Systemic Diseases Characterized by Immune-Mediated Injury

Valve Disease and Thromboembolism

The typical valve disease in SLE is Libman-Sacks endocarditis, which is characterized by Libman-Sacks vegetations. The pathogenesis of Libman-Sacks endocarditis includes an immune complex–mediated inflammation exacerbated by associated increased thrombogenesis. ^, Active Libman-Sacks vegetations have central myxoid degeneration, fibrinoid necrosis, and hemorrhages surrounded by polymorphonuclear cell inflammation; platelet and fibrin thrombi occur peripherally.

Healed vegetations are those with fibroblastic proliferation, central fibrosis, neovascularization, and minimal to no inflammation. Peripherally, there are organized and partially or fully endothelialized thrombi or no thrombi. Mixed vegetations have intermixed areas of activity and healing and superimposed thrombi with various degrees of organization and endothelialization ( Fig. 37.1 ).

Echocardiographic studies using two-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE) have characterized Libman-Sacks vegetations as predominantly affecting the mitral and aortic valves. They are usually smaller than 1 cm in diameter; are sessile, oval or tubular, protuberant, or coalescent; are more often heterogeneously echoreflectant; are located on the leaflets’ coaptation point (atrial side of mitral leaflets and ventricular side of aortic cusps) but frequently extend through the leaflets into the opposite side; and usually are associated with some degree of leaflet thickening and valve regurgitation or rarely with valve stenosis ( Fig. 37.2 ; see Fig. 37.1 ). Rarely, vegetations are seen on the right-sided heart valves, atrial or ventricular endocardium, mitral or tricuspid subvalvular apparatus, or aortic root ( Fig. 37.3 ).

The estimated prevalence of Libman-Sacks vegetations is less than 15% with transthoracic echocardiography (TTE) and 35% to 45% with TEE. ^, With TEE as the standard, TTE has a very low sensitivity and a low negative predictive value for detection of vegetations (11% and 57%, respectively). Compared with 2D TEE, 3D TEE detects more vegetations and determines larger sizes of vegetations; better defines the location, extent, shape, and appearance of vegetations; more often detects associated valve commissural fusion; and detects a higher frequency of vegetations in patients with cerebrovascular disease ( Table 37.2 ).

TEE is the most accurate diagnostic method for detecting Libman-Sacks endocarditis, but it is semi-invasive and has potential risks. Preliminary data suggest that acute stroke or transient ischemic attack (TIA), SLE with a duration of 12 years or longer without a stroke or TIA, or SLE with a duration of 5 years or longer and age of 32 years or older without stroke or TIA provides high sensitivity (85%), specificity (81%), and positive and negative predictive values (both 83%) for detection of Libman-Sacks endocarditis on TEE.

Embolic cerebrovascular disease is the most common complication of Libman-Sacks endocarditis. A multimodality imaging study using 2D TEE demonstrated that patients with vegetations, compared with patients without vegetations, have more cerebromicroembolisms per hour, lower cerebral perfusion, greater brain injury, more strokes and TIAs, and greater neurocognitive dysfunction. Valve vegetations are a strong independent risk factor for stroke and TIA, neurocognitive dysfunction, focal brain lesions, and all three outcomes combined. Patients with vegetations also have reduced event-free survival time to stroke or TIA, cognitive disability, or death ( Table 37.3 and Figs. 37.4 and 37.5 ; see Fig. 37.2 ).

Left-sided vegetations embolize to peripheral arteries and rarely to the coronary and visceral arteries. Right-sided lesions can embolize to the lungs or cause paradoxical embolism. Libman-Sacks endocarditis can also be complicated by severe valve regurgitation that results from recurrent or acute valvulitis; noninfective valvulitic perforations, including bioprosthetic leaflets; noninfective mitral valve chordal rupture; or overimposed infective endocarditis. ^, Patients with moderate to severe valve dysfunction have a threefold to fourfold higher rate of valve surgery and death compared with patients without valve disease or only mild valve disease.

There is no expert consensus or guidelines about the medical treatment of Libman-Sacks endocarditis. Recent data suggest that antiinflammatory and anti-thrombotic therapies resolve or significantly improve Libman-Sacks endocarditis and its associated embolic cerebrovascular disease ^, ( Table 37.4 ; see Figs. 37.2, 37.4 , and 37.5 ). Although valve surgery may be beneficial in selected cases, it is associated with three to five times higher morbidity and mortality rates than for non-SLE patients and should be deferred until failure of medical therapy. However, medical therapy alone and medical versus surgical therapy needs to be studied in randomized, controlled trials.

Although Libman-Sacks endocarditis has a distinctive echocardiographic appearance, some of its characteristics may overlap with those of thrombotic and infective vegetations, acute or chronic rheumatic valve disease, degenerative valve disease, and Lambl excrescences ( Table 37.5 ). ^{, ,}

Atherosclerosis

Premature atherosclerosis is prevalent among patients with SLE, and it is a major cause of morbidity and mortality. After controlling for traditional atherogenic risk factors, the prevalence of subclinical and clinical atherosclerosis among SLE patients is two to four times higher than among matched controls. ^,

Early functional atherosclerosis, the most common form, manifests as decreased coronary flow reserve by dipyridamole or adenosine Doppler TTE, decreased peripheral arterial vasodilation, or increased carotid arteries or aortic stiffness ( Fig. 37.6A–C ). Premature subclinical atherosclerosis also manifests as an increased prevalence (30%–45%) of aortic and coronary artery calcifications (with two to three times higher rates in the aorta than in the coronary arteries) on computed tomography (CT), increased carotid and aortic intima media thickening and plaques on carotid ultrasonography and TEE (see Fig. 37.6D–E ), and a more diffuse coronary vessel wall inflammation by contrast magnetic resonance imaging (MRI). ^,

Imaging and pathologic studies of the aorta and coronary arteries demonstrate that adventitial thickening is greater in people with atherosclerosis and abnormal arterial stiffness compared with those who do not have these abnormalities, suggesting that adventitial thickening is associated with and may be a pathogenic factor for atherosclerosis and arterial stiffness in SLE (see Fig. 37.6D–E ). ^, In SLE patients and in relation to age, atherosclerosis and stiffness progress within the aorta and within the carotid arteries in a parallel manner. However, aortic atherosclerosis and stiffness progress at two times the rate of carotid atherosclerosis and stiffness. For SLE patients, premature subclinical atherosclerosis portends a 35% increased risk of myocardial infarction, percutaneous coronary interventions, coronary artery bypass grafting, stroke, and death.

In patients with active SLE, an acute coronary syndrome more often results from nonobstructive epicardial atherosclerosis exacerbated by increased vasomotor tone or thrombogenesis and rarely from coronary arteritis, embolism from a valve vegetation, or in situ thrombosis without atherosclerosis. Resting and exercise echocardiography may have decreased sensitivity and specificity for detecting epicardial coronary artery disease (CAD), and consequently, coronary angiography may be warranted in patients with acute coronary syndrome.

Although no randomized, controlled data exist, hydroxychloroquine therapy may have a protective effect against the development and progression of atherosclerosis. Standard medical therapy in combination with immunosuppressive antiinflammatory therapy may be considered concomitantly with percutaneous coronary intervention in patients with active SLE and acute coronary syndrome.

Myocardial Disease

Myocardial disease, manifested predominantly in the form of subclinical ventricular diastolic dysfunction, is common in SLE patients. The predominant cause is microvascular CAD. ^, Arterial hypertension may be the second most common cause, with a prevalence of 25% to 35%. Premature peripheral arterial stiffness can cause left ventricular (LV) diastolic dysfunction. A controlled study in young patients with SLE who were undergoing TEE for simultaneous assessment of LV diastolic function and aortic stiffness demonstrated that patients have higher degrees of aortic stiffness independent of traditional atherogenic risk factors and aortic atherosclerosis; they also have higher LV mass and greater degrees of LV diastolic dysfunction. Aortic stiffness correlated with increased left atrial (LA) volume, LV mass, and LV diastolic dysfunction in this study, and aortic stiffness was independently associated with LV diastolic dysfunction (see Fig. 37.6A–C ). Acute myocarditis is uncommon; it rarely can be the initial manifestation of SLE, and it may manifest with heart failure and global or segmental LV dysfunction on echocardiography and MRI. ^, Small-vessel vasculitis and coronary arteritis are rare. Hydroxychloroquine sulfate–induced dilated or restrictive cardiomyopathy has been reported.

Controlled Doppler and speckle-tracking echocardiography (STE) in asymptomatic patients without systemic or pulmonary hypertension (PH) who have normal LV systolic function have shown a 15% to 35% prevalence of LV and right ventricular (RV) diastolic dysfunction. Longitudinal, circumferential, and radial myocardial strain and strain rate followed by tissue Doppler parameters provide a more sensitive measure than mitral inflow Doppler parameters for detecting subclinical ventricular diastolic and systolic dysfunction. Similarly, STE has demonstrated impairment of LA conduit and storage functions with associated increased LA volumes but preserved pump function.

Indicative of microvascular CAD, LV diastolic dysfunction is associated with reversible, fixed, and mixed myocardial perfusion defects in young patients with active SLE and normal coronary arteries. In contrast to ventricular diastolic dysfunction, the prevalence of systolic dysfunction is less than 20% among unselected patients. The clinical and prognostic implications of subclinical LV and RV diastolic and systolic dysfunction in SLE are undefined.

Pericardial Disease

As many as 50% of SLE patients have at least one episode of symptomatic pericarditis. Pericardial disease is associated with myocarditis and with valve and renal disease. ^{, ,} Cardiac tamponade and constrictive pericarditis are rare. Acute pericarditis and cardiac tamponade rarely may be the initial manifestation of SLE. Up to 20% of female patients younger than 50 years of age with acute pericarditis have SLE. Asymptomatic pericardial effusions may result from mild pericarditis, hypoalbuminemia, or cor pulmonale.

Echocardiography is the standard method for evaluating suspected SLE pericarditis. A large pericardial effusion with or without indicators of tamponade in a patient with active SLE prompts an earlier echocardiography-guided pericardiocentesis, either diagnostic (i.e., aimed to exclude infection) or therapeutic (due to rapid progression or hemorrhagic transformation), followed by immunosuppressive antiinflammatory therapy. A pericardial window should be avoided because of the commonly associated peritonitis and pleuritis with increased risk of infection. Echocardiography is an effective screening method when constriction is under consideration. Cardiac MRI and CT are preferred methods for assessment of pericardial thickness when echocardiography suggests constriction.

Pulmonary Hypertension

PH, defined as pulmonary artery systolic pressure of 40 mmHg or more by Doppler echocardiography, occurs in 5% to 15% of patients with SLE and is associated with increased mortality rates independent of its cause. ^, The most common causes are thromboembolism, interstitial lung disease, left heart disease, and vasculitis. The association of PH with Raynaud phenomenon suggests a vasospastic cause.

Predictors of PH include ribonucleoprotein, soluble substance A, anticentromere and endothelin receptor type A antibodies, and SLE-scleroderma overlap syndrome. ^, STE detects early effects of PH on the right heart. Compared with patients without PH and with controls, patients with PH have decreased RV and right atrial (RA) free wall longitudinal peak systolic strain, systolic strain rate, and early and late diastolic strain rates, while they have increased maximum, preatrial contraction, and minimum RA volumes. ^, Doppler echocardiography at rest and, in selected cases, with exercise is commonly used for diagnosis and assessment of the cause, severity, response to therapy, and follow-up outcomes of SLE-associated PH.

Valve Disease and Thromboembolism

Valve disease is the most common cardiac manifestation of PAPS. The prevalence, distribution, characteristics, and clinical implications of valve disease in PAPS mimic those of Libman-Sacks endocarditis in SLE ( Fig. 37.7 ). Valve disease manifests as valve vegetations (consisting mainly of platelet or fibrin thrombi), valve thickening, and, uncommonly, valve regurgitation. Vegetations are uncommonly identified on the right heart valves and on the atrial or ventricular endocardium. Endocardial injury caused by intracardiac catheters, wires, or prostheses is associated with a higher rate of device-associated thrombosis and thromboembolism.

The prevalence of left-sided valve disease ranges from 30% to 40% by TTE and up to 60% by TEE, compared with less than 5% in controls. 3D TEE may provide superior detection and characterization of valve vegetations, but data are limited (see Fig. 37.7 ). As in patients with SLE, left-sided valve vegetations are associated with thromboembolism, most commonly to the brain, uncommonly to the peripheral and coronary arteries, and rarely to intraabdominal viscera. Right-sided valve, endocardial, or device-associated vegetations can cause pulmonary or paradoxical embolism. The effect of anticoagulation therapy on vegetations is beneficial, but the effect of immunosuppressive antiinflammatory therapy is undefined.

Pulmonary Hypertension

The prevalence of PH in a prospective echocardiographic series of patients with PAPS is at least 20% to 25%; it results predominantly from chronic and recurrent pulmonary embolism and uncommonly from vasospastic or in situ thrombotic vasculopathy. Doppler echocardiography has diagnostic and clinical implications for PAPS-associated PH similar to those for SLE.

Atherosclerosis

A high prevalence (20% to 35%) of myocardial infarction has been reported for patients with PAPS. It results from microvascular disease or rarely from in situ coronary thrombosis ( Fig. 37.8A –D) or coronary thromboembolism. However, these patients have increased intima media thickness of the carotid arteries. Resting or stress echocardiography for detection of epicardial CAD in patients with PAPS may have low sensitivity given the low prevalence of epicardial atherosclerosis.

Myocardial Disease

In controlled studies using Doppler and STE in asymptomatic patients, a high prevalence of mild LV and RV diastolic dysfunction has been reported, independent of arterial hypertension or PH, respectively. The mechanisms of diastolic dysfunction include microvascular CAD, thrombotic microangiopathy, and, rarely, primary myocardial disease.

Atherosclerosis

After controlling for traditional atherogenic risk factors, the prevalence of atherosclerosis in patients with rheumatoid arthritis is two to three times higher than in matched controls. Among unselected patients, functional microvascular CAD is the predominant type (≈50%), followed by nonobstructive (≈25%) and obstructive (≈25%) epicardial CAD. By age 65 to 70 years, 75% to 80% of patients with rheumatoid arthritis have angiographic evidence of CAD (30% with three-vessel CAD), and there is a high incidence of myocardial infarction (4.8 to 5.9 events per 1000 person-years). Coronary arteritis ( Fig. 37.9 ), in situ coronary thrombosis without atherosclerosis or arteritis, and coronary embolism are rare.

Patients who have rheumatoid arthritis with an acute coronary syndrome have 30% to 40% higher rates of event recurrence and death at 1 year than matched controls. Their morbidity and mortality rates after percutaneous or surgical coronary revascularization are two to four times higher than those of matched controls.

Resting and stress echocardiography are useful for detection of wall motion abnormalities in those with obstructive CAD but have decreased sensitivity for microvascular CAD or coronary arteritis. Dipyridamole or adenosine TTE is used to assess coronary flow reserve in those with microvascular disease. Symptomatic patients with rheumatoid arthritis who have evidence of ischemia on resting and exercise echocardiography have a two to three times higher risk of death than matched controls with negative resting or exercise study results.

For patients who have active rheumatoid arthritis with acute coronary syndromes, standard general medical therapy in combination with immunosuppressive antiinflammatory therapy may be considered concomitantly with high-risk percutaneous coronary revascularization (see Fig. 37.9 ).

Pericardial Disease

In patients with acute pericarditis, the pericardial effusion is exudative and bloody with a low glucose level, and it may contain rheumatoid factor. Large pericardial effusion with typical tamponade, large focal masses of fibrinous deposition causing focal tamponade, and constriction are rarely reported. Asymptomatic pericardial effusions, seen in about 25% of patients, are associated with renal disease, hypoalbuminemia, and cor pulmonale. The role of echocardiography in rheumatoid pericardial disease parallels its role in SLE.

Valve Disease

The reported prevalence of valve abnormalities among unselected patients younger than 60 years of age is as low as 30% with TTE and almost 60% with TEE. Valve disease occurs in four forms:

• 1.

  Valve nodules

• 2.

  Healed valvulitis with residual leaflet fibrosis and regurgitation, rarely stenosis

• 3.

  Acute valvulitis with Libman-Sacks–like vegetations and/or significant regurgitation

• 4.

  Superimposed infective endocarditis

Although acute and chronic valvulitis with leaflet thickening or fibrosis may have clinical and echocardiographic manifestations similar to those of SLE, rheumatoid arthritis–related valvulitis has a much lower prevalence and incidence of noninfective vegetations. In contrast, valve nodules appear to be unique to rheumatoid arthritis. These nodules can also be seen on valve rings, papillary muscles, and atrial or ventricular endocardium. Histologically, valve nodules resemble subcutaneous nodules and may result from focal vasculitis.

On TEE, rheumatoid valve nodules are detected in one third of patients; they are small (<0.5 cm ² ), spheroid masses with homogeneous reflectance, typically appearing singly on any portion of the leaflet. The adjacent leaflet appears normal or shows mild sclerosis. This picture is unlike that of Libman-Sacks vegetations (compare Fig. 37.10 with Figs. 37.1–37.5 ). Valve thickening is detected in one half of patients and is equally diffuse or localized; it is usually mild, involves the left heart valves equally, and rarely involves the annulus and subvalvular apparatus. Mild or worse valve regurgitation is seen in 20% to 25% of patients, but stenosis is rare.

Rheumatoid valve disease is typically mild and asymptomatic. However, several uncommon severe manifestations of the disease have been described :

• 1.

  A mixed picture of nodular disease, active or healed valvulitis, and regurgitation ( Fig. 37.10 )

• 2.

  Acute or recurrent valvulitis resulting in severe valve regurgitation ( Fig. 37.11 )

  

• 3.

  Valve thrombus on top of a valve nodule, Libman-Sacks–like vegetations, or superimposed valve strands complicated by systemic embolism

• 4.

  Acute severe valve regurgitation due to rupture of a single or coalescent nodule or a large nodule that affects leaflet coaptation

• 5.

  Aortitis with aortic root dilation and aortic regurgitation

• 6.

  Superimposed infective endocarditis

The short- and long-term mortality rates of patients with rheumatoid valve disease are significantly higher than those of matched controls. The 30-day and 1-year morbidity and mortality rates for patients undergoing valve replacement or, rarely, valve repair are two to three times higher than those of patients without rheumatoid arthritis. Early diagnosis and immunosuppressive antiinflammatory therapy may improve or decrease the progression of valve disease and improve patient survival without high-risk valve surgery.