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CURRENT Diagnosis & Treatment in Cardiology > Chapter 33. Connective Tissue Diseases & the Heart >

Introduction

The connective tissue diseases are immune-mediated inflammatory diseases, primarily of the musculoskeletal system; however, they frequently also involve the cardiovascular system. The most important of these diseases are systemic lupus erythematosus, rheumatoid arthritis, scleroderma, ankylosing spondylitis, polymyositis/dermatomyositis, and mixed connective tissue disease. They affect the valve leaflets, coronary arteries, pericardium, myocardium, conduction system, and great vessels with different rates of prevalence and degrees of severity. Although heart involvement in patients with connective tissue diseases contributes significantly to their morbidity and mortality rates, there is a large discrepancy between clinically recognized heart disease and postmortem series. Furthermore, the pathogenesis, natural history, and effects of therapy are incompletely understood. Increased awareness and better understanding of the cardiovascular disease associated with connective tissue diseases may lead to earlier recognition, treatment and, perhaps, increased longevity.

Systemic Lupus Erythematosus

Essentials of Diagnosis

  • Musculoskeletal and mucocutaneous manifestations of systemic lupus erythematosus (SLE).
  • Libman-Sacks vegetations, atrioventricular (AV) valve regurgitation, myocarditis, vascular thrombotic disease, and SLE.
  • Cardioembolism and SLE.
  • Acute pericarditis with antinuclear antibodies detected in the pericardial fluid.

General Considerations

Systemic lupus erythematosus is a multisystem chronically recurrent inflammatory disease that affects the musculoskeletal, mucocutaneous, visceral, and central nervous systems. Symptoms include fatigue, myalgias, arthralgias or arthritis, photosensitivity, and serositis. The prevalence of SLE varies widely, from 4 to 250 cases per 100,000 persons. It is more frequent in a patient’s relatives than in the general population. Systemic lupus erythematosus is predominantly seen in females, with a female-to-male ratio of 10:1. The pathophysiology of the disease is related to the multiorgan deposition of circulating antigen-antibody complexes and activation of the complement system, leading to humoral- and cellular-mediated inflammation.

Although SLE affects the cardiovascular system with varied frequency and degrees of severity, cardiovascular disease is the third most important cause of death in SLE patients (after infectious, renal, and central nervous system diseases). The most significant SLE-associated heart diseases are valvular heart disease, arterial or venous thrombosis and systemic thromboembolism, coronary artery disease (CAD), and pericarditis. Myocarditis or cardiomyopathy and cardiac arrhythmias or conduction disturbances are less common.

The pathogenesis of SLE-associated cardiovascular disease is believed, as it is for the primary disease, that the immune complex deposition and complement activation lead to an acute, chronic, or recurrent inflammation of the valve leaflets, endocardium, vascular endothelium, pericardium, myocardium, or conduction system. The presence in these tissues of immune complexes, complement, antinuclear antibodies, lupus erythematosus cells, mononuclear inflammatory cells, necrosis, hematoxylin bodies, and deposits of fibrin and platelet thrombi support this theory. Many studies suggest that antiphospholipid antibodies (aPL) (IgA, IgG, or IgM anticardiolipin antibodies [aCL], lupus-anticoagulant [LA], or antibodies to plasma phospholipid-binding protein 2-glycoprotein I) cause cardiovascular injury. These antibodies, present in as many as half of SLE patients, are directed against negatively charged phospholipids present in the membrane of endothelial cells causing endothelial dysfunction, vascular injury, and increased arterial or venous thrombogenesis.

Valvular Heart Disease

General Considerations

Valvular heart disease is the clinically most important and frequent of the SLE-associated cardiovascular manifestations. Valvular heart disease is associated with an increased morbidity and mortality of SLE patients. It has been categorized as vegetations (Libman-Sacks endocarditis), leaflet thickening, valve regurgitation and, infrequently, valve stenosis. The actual prevalence of clinically recognized valve disease is unknown. Although not consistently demonstrated, rates of valve disease are probably higher in patients who have had SLE for more than 5 years, in those treated with corticosteroids, in those with higher disease damage scores, in those with moderate to high levels of aPL, and in those older than 50 years of age.

The pathogenesis of SLE valve disease include (1) an immune-complex mediated inflammation with subendothelial deposition of immunoglobulins and complement leading to an increased expression of 31-integrin on the endothelial cells; (2) increased amount of collagen IV, laminin, and fibronectin; (3) proliferation of blood vessels; (4) inflammation and fibrosis; and finally, (5) commonly associated increased local or systemic thrombogenesis.

The proposed mechanisms of valve damage by aPL include (1) binding of aPL, which induces activation of endothelial cells and up regulation of the expression of adhesion molecules, secretion of cytokines, and abnormal metabolism of prostacyclins; (2) increased oxidized low-density lipoprotein (LDL taken up by macrophages leads to macrophage activation and further damage to endothelial cells); (3) aPL interference with the regulatory functions of prothrombin and with the production of prostacyclin and endothelial relaxing factor, protein C, protein S, and tissue factor; and (4) a heparin-like–induced thrombocytopenia.All these factors lead to increased vasoconstriction, platelet aggregation, and thrombus formation.

Valve Vegetations, or Libman-Sacks Endocarditis

Considered pathognomonic of SLE-associated valve disease, noninfective valve vegetations are almost exclusively seen on the mitral and aortic valves. Most vegetations are located on the coaptation portions of the leaflets, on the atrial side for the mitral valve, and the aortic vessel or ventricular side for the aortic valve. The valve vegetations are usually less than 1 cm2 in size, have irregular borders and heterogeneous echodensity, and have no independent motion (Figures 33–1 and 33–2). Most valves with vegetations have associated thickening or regurgitation. Although valve vegetations have been seen more commonly in younger persons (younger than 40 years), their temporal association with SLE activity, severity, duration, and therapy has been variable.

Figure 33–1.

Recurrent strokes and mitral valve thickening with a large Libman-Sacks vegetation in a 47-year-old woman with systemic lupus erythematosus. A: This T2-weighted magnetic resonance imaging of the brain demonstrates generalized cortical atrophy, multiple areas of old cerebral infarcts characterized by loss of both gray and white matter (arrows) in a cortical and subcortical pattern. Also, multiple areas of deep white matter abnormality consistent with widespread ischemic cerebrovascular disease is noted. B: This transesophageal four-chamber echocardiographic view shows diffuse thickening predominantly of the middle and tip portions of the anterior (aml) and posterior (pml) mitral leaflets. A large vegetation with heterogeneous echoreflectance and irregular borders is noted on the atrial side of the posterior mitral leaflet (arrow). Moderate mitral regurgitation was present. LA, left atrium; LV, left ventricle; RV, right ventricle.

Figure 33–2.

Mitral valve Libman-Sacks vegetations in a 37-year-old woman with systemic lupus erythematosus and a stroke. This transesophageal echocardiogram demonstrates a Libman-Sacks vegetation on the atrial side and tip of the anterior mitral leaflet (aml) (arrow) and a second vegetation on the midportion of the posterior leaflet (pml) (arrowhead). Associated diffuse thickening of both mitral leaflets is also noted. Moderate mitral regurgitation was demonstrated by color-Doppler.

Pathologic examination reveals that active Libman-Sacks vegetations have central fibrinoid necrosis with fibroblastic proliferation and fibrosis, surrounded by mononuclear and polymorphonuclear cellular infiltration, small hemorrhages, and platelet thrombus. Healed vegetations have central fibrosis, minimal or no inflammatory cell deposition, and no or hyalinized and endothelialized thrombus. Active, healed, and mixed vegetations can be seen in the same valve.

Valve Thickening

Leaflet thickening with or without abnormal mobility results from replacement of the normal spongiosum and endothelial layers by postinflammatory fibrous tissue and infrequently by calcification. Valve thickening may be seen in up to half of patients; it is generally diffuse, with greater involvement of the middle and tip portions (Figures 33–1 and 33–2). When leaflet thickening is localized, the basal, middle, and tip portions are equally affected. Valve thickening predominantly affects the mitral and aortic valves and is commonly associated with valve regurgitation, valve vegetations, or both. In young patients with no atherogenic risk factors, associated valve calcification is uncommon (< 5%). However, in middle age patients with traditional atherogenic risk factors, mitral annular and aortic valve calcification are common (20%).

Valve Regurgitation

This most frequent abnormality is predominantly mild in severity and therefore usually clinically silent. Although the prevalence of regurgitation is similar for the mitral, tricuspid, and pulmonic valves (about 50–75%) and the lowest for the aortic valve (25%), the mitral and aortic valves are those most commonly associated with complications. Mitral or aortic valve stenosis associated with respective valve regurgitation is uncommon.

Clinical Findings

Symptoms and Signs

Unless it is severe, valve disease is generally asymptomatic or overshadowed by the musculoskeletal and systemic inflammatory symptoms. However, subclinical valve disease is commonly first manifested with cardioembolism. Recent studies report that valve disease detected by transesophageal echocardiography (TEE), especially mitral valve vegetations, are two to four times more common in patients with focal ischemic brain injury on magnetic resonance imaging (MRI), in those with stroke or transient ischemic attack (TIA), and in those with nonfocal neuropsychiatric manifestations of cognitive dysfunction, acute confusional state, seizures, or psychosis (Figure 33–1). In these series, valve vegetations were strong independent predictor of brain injury and focal or nonfocal neuropsychiatric manifestations. These data suggest that valve disease in lupus patients is a source of fibrin or platelet macro- or microembolism to the brain. Also, severe valve regurgitation resulting from recurrent or acute native and bioprosthetic valvulitis, noninfective mitral valve chordal rupture, or infective endocarditis occur in at least 20% of patients. Infective endocarditis can mimic, accompany, or trigger a flare of SLE and lead to severe valvular dysfunction, heart failure, and death from septicemia. Similarly, a flare of SLE can mimic infective endocarditis (pseudo-infective endocarditis). A low white count, elevated aPL and anti-DNA antibodies, depressed complements, and negative or low C-reactive protein support the diagnosis of active SLE with pseudo-infective endocarditis.

Physical Examination

The physical findings of musculoskeletal and mucocutaneous disease generally predominate in SLE patients, even in those with cardiovascular disease. If moderate-to-severe mitral or aortic regurgitation or stenosis is present, the auscultatory findings found on physical examination will be typical. Less significant degrees of regurgitation (these are the majority) may not be clinically detected or may be mistaken for functional murmurs related to fever, anemia, hypertension, or volume overload.

Diagnostic Studies

Electrocardiography

Results of electrocardiographic (ECG) studies are nonspecific. Left atrial abnormality and left ventricular (LV) hypertrophy can be seen in patients with chronic and severe aortic or mitral regurgitation.

Chest Radiography

Cardiomegaly with LV and left atrial enlargement may be seen in the presence of significant mitral or aortic regurgitation.

Echocardiography

Transthoracic color-flow Doppler echocardiography (TTE) is the most commonly applied technique for the diagnosis of SLE-associated valve disease. This technique accurately determines the presence and severity of valve regurgitation or stenosis and abnormal leaflet thickening, but not of vegetations. The prevalence of Libman-Sacks vegetations by TTE is less than 10%. This technique will also detect associated increased wall thickness, chamber enlargement, ventricular diastolic or systolic dysfunction, and associated left atrial and pulmonary hypertension. Transesophageal echocardiography is superior to TTE in detecting and characterizing SLE-associated valve masses and leaflet thickening. Transesophageal echocardiography detects valve vegetations in up to 35% of patients. By serial TEE, Libman-Sacks vegetations resolve, appear de novo, or change their morphology over time and are not temporally related to SLE activity, severity, duration, or therapy. Therefore, TEE is indicated to exclude sources of cardioembolism in patients with a focal neurologic defect or in patients with a nonfocal neurologic deficit (moderate or worse cognitive dysfunction, seizures, acute confusional state, or psychosis) and cerebral infarcts on MRI, and in patients with suspected complicating infective endocarditis.

Treatment

Specific Antiinflammatory Therapy

Currently, prospective data are limited regarding whether corticosteroids, disease modifying antirheumatic drugs (DMARDs), or immunosuppressive therapy are beneficial in treating SLE-associated valve disease. In general, treatment focuses on managing active SLE disease with antiinflammatory or immunosuppressive agents rather than on managing valve disease specifically.

Long-Term Anticoagulation

Long-term anticoagulation is beneficial in patients with Libman-Sacks vegetations and previous systemic embolism independently of aPL.

Other Therapy

Diuretics, vasodilators, or high-risk prosthetic valve replacement is indicated in severe symptomatic valve disease, including those cases complicated by infective endocarditis. The mortality rate associated with valve replacement in SLE patients is twice that for patients without SLE.

Pericarditis

General Considerations

Pericarditis, with or without effusion or pericardial thickening, is common in postmortem series. Also, about half of lupus patients suffer at least one episode of symptomatic pericarditis. Most episodes are acute and are frequently associated with active SLE and valvulitis, myocarditis, pleuritis, or nephritis. Cardiac tamponade or constrictive pericarditis rarely occurs (< 2%).

Clinical Findings

Symptoms and Signs

The diagnosis of pericarditis is based on clinical manifestations rather on the echocardiogram, because an effusion or pericardial thickening are frequently absent. Symptomatic pericarditis is generally acute and uncomplicated and is most commonly seen during flare-ups of the disease. Asymptomatic pericardial disease may be present in some patients. It is manifested by incidentally detected small effusions in most cases and far less frequently by pericardial thickening found on echocardiography. Asymptomatic pericardial disease is generally seen in patients with stable disease that is either mildly active or in remission. Occasionally, acute pericarditis, cardiac tamponade, or both may be the initial manifestation of SLE. Chronic constrictive pericarditis is rare. Infectious pericarditis is rare but catastrophic and most commonly caused by Staphylococcus aureus. Finally, a pericardial effusion in SLE patients may also be secondary to severe uremia or nephrotic syndrome.

Because it is frequently symptomatic, acute pericarditis is the SLE-related cardiovascular disease most often detected clinically. It may present with fever, tachycardia, pleuritic chest pain and, on auscultation, the presence of a pericardial rub. If a large effusion is present, decreased heart sounds, jugular venous distention, and pulsus paradoxus may be noted.

Laboratory Findings

Pericarditis typically yields serofibrinous, fibrinous or, rarely, serosanguineous exudative fluid containing low complement level and antinuclear antibodies. By immunofluorescence, the pericardium shows granular deposition of immunoglobulins and C3.

Diagnostic Studies

Electrocardiography

The ECG most frequently shows no abnormalities or nonspecific ST segment and T wave changes. The characteristic diffuse ST-segment elevation with upward concavity and PR segment depression of acute pericarditis are common. Low voltage or electrical alternans may also be seen if a large pericardial effusion is present.

Chest Radiography

The chest radiography is generally of little diagnostic value because most patients with acute pericarditis have no—or only small—pericardial effusions. If a large pericardial effusion is present, cardiomegaly with a characteristic water-bottle shape may be seen.

Echocardiography

Since pericardial chest pain can be masked by musculoskeletal or pleural pain, echocardiography has complementary diagnostic value. Echocardiography may demonstrate small pericardial effusions, or none. Small, asymptomatic pericardial effusions have also been found in up to 20% of SLE patients hospitalized with active disease. However, the absence of an effusion on echocardiography does not exclude a clinically suspected pericarditis. In cases of pericarditis with large pericardial effusion and clinically suspected cardiac tamponade, echocardiography may demonstrate right atrial or ventricular diastolic collapse and significant respiratory variability of the mitral or tricuspid Doppler inflows, indicating the need for therapeutic pericardiocentesis. Also, echocardiographically guided pericardiocentesis has been successfully performed in lupus patients with hemodynamically significant pericardial effusions. Also, serial follow-up echocardiography after pericardiocentesis or after antiinflammatory therapy is helpful to guide the need of future interventions. Echocardiography is less useful in detecting pericardial thickening or calcification in cases of suspected chronic pericardial constriction.

Computed Tomography and Magnetic Resonance Imaging

These techniques are preferred methods for assessing pericardial thickening when the echocardiogram suggests constriction.

Treatment

Medical Therapy

Most rheumatologists use low-dose prednisone (10–20 mg/day for 7–14 days) rather than nonsteroidal antiinflammatory drugs (NSAIDs) for symptomatic pericarditis. The use of NSAIDs is limited by associated renal disease, thrombocytopenia, or anticoagulation. Chronically recurrent pericarditis is treated with hydroxychloroquine or immunosuppressive agents.

Surgical Therapy

Pericardiocentesis should be performed when large effusions are unresponsive to medical therapy and when cardiac tamponade or complicating infectious pericarditis with effusion are suspected.

Pericardiectomy has been performed in isolated cases of SLE-associated chronic pericardial constriction.

Myocarditis or Cardiomyopathy

General Considerations

Myocarditis can be seen in autopsy series in up to 80% of patients with SLE; by contrast, only 20% of cases can be clinically detected. Myocardial disease in SLE patients has four principal causes. First, a primary acute, chronic, or recurrent myocarditis is the most common. Primary myocarditis with LV diastolic and, rarely, global or regional systolic dysfunction occur in at least 10% of patients. Rarely, acute myocarditis complicated with heart failure may be the initial manifestation of active SLE. An association of cellular antigen Ro (SS-A) and La (SS-B) antibodies and this type of myocarditis has been established, but their primary pathogenic role is still undefined. The second most common cause of myocardial diastolic and uncommonly systolic dysfunction results from endothelial dysfunction–mediated microvascular CAD. Small vessel vasculitis or epicardial coronary arteritis is rare. The third cause is myocardial dysfunction resulting from severe mitral or aortic regurgitation. Finally, a potentially reversible chloroquine sulfate–induced dilated or restrictive cardiomyopathy has been reported.

Clinical Findings

Symptoms and Signs

Acute myocarditis typically manifests with fever, tachycardia, chest pain and, rarely, with symptoms of heart failure, arrhythmias, or conduction disturbances. The myocarditis is generally mild and usually does not cause LV systolic dysfunction. However, up to one-third of young patients with active SLE have asymptomatic diastolic dysfunction. Occasionally, severe dilated cardiomyopathy is seen. Characteristic manifestations of an acute coronary syndrome will be present in those patients with myocardial dysfunction secondary to coronary arteritis, coronary atherosclerosis, small-vessel vasculitis, acute coronary thrombosis without underlying atherosclerosis, or coronary embolism from aortic or mitral valve masses.

If diastolic or systolic dysfunction is present, tachycardia, fourth and third heart sounds, pulmonary rales, and edema may be found.

Diagnostic Studies

Electrocardiography

Nonspecific ST segment and T wave abnormalities and atrial or ventricular ectopic complexes are common. Rarely, atrial or ventricular tachyarrhythmias can be detected.

Chest Radiography

Cardiomegaly may be present if dilated cardiomyopathy has developed.

Echocardiography

Generally, no abnormalities are detected in acute myocarditis. When the myocarditis is severe, diffuse or regional wall motion abnormalities may be observed. Doppler echocardiography series, including tissue Doppler in asymptomatic young patients without systemic or pulmonary hypertension and normal LV systolic function, have demonstrated up to one-third of LV and right ventricular (RV) diastolic dysfunction, predominantly of impaired relaxation. Diastolic dysfunction occurs three to four times more frequently in patients with active SLE. In unselected patients, the prevalence of LV systolic dysfunction is low.

Radionuclide Studies

Either first-transit or gated-acquisition radionuclide angiography also can be used to assess ventricular systolic and diastolic dysfunction, wall motion abnormalities, and chamber enlargement. In up to one-third of SLE patients, this technique has shown an abnormal ventricular function response to exercise, as evidenced by a fall or subnormal rise in ejection fraction and the appearance of new or worsened wall motion abnormalities indicative of myocarditis or CAD. Reversible, fixed, or mixed myocardial perfusion defects can be seen in patients with normal epicardial coronary arteries indicative of active or past myocarditis or small vessel disease.

Endomyocardial Biopsy

Tissue samples may demonstrate SLE-associated myocarditis or cardiomyopathy when a clinical or serologic diagnosis cannot be made.

Cardiac Biomarkers

Mild elevation of troponin I will be more common than elevation of creatine phosphokinase (CPK).

Treatment

Specific Antiinflammatory Therapy

In outpatients, acute myocarditis is treated with high-dose oral prednisone; in hospitalized patients with acute myocarditis, intravenous methylprednisolone (1–2 mg/kg/day) is given. A course of 7–14 days is generally recommended, but the dose and duration can be titrated based on the clinical response. Long-term immunosuppression with intravenous cyclophosphamide or oral mycophenolate may be required.

Other Therapy

Symptomatic therapy with NSAIDs or other analgesics, bed rest, and ECG monitoring for detection of arrhythmias are indicated. If symptomatic dilated cardiomyopathy is present, diuretics, vasodilators, and digoxin therapy are used.

Thrombotic Diseases

General Considerations

Deep venous thrombosis, pulmonary embolism, and peripheral or cerebral arterial thrombosis are common in SLE patients. Acute coronary thrombosis in the absence of angiographic CAD has also been reported. Both arterial and venous thrombotic events have been associated with aPL. Patients with SLE are subject to intracardiac thrombosis and cerebral or systemic thromboembolism independently of or exacerbated by aPL. Current data support that SLE cerebrovascular disease is commonly associated and likely causally related to cardioembolism from Libman-Sacks endocarditis. In recent series, mitral or aortic valve vegetations were two to four times more common and strong independent predictors of focal ischemic brain injury on MRI; stroke or TIA; and nonfocal neurologic dysfunction, such as cognitive dysfunction, acute confusional state, or seizures. In fact, microembolic events during transcranial Doppler echocardiography are common in patients with cerebral ischemic events.

Clinical Findings

Symptoms and Signs

Although acute pleuritic chest pain and tachycardia could be related to the presence of pericarditis, pleuritis, or pneumonitis, they should prompt the suspicion of pulmonary embolism and DVT. Focal and nonfocal transient or permanent neurologic deficits are commonly due to cardioembolism from valvular or myocardial disease and rarely due to vasculitis or cerebritis.

Laboratory Findings

Antiphospolipid antibodies are highly associated with venous or arterial thrombotic events. However, these antibodies can be present in SLE patients without thrombosis and infrequently in patients who do not have SLE. Therefore, routine measurement of aPL to identify patients at high thrombotic risk and as a basis for prophylactic anticoagulant therapy is still undefined.

Diagnostic Studies

Transesophageal Echocardiography

Transesophageal echocardiography should be considered in SLE patients with focal neurologic deficits, in those with nonfocal neurologic deficits and focal brain injury on brain MRI, and in those with peripheral arterial thrombosis to exclude cardioembolism as the cause.

Doppler Echocardiography, Plethysmography, Scintigraphy, or Venogram

These imaging methods of the lower extremities should be performed if DVT is suspected.

High Resolution Computed Tomography of the Chest or Pulmonary Ventilation-Perfusion Scan

These methods should be considered if pulmonary embolism is clinically suspected.

Treatment

Specific Antiinflammatory Therapy

Corticosteroids or immunosuppressive agents may be beneficial in patients with active SLE and noninfective vegetations with or without thrombosis or thromboembolism.

Other Therapy

Anticoagulation with warfarin is the therapy of choice in patients with DVT, pulmonary embolism, and in those with noninfective valve vegetations and stroke or TIA or cerebral infarcts on MRI.

Coronary Artery Disease

General Considerations

Postmortem studies in SLE patients have demonstrated up to a 25% prevalence of CAD, but clinically evident disease or arteritis is uncommon. Functional or small vessel CAD is more frequent than epicardial coronary disease in clinical and postmortem series.

After controlling for traditional risk factors for CAD, the risk of functional (abnormal vasodilation or microvascular disease) or subclinical atherosclerotic epicardial CAD in lupus patients is four to eight times higher than matched controls. Risk factors for CAD in SLE patients are a longer mean duration of the disease, a longer mean duration and dose of prednisone therapy, a high disease damage score, and SLE-induced dyslipidemia (high levels of oxidative LDL, low levels of HDL, or high levels of pro-inflammatory HDL). However, a high Framingham risk score is also an important predictor.

The proposed pathogenetic mechanisms for CAD include (1) activation of cellular and humoral immunity (including aPL) with activation of macrophages, CD4+CD28–T cells and dendritic cells. The cytotoxicity of these cells to the endothelium and vascular wall result in decreased production of prostacyclin and prostaglandin I and consequently in increased vasoconstriction. Also, vascular wall cytotoxicity result in an increased thrombosis via release of platelet-derived growth factor and thromboxane A2. Cytotoxic cells also produce interferon-, which destabilizes atherosclerotic plaques by suppressing synthesis of collagen, increase proliferation of smooth muscle cells, and activation of macrophages to release free radicals and matrix metalloproteinases; (2) increased oxidation of LDL; (3) increased production of inflammatory cytokines and chemokines such as heat shock proteins, C-reactive protein, rheumatoid factor, tumor necrosis factor-, and interleukins. These cytokines are expressed on the endothelium of coronary arteries, recruit inflammatory cells, promote abnormal vascular smooth cell proliferation, induce oxidative stress, endothelial apoptosis, and further up-regulation of adhesion molecules and chemokines; and (4) exacerbation of dyslipidemia (high levels of very low density lipoproteins and triglycerides and low levels of high-density lipoproteins), homocysteinemia, and insulin resistance. Uncommon pathogenetic factors include coronary arteritis, in situ coronary thrombosis, or embolization from a Libman-Sacks vegetation.

Clinical Findings

Symptoms and Signs

The presentation of CAD in SLE patients is not unique and involves stable or exertional angina, unstable angina, acute ST or non-ST elevation MI or, rarely, heart failure from ischemic LV dysfunction. In addition, fatal MI can occur in SLE patients, and some data suggest an increased risk of myocardial rupture after MI in SLE patients treated with corticosteroids. Coronary arteritis should be suspected in a young patient with an acute ischemic syndrome, active SLE, and evidence of vasculitis affecting other organs. Also, coronary embolism or in situ thrombosis warrant consideration when MI occurs in the presence of a cardioembolic substrate (valve vegetations) or moderate to high levels of aPL.

Diagnostic Studies

Electrocardiography, exercise testing with or without perfusion scanning, and echocardiography, can be used in SLE patients in whom CAD is suspected. However, the diagnostic value of these techniques is inferior to that in the general population due to their young age, female predominance, and lower prevalence of obstructive epicardial CAD. Electron beam computed tomography has demonstrated a high prevalence (30–45%) of coronary calcification in asymptomatic patients. None of these techniques, including angiography, can reliably differentiate coronary arteritis from common coronary atherosclerosis. Suspected epicardial CAD may warrant coronary angiography because of the confounding clinical, echocardiographic, and myocardial perfusion features of functional or small vessel CAD or lupus myocarditis.

Treatment

Specific Antiinflammatory Therapy

If coronary arteritis is suspected, high-dose corticosteroids (1–2 mg/kg/day) are used initially, and followed by intravenous cyclophosphamide or oral mycophenolate. The duration of therapy is usually based on clinical response. Corticosteroids may have some additional danger in patients with recent transmural MI.

Other Therapy

Except for the use of immunosuppressive agents in suspected arteritis, the treatment of epicardial CAD is not different from that in the general population. Both percutaneous coronary intervention (PCI) and bypass surgery have been successfully performed in SLE patients.

Cardiac Arrhythmias & Conduction Disturbances

General Considerations

The prevalence of these abnormalities is unknown. Although they are common with myocarditis and highly associated with the presence of anti-Ro antibodies, no primary pathogenetic role of these antibodies has been demonstrated. Atrial fibrillation or flutter may be seen during episodes of acute pericarditis. Rarely, ventricular arrhythmias or conduction disturbances may be associated with acute myocarditis. Chronic conduction disturbances may be due to the inflammation and fibrosis of the conduction system frequently found at autopsy. Electrocardiography is the most valuable technique for detecting arrhythmias and conduction disturbances.

Treatment

Specific Antiinflammatory Therapy

Although experience is limited, acute high-degree AV blocks may resolve with the use of high-dose corticosteroids.

Other Therapy

Temporary pacing is an alternative treatment for acute AV blocks. Permanent pacemakers should be used in cases of symptomatic high-grade AV blocks that are unresponsive to corticosteroids.

Prognosis

The overall survival rate of SLE patients is about 75% over 10 years. If the heart, lung, kidney, or central nervous system is clinically involved, the prognosis is worse. Cardiovascular disease is the third major cause of mortality in SLE patients, after infectious and renal diseases. Valvular, myocardial, or CAD are known to decrease the survival of SLE patients.

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Rheumatoid Arthritis

Essentials of Diagnosis

  • Clinical evidence of rheumatoid arthritis.
  • Granulomatous valve disease, predominantly of the mitral and aortic valves.
  • Pericarditis and myocarditis with granuloma on biopsy.

General Considerations

Rheumatoid arthritis is an immune-mediated chronic inflammatory disease characterized by morning stiffness, arthralgias, or arthritis, predominantly of the metacarpophalangeal or proximal interphalangeal joints; rheumatoid nodules; serum IgM or IgG rheumatoid factor; and articular erosions seen on a radiograph. The disease prevalence is about 1%, and it affects females more than males with a ratio of 2–4:1. The natural history of the disease is such that the median life expectancy is reduced by 7 years in men and 3 years in women. The most common causes of death are articular and extra-articular complications such as atlantoaxial subluxation, cricoarytenoid synovitis, sepsis, cardiopulmonary complications, and diffuse vasculitis. Rheumatoid arthritis patients with the worst prognosis are those with positive rheumatoid factor, nodular disease, and male gender.

Rheumatoid cardiovascular disease is produced by a nonspecific immune-complex mediated inflammation, vasculitis, or granulomatous deposition on the pericardium, myocardium, heart valves, coronary arteries, aorta, or the conduction system. Clinically apparent rheumatoid heart disease occurs in one-third of patients, compared with up to 80% in autopsy series. Rheumatoid heart disease may appear as pericarditis, myocarditis, valvular heart disease, conduction disturbances, coronary arteritis, aortitis, or cor pulmonale.

Predictors for clinically apparent cardiovascular disease vary among reported series and include male sex, advanced age at the onset of the disease, hypertension, corticosteroid therapy early in the disease, long-standing disease; active extra-articular, erosive polyarticular, and nodular disease; systemic vasculitis; and high serum titers of rheumatoid factor, higher erythrocyte sedimentation rates (ESR), and higher levels of haptoglobin, von Willebrand factor, and plasminogen activator inhibitor. These findings suggest an inflammatory and prothrombotic processes leading to cardiovascular disease. Heart disease is the third leading cause of death in patients with rheumatoid arthritis and accounts for nearly 40% of their mortality.

Rheumatoid Pericarditis

The prevalence of pericarditis is higher in hospitalized patients with active disease. Pericarditis generally follows the diagnosis of rheumatoid arthritis. There is a high association between pericarditis and IgG or IgM rheumatoid-factor positivity, rheumatoid nodular disease, and ESR of > 55 mm/h. Rheumatoid pericarditis occurs by three mechanisms: a nonspecific immune-complex inflammatory process, vasculitis and, less frequently, granulomatous or nodular disease.

Clinical Findings

Symptoms and Signs

Rheumatoid pericarditis is generally uncomplicated and most commonly is evidenced by typical pleuritic pain. About one-third of patients are asymptomatic. On physical examination most will have a pericardial rub. Rarely, complicating cardiac tamponade or constrictive pericarditis may occur, generally in adult patients with active and severe disease of a longer duration and in those with extra-articular involvement. Dyspnea and orthopnea, edema, jugular venous distention, rales, pulsus paradoxus, Kussmaul sign, and hepatojugular venous distention are common when cardiac compression is present.

Laboratory Findings

Findings commonly associated with rheumatoid pericarditis include an ESR > 55 mm/h and high titers of rheumatoid factor. Pericardial fluid is exudative and serosanguineous, with a high protein content and high lactate dehydrogenase (LDH) but a characteristically low glucose level, and may contain rheumatoid factor. The cellular content is usually more than 2000 cells/mcL, predominantly neutrophils. On pericardial biopsy (by immunofluorescence), granular deposits of IgG, IgM, C3, and C1q are seen in the interstitium and blood vessel walls of the pericardium.

Diagnostic Studies

Electrocardiography

An electrocardiogram commonly shows nonspecific ST segment and T wave changes; a classic diffuse ST segment elevation and PR depression can be seen. Low voltage or electrical alternans may be seen with large pericardial effusions.

Chest Radiography

The chest radiography is generally normal. Cardiomegaly is seen in patients with large pericardial effusions. Pericardial calcifications are rarely seen.

Echocardiography

This is the most important diagnostic technique for rheumatoid pericardial disease. The most common findings are pericardial effusion and pericardial thickening. Right atrial or ventricular diastolic compression may be seen with large pericardial effusions and may indicate tamponade hemodynamics. The presence of pericardial thickening and calcification without significant effusion, and the presence of symptoms or signs of cardiac compression, suggest constrictive pericarditis, which can be confirmed by cardiac catheterization. However, absence of pericardial abnormalities on echocardiography does not exclude the presence of pericarditis in a patient with typical symptoms or a pericardial rub. Finally, echocardiography is commonly used to guide pericardiocentesis.

Computed Tomography or Magnetic Resonance Imaging

These imaging methods are superior to echocardiography in detecting pericardial thickening and calcification in patients with suspected constrictive pericarditis.

Treatment

Corticosteroids are frequently successful in treating most cases. If large pericardial effusions or tamponade are present, pericardiocentesis is indicated. For chronic constrictive pericarditis, high-risk pericardiectomy has been performed. The use of intrapericardial corticosteroids at the time of pericardiocentesis is controversial.

Prognosis

The prognosis of rheumatoid arthritis in the presence of pericardial disease is unaltered when the pericardial involvement is mild. Large pericardial effusions with tamponade or chronic constrictive pericarditis, however, increases the morbidity and mortality rates among rheumatoid patients.

Rheumatoid Valvular Heart Disease

General Considerations

Rheumatoid valvular heart disease is produced by a nonspecific acute, chronic, or recurrent immune-complex inflammatory process, vasculitis, or deposition of granulomata on the valve leaflets. The inflammatory process consists of infiltration with plasma cells, histiocytes, lymphocytes, and eosinophils that lead to leaflet fibrosis, thickening, and retraction. The valve granulomata, which resemble rheumatoid nodules, are present inside any portion of the four valves, valve rings, papillary muscle tips, and atrial or ventricular endocardium. The aortic and mitral valves are most often affected. The granulomata are most commonly located at the basal or mid portion of the valves; usually focal, and generally produce none or mild valve dysfunction.

Rheumatoid valvular heart disease is more commonly subclinical and can manifest in 4 forms: (1) healed valvulitis with residual leaflet fibrosis and regurgitation and rarely stenosis; (2) valve nodules; (3) acute or chronic valvulitis with variable degrees of regurgitation and with Libman-Sacks–like vegetations; and rarely, (4) aortitis with aortic root dilatation and aortic regurgitation. Acute and chronic valvulitis with resulting leaflet thickening and fibrosis is indistinguishable from that seen in SLE. In contrast, valve nodules appear to be unique to rheumatoid arthritis.

In previous series using TTE, rheumatoid valve disease has been reported in patients with long-standing rheumatoid disease and severe cases with erosive polyarticular and nodular disease, systemic vasculitis, and high levels of rheumatoid factor. In a recent TEE series, no correlation was found between valve disease and the duration, activity, severity, pattern of onset and course, extra-articular disease, serology, or therapy of rheumatoid arthritis. Therefore, a clinical or laboratory predictor or marker of rheumatoid valve disease is still undefined.

Clinical Findings

Physical Examination

The physical examination in rheumatoid valve disease may not be revealing because in most cases the degree of valve dysfunction is mild. In the rare cases of acute mitral or aortic valvulitis resulting in severe valve regurgitation or acute severe valve regurgitation from “rupture” of a nodule or a large nodule affecting leaflets coaptation, classic auscultatory findings and associated signs of left or biventricular failure may be present. Uncommonly, a clinical syndrome of systemic embolism can result from a thrombus or a valve strand over imposed on a valve nodule or valve thickening or from Libman-Sacks–like vegetations complicating acute valvulitis.

Diagnostic Studies

Electrocardiography and Chest Radiography

The ECG and chest radiography have limited diagnostic value. Both techniques may show chamber enlargement in cases of severe valve disease.

Color-flow Doppler Echocardiography

Transthoracic echocardiography is the most used test for detecting and assessing the severity of rheumatoid valve disease. In a recent series using TEE in 34 patients with rheumatoid arthritis, 20 (59%) patients had mainly left-sided valve disease (valve nodules in 11 [32%], valve thickening in 18 [53%], at least moderate mitral or mild aortic regurgitation in 7 [21%], and valve stenosis in 1 [3%]). Valve nodules were generally single and small (4–12 mm), of homogenous echoreflectance and of oval-shape with regular borders, typically located at the leaflets’ basal or mid portions, and equally affected the aortic and mitral valves. In one patient, mitral and aortic valve thickening was associated with mitral valve Libman-Sacks–like vegetations. Valve thickening was equally diffuse or localized. When the thickening was localized, it affected any leaflet portion, was usually mild, involved the mitral and aortic valves similarly, and rarely involved the annulus and subvalvular apparatus (Figure 33–3).

Figure 33–3.

Rheumatoid aortic valve nodule in a 48-year-old woman with rheumatoid arthritis. This transesophageal echocardiographic view longitudinal of the left ventricular outflow tract demonstrates a well defined nodule with oval shape and homogeneous soft tissue echoreflectance within the midportion of the aortic noncoronary cusp (ncc) (arrowhead). In contrast, the right coronary cusp (rcc) is normal. Aortic valve regurgitation was not demonstrated. aml, anterior mitral leaflet; LA, left atrium; LV, left ventricle.

Treatment

No specific antiinflammatory therapy for rheumatoid valve disease has been established. The use of corticosteroids, other immunosuppressive agents, or tumor necrosis factor- receptor inhibitors in cases of acute severe valvulitis has resulted in significant improvement. Also, in patients with Libman-Sacks–like vegetations, anticoagulation and antiinflammatory therapy has resulted in improvement of valve masses and prevention of recurrent embolic events. Although no prospective trial is available, prophylactic antiplatelet therapy may prevent cardioembolism in patients with valve nodules or thickening. Although the morbidity and mortality rates associated with valve surgery are higher in patients with rheumatoid arthritis than in those without rheumatoid arthritis, mitral or aortic valve replacement or homograft root-and-valve replacement has been successfully performed in acute or chronic severe valve regurgitation.

Rheumatoid Myocarditis

General Considerations

Rheumatoid myocarditis is observed in as much as 30% of patients in postmortem series but is rare in clinical and echocardiographic reports. Rheumatoid myocarditis is more common in patients with active and extra-articular disease, highly positive rheumatoid factor, and in those with systemic vasculitis. Rheumatoid myocarditis may result from autoimmunity, vasculitis, or granulomata deposition; rarely, it is due to amyloid infiltration. Recently, a dilated or restrictive cardiomyopathy due to chloroquine therapy and characterized by myocyte enlargement due to perinuclear vacuolization and abundant myelinoid figures within myocytes has been reported. Unless granulomata are present, rheumatoid myocarditis is difficult to differentiate on histopathology from other types of myocarditis.

Clinical Findings

The clinical presentation of rheumatoid myocarditis is similar to that for myocarditis from other causes. Most commonly it is mild, asymptomatic, and clinically unrecognized. When it is symptomatic, nonspecific symptoms of fatigue, dyspnea, palpitations, and chest pain may be present. The chest pain is usually pleuritic and probably reflects the presence of myopericarditis. Rarely, severe acute myocarditis with LV dysfunction may present as congestive heart failure or symptomatic atrial or ventricular arrhythmias.

Physical Examination

Fever and sinus tachycardia are common. First and second heart sounds are normal; a third or fourth heart sound may rarely be present. Functional systolic murmurs are common. If myopericarditis is present, a pericardial rub may be detected.

Laboratory Findings

Myocarditis has been associated with the presence of anti-SS-A/anti-SS-B autoantibodies. In some cases, elevation of myocardial isoenzymes, such as troponin I and CPK-MB may be seen.

Diagnostic Studies

Electrocardiography

An ECG generally shows nonspecific ST segment and T wave abnormalities. Atrioventricular conduction disturbances and atrial or ventricular ectopy can be detected. As a result of residual interstitial myocardial fibrosis, patients have higher dispersion of repolarization as manifested by prolongation of the uncorrected and corrected QT intervals.

Echocardiography

Recent series using pulse and tissue Doppler, transmitral color flow propagation velocity, and myocardial performance index in young asymptomatic and nonhypertensive patients have demonstrated a high prevalence of diastolic dysfunction, predominantly of impaired relaxation. Also, longitudinal series have demonstrated a high incidence (40%) of clinical diastolic heart failure independent of traditional cardiovascular risk factors for diastolic dysfunction. Less commonly, echocardiography may show segmental wall motion abnormalities or diffuse LV contractile dysfunction and chamber dilatation in cases of severe myocarditis. The echocardiographic features of amyloidosis due to rheumatoid arthritis are nonspecific but may coexist or mimic rheumatoid constrictive pericarditis.

Radionuclide Scanning

Scanning with indium-111, gallium-67, or technetium-99 may show focal patchy or diffuse myocardial uptake indicative of myocardial inflammation, necrosis, or both.

Treatment & Prognosis

Few data are available about the treatment of rheumatoid myocarditis. Few patients have shown benefit with high oral or intravenous doses of corticosteroids in severe cases. Also, the incidence of heart failure decreases with tumor necrosis factor- blocker therapy. The value of cytotoxics is undefined. Nonspecific therapy includes bed rest, analgesics, and cardiac monitoring for at least 48–72 hours. The natural history and prognosis of rheumatoid myocarditis are unknown.

Rheumatoid Coronary Artery Disease

General Considerations

After controlling for traditional atherogenic risk factors, patients with rheumatoid arthritis have two to three times more common epicardial and small vessel CAD than matched controls. Except for aPL, the pathogenetic factors for these two types of CAD in rheumatoid patients is similar to those described for patients with SLE. Obstructive epicardial CAD is probably as common as abnormal coronary artery vasodilation or microvascular disease. Patients older than 50 years are more prone to epicardial atherosclerotic CAD. About 66% of asymptomatic patients with established rheumatoid arthritis have coronary artery calcification on electron-beam CT, compared with 40% in those with recent onset of the disease. Patients with parameters of active and chronic inflammation have reduced small and large arteries elasticity and have a twofold independent risk of MI, heart failure, stroke, and cardiovascular mortality compared with matched controls. Also, rheumatoid patients with acute coronary syndromes have two times higher recurrence rate of events and mortality than matched controls. Coronary arteritis is rare and occur in patients with rheumatoid nodules, overt vasculitis, rapidly progressive rheumatoid disease, and high titers of rheumatoid factor.

Clinical Findings

Symptoms and Signs

Most patients with rheumatoid arthritis who have CAD are asymptomatic. Atherosclerotic CAD will manifest as chronic stable angina, unstable angina, or acute MI, whereas coronary arteritis is more commonly seen as unstable angina or acute MI.

Tachycardia, third or fourth heart sounds, and pulmonary rales, if LV failure is present, are seen during acute ischemic syndromes.

Diagnostic Studies

Electrocardiography

An ECG will show diagnostic Q waves indicative of previous MI, ST elevation or depression suggestive of epicardial or subendocardial ischemic injury, or T wave inversion suggestive of ischemia.

Echocardiography

Resting and stress echocardiography are useful in the detection of wall motion abnormalities in those with obstructive CAD, but have decreased sensitivity for microvascular disease. Transthoracic echocardiography has also been used to assess coronary flow reserve in those with microvascular disease. During severe ischemia, echocardiography may show segmental wall motion abnormalities or myocardial scars if previous infarction has occurred. This technique will also determine the presence (or absence) of LV dysfunction and its severity.

Other Tests

Patients with high ESR ( 60 mm/h), C-reactive protein, serum amyloid, soluble vascular adhesion molecule-1, and interferon- have abnormal small and large arteries vasodilatory response and are at increased risk for cardiovascular events and mortality. Electron-beam CT detects subclinical coronary artery calcification in patients with established disease.

Myocardial isoenzymes, such as troponin I, CPK-MB or LDH1, may be elevated if myocardial necrosis has occurred. Exercise treadmill testing, with or without radionuclide scanning or echocardiography, can be used to detect suspected CAD. Coronary angiography should be considered when there is a high suspicion of CAD, an abnormal exercise treadmill test, or incapacitating symptoms. The diagnosis of coronary arteritis can be suspected if multiple stenotic lesions and aneurysmal lesions are found in the epicardial coronary arteries.

Treatment

Although experience in this area is limited, suspected severe and symptomatic coronary arteritis can initially be treated with high doses of corticosteroids and intravenous cyclophosphamide or oral mycophenylate in conjunction with heparin, aspirin, nitrates, and calcium channel or -blockers. No data are available about PCIs in coronary arteritis. Symptomatic atherosclerotic CAD should be treated medically or with coronary revascularization as appropriate. Amelioration of inflammation with low-dose corticosteroids, tumor necrosis factor- blockers, or statins may decrease the effects of vascular inflammation and dysfunction and consequently of coronary events. Furthermore, cyclooxygenase-2 selective inhibitors, which inhibit prostaglandin I-2 (a vasodilator and inhibitor of platelet aggregation) and NSAIDs increase the risk of acute coronary syndromes in rheumatoid patients.

Conduction Disturbances

General Considerations

The prevalence of AV or intraventricular conduction disturbances in patients with rheumatoid arthritis may not be different from that in age-matched controls in the general population. Possible mechanisms include acute inflammation of the AV node or His bundle (related to pancarditis), vasculitis of the arterioles supplying the conduction pathway, granulomata deposition in the conduction system, and amyloid infiltration.

Clinical Findings

The mean age of patients with conduction disturbances is generally more than 60 years, and most of these patients have severe forms of rheumatoid arthritis with nodular disease, requiring corticosteroid therapy. The conduction disturbances are generally mild, asymptomatic, and incidentally diagnosed by ECG.

Symptoms and Signs

In extremely rare cases, high-degree AV block may be evidenced with tiredness, dizziness, presyncope, or syncope. Although it is uncommon, complete AV block may be asymptomatic because the joint disease severely limits the patient’s activity. Rarely, AV block is transient and can be reversed with antiinflammatory therapy.

Diagnostic Studies

The best diagnostic methods are routine ECG, 24-hour or longer ECG monitoring, or both.

Treatment

The treatment of severe and symptomatic high-degree AV or intraventricular blocks associated with acute myocarditis or valvulitis consists of temporary pacing and high-dose corticosteroids. Patients who are unresponsive to this therapy should receive permanent pacemakers.

Rheumatoid Pulmonary Hypertension

General Considerations

The causes of pulmonary hypertension with normal pulmonary venous pressure include serum hyperviscosity, interstitial fibrosis, obliterative bronchiolitis, and pulmonary vasculitis. The prevalence of these diseases is uncertain, but low. Since the mortality rate is high within 1 year of diagnosis, prompt diagnosis is vital. Lung biopsy or bronchoalveolar lavage may confirm pulmonary vasculitis and bronchiolitis obliterans, both of which are responsive to immunosuppressive therapy.

Severe pulmonary hypertension may lead to RV hypertrophy, enlargement, and dysfunction (cor pulmonale) and produce the symptoms and signs of right-sided heart failure.

Clinical Findings

Symptoms and Signs

Dyspnea is a common manifestation of pulmonary hypertension and cor pulmonale. However, moderate pulmonary hypertension not associated with cor pulmonale can be asymptomatic.

Findings on physical examination include a parasternal heave, split second heart sound with loud pulmonic component, tricuspid regurgitation, right-sided S3 gallop and, rarely, hepatomegaly and edema.

Diagnostic Studies

Electrocardiography

An ECG may show right atrial and ventricular enlargement and right bundle branch block.

Color-Flow Doppler Echocardiography

This technique may show right atrial and ventricular enlargement, hypertrophy or dysfunction, tricuspid regurgitation, and evidence of high pulmonary artery systolic pressure. Pulmonary hypertension may not be accompanied by echocardiographic evidence of cor pulmonale, especially if the pulmonary artery pressure is less than 50 mm Hg. In controlled series of asymptomatic patients, the prevalence of pulmonary hypertension on echocardiography is five times higher in rheumatoid patients than in controls (21% versus 4%). Echocardiography can rule out left-sided heart disease as a cause of pulmonary hypertension. Echocardiography can also assess response to therapy.

Open-Lung Biopsy and Bronchoalveolar Lavage

These methods should be done if severe pulmonary vasculitis or bronchiolitis obliterans is suspected as the cause of pulmonary hypertension.

Treatment & Prognosis

The treatment of pulmonary hypertension from pulmonary vasculitis is immunosuppressive agents or corticosteroids, but the prognosis is poor, and most patients die within 1 year of diagnosis.

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Scleroderma

Essentials of Diagnosis

  • Sclerotic skin, esophageal dysfunction, Raynaud phenomenon.
  • Functional or structural small vessel CAD.
  • Multisegmental myocardial perfusion abnormalities.
  • Diastolic heart failure.
  • Pulmonary hypertension and cor pulmonale.

General Considerations

Scleroderma, or systemic sclerosis, is a generalized disorder characterized by excessive accumulation of connective tissue; fibrosis; and degenerative changes of the skin, skeletal muscles, synovium, blood vessels, gastrointestinal tract, kidney, lung, and heart. Raynaud phenomenon, esophageal dysfunction, and sclerotic skin characterize the disease and are present in more than 90% of patients. The two major clinical variants are diffuse cutaneous (20% of cases) and limited cutaneous disease (80%). The less common diffuse type is characterized by skin thickening of the distal and proximal extremities and the trunk, with frequent involvement of the kidney, lung, or heart. In the more common limited type, which includes the CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), the skin changes are limited to the face, fingers, and distal portions of the extremities. A third, uncommon variant is the overlap syndrome that includes scleroderma in association with other connective tissue disease.

The incidence of scleroderma is 10–20 per million population per year. The disease affects all races, is three times more common in women than in men, and usually occurs between the ages of 30 and 50 years. The diffuse cutaneous type has a poorer prognosis than does the limited type. The overall cumulative survival rates after 3, 6, and 9 years are 86%, 76%, and 61%, respectively. The prognosis is worst for males who are older than 50 years with kidney, lung, or heart disease. Pulmonary disease, including pulmonary hypertension, and renal diseases are the major causes of death; these are followed by heart disease, with a cumulative survival of only 20% at 7 years. The major causes of cardiac death are strucutural and functional microvascular ischemic heart disease, followed by refractory heart failure, sudden death, and pericarditis. Scleroderma cardiac disease manifests predominantly as microvascular CAD, myocarditis, and pulmonary hypertension with or without cor pulmonale. Pericarditis, conduction disturbances, and arrhythmias are less common. Clinically overt scleroderma heart disease is reported in less than one-fourth of patients; the rate rises to as high as 80% in autopsy series. Scleroderma heart disease is generally less common and less severe in the limited type than in the diffuse type.

Coronary Artery Disease

Pathophysiology

In scleroderma, the intramyocardial coronary arteries and arterioles are affected by abnormally increased small vessel vasoconstriction due to an immune-mediated endothelial cell injury and increased production of platelet-derived growth factor impairing the endothelial response to vasodilation. The intramyocardial coronary arteries and arterioles are also affected by mast cell degranulation of histamine, prostaglandin D2, and leukotrienes C4 and D4,leading to coronary vasoconstriction. Also, obstructive microvascular disease occurs due to immune-complex mediated intimal inflammation, fibrinoid necrosis, stimulation of fibroblasts, collagen deposition, and ultimately vessel thrombosis. In contrast, the prevalence of epicardial atherosclerotic disease in patients with scleroderma is probably similar to that of a general population. The common finding on autopsy of myocardial contraction-band necrosis (necrotic myocardial cells with dense eosinophilic bands) is likely related to intermittent intramyocardial coronary spasm or intramyocardial Raynaud phenomenon. Furthermore, almost all patients with evidence of intramyocardial CAD have peripheral Raynaud phenomenon.

Clinical Findings

Symptoms and Signs

Chest pain is uncommon; when present, it is related more commonly to pericarditis or esophageal reflux than to myocardial ischemia. Most patients, even with resting or stress-induced myocardial perfusion imaging defects or wall motion abnormalities, are asymptomatic. Although intramyocardial coronary vasospasm is the rule, severe vasospasm of the epicardial coronary arteries leading to transmural MI has rarely been reported.

Diagnostic Studies

Electrocardiographic Exercise Testing

This method has limited sensitivity because the prevalence of epicardial CAD in patients with scleroderma is low.

Radionuclide Studies

Resting or exercise-induced multisegmental perfusion abnormalities are common; they are frequently reversed or improved with nifedipine or dipyridamole, which suggests recurrent vasospastic episodes leading to myocardial ischemia or fibrosis. Cold-induced reversible or partially reversible myocardial perfusion defects, further support coronary vasospasm. On myocardial perfusion, most patients show fixed defects and some show reversible defects or both fixed and reversible defects (Figure 33–4). Most patients have normal LV function at rest despite the high frequency of perfusion defects, but almost half have an abnormal LV response (a failure to increase the ejection fraction more than 5% from baseline) during exercise radionuclide ventriculography.

Figure 33–4.

Intramural coronary artery disease in a patient with scleroderma. A: This short-axis postexercise perfusion scan of the left ventricle shows septal and inferoseptal wall ischemia (small arrows) that resolve on the resting images. B: This patient had normal epicardial coronary arteries.

Echocardiography

Due to the predominant involvement of the intramyocardial coronary arteries, echocardiographic findings typical of transmural MI are uncommon. Using contrast-enhanced pulse wave Doppler TTE in a series of 27 patients without clinical evidence of ischemic heart disease, reduction in coronary flow reserve ( 2.5) in the left anterior descending coronary artery during adenosine infusion was detected in 52% of patients, compared with 4% of matched controls. Reduction in coronary flow reserve is more common in the diffuse form of scleroderma and is related to the duration and severity of the disease. As a result of functional and later on of obliterative microvascular disease, LV and RV diastolic and uncommonly systolic dysfunction can occur. Occasionally, a transmural MI due to epicardial coronary vasospasm can occur, and its echocardiographic diagnosis relies on the same findings as those of atherosclerotic disease. The cold pressor test with simultaneous echocardiography demonstrates transient wall motion abnormalities in patients with angiographically normal or mild epicardial CAD.

Coronary Angiography

This diagnostic study usually shows normal epicardial coronary arteries, a slow dye flow indicative of increased intramyocardial coronary resistance, and impaired coronary sinus blood flow indicative of abnormal coronary flow reserve.

Treatment

Nifedipine and nicardipine have demonstrated short-term improvement in the number and severity of perfusion defects, but their long-term benefit is unknown. Captopril has shown similar beneficial effects.

Myocarditis

General Considerations

Two types of scleroderma myocardial disease are described. The most common is due to recurrent intramyocardial ischemia leading to fibrosis; the second and less common, an acute inflammatory myocarditis. Patients with scleroderma who have skeletal myopathy have twice the prevalence of myocardial disease, compared with those patients without peripheral myopathy. Myocardial disease is also more common and severe in patients with diffuse cutaneous disease, anti-Scl70 antibodies, and older than 60 years.

Clinically apparent myocarditis is rare, but postmortem series report a high prevalence. Focal or diffuse myocardial fibrosis and contraction-band necrosis are common. Contraction-band necrosis typical of transient coronary occlusion and reperfusion is common but not pathognomonic. These pathologic findings differ from atherosclerotic myocardial disease by their lack of relation to coronary arteries and frequent involvement of the RV and subendocardium.

Clinical Findings

Symptoms and Signs

Focal or diffuse myocardial fibrotic disease may result in significant LV diastolic or systolic dysfunction, arrhythmias, and conduction disturbances. Patients with skeletal myopathy and those with myocarditis more commonly have clinical heart failure. Insidious symptoms are most common and the physical findings of heart failure are similar to those of other conditions. Acute symptoms of heart failure and sudden death rarely occur.

Diagnostic Studies

If clinical or laboratory evidence of myositis is present, diagnostic screening for asymptomatic cardiac involvement is warranted.

Electrocardiography

A septal infarction pattern is seen in some patients, correlating with septal or anteroseptal thallium perfusion abnormalities, despite the presence of normal epicardial coronary arteries. This may represent septal fibrosis.

Echocardiography

Left ventricular systolic dysfunction is uncommon in asymptomatic patients, but when associated with heart failure portends an 80% mortality rate at 1 year. In contrast, a high prevalence (30–50%) of LV diastolic dysfunction is seen in patients with either diffuse or limited cutaneous disease, compared with < 10% in controls. Similarly, a high prevalence (40%) of RV diastolic dysfunction independently of pulmonary hypertension has been reported. Left ventricular diastolic dysfunction correlates with high levels of soluble vascular cell adhesion molecules-1 and ESR as well as the duration and severity of Raynaud phenomenon. Also, RV dysfunction in patients with normal pulmonary artery pressure improves with nicardipine therapy. These data support functional microvascular CAD as the cause of diastolic dysfunction. However, a decreased and heterogeneous integrated backscatter in the subendocardium by ultrasonic videodensitometry in young, nonhypertensive patients supports interstitial collagen deposition and fibrosis as another cause of myocardial dysfunction.

Radionuclide Studies

Radionuclide angiography demonstrates abnormal resting ejection fraction in 15% of patients. Myocardial perfusion scanning is a sensitive method for diagnosis and follow-up of the myocardial disease and for assessing therapeutic responses.

Endomyocardial Biopsy

This technique has been used occasionally to diagnose scleroderma myocardial disease; however, the heterogenous and nonspecific pattern of involvement limit the sensitivity and specificity of this technique.

Treatment

Calcium channel blockers may abolish or decrease the frequency and severity of episodes of ischemia and thereby of myocardial fibrosis, but this hypothesis has not been longitudinally tested. The use of intravenous methylprednisolone in acute inflammatory myocarditis is controversial. Otherwise, symptomatic LV systolic or diastolic dysfunction is treated with current standard therapy.

Prognosis

The presence of an S3 gallop is indicative of LV systolic dysfunction and increases the risk of death by more than 500%. Patients with heart failure have a 100% mortality rate at 7 years, with the highest number (80%) occurring during the first year after diagnosis.

Conduction Disturbances & Arrhythmias

General Considerations

Conduction defects occur in up to 20% of patients with scleroderma; the highest prevalence is seen in those patients with demonstrated myocarditis or myocardial perfusion defects. Fibrous replacement of the sinoatrial and AV nodes, bundle branches, and surrounding myocardium is seen on postmortem series of patients with conduction disturbances.

Clinical Findings

Symptoms and Signs

Arrhythmias are common and frequently associated with active myocarditis. Atrial or ventricular premature contractions, supraventricular tachycardias, and nonsustained ventricular tachycardia are also common. Ventricular and supraventricular arrhythmias are more common in patients with diffuse cutaneous disease than in those with the limited type. Palpitations occur in 50% of patients. Syncope (Stokes-Adams attacks) can occur and are related to either high-degree AV block or ventricular arrhythmias; it may occasionally be the primary manifestation of scleroderma. Syncope can also occur in patients with severe pulmonary hypertension. Forty percent to 60% of cardiac deaths in patients with scleroderma who have active myocarditis may be sudden and related to ventricular arrhythmias.

Diagnostic Studies

Electrocardiography

Most patients have a normal ECG, which is highly predictive of normal LV function. The presence of left or right bundle branch block or bifascicular block generally correlates with resting or exercise-induced LV systolic dysfunction. Also, LV potentials on signal-averaged ECG, complex atrial and ventricular arrhythmias, or conduction abnormalities on ECG are common and correlate with LV dysfunction or myocardial perfusion defects.

Electrophysiologic Studies

These studies show a high prevalence of abnormal sinoatrial and AV nodes and His-Purkinje function and conduction. However, electrophysiologic studies are recommended only for patients with syncope of undefined origin, for those with sustained ventricular tachycardia, or for survivors of sudden cardiac death.

Treatment

A pacemaker is indicated for symptomatic high-grade conduction disturbances, and antiarrhythmic or implantable cardioverter-defibrillator therapy is appropriate for symptomatic arrhythmias.

Prognosis

The presence on ambulatory ECG of frequent ventricular and supraventricular arrhythmias predicts a mortality risk two to six times higher than that of patients without arrhythmias. Because these arrhythmias are strong independent predictors of sudden cardiac death, 24-hour ambulatory ECG monitoring should be considered in patients with scleroderma to identify patients at high risk for sudden cardiac death. Cardiac conduction defects on the resting ECG also indicate a poor prognosis with a mortality rate of 50% by 6 years following diagnosis.

Pericarditis

General Considerations

The pathogenesis of scleroderma pericardial disease is unknown and is usually clinically silent. A low clinical prevalence of pericardial disease contrast with that of postmortem and echocardiographic series (~50%). Fibrinous pericarditis, chronic fibrous pericarditis, pericardial adhesions, and pericardial effusion are the pathologic types described.

Clinical Findings

Symptoms and Signs

Pericardial disease is rarely the initial manifestation of scleroderma. Symptomatic pericardial disease occurs in less than 20% of patients. The most common clinical presentation is a chronic pericardial effusion with dyspnea, orthopnea, and edema; it is less frequently seen as an acute pericarditis with fever, pleuritic chest pain, dyspnea, and pericardial rub. Cardiac tamponade or pericardial constriction is rare. Symptomatic pericardial disease is two to four times more common in patients with the diffuse form of scleroderma than in those with the limited cutaneous form of the disease.

Diagnostic Studies

Echocardiography

Echocardiography commonly shows asymptomatic small pericardial effusions and uncommonly pericardial thickening. It can also confirm clinically suspected cardiac tamponade.

Computed Tomography and Magnetic Resonance Imaging

These imaging studies are important diagnostic adjuncts to echocardiography. They aid in the assessment of pericardial thickening or calcification in patients with suspected chronic constriction (Figure 33–5).

Figure 33–5.

This CT scan of the chest shows a large pericardial effusion (pe) predominantly posteriorly located in a patient with scleroderma and pericarditis. No pericardial thickening or calcification was detected. Esophageal (e) dilatation is noted. H, heart; L, liver.

Other Tests

Pericardial fluid aspirates are usually exudative without autoantibodies, immune complexes, or complement depletion. Antiphospholipid antibodies may be associated with pericardial disease.

Treatment

Symptomatic pericarditis or significant pericardial effusions can be treated with NSAIDs. If tamponade is suspected, pericardiocentesis is usually successful. Corticosteroids alone are not effective in patients with large, chronic pericardial effusions.

Prognosis

Patients with pericarditis and moderate pericardial effusion have a cumulative survival of only 25% after 6–7 years, with the highest mortality rates the first year after diagnosis. This high mortality rate is believed to be related to complicating or accompanying progressive renal failure in patients with chronic pericardial effusions and to sudden death in those with associated acute myopericarditis or myocarditis.

Valvular Heart Disease

The true prevalence of valvular heart disease in patients with scleroderma is unknown, but it is rarely recognized clinically. Postmortem series report a prevalence of up to 18%. Systemic embolism in association with echocardiographically defined noninfective mitral valve vegetations, similar to those of SLE, has been described. One echocardiographic series reported a 67% frequency of mitral regurgitation in scleroderma patients, compared with only 15% in controls. Nonspecific thickening of the mitral or aortic valves without significant regurgitation also can be seen. In addition, a disproportionately high clinical and echocardiographic prevalence of mitral valve prolapse has been described in patients with either diffuse or limited scleroderma.

Secondary Scleroderma Heart Disease

Secondary causes of scleroderma heart disease are related to pulmonary and systemic hypertension. Pulmonary fibrosis can occur in up to 80% and pulmonary hypertension with cor pulmonale in up to 40–50% of patients. Pulmonary hypertension secondary to inflammatory vasculopathy or pulmonary vasospasm is less common and more commonly associated with the limited cutaneous type and overlap syndrome. Abnormal pulmonary function tests, abnormal lung uptake of gallium and technetium-99m sestamibi, and radiographic abnormalities often precede cor pulmonale on echocardiography. In patients with pulmonary hypertension, a higher prevalence and severity of RV diastolic dysfunction independently of age and LV mass has been reported. An RV tissue Doppler E velocity of < 0.11 m/sec select patients with pulmonary artery pressure > 35 mm Hg. Patients with pulmonary hypertension have a decreased survival of 81%, 63%, and 56% at 1, 2, and 3 years, respectively, from the diagnosis.

Oxygen, calcium channel blockers, and angiotensin-converting enzyme inhibitors have provided long-term benefits. Selected patients with severe scleroderma–related lung disease can undergo lung transplantation with similar morbidity and mortality to that of patients without scleroderma.

Hypertension and hypertensive heart disease are generally related to renovascular disease. The prognosis is related to the severity of the heart disease.

Ferri C et al. Heart involvement in systemic sclerosis. Lupus. 2005;14(9):702–7. [PMID: 16218471]

Maione S et al. Echocardiographic alterations in systemic sclerosis: a longitudinal study. Semin Arthritis Rheum. 2005;34(5):721–7. [PMID: 15846587]

Meune C et al. Myocardial contractility is early affected in systemic sclerosis: a tissue Doppler echocardiography study. Eur J Echocardiogr. 2005 Oct;6(5):351–7. [PMID: 16153555]

Tarek el-G et al. Coronary angiographic findings in asymptomatic systemic sclerosis. Clin Rheumatol. 2006 Jul;25(4):487–90. [PMID: 16440131]

Vacca A et al. Absence of epicardial coronary stenosis in patients with systemic sclerosis with severe impairment of coronary flow reserve. Ann Rheum Dis. 2006 Feb;65(2):274–5. [PMID: 16410537]

Ankylosing Spondylitis

Essentials of Diagnosis

  • Characteristic lumbar spine and sacroiliac arthritis.
  • Positive HLA-B27 assay.
  • Aortic root sclerosis and dilation, leaflet thickening, and subaortic bump on echocardiography.
  • Aortic regurgitation.

General Considerations

Ankylosing spondylitis, also known as Marie-Strümpell, or Bekhterev disease, is an inflammatory disorder that affects predominantly the vertebral and sacroiliac joints. It manifests itself as chronic low back pain and limitation of back motion and chest expansion. Less frequently, it affects the peripheral joints and extra-articular organs such as the heart. The disease is estimated to affect 1 in 2000 of the general population, predominantly white men less than 40 years old; the male-to-female ratio is 3–12:1. More than 90% of patients are positive for the histocompatibility antigen HLA-B27. Although the manifestations of the cardiovascular disease generally follow the arthritic syndrome by 10–20 years, they sometimes precede it. The most important cardiovascular manifestations of the disease are aortitis, with or without aortic regurgitation; conduction disturbances; mitral regurgitation; myocardial dysfunction; and pericardial disease. The clinical prevalence of cardiovascular disease in ankylosing spondylitis varies widely. The rates are higher in patients with more than 20 years of disease duration, in those who are older than age 50, and in those with peripheral articular involvement.

Aortitis & Aortic Regurgitation

General Considerations

The pathogenesis of aortitis is still undefined. Increased platelet-aggregating activity and platelet-derived growth factor are believed to be pathogenetic factors in the characteristic proliferative endarteritis of aortic root disease. The inflammatory process also is mediated by plasma cells and lymphocytes. It occurs in the intima, media, and adventitia of the proximal aortic wall and sinus of Valsalva and results in a marked fibroblastic reparative response, fibrous thickening, and calcification, especially of the adventitia and intima. This process extends proximally to the aortic annulus, valve cusps, and adjacent commissures. The consequent dilatation and thickening of the aortic root and annulus and the thickening or retraction of the aortic valve cusps cause aortic regurgitation generally of mild to moderate degree. Severe aortic regurgitation is rare. The mitral valve is frequently involved by downward extension of the aortic root fibrosis into the intervalvular fibrosa and base of the anterior mitral leaflet. This often results in localized fibrotic thickening at the base of the anterior mitral leaflet forming the characteristic “subaortic bump.”

Clinical Findings

The most common and characteristic manifestation of ankylosing spondylitis–associated heart disease is proximal aortitis, with or without aortic regurgitation. Associated mitral valve disease is also common. Aortitis and aortic regurgitation are generally mild to moderate, clinically silent, and chronic. In rare cases, severe aortic regurgitation from severe acute or chronic aortitis or valvulitis or complicating infective endocarditis occurs. Clinically silent aortic root or valve disease, with or without aortic regurgitation, can be present in one-third of patients before the joint disease manifests itself. Although it happens rarely, severe aortic regurgitation may present with mild or no articular disease.

Physical Examination

The most common and salient clinical findings in patients with ankylosing spondylitis will be those of the articular disease because cardiac disease when present is generally mild to moderate and asymptomatic.

Diagnostic Studies

Chest Radiography

The appearance of the cardiac silhouette and great vessels is usually normal. If severe aortic root disease or aortic regurgitation is present, the ascending aorta may appear dilatated or elongated, and LV and atrial enlargement may be noted.

Color-Flow Doppler Echocardiography

By TEE, aortic root thickening, increased stiffness, and dilatation is seen in 60%, 60%, and 25% of patients, respectively. Aortic valve thickening detected in 40% of patients is manifested mainly as nodularities of the aortic cusps. Mitral valve thickening seen in 30% of patients manifests predominantly as basal thickening of the anterior mitral leaflet, forming the characteristic “subaortic bump” (Figure 33–6). Valve regurgitation seen in almost 50% of patients is moderate in one-third of them. Aortic root disease and valve disease is related to the duration of ankylosing spondylitis but not to its activity, severity or therapy. Associated LV enlargement, hypertrophy, and systolic or diastolic function can also be assessed.

Figure 33–6.

Aortic root and valve disease in a patient with ankylosing spondylitis. A: This transesophageal basilar short-axis view shows marked aortic root thickening, predominantly of the posterolateral and anteromedial walls (arrows). Mild aortic root dilation is present. B: Transesophageal basilar longitudinal close-up view of the aortic root also shows the marked thickening of the posterior wall (arrow) extending to the basilar portion of the anterior mitral leaflet (subaortic bump; arrowhead). Mild localized thickening of the right coronary cusp tip is noted. Moderately severe aortic regurgitation was detected on color-flow mapping. The distance between the dots at the edge of the image is 1 cm. aml, anterior mitral leaflet; AoR, aortic root; LA, left atrium; LV, left ventricle; rcc, right coronary cusp.

Radionuclide Ventriculography

This method can assess LV systolic or diastolic function and LV enlargement.

Treatment

Medical Therapy

Specific Antiinflammatory Therapy

No data are available regarding the role of corticosteroids in the aortic root and valve disease associated with ankylosing spondylitis.

Other Therapy

Vasodilators can be used in patients with significant aortic regurgitation.

Surgical Therapy

Aortic valve replacement has been successfully performed in patients with severe and symptomatic aortic regurgitation.

Conduction Disturbances

Conduction disturbances are the second most common associated heart disease, although their pathogenesis is unknown. Although the prevalence of HLA-B27 is increased in patients with ankylosing spondylitis who have implanted pacemakers for heart block, it may be absent in these patients. Furthermore, because HLA-B27 may be present in 6% of normal patients, it cannot be implicated as a primary pathogenetic factor in ankylosing spondylitis–associated conduction disturbances. Conduction disturbances can be the result of the subaortic fibrotic process extending to the basilar septum, leading to destruction or dysfunction of the AV node, the proximal portion of the bundle of His, bundle branches, and fascicles. In fact, echocardiographic studies have demonstrated an association of conduction disturbances with aortic root thickening and subaortic bump.

Clinical Findings

The prevalence of conduction disturbances varies greatly, but is at least 20%. Atrioventricular blocks (first, second and, rarely, third degree) are most frequent, followed by sinus node dysfunction (sinus arrhythmias, sinoatrial block, sinus arrest, and sick sinus syndrome) and bundle branch or fascicular block.

Patients with conduction disturbances are generally asymptomatic and can be detected before clinically manifested in less than one-fifth of patients. The conduction disturbances can occasionally be transient, and symptomatic patients can be treated with temporary pacing. The prevalence of aortic root disease and valve regurgitation is high in the presence of conduction disturbances, in contrast to the small number of cases of aortic regurgitation in patients without conduction disturbances. Occasionally, severe conduction disturbances associated with symptoms requiring cardiac pacing may precede the diagnosis of ankylosing spondylitis. Therefore, unrecognized ankylosing spondylitis should be considered in patients with unexplained conduction disturbances or aortic regurgitation.

Physical Examination

Severe bradyarrhythmias will be clinically detected if patients are symptomatic; otherwise, conduction disturbances are generally incidentally detected with ECG.

Diagnostic Studies

Electrocardiography, including 24-hour ambulatory and event monitoring, can detect the described conduction disturbances.

Treatment

Specific Antiinflammatory Therapy

Antiinflammatory therapy has not proved beneficial in patients with conduction disturbances.

Other Therapy

Permanent pacing has been successfully performed. The most common indications for pacing are complete heart block and sick sinus syndrome.

Mitral Valve Disease

The prevalence of mitral valve disease is about 30%, but it is generally not significant and therefore frequently unrecognized. Mitral valve disease is generally asymptomatic and frequently incidentally detected by echocardiography. The pathogenesis of mitral valve disease is related to the extension of the aortic root fibrosis into the subaortic basilar portion of the anterior mitral leaflet, producing the characteristic subaortic bump. Mitral regurgitation results from either the decreased anterior leaflet mobility caused by the basilar subaortic bump or, less frequently, from LV dilatation caused by aortic regurgitation. Only a few cases of mitral regurgitation severe enough to require valve replacement have been reported.

Myocardial Disease, Pericardial Disease, & Bacterial Endocarditis

Primary myocardial disease is rare. Although its pathogenesis is unknown, it is caused by a diffuse increase in the myocardial interstitial connective tissue and reticulum fibers. It may manifest as LV systolic dysfunction and dilatation in up to one-fifth of patients. Doppler echocardiography series in patients younger than 50 years old with no clinical heart disease have uncommonly reported LV systolic dysfunction. In contrast, about one-third of patients have diastolic dysfunction, predominantly impaired relaxation. Diastolic dysfunction is unrelated to age, disease duration, or disease activity. Rarely, cardiac amyloidosis with diastolic heart failure has been reported. Rarely, secondary myocardial dysfunction relates to chronic volume overload of aortic or mitral regurgitation. If significant LV systolic or diastolic dysfunction is present, third or fourth heart sounds and pulmonary rales may be present. Echocardiography is the best diagnostic method to show primary or secondary LV dysfunction. No specific therapy is available for primary myocardial disease.

Although the true prevalence of pericardial disease is unknown, it is rare in ankylosing spondylitis, and its pathogenesis is also undefined. It is generally asymptomatic and usually incidentally detected by echocardiography as pericardial thickening or small pericardial effusions. No specific therapy is available.

Prognosis

The overall prognosis of patients with ankylosing spondylitis is good and almost comparable to that of a general population. In the past, the presence of severe cardiovascular disease significantly decreased the survival of these patients. Currently, improved diagnostic and therapeutic technologies have allowed early diagnosis, appropriate follow-up, and proper timing of valve replacement or pacemaker implantation in patients with cardiovascular disease. These factors have made the prognosis of ankylosing spondylitis with cardiovascular disease more benign.

Brunner F et al. Ankylosing spondylitis and heart abnormalities: do cardiac conduction disorders, valve regurgitation and diastolic dysfunction occur more often in male patients with diagnosed ankylosing spondylitis for over 15 years than in the normal population? Clin Rheumatol. 2006 Feb;25(1):24–9. [PMID: 16247583]

Divecha H et al. Cardiovascular risk parameters in men with ankylosing spondylitis in comparison with non-inflammatory control subjects: relevance of systemic inflammation. Clin Sci (Lond). 2005 Aug;109(2):171–6. [PMID: 15801904]

Han C et al. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006 Nov;33(11):2167–72. [PMID: 16981296]

Polymyositis/Dermatomyositis

Essentials of Diagnosis

  • Muscle weakness, characteristic skin lesions.
  • Myocarditis and arrhythmias or conduction disturbances.
  • Pericarditis, coronary arteritis, valve disease.

General Considerations

Polymyositis or dermatomyositis is an acquired, chronic, inflammatory myopathy that presents clinically as symmetric proximal muscle weakness of the extremities, trunk, and neck. Dermatomyositis differs from polymyositis by the presence of a rash on the face, neck, chest and extremities, most commonly over the extensor surfaces, especially the dorsum of the hands and fingers. The incidence of polymyositis and dermatomyositis is estimated to be one to five new cases per million population per year in the United States. Overlap syndrome is the association of polymyositis/dermatomyositis with other connective tissue diseases, such as scleroderma, SLE, and rheumatoid arthritis. Rarely, polymyositis or dermatomyositis can be associated with the aPL syndrome. Adults in the fourth to sixth decades are most commonly affected. Both childhood polymyositis/dermatomyositis and that with malignancy are less common. Females, especially black females, are predominantly affected. A cumulative survival rate of 50–75% after 6–8 years has been reported. The major causes of death (in descending order) are malignancy, sepsis, and cardiovascular disease. Poor prognostic indicators of the disease include an age older than 45 years, cardiopulmonary disease, and cutaneous necrotic lesions.

Clinical Findings

Polymyositis/dermatomyositis–associated heart disease is not uncommon and is manifested predominantly as myocarditis and arrhythmias or conduction disturbances. Dilated cardiomyopathy, pericarditis, coronary vasculitis, pulmonary hypertension with cor pulmonale, mitral valve prolapse, and hyperkinetic heart syndrome have also been reported. Clinically overt heart disease is less common than that found in postmortem series. Clinical heart disease is more common in polymyositis and overlap syndrome than in dermatomyositis or in malignant and childhood polymyositis/dermatomyositis. The presence of heart disease does not correlate with age, disease activity, severity, or duration and does not differ between men and women.

Myocarditis

Myocarditis is characterized at postmortem by diffuse interstitial and perivascular lymphocytic infiltration, contraction-band necrosis, and fibrosis. In one postmortem series, myocarditis was seen in half the patients, manifested equally as active myocarditis or focal myocardial fibrosis. Approximately 10–20% of them have dilated cardiomyopathy. Acute myocarditis as the principal manifestation of polymyositis has been reported in only two cases, one case mimicking acute MI, and the second case leading to fatal cardiac arrhythmias. A high correlation has been demonstrated between myocarditis and active myositis. About half of patients with peripheral myositis, as indicated by uptake of technetium-99m pyrophosphate, also have myocardial uptake. Increased myocardial uptake is also frequently associated with depressed ejection fraction and abnormal wall motion (shown by radionuclide ventriculography), which is further supportive of myocardial inflammation. Myocarditis may manifest itself clinically as congestive heart failure or as dilated cardiomyopathy.

Arrhythmias & Conduction Disturbances

Right bundle branch block, left anterior fascicular block, bifascicular block, nonspecific intraventricular conduction block, left bundle branch block, and AV block can occur. Occasionally, conduction disturbances can progress to more severe forms, despite remission of the disease, and permanent pacing has been required in a few cases.

The prevalence of arrhythmias varies. The most common arrhythmias are premature ventricular and atrial beats. Supraventricular tachyarrhythmias and ventricular tachycardia are rare. Sudden cardiac death may occur in a small number of patients. Active myocarditis or residual myocardial degeneration and fibrosis extending to the sinoatrial, AV nodal, and bundle branches explain the arrhythmias and conduction abnormalities.

Coronary Arteritis

The clinical prevalence is unknown. One postmortem series demonstrated the presence of coronary arteritis in 30% of patients, manifested as active vasculitis with intimal proliferation or as medial necrosis with calcification.

Valvular Heart Disease

Except for a higher prevalence of mitral valve prolapse, no other specific valve disease has been reported. The cause of mitral prolapse has not been determined.

Pericarditis

Acute uncomplicated pericarditis with small-to-moderate pericardial effusions has been described; acute pericarditis with cardiac tamponade and chronic constrictive pericarditis are rare. Pericarditis affects less than 20% of adults and slightly more than that in children. Echocardiography, however, shows a prevalence of pericardial effusion, usually small, in up to 25% in adults and up to 50% in children. One large series reported a higher prevalence of pericarditis in overlap syndrome than in isolated polymyositis or dermatomyositis. Only rarely does pericarditis form part of the initial clinical presentation of polymyositis/dermatomyositis.

Pulmonary Hypertension, Cor Pulmonale, & Hyperkinetic Heart Syndrome

Both pulmonary hypertension secondary to interstitial lung disease and primary pulmonary vasculopathy leading to cor pulmonale have been found. In hyperkinetic heart syndrome, abnormally increased LV performance has been demonstrated in up to one-third of patients with polymyositis. The cause of this asymptomatic abnormality is unknown.

Treatment & Prognosis

The benefit of corticosteroid therapy in patients with conduction disturbances, myocarditis, or pericarditis is uncertain. Available data are limited about the natural history, effect of therapy, and prognosis in polymyositis/dermatomyositis–associated heart disease.

Finsterer J et al. Restrictive cardiomyopathy in dermatomyositis. Scand J Rheumatol. 2006 May–Jun;35(3):229–32. [PMID: 16766371]

Allanore Y et al. Effects of corticosteroids and immunosuppressors on idiopathic inflammatory myopathy related myocarditis evaluated by magnetic resonance imaging. Ann Rheum Dis. 2006 Feb;65(2):249–52. [PMID: 16410529]

Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus. 2005;14(9):708–12. [PMID: 16218472]

Mixed Connective Tissue Disease

Essentials of Diagnosis

  • Raynaud phenomenon, sclerodactyly.
  • Myopathy.
  • Pericarditis, pulmonary hypertension.
  • High ribonucleoprotein antibody titers.

General Considerations

Patients with mixed connective tissue disease are those with clinical findings of SLE, rheumatoid arthritis, scleroderma, and polymyositis. Characteristically, these patients have high titers of antibodies to nuclear ribonucleoprotein (RNP) and speckled antinuclear antibodies. Rheumatoid agglutinins also occur in more than half of patients. The disease occurs at all ages, affecting predominantly females (80%). Its prevalence is similar to that of scleroderma, more common than polymyositis, but less than SLE. This disease has no particular racial or ethnic predominance. Primary cardiac involvement in mixed connective tissue disease is infrequent and less common than in other connective tissue diseases.

Clinical Findings

Symptoms and Signs

Pericardial disease manifested as pericarditis, small pericardial effusions, or pericardial thickening is the most common. Pericarditis is more common in children, affecting almost half of patients. In rare cases, pericarditis is the initial presentation of the disease. Mitral valve prolapse has also been reported in this disease, with an unusually high prevalence (30%). Verrucous thickening of the mitral valve and regurgitation have been infrequently detected and are indistinguishable from those of SLE. Infrequently, supraventricular or ventricular arrhythmias and conduction disturbances have been reported. Functional or microvascular disease is the most common type of associated CAD. Acute coronary syndromes may also result from coronary vasospasm, in situ thrombosis, coronary embolism form a valve vegetation, and rarely arteritis. Myocarditis is characterized on histology by interstitial lymphocytic infiltrates and variable degrees of myocardial fibers necrosis and when acute can be reversible with corticosteroids and intravenous pulse cyclophosphamide. On echocardiography, the spectrum of the disease ranges from diastolic dysfunction to global or regional LV systolic dysfunction and heart failure. Acute myocarditis may mimic a myocardial infarction, can be complicated by congestive heart failure and death. Because of the high frequency of pulmonary disease (80%) in patients with mixed connective tissue disease, pulmonary hypertension associated with pulmonary fibrosis or proliferative pulmonary vasculopathy of the small and medium-sized pulmonary arteries can occur, especially in patients with features of scleroderma. Pulmonary thromboembolism is rare.

The clinical manifestations of primary cardiac disease, pulmonary hypertension, and cor pulmonale associated with mixed connective tissue disease do not differ from the other connective tissue diseases.

Diagnostic Studies

The methods used to diagnose cardiac disease associated with mixed connective tissue disease are the same used for other connective tissue diseases.

Treatment

Little data are available about the treatment of heart disease associated with mixed connective tissue disease. Pericarditis generally responds well to corticosteroids. Nifedipine has demonstrated both acute and sustained reduction in pulmonary vascular resistance in patients with pulmonary hypertension.

Prognosis

The overall mortality rate of patients with mixed connective tissue disease is 13% at 6–12 years. The prognostic implications of cardiac disease associated with mixed connective tissue disease are unknown.

Bezerra MC et al. Cardiac tamponade due to massive pericardial effusion in mixed connective tissue disease: reversal with steroid therapy. Lupus. 2004;13(8):618–20. [PMID: 15470773]

Jang JJ et al. A teenager with mixed connective tissue disease presenting with acute coronary syndrome. Vasc Med. 2004 Feb;9(1):31–4. [PMID: 15230486]

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