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Introduction
Autoimmune rheumatic diseases, including rheuma- arterial intima. Chronic inflammation can result in blood
toid arthritis (RA), systemic lupus erythematosus (SLE), mononuclear cell recruitment, upregulation of adhesion
spondyloarthropathies, and vasculitides, are inflam- molecules, release of proinflammatory cytokines, and
matory disorders that can involve multiple organs. production of matrix-degrading enzymes—all factors
Cardiovascular manifestations of rheumatological that can perpetuate inflammatory rheumatological con-
diseases have become increasingly recognized, and, in ditions and promote formation of atherosclerotic vas-
some patients, might even constitute the initial pres- cular plaques.2–4 Immune and endothelial dysfunction
entation of a rheumatological disorder. The spectrum also has an important part in accelerated atherosclerosis;
of cardiovascular manifestations associated with rheu- however, the pathophysiological link between endothelial
matic diseases (Figure 1) is considerably broad, given dysregulation and atherosclerosis has not been demon-
that rheumatological disorders can directly affect the strated. Accelerated atherosclerosis is common in patients
Division of
Cardiovascular
myocardium, cardiac valves, the pericardium, the con- with rheumatic conditions owing to the presence of
Disease, Department duction system, and the vasculature. 1 Whereas the underlying autoimmune and inflammatory mechanisms,
of Internal Medicine cardiovascular manifestations of autoimmune disease which promote accelerated vascular plaque formation.4
(M.P., J.H., S.M., R.M.,
J.K.O., A.L.), can be mild and clinically silent, they can also increase In this Review, we explore each of the vascular, valvu-
and Division of morbidity and mortality substantially, and thus warrant lar, myocardial, pericardial, and electrical manifestations
Rheumatology and
Department of Health
early diagnosis and treatment. of rheumatic diseases individually (Figure 1). We also
Sciences Research Patients with systemic autoimmune conditions often highlight the need to raise awareness to the interface
(S.E.G., E.L.M.), Mayo develop atherosclerosis, contributing to a higher mor- between cardiology and rheumatology—the field of
Clinic College of
Medicine, 200 First tality than in the general population; however, the ‘cardiorheumatology’—and explore strategies to improve
Street SW, Rochester, mechanisms at work during the development of this the cardiovascular care of patients with rheumatic diseases.
MN 55905, USA.
Division of
complication remain incompletely understood, and
Rheumatology, Stanford the processes that cause accelerated atherosclerosis are Vascular manifestations
University, 300 Pasteur largely unknown. Atherosclerosis has been labelled as Mechanisms of accelerated atherosclerosis
Drive, A100 MC5309,
Stanford, CA 94305, an inflammatory disease that manifests primarily in the The mechanisms that contribute to accelerated athero-
USA (C.M.W.). sclerosis are not well defined, but chronic inflammation
Correspondence to: A.L. Competing interests has been suggested as a contributing factor to the devel-
lerman.amir@mayo.edu The authors declare no competing interests. opment of atherosclerotic disease—whereas differences
Systemic sclerosis
patients with RA is ischaemic heart disease26,27—several In addition to RA and SLE, patients with systemic scler
studies have shown a more than twofold increase in the osis (SSc) might also have an increased risk of athero-
frequency of myocardial infarction (MI) in patients with sclerosis secondary to changes in the vascular wall. The
RA when compared with age-matched individuals.25,28,29 underlying mechanisms for atherosclerosis in patients
Patients with RA were also shown to have higher case with SSc involve endothelial injury and reduced oxygen
fatality after an acute MI than patients without RA. 29 transport to tissues.27 Patients with SSc have diffuse
Scoring systems such as the Framingham Risk Score do involvement of the entire microcirculation and macro
not adequately capture this increased risk in patients circulation, and undergo oxidation which promotes
with RA.30 Therefore, RA might have an important effect inflammation of the vessel wall, injury to the endothelium,
on the development of premature atherosclerosis, even in and subsequent release of cytokines. This inflammatory
the absence of traditional risk factors.22,31,32 cascade leads to upregulation of inflammatory markers
As a result of chronic inflammation, patients with RA such as CRP and homocysteine, further contributing to
also have dyslipidaemia, including a decreased HDL- an increase in the risk of atherosclerosis.43,46,47
cholesterol level, and an increased small LDL-cholesterol SSc is also associated with increased stiffness of the
level.26,27 Intriguingly, the coronary vasculature is affected vasculature: a study of patients with both limited and
by accelerated atherosclerosis.18–23 An increase in the diffuse disease showed increased carotid artery stiff-
cumulative incidence of silent MI and sudden cardiac ness when compared with control individuals.48 Statins
death is observed in patients with RA compared with can help to manage microvascular and macrovascular
individuals without RA (Figure 3).33 Moreover, when involvement of SSc.27 Additional invasive or noninvasive
compared with healthy individuals, patients with RA testing to assess endothelial function might be useful to
and patients with type 2 diabetes mellitus have a similar estimate the cardiovascular risk in these patients.
risk of developing cardiovascular events, suggesting that
RA, similarly to diabetes, is an important risk factor for Antiphospholipid syndrome
cardiovascular disease (Figure 4).34 Patients with antiphospholipid syndrome (APS), a dis-
Patients with RA have higher case fatality after an acute order characterized by a prothrombotic state with a high
MI than the general population.29 Given the increased propensity for recurrent arterial and venous throm-
risk of premature atherosclerosis, aggressive control of bosis, and by the presence of antiphospholipid anti-
traditional risk factors is particularly important in these bodies, also have an increased risk of atherosclerosis.49
patients.18 Additional, noninvasive assessments might be Atherosclerosis in patients with APS is thought to result
considered, but widespread screening of patients with from direct proinflammatory and prothrombotic activ-
RA with carotid ultrasonography and calcium scoring ity of antiphospholipid antibodies on endothelial cells, as
is not currently mandated owing to limited support- well as other inflammatory mechanisms that can result
ing data on the efficacy of these tools in patients with in autoantibody-mediated thrombosis. 45,50–52 A high
RA.18 Nevertheless, these approaches are used in focused prevalence of antibodies to β2‑glycoprotein I (also known
subspecialty clinics to define and assess the effect of as apolipoprotein H) in patients with APS has also been
autoimmune disorders on increased cardiovascular risk. observed; the measurement of such mediators might be
10
0
0 10 20 30 0 10 20 30 0 10 20 30
Time since index date (years) Time since index date (years) Time since index date (years)
Figure 3 | Cumulative incidence of cardiovascular manifestations in patients with or without RA. Cumulative incidence of
silent MI, sudden cardiac death, and angina in cohorts with or without RA, after adjusting for the competing risk of death
from other causes. Abbreviations: MI, myocardial infarction; RA, rheumatoid arthritis. Permission obtained from Wiley
© Maradit-Kremers, H. et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis:
a population-based cohort study. Arthritis Rheum. 52, 402–411 (2005).
helpful in predicting the risk of venous and arterial throm- Several studies have shown that patients with RA and
bosis.53 Additionally, antiphospholipid antibodies might SLE are more likely to have valvular calcifications, which
be able to crossreact with oxLDL in patients with SLE. can affect up to 80% of patients; this effect might be
Whereas patients with APS do not have an increased mediated by mechanisms similar to those promoting
likelihood of developing cardiovascular risk factors, accelerated atherosclerosis.56
the pathogenesis of accelerated atherosclerosis is prob-
ably secondary to nontraditional risk factors, such as Rheumatoid arthritis
antiphospholipid antibodies, which are thought to have Patients with RA have an increased incidence of valvu-
an important role in the development of arterial athero- lar disease when compared with the general population.
sclerosis.51,52 As such, patients with APS should be treated Valvular disease can be seen by echocardiography or in
with aggressive management of traditional risk factors.49 autopsies in ~30% of patients with RA, but is normally
clinically silent.1 Mitral regurgitation is the most common
Vasculitis valvular disorder among patients with RA, affecting up
Systemic vasculitides, such as giant cell arteritis, Takayasu to 80% of patients, but, again, is not necessarily clinically
arteritis, polyarteritis nodosa, and anti-neutrophil cyto- relevant.38 In a study of individuals undergoing trans
plasmic antibody (ANCA)-associated vasculitis, are oesophageal echocardiography, mitral regurgitation was
immune-mediated rheumatological diseases character- reported in 80% of patients with RA compared with 37%
ized by inflammation of the vasculature that results in of the control population; no differences in the preva-
accelerated atherosclerosis. In patients with vasculitis, lence of aortic or tricuspid regurgitation were observed
the intima of affected blood vessels becomes activated, between the two groups.57
leading to endothelial cell activation and damage, and an
ensuing immune response—factors that can all promote Systemic lupus erythematosus
atherosclerosis.4 After activation, endothelial cells can SLE is associated with both endocarditis and the pres-
expose adhesion molecules and secrete cytokines. This ence of valve nodules, and transoesophageal echocardio
increase in secretion of mediators of inflammation pro- graphy has revealed that >50% of patients with SLE have
motes enhanced adhesion between the endothelial cells valvular abnormalities.18 Valvular nodules are fairly
and monocytes, and serves as a proatherogenic sub- common on autopsy reports of patients with SLE, but
strate by promoting plaque formation. In addition to are not clinically relevant.18 Endocarditis is a common
inflammatory reactions that can lead to atherosclerosis, complication of SLE, but is often asymptomatic and
vasculitis might also promote increased expression of detected only on autopsy studies.18 Nonbacterial veg-
autoantigens (such as heat shock proteins) on activated etations, also referred to as Libman–Sacks vegetations,
endothelial cells. Furthermore, accumulation of oxLDL have been reported in up to 60% of patients with SLE
can promote activation of endothelial cells, mono- in autopsy studies. 58 These vegetations are generally
cytes, and macrophages, as well as formation of foam univalvular, small, and left-sided, and can be seen in up
cells. Importantly, patients with vasculitis have general- to 15% of mitral valves and 19% of aortic valves.18,59,60
ized endothelial dysfunction characterized by impaired Nonbacterial vegetations are often associated with the
endothelium-dependent vasodilatation.54 presence of antiphospholipid antibodies.
Although any valve can be affected in patients with SLE,
Valvular manifestations vegetations are most commonly located on the atrial sides
Valvular manifestations are common among patients with of the mitral and aortic valves.18 Currently, no guidelines
rheumatological conditions, particularly in patients exist on when to initiate antibiotic prophylaxis, but admin-
with RA, SLE, APS, or ankylosing spondylitis. 21,38,55 istration of prophylactic antibiotics should be considered.38
to 50% of patients as detected on post-mortem exami- marker of cardiovascular morbidity and mortality that is
nation. Howe ver, clinical evidence of pericarditis is useful in predicting ventricular arrhythmias, is consider-
considerably less frequent, and generally affects ≤10% ably longer in patients with RA than in healthy controls,
of patients with severe RA. 1,69 Pericarditis is mostly further suggesting an increase in cardiovascular risk in
diagnosed on autopsy or using echocardiography, and these patients.78
silent pericardial effusions are encountered frequently.
Chronic pericarditis has the potential to result in pericar- Systemic lupus erythematosus
dial calcification, and both immune complexes and rheu- Sinus tachycardia, atrial fibrillation, and ectopic atrial
matoid factor can be found in pericardial fluid, which beats are the most common electrophysiological abnor-
is characterized by neutrophil infiltrates, high protein malities in SLE. Supraventricular arrhythmias are often
levels, low glucose levels, and low complement levels.38 associated with exacerbation of SLE or are caused by
Constrictive pericarditis can also develop in patients myocarditis.74 Hydroxychloroquine therapy has been
with RA, but is usually clinically silent.70 associated with prolonged QT interval on electrocardio
graphy and sinus bradycardia. 80 Patients with anti
Systemic lupus erythematosus bodies to small cytoplasmic ribonucleoproteins have an
Pericarditis and pericardial effusion are the most common increased risk of sinus bradycardia and QT-interval pro-
cardiac manifestations of SLE.63 In several clinical studies, longation.81,82 Sinus tachycardia, suggested as a marker
20–50% of patients had pericardial involvement,38,63,71–73 of disease severity in patients with SLE, can be resolved
and an even higher prevalence of pericardial involvement with corticosteroid therapy.83
(≥60% of patients) has been suggested in autopsy series.72
Patients typically present with chest pain, but pericardial Systemic sclerosis
effusions are usually mild and mostly do not result in Myocardial fibrosis predisposes patients with SSc to
cardiac tamponade and haemodynamic compromise.71 electrical abnormalities. Up to 30% of patients with SSc
Constrictive pericarditis is rare in patients with SLE. might have supraventricular arrhythmias, including
Analysis of pericardial fluid has revealed exudative fluid atrial fibrillation, flutter, or paroxysmal supraventricular
with neutrophilic predominance, elevated protein levels, tachycardia.74 Ventricular arrhythmias have been dem-
and low or normal glucose levels.72 onstrated in up to 67% of patients with SSc.84 Premature
ventricular contractions are associated with a 50% mor-
Systemic sclerosis tality, compared with 8% in patients without ectopy. SSc
In patients with SSc, autopsy studies have shown peri- can also predispose patients to an increase in the risk
cardial involvement, but clinically relevant pericardial of electrical abnormalities owing to fibrosis of the sinus
disease is rare. Pericardial effusions have been noted in node and bundle branches. These conditions have been
up to 14% of echocardiographic studies.68 explored in invasive electrophysiological studies, reveal-
ing diffuse conduction system disease and increased risk
Electrical abnormalities of tachyarrhythmias in patients with SSc.18,85
Conduction abnormalities are an important cause of
cardiovascular morbidity and mortality in patients with Ankylosing spondylitis
rheumatological disease, and predominantly affect those Ankylosing spondylitis can cause conduction abnor-
with RA, SSc, and ankylosing spondylitis.74 Notably, malities primarily owing to postinflammatory scarring
patients with rheumatic disease have a higher incidence of the myocardium. The most common manifestation is
of conduction abnormalities and sudden cardiac death first-degree atrioventricular block,18 and human leuko
than the general population.74,75 cyte antigen (HLA)‑B27-positive patients with spondylo
arthritis are at elevated risk of developing heart block.86
Rheumatoid arthritis
In patients with RA, underlying coronary artery disease Cardiovascular care in rheumatology
predisposes patients to an increased risk of sudden The increased risk of cardiovascular disease in patients
cardiac death and ventricular arrhythmias.74,76 Rheuma with systemic autoimmune rheumatic disease requires
toid nodules are also thought to predispose patients to appropriate management. Given the increased risk
cardiac involvement.77 In a study to compare patients of premature atherosclerosis—despite lack of tradi-
with non-nodular RA or nodular RA with control indi- tional risk factors—in patients with RA, adherence to
viduals, patients with nodular RA had not only larger primary prevention guidelines is crucial.18 Patients with
aortic root diameter and lower ejection fraction, but RA might have a lower target LDL-cholesterol level;
also had <1 mm ST-segment depression on 24 h Holter therefore, aspirin therapy might be considered owing
monitoring, when compared with individuals in the to the increased cardiovascular risk observed in this
control group.77 patient population. Nevertheless, widespread screen-
Patients with RA can develop electrical abnormalities ing of patients with RA using carotid ultrasonography
owing to rheumatoid nodules, underlying amyloidosis, and calcium scoring is not currently mandated owing
or cardiomyopathy, 78 and are also thought to have to limited data.18
increased sympathetic activity—a potential risk factor Several drugs have been suggested to be appropri-
for ventricular tachyarrhythmias.79 QT dispersion, a ate to manage cardiovascular disease in patients with
autoimmune disorders. Disease-modifying antirheumatic Cardiovascular morbidity and mortality are recog-
drugs (DMARDs) were shown to reduce progression of nized consequences of autoimmune rheumatic diseases,
atherosclerosis in patients with RA in several studies.87–89 and efforts must be made to manage and treat patients
For example, methotrexate seemed to increase survival, with these conditions. The field of cardiorheumatology is
potentially suggesting that early initiation of DMARD emerging with the development of several focused clinics
therapy might be appropriate for cardiovascular pre- worldwide that indicate the increased need for cardio-
vention, in addition to the management of the systemic vascular care among patients with autoimmune inflam-
disease.87 Interestingly, a group of patients with RA, sub- matory rheumatological diseases. The high prevalence of
clinical atherosclerosis, and endothelial dysfunction was cardiovascular abnormalities and diverse sequelae require
reassessed prospectively after DMARD therapy: after focused management and diagnosis of potential cardio-
1 year, both the carotid intima–media thickness and vascular abnormalities to reduce cardiovascular mor-
endothelial-dependent flow-mediated vasodilatation bidity and mortality. Whereas several cardiovascular
were improved.89 Anti-TNF therapies can also reduce manifestations of rheumatological diseases are clinically
atherosclerosis-promoting systemic inflammation. silent, the diagnosis and management of these disease
Consequently, these agents might be associated with processes is crucial. Endothelial dysfunction is a precur-
improvement of cardiovascular disorders in patients sor to atherosclerosis, and patients with early athero
with autoimmune rheumatic disease. Improvement sclerosis can be diagnosed by noninvasive assessment of
in inflammatory joint disease might also be associated endothelial function. Currently, no studies supporting
with a reduction in the number of cardiac events, further routine screening for endothelial function exist. However,
supporting the use of disease-modifying agents.90,91 given the high risk of cardiovascular disease, noninvasive
Management of electrical abnormalities is based on risk-factor assessment—including endothelial function
the underling pathogenesis, and is similar to the man- assessment—might be warranted in patients with a high
agement of patients who have no rheumatic disease. propensity for development of atherosclerosis, especially
Primarily, antiarrhythmic pharmacological therapy those with RA or SLE. Early diagnosis and appropriate
is used to manage electrical abnormalities. Digoxin is preventive management are the cornerstones to reducing
often used to decrease ventricular response in end-stage the burden of cardiovascular disease among patients with
heart failure, similarly to approaches used in patients inflammatory autoimmune disease.
without rheumatological complications. β‑Blockers are
used to manage sinus tachycardia in patients with SLE Conclusions
but, in general, should be avoided in patients with SSc, Autoimmune rheumatic diseases can cause a variety of
vasculitis, and those who might have pulmonary hyper cardiovascular complications that affect the vascula-
tension.63 Patients with a history of ventricular fibrilla- ture, valves, myocardium, pericardium, and conduction
tion undergo implantation of a cardioverter–defibrillator, system. Whereas many of these manifestations are often
and might be considered for cardiac resynchronization clinically silent, the high prevalence of cardiovascular
therapy depending on overall prognosis and degree of disease in patients with rheumatic conditions should be
the myocardial dysfunction. Additionally, radiofrequency recognized by clinicians and adequately managed. Early
ablation can be considered for patients with symptomatic, recognition and management of traditional cardio
sustained monomorphic ventricular tachycardia, espe- vascular risk factors is essential, along with aggressive
cially if they are also drug-resistant, as well as for those treatment with disease-modifying agents to improve the
with symptomatic, premature ventricular contractions. long-term prognosis of these patients.
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