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
- 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.
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 β2-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 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 α3β1-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.
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 ...
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