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InternalMed_Harrison. MVP is more common in women and occurs most frequently between the ages of 15 and 30 years; the clinical course is most often benign. MVP may also be observed in older (>50 years) patients, often men, in whom MR is often more severe and requires surgical treatment. There is an increased familial incidence for some patients, suggesting an autosomal dominant form of inheritance with incomplete penetrance. MVP varies in its clinical expression, ranging from only a systolic click and murmur with mild prolapse of the posterior leaflet to severe MR due to chordal rupture and leaflet flail. The degree of myxomatous change of the leaflets can also vary widely. In many patients, the condition progresses over years or decades; in others, it worsens rapidly as a result of chordal rupture or endocarditis.


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InternalMed_Harrison. Most patients are asymptomatic and remain so for their entire lives. However, in North America, MVP is now the most common cause of isolated severe MR requiring surgical treatment. Arrhythmias, most commonly ventricular premature contractions and paroxysmal supraventricular and ventricular tachycardia, as well as AF, have been reported and may cause palpitations, light-headedness, and syncope. Sudden death is a very rare complication and occurs most often in patients with severe MR and depressed LV systolic function. There may be an excess risk of sudden death among patients with a flail leaflet. Many patients have chest pain that is difficult to evaluate; it is often substernal, prolonged, and not related to exertion, but may rarely resemble angina pectoris. Transient cerebral ischemic attacks secondary to emboli from the mitral valve due to endothelial disruption have been reported. Infective endocarditis may occur in patients with MR and/or leaflet thickening.


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InternalMed_Harrison. Auscultation A frequent finding is the mid or late (nonejection) systolic click, which occurs 0.14 s or more after S1 and is thought to be generated by the sudden tensing of slack, elongated chordae tendineae or by the prolapsing mitral leaflet when it reaches its maximal excursion. Systolic clicks may be multiple and may be followed by a high-pitched, mid-late systolic crescendo-decrescendo murmur, which occasionally is “whooping” or “honking” and is heard best at the apex. The click and murmur occur earlier with standing, during the strain phase of the Valsalva maneuver, and with any intervention that decreases LV volume, exaggerating the propensity of mitral leaflet prolapse. Conversely, squatting and isometric exercises, which increase LV volume, diminish MVP; the click-murmur complex is delayed, moves away from S1, and may even disappear. Some patients have a mid-systolic click without a murmur; others have a murmur without a click. Still others have both sounds at different


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InternalMed_Harrison. is delayed, moves away from S1, and may even disappear. Some patients have a mid-systolic click without a murmur; others have a murmur without a click. Still others have both sounds at different times.


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InternalMed_Harrison. The ECG most commonly is normal but may show biphasic or inverted T waves in leads II, III, and aVF, and occasionally supraventricular or ventricular premature beats. TTE is particularly effective in identifying the abnormal position and prolapse of the mitral valve leaflets. A useful echocardiographic definition of MVP is systolic displacement (in the parasternal long axis view) of the mitral valve leaflets by at least 2 mm into the LA superior to the plane of the mitral annulus. Color flow and continuous wave Doppler imaging is helpful to evaluate the associated MR and provide semiquantitative estimates of severity. The jet lesion of MR due to MVP is most often eccentric, and assessment of RF and effective regurgitant orifice area can be difficult. TEE is indicated when more accurate information is required and is performed routinely for intraoperative guidance for valve repair. Invasive left ventriculography is rarely necessary but can also show prolapse of the posterior and


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InternalMed_Harrison. information is required and is performed routinely for intraoperative guidance for valve repair. Invasive left ventriculography is rarely necessary but can also show prolapse of the posterior and sometimes of both mitral valve leaflets.


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InternalMed_Harrison. Infective endocarditis prophylaxis is indicated only for patients with a prior history of endocarditis. Beta blockers sometimes relieve chest pain and control palpitations. If the patient is symptomatic from severe MR, mitral valve repair (or rarely, chord-sparing replacement) is indicated (Fig. 284-4). Antiplatelet agents, such as aspirin, should be given to patients with transient ischemic attacks, and if these are not effective, warfarin should be considered. Warfarin is also indicated once AF intervenes.


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InternalMed_Harrison. Tricuspid and Pulmonic valve Disease Patrick T. O’Gara, Joseph Loscalzo TRICUSPID STENOSIS Tricuspid stenosis (TS), which is much less prevalent than mitral 285 stenosis (MS) in North America and Western Europe, is generally rheumatic in origin, and is more common in women than men (Table 285-1). It does not occur as an isolated lesion and is usually associated with MS. Hemodynamically significant TS occurs in 5–10% of patients with severe MS; rheumatic TS is commonly associated with some degree of tricuspid regurgitation (TR). Nonrheumatic causes of TS are rare.


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InternalMed_Harrison. A diastolic pressure gradient between the right atrium (RA) and right ventricle (RV) defines TS. It is augmented when the transvalvular blood flow increases during inspiration and declines during expiration. A mean diastolic pressure gradient of 4 mmHg is usually sufficient to elevate the mean RA pressure to levels that result in systemic venous congestion. Unless sodium intake has been restricted and diuretics administered, this venous congestion is associated with hepatomegaly, ascites, and edema, sometimes severe. In patients with sinus rhythm, the RA a wave may be extremely tall and may even approach the level of the RV systolic pressure. The y descent is prolonged. The cardiac output (CO) at rest is usually depressed, and it fails to rise during exercise. The low CO is responsible for the normal or only slightly elevated left atrial (LA), pulmonary artery (PA), and RV systolic pressures despite the presence of MS. Thus, the presence of TS can mask the hemodynamic and clinical


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InternalMed_Harrison. for the normal or only slightly elevated left atrial (LA), pulmonary artery (PA), and RV systolic pressures despite the presence of MS. Thus, the presence of TS can mask the hemodynamic and clinical features of any associated MS.


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InternalMed_Harrison. Because the development of MS generally precedes that of TS, many patients initially have symptoms of pulmonary congestion and fatigue. Characteristically, patients with severe TS complain of relatively little dyspnea for the degree of hepatomegaly, ascites, and edema that they have. However, fatigue secondary to a low CO and discomfort due to refractory edema, ascites, and marked hepatomegaly are common in patients with advanced TS and/or TR. In some patients, TS may be Secondary (functional) RV and tricuspid annular dilatation due to multiple causes of RV enlargement (e.g., long-standing pulmonary HTN, remodeling post-RV MI) Chronic RV apical pacing Abbreviations: HTN, hypertension; MI, myocardial infarction; RV, right ventricular; TVP, tricuspid valve prolapse. suspected for the first time when symptoms of right-sided failure persist after an adequate mitral valvotomy.


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InternalMed_Harrison. suspected for the first time when symptoms of right-sided failure persist after an adequate mitral valvotomy. Because TS usually occurs in the presence of other obvious valvular disease, the diagnosis may be missed unless it is considered. Severe TS is associated with marked hepatic congestion, often resulting in cirrhosis, jaundice, serious malnutrition, anasarca, and ascites. Congestive hepatomegaly and, in cases of severe tricuspid valve disease, splenomegaly are present. The jugular veins are distended, and in patients with sinus rhythm, there may be giant a waves. The v waves are less conspicuous, and because tricuspid obstruction impedes RA emptying during diastole, there is a slow y descent. In patients with sinus rhythm, there may be prominent presystolic pulsations of the enlarged liver as well.


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InternalMed_Harrison. On auscultation, an opening snap (OS) of the tricuspid valve may rarely be heard approximately 0.06 s after pulmonic valve closure. The diastolic murmur of TS has many of the qualities of the diastolic murmur of MS, and because TS almost always occurs in the presence of MS, it may be missed. However, the tricuspid murmur is generally heard best along the left lower sternal border and over the xiphoid process, and is most prominent during presystole in patients with sinus rhythm. The murmur of TS is augmented during inspiration, and it is reduced during expiration and particularly during the strain phase of the Valsalva maneuver, when tricuspid transvalvular flow is reduced.


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InternalMed_Harrison. The electrocardiogram (ECG) features of RA enlargement (see Fig. 268-8) include tall, peaked P waves in lead II, as well as prominent, upright P waves in lead V1. The absence of ECG evidence of RV 1548 hypertrophy (RVH) in a patient with right-sided heart failure who is believed to have MS should suggest associated tricuspid valve disease. The chest x-ray in patients with combined TS and MS shows particular prominence of the RA and superior vena cava without much enlargement of the PA and with less evidence of pulmonary vascular congestion than occurs in patients with isolated MS. On echocardiographic examination, the tricuspid valve is usually thickened and domes in diastole; the transvalvular gradient can be estimated by continuous wave Doppler echocardiography. Severe TS is characterized by a valve area ≤1 cm2 or pressure half-time of ≥190 ms. The RA and inferior vena cava (IVC) are enlarged. Transthoracic echocardiography (TTE) provides additional information regarding the


InternalMed_Harrison

InternalMed_Harrison. by a valve area ≤1 cm2 or pressure half-time of ≥190 ms. The RA and inferior vena cava (IVC) are enlarged. Transthoracic echocardiography (TTE) provides additional information regarding the severity of any associated TR, mitral valve structure and function, left ventricle (LV) and RV size and function, and PA pressure. Cardiac catheterization is not routinely necessary for assessment of TS.


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InternalMed_Harrison. Patients with TS generally exhibit marked systemic venous congestion; salt restriction, bed rest, and diuretic therapy are required during the preoperative period. Such a preparatory period may diminish hepatic congestion and thereby improve hepatic function sufficiently so that the risks of operation, particularly bleeding, are diminished. Surgical relief of the TS should be carried out, preferably at the time of surgical mitral valvotomy or mitral valve replacement (MVR) for mitral valve disease, in patients with moderate or severe TS who have mean diastolic pressure gradients exceeding ~4 mmHg and tricuspid orifice areas <1.5–2 cm2. TS is almost always accompanied by significant TR. Operative repair may permit substantial improvement of tricuspid valve function. If repair cannot be accomplished, the tricuspid valve may have to be replaced. Meta-analysis has shown no difference in overall survival between mechanical and tissue valve replacement. Mechanical valves in the tricuspid


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InternalMed_Harrison. the tricuspid valve may have to be replaced. Meta-analysis has shown no difference in overall survival between mechanical and tissue valve replacement. Mechanical valves in the tricuspid position are more prone to thromboembolic complications than in other positions. Percutaneous tricuspid balloon valvuloplasty for isolated severe TS without significant TR is very rarely performed.


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InternalMed_Harrison. In at least 80% of cases, TR is secondary to marked dilation of the tricuspid annulus from RV enlargement due to PA hypertension (Table 285-1). Functional TR may complicate RV enlargement of any cause, however, including an inferior myocardial infarction (MI) that involves the RV. It is commonly seen in the late stages of heart failure due to rheumatic or congenital heart disease with severe PA hypertension (PA systolic pressure >55 mmHg), as well as in ischemic and idiopathic dilated cardiomyopathies. It is reversible in part if PA hypertension can be relieved. Functional TR can also develop from chronic RV apical pacing. Rheumatic fever may produce primary (organic) TR, often associated with TS. Infarction of RV papillary muscles, tricuspid valve prolapse, carcinoid heart disease, endomyocardial fibrosis, radiation, infective endocarditis, and leaflet trauma all may produce TR. Less commonly, TR results from congenitally deformed tricuspid valves, and it occurs with defects of the


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InternalMed_Harrison. fibrosis, radiation, infective endocarditis, and leaflet trauma all may produce TR. Less commonly, TR results from congenitally deformed tricuspid valves, and it occurs with defects of the atrioventricular canal, as well as with Ebstein’s malformation of the tricuspid valve (Chap. 282).


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InternalMed_Harrison. The incompetent tricuspid valve allows blood to flow backward from the RV into the RA, the volume of which is dependent on the driving pressure (i.e., RV systolic pressure) and the size of the regurgitant orifice. The severity and physical signs of TR can vary as a function of PA systolic pressure (in the absence of RV outflow tract stenosis), the dimension of the tricuspid valve annulus, the respiratory cycle– dependent changes in RV preload, and RA compliance. RV filling is increased during inspiration. Forward CO is reduced and does not augment with exercise. Significant degrees of TR will lead to RA enlargement and elevation of the RA and jugular venous pressures with prominent c-v waves in the pulse tracings. Progressively severe TR can lead to “ventricularization” of the RA wave form (see Fig. 267-1B). Severe TR is also characterized by RV dilation (RV volume overload) and eventual systolic dysfunction, the rate of which can be accelerated by a concomitant pressure load from PA


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InternalMed_Harrison. (see Fig. 267-1B). Severe TR is also characterized by RV dilation (RV volume overload) and eventual systolic dysfunction, the rate of which can be accelerated by a concomitant pressure load from PA hypertension or by myocardial fibrosis from previous injury.


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InternalMed_Harrison. Mild or moderate degrees of TR are usually well tolerated in the absence of other hemodynamic disturbances. Because TR most often coexists with left-sided valve lesions, LV dysfunction, and/or PA hypertension, symptoms related to these lesions may dominate the clinical picture. Fatigue and exertional dyspnea owing to reduced forward CO are early symptoms of isolated, severe TR. As the disease progresses and RV function declines, patients may report cervical pulsations, abdominal full-ness/bloating, diminished appetite, and muscle wasting, although with progressive weight gain and painful swelling of the lower extremities.


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InternalMed_Harrison. The neck veins in patients with severe TR are distended with prominent c-v waves and rapid y descents (in the absence of TS). TR is more often diagnosed by examination of the neck veins than by auscultation of the heart sounds. Other findings may include marked hepatomegaly with systolic pulsations, ascites, pleural effusions, edema, and a positive hepatojugular reflex. A prominent RV pulsation along the left parasternal region and a blowing holosystolic murmur along the lower left sternal margin, which may be intensified during inspiration (Carvallo’s sign) and reduced during expiration or the strain phase of the Valsalva maneuver, are characteristic findings. The murmur of TR may sometimes be confused with that of MR unless attention is paid to its variation during the respiratory cycle and the extent of RV enlargement is appreciated. Atrial fibrillation (AF) is usually present in the chronic phase of the disease.


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InternalMed_Harrison. The ECG may show changes characteristic of the lesion responsible for the TR, e.g., an inferior Q-wave MI suggestive of a prior RV MI, RVH, or a bizarre right bundle branch block type pattern with preexcitation in patients with Ebstein’s anomaly. ECG signs of RA enlargement may be present in patients with sinus rhythm; AF is frequently noted. The chest x-ray may show RA and RV enlargement, depending on the chronicity and severity of TR. TTE is usually definitive with demonstration of RA dilation and RV volume overload and prolapsing, flail, scarred, or displaced/tethered tricuspid leaflets; the diagnosis and assessment of TR can be made by color flow Doppler imaging (see Fig. 270e-8). Severe TR is accompanied by hepatic vein systolic flow reversal. Continuous wave Doppler of the TR velocity profile is useful in estimating PA systolic pressure. Accurate assessment of TR severity, PA pressures, and RV size and systolic function with TTE can be quite challenging in many patients.


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InternalMed_Harrison. velocity profile is useful in estimating PA systolic pressure. Accurate assessment of TR severity, PA pressures, and RV size and systolic function with TTE can be quite challenging in many patients. Real-time three-dimensional echocardiography and cardiac magnetic resonance (CMR) imaging provide alternative imaging modalities, although they are not widely available. In patients with severe TR, the CO is usually markedly reduced, and the RA pressure pulse may exhibit no x descent during early systole but a prominent c-v wave with a rapid y descent. The mean RA and RV end-diastolic pressures are often elevated. Exercise testing can be used to assess functional capacity in patients with asymptomatic severe TR. The prognostic significance of exercise-induced changes in TR severity and RV function has not been well studied.


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InternalMed_Harrison. TREATMEnT tricuSPid regurgitation (fig. 285-1) Diuretics can be useful for patients with severe TR and signs of right heart failure. An aldosterone antagonist may be particularly helpful because many patients have secondary hyperaldosteronism from marked hepatic congestion. Therapies to reduce elevated PA pressures and/or pulmonary vascular resistance, including those targeted at left-sided heart disease, can also be considered for patients with PA hypertension and severe functional TR. Tricuspid valve surgery is recommended for patients with severe TR who are undergoing


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InternalMed_Harrison. FIGURE 285-1 Management of tricuspid regurgitation. See legend for Fig. 283-2 for explanation of treatment recommendations (Class I, IIa, IIb) and disease stages (B, C, D). Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. PHTN, pulmonary hypertension; RV, right ventricular; TA, tricuspid annular; TTE, transthoracic echocardiogram; TR, tricuspid regurgitation; TV, tricuspid valve; TVR, tricuspid valve replacement. ∗ TA dilation is defined by >40 mm on TTE (>21 mm/m2) or >70 mm on direct intraoperative measurement. (Adapted from RA Nishimura et al: 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease. J Am Coll Cardiol doi: 10.1016/j.jacc.2014.02.536, 2014, with permission.) left-sided valve surgery and is also undertaken frequently for treatment of even


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InternalMed_Harrison. of Patients with Valvular Heart Disease. J Am Coll Cardiol doi: 10.1016/j.jacc.2014.02.536, 2014, with permission.) left-sided valve surgery and is also undertaken frequently for treatment of even moderate TR in patients undergoing left-sided valve surgery who have tricuspid annular dilation (>40 mm), a history of right heart failure, or PA hypertension. Operation most often comprises repair rather than replacement in these settings and has become routine in most major surgical centers. Surgery may also infrequently be required for treatment of severe, primary TR with right heart failure not responsive to standard medical therapy or because of progressively declining RV systolic function. Reported perioperative mortality rates for isolated tricuspid valve surgery (repair and replacement) are high (~8-9%) and likely are influenced by the hazards encountered during reoperation on patients who have undergone previous left-sided valve surgery and have reduced RV function. Indwelling


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InternalMed_Harrison. are high (~8-9%) and likely are influenced by the hazards encountered during reoperation on patients who have undergone previous left-sided valve surgery and have reduced RV function. Indwelling pacemaker or defibrillator leads can also pose technical challenges.


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InternalMed_Harrison. Pulmonic valve stenosis (PS) is essentially a congenital disorder (Table 285-1). With isolated PS, the valve is typically domed. Dysplastic pulmonic valves are seen as part of the Noonan’s syndrome (Chap. 302), which maps to chromosome 12. Much less common etiologies include carcinoid and obstructing tumors or bulky vegetations. The pulmonic valve is only very rarely affected by the rheumatic process.


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InternalMed_Harrison. PS is defined hemodynamically by a systolic pressure gradient between the RV and main PA. RV hypertrophy develops as a consequence of sustained obstruction to RV outflow, and systolic ejection is prolonged. Compared with the ability of the LV to compensate for the pressure overload imposed by aortic stenosis (AS), RV dysfunction from afterload mismatch occurs earlier in the course of PS and at lower peak systolic pressures, because the RV adapts less well to this type of hemodynamic burden. With normal systolic function and CO, severe PS is defined by a peak systolic gradient across the pulmonic valve of >50 mmHg; moderate PS correlates with a peak gradient of 30–50 mmHg. PS rarely progresses in patients with peak gradients less than 30 mmHg, but may worsen in those with moderate disease due to valve thickening and calcification with age. The RA a wave elevates in relation to the higher pressures needed to fill a noncompliant, hypertrophied RV. A prominent RA v wave signifies


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InternalMed_Harrison. disease due to valve thickening and calcification with age. The RA a wave elevates in relation to the higher pressures needed to fill a noncompliant, hypertrophied RV. A prominent RA v wave signifies functional TR from RV and annular dilation. The CO is maintained until late in the course of the disease.


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InternalMed_Harrison. Patients with mild or even moderate PS are usually asymptomatic and first come to medical attention because of a heart murmur that leads to echocardiography. With severe PS, patients may report exertional dyspnea or early-onset fatigue. Anginal chest pain from RV oxygen supply-demand mismatch and syncope may occur with very severe forms of obstruction, particularly in the presence of a destabilizing trigger such as atrial fibrillation, fever, infection, or anemia.


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InternalMed_Harrison. The murmur of mild or moderate PS is mid-systolic in timing, crescendo-decrescendo in configuration, heard best in the left second interspace, and usually introduced by an ejection sound (click) in younger adults whose valves are still pliable. The ejection sound is the only right-sided acoustic event that decreases in intensity with inspiration. This phenomenon reflects premature opening of the pulmonic valve by the elevated RV end-diastolic (postatrial a wave) pressure. The systolic murmur increases in intensity during inspiration. With progressively severe PS, the ejection sound moves closer to the first heart sound and eventually becomes inaudible. A right-sided fourth heart sound may emerge. The systolic murmur peaks later and may persist through the aortic component of the second heart sound (A2). Pulmonic valve 1550 closure is delayed, and the pulmonic component of the second heart sound (P2) is reduced or absent. A prominent a wave, indicative of the higher atrial pressure


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InternalMed_Harrison. heart sound (A2). Pulmonic valve 1550 closure is delayed, and the pulmonic component of the second heart sound (P2) is reduced or absent. A prominent a wave, indicative of the higher atrial pressure necessary to fill the noncompliant RV, may be seen in the jugular venous pulse. A parasternal or RV lift can be felt with significant pressure overload. Signs of right heart failure, such as hepatomegaly, ascites, and edema, are uncommon but may appear very late in the disease.


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InternalMed_Harrison. The ECG will show right axis deviation, RVH, and RA enlargement in adult patients with severe PS. Chest x-ray findings include poststenotic dilation of the main PA in the frontal plane projection and filling of the retrosternal airspace due to RV enlargement on the lateral film. In some patients with RVH, the cardiac apex appears to be lifted off the left hemidiaphragm. The RA may also be enlarged. TTE allows definitive diagnosis and characterization in most cases, with depiction of the valve and assessment of the gradient, RV function, PA pressures (which should be low), and any associated cardiac lesions. TEE may be useful in some patients for improved delineation of the RV outflow tract (RVOT) and assessment of infundibular hypertrophy. Cardiac catheterization is not usually necessary, but if performed, pressures should be obtained from just below and above the pulmonic valve with attention to the possibility that a dynamic component to the gradient may exist. The correlation


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InternalMed_Harrison. but if performed, pressures should be obtained from just below and above the pulmonic valve with attention to the possibility that a dynamic component to the gradient may exist. The correlation between Doppler assessment of peak instantaneous gradient and catheterization-measured peak-to-peak gradient is weak. The latter may correlate better with the Doppler mean gradient.


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InternalMed_Harrison. Diuretics can be used to treat symptoms and signs of right heart failure. Provided there is less than moderate pulmonic regurgitation, pulmonic balloon valvotomy is recommended for symptomatic patients with a domed valve and a peak gradient >50 mmHg (or mean gradient >30 mmHg) and for asymptomatic patients with a peak gradient >60 mmHg (or mean gradient >40 mmHg). Surgery may be required when the valve is dysplastic (as seen in patients with Noonan’s syndrome and other disorders). A multidisciplinary heart team is best positioned to make treatment decisions of this nature.


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InternalMed_Harrison. Pulmonic regurgitation (PR) may develop as a consequence of primary valve pathology, annular enlargement, or their combination; after surgical treatment of RVOT obstruction in children with such disorders as tetralogy of Fallot; or after pulmonic balloon valvotomy (Table 285-1). Carcinoid usually causes mixed pulmonic valve disease with PR and PS. Long-standing severe PA hypertension from any cause can result in dilation of the pulmonic valve ring and PR.


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InternalMed_Harrison. Severe PR results in RV chamber enlargement and eccentric hypertrophy. As is the case for aortic regurgitation (AR), PR is a state of increased preload and afterload. The reverse pressure gradient from the PA to the RV, which drives the PR, progressively decreases throughout diastole and accounts for the decrescendo nature of the diastolic murmur. As RV diastolic pressure increases, the murmur becomes shorter in duration. The forward CO is preserved during the early stages of the disease, but may not increase normally with exercise and declines over time. A reduction in RV ejection fraction may be an early indicator of hemodynamic compromise. In advanced stages, there is significant enlargement of the RV and RA with marked elevation of the jugular venous pressure.


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InternalMed_Harrison. Mild or moderate degrees of PR do not, by themselves, result in symptoms. Other problems, such as PA hypertension, may dominant the clinical picture. With progressively severe PR and RV dysfunction, fatigue, exertional dyspnea, abdominal fullness/bloating, and lower extremity swelling may be reported.


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InternalMed_Harrison. The physical examination hallmark of PR is a high-pitched, decrescendo diastolic murmur (Graham Steell murmur) heard along the left sternal border that can be difficult to distinguish from the more frequently appreciated murmur of aortic regurgitation. The Graham Steell murmur may become louder with inspiration and is usually associated with a loud and sometimes palpable P2 and an RV lift, as would be expected in patients with significant PA hypertension of any cause. Survivors of childhood surgery for tetralogy of Fallot or PS/pulmonary atresia may have an RV-PA conduit that is freely regurgitant because it does not contain a valve. PA pressures in these individuals are not elevated and the diastolic murmur can be misleadingly low pitched and of short duration despite significant degrees of PR and RV volume overload.


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InternalMed_Harrison. Depending on both the etiology and severity of PR, the ECG may show findings of RVH and RA enlargement. On chest x-ray, the RV and RA may be enlarged. Pulmonic valve morphology and function can be assessed with transthoracic Doppler echocardiography. PA pressures can be estimated from the tricuspid valve systolic jet velocity. CMR provides greater anatomic detail, particularly in patients with repaired congenital heart disease, and more precise assessment of RV volumes. Cardiac catheterization is not routinely necessary but would be performed as part of a planned transcatheter procedure.


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InternalMed_Harrison. In patients with functional PR due to PA hypertension and annular dilation, efforts to reduce PA vascular resistance and pressure should be optimized. Such efforts may include pharmacologic/ vasodilator and/or surgical/interventional strategies, depending on the cause of the PA hypertension. Diuretics can be used to treat the manifestations of right heart failure. Surgical valve replacement for primary, severe, pulmonic valve disease, such as carcinoid or endocarditis, is rarely undertaken. Transcatheter pulmonic valve replacement has been successfully performed in many patients with severe PR after childhood repair of tetralogy of Fallot or pulmonic valve stenosis or atresia. This procedure was introduced clinically prior to transcatheter aortic valve replacement. Patrick T. O’Gara, Joseph Loscalzo


InternalMed_Harrison

InternalMed_Harrison. Many acquired and congenital cardiac lesions may result in stenosis and/or regurgitation of one or more heart valves. For example, rheumatic heart disease can involve the mitral (mitral stenosis [MS], mitral regurgitation [MR], or MS and MR), aortic (aortic stenosis [AS], aortic regurgitation [AR], or AS and AR), and/or tricuspid (tricuspid stenosis [TS], tricuspid regurgitation [TR], or TS and TR) valve, alone or in combination. The common association of functional TR with significant mitral valve disease is discussed in Chap. 285. Severe mitral annular calcification can result in regurgitation (due to decreased annular shortening during systole) and mild stenosis (caused by extension of the calcification onto the leaflets resulting in restricted valve opening). Patients with severe AS may develop functional MR that may not improve after isolated aortic valve replacement (AVR). Chordal rupture has been described infrequently in patients with severe AS. Aortic valve infective


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InternalMed_Harrison. AS may develop functional MR that may not improve after isolated aortic valve replacement (AVR). Chordal rupture has been described infrequently in patients with severe AS. Aortic valve infective endocarditis may secondarily involve the mitral apparatus either by abscess formation and contiguous spread via the inter-valvular fibrosa or by “drop metastases” from the aortic leaflets onto the anterior leaflet of the mitral valve. Mediastinal radiation may result in aortic, mitral, and even tricuspid valve disease, most often with mixed stenosis and regurgitation. Carcinoid heart disease may cause mixed lesions of either or both the tricuspid and pulmonic valves. Ergotamines, and the previously used combination of fenfluramine and phentermine, can rarely result in mixed lesions of the aortic and/ or mitral valve. Patients with Marfan’s syndrome may have both AR from aortic root dilation and MR due to mitral valve prolapse (MVP). Myxomatous degeneration causing prolapse of multiple valves


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InternalMed_Harrison. and/ or mitral valve. Patients with Marfan’s syndrome may have both AR from aortic root dilation and MR due to mitral valve prolapse (MVP). Myxomatous degeneration causing prolapse of multiple valves (mitral, aortic, tricuspid) can also occur in the absence of an identifiable connective tissue disorder. Bicuspid aortic or pulmonic valve disease can result in mixed stenosis and regurgitation.


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InternalMed_Harrison. In patients with multivalvular heart disease, the pathophysiologic derangements associated with the more proximal valve disease can mask the full expression of the attributes of the more distal valve lesion. For example, in patients with rheumatic mitral and aortic valve disease, the reduction in cardiac output (CO) imposed by the mitral valve disease will decrease the magnitude of the hemodynamic derangements related to the severity of the aortic valve lesion (stenotic, regurgitant, or both). Alternatively, the development of atrial fibrillation (AF) during the course of MS can lead to sudden worsening in a patient whose aortic valve disease was not previously felt to be significant. The development of reactive pulmonary vascular disease, sometimes referred to as a “secondary obstructive lesion in series,” can impose an additional challenge in these settings. As CO falls with progressive tricuspid valve disease, the severity of any associated mitral or aortic disease can be


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InternalMed_Harrison. lesion in series,” can impose an additional challenge in these settings. As CO falls with progressive tricuspid valve disease, the severity of any associated mitral or aortic disease can be underestimated.


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InternalMed_Harrison. One of the most common examples of multivalve disease is that of functional TR in the setting of significant mitral valve disease. Functional TR occurs as a consequence of right ventricular and annular dilation; pulmonary artery (PA) hypertension is often present. The tricuspid leaflets are morphologically normal. Progressive degrees of TR lead to right ventricular volume overload and continued chamber and annular dilation. The TR is usually central in origin; reflux into the right atrium (RA) is expressed as large, systolic c-v waves in the RA pressure pulse. The height of the c-v wave is dependent on RA compliance and the volume of regurgitant flow. The RA wave form may become “ventricularized” in advanced stages of chronic, severe TR with PA hypertension. CO falls and the severity of the associated mitral valve disease may become more difficult to appreciate. Primary rheumatic tricuspid valve disease may occur with rheumatic mitral disease and cause hemodynamic changes reflective


InternalMed_Harrison

InternalMed_Harrison. the associated mitral valve disease may become more difficult to appreciate. Primary rheumatic tricuspid valve disease may occur with rheumatic mitral disease and cause hemodynamic changes reflective of TR, TS, or their combination. With TS, the y descent in the RA pressure pulse is prolonged.


InternalMed_Harrison

InternalMed_Harrison. Another example of rheumatic, multivalve disease involves the combination of mitral and aortic valve pathology, frequently characterized by MS and AR. In isolated MS, left ventricular (LV) preload and diastolic pressure are reduced as a function of the severity of inflow obstruction. With concomitant AR, however, LV filling is enhanced and diastolic pressure may rise depending on the compliance characteristics of the chamber. Because the CO falls with progressive degrees of MS, transaortic valve flows will decline, masking the potential severity of the aortic valve lesion (AR, AS, or its combination). As noted above, onset of AF in such patients can be especially deleterious.


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InternalMed_Harrison. Functional MR may complicate the course of some patients with severe AS. The mitral valve leaflets and chordae tendineae are usually normal. Incompetence is related to changes in LV geometry (remodeling) and abnormal systolic tethering of the leaflets in the context of markedly elevated LV systolic pressures. Relief of the excess afterload with surgical or transcatheter AVR often, but not always, results in reduction or elimination of the MR. Persistence of significant MR following AVR is associated with impaired functional outcomes and reduced survival. Identification of patients who would benefit from concomitant treatment of their functional MR at time of AVR is quite challenging. Most surgeons advocate for repair of moderate-to-severe 1551 or severe functional MR at time of surgical AVR.


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InternalMed_Harrison. In patients with mixed AS and AR, assessment of valve stenosis can be influenced by the magnitude of the regurgitant valve flow. Because transvalvular systolic flow velocities are augmented in patients with AR and preserved LV systolic function, the LV-aortic Doppler-derived pressure gradient and the intensity of the systolic murmur will be elevated to values higher than expected for the true systolic valve orifice size as delineated by planimetry. Uncorrected, the Gorlin formula, which relies on forward CO (systolic transvalvular flow) and the mean pressure gradient for calculation of valve area, is not accurate in the setting of mixed aortic valve disease. Similar considerations apply to patients with mixed mitral valve disease. The peak mitral valve Doppler E wave velocity (v0) is increased in the setting of severe MR because of enhanced early diastolic flow and may not accurately reflect the contribution to left atrial (LA) hypertension from any associated MS. When either AR or MR


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InternalMed_Harrison. in the setting of severe MR because of enhanced early diastolic flow and may not accurately reflect the contribution to left atrial (LA) hypertension from any associated MS. When either AR or MR is the dominant lesion in patients with mixed aortic or mitral valve disease, respectively, the LV is dilated. When AS or MS predominates, LV chamber size will be normal or small. It can sometimes be difficult to ascertain whether stenosis or regurgitation is the dominant lesion in patients with mixed valve disease, although an integrated clinical and noninvasive assessment can usually provide clarification for purposes of patient management and follow-up.


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InternalMed_Harrison. Patients with significant AS, a nondilated LV chamber, and concentric hypertrophy will poorly tolerate the abrupt development of aortic regurgitation, as may occur, for example, with infective endocarditis or after surgical or transcatheter AVR complicated by paravalvular leakage. The noncompliant LV is not prepared to accommodate the sudden volume load, and as a result, LV diastolic pressure rises rapidly and severe heart failure develops. Indeed, paravalvular regurgitation is a significant risk factor for shortto intermediate-term death following transcatheter AVR. Conditions in which the LV may not be able to dilate in response to chronic AR (or MR) include radiation heart disease and, in some patients, the cardiomyopathy associated with obesity and diabetes. Noncompliant ventricles of small chamber size predispose to earlier onset diastolic dysfunction and heart failure in response to any further perturbation in valve function.


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InternalMed_Harrison. Compared with patients with isolated, single-lesion valve disease, patients with multiple or mixed valve disease may develop symptoms at a relatively earlier stage in the natural history of their disease. Symptoms such as exertional dyspnea and fatigue are usually related to elevated filling pressures, reduced CO, or their combination. Palpitations may signify AF and identify mitral valve disease as an important component of the clinical presentation, even when not previously suspected. Chest pain compatible with angina could reflect left or right ventricular oxygen supply/demand mismatch on a substrate of hypertrophy and pressure/volume overload with or without superimposed coronary artery disease. Symptoms related to right heart failure (abdominal fullness/bloating, edema) are late manifestations of advanced disease.


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InternalMed_Harrison. Mixed disease of a single valve is most often manifested by systolic and diastolic murmurs, each with the attributes expected for the valve in question. Thus, patients with AS and AR will have characteristic mid-systolic, crescendo-decrescendo and blowing, decrescendo diastolic murmurs at the base of the heart in the second right interspace and along the left sternal edge, respectively. Many patients with significant AR have mid-systolic outflow murmurs even in the absence of valve sclerosis/stenosis, and other findings of AS must be sought. The separate murmurs of AS and AR can occasionally be difficult to distinguish from the continuous murmurs associated with either a patent ductus arteriosus (PDA) or ruptured sinus of Valsalva aneurysm. With mixed aortic valve disease, the systolic murmur should end before, and not envelope or extend through, the second heart sound (S2). The murmur associated with a PDA is heard best to the left of the upper sternum. The continuous murmur heard


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InternalMed_Harrison. murmur should end before, and not envelope or extend through, the second heart sound (S2). The murmur associated with a PDA is heard best to the left of the upper sternum. The continuous murmur heard with a ruptured sinus of Valsalva 1552 aneurysm is often first appreciated after an episode of acute chest pain. An early ejection click, which usually defines bicuspid aortic valve dis- ease in young adults, is often not present in patients with congenital, mixed AS and AR. As noted above, both the intensity and duration of these separate murmurs can be influenced by a reduction in CO and transvalvular flow due to coexistent mitral valve disease. In patients with isolated MS and MR, expected findings would include a blowing, holosystolic murmur and a mid-diastolic rumble (with or without an opening snap) best heard at the cardiac apex. An irregularly irregular heart rhythm in such patients would likely signify AF. Findings with TS and TR would mimic those of left-sided MS and MR, save


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InternalMed_Harrison. opening snap) best heard at the cardiac apex. An irregularly irregular heart rhythm in such patients would likely signify AF. Findings with TS and TR would mimic those of left-sided MS and MR, save for the expected changes in the murmurs with respiration. The murmurs of pulmonic stenosis and regurgitation behave in a fashion directionally similar to AS and AR; dynamic changes during respiration should be noted. Specific attributes of these cardiac murmurs are reviewed in Chap. 285.


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InternalMed_Harrison. The electrocardiogram (ECG) may show evidence of ventricular hypertrophy and/or atrial enlargement. ECG signs indicative of right-sided cardiac abnormalities in patients with left-sided valve lesions should prompt additional assessment for PA hypertension and/or right-sided valve disease. The presence of AF in patients with aortic valve disease may be a clue to the presence of previously unsuspected mitral valve disease in the appropriate context. The chest x-ray can be reviewed for evidence of cardiac chamber enlargement, valve and/or annular calcification, and any abnormalities in the appearance of the pulmonary vasculature. The latter could include enlargement of the main and proximal pulmonary arteries with PA hypertension and pulmonary venous redistribution/engorgement or Kerley B lines with increasing degrees of LA hypertension. An enlarged azygos vein in the frontal projection indicates RA hypertension. Roentgenographic findings not expected based on a single or mixed valve


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InternalMed_Harrison. lines with increasing degrees of LA hypertension. An enlarged azygos vein in the frontal projection indicates RA hypertension. Roentgenographic findings not expected based on a single or mixed valve lesion may reflect other valve disease.


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InternalMed_Harrison. Transthoracic echocardiography (TTE) is the most commonly used imaging modality for the diagnosis and characterization of multiple and/or mixed valvular heart disease and may often demonstrate findings not clinically suspected. Transesophageal echocardiography (TEE) may sometimes be required for more accurate assessment of valve anatomy (specifically, the mitral valve) and when infective endocarditis (IE) is considered responsible for the clinical presentation. TTE findings of particular interest include those related to valve morphology and function, calcification, chamber size, ventricular wall thickness, estimated PA systolic pressure, and the dimensions of the great vessels, including the root and ascending aorta, PA, and inferior vena cava. Exercise testing (with or without echocardiography) can be useful when the degree of functional limitation reported by the patient is not adequately explained by the findings on TTE performed at rest. An integrated assessment of the clinical


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InternalMed_Harrison. can be useful when the degree of functional limitation reported by the patient is not adequately explained by the findings on TTE performed at rest. An integrated assessment of the clinical and TTE findings is needed to help determine the dominant valve lesion(s) and establish an appropriate plan for treatment and follow-up. Natural history is usually influenced to a relatively greater degree by the dominant lesion. Exercise testing (with or without echocardiography) can


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InternalMed_Harrison. Cardiac magnetic resonance (CMR) can be used to provide additional anatomic and physiologic information when echocardiography proves suboptimal, but is less well suited to the evaluation of valve morphology. Cardiac computed tomography (CT) has been used to assess intracardiac structures in patients with complicated IE. Coronary CT angiography provides a noninvasive alternative for the assessment of coronary artery anatomy prior to surgery.


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InternalMed_Harrison. Invasive hemodynamic evaluation with right and left heart catheterization may be required to characterize more completely the individual contributions of each lesion in patients with either multiple or mixed valvular heart disease. Measurement of PA pressures and calculation of pulmonary vascular resistance (PVR) can help inform clinical decision-making in certain patient subsets, such as those with advanced mitral and tricuspid valve disease. Attention to the accurate assessment of CO is essential. Coronary angiography (if indicated) can be performed as part of the procedure. Contrast ventriculography and great vessel angiography are performed infrequently.


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InternalMed_Harrison. Management of patients with multiple or mixed valve disease can be challenging. As noted above, it is helpful to determine the dominant valve lesion and proceed according to the treatment and follow-up recommendations for it (Chaps. 283 to 285), being mindful of deviations from the expected course because of problems related to another valve disorder. For example, AF that emerges in the course of moderate mitral valve disease may precipitate heart failure in patients with concomitant, severe aortic valve disease.


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InternalMed_Harrison. Medical therapies are limited and include diuretics when indicated for relief of congestion and vitamin K antagonists for anticoagulation to prevent stroke and thromboembolism in patients with AF. The novel oral anticoagulants are not approved for use in the setting of significant valvular heart disease. Blood pressure–lowering medications may be needed to treat systemic hypertension, which may aggravate left-sided regurgitant valve lesions, but should be initiated and titrated carefully. Pulmonary vasodilators to lower PVR are not generally effective in this context.


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InternalMed_Harrison. There is a paucity of evidence to inform practice guidelines for surgical and/or transcatheter valve intervention in patients with multiple or mixed valve disease. When there is a clear, dominant lesion, as for example in a patient with severe AS and mild AR, indications for intervention are straightforward and follow those recommended for patients with AS (Chap. 283). In other patients, however, there is less clarity, and decisions regarding intervention should be based on several considerations, including those related to lesion severity, ventricular remodeling, functional capacity, and PA pressures. In this regard, it is important to realize that patients with multiple and/or mixed valve disease may develop limiting symptoms or signs of physiologic impairment even with moderate valve lesions.


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InternalMed_Harrison. Concomitant aortic and mitral valve replacement surgery is associated with a significantly higher perioperative mortality risk than replacement of either valve alone (see Tables 283-2 and 284-2), and operation should be carefully considered. Double valve replacement surgery is usually performed for treatment of severe (unrepairable) valve disease at both locations and for the combination of severe disease at one location with moderate disease at the other, so as to avoid the hazards of reoperation in the intermediate to late term for progressive disease of the unoperated valve. In addition, the presence of a prosthesis in the aortic position significantly restricts surgical exposure of the native mitral valve. The need for double valve replacement may also impact the decision regarding the type of prosthesis (i.e., mechanical vs tissue).


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InternalMed_Harrison. Tricuspid valve repair for moderate or severe functional TR at the time of left-sided valve surgery is now commonplace, particularly if there is dilation of the tricuspid annulus (>40 mm). The addition of tricuspid valve repair, consisting usually of insertion of an annuloplasty ring, adds little time or complexity to the procedure and is well tolerated. Reoperation for repair (or replacement) of progressive TR years after initial surgery for left-sided valve disease, on the other hand, is associated with a relatively high perioperative mortality risk. Repair of moderate or severe functional MR at time of AVR for AS can usually be undertaken with acceptable risk for perioperative death or major complication.


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InternalMed_Harrison. The presence of moderate or severe MR in patients with rheumatic MS is a contraindication to percutaneous mitral balloon valvotomy (PMBV). Likewise, the presence of significant AR in patients with AS disqualifies them from percutaneous aortic balloon valvotomy (PABV). The presence of severe, coexistent AR was an exclusion criterion for enrollment in the initial PARTNER trials of transcatheter AVR (TAVR) in prohibitiveand high-surgical-risk patients with severe, calcific AS. Transcatheter management of both severe AS (with TAVR) and functional MR (with deployment of a MitralClip) has been reported. Further advances in transcatheter treatments for multiple and mixed valve disease are anticipated.


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InternalMed_Harrison. Cardiomyopathy and Myocarditis Neal K. Lakdawala, Lynne Warner Stevenson, Joseph Loscalzo DEFINITION AND CLASSIFICATION Cardiomyopathy is disease of the heart muscle. It is estimated 287 that cardiomyopathy accounts for 5–10% of the heart failure in the 5–6 million patients carrying that diagnosis in the United States. This term is intended to exclude cardiac dysfunction that results from other structural heart disease, such as coronary artery disease, primary valve disease, or severe hypertension; however, in general usage, the phrase ischemic cardiomyopathy is sometimes applied to describe diffuse dysfunction attributed to multivessel coronary artery disease, and nonischemic cardiomyopathy to describe cardiomyopathy from other causes. As of 2006, cardiomyopathies are defined as “a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and


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InternalMed_Harrison. group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic.”1


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InternalMed_Harrison. The traditional classification of cardiomyopathies into a triad of dilated, restrictive, and hypertrophic was based initially on autopsy specimens and later on echocardiographic findings. Dilated and hypertrophic cardiomyopathies can be distinguished on the basis of left ventricular wall thickness and cavity dimension; however, restrictive cardiomyopathy can have variably increased wall thickness and chamber dimensions that range from reduced to slightly increased, with prominent atrial enlargement. Restrictive cardiomyopathy is now defined more on the basis of abnormal diastolic function, which is also present but initially less prominent in dilated and hypertrophic cardiomyopathy. Restrictive cardiomyopathy can overlap in presentation, gross morphology, and etiology with both hypertrophic and dilated cardiomyopathies (Table 287-1).


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InternalMed_Harrison. Expanding information renders this classification triad based on phenotype increasingly inadequate to define disease or therapy. Identification of more genetic determinants of cardiomyopathy has suggested a four-way classification scheme of etiology as primary (affecting primarily the heart) and secondary to other systemic disease. The primary causes are then divided into genetic, mixed genetic and acquired, and acquired; however, genetic information is often unavailable at the time of initial presentation, the phenotypic expression of a given mutation varies widely, and genetic predisposition influences the clinical phenotype of acquired cardiomyopathies, as well. Although the proposed genetic classification does not yet guide many current clinical strategies, it will likely become increasingly relevant as classification of disease moves beyond individual organ pathology to more integrated systems approaches.


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InternalMed_Harrison. For all cardiomyopathies, the early symptoms often relate to exertional intolerance with breathlessness or fatigue, usually from inadequate cardiac reserve during exercise. These symptoms may initially go unnoticed or be attributed to other causes, commonly lung disease or age-dependent exercise limitation. As fluid retention leads to elevation of resting filling pressures, shortness of breath may occur during routine daily activity such as dressing and may manifest as dyspnea or cough when lying down at night. Although often considered the hallmark of congestion, peripheral edema may be absent despite severe fluid retention, particularly in younger patients in whom ascites and abdominal discomfort may dominate. The nonspecific term congestive heart failure describes only the resulting syndrome of fluid retention, which is common to all three types of cardiomyopathy and also to cardiac structural diseases associated 1From BJ Maron et al: Circulation 113:1807, 2006.


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InternalMed_Harrison. with elevated filling pressures. All three types of cardiomyopathy 1553 can be associated with atrioventricular valve regurgitation, typical and atypical chest pain, atrial and ventricular tachyarrhythmias, and embolic events (Table 287-1). Initial evaluation begins with a detailed clinical history and examination, looking for clues to cardiac, extracardiac, and familial disease (Table 287-2).


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InternalMed_Harrison. Estimates for the prevalence of genetic etiology for cardiomyopa thy continue to rise, with increasing attention paid to the family history and the availability of genetic testing. Well-recognized in hypertrophic cardiomyopathy, heritability is also present in at least 30% of dilated cardiomyopathy without other clear etiology. Careful family history should elicit not only known cardiomyopathy and heart failure, but also family members who have had sudden death, often incorrectly attributed to “a massive heart attack,” who have had atrial fibrillation or pacemaker implantation by middle age, or who have muscular dystrophy.


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InternalMed_Harrison. Most familial cardiomyopathies are inherited in an autosomal dominant pattern, with occasional autosomal recessive and X-linked inheritance (Table 287-3). Missense mutations with amino acid substitutions are the most common in cardiomyopathy. Expressed mutant proteins may interfere with function of the normal allele through a dominant negative mechanism. Mutations introducing a premature stop codon (nonsense) or shift in the reading frame (frameshift) may create a truncated or unstable protein the lack of which causes cardiomyopathy (haploinsufficiency). Deletions or duplications of an entire exon or gene are uncommon causes of cardiomyopathy, except for the dystrophinopathies.


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InternalMed_Harrison. Many different genes have been implicated in human cardiomyopathy (locus heterogeneity), and many mutations within those genes have been associated with disease (allelic heterogeneity). Although most identified mutations are “private” to individual families, several specific mutations are found repeatedly, either due to a founder effect or recurrent mutations at a common residue.


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InternalMed_Harrison. Genetic cardiomyopathy is characterized by age dependence and incomplete penetrance. The defining phenotype of cardiomyopathy is rarely present at birth and, in some individuals, may never manifest. Related individuals who carry the same mutation may differ in the severity of cardiomyopathy and associated consequences of rhythm disorders and need for transplantation, indicating the important role of other genetic, epigenetic, and environmental modifiers in disease expression. Sex appears to play a role, as penetrance and clinical severity may be greater in men for most cardiomyopathies. Clinical disease expression is generally more severe in the 3–5% of individuals who harbor two or more mutations linked to cardiomyopathy. However, the clinical course of a patient usually cannot be predicted based on which mutation is present; thus, current therapy is based on the phenotype rather than the genetic defect. Currently, the greatest utility of genetic testing for cardiomyopathy is to


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InternalMed_Harrison. based on which mutation is present; thus, current therapy is based on the phenotype rather than the genetic defect. Currently, the greatest utility of genetic testing for cardiomyopathy is to inform family evaluations. However, genetic testing occasionally enables the detection of a disease for which specific therapy is indicated, such as the replacements for defective metabolic enzymes in Fabry’s disease and Gaucher disease.


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InternalMed_Harrison. Mutations in sarcomeric genes, encoding the thick and thin myofilament proteins, are the best characterized. While the majority are associated with hypertrophic cardiomyopathy, an increasing number of sarcomeric mutations have now been implicated in dilated cardiomyopathy, and some in left ventricular noncompaction. Few mutations have been identified in excitation-contraction coupling proteins, perhaps because they are too crucial for survival to allow variation. The most commonly recognized genetic causes of dilated cardiomyopathy are structural mutations of the giant protein titin, encoded TTN, which maintains sarcomere structure and acts as a key signaling molecule. As cytoskeletal proteins play crucial roles in the structure, connection, and stability of the myocyte, multiple defects in these proteins can lead to cardiomyopathy, usually with a dilated phenotype (Fig. 287-1). For example, desmin forms intermediate filaments that connect the nuclear and plasma membranes, Z-lines,


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InternalMed_Harrison. Normal or decreased Increased, may also be primarily affected Related to annular dilation; mitral appears earlier during decompensation; tricuspid regurgitation with right ventricular dysfunction Left before right, except right prominent in young adults Ventricular tachyarrhythmia; conduction block in Chagas’ disease, and some families. Atrial fibrillation. Normal or increased Markedly increased Increased; may be massive Increased; related to elevated filling pressures Related to endocardial involvement; Related to valve-septum frequent mitral and tricuspid interaction; mitral regurgitation regurgitation, rarely severe Exertional intolerance, fluid retention Exertional intolerance; may early, may have dominant right-sided have chest pain symptoms Right often dominates Left-sided congestion at rest may develop late Ventricular uncommon except in Ventricular tachyarrhythmias; sarcoidosis, conduction block in atrial fibrillation sarcoidosis and amyloidosis. Atrial fibrillation.


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InternalMed_Harrison. aLeft-sided symptoms of pulmonary congestion: dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea. Right-sided symptoms of systemic venous congestion: hepatic and abdominal distention, discomfort on bending, peripheral edema. Thorough history and physical examination to identify cardiac and noncardiac disordersa Detailed family history of heart failure, cardiomyopathy, skeletal myopathy, conduction disorders, tachyarrhythmias, and sudden death History of alcohol, illicit drugs, chemotherapy or radiation therapya Assessment of ability to perform routine and desired activitiesa Assessment of volume status, orthostatic blood pressure, body mass indexa Chest radiographa Two-dimensional and Doppler echocardiograma Magnetic resonance imaging for evidence of myocardial inflammation and


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InternalMed_Harrison. Chest radiographa Two-dimensional and Doppler echocardiograma Magnetic resonance imaging for evidence of myocardial inflammation and Chemistry: Serum sodium,a potassium,a calcium, a magnesiuma Fasting glucose (glycohemoglobin in diabetes mellitus) Creatinine,a blood urea nitrogena Albumin,a total protein,a liver function testsa Lipid profile Thyroid-stimulating hormonea Serum iron, transferrin saturation Urinalysis Creatine kinase isoforms Cardiac troponin levels Hematology: Hemoglobin/hematocrita White blood cell count with differential,a including eosinophils Erythrocyte sedimentation rate Titers for infection in the setting of clinical suspicion: Acute viral (coxsackie, echovirus, influenza) Human immunodeficiency virus Chagas’ (Trypanosoma cruzi), Lyme (Borrelia burgdorferi), toxoplasmosis Catheterization with coronary angiography in patients with angina who are candidates for interventiona


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InternalMed_Harrison. Catheterization with coronary angiography in patients with angina who are candidates for interventiona Serologies for active rheumatologic disease Endomyocardial biopsy including sample for electron microscopy when suspecting specific diagnosis with therapeutic implications aLevel I recommendations from ACC/AHA Practice Guidelines for Chronic Heart Failure in the Adult. and the intercalated disks between muscle cells. Desmin mutations impair the transmission of force and signaling for both cardiac and skeletal muscle and may cause combined cardiac and skeletal myopathy.


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InternalMed_Harrison. Sarcolemmal membrane protein defects are associated with dilated cardiomyopathy. The best known is dystrophin, encoded by the X chromosome gene DMD, abnormalities of which cause Duchenne’s and Becker’s muscle dystrophy. (Interestingly, abnormal dystrophin can be acquired when the coxsackie virus cleaves dystrophin during viral myocarditis.) This protein provides a network that supports the sarcolemma and also connects to the sarcomere. The progressive functional defect in both cardiac and skeletal muscle reflects vulnerability to mechanical stress. Dystrophin is associated at the membrane with a complex of other proteins, such as metavinculin, abnormalities of which also cause dilated cardiomyopathy. Defects in the sarcolemmal channel proteins (channelopathies) are generally associated with primary arrhythmias, but mutations in SCN5A, distinct from those that cause the Brugada or long-QT syndromes, have been implicated in dilated cardiomyopathy with conduction disease.


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InternalMed_Harrison. Nuclear membrane protein defects in cardiac and skeletal muscle occur in either autosomal (lamin A/C) or X-linked (emerin) patterns. These defects are associated with a high prevalence of atrial arrhythmias and conduction system disease, which can occur in some family members without or before detectable cardiomyopathy. Intercalated disks contribute to intracellular connections, allowing mechanical and electrical coupling between cells and also connections to desmin filaments within the cell. Mutations in proteins of the desmosomal complex compromise attachment of the myocytes, which can become disconnected and die, to be replaced by fat and fibrous tissue. These areas are highly arrhythmogenic and may dilate to form aneurysms. Although more often noted in the right ventricle (arrhythmogenic right ventricular dysplasia), this condition can affect both ventricles and has also been termed “arrhythmogenic cardiomyopathy.”


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InternalMed_Harrison. Owing to the conservation of signaling pathways in multiple systems, we may expect to discover more extracardiac manifestations of genetic abnormalities initially considered to manifest exclusively in the heart. In contrast, the monogenic disorders of metabolism that affect the heart are already clearly recognized to affect multiple organ systems. Currently, it is most important to diagnose defective enzymes for which specific enzyme replacement therapy can now ameliorate the course of disease, such as with alpha-galactosidase A deficiency (Fabry’s disease). Abnormalities of mitochondrial DNA (maternally transmitted) impair energy production with multiple clinical manifestations, including impaired cognitive function and skeletal myopathy. The phenotypic expression is highly variable depending on the


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InternalMed_Harrison. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ARVC, arrhythmogenic right ventricular cardiomyopathy; CDDC, conduction disease with dilated cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HCM+, HCM with preexcitation; HCMc, HCM with conduction disease; LVNC, left ventricular noncompaction; MELAS, (mitochondrial) myopathy, encephalopathy, lactic acidosis, and strokelike episodes syndrome; MERRF, myoclonic epilepsy with ragged red fibers; RCM, restrictive cardiomyopathy. distribution of the maternal mitochondria during embryonic development. Heritable systemic diseases, such as familial amyloidosis and hemochromatosis, can affect the heart without mutation of genes expressed in the heart.


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InternalMed_Harrison. For any patient with suspected or proven genetic disease, family members should be considered and evaluated in a longitudinal fashion. Screening includes an echocardiogram and electrocardiogram (ECG). The indications and implications for confirmatory specific genetic testing vary depending on the specific mutation. The profound questions raised by families about diseases shared and passed down merit serious and sensitive discussion, ideally provided by a trained genetic counselor.


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InternalMed_Harrison. An enlarged left ventricle with decreased systolic function as measured by left ventricular ejection fraction characterizes dilated cardiomyopathy (Figs. 287-2, 287-3, and 287-4). Systolic failure is more marked than diastolic dysfunction. Although the syndrome of dilated cardiomyopathy has multiple etiologies (Table 287-4), there appear to be common pathways of secondary response and disease progression. When myocardial injury is acquired, some myocytes may die initially, whereas others survive only to have later programmed cell death (apoptosis), and remaining myocytes hypertrophy in response to increased wall stress. Local and circulating factors stimulate deleterious secondary responses that contribute to progression of disease. Dynamic remodeling of the interstitial scaffolding affects diastolic function and the amount of ventricular dilation. Mitral regurgitation commonly develops as the valvular apparatus is distorted and is usually substantial by the time heart failure is


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InternalMed_Harrison. diastolic function and the amount of ventricular dilation. Mitral regurgitation commonly develops as the valvular apparatus is distorted and is usually substantial by the time heart failure is severe. Many cases that present “acutely” have progressed silently through these stages over months to years. Dilation and decreased function of the right ventricle may result from the initial injury and occasionally dominate, but more commonly appear later in relation to mechanical interactions with the failing left ventricle and the elevated afterload presented by secondary pulmonary hypertension.


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InternalMed_Harrison. FIGURE 287-1 Drawing of myocyte indicating multiple sites of abnormal gene products associated with cardiomyopathy. Major func-tional groups include the sarcomeric proteins (actin, myosin, tropomyosin, and the associated regulatory proteins), the dystrophin complex stabilizing and connecting the cell membrane to intracellular structures, the desmosome complexes associated with cell-cell connections and stability, and multiple cytoskeletal proteins that integrate and stabilize the myocyte. ATP, adenosine triphosphate. (Figure adapted from Jeffrey A. Towbin, MD, University of Cincinnati, with permission.)


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InternalMed_Harrison. Regardless of the nature and degree of direct cell injury, the resulting functional impairment often includes some contribution from secondary responses that may be modifiable or reversible. Almost half of all patients with new-onset cardiomyopathy demonstrate substantial spontaneous recovery. Even with long-standing disease, some patients have dramatic improvement to near-normal ejection fractions during pharmacologic therapy, particularly notable with the β-adrenergic antagonists coupled with renin-angiotensin system inhibition. For patients in whom left bundle branch block precedes clinical heart failure by many years, cardiac resynchronization pacing may be particularly likely to improve ejection fraction and decrease ventricular size. Interest in the potential for recovery of cardiomyopathy has been


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InternalMed_Harrison. FIGURE 287-2 Dilated cardiomyopathy. This gross specimen of a heart removed at the time of transplantation shows massive left ventricular dilation and moderate right ventricular dilation. Although the left ventricular wall in particular appears thinned, there is significant hypertrophy of this heart, which weighs more than 800 g (upper limit of normal = 360 g). A defibrillator lead is seen traversing the tricuspid valve into the right ventricular apex. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) further stimulated by occasional “recovery” of left ventricular function after prolonged mechanical circulatory support. The diagnosis and therapy for dilated cardiomyopathy are generally dictated by the stage of heart failure (Chap. 279), with specific aspects discussed for relevant etiologies below.


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InternalMed_Harrison. Myocarditis (inflammation of the heart) can result from multiple causes but is most commonly attributed to infective agents that can injure the myocardium through direct invasion, production of cardiotoxic substances, or chronic inflammation with or without persistent infection. Myocarditis cannot be assumed from a presentation of decreased systolic function in the setting of an acute infection, as any severe infection causing systemic cytokine release can depress cardiac function transiently. Infectious myocarditis has been reported with almost all types of infective agents but is most commonly associated with viruses and the protozoan Trypanosoma cruzi.


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InternalMed_Harrison. The pathogenesis of viral myocarditis has been extensively studied in murine models. After viruses gain entry through the respiratory or gastrointestinal tract, they can infect organs possessing specific receptors, such as the coxsackie-adenovirus receptor on the heart. Viral infection and replication can cause myocardial injury and lysis. For example, the enteroviral protease 2A facilitates viral replication and infection through degradation of the myocyte protein dystrophin, which is crucial for myocyte stability. Activation of viral receptor proteins can also activate host tyrosine kinases, which modify the cytoskeleton to facilitate further viral entry.


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InternalMed_Harrison. The first host response to infection is the nonspecific innate immune response, heavily dependent on Toll-like receptors that recognize common antigenic patterns. Cytokine release is rapid, followed by triggered activation and expansion of specific Tand B-cell populations. This initial response appears to be crucial, as early immunosuppression


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InternalMed_Harrison. FIGURE 287-3 Dilated cardiomyopathy. This echocardiogram of a young man with dilated cardiomyopathy shows massive global dilation and thinning of the walls of the left ventricle (LV). The left atrium (LA) is also enlarged compared to normal. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. RA, right atrium; RV, right ventricle. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.) in animal models can increase viral replication and worsen cardiac injury. However, successful recovery from viral infection depends not only on the efficacy of the immune response to limit viral infection, but also on timely downregulation to prevent overreaction and autoimmune injury to the host.


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InternalMed_Harrison. FIGURE 287-4 Dilated cardiomyopathy. Microscopic specimen of a dilated cardiomyopathy showing the nonspecific changes of interstitial fibrosis and myocyte hypertrophy characterized by increased myocyte size and enlarged, irregular nuclei. Hematoxylin and eosin– stained section, 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) The secondary acquired immune response is more specifically addressed against the viral proteins and can include both T-cell infiltration and antibodies to viral proteins. If unchecked, the acquired immune response can perpetuate secondary cardiac damage. Ongoing Viral (coxsackie,a adenovirus,a HIV, hepatitis C) Parasitic (T. cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis) Bacterial (diphtheria) Spirochetal (Borrelia burgdorferi—Lyme disease) Rickettsial (Q fever) Fungal (with systemic infection)


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InternalMed_Harrison. Eosinophilic myocarditis Polymyositis, dermatomyositis Collagen vascular disease Peripartum cardiomyopathy Transplant rejection Alcohol Catecholamines: amphetamines, cocaine Chemotherapeutic agents (anthracyclines, trastuzumab) Interferon Other therapeutic agents (hydroxychloroquine, chloroquine) Drugs of misuse (emetine, anabolic steroids) Heavy metals: lead, mercury Occupational exposure: hydrocarbons, arsenicals Nutritional deficiencies: thiamine, selenium, carnitine Electrolyte deficiencies: calcium, phosphate, magnesium Endocrinopathy Skeletal and cardiac myopathy Dystrophin-related dystrophy (Duchenne’s, Becker’s) Mitochondrial myopathies (e.g., Kearns-Sayre syndrome) Arrhythmogenic ventricular dysplasia Hemochromatosis Associated with other systemic diseases Susceptibility to immune-mediated myocarditis Overlap with Nondilated Cardiomyopathy Miscellaneous (Shared Elements of Above Etiologies)


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InternalMed_Harrison. Overlap with Nondilated Cardiomyopathy Miscellaneous (Shared Elements of Above Etiologies) Supraventricular arrhythmias with uncontrolled rate Very frequent nonsustained ventricular tachycardia or high premature ventricular complex burden Left bundle branch block (LBBB) has been implicated as a cause of dilated cardiomyopathy appearing late after idiopathic LBBB and responding with near-normal left ventricle size and function after cardiac resynchronization therapy. aSome specific cases can be linked now to specific genetic mutation in a familial cardiomyopathy; others with similar phenotypes that appear to be acquired or idiopathic may represent genetic factors not yet identified.


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InternalMed_Harrison. cytokine release activates matrix metalloproteinases that can disrupt the collagen and elastin scaffolding of the heart, potentiating ventricular dilation. Stimulation of profibrotic factors leads to pathologic interstitial fibrosis. Some of the antibodies triggered through co-stimulation or molecular mimicry also recognize targets within the host myocyte, such as the β-adrenergic receptor, troponin, and Na+/K+ ATPase, but it remains unclear whether these antibodies contribute actively to cardiac dysfunction in humans or merely serve as markers of cardiac injury.


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InternalMed_Harrison. It is not known how long the viruses persist in the human heart, whether late persistence of the viral genome continues to be deleterious, or how often a dormant virus can again become pathogenic. Genomes of common viruses have frequently been detected in patients with clinical diagnoses of myocarditis or dilated cardiomyopathy, but there is little information on how often these are present in patients without cardiac disease (see below). Further information is needed to understand the relative timing and contribution of infection, immune responses, and secondary adaptations in the progression of heart failure after viral myocarditis (Fig 287-5).


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InternalMed_Harrison. Clinical Presentation of Viral Myocarditis Acute viral myocarditis often presents with symptoms and signs of heart failure. Some patients present with chest pain suggestive of pericarditis or acute myocardial infarction. Occasionally, the presentation is dominated by atrial or ventricular tachyarrhythmias, or by pulmonary or systemic emboli from intracardiac thrombi. Electrocardiographic or echocardiographic abnormalities may also be detected incidentally during evaluation for other diagnoses. The typical patient with presumed viral myocarditis is a young to middle-aged adult who develops progressive dyspnea and weakness within a few days to weeks after a viral syndrome that was accompanied by fever and myalgias.


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InternalMed_Harrison. A small number of patients present with fulminant myocarditis, with rapid progression from a severe febrile respiratory syndrome to cardiogenic shock that may involve multiple organ systems, leading to renal failure, hepatic failure, and coagulopathy. These patients are typically young adults who have recently been dismissed from urgent care settings with antibiotics for bronchitis or oseltamivir for viral syndromes, only to return within a few days in rapidly progressive cardiogenic shock. Prompt triage is vital to provide aggressive support with high-dose intravenous catecholamine therapy and sometimes with temporary mechanical circulatory support. Recognition of patients with this fulminant presentation is potentially life-saving as more than half can survive, with marked improvement demonstrable within the first few weeks. The ejection fraction function of these patients often recovers to near-normal, although residual diastolic dysfunction may limit vigorous exercise for some


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InternalMed_Harrison. demonstrable within the first few weeks. The ejection fraction function of these patients often recovers to near-normal, although residual diastolic dysfunction may limit vigorous exercise for some survivors.


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InternalMed_Harrison. Chronic viral myocarditis is often invoked, but rarely proven, as a diagnosis when no other cause of dilated cardiomyopathy can be identified. However, some cases of otherwise unexplained cardiomyopathy will later be recognized to have a genetic basis, or ultimately found to have resulted from excess alcohol consumption or illicit drugs. There are likely many other causes that cannot yet be identified. The prevalence of previous or persistent viral infection as the cause for chronic dilated cardiomyopathy remains highly controversial. Laboratory evaluation for myocarditis The initial evaluation for suspected myocarditis includes an ECG, an echocardiogram, and serum levels of troponin and creatine phosphokinase fractions. Magnetic resonance imaging is increasingly used for the diagnosis of myocarditis, which is supported by evidence of increased tissue edema and gadolinium enhancement (Fig. 287-6), particularly in the mid-wall (as distinct from usual coronary artery territories).


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InternalMed_Harrison. Endomyocardial biopsy is not often indicated for the initial evaluation of suspected viral myocarditis unless ventricular tachyarrhythmias suggest possible etiologies of sarcoidosis or giant cell myocarditis. The indications and benefit of endomyocardial biopsy for evaluation of myocarditis or new-onset cardiomyopathy remain controversial. FIGURE 287-5 Schematic diagram demonstrating the possible progression from infection through direct, secondary, and autoimmune responses to dilated cardiomyopathy. Most of the supporting evidence for this sequence is derived from animal models. It is not known to what degree persistent infection and/or ongoing immune responses contribute to ongoing myocardial injury in the chronic phase.


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InternalMed_Harrison. The Dallas Criteria for myocarditis on endomyocardial biopsy include lymphocytic infiltrate with evidence of myocyte necrosis (Fig. 287-7) and are negative in 80–90% of patients with clinical myocarditis. Negative Dallas Criteria can reflect sampling error or early resolution of lymphocytic infiltrates, but also the insensitivity of the test when inflammation results from cytokines and antibody-mediated injury. Routine histologic examination of endomyocardial biopsy rarely reveals a specific infective etiology, such as toxoplasmosis or Cytomegalovirus. Immunohistochemistry of myocardial biopsy samples is commonly used to identify active lymphocyte subtypes and may also detect upregulation of HLA antigens and the presence of complement components attributed to inflammation, but the specificity and significance of these findings are uncertain.


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InternalMed_Harrison. An increase in circulating viral titers between acute and convalescent blood samples supports a diagnosis of acute viral myocarditis with potential spontaneous improvement. There is no established role for measuring circulating anti-heart antibodies, which may be the result, rather than a cause, of myocardial injury and have been found also in patients with coronary artery disease and genetic cardiomyopathy. FIGURE 287-6 Magnetic resonance image of myocarditis showing the typical mid-wall location (arrow) for late gadolinium enhance-ment from cardiac inflammation and scarring. (Image courtesy of Ron Blankstein, MD, and Marcelo Di Carli, MD, Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston.) Patients with recent or ongoing viral syndromes can be classified into three levels of diagnosis: 1. Possible subclinical acute myocarditis is diagnosed when a patient has a typical viral syndrome but no cardiac symptoms, with one or more of the following:


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InternalMed_Harrison. Elevated biomarkers of cardiac injury (troponin or CK-MB) ECG findings suggestive of acute injury Abnormality on cardiac imaging, usually echocardiography FIGURE 287-7 Acute myocarditis. Microscopic image of an endomyocardial biopsy showing massive infiltration with mononuclear cells and occasional eosinophils associated with clear myocyte damage. The myocyte nuclei are enlarged and reactive. Such extensive involvement of the myocardium would lead to extensive replacement fibrosis even if the inflammatory response could be suppressed. Hematoxylin and eosin–stained section, 200× original magnification.


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InternalMed_Harrison. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) 1560 2. Probable acute myocarditis is diagnosed when the above criteria are met and accompanied also by cardiac symptoms, such as shortness of breath or chest pain, which can result from pericarditis or myocarditis. When clinical findings of pericarditis (pleuritic chest pain, ECG abnormalities, pericardial rub or effusion) are accompanied by elevated troponin or CK-MB or abnormal cardiac wall motion, the terms perimyocarditis or myopericarditis are sometimes used. 3. Definite myocarditis is diagnosed when there is histologic or immunohistologic evidence of inflammation on endomyocardial biopsy (see below) and does not require any other laboratory or clinical criteria.


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InternalMed_Harrison. In humans, viruses are often suspected but rarely proven to be the direct cause of clinical myocarditis. First implicated was the picornavirus family of RNA viruses, principally the enteroviruses, coxsackie virus, echovirus, and poliovirus. Influenza, another RNA virus, is implicated with varying frequency every winter and spring as epitopes change. Of the DNA viruses, adenovirus, vaccinia (smallpox vaccine), and the herpesviruses (varicella zoster, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 [HHV6]) are well-recognized to cause myocarditis but also occur commonly in the healthy population. Polymerase chain reaction (PCR) detects viral genomes in the majority of patients with dilated cardiomyopathy, but also in normal “control” hearts. Most often detected are parvovirus B19 and HHV6, which may affect the cardiovascular system, in part, through infection of vascular endothelial cells. However, their contribution to chronic cardiomyopathy is uncertain, as serologic


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InternalMed_Harrison. B19 and HHV6, which may affect the cardiovascular system, in part, through infection of vascular endothelial cells. However, their contribution to chronic cardiomyopathy is uncertain, as serologic evidence of exposure is present in many children and most adults.


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InternalMed_Harrison. Human immunodeficiency virus (HIV) was associated with an incidence of dilated cardiomyopathy of 1–2%; however, with the advent of highly active antiretroviral therapy (HAART), HIV has been associated with a significantly lower incidence of cardiac disease. Cardiomyopathy in HIV may result from cardiac involvement with other associated viruses, such as cytomegalovirus and hepatitis C, as well as by HIV directly. Antiviral drugs to treat chronic HIV can cause cardiomyopathy, both directly and through drug hypersensitivity. The clinical picture may be complicated by pericardial effusions and pulmonary hypertension. There is a high frequency of lymphocytic myocarditis found at autopsy, and viral particles have been demonstrated in the myocardium in some cases, consistent with direct causation.


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InternalMed_Harrison. Hepatitis C has been repeatedly implicated in cardiomyopathy, particularly in Germany and Asia. Cardiac dysfunction may improve after interferon therapy. As this cytokine itself often depresses cardiac function transiently, careful coordination of administration and ongoing clinical evaluation are critical. Involvement of the heart with hepatitis B is uncommon, but can be seen when associated with systemic vasculitis (polyarteritis nodosa). Additional viruses implicated specifically in myocarditis include mumps, respiratory syncytial virus, the arboviruses (dengue fever and yellow fever), and arenaviruses (Lassa fever). However, for any serious infection, the systemic inflammatory response can cause nonspecific depression of cardiac function, which is generally reversible if the patient survives.


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InternalMed_Harrison. There is currently no specific therapy recommended during any stage of viral myocarditis. During acute infection, therapy with anti-inflammatory or immunosuppressive medications is avoided, as their use has been shown to increase viral replication and myocardial injury in animal models. Therapy with specific antiviral agents (such as oseltamivir) has not been studied in relation to cardiac involvement. There is ongoing investigation into the impact of antiviral therapy to treat chronic viral persistence identified from endomyocardial biopsy. Large trials of immunosuppressive therapy for Dallas Criteria–positive myocarditis have been negative. There are some initial encouraging results and ongoing investigations with immunosuppressive therapy for immune-mediated myocarditis defined by immunohistologic criteria on biopsy or circulating anti-heart antibodies in the absence of myocardial viral genomes. However, neither antiviral nor anti-inflammatory therapies are currently recommended.


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InternalMed_Harrison. criteria on biopsy or circulating anti-heart antibodies in the absence of myocardial viral genomes. However, neither antiviral nor anti-inflammatory therapies are currently recommended. Until we have a better understanding of the different phases of viral myocarditis and its sequelae and the effects of timed or targeted therapies, treatment will continue to be directed to the clinical cardiovascular stage of the disease, for dilated cardiomyopathy in general.


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InternalMed_Harrison. Parasitic Myocarditis Chagas’ disease is the third most common parasitic infection in the world and the most common infective cause of cardiomyopathy. The protozoan T. cruzi is transmitted by the bite of the reduviid bug, endemic in the rural areas of South and Central America. Transmission can also occur through blood transfusion, organ donation, from mother to fetus, and occasionally orally. While programs to eradicate the insect vector have decreased the prevalence from about 16 million to less than 10 million in South America, cases are increasingly recognized in Western developed countries. Approximately 100,000 affected individuals are currently living in the United States, most of whom contracted the disease in endemic areas.


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InternalMed_Harrison. Multiple pathogenic mechanisms are implicated. The parasite itself can cause myocyte lysis and primary neuronal damage, and specific immune responses may recognize the parasites or related antigens and lead to chronic immune activation in the absence of detectable parasites. Molecular techniques have revealed persistent parasite DNA fragments in infected individuals. Further evidence for persistent infection is the eruption of parasitic skin lesions during immunosuppression after cardiac transplantation. As with viral myocarditis, the relative roles of persistent infection and of secondary autoimmune injury have not been resolved (Fig. 287-5). An additional factor in the progression of Chagas’ disease is the autonomic dysfunction and microvascular damage that may contribute to cardiac and gastrointestinal disease.


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InternalMed_Harrison. The acute phase of Chagas’ disease with parasitemia is usually unrecognized, but in fewer than 5% of cases, it presents clinically within a few weeks of infection, with nonspecific symptoms or occasionally with acute myocarditis and meningoencephalitis. In the absence of antiparasitic therapy, the silent stage progresses slowly over 10–30 years in almost half of patients to manifest in the cardiac and gastrointestinal systems in the chronic stages. Features typical of Chagas’ disease are conduction system abnormalities, particularly sinus node and atrioventricular (AV) node dysfunction and right bundle branch block. Atrial fibrillation and ventricular tachyarrhythmias also occur. Small ventricular aneurysms are common, particularly at the ventricular apex. These dilated ventricles are particularly thrombogenic, giving rise to pulmonary and systemic emboli. Xenodiagnosis, detection of the parasite itself, is rarely performed. The serologic tests for specific IgG antibodies against the


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InternalMed_Harrison. thrombogenic, giving rise to pulmonary and systemic emboli. Xenodiagnosis, detection of the parasite itself, is rarely performed. The serologic tests for specific IgG antibodies against the trypanosome lack sufficient specificity and sensitivity, thereby requiring two separate positive tests required to make a diagnosis.


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InternalMed_Harrison. Treatment of the advanced stages focuses on clinical manifestations of the disease and includes heart failure medications, pacemakerdefibrillators, and anticoagulation. Increasing attention is directed to antiparasitic therapy even in chronic disease without obvious active infection. The most common effective antiparasitic therapies are benznidazole and nifurtimox, both associated with multiple severe reactions, including dermatitis, gastrointestinal distress, and neuropathy. Survival is less than 30% at 5 years after the onset of overt clinical heart failure. Patients without major extracardiac disease have occasionally undergone transplantation, after which they may require lifelong therapy to suppress reactivation of infection.


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InternalMed_Harrison. African trypanosomiasis infection results from the tsetse fly bite and can occur in travelers exposed during trips to Africa. The West African form is caused by Trypanosoma brucei gambiense and progresses silently over years. The East African form caused by T. brucei rhodesiense can progress rapidly through perivascular infiltration to myocarditis and heart failure, with frequent arrhythmias. The diagnosis is made by identification of trypanosomes in blood, lymph nodes, or other affected sites. Antiparasitic therapy has limited efficacy and is determined by the specific type and the stage of infection (hemolymphatic or neurologic).


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InternalMed_Harrison. Toxoplasmosis is contracted through undercooked infected beef or pork, transmission from feline feces, organ transplantation, transfusion, or maternal-fetal transmission. Immunocompromised hosts are most likely to experience reactivation of latent infection from cysts. The cysts have been found in up to 40% of autopsies of patients dying from HIV infection. Toxoplasmosis may present with encephalitis or chorioretinitis and, in the heart, can cause myocarditis, pericardial effusion, constrictive pericarditis, and heart failure. The diagnosis in an immunocompetent patient is made when the IgM is positive and the IgG becomes positive later. Active toxoplasmosis may be suspected in an immunocompromised patient with myocarditis and a positive IgG titer for toxoplasmosis, particularly when avidity testing identifies high specificity of the antibody. Fortuitous sampling occasionally reveals the cysts in the myocardium. Combination therapy can include pyrimethamine and sulfadiazine or


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InternalMed_Harrison. avidity testing identifies high specificity of the antibody. Fortuitous sampling occasionally reveals the cysts in the myocardium. Combination therapy can include pyrimethamine and sulfadiazine or clindamycin.


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InternalMed_Harrison. Trichinellosis is caused by Trichinella spiralis larva ingested with undercooked meat. Larvae migrating into skeletal muscles cause myalgias, weakness, and fever. Periorbital and facial edema and conjunctival and retinal hemorrhage may also be seen. Although the larva may occasionally invade the myocardium, clinical heart failure is rare and, when observed, attributed to the eosinophilic inflammatory response. The diagnosis is made from the specific serum antibody and is further supported by the presence of eosinophilia. Treatment includes antihelminthic drugs (albendazole, mebendazole) and glucocorticoids if inflammation is severe. Cardiac involvement with Echinococcus is rare, but cysts can form and rupture in the myocardium and pericardium.