Systemic lupus erythematosus is a common chronic autoimmune disorder causing injury to many organ systems. Cardiac complications of lupus affect most parts of the heart. These include pericarditis, myocarditis, endocarditis and coronary artery disease. While many histopathological findings in lupus-related cardiac diseases are non-specific, there are a few important findings which pathologists should be aware of. This review provides pathological descriptions of these entities.
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Systemic lupus erythematosus (SLE) is a common chronic multi-system autoimmune disorder that predominantly affects young women. The disease is known to physicians in every specialty because of its multifaceted symptomatology.1 SLE affects 40–200 per 100 000 persons, with the higher values seen in black populations. SLE is impacted on by both genetic and environmental factors. New developments regarding the aetiology of the disease process, genetic discoveries, and potential therapeutics have been recently reviewed and are not discussed here.2 Cardiac manifestations develop in the majority of patients with SLE at some time during the course of their disease. Cardiovascular complications have now become a major cause of death in this population as treatments of other complications have improved.3 Cardiac complications of SLE involve the pericardium, myocardium, endocardium, valvular apparatus, conducting system and coronary vessels.4 These complications are the result of a complex interplay of primary disease, traditional risk factors, and treatment related effects.5 Historically, one or more of these complications are seen in >50% of lupus patients.4 6 7 This review summarises the key clinical and histopathological findings of lupus heart disease that are useful for the practising pathologist.
Pericarditis is the most common cardiovascular manifestation of SLE. Combined autopsy series revealed pericardial involvement in 43–83% of patients with SLE, although only ∼25% of cases cause clinical pericardial symptoms (table 1).4–15
Common clinicopathological types of lupus pericarditis include acute fibrinous, serous, chronic focal adhesive, generalised adhesive, and haemorrhagic pericarditis. Cases of suppurative and constrictive pericarditis along with pericardial tamponade are less frequently reported in the literature.16–20
Signs and symptoms of acute pericarditis include a typical precordial or substernal chest pain, with or without dyspnoea. Patients may have fever, tachycardia, decreased heart sounds and pericardial rubs. Pericardial involvement in SLE is more frequent at the onset of disease or during relapses. Echocardiography and chest x ray are the standard methods to investigate pericarditis.21
Pathological descriptions of pericardial findings in lupus are predominantly from the autopsy-based literature (table 1).4–15 Surgical pathology specimens of the pericardium are rare, with direct pericardial biopsy only being performed for recurrent or persistent pericardial effusions.18 22 Early studies classified most lupus pericarditis as fibrinous; however since the use of corticosteroids, pericarditis has been more routinely described as fibrous.5 Grossly, the pericardium is usually thickened. Longstanding pericarditis can result in adhesions between the visceral and parietal layers, obliterating the pericardial space. This can be focal or diffuse.4
Microscopic examination of the pericardium often shows thickening due to fibroblastic proliferation, oedema, and infiltration by mononuclear inflammatory cells including plasma cells and lymphocytes. These histological features are non-specific and may mimic tuberculous pericarditis, lymphocytic pericarditis secondary to other rheumatic diseases such as rheumatoid arthritis, and organising pericarditis. Rarely, haematoxylin bodies (dense, homogeneous particles of denatured nuclei, specific to SLE), calcific deposits and fibrinoid necrosis may be present.4 23 Haematoxylin bodies may represent the only specific finding in SLE pericarditis, and a diligent search for this finding is warranted.
Direct immunofluorescence studies on SLE pericarditis tissue demonstrate granular deposition of immunoglobulin, C1q and C3 in the walls of pericardial vessels. Inflammation and immune reactants are found in close proximity in examined tissues.24
Effusions are observed in acute cases of pericarditis with variability in the amount of fluid and composition of the effluent. Pericardial fluid analysis has tended to show a leucocytosis with increased neutrophils.16 An acidic effusion fluid (pH <7) suggests a diagnosis of SLE, as reported in one small series.25 Rare cases of purulent pericarditis have been described, with Staphylococcus aureus being the most frequent causative microorganism.5 7 26 Lupus erythematosus (LE) cells, granulocytes that ingest haematoxylin bodies, are also described in pericardial specimens and fluids.4 27
Steroids, chronic immunosuppression, and intravenous immunoglobulins are used in severe cases of pericarditis to decrease inflammation and reduce symptoms.28
MYOCARDIAL DISEASE IN LUPUS
The major causes of myocardial dysfunction in SLE patients are myocarditis, drug-induced dysfunction, and ischaemic injury secondary to atherosclerotic disease. Myocarditis is an uncommon but clinically important complication of SLE. Though myocarditis is found in up to 80% of patients in old autopsy series, often the myocarditis is clinically silent (table 1). With the improved management of the disease, the prevalence of myocarditis has decreased to ∼6%.23 29 30
The clinical features of myocarditis are variable and non-specific. They include symptoms that resemble chest infection, ischaemic heart disease and heart failure. If untreated, lupus myocarditis rarely may lead to arrhythmia, dilated cardiomyopathy, cardiac failure or death.31 32 Myocarditis may be associated with skeletal myositis.33 In SLE patients with cardiac symptoms, more common causes of heart failure such as viral and ischaemic injury should be excluded by viral serology, echocardiography and coronary angiogram before establishing a clinical diagnosis of lupus myocarditis.20
Lupus myocarditis is thought to be an immune-complex mediated disease that leads to complement activation, inflammation and myocardial injury. Anti-heart antibodies have been detected in 20 of 32 SLE patients in one series.34 Low complements C3 and C4, hypoalbuminaemia, raised erythrocyte sedimentation rate (ESR) and positive anti-dsDNA are also found in patients with lupus myocarditis.32 Laboratory tests in this population may show a leucocytosis, and/or increases in the following markers: ESR, C-reactive protein, cardiac fraction of creatine kinase (CK-MB), cardiac troponin T and troponin I.29 35 36
Another cause of cardiac dysfunction in this population is hydroxychloroquine/chloroquine cardiotoxicity. This class of drugs, originally developed as anti-malarial agents, is now a mainstay pharmacotherapy for SLE. Clinical symptoms of anti-malarial toxicity are non-specific and importantly overlap with lupus-related myocarditis.37
A final cause of myocardial dysfunction is infarctions secondary to coronary artery disease. Lupus patients have an increased incidence of coronary artery disease that has particularly increased the rate of myocardial infarctions in young women (see below).38–40 Coronary artery disease can be determined by coronary angiograms or non-invasive methods such as 64-slice CT scanners which, if positive, may exclude the need for an endomyocardial biopsy to determine the aetiology of heart failure.41
Role of endomyocardial biopsy in the diagnosis of heart failure in SLE
Patients with lupus and poor cardiac function should undergo cardiac biopsies after exclusion of coronary vascular causes. It has been recommended that five specimens be obtained from the right ventricle, including apical and non-apical portions of the ventricular septum, to increase diagnostic yield of the endomyocardial biopsy.42 Specific diagnoses that can be made on heart biopsy material from patients with SLE are most commonly myocarditis and drug toxicity. We compiled a table of all 58 reported endomyocardial biopsy cases from SLE patients (table 2).
Thirty-eight per cent of biopsies are positive for myocarditis, 22% are positive for antimalarial cardiotoxicity, and 29% have non-specific findings. This collection, of mostly case reports, is likely biased towards the reporting of positive or novel findings, thus underestimating the percentage of non-specific diagnoses rendered. Despite the usefulness of biopsy, the sensitivity of the procedure is low as lupus myocarditis can be patchy and therefore missed. Thus the clinical diagnosis remains an important tool in directing disease therapy.74
The histological findings of lupus myocarditis are non-specific and resemble other forms of myocarditis, including viral induced myocarditis. There is a perivascular and interstitial infiltrate of mononuclear cells (lymphocytes, plasma cells, macrophages) (fig 1). Myocyte injury is seen along with myocardial degeneration, fibrosis, and scarring in more advanced cases.75 Immunohistochemistry for lymphocytes (CD3 or CD8) and macrophages (CD68) may help in identifying clusters of inflammatory cells, which may be difficult to detect on H&E stained material. Degeneration of the nuclei of infiltrating cells may produce Feulgen positive haematoxylin bodies and may contribute fibrinoid material.4 Myocardial lesions with necrosis and replacement fibrosis may progress to chronic active myocarditis and/or dilated cardiomyopathy.4 24 30 44
The major differential diagnosis for lupus myocarditis is chloroquine/hydroxychloroquine cardiotoxicity in patients taking this medication. Light microscopic examination reveals diffuse myocardial fibre enlargement, fibre size variation, endocardial fibrosis, and most importantly myocyte vacuolisation (fig 2).60 61 Generally, there is no sign of ischaemic injury or myocyte damage suggestive of lupus myocarditis. Vacuoles arise from dilatation of the longitudinal component of the sarcoplasmic reticulum and contain amorphous and laminar material composed of phospholipids, mannose, and glycogen within lysosomes.76
Transmission electron microscopy (TEM) is necessary to detect myeloid bodies (myelin figures) and curvilinear bodies, the pathognomonic findings of anti-malarial toxicity.53 Megamitochondria have also been observed.64 Myeloid bodies can be seen in Fabry disease, so when present, clinical correlation is advised.60 We routinely perform TEM on all biopsies performed on patients using anti-malarials, as myocyte vacuolisation can be subtle.
SLE induced small vessel disease can be observed in cardiac tissues. Small vessel disease is histologically noted by the appearance of thrombi, endothelial activation/blebbing or perivascular inflammation. No cases diagnosed by endomyocardial biopsy exist in the literature, but we have documented this finding in two cases from our own practice. One case involved a 24-year-old white woman with concurrent SLE and anti-phospholipid syndrome. She had a myriad of lupus complications including renal failure, pulmonary hypertension, mouth ulcers, alopecia, Raynaud’s phenomenon, arthralgias, haemolytic anaemia, leucopenia and thrombocytopenia. Her medication list included prednisone, rituximab, mycophenolate mofetil, plaquenil and multiple antihypertensive medications. She underwent biopsy to exclude myocarditis as a cause of acute onset chest pain. The second case was of a 76-year-old white woman with a history of SLE, hypertension, non-insulin dependent diabetes mellitus and hypothyroidism. Her medications included prednisone, hydroxychloroquine, synthroid, multiple antihypertensive drugs and glucose lowering agents. She underwent biopsy during a right heart catheterisation for pulmonary oedema and cardiac dysfunction. These cases and additional material from non-biopsy cases show acute processes, recent thrombi and remodelled recanalised thrombi from earlier injury (fig 3). Fibrin and platelet thrombi that correlate with an active phase in the patient’s disease have also been reported.24 Infiltration of the vascular walls by inflammatory cells can result in small areas of fibrinoid necrosis. Intramural arteries can be plugged by thromboembolic material, which later organises into multiple luminal channels.4 9
Rare reports of haemorrhagic myocarditis and giant cell myocarditis in patients with SLE have been reported in the literature.68 77 Whether these cardiac problems are related to SLE or coincident in a patient with SLE is unclear.
Immunofluorescence staining, when performed in lupus myocarditis cases, demonstrates fine granular immune complex (IgG) and complement deposition (C1q) in the walls and perivascular tissues of myocardial blood vessels, even in areas where histology is normal by light microscopy.24
Although optimal dosage and duration of treatment for lupus myocarditis is not established, high dose parenteral corticosteroids and pulse intravenous cyclophosphamide result in a good outcome. Maintenance therapy with azathioprine, hydroxychloroquine and/or low dose corticosteroids may reduce the recurrence.32 Hydroxychloroquine cardiotoxicity necessitates discontinuation of the drug. A subset of these subjects can make a full recovery of heart function.61 63
VALVULAR HEART DISEASE/LUPUS ENDOCARDITIS
Valvular involvement in systemic lupus erythematosus is one of the most prevalent and clinically important forms of lupus carditis. By echocardiography, ∼60% of SLE patients have a valvular abnormality.78 In postmortem series the frequency of valvular disease ranges from 13% to 74% (table 1) and include thickening, vegetations, regurgitation, and stenosis.79 80 The most common valvular abnormalities seen in the current era of SLE treatments are thickening of left-sided valves and regurgitation.78 81 Libman–Sacks endocarditis is the most characteristic finding in SLE, but has become rarer since treatment with corticosteroids was introduced.26
Libman–Sacks endocarditis was described by Libman and Sacks in 1924 as atypical sterile verrucous lesions of the valvular and mural endocardium.82 Libman–Sacks vegetations are non-infective (marantic) lesions that develop mostly on the mitral valve, but can also be seen on other valves, chordae tendineae and endocardium.5 26 83 Libman–Sacks vegetations are associated with longer disease duration, higher lupus activity, positive anticardiolipin antibodies and secondary antiphospholipid syndrome.84
Valve fibrosis, most commonly of the mitral valve, leads to regurgitation and more rarely stenosis.30 84 Libman–Sacks endocarditis is asymptomatic in most individuals as the lesions are present near the edge of the valves and tend not to deform the closing line.4 9 11 12 However, extensive lesions associated with marked clinical and haemodynamic dysfunction do occur and may eventually require valve replacement. Patients with Libman–Sacks endocarditis are at increased risk for thrombotic events, including myocardial infarctions, strokes and transient ischaemic attacks from fibrin or platelet macroemboli or microemboli (fig 4).85 Involved heart valves are also more susceptible to secondary bacterial endocarditis (fig 5).4 8 26
Libman–Sacks vegetations are variably tan-red, granular, and flat to cauliflower-like spreading projections. They can be sessile or wart-like and generally range in size from pinhead to 4 mm. Infrequently, they may become massive thrombotic lesions and form mulberry-like clusters, up to 10–12 mm, or larger. Vegetations are densely adherent to the valve margins, commissures of the leaflets, chordae tendineae and papillary muscles.8 These vegetations have a propensity for the left-sided valves (particularly in patients on steroid therapy), predominantly along the ventricular surface of the mitral valve.5 Generally these vegetations are small. Thus a thorough examination of the cardiac valves should be performed in any patient with a diagnosis of SLE.
Histologically, the verrucae consist of platelets, fibrin, degenerating blood products, chronic fibrosis, active fibroblasts and neovascularisation.86 Numerous endothelial cells, proliferation of Anitschow cells, calcifications, and infiltration of inflammatory mononuclear cells in the valve ring and valve pocket are also described.4 8 Neutrophilic infiltration is not seen and, when noted, suggests secondary infectious endocarditis.16 The mural endocardium, particularly adjacent to the involved valve, shows a proliferation of fibroblasts and myocytes which can form a dense palisading granulomatous layer.4
Libman–Sacks vegetations have been classified as active or healed. Active vegetations are comprised of three distinct zones: an inner zone of neovascularisation, fibrinoid degeneration, and focal necrosis; a middle zone of organisation with proliferating capillaries and fibroblasts; and an outer zone of exudation with mononuclear cell infiltrates, small haemorrhages and fibrin rich platelet thrombi.87 Healed vegetations, considered to be related to chronic corticosteroid therapy, are characterised by central fibrosis sometimes associated with calcifications, little to no inflammation, and little to no endothelialised thrombus. Active, healed and mixed vegetations can occur in a single valve.4 5 The long term sequelae of multiple healed vegetations is a resultant thickening of the heart valve.5
Bacterial endocarditis can occur on injured heart valves due to any aetiology, thus it is not surprising that its incidence is increased in SLE patients.88 Reviews show that 4.9% of autopsied and 1.3% of clinical cases are complicated by infective endocarditis.16 26
Immunofluorescence studies of heart valves show immune reactant deposition confined to the thin-walled blood vessels in the zone of neovascularisation of active lesions and subendothelial connective tissue of deformed valves.87 Both complements and immunoglobulins are described in heart valves from patients with SLE and concurrent antiphospholipid syndrome (APS).89
Valvular abnormalities frequently resolve over time. Lesions are haemodynamically significant in only 3–4% of SLE patients, requiring surgical excision.90 There is no direct evidence that treatment with steroids can prevent valvular damage; however, the decline in prevalence of Libman–Sacks lesions at autopsy following the introduction of corticosteroids supports a possible indirect beneficial role.91 There is an association between valvular abnormalities, arterial diseases and raised levels of homocysteine and triglycerides in SLE patients. Therefore, patients with valvular disease should be screened for atherosclerosis.92
CORONARY ARTERY DISEASE
Large observational cohort studies indicate that SLE is associated with a more than fivefold increased risk of coronary artery disease, with a sharp increase in younger individuals. The prevalence of subclinical coronary artery disease (CAD), mainly as coronary calcifications, is at least three times higher than that of matched controls.93 94 Most worrisome, the rate of myocardial infarction is 50-fold higher in female SLE patients aged 35–44 compared with the general population.95 Overall the cumulative prevalence of cardiovascular events in lupus is 6–10% and the annual incidence is 1.5%.39 95 96 In postmortem studies, significant atherosclerosis is observed in more than 50% of deceased SLE patients regardless of the actual cause of death.7 Less common coronary vascular diseases observed in SLE patients are coronary arteritis and aneurysms.13 97 98
The aetiology of the accelerated atherosclerosis in SLE is not known, but has been linked to inflammation and endothelial dysfunction. Some of the risk factors that contribute to the development of CAD in SLE patients include elevated total cholesterol, previous cardiac involvement with SLE, obesity, anticardiolipin antibodies and long duration of corticosteroid (prednisone) use.38 39 99 Also, azathioprine and cyclosporine A use are implicated in increased atherosclerosis.100 Conversely, antimalarials improve the lipid profile, decrease cholesterol levels, and may exert anticoagulant effects.101 Even in patients without atherosclerotic disease, abnormalities of the coronary microcirculation or coronary vasospasm may cause myocardial infarctions.102 103
Coronary artery aneurysms are rare, with only 14 reported cases. These have been described predominantly in young or middle-aged women, with individual reports of affected young and middle-aged men. These aneurysms can be the result of primary SLE or a complication of long-term steroid therapy.104 Even rarer are coronary artery dissections, which have been reported in 3 subjects.105
Clinical manifestations of CAD in SLE patients are similar to those of the general population. However, due to the young ages of the patients, ischaemic pain is sometimes mistaken for pericarditis and pleuritis, more frequent complications of SLE. Therefore, it is advisable for clinicians to have a low threshold for cardiac evaluation in patients with SLE.40 Patients with coronary arteritis may present with an acute coronary syndrome. Distinguishing between coronary atherosclerosis and coronary arteritis is difficult on a clinical basis.106
Non-invasive cardiovascular investigations include measurement of intima–media thickness and determining the presence of plaque lesions and coronary artery calcifications.107 In asymptomatic SLE patients, a higher prevalence and extent of coronary calcification has been reported compared to matched controls.93 However, none of the non-invasive imaging techniques can reliably differentiate functional CAD, coronary atherosclerosis, coronary arteritis or myocarditis.
Coronary artery disease in SLE is pathologically similar to other causes. Briefly atheromatous plaques comprised of macrophages, foam cells, inflammatory cells and extracellular lipid cores are observed in the full range of lesions that have been described.108 Intimal narrowing secondary to these lesions is common.109
In coronary arteritis, accumulation of neutrophilic and lymphocytic infiltrate, fibrinoid necrosis, immune complex deposition and oedema of all vessel wall layers leads to arterial obstruction and thrombosis.106 This same process can weaken the wall, resulting in aneurysm.110
Cholesterol-lowering diet, statins, reduced glucocorticoid dosages, and addition of an antimalarial are appropriate mechanisms to lower coronary artery disease risk in this population.111
ANTIPHOSPHOLIPID SYNDROME AND SLE
A special mention of secondary antiphospholipid syndrome (APS) impacting on SLE coronary artery disease is warranted. APS is characterised by hypercoagulability and thrombotic events as the result of antiphosopholipid antibodies (aPLs).112 Although controversial, aPLs are believed to augment the full spectrum of cardiovascular complications of SLE, including accelerated atherosclerosis, valvular heart disease, intracardiac thrombi, and ventricular hypertrophy and dysfunction.113 Thirty-six per cent of SLE patients have concurrent aPLs.114
Coronary artery disease
Due to the proinflammatory and prothrombotic nature of APS, the presence of aPL is a predictor of coronary artery disease in SLE patients.115 Additionally, APS can precipitate a thrombosis, resulting in myocardial infarction in the absence of coronary artery disease.116
Valvular lesions in the SLE population are increased in patients with concurrent APS.117 A meta-analysis of 10 studies of SLE patients reports that 48% of the patients with coincident APL had valvular lesions compared to a prevalence of only 21% in APL-negative patients.118 Gross and microscopic appearances of valvular disease in patients with concurrent APS do not differ.89 118 119
CARDIAC MANIFESTATIONS OF PULMONARY ARTERY HYPERTENSION INDUCED BY SLE
SLE-induced pulmonary artery hypertension (PAH) is another entity that can impact on cardiac pathology. PAH is found in ∼4–9% of patients with SLE.120 121 Compared to idiopathic PAH, SLE-induced PAH is associated with significantly more cardiomegaly.122 While specific studies of cardiac pathology in the setting of SLE-induced PAH are not described, like other forms of PAH, chronic cor pulmonale is expected to occur. Namely, the right ventricle will be grossly dilated and/or hypertrophied. Microscopically, there will be myocyte hypertrophy and increased interstitial fibrosis dependent upon the severity of the PAH and the time course of the disease.
As we have described, patients with SLE can have pathological conditions affecting most parts of their hearts. Pathologists rarely encounter cardiac materials from SLE patients; however an appreciation of non-specific and specific findings in these specimens is important. As newer and better treatment regimens have altered the course of SLE, it will be important to determine if and how cardiac pathology changes in concert. As described herein, most of the pathological descriptions of SLE cardiac complications are based on autopsy studies performed 30+ years ago; new pathological series in contemporary SLE populations are needed to better characterise the incidence and distribution of cardiac manifestations in SLE in the face of new treatments.
Cardiac complications of lupus include pericarditis, myocarditis, endocarditis and coronary artery disease.
Lupus myocarditis and antimalarial cardiotoxicity need to be differentiated by endomyocardial biopsy.
Resected heart valves with Libman–Sacks endocarditis should be investigated for secondary bacterial endocarditis.
The authors are grateful for the assistance of Norman Barker and Jon Christofersen with the histological and gross photographs.
Competing interests: None.
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