hemoglobins S and C (HbSC – intermediate severity), and sickle cell trait (HbS – benign). Patients with homozygous hemoglobin S have more severe anemia and are more likely to get recurrent vaso-occlusive phenomena. Acute painful episodes, cerebrovascular complications, splenic dysfunction, bone infarctions, leg ulcers, priapism, and acute chest syndrome are examples of such vaso-occlusive phenomena. Similar vaso-occlusive phenomenon occurs in the heart and may cause progressive myocardial damage. However, cardiac effects of sickle cell disease have several etiologies. Chronic anemia along with decreased oxygen saturation result in increased cardiac output leading to progressive chamber enlargement and cardiomegaly. Decreased oxygen-carrying capacity and increased myocardial demand can lead to myocardial infarction, even when the coronary arteries are completely normal. Pulmonary hypertension is commonly seen in sickle cell disease and can lead to right heart failure. Left ventricular diastolic dysfunction can be identified in most of these patients. Cardiomyopathy due to hemosiderosis from repeated blood transfusions can also be seen in these patients. As with cerebrovascular abnormalities, the myocardial microvasculature can also be abnormal.

Goals of Imaging

Assessment of myocardial function is the primary objective of echocardiographic imaging in sickle cell disease. When systolic ventricular function is normal, detailed assessment of diastolic function must be performed. Left ventricular diastolic dimensions need to be monitored. Myocardial infarction should be suspected if regional wall motion abnormalities are seen. Estimation of pulmonary artery pressure is important. If hemosiderosis is suspected, cardiac MRI with T2* quantification must be performed to guide the need for chelation.

The goals of imaging in sickle cell disease are summarized in Table 25.13.

CHRONIC KIDNEY DISEASE

According to the 2011 guidelines of the National Heart, Lung, and Blood Institute, children with chronic renal disease, end-stage renal disease, and postrenal transplant are at high risk for accelerated atherosclerosis and early cardiovascular disease. Uremic cardiomyopathy is another common complication in patients with chronic renal disease. Moreover, left ventricular hypertrophy can be seen in up to 85% of children with advanced chronic kidney disease. Left ventricular hypertrophy and dilation occur in response to volume overload from renal dysfunction, as well as pressure overload from systemic hypertension. Coexisting anemia may further increase the cardiac workload. The left ventricular hypertrophy and elevated left ventricular body mass index have important prognostic value in patients with advanced chronic kidney disease. These are often associated with adverse outcomes such as heart failure, myocardial ischemia, arrhythmia, and cardiac death. Left ventricular filling pressure may be elevated with or without left ventricular hypertrophy. Left ventricular systolic dysfunction is a poor prognostic factor in patients on hemodialysis. Pericardial effusion can be seen due to volume overload or azotemia leading to uremic pericarditis.

The goals of imaging in chronic renal disease are summarized in Table 25.14.

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Questions

1.Calcification and thickening of the mitral valve annulus is seen on a transthoracic echocardiogram. This is typical valvular involvement in which of the following diseases?

A.Rheumatic carditis

B.Infective endocarditis

C.Non-bacterial thrombotic endocarditis

D.Radiation exposure

E.Kawasaki disease

2.The endocarditis in systemic lupus erythematosus is characterized by which of the following?

A.Needs prophylaxis against infective endocarditis with antibiotics

B.The vegetations can embolize

C.The vegetations are infective

D.The vegetations are completely benign

E.The vegetations often require surgical resection

3.Which of the following coronary abnormalities is not a part of Kawasaki disease?

A.Coronary artery fistula

B.Coronary artery aneurysm

C.Coronary artery ectasia

D.Coronary artery stenosis

E.Coronary artery thrombosis

4.The most common finding on echocardiography in children with systemic lupus erythematosus is which of the following?

A.Impaired systolic function of the left ventricle

B.Nonbacterial thrombotic (Libman-Sacks) endocarditis

C.Left-ventricular hypertrophy

D.Coronary artery stenosis

E.Pericardial effusion

5.Which cardiac valves are most commonly involved in acute rheumatic carditis?

A.Mitral and aortic valves

B.Mitral valve alone

C.Aortic valve alone

D.Mitral and tricuspid valves

E.Aortic and pulmonary valves

F.Tricuspid and pulmonary valves

6.Which of the following systemic diseases does NOT involve pericardial effusion ?

A.Rheumatic fever

B.Kawasaki Disease

C.Autoimmune diseases

D.Human immunodeficiency virus infection

E.Metabolic syndrome

7.Which of the systemic diseases below do NOT involve endocarditis and valvulitis?

A.Rheumatic fever

B.Kawasaki Disease

C.Autoimmune diseases

D.Human immunodeficiency virus infection

E.Metabolic syndrome

8.Which of the following systemic diseases do NOT predispose to early coronary artery disease ?

A.Rheumatic fever

B.Kawasaki Disease

C.Autoimmune diseases

D.Human immunodeficiency virus infection

E.Metabolic syndrome

9.Which of the following echocardiographic findings is most likely to be seen on transthoracic echocardiography in acute rheumatic carditis?

A.Mitral stenosis

B.Mitral regurgitation

C.Aortic stenosis

D.Aortic regurgitation

E.Tricuspid stenosis

10.The late effect of mediastinal exposure to radiation includes which of the following?

A.Left ventricular hypertrophy

B.Mitral valve prolapse

C.Abnormal pericardial thickening

D.Predisposition to infective endocarditis

E.Coronary artery aneurysms

Answers

1.Answer: D. After radiation exposure, valve tissue degenerates in long-term cancer survivors. The typical degenerative process of the valve apparatus usually starts from the annulus and progresses toward the leaflet tips. Rheumatic valvulitis typically involves all the valve tissue and the calcification usually starts from the leaflet edges and progresses toward the annulus. Infective endocarditis and Kawasaki Disease do not have any typical pattern of involvement. The posterior mitral leaflet is typically involved in nonbacterial thrombotic endocarditis.

2.Answer: B. The marantic endocarditis in systemic lupus erythematosus is called “nonbacterial thrombotic endocarditis.” As the name implies, these are not infective in nature and do not require prophylaxis against infective endocarditis. However, these vegetations can embolize and are not completely benign. Surgical intervention is rarely needed.

3.Answer: A. Kawasaki Disease does not cause coronary artery fistulae. Coronary ectasia can be seen in acute or subacute phases of Kawasaki Disease. Coronary artery aneurysms, stenosis and thrombosis occur in Kawasaki Disease.

4.Answer: E. Pericardial effusion is the most common finding on echocardiography in children with systemic lupus erythematosus. All the other options are possible in lupus, but are less common.

5.Answer: B. The mitral valve is usually the first valve to be affected (in 60% to 70% of cases); the aortic valve is the second most common (in 25% of cases); and the tricuspid valve is involved in only about 10% of cases. The aortic valve is rarely involved in the absence of mitral valve disease. Pulmonary valve involvement is very rare.

6.Answer: E. Pericardial effusion is not an echocardiographic finding associated with metabolic syndrome. All other systemic diseases can cause pericardial effusion.

7.Answer: E. Endocarditis and valvulitis are not the echocardiographic findings seen in metabolic syndrome. All other systemic diseases listed can cause endocarditis.

8.Answer: E. Rheumatic fever does not predispose to early coronary artery disease. All other systemic diseases listed predispose to early coronary artery disease.

9.Answer: B. The mitral valve is usually the first valve to be involved in acute rheumatic fever. Annular dilatation and lengthening of chordae causes mitral valve regurgitation. Stenosis of any valve occurs primarily in the chronic phase. The aortic valve is rarely involved in the absence of mitral valve disease. Tricuspid valve involvement is rare.

10.Answer: C. The long-term effect of mediastinal radiation is increased fibrosis in the mediastinum, including an increase in the thickness of the pericardium and constrictive pericarditis. The acute cardiotoxic effects of chemotherapy and radiation may be acute pericarditis. Left ventricular hypertrophy can occur in systemic hypertension and metabolic syndrome. Mitral valve prolapse can occur in acute rheumatic carditis. Radiation exposure does not predispose to infective endocarditis of coronary artery aneurysm formation.