Pathogenesis.

Although many individuals with DCM have a familial (genetic) form, DCM can also result from various acquired myocardial insults or interactions of genetics and the environment that ultimately may yield a similar clinicopathologic pattern.⁹⁶ These include (1) myocarditis (an inflammatory disorder that precedes the development of cardiomyopathy in at least some cases, and is sometimes caused by viral infections), (2) toxicities (including adverse effects of chemotherapeutic agents and chronic alcoholism, a history of which can be elicited in 10% to 20% of patients), and (3) childbirth. Each of these subgroups are summarized in Figure 12-32 and described below.

FIGURE 12-32 Causes and consequences of dilated and hypertrophic cardiomyopathy. Some dilated cardiomyopathies and virtually all hypertrophic cardiomyopathies are genetic in origin. The genetic causes of dilated cardiomyopathy involve mutations in any of a wide variety of proteins, predominantly of the cytoskeleton, but also the sarcomere, mitochondria, and nuclear envelope. In contrast, the mutated genes that cause hypertrophic cardiomyopathy encode proteins of the sarcomere. Although these two forms of cardiomyopathy differ greatly in subcellular basis and morphologic phenotypes, they share a common set of clinical complications. LV, left ventricle.

FIGURE 12-33 Schematic of a myocyte, showing key proteins mutated in dilated cardiomyopathy (red), hypertrophic cardiomyopathy (blue), or both (green).

Clinical Features.

DCM may occur at any age, including in childhood, but it most commonly affects individuals between the ages of 20 and 50. It presents with slowly progressive signs and symptoms of CHF such as shortness of breath, easy fatigability, and poor exertional capacity. In the end stage, patients often have ejection fractions of less than 25% (normal, ∼50% to 65%). Fifty percent of patients die within 2 years, and only 25% survive longer than 5 years, but some severely affected patients may unexpectedly improve on therapy. Secondary mitral regurgitation and abnormal cardiac rhythms are common. Death is usually attributable to progressive cardiac failure or arrhythmia and can occur suddenly. Embolism from dislodgment of an intracardiac thrombus can occur. Cardiac transplantation is frequently done, and long-term ventricular assist may be beneficial in some patients. Interestingly, mechanical cardiac assist may induce lasting regression of cardiac dysfunction in some patients.¹⁰⁴

Pathogenesis.

HCM is caused by mutations in any one of several genes that encode sarcomeric proteins.¹⁰⁸ In most cases the pattern of transmission is autosomal dominant with variable penetrance. Remaining cases seem to be sporadic. More than 400 different mutations have been found in nine different genes in HCM, most being missense mutations. Mutations causing HCM are found most commonly in the gene encoding β-myosin heavy chain (β-MHC), with the genes for cardiac TnT, α-tropomyosin, and myosin-binding protein C (MYBP-C) being the next most frequently mutated. Mutations in β-MHC, MYBP-C, and TnT account for 70% to 80% of all cases of HCM. Different affected families may have distinct mutations involving the same protein. For example, approximately 50 different mutations of β-MHC are known to cause HCM. The prognosis of HCM varies widely and correlates strongly with specific mutations. Although it is clear that these genetic defects are critical to the etiology of HCM, the sequence of events leading from mutations to disease is still poorly understood. To make matters even more complicated, changes in certain genes, depicted in Figure 12-33, can give rise to both HCM and DCM.

Clinical Features.

The basic physiologic abnormality in HCM is reduced stroke volume due to impaired diastolic filling, which results from the reduced chamber size and compliance of the massively hypertrophied left ventricle. In addition, approximately 25% of patients with HCM have dynamic obstruction to the left ventricular outflow. The limitation of cardiac output and a secondary increase in pulmonary venous pressure cause exertional dyspnea. Auscultation discloses a harsh systolic ejection murmur, caused by ventricular outflow obstruction as the anterior mitral leaflet moves toward the ventricular septum during systole. Because of the massive hypertrophy, high left ventricular chamber pressure, and frequently abnormal intramural arteries, focal myocardial ischemia commonly results, even in the absence of concomitant coronary artery disease; thus, anginal pain is frequent. The major clinical problems in HCM are atrial fibrillation, mural thrombus formation leading to embolization and possible stroke, intractable cardiac failure, ventricular arrhythmias, and, not infrequently, sudden death, especially in some affected families. Indeed, HCM is one of the most common causes of sudden, otherwise unexplained death in young athletes.¹⁰⁹

The natural history of HCM is highly variable. Most patients can be helped by treatment with drugs that decrease heart rate and contractility, such as β-adrenergic blockers. Some benefit may also be gained from reduction of the mass of the septum, which relieves the outflow tract obstruction. This can be achieved either by surgical excision of muscle or carefully controlled septal infarction, which is induced by infusion of alcohol through a catheter.

As discussed above, HCM is a disease caused by mutations in proteins of the sarcomere, and DCM is mostly associated with abnormalities of cytoskeletal proteins (Fig. 12-33). DCM seems to be a disease of abnormal force generation, force transmission, or myocyte signaling. In the past, HCM has been considered a disorder of sarcomeres that impairs cardiac function and induces a compensatory hypertrophic response. However, recent evidence suggests that HCM may stem from a defect in energy transfer from its source of generation (mitochondria) to its site of use (sarcomeres), leading to subcellular energy deficiency. Despite these etiologic differences, there are some common mechanistic and clinicopathologic threads between HCM and the genetic and acquired forms of DCM, as summarized in Figure 12-32.

Etiology and Pathogenesis.

In the United States, viral infections are the most common cause of myocarditis. Coxsackieviruses A and B and other enteroviruses probably account for most of the cases. Other less common etiologic agents include cytomegalovirus, HIV, and a host of other agents (listed in Table 12-12). The responsible virus can sometimes be identified by serologic studies or, more recently, identification of viral nucleic acids (DNA or RNA) in myocardial biopsies. Whether viruses cause the myocardial injury directly or initiate a destructive immune response is unclear.

TABLE 12-12 Major Causes of Myocarditis

HIV, human immunodeficiency virus.

Nonviral agents are also important causes of infectious myocarditis, particularly the protozoa Trypanosoma cruzi, the agent of Chagas disease.¹¹² Chagas disease is endemic in some regions of South America; myocardial involvement is present in most infected individuals. About 10% of patients die during an acute attack; others develop a chronic immune-mediated myocarditis that may progress to cardiac insufficiency 10 to 20 years later. Trichinosis is the most common helminthic disease associated with myocarditis. Parasitic diseases, including toxoplasmosis, and bacterial infections, including Lyme disease and diphtheria, can also cause myocarditis. In the case of diphtheritic myocarditis, toxins released by Corynebacterium diphtheriae seem to be responsible for the myocardial injury. Myocarditis occurs in approximately 5% of patients with Lyme disease, a systemic illness caused by the bacterial spirochete Borrelia burgdorferi (Chapter 8). Lyme myocarditis manifests primarily as a self-limited conduction system disorder that frequently requires a temporary pacemaker. Myocarditis occurs in many patients with AIDS. Two types have been identified: (1) inflammation and myocyte damage without a clear etiologic agent and (2) myocarditis caused by HIV directly or by an opportunistic pathogen.

There are also noninfectious causes of myocarditis. Myocarditis can be caused by hypersensitivity reactions (hypersensitivity myocarditis), often to drugs such as antibiotics, diuretics, or antihypertensive agents. Myocarditis can also be associated with systemic diseases of immune origin, such as rheumatic fever, systemic lupus erythematosus, and polymyositis. Cardiac sarcoidosis and rejection of a transplanted heart (see Figure 12-40) are also considered forms of myocarditis.

FIGURE 12-40 Complications of heart transplantation. A, Cardiac allograft rejection typified by lymphocytic infiltrate, with associated damage to cardiac myocytes. B, Graft coronary arteriosclerosis, demonstrating severe diffuse concentric intimal thickening producing critical stenosis. The internal elastic lamina (arrow) and media are intact (Movat pentachrome stain, elastin black).

(B, Reproduced by permission from Salomon RN et al.: Human coronary transplantation-associated arteriosclerosis. Evidence for chronic immune reaction to activated graft endothelial cells. Am J Pathol 138:791, 1991.)

Morphology. During the active phase of myocarditis the heart may appear normal or dilated; some hypertrophy may be present depending on disease duration. In advanced stages the ventricular myocardium is flabby and often mottled by either pale foci or minute hemorrhagic lesions. Mural thrombi may be present in any chamber.

During active disease, myocarditis is most frequently characterized by an interstitial inflammatory infiltrate associated with focal myocyte necrosis (Fig. 12-36). A diffuse, mononuclear, predominantly lymphocytic infiltrate is most common (Fig. 12-36A). Although endomyocardial biopsies are diagnostic in some cases, they can be spuriously negative because inflammatory involvement of the myocardium may be focal or patchy. If the patient survives the acute phase of myocarditis, the inflammatory lesions either resolve, leaving no residual changes, or heal by progressive fibrosis.

FIGURE 12-36 Myocarditis. A, Lymphocytic myocarditis, associated with myocyte injury. B, Hypersensitivity myocarditis, characterized by interstitial inflammatory infiltrate composed largely of eosinophils and mononuclear inflammatory cells, predominantly localized to perivascular and expanded interstitial spaces. C, Giant-cell myocarditis, with mononuclear inflammatory infiltrate containing lymphocytes and macrophages, extensive loss of muscle, and multinucleated giant cells. D, The myocarditis of Chagas disease. A myofiber distended with trypanosomes (arrow) is present along with inflammation and necrosis of individual myofibers.

Hypersensitivity myocarditis has interstitial infiltrates, principally perivascular, composed of lymphocytes, macrophages, and a high proportion of eosinophils (Fig. 12-36B). A morphologically distinctive form of myocarditis of uncertain cause, called giant-cell myocarditis, is characterized by a widespread inflammatory cellular infiltrate containing multinucleate giant cells interspersed with lymphocytes, eosinophils, plasma cells, and macrophages. Focal to frequently extensive necrosis is present (see Fig. 12-36C). This variant carries a poor prognosis.

The myocarditis of Chagas disease is rendered distinctive by parasitization of scattered myofibers by trypanosomes accompanied by an inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and occasional eosinophils (see Fig. 12-36D).

Clinical Features.

The clinical spectrum of myocarditis is broad. At one end the disease is entirely asymptomatic, and such patients recover completely without sequelae; at the other extreme is the precipitous onset of heart failure or arrhythmias, occasionally with sudden death. Between these extremes are the many levels of involvement associated with symptoms such as fatigue, dyspnea, palpitations, precordial discomfort, and fever. The clinical features of myocarditis can mimic those of acute MI. Occasionally, patients develop dilated cardiomyopathy as a late complication of myocarditis.

Cardiotoxic Drugs.

Cardiac complications of cancer therapy are an important clinical problem.¹¹³ Cardiotoxicity can be associated with conventional chemotherapeutic agents, targeted drugs such as tyrosine kinase inhibitors, and certain forms of immunotherapy.^114,115 The anthracyclines doxorubicin and daunorubicin are the chemotherapeutic agents that are most often associated with toxic myocardial injury, which often leads to a dilated cardiomyopathy and heart failure. Anthracycline toxicity is dose-dependent (cardiotoxicity becomes progressively more frequent above a total dose of 500 mg/m²) and is attributed primarily to peroxidation of lipids in myocyte membranes.

Many other pharmaceuticals and other agents, such as lithium, phenothiazines, chloroquine, and cocaine, have been implicated in myocardial injury and sometimes sudden death. Common findings in hearts injured by many of these chemicals and drugs (including diphtheria exotoxin and doxorubicin) are myofiber swelling, cytoplasmic vacuolization, and fatty change. With discontinuance of the toxic agent these changes may resolve completely, leaving no apparent sequelae. Sometimes, however, more extensive damage produces myocyte necrosis, which can evolve to a dilated cardiomyopathy.

Catecholamines.

Foci of myocardial necrosis with contraction bands, often associated with a sparse mononuclear inflammatory infiltrate consisting mostly of macrophages, can occur in individuals with a pheochromocytoma, a tumor that elaborates catecholamines (Chapter 24). This is considered to be a manifestation of the general problem of “catecholamine effect,” also seen in association with intense autonomic stimulation (secondary to intracranial lesions or stress), or the exogenous administration of large doses of vasopressor agents such as dopamine.¹¹⁶ Sudden, intense emotional or physical stress can also induce acute left ventricular dysfunction due to myocardial stunning, a phenomenon known as Takotsubo cardiomyopathy.¹¹⁷ Cocaine also causes similar catecholamine-mediated damage. The mechanism of catecholamine cardiotoxicity is uncertain, but it seems to relate either to direct toxicity of catecholamines to cardiac myocytes via calcium overload or to focal vasoconstriction in the coronary arterial macro- or microcirculation in the face of an increased heart rate. The mononuclear cell infiltrate is probably a secondary reaction to the foci of myocyte cell death. Similar changes may be encountered in individuals who have recovered from hypotensive episodes or have been resuscitated from a cardiac arrest; in such cases the damage is a result of ischemia-reperfusion (see earlier) with subsequent inflammation.

Amyloidosis.

Amyloidosis is a prototypical myocardial disorder caused by deposition of an abnormal substance in the heart. Amyloidosis (Chapter 6) is caused by insoluble extracellular fibrillar deposits of protein fragments that are prone to forming β-pleated sheets.¹¹⁸ Cardiac amyloidosis may appear along with systemic amyloidosis or be restricted to the heart, particularly in the aged (senile cardiac amyloidosis).¹¹⁹ In senile cardiac amyloidosis, the amyloid deposits generally occur in the ventricles and atria. Senile cardiac amyloidosis occurs in older individuals and is caused by the deposition of transthyretin, a normal serum protein synthesized in the liver that is responsible for transporting thyroxine and retinol-binding protein. Senile cardiac amyloidosis¹²⁰ has a far better prognosis than systemic amyloidosis. Mutant forms of transthyretin can accelerate cardiac (and associated systemic) amyloidosis. For example, the risk of isolated cardiac amyloidosis is four times greater in African Americans than in Caucasians after 60 years of age because 4% of African Americans have a transthyretin mutation leading to the substitution of isoleucine for valine at position 122. This substitution produces an amyloidogenic form of transthyretin (responsible for autosomal-dominant familial transthyretin amyloidosis). Isolated atrial amyloidosis can also occur secondary to deposition of atrial natriuretic peptide, but its clinical significance is uncertain.

Cardiac amyloidosis most frequently produces a restrictive cardiomyopathy, but it can also be asymptomatic or manifest as dilation, arrhythmias, or symptoms mimicking those of ischemic or valvular disease. These varied presentations depend on the predominant location of the deposits, which can be found in the interstitium, conduction system, vasculature, or valves.

Morphology. The heart varies in consistency from normal to firm and rubbery. Usually the chambers are of normal size, but in some cases they are dilated and have thickened walls. Numerous small, semitranslucent nodules resembling drips of wax may be seen at the atrial endocardial surface, particularly on the left. Eosinophilic deposits of amyloid may be found in the interstitium, conduction tissue, valves, endocardium, pericardium, and small intramural coronary arteries; they can be distinguished from other hyaline deposits by special stains such as Congo red, which produces classic apple-green birefringence when viewed under polarized light (Fig. 12-37). Amyloid deposits often form rings around cardiac myocytes and capillaries. Intramural arteries and arterioles may have sufficient amyloid in their walls to compress and occlude their lumens, inducing myocardial ischemia (“small-vessel disease”).

FIGURE 12-37 Cardiac amyloidosis. A, Hematoxylin and eosin stain, showing amyloid appearing as amorphous pink material around myocytes. B, Congo red stain viewed under polarized light, in which amyloid shows characteristic apple-green birefringence (compared with collagen, which appears white).

Iron Overload.

Iron overload can result from either hereditary hemochromatosis (Chapter 18) or multiple blood transfusions (hemosiderosis). The heart in each is usually dilated. Iron deposition is more prominent in ventricles than atria and in the myocardium than in the conduction system. It is thought that iron causes systolic dysfunction by interfering with metal-dependent enzyme systems or by inducing oxygen free-radical injury.

Hyperthyroidism and Hypothyroidism.

Cardiac manifestations are among the earliest, most consistent features of hyperthyroidism and hypothyroidism, and they reflect direct and indirect effects of thyroid hormones on the cells of the heart.¹²¹ In hyperthyroidism (Chapter 24), tachycardia, palpitations, and cardiomegaly are common; supraventricular arrhythmias occasionally appear. Cardiac failure is uncommon; when it occurs in this setting, it is usually superimposed on other cardiac diseases. In hypothyroidism (Chapter 24), cardiac output is decreased, due to reductions in stroke volume and heart rate. Increased peripheral vascular resistance and decreased blood volume result in narrowing of the pulse pressure, prolongation of circulation time, and decreased flow to peripheral tissues.

Serous Pericarditis.

This is characteristically produced by noninfectious inflammatory diseases, such as rheumatic fever, SLE, and scleroderma, tumors, and uremia. An infection in the tissues contiguous to the pericardium—for example, a bacterial pleuritis—may incite sufficient irritation of the parietal pericardial serosa to cause a sterile serous effusion that may progress to serofibrinous pericarditis and ultimately to a frank suppurative reaction. In some instances a well-defined viral infection elsewhere—upper respiratory tract infection, pneumonia, parotitis—antedates the pericarditis and serves as the primary focus of infection. Infrequently, usually in young adults, a viral pericarditis occurs as an apparent primary infection that may be accompanied by myocarditis (myopericarditis). Histologically, there is a mild inflammatory infiltrate in the epipericardial fat consisting predominantly of lymphocytes. Organization into fibrous adhesions rarely occurs.

Fibrinous and Serofibrinous Pericarditis.

These two anatomic forms are the most frequent type of pericarditis and are composed of serous fluid mixed with a fibrinous exudate. Common causes include acute MI (recall Fig. 12-19D), the postinfarction (Dressler) syndrome (probably an autoimmune condition appearing several weeks after an MI), uremia, chest radiation, rheumatic fever, SLE, and trauma. A fibrinous reaction also follows routine cardiac surgery.

From the clinical standpoint the development of a loud pericardial friction rub is the most striking characteristic of fibrinous pericarditis, and pain, systemic febrile reactions, and signs suggestive of cardiac failure may be present. However, the collection of serous fluid may sometimes prevent rubbing by separating the two layers of the pericardium.

Purulent or Suppurative Pericarditis.

This form of pericarditis is caused by invasion of the pericardial space by microbes, which may reach the pericardial cavity by several routes: (1) direct extension from neighboring infections, such as an empyema of the pleural cavity, lobar pneumonia, mediastinal infections, or extension of a ring abscess through the myocardium or aortic root; (2) seeding from the blood; (3) lymphatic extension; or (4) direct introduction during cardiotomy. Immunosuppression predisposes to infection by all of these pathways. The exudate ranges from a thin cloudy fluid to frank pus up to 400 to 500 mL in volume. The serosal surfaces are reddened, granular, and coated with the exudate (Fig. 12-38). Microscopically there is an acute inflammatory reaction, which sometimes extends into surrounding structures to induce mediastinopericarditis. Complete resolution is infrequent, and organization by scarring is the usual outcome. The intense inflammatory response and the subsequent scarring frequently produce constrictive pericarditis, a serious consequence (see later).

FIGURE 12-38 Acute suppurative pericarditis arising from direct extension of a pneumonia. Extensive purulent exudate is evident.

The clinical findings in the active phase are essentially the same as those present in fibrinous pericarditis, but signs of systemic infection are usually marked: for example, spiking temperatures, chills, and fever.

Hemorrhagic Pericarditis.

In this type of pericarditis the exudate is composed of blood mixed with a fibrinous or suppurative effusion; it is most commonly caused by the spread of a malignant neoplasm to the pericardial space. In such cases, cytologic examination of fluid removed through a pericardial tap often reveals the presence of neoplastic cells. Hemorrhagic pericarditis can also be found in bacterial infections, in persons with an underlying bleeding diathesis, and in tuberculosis. Hemorrhagic pericarditis often follows cardiac surgery and is occasionally responsible for significant blood loss or even tamponade, requiring a “second-look” operation. The clinical significance is similar to that of fibrinous or suppurative pericarditis.

Caseous Pericarditis.

This rare type of pericarditis is, until proved otherwise, tuberculous in origin; infrequently, fungal infections evoke a similar reaction. Pericardial involvement occurs by direct spread from tuberculous foci within the tracheobronchial nodes. Caseous pericarditis is a frequent antecedent of disabling, fibrocalcific, chronic constrictive pericarditis.