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The clinical manifestations of autoimmune/immune-mediated cardiac involvement are heterogeneous and include ischemic heart disease when epicardial or intramural coronary arteries are involved, valve disease with possible dysfunction, conduction defects, arrhythmias, pericarditis, and myocardial damage, either showing chronic low-grade inflammation and fibrosis or isolated fibrosis (see also Chap. 100). Pulmonary hypertension (see Chap. 74) can complicate autoimmune diseases.
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Cardiac involvement can either follow a proven diagnosis of autoimmune diseases or be the first manifestation in undiagnosed patients. In this latter case, the cardiology workup should extensively investigate the entire spectrum of possible traits associated with each of the suspected diseases: ocular (ie, uveitis), cutaneous (ie, both diffuse cutaneous and limited cutaneous systemic sclerosis), respiratory (ie, pulmonary hypertension and fibrosis), thyroid (common in many autoimmune diseases), renal (either renal failure or acute crises in certain diseases), gastrointestinal (ie, esophagus in systemic sclerosis), and nervous and skeletal systems. Routine cardiologic evaluation includes history and physical examination, ECG, and transthoracic echocardiogram; further imaging investigations are planned according to the diagnosis and individual needs.
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Familial clustering may manifest with the presence of different autoimmune diseases in more than one family member (Fig. 58–6). The emerging autoinflammatory genetic diseases constitute a novel clinical need for differential diagnoses; accordingly, collection of family data may also be clinically and scientifically useful for sporadic diseases.
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Autoimmune diseases that commonly involve the heart and include DCM-like phenotype/HF in the spectrum of their possible cardiac manifestations are systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis/dermatomyositis, and Sjögren syndrome, as well as overlapping syndromes (Table 58–3). Iatrogenic “cardiomyopathy” can result from common medications used for autoimmune diseases; the cardiac phenotypes are restrictive/dilated in case of hydroxychloroquine toxicity107 and dilated in case of tumor necrosis factor (TNF)-α inhibitors (eg, etanercept, infliximab, adalimumab; see Chap. 61). Iatrogenic cardiomyopathy should be distinguished from the intrinsic risk of HF directly related to the different autoimmune diseases.
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Systemic Sclerosis (Scleroderma)
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Systemic sclerosis (SS) is a clinically heterogeneous disorder of the connective tissue characterized by fibrosis of the skin and internal organs, vascular abnormalities, and presence of autoantibodies against various cellular antigens.108 In limited cutaneous scleroderma, fibrosis mainly affects the face, arms, and hands; patients may demonstrate Raynaud phenomenon years before the skin manifestation and may develop pulmonary hypertension (see Chap. 74). In diffuse cutaneous scleroderma, fibrosis involves large cutaneous areas and internal organs, including the heart. Cardiologists contribute to the clinical workup, differential diagnosis, characterization of cardiac involvement, treatment of the heterogeneous clinical phenotypes, risk stratification, and decision making in emergency (eg, cardiac tamponade) or in chronic management of the disease. In the past decade, better awareness of the disease and early diagnoses have contributed to improved care.109
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Currently available data indicate a prevalence of SS ranging from 50 to 300 cases per 1 million persons and an incidence ranging from 2.3 to 22.8 cases per 1 million persons per year.110 This wide range of prevalence variability reflects the diagnostic complexity of multifactorial syndromes with overlapping traits and manifestations and the different diagnostic criteria currently used to establish a precise diagnosis.111 Classification and diagnostic criteria are a matter of continuous revision by scientific societies and experts.112 Overlap syndromes, as well as silent, asymptomatic, early phases of the disease, impact the prevalence data. Female-to-male ratio ranges from 3:1 to 14:1; susceptibility to scleroderma demonstrates ethnic variations.113
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Causes and Major Pathology Features
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SS is a sporadic multifactorial disease in the majority of cases. Environmental factors and occupational risk factors have been reported in patients with scleroderma-like phenotypes.108,114 Less commonly, SS clusters in families where members may show different autoimmune diseases.115 These data suggest the contribution of genetic factors that could contribute with a small dose effect of multiple genes whose products are involved in innate and adaptive immunity, autoinflammation, cell signaling, extracellular matrix architecture, DNA or RNA degradation, and apoptosis or autophagy diseases.116,117 Replication of genome-wide association studies independently confirmed the candidacy of many susceptibility genetic variants, including selected human leukocyte antigen (HLA) class II molecules.118 The maternal-fetal microchimerism hypothesis may help explain the higher prevalence of SS in females: according to this hypothesis, fetal and maternal lymphocytes can cross the placenta during pregnancy and trigger a graft-versus-host-like microreaction that may culminate in scleroderma.119 This hypothesis is further supported by the presence of allogeneic cells in peripheral blood and in skin biopsy samples obtained from patients with scleroderma,120 and by the short interval between pregnancy and onset of the disease, in particular in the first year after delivery.121
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Interstitial fibrosis is the main pathologic feature observed in hearts affected by scleroderma (Fig. 58–7). Early features are microvascular damage and mononuclear cell infiltrates. In later stages, the main pathology features are dense fibrosis of the dermis, loss of interstitial cells and vasculature, and tissue atrophy.122 Table 58–4 summarizes pathologic tissue and cellular changes as well as the expression of possible markers in affected tissue and autoantibodies.
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The heterogeneous clinical manifestations include myocarditis, pericarditis, and pericardial effusion; conduction disturbances; LV systolic and diastolic dysfunction; valve dysfunction; myocardial ischemia and coronary artery disease; and pulmonary hypertension.123 Cardiac involvement (all manifestations) occurs in about 15% to 30% of patients with diffuse scleroderma.124 A dilated cardiac phenotype (any cause) has been reported in up to 40% of patients with diffuse scleroderma.125 However, because several potential causes may cause HF, the proportion of HF attributable to heart muscle involvement rather than to an alternative mechanism (eg, ischemic heart disease, valvular heart disease, or hypertension caused by scleroderma renal crises) is difficult to establish.126 Myocardial fibrosis is common127 and differs from that observed in ischemic heart disease; in fact, it does not occur in tributary areas of affected arteries, and hemosiderin deposits that are typically seen in post-ischemic myocardium are characteristically absent.128 Low-grade inflammation can involve either small vessels or the myocardial interstitium. In patients with newly developed cardiac manifestations, myocardial inflammation can occur,129 but with very low inflammatory burden. Involvement of cardiac vessels (capillaries, arteriolar and epicardial coronary arteries) can now be well assessed using CMR imaging and coronary angiotomography.130 Pericardial involvement includes fibrinous or fibrous pericardial thickening, and focal adhesions and effusion are common; these abnormalities are often clinically silent and benign128 (see. Chap. 66). In the majority of cases, small pericardial effusions do not cause clinical symptoms or impact prognosis.131 Hemodynamically significant pericardial effusions can be associated with HF; a small amount of rapidly accumulating pericardial fluid in the rigid, fibrosclerotic pericardium may occasionally cause tamponade.131,132 The pericardial fluid is generally noninflammatory and does not contain autoantibodies, immune complexes, or evidence of complement depletion. Histologically, the pericardium shows fibrous thickening and nonspecific inflammation. Valve disease and pulmonary artery hypertension can be part of the complex cardiac involvement in scleroderma.123,126,128,132
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The increasing availability of disease- and organ-specific treatments targeting unique biologic networks and signaling pathways makes a precise diagnosis imperative: DCM-like end-phenotypes may benefit from common treatments for HF. Biologic therapies can target molecules involved in the mechanisms of the immune system, such as cytokines (TNF-α, interleukin [IL]-6), immune cells (B cells), or co-stimulation molecules (cytotoxic T-lymphocyte–associated antigen 4 [CTLA4]), and are currently used in several autoimmune diseases. These drugs provide an alternative to the existing treatment methods of disease-modifying antirheumatic drugs and other immunosuppressive medications.133 Therefore, confounding scleroderma DCM with genetic DCM or other DCM phenotypes prevents or limits the identification of disease-specific causes.
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In patients diagnosed with rheumatoid arthritis (RA), DCM accounts for about 20% of mortality.134 Compared to the general population, patients with RA still demonstrate higher mortality. In autopsy series, heart involvement was demonstrated in up to 60% of patients with RA.134 As with other autoimmune diseases, RA hearts may show a variety of cardiovascular manifestations: DCM; pericarditis in up to 50% of cases135 (but hemodynamically significant pericardial effusions is uncommon, 0.5% of patients); pericardial calcifications136; nodular thickening and calcifications of cardiac valves137; and coronary atherosclerosis.134
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Dilated Cardiomyopathy and Heart Failure
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Congestive HF is a major cause of morbidity and mortality in RA patients.138 The risk of HF remains high after adjustment for underlying coronary artery disease; in long-term follow-up studies, the burden of HF was significantly higher in RA patients than in a control population. Markers such as rheumatoid factor positivity and erythrocyte sedimentation rate, clinical traits such as extra-articular involvement, and treatments such as steroids are associated with risk of congestive HF after adjusting for coronary artery disease and risk factors, suggesting that RA is an independent risk factor for HF.138 Diastolic dysfunction adds to systolic dysfunction in RA hearts.139,140 The modification of cardiac mass in RA hearts is debated, with transthoracic echocardiography supporting this hypothesis versus CMR studies that did not confirm an increase in cardiac mass, but rather showed lower LV volumes compared with age-matched controls.141 The cause of diastolic dysfunction may be ascribed to the effects of inflammatory cytokines such as TNF-α, IL-1, and IL-6, all of which mediate inflammation and fibrosis; cytokine profiles seem to distinguish patients with moderate-to-severe diastolic dysfunction from those with normal heart function142; higher myocardial levels of citrullinated proteins compared with controls may partly account for myocardial involvement in RA.143
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Iatrogenic Myocardial Damage Caused by Rheumatoid Arthritis Treatment
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Disease-modifying drugs used to treat RA (and other connective tissue diseases) may lead to iatrogenic myocardial damage. Toxicity may result from long-term use of TNF inhibitors (TNF-I) and antimalarial agents such as hydroxychloroquine.107,144,145 Hydroxychloroquine toxicity manifests with either hypertrophic-restrictive cardiomyopathy or DCM and is diagnosed with endomyocardial biopsy demonstrating myelin figures and curvilinear bodies (Fig. 58–8) (see Chaps. 61 and 100). The role of TNF-I in causing HF is debated. Etanercept and infliximab trials concordantly showed unfavorable outcomes.146,147 However, other studies/registries reported that the prevalence of congestive HF is lower or comparable in treated patients versus nontreated patients; a meta-analysis of data from these registries concluded that the incidence of congestive HF is lower in treated than in nontreated patients.148 In the most-recent guidelines (2015) for treatment of RA, the Voting Panel of the American College of Rheumatology reported that recommendations are conditional because the evidence is of very low quality and noted that “there are no reports of exacerbation of HF using non-TNF biologics and the US Food and Drug Administration (FDA) warns against using TNF-I in this population based on worsening of congestive HF with TNF-I in the Adverse Event Reporting System database. TNF-I should only be used if there are no other reasonable options, and then, perhaps, only in compensated HF”149 (see Chap. 100).
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Reactive amyloid A deposition occurs in RA as a result of long-term, uncontrolled inflammation. The rate of pathologic detection is 21% to 30% of patients with RA, with cardiac involvement in 28%.150 Cardiac amyloidosis causes a restrictive phenotype with myocardial wall thickening and biventricular enlargement and atrial dilation. The diagnosis is suspected by imaging and by demonstration of involvement of other organs (renal or gastrointestinal tract, heart, spleen, liver, adrenal glands, and, less frequently, lungs, pancreas, thyroid, aorta, muscle, synovial membranes, lymph nodes, peripheral nerves, bones, and skin). The incidence of amyloidosis is likely related to the severity and duration of inflammation. Biologic therapy with anti-TNF agents may reverse amyloid deposition.151
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Accelerated Atherosclerosis
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Vascular heart disease may contribute to HF. Accelerated atherosclerosis is a major cause of morbidity and mortality in RA. A meta-analysis in 41,490 patients with RA from 14 studies showed a 48% increased risk of cardiovascular events compared with the general population.152 Both classic risk factors (diabetes, dyslipidemia, obesity, hypertension, and smoking) and disease-related factors, such as RA disease duration, RA positivity, and disease activity, contribute to increase the risk of cardiovascular diseases.152,153 Paradoxically, decreased lipid levels may precede the diagnosis of RA,154 but evolve during and after treatments, when cholesterol increases in particular in treated and responder patients.155 TNF-I increase total cholesterol and high-density lipoprotein levels without an equivalent effect on low-density lipoprotein levels156; statins may be required in treated patients with high low-density lipoprotein levels,157 and discontinuation of statins in RA can increase the risk of myocardial infarction.158
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Rheumatoid Arthritis Heart Can Display a Pan-Cardiac Involvement
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Cardiac involvement in RA can clinically manifest with cardiomyopathy, pericarditis, and valve disease, and can further be complicated by the development of reactive amyloidosis. Iatrogenic myocardial damage is proven for hydroxyl-chloroquine, but not confirmed for biologic drugs such as TNF-I, in particular regarding the development of HF. Several disease-specific risk factors and effects of medications add to traditional risk factors in the pathogenesis of the accelerated coronary atherosclerosis. Cardiovascular risk seems to decrease when combined methotrexate and TNF-I achieve a good control of the disease.159
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Systemic Lupus Erythematosus
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Dilated Cardiomyopathy in Systemic Lupus Erythematosus
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SLE is a multiorgan autoimmune disease demonstrating higher prevalence in African Americans than in whites, and typically affects women of childbearing age.160,161 The clinical course is characterized by cyclic evolution, with periods of quiescence alternating with periods of disease activity. The heart is commonly involved: DCM is one of the most serious forms of organ involvement in SLE,160,161 and LV systolic dysfunction is associated with poor outcome.162 In 2012, a consensus group of experts on SLE (the Systemic Lupus International Collaborating Clinics) revised the prior American College of Rheumatology criteria163 for SLE and established the diagnostic criteria (Table 58–5).164,165 Myocardial involvement is not included in diagnostic criteria; pericarditis is listed in the context of serositis and occurs in 10% to 30% of patients.160,166 Although myocardial involvement does not provide a diagnostic contribution, it is common in early and late phases of the disease; diastolic dysfunction is detected in 45% of patients without evidence of cardiac disease167; it also accounts for the majority of deaths.168,169
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Most SLE manifests between the ages of 16 and 50 years; estimated incidence rates in North America, South America, and Europe range from 1 to 23 per 100,000 per year.169,170,171,172 Pediatric-onset SLE represents 10% to 20% of all SLE cases and is associated with greater disease severity than adult-onset SLE; the majority of pediatric-onset SLE patients will have developed irreversible disease manifestations within 5 to 10 years of disease onset, most commonly involving the musculoskeletal, ocular, renal, and neuropsychiatric systems.170
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The current pathogenic hypothesis integrates the effects of both environmental factors and genetic predisposition; risk factors are both SLE specific and traditional. Women are more commonly affected; the role of estrogens (17β-estradiol) and related receptors has been investigated. Estrogens are involved in the regulation of cellular subsets of the immune system through estrogen receptor–dependent and –independent mechanisms173; estrogen receptors regulate innate immune cells and signaling pathways,174 including all subsets of T cells and related cytokines,175 and B cells, influencing B-cell differentiation, activity, function, and survival.176
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Epigenetic factors, specifically hypomethylation of CpG sites within genes involved in different pathways, seem to be associated with increased production of autoantibodies (anti-dsDNA, anti-SSA, anti-Sm, and anti-RNP antibodies)177 and also influence endothelial-inflammatory cell interactions and inflammatory responses. Among susceptibility alleles identified with genome-wide association studies, NCF2, encoding a core component of the multiprotein NADPH oxidase, confers susceptibility to SLE in individuals of European ancestry178; HLA-DRB1*15-DQB1*06 haplotype has recently been proposed as the greatest risk factor for development of disease in certain ethnic groups.179 In a recent meta-analysis, the HLA-G 14-base pair insertion/deletion polymorphism was associated with susceptibility to a subgroup of autoimmune diseases such as SLE, but not RA.180 Additional genes/loci have been assigned to SLE: PTPN22, FCGR2A, FCGR2B, CTLA4, TEX1, and DNAS1 are all included in the Mendelian Inheritance in Man (MIM) catalogue as associated with increased susceptibility to SLE. However, at present, there is no evidence supporting a Mendelian inheritance of SLE, which thus remains a potential multifactorial autoimmune disorder.
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Myocardial Involvement
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Heart and vessels are commonly involved in SLE. The major pathology features include accelerated atherosclerosis, myocardial fibrosis, and HF.
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Accelerated atherosclerosis181 is not explained by traditional risk factors, but likely promoted by systemic inflammation.182 Traditional risk factors (eg, diabetes, hypertension, hyperlipidemia) are common in young SLE patients, often as a side effect of immunosuppressant therapy.183 SLE-related risk factors include the presence of autoantibodies, such as antiphospholipid antibodies, anticardiolipin antibodies, and lupus anticoagulant,183 which are produced in 30% to 40% of SLE patients. These antibodies do not fully explain the increased thrombotic risk in SLE; in fact, published data show that only 10% of “positive” patients experience a thrombotic event, and 40% of SLE thrombosis cases are in patients without such antibodies.184 Treatment-related risk includes the effects of both corticosteroids and immunosuppressant drugs.185 Risk stratification and modification for cardiovascular events should, therefore, be tailored on individual risk profile, based on modifiable risk factors and SLE-specific risk factors. Atherosclerosis is associated with increased risk of cardiac, cerebral, or peripheral arterial ischemic events and mortality; in a systematic review and meta-analysis including 17,187 patients from 32 studies, the incidence of cardiovascular events was almost 25%, and 4.5% of the patients had an acute myocardial infarction.183 Although early subclinical atherosclerosis can manifest as intima-media thickening of carotid arteries, recent studies demonstrated that atherosclerotic plaque lesions can be found frequently in the absence of intima-media thickening in both SLE and SS patients; sonography of carotid and femoral arteries may identify additional atherosclerotic lesions and detect patients at a high risk for cardiovascular events.186 Coronary contrast enhancement by CMR may detect subclinical disease in the coronary vessel wall, thus providing a novel direct marker of vessel wall disease.187 Considering that traditional Framingham cardiovascular risk factors do not fully explain the excess of the risk of coronary artery disease in SLE,181 it is likely that inflammatory and autoimmune mechanisms interact with genetic, environmental, and treatment-related factors.
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Myocardial fibrosis represents a significant independent predictor of adverse cardiac outcomes in both ischemic and nonischemic cardiomyopathies.188,189 Recent CMR studies confirmed that mid-wall myocardial fibrosis is frequent in SLE and is associated with age, but not with disease duration or severity; in addition, late gadolinium enhancement comprising > 15% of LV mass may be associated with diastolic dysfunction and impaired exercise capacity.190
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DCM/HF is common in patients with SLE; although the causes can be related to the systemic (cytokine burden) and local inflammation, the role of accelerated atherosclerosis is not easy to dissect from local damage potentially induced by chronic inflammation. However, SLE patients with cardiomyopathy have a prognosis similar to those with idiopathic DCM.191
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The European League Against Rheumatism recommends baseline cardiovascular evaluation and regular, yearly cardiovascular follow-up to assess smoking, vascular events (cerebral/cardiovascular), physical activity, oral contraceptives, hormonal therapies, and family history of cardiovascular disease; to perform blood tests, including blood cholesterol and glucose; and to measure blood pressure and body mass index (and/or waist circumference).192