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Cardiovascular Involvement in General Medical Conditions

Cardiovascular Manifestations of Rheumatologic Diseases

Mary J. Roman, MD; Jane E. Salmon, MD

he prevalence and importance of cardiovascular disease

in rheumatologic disorders have increased in the setting
of therapeutic advances, resulting in longer life expectancy, a
growing understanding of the importance of inflammation
and the immune system in the initiation and progression of
atherosclerosis, and enhanced disease detection with the use
of sophisticated noninvasive cardiac and vascular diagnostic
technology. This article will briefly review cardiovascular
manifestations of rheumatologic diseases with an emphasis
on recent clinical research. Rheumatologic diseases will be
discussed individually for ease of reference, although pathophysiology and basis for cardiovascular abnormalities may be
common among some of them. When applicable, cardiovascular disease will be categorized as vascular (accelerated
atherosclerosis, arterial stiffness, small-vessel disease, aortic
disease), myocardial (abnormalities of structure and function), valvular, pericardial, and conduction diseases. Endothelial dysfunction, although reported in some rheumatologic
diseases, will not be systematically discussed in view of space
limitations and the nonspecific and incompletely characterized nature of this abnormality. Discussion of suggested
mechanisms underlying cardiovascular manifestations of
rheumatologic diseases is beyond the scope of this review.
Rheumatologic diseases with vasculitis as the primary manifestation, such as giant cell arteritis and Takayasus arteritis,
will not be discussed.

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a common chronic autoimmune
disease associated with systemic inflammation, a female
predominance, and a prevalence of 1% that increases with
age.1 The diagnosis is a clinical one, based on the characteristic joint manifestations (Table 1).2 The presence of rheumatoid factor is included in the diagnostic criteria, although
antibodies to cyclic citrullinated peptides are more specific
for RA.3 Although the precise antigenic stimulus driving the
autoimmunity in RA has not been identified, a recent study
demonstrated an increased risk of developing RA in smokers
in whom citrullinated antigens are expressed on bronchoalveolar immune cells.4 RA is associated with specific human
leukocyte antigen (HLA) class II molecules; antigen-activated
CD4 T cells contribute to the initiation of the cascade of
cellular and soluble inflammatory mediators that result in the
characteristic joint damage.5

Vascular Disease
The excess mortality associated with RA is due largely to
cardiovascular disease, particularly ischemic heart disease.6 12 Recent observational studies suggest that the heightened risk is not related primarily to traditional atherosclerosis
risk factors8,10,12,13 or to corticosteroid and disease-modifying
therapy.7 In view of the importance of chronic inflammation
in atherogenesis,14 the presence of RA per se may be of
primary importance. Unequivocal evidence of independence
of atherosclerosis from traditional risk factors and direct
relation to the presence of RA was provided in a case-control
study of preclinical atherosclerosis wherein RA patients had
a 3-fold increase (44% versus 15%) in carotid atherosclerosis
prevalence despite a similar risk profile (Figure).15 In this
study, atherosclerosis risk was related to duration of disease
and use of antitumor necrosis factor (TNF) therapy, a
surrogate for disease severity as such therapy was limited to
patients with refractory disease at the time of our study. A
smaller study likewise detected a relation between carotid
atherosclerosis and RA duration as well as more extensive
extra-articular disease.16 The presence and amount of coronary calcification are also related to duration of RA.17 In
addition, lower levels of circulating endothelial progenitor
cells, markers of the capacity for vascular regeneration that
are inversely related to cardiovascular risk, are associated
with heightened disease activity in RA patients.18 Taken
together, these studies suggest that extent and duration of
inflammatory burden, as opposed to specific disease aspects,
determine premature atherosclerosis in RA. Evidence that
therapy with methotrexate19,20 reduces risk of cardiovascular
disease further supports the hypothesis that chronic inflammation is primarily responsible for accelerated atherosclerosis in RA. Although use of TNF blockers was associated with
more severe and refractory disease in a large observational
study in Sweden, RA patients who received such therapy had
lower rates of cardiovascular events and death during limited
follow-up,21 again suggesting that aggressive antiinflammatory therapy might additionally reduce clinical manifestations
of cardiovascular disease.
Because of the heightened risk of premature atherosclerosis, adherence to primary prevention guidelines is mandatory.
Because the prevalence of carotid atherosclerosis in RA is at
least as high as in diabetes mellitus,15 which is considered a

From the Divisions of Cardiology (M.J.R.) and Rheumatology (J.E.S.), Weill Medical College of Cornell University and the Hospital for Special
Surgery, New York, NY.
Correspondence to Mary J. Roman, MD, Division of Cardiology, 525 E 68th St, New York, NY 10021. E-mail
(Circulation. 2007;116:2346-2355.)
2007 American Heart Association, Inc.
Circulation is available at

DOI: 10.1161/CIRCULATIONAHA.106.678334

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Roman and Salmon

Table 1.

Cardiovascular Features of Rheumatologic Diseases

Diagnostic Criteria for RA*

Morning stiffness lasting at least 1 hour for 6 weeks

Arthritis (soft tissue swelling) of 3 joint areas for 6 weeks
Arthritis of hand joints (proximal interphalangeal, metacarpophalangeal, or
wrist) for 6 weeks
Symmetrical arthritis for 6 weeks
Rheumatoid nodules (subcutaneous nodules over bony prominences or
extensor surfaces)
Presence of rheumatoid factor
Radiographic changes (erosion and/or periarticular osteopenia)
*The American Rheumatism Association 1987 revised criteria for the
classification of rheumatoid arthritis2: 4 of 7 features must be present to qualify
for a definite diagnosis.

coronary heart disease equivalent and an indication for

secondary prevention targets even in the absence of clinical
cardiovascular disease, it is attractive to consider application
of secondary prevention guidelines to patients with RA. From
a practical standpoint, a lower target for low-density lipoprotein cholesterol and aspirin therapy would be the main
differences in strategy. Secondary prevention measures
should certainly be applied in the setting of established
cardiovascular disease. Data are lacking to support widespread screening of RA patients with imaging studies such as
carotid ultrasonography or computed tomography to detect
coronary calcium. Because a negative screening study does
not preclude development of atherosclerosis in the short-term
future and because both cardiovascular disease prevention
efforts and control of disease activity should be aggressive,
the presence or absence of subclinical atherosclerosis would
arguably not alter overall management. It has been suggested
that anti-TNF therapy be temporarily suspended in the perioperative period in patients undergoing major orthopedic
surgery to limit increased risk of infection,22 and similar
considerations are likely to apply to cardiac surgery.
Arterial Stiffness
Arterial stiffness, which can be quantified accurately with the
use of noninvasive techniques, is recognized increasingly as
an important independent risk factor for adverse cardiovas100

Plaque (%)

cular outcomes in population-based studies.23,24 In view of

the development of premature atherosclerosis in RA and of
the observation that arterial stiffening is associated with
inflammatory markers in the general population,25 it is not
surprising that arterial stiffness is increased in RA,2528 even
in the absence of atherosclerosis.28 Arterial stiffening is
related to disease duration, as described for atherosclerosis,15
and to inflammatory mediators.28,29 That arterial stiffening in
RA patients is reduced by treatment with anti-TNF therapy29
or atorvastatin30 is promising, although these findings are
based on small numbers (9 and 29, respectively) of patients
followed for short periods of time.
Coronary Arteritis
Although coronary arteritis was detected at autopsy in 20% of
100 patients succumbing to active disease in the era before
effective antiinflammatory therapy,31 at present it is rarely of
clinical significance.32 In fact, the occurrence of rheumatoid
vasculitis, in general, has markedly declined in the setting of
effective antiinflammatory therapy.33

Myocardial Disease
RA is associated with an increased risk of congestive heart
failure,34 36 but the underlying pathophysiology (ie, systolic
versus diastolic dysfunction) is uncertain. Data from the
Mayo Clinic indicate that heart failure in RA patients primarily affects those who are positive for rheumatoid factor, may
occur before the onset of the arthritis, and is independent of
traditional risk factors for cardiovascular disease.35 Although
the prevalence of left ventricular (LV) systolic dysfunction
was reported recently to be higher in patients with RA,37 the
extent to which traditional risk factors, including hypertension, diabetes mellitus, and smoking, contributed to this
association was not evaluated statistically. In contrast, 4 other
case-control studies reported similar LV ejection fractions in
RA patients and controls but higher rates of impaired
diastolic relaxation based on reductions in transmitral ratios
of early to late ventricular filling (E/A ratios) in RA.37 41
Similar to evidence in atherosclerosis, anti-TNF therapy may
protect RA patients from developing heart failure.34

Valvular Disease






Age (years)



Figure. Prevalences of carotid atherosclerosis in groups of control subjects and patients with SLE and RA matched for age
and gender with comparable cardiovascular disease risk factor
profiles. Adapted from Roman et al.15,58

Clinically significant valvular disease attributable to RA

appears to be uncommon. Studies using transthoracic echocardiography have detected no differences in valvular disease
between groups of RA patients and controls39 and no evidence of otherwise unexplained valvular disease.42 In contrast, mitral regurgitation was detected in 80% of 30 RA
patients undergoing transesophageal echocardiography versus 37% of a control population, although the severity of
mitral regurgitation was not reported, and almost 20% of
patients were additionally reported to have mitral prolapse,
indicative of a select population and/or causes of mitral
regurgitation unrelated to RA.43 Prevalences of aortic and
tricuspid regurgitation were not different between RA patients and control subjects undergoing transesophageal

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November 13, 2007

Table 2.

Pericardial Disease
Fibrinous pericarditis may be detected at autopsy in RA
patients but is generally not of clinical relevance.44,45 Pericardial effusions may also be seen in echocardiographic
studies of RA patients. Although usually clinically silent,42,43,46 constrictive pericarditis may develop.45 Casecontrol studies using echocardiography have variably reported similar41 or increased43 rates of pericardial effusion.

Diagnostic Criteria for SLE*



Malar rash

Fixed erythema, flat or raised, over the malar

eminences, tending to spare the nasolabial folds

Discoid rash

Erythematosus raised patches with adherent

keratotic scaling and follicular plugging; atrophic
scarring may occur in older lesions


Skin rash as a result of unusual reaction to sunlight


Oral ulcers

Oral or nasopharyngeal ulcerations, usually painless

RA results in premature development of atherosclerosis,

myocardial infarction, and arterial stiffening. Congestive
heart failure is likewise independently related to RA, possibly
because of impairment of LV diastolic filling, although
large-scale studies with sophisticated assessment of diastolic
function are lacking. Effective control of disease activity may
be beneficial in ameliorating vascular and myocardial disease. Pericardial disease due to RA is usually of limited
clinical significance.


Nonerosive arthritis involving 2 peripheral joints,

characterized by swelling or effusion


Pleuritis: convincing history of pleuritic pain, or rub

heard by physician, or evidence of pleural effusion

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic systemic
autoimmune disease with a prevalence of 1:2500.1 A
marked female predominance exists, even greater than that
associated with RA. Black women and men have substantially higher rates of disease and more severe disease manifestations than do whites.1 The diagnosis is based on demonstration of multisystem clinical and laboratory manifestations
(Table 2).47 The pathogenesis of SLE is unknown, but its
expression is determined by interactions among genetic,
environmental, hormonal, and immunologic factors. Valvular
disease associated with Libman-Sacks lesions, serositis resulting in pericardial disease, and venous and arterial thromboses associated with the presence of antiphospholipid antibodies are well-established cardiovascular manifestations of
SLE. However, premature development of atherosclerosis has
emerged as an important cause of morbidity and mortality in
patients with SLE as effective treatments for other causes of
early mortality, particularly infections and lupus nephritis,
have become available.
Vascular Disease
The premature development of atherosclerotic coronary artery disease has been documented in autopsy,48 mortality,49
and population-based observational50,51 studies. Although
initial speculation centered on the importance of corticosteroid therapy48,49 and/or excess traditional risk factors,5254 the
risk of myocardial infarction is, as least in part, independent
of traditional risk factors.55 SLE-related factors associated
with clinical manifestations of coronary artery disease include older age at diagnosis,51,52 longer duration of
SLE,51,52,56 higher damage score (a quantitative measure of
cumulative organ damage attributable to SLE or its treatment),56 longer duration of steroid therapy,49,51,52,57 and
higher levels of oxidized low-density lipoprotein cholesterol
and homocysteine.57 Case-control studies examining preclinical carotid atherosclerosis58 and coronary artery calcification59 clearly indicate that premature atherosclerosis occurs in

Pericarditis: documented by ECG, or rub, or evidence

of pericardial effusion

Persistent proteinuria: 0.5 g/d, or 3, if

quantification not performed
Cellular casts: may be red, granular, tubular, or mixed


Seizures: in the absence of offending drugs or

known metabolic derangements
Psychosis: in the absence of offending drugs or
known metabolic derangements


Anemia with reticulocytosis

Leukopenia: 4000/mL total on 2 occasions
Lymphopenia: 1500/mL on 2 occasions
Thrombocytopenia: 100 000/mL in the absence of
offending drugs


Anti-DNA: antibody to native DNA in abnormal titer

Anti-Sm: presence of antibody to Sm nuclear antigen
Positive test for antiphospholipid antibody including:
(1) abnormal serum IgG or IgM anticardiolipin
antibody, (2) positive test for LA, (3) false-positive
test for syphilis known to be positive for at least 6
months and confirmed by Treponema pallidum
immobilization of fluorescent treponemal antibody
absorption test


Abnormal titer of antinuclear antibody by IF or an

equivalent assay at any point in time in the absence
of drugs known to be associated with drug-induced
lupus syndrome

LA indicates lupus anticoagulant; IF, immunofluorescence.

*The 1982 revised criteria for the classification of SLE47: 4 criteria must be
present to qualify for a definite diagnosis.

SLE as a consequence of the disease itself (Figure). Furthermore, imaging studies indicate that the underlying pathophysiology is primarily atherosclerosis rather than in situ thrombosis associated with antiphospholipid antibodies.53,58 60
Features of SLE associated with the presence of subclinical
atherosclerosis include older age at diagnosis,58 longer duration of disease,58,61 longer duration of steroid therapy,53 less
aggressive immunosuppressive therapy,58 higher damage
score,58 and higher homocysteine concentrations.61 Atherosclerosis progresses at twice the rate seen in non-SLE
populations; rate of progression is directly related to duration
of disease and homocysteine levels.62 Similar considerations
regarding preventive and screening strategies as discussed in
the RA section apply to patients with SLE.

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Arterial Stiffness
Similar to RA, arterial stiffness is increased in SLE, even in
the absence of atherosclerosis.28 Arterial stiffening is related
to disease duration and to circulating levels of C-reactive
protein and interleukin-6.28 Among postmenopausal women
with SLE, arterial stiffness is independently related to the
organ damage index.63 The impact of antiinflammatory and
immunosuppressive therapy or of statin therapy on arterial
stiffening has not been examined in SLE.
Myocardial Disease
Abnormalities of LV structure and function have been reported in patients with SLE.64 67 However, the extent to
which associated conditions, such as significant valvular
regurgitation, ischemic heart disease, and renal failure, contribute to these abnormalities has been uncertain. In a casecontrol study that excluded SLE patients with any of these
associated conditions, we detected substantially higher LV
mass index in SLE patients that was further elevated by
concomitant hypertension.68 Arterial stiffness was independently related to LV mass, suggesting that inflammationrelated arterial stiffening is the likely mechanism of LV
hypertrophy in SLE. LV ejection fractions were higher in
SLE patients, likely as a result of the Starling phenomenon (higher end-diastolic and comparable end-systolic
Myocarditis is rarely diagnosed clinically or detected at
autopsy in SLE patients in the current treatment era.48,69,70 It
is associated with active disease, including myositis and
serositis.69 Impaired systolic function and segmental wall
motion abnormalities associated with lupus myocarditis are
reversible by aggressive immunosuppressive therapy.70
Valvular Disease
Although valvular nodules have been described in the majority of patients with SLE at autopsy,48,71 clinically significant
valvular heart disease is much less common.65,7274 Furthermore, Bulkley and Roberts observed a reduction in the
number and size of valvular nodules associated with the
introduction of corticosteroid therapy.48 Varying prevalences
of valvular abnormalities have been reported in the echocardiographic literature, reflecting variable inclusion of nonspecific valvular thickening (separate from the presence of a
vegetation or nodule) and valvular regurgitation that may be
mild and/or due to other causes. Echocardiographic studies
vary with regard to the frequency of vegetations or nodules
detected on the mitral (7% to 15%) and aortic (3% to 19%)
valves.60,72,75,76 Significant (moderate or severe) valvular
regurgitation occurs in 20% of relatively unselected patients undergoing Doppler echocardiography.60,65,76,77 Independent of the definition of valvular disease, longitudinal
echocardiographic studies indicate that abnormalities may
persist, resolve, or develop anew over time, independent of
disease activity or therapy.78 The development of severe
valvular regurgitation may be related to high levels of IgG
anticardiolipin antibodies.77
A summary of the association of the presence of antiphospholipid antibodies and valvular disease in SLE is also
difficult because of differences in definitions of valvular
disease (thickening, nodules, presence of regurgitation) and


of antiphospholipid antibody positivity. Nevertheless, large

transthoracic echocardiographic studies of unselected patients
document an association between higher anticardiolipin titers,
valvular nodules, and significant regurgitation, particularly
involving the mitral valve.60,79,80
Formal guidelines for antibiotic prophylaxis in the setting
of valvular nodules do not exist. The presence of significant
regurgitation, even in the absence of nodules, may heighten
the risk of bacterial endocarditis, particularly in the setting of
jet lesions, and warrants antibiotic prophylaxis. Indications
for surgical intervention for valvular heart disease do not
differ from those applied in the general population. The major
added risks involve anticoagulation concerns and thrombotic
complications if antiphospholipid antibody syndrome coexists. In addition, wound healing may be impaired and infection risk may be increased in the setting of long-term and/or
perioperative stress doses of corticosteroid therapy. An unresolved issue concerns causal relations between valvular and
cerebrovascular disease and hence the indications for valve
replacement in the absence of other explanations for cerebrovascular complications.81
Pericardial Disease
Pericardial disease, as a manifestation of serositis, is a
diagnostic feature of SLE and its most common clinical
cardiovascular manifestation. Clinical features of pericarditis
with or without pericardial effusion occur in 20% to 50% of
patients in relatively large series.64,65,72,76,79,82 Pericardial
effusions occur most commonly in the setting of active
disease (flares)64,65,76 but may be asymptomatic.65 The effusions are usually small, although moderate to large pericardial
effusions were detected in 5 of 70 patients (7%) in 1 series.65
Interestingly, mild pericardial effusions associated with lupus
pericarditis are usually not associated with typical electrocardiographic changes.65,72,81 None of the relatively large series
of echocardiographic studies has reported major complications (cardiac tamponade or constrictive pericarditis) of lupus
pericarditis in the absence of renal failure. Treatment of
symptomatic pericarditis and pericardial effusions includes
high-dose aspirin, nonsteroidal antiinflammatory drugs, or
corticosteroid therapy, particularly if prednisone is required
for management of other manifestations of active disease. In
rare instances of tamponade or constrictive pericarditis,
treatment is not specific to SLE.
Like RA, SLE results in premature development of atherosclerosis, myocardial infarction, and arterial stiffening. LV
hypertrophy develops in SLE unrelated to traditional stimuli
to hypertrophy and may be due to inflammation-related
arterial stiffening. Pericardial disease is common, and clinically significant valvular disease due to SLE develops in a
minority of patients.

Systemic Sclerosis
Systemic sclerosis is a systemic, autoimmune disorder characterized by tissue fibrosis due to excess accumulation of
collagen and other extracellular matrix proteins. Its cause is
unknown, but its pathophysiology involves microvascular
abnormalities, secondary ischemia, and fibroblast overreac-

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November 13, 2007

tivity. The disease is rare (prevalence of 2 in 10 000) and

occurs predominantly in women.1 The frequency and serological and clinical features of the disease vary in different
races.83 The diagnosis is based on the presence of proximal
scleroderma, defined as symmetrical thickening, tightening,
and induration of the skin of the fingers and the skin proximal
to the metacarpophalangeal or metatarsophalangeal joints; the
face, neck, and trunk may also be involved. Diagnostic
criteria are also met if 2 of the following 3 minor manifestations are present: sclerodactyly (skin changes limited to the
fingers); digital pitting scars or loss of substance of the finger
pad; and basilar pulmonary fibrosis.84 Systemic sclerosis may
be further subdivided into limited cutaneous disease, including CREST syndrome (calcinosis, Raynauds phenomenon,
esophageal dysmotility, sclerodactyly, telangiectasia), and
diffuse cutaneous disease, in which organ involvement (kidneys, lungs, heart) may be seen. Visceral involvement,
particularly heart, substantially increases mortality.85 The
most specific autoantibodies found in patients with systemic
sclerosis are antinuclear antibodies with a nucleolar staining
pattern, anticentromeric antibodies (for CREST syndrome),
and antitopoisomerase antibodies. Recent data indicate that
stimulatory autoantibodies to platelet-derived growth factor
receptor may be both highly specific and sensitive for
systemic sclerosis as well as potentially causally related to the
fibrotic phenotype of the disease.86
Myocardial and Coronary Vascular Disease
Myocardial disease in systemic sclerosis may be multifactorial: related to associated pulmonary or renal involvement or
to hypertension. However, of note is an autopsy study that
suggested the existence of primary myocardial disease.87
Nearly half (23 of 52) of patients with systemic sclerosis
(mean age of 45 years and 67% female) who underwent
autopsy at Johns Hopkins Hospital had focal areas of contraction band necrosis, a reperfusion lesion, and fibrosis in
both ventricles despite patent epicardial coronary arteries and
normal intramural coronary arteries. The severity of these
lesions was unrelated to concomitant pulmonary and systemic
hypertension, Raynauds phenomenon, and renal disease but
was related to the presence of congestive heart failure,
conduction abnormalities, ventricular arrhythmias, and cardiovascular death. Given the absence of large- or small-vessel
disease, the authors speculated that intermittent obstruction
due to vasospasm of the intramyocardial arteries might be
responsible for the myocardial abnormalities.
The presence of myocardial disease, including segmental
wall motion abnormalities and impaired coronary flow reserve, in the absence of epicardial coronary artery disease, has
been confirmed repeatedly.88 90 Furthermore, a recent angiographic study of 172 systemic sclerosis patients with suspected coronary artery disease (based on the presence of
angina or exertional dyspnea) detected rates of epicardial
coronary disease similar to those in a comparison population
with similar symptoms, age, and gender.91 Further support for
the existence of microvascular disease, particularly spasm,
derives from the demonstration of improvement in myocardial perfusion with oral nifedipine therapy89,92 and the detection of cold-induced perfusion defects and wall motion

abnormalities93 in systemic sclerosis patients with Raynauds

phenomenon. The presence of endothelial damage is supported by the presence of markedly increased numbers of
circulating endothelial cells that, in turn, were related to an
index of disease activity.94
The right ventricle may likewise be abnormal in systemic
sclerosis, even in the absence of pulmonary hypertension,
likely due to microvascular disease similar to that detected in
the left ventricle.88 Significantly lower right ventricular (RV)
ejection fractions determined by radionuclide ventriculography in the setting of normal pulmonary artery pressure
estimated by Doppler echocardiography were reported in 42
patients with systemic sclerosis compared with control subjects.95 After administration of oral nicardipine, RV ejection
fraction improved significantly; because changes in estimated
pulmonary pressure were not reported, it is uncertain whether
the increase in RV ejection fraction was related to a reduction
in afterload or to improvement in functional microvascular
disease. A more recent report of reductions in RV systolic
function and diastolic relaxation measured by tissue Doppler
imaging, with reduced RV ejection fraction being unrelated to
pulmonary artery systolic pressure,96 supports the earlier
Vascular Stiffness
Although systemic sclerosis is usually associated with microvascular abnormalities, abnormalities of the large conduit
arteries have been reported recently. Carotid artery stiffness
was increased in 52 patients with both limited and diffuse
cutaneous disease compared with control subjects, whereas
stiffness of the muscular femoral artery was not abnormal.97
Of note, intimal-medial thicknesses of the carotid and femoral
arteries were not increased in systemic sclerosis patients after
adjustment for relevant covariates. A large study of 106
systemic sclerosis patients reported reduced aortic distensibility in comparison to control subjects.98 Distensibility was
independently (inversely) related to systolic pressure gradient
across the tricuspid valve (an estimate of pulmonary artery
systolic pressure), although the mechanism for this association is not apparent from the data provided.98 The large artery
stiffening parallels that described above in RA and SLE. The
contributions of microvascular disease, possibly of the vasa
vasorum, or of inflammation to arterial stiffening in systemic
sclerosis are unknown.
Conduction Disease
Fibrosis of the sinus node and bundle branches at autopsy87
and diffuse conduction abnormalities and arrhythmias detected by ambulatory electrocardiography99 101 have been
described in patients with systemic sclerosis. Invasive electrophysiological studies have confirmed the presence of
diffuse conduction system disease and increased susceptibility to tachyarrhythmias.102 The extent to which conduction
abnormalities and arrhythmias are primarily related to fibrosis, as opposed to ischemic microvascular disease, likely
varies with underlying anatomic and functional vascular and
myocardial disease.
Pericardial Disease
Pericardial disease unrelated to uremia and characterized
histologically by chronic inflammatory changes has been

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Cardiovascular Features of Rheumatologic Diseases

described in autopsy studies of patients with systemic sclerosis.88,103 Clinically important pericardial disease, however,
appears to be very rare. Two large echocardiographic studies
reported small pericardial effusions in 14% of 77 patients104
and none of 106 patients.98
The most prominent cardiovascular abnormalities associated
with systemic sclerosis are microvascular perfusion abnormalities of the ventricular myocardium resulting in ischemia,
fibrosis, systolic dysfunction, and conduction disease. In
addition, fibrosis may occur independent of ischemia. Stiffening of the conduit arteries develops as a consequence of
inflammation and/or microvascular disease. Prognosis in
systemic sclerosis is adversely affected by evidence of
cardiac involvement. Although short-term nifedipine therapy
may improve myocardial perfusion in patients with
Raynauds phenomenon, long-term effects of such therapy in
limiting cardiovascular complications of systemic sclerosis
are unknown.

Ankylosing Spondylitis


were diffusely thickened and shortened and thereby rendered

incompetent. The presence of aortic root and aortic valve
thickening has been described in subsequent transthoracic
and transesophageal echocardiographic studies. Echocardiographic evidence of aortic regurgitation, in most instances
mild, has been described in 5% to 13% of patients with
ankylosing spondylitis,109 113 although higher estimates have
been reported in small studies114 or in select populations
undergoing transesophageal echocardiography.115 Detection
of aortic regurgitation may precede development of joint
manifestations.108,109 Although mild aortic root dilatation has
been described in ankylosing spondylitis, the impact of age
and body size on diameters has not always been considered.116 In addition, it is possible that increases in aortic
diameter are due to the presence of significant aortic regurgitation rather than a direct consequence of aortitis.117 Other
studies have not detected increases in aortic diameter.114,118
Conduction Disease
Conduction disease may develop in ankylosing spondylitis as
a consequence of postinflammatory scarring of myocardial
tissue. Prevalences of conduction abnormalities in clinical
series of patients with ankylosing spondylitis range from 2%
to 20%.109 113,117 First-degree atrioventricular block is most
common; however, higher-grade atrioventricular block and
right and left bundle-branch block have also been reported.
Interestingly, heart block appears to occur more frequently in
HLA-B27positive individuals, even in the absence of clinical manifestations of rheumatologic disease.119,120

Ankylosing spondylitis, the prototypical spondyloarthropathy, is a systemic, inflammatory disorder that involves the
entire spine and sacroiliac joints, with lesser effects on
peripheral joints. The characteristic musculoskeletal lesion is
enthesitis, inflammation of the enthesis (the site where
tendons and ligaments attach to bone). Associated extraarticular manifestations include uveitis, fibrocavitary apical
lung lesions, and serum amyloid Arelated amyloidosis. The
prevalence of ankylosing spondylitis is 1 to 2 per 1000
among whites with a 3:1 to 4:1 male predominance.1,105,106
Onset of clinical features usually begins in the third to fourth
decades. Roughly 90% of affected individuals are HLA-B27
positive, with racial prevalences of ankylosing spondylitis
varying according to HLA-B27 frequency (lower in blacks
and higher in American Indians).1 The likelihood of developing ankylosing spondylitis among HLA-B27positive individuals is 1.3% based on a Dutch study but substantially
higher (21%) if an HLA-B27positive relative has ankylosing
spondylitis.107 Its cause is unknown, but it is thought to be
triggered by an as yet undefined infection in a genetically
predisposed host. TNF- antagonists have been shown only
recently to treat this disorder effectively; thus, few data are
available to demonstrate their capacity to ameliorate associated cardiovascular disease.

Myocardial Disease
Diastolic filling abnormalities have been described in ankylosing spondylitis. Among 59 patients without clinical cardiovascular disease, 12 (20%) had abnormal filling patterns
characterized as E/A ratio 0.9 in 7, prolonged deceleration
time and isovolumic relaxation time in 2, and a restrictive
filling pattern in 3.121 Similarly, lower E/A ratio on average
was found in 88 patients compared with 31 healthy control
subjects; however, no adjustment was made for the presence
of aortic regurgitation (which may influence E/A ratio) in the
patients.111 In contrast, early diastolic relaxation as assessed
by the more specific technique of tissue Doppler imaging did
not differ between 40 ankylosing spondylitis patients and 35
control subjects.122 LV systolic dysfunction and hypertrophy
have not been reported in the absence of significant aortic

Aortic Disease
Aortic disease and aortic regurgitation associated with ankylosing spondylitis were recognized even before ankylosing
spondylitis (previously termed rheumatoid spondylitis) was
distinguished from RA. In 1973, Bulkley and Roberts described autopsy findings in 8 male patients with ankylosing
spondylitis and congestive heart failure due to severe aortic
regurgitation.108 Distinctive features included thickening of
the aortic wall due to adventitial scarring and intimal proliferation that was limited to the aortic root but extended into the
membranous ventricular septum. Conduction abnormalities
present in 6 of 8 patients were attributed to fibrous scarring of
the interventricular septum. In addition, aortic valve leaflets

Patients with ankylosing spondylitis may have higher death
rates than the general population.105,123 Congestive heart
failure and peripheral vascular disease, but not ischemic heart
disease, appear to develop earlier on the basis of analyses
using a large health plan database; however, the heightened
risk may be due to greater burden of hypertension and
dyslipidemia.124 Coronary flow reserve, a measure of microvascular function, measured from transthoracic Doppler evaluation of flow in the left anterior descending artery was
significantly reduced in 40 ankylosing spondylitis patients
compared with 35 control subjects.122 This result was based
largely on 2 outliers in the control group with otherwise

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November 13, 2007

complete overlap of the ankylosing spondylitis and control

groups. Severity of sacroiliitis and TNF- level were independently, negatively related to coronary flow reserve. Although the authors concluded that C-reactive protein was
inversely related to coronary flow reserve, C-reactive protein
was eliminated in multivariate analyses including as many as
15 independent variables in a study population of only 40
patients. Interestingly, carotid intimal-medial thickness is
not increased in patients with ankylosing spondylitis compared with controls,125 similar to observations in SLE and

lences of both cardiovascular disease risk factors and ischemic heart disease, peripheral vascular disease, and congestive
heart failure than age- and sex-matched control subjects.124
However, the higher prevalences of diseases were not adjusted for risk factors. Interestingly, the risk of incident
myocardial infarction was increased in a large UK study of
130 976 psoriasis patients, particularly in younger patients
and in those with more severe disease (defined by type of
therapy), even after adjustment for traditional risk factors.131
Unfortunately, a subgroup analysis was not performed on
patients with psoriatic arthritis.

Ankylosing spondylitis causes thickening of the aortic root
and aortic valve resulting in aortic regurgitation. Associated
enlargement of the aortic root, independent of age, body size,
and the hemodynamic impact of aortic regurgitation, has not
been clearly established. Conduction abnormalities, primarily
atrioventricular block, are more commonly encountered in
ankylosing spondylitis. Tissue Doppler imaging of velocity of
early myocardial relaxation (Em) is not altered in ankylosing
spondylitis, whereas less specific measures (reduced E/A
ratio) are abnormal. Definitive evidence of microvascular
disease and premature atherosclerosis or coronary heart
disease is lacking.

Although psoriatic arthritis may be associated with an excess
prevalence of cardiovascular disease risk factors, it remains
uncertain whether higher rates of clinical cardiovascular
disease are independently associated with the disease itself.

Psoriatic Arthritis
Psoriatic arthritis is defined as the coexistence of an inflammatory arthritis with psoriasis and affects 6% to 11% of
individuals with psoriasis.126,127 Data from population-based
studies in Norway and the United States indicate a prevalence
of 1 to 2 per 1000, with men and women being affected
equally.126,128 Its exact cause is unknown; however, similar to
other rheumatologic diseases, its expression appears to be
modulated by immunologic, genetic, and environmental factors. Recent research has differentiated it immunologically
and pathologically from RA. Like ankylosing spondylitis, it
fits into the group of disorders called spondyloarthropathies.
However, only 25% of patients develop spine and sacroiliac
joint disease, and the arthritis usually involves 4 large,
lower-extremity joints or the distal interphalangeal joints. In
addition, nail involvement with pitting of the nails and
onycholysis, separation of the nail from its bed, is frequently
present, and patients can develop uveitis.
Data from Olmstead County, Minnesota, indicate comparable death rates in individuals with psoriatic arthritis and the
general population.126 Consistent with this observation, a
recent echocardiographic study from Spain involving 50
patients with psoriatic arthritis and no cardiovascular disease
risk factors or clinical disease found prevalences of valvular
regurgitation, normal pulmonary artery pressures, and abnormal diastolic relaxation comparable to those in 50 matched
control subjects.129 In contrast, data from Canada suggest that
death rates are higher in both men and women with psoriatic
arthritis. However, only deaths due to respiratory diseases,
and not those due to cardiovascular disease (the leading cause
of death), were increased in comparison to the general
population.130 A recent US study based on health plan data
found that patients with psoriatic arthritis had higher preva-

The authors gratefully acknowledge the contributions of Drs Stephen
A. Paget and Richard B. Devereux to this manuscript.


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KEY WORDS: spondylitis, ankylosing arthritis, psoriatic rheumatoid

arthritis systemic lupus erythematosus systemic sclerosis

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Cardiovascular Manifestations of Rheumatologic Diseases

Mary J. Roman and Jane E. Salmon
Circulation. 2007;116:2346-2355
doi: 10.1161/CIRCULATIONAHA.106.678334
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