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CHAPTER 88
The Connective Tissue Diseases
and the Cardiovascular System
Jose F. Roldan / Robert A. O’Rourke / William C. Roberts
HERITABLE CONNECTIVE TISSUE
DISEASES
2033
Marfan Syndrome / 2033
Loeys-Dietz Syndrome / 2035
Ehlers-Danlos Syndrome / 2037
Pseudoxanthoma Elasticum / 2037
Osteogenesis Imperfecta / 2038
Annuloaortic Ectasia / 2038
Familial Aneurysms / 2039
NONHERITABLE CONNECTIVE
TISSUE DISEASES
2039
Systemic Lupus Erythematosus / 2039
Rheumatoid Arthritis / 2043
Ankylosing Spondylitis / 2043
Cardiovascular Syphilis / 2044
Systemic Sclerosis (Scleroderma) / 2045
Primary Systemic Sclerosis of the
Heart / 2045
The term connective tissue disease includes both a group of heritable
conditions and a group of nonheritable acquired disorders. The heritable disorders of connective tissue associated with cardiovascular
disease include the Marfan syndrome, Loeys-Dietz syndrome,
Ehlers-Danlos syndrome (EDS), pseudoxanthoma elasticum (PXE),
osteogenesis imperfecta, annuloaortic ectasia, and familial aneurysms.1 The nonheritable disorders of connective tissue that may involve the cardiovascular system include systemic lupus erythematosus (SLE), polyarteritis nodosa, rheumatoid arthritis (RA),
ankylosing spondylitis (AS), systemic sclerosis, polymyositis and
dermatomyositis, giant-cell arteritis, Churg-Strauss syndrome, antiphospholipid syndrome, and possibly syphilis.
HERITABLE CONNECTIVE TISSUE DISEASES
MARFAN SYNDROME
Epidemiology
Polymyositis and Dermatomyositis / 2047
Polyarteritis Nodosa / 2048
Giant Cell (Cranial, Temporal,
Granulomatous) Arteritis / 2049
Churg-Strauss Syndrome / 2049
Antiphospholipid Antibody
Syndrome / 2050
Molecular Genetics
Marfan syndrome is associated with defects in the ﬁbrillin-1 gene
(FBN1) on chromosome 15, where more than 125 reported and
unreported mutations (of several types) have been described (see
Chap. 81).3–6 More recently, a mutation of the transforming
growth factor (TGF) β receptor 2 (TGFBR2) and TGFβ receptor
1 (TGFBR1) has been identiﬁed in 10 percent of the cases.7,8
Nearly every genotyped family has a unique mutation in the ﬁbrillin genes, with the most common single mutation identiﬁed in
just four unrelated pedigrees. This intragenic heterogenicity and
the large size of the gene have precluded the routine screening of
mutations to establish the diagnosis of the Marfan syndrome. Genetic testing is most helpful if (1) a mutation is detected in either
of the two genes and (2) informative data are available about the
phenotype of the patient’s family.
Clinical Features
The prevalence of classic Marfan syndrome approximates 5 per
100,000 persons worldwide, without gender, racial, or ethnic predilection. Considering the great heterogeneity of the syndrome,
the actual prevalence may be considerably greater, at about 1 per
10,000 persons.2 Marfan syndrome has an autosomal dominant
inheritance with high penetrance. In one-third of patients, the disorder occurs with no positive family history and is likely caused by
a new mutation.
Considerable variation in the clinical manifestations of Marfan
syndrome occurs even within the same family. The ocular, skeletal,
and cardiovascular systems are usually involved. The four major
manifestations include a positive family history, ectopia lentis, aortic root dilatation or dissection, and dural ectasia (see Chap. 12).
Other relatively mild characteristics of Marfan syndrome occur
with a relatively high prevalence in the general population. These
features include mitral valve prolapse (MVP), early myopia, scoliosis, and joint hypermobility. Other ﬁndings in Marfan syndrome
2033
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2034 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
FIGURE 88–1. Mechanism of aortic regurgitation in the Marfan syndrome.
include anterior chest deformity, especially asymmetric pectus excavatum or carinatum; long, thin extremities with arachnodactyly;
tall stature with increased lower body height; high, narrowly
arched palate; myopia; fusiform ascending aortic aneurysm (anuloaortic ectasia) with aortic regurgitation (Fig. 88–1); and/or aortic
dissection. Mitral regurgitation is caused by MVP, dilatation of the
mitral annulus, mitral annular calcium, rupture of mitral chordae
tendineae, papillary muscle dysfunction, infective endocarditis, or
the combination of two or more.1–3
In the absence of an unequivocally affected ﬁrst-degree relative,
requirements for the diagnosis include at least one major manifestation with involvement of the skeleton and at least two other systems.6–8 In the presence of at least one unequivocally affected
ﬁrst-degree relative, there should be involvement of at least two
systems; the presence of a major manifestation is still preferred,
but this can vary depending on the family’s phenotype.9
By echocardiogram, MVP occurs in 60 percent or more and
aortic root enlargement in approximately 70 percent of adults
with the Marfan syndrome. It has been suggested that the Marfan
syndrome and MVP are part of a phenotypic continuum.
General Evaluation
In addition to carefully recording the personal and family history
and physical examination, the patient’s height, arm span, and ﬂoorto-pelvis distance should be measured. A slit-lamp ophthalmic examination and an electrocardiograph (ECG) should be obtained.
Patients with Marfan syndrome should be evaluated at least yearly,
and a transthoracic echocardiogram (TTE) should be obtained annually. Usually a transesophageal echocardiogram (TEE) or magnetic resonance imaging (MRI) will be obtained at least once.10 If
the diagnosis is deﬁnite or probable, screening of ﬁrst-degree relatives by TTE is recommended. Genetic counseling should be offered to all patients. Psychiatric counseling also is often useful. If a
patient develops suggestive widening of the proximal aorta, repeat
TTE or, in some instances, TEE should be performed more frequently. Patients with possible or deﬁnite Marfan syndrome and evidence of mitral valve abnormality should receive standard antibiotic
prophylaxis prior to any surgical procedure (see Chap. 88).
Management
Patients with Marfan syndrome should avoid isometric, abrupt, or
strenuous exertion; contact sports; scuba diving; and trauma. Pa-
tients with aortic dilatation and aortic or mitral regurgitation
should avoid competitive sports.11,12 Patients without aortic dilatation and aortic or mitral regurgitation should be allowed to perform low-to-moderate intensity static and low-intensity dynamic
sports, including bowling, golf, and archery. β-Adrenergic blockade therapy should be used in all patients, including in children
with Marfan syndrome, to retard the rate of dilatation of the aortic
root.12–14 Although the optimal dose has not been established,
some have suggested giving the largest dose that is clinically tolerated. Selective β1-adrenergic blocking agents are preferred, although no randomized studies have been performed.
In asymptomatic patients, repair of aortic aneurysms has been recommended at different degrees of enlargement. Thus, some have advocated repair when the aortic diameter is 55 mm or greater, when it
is 60 mm or greater,15 or when the aortic diameter increases to twice
that of the uninvolved distal aorta. Some patients develop aortic dissection with aortic root dimensions less than 50 to 55 mm.15 Surgical
repair is generally recommended when the diameter reaches 55 to 60
mm (see Chap. 105) and probably earlier if there is rapid progression
or a family history of aortic dissection or rupture.16 The asymmetry
of the aortic root as visualized by MRI might be of clinical importance in the diagnosis of unexpected aortic root dissection.17
Factors resulting in earlier surgical intervention include a positive
family history for aortic dissection or rupture, severe aortic or mitral
regurgitation, progressive dilatation of the aortic root on serial
echocardiograms, need for other major abdominal aortic or spinal
surgical procedures, and planning for a pregnancy. In most patients,
the ascending aorta and aortic valve are replaced, and the portion of
the aorta containing the coronary ostia is reimplanted,18 but there
are exceptions.19 Coronary ostial aneurysms have been observed in
43 percent of 40 patients with Marfan syndrome after coronary artery implantation.20 Postoperatively annual assessment of the entire
aorta by MRI may be useful (see Chap. 105).
When a mitral valve procedure is necessary, valve repair is usually preferred to replacement, although repair often may not be
possible because of a large number of ruptured chordae tendineae,
extensive annular calcium, or greatly dilated annuli.
Prognosis
Although earlier studies indicated that the average patient’s lifetime
is decreased by approximately 35 percent,2 β-blocker therapy, endocarditis prophylaxis, and aorta and aortic valve surgery have probably improved longevity. The most common causes of death of adolescents or adults with Marfan syndrome are rupture of a fusiform
aneurysm of the ascending aorta without longitudinal dissection
(Fig. 88–2), ascending aortic dissection with rupture, or congestive
heart failure from aortic and/or mitral regurgitation (Fig. 88–3).15
The major histologic feature in the media of the wall of an aortic aneurysm is a massive loss of elastic ﬁbers (Fig. 88–4).15 Factors that
can predispose to either aortic aneurysm or aortic dissection include
systemic arterial hypertension, coarctation of the aorta, pregnancy,
and trauma. In children with Marfan syndrome, the most common
cause of death is severe mitral regurgitation (Fig. 88–5). In a longitudinal study of 70 patients with Marfan syndrome followed for 24
years, no patient died of aortic dissection whereas 4 percent died of
arrhythmias.21 Athletes with Marfan syndrome must be counseled
about the type of exercise that is permitted (Table 88–1).22
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
2035
FIGURE 88–2. Heart and aorta of a 38-year-old man who was asymptomatic until exertional dyspnea appeared 5 months before death. Top
left: Exterior view. Ao, ascending aorta; PT, pulmonary trunk; RCA, right coronary artery. Bottom left: Closer view of the massive aortic aneurysm
after retracting the pulmonary trunk. LCA, left main coronary artery. The aneurysm does not involve the distal portion of the ascending aorta. Bottom middle: View of heart and aorta after removing their anterior half. Death resulted from rupture of the right lateral wall of the aorta at a point
where blood ejected from the left ventricle contacts the aortic wall (arrow). The aneurysmal bulge is mainly to the right. Bottom right: Close-up of
the multiple healed tears in the ascending aorta. One of the previously incomplete tears ruptured through and through. Posteroanterior chest roentgenogram (top middle) and lateral aortogram (top right ) show massive dilatation of the ascending aorta. Source: From Roberts WC, Honig HS.
The spectrum of cardiovascular disease in the Marfan syndrome: a clinico-morphologic study of 18 necropsy patients and comparison to 151
previously reported necropsy patients. Am Heart J 1982;104:115–135. Reproduced with permission of the publisher and authors.
Pregnancy
Women with Marfan syndrome should be counseled regarding the
up to 50 percent risk of genetic transmission of the condition. If the
woman has moderate or severe aortic regurgitation or an aortic root
diameter exceeding 40 mm, she should be advised against pregnancy.
Women with an aortic root diameter of less than 40 mm usually tolerate pregnancy well, but the chance of aortic dissection is still increased by pregnancy. β-Adrenergic blockers should be administered
at least from the midtrimester onward.
During pregnancy, TEE should be performed every 6 to 10 weeks,
depending on the initial ﬁndings. Using epidural anesthesia, vaginal
delivery in the lateral decubitus position is preferred, and forceps or
vacuum delivery is recommended to shorten the second stage of la-
bor. The increases in systemic blood pressure during uterine contractions should be prevented with β-blocking agents. Postpartum hemorrhage should be anticipated. If fetal maturity can be conﬁrmed in a
patient who requires aortic surgery during pregnancy, a cesarean section can be done before or concomitantly with thoracic surgery.
LOEYS-DIETZ SYNDROME
Mutations in the genes encoding TGFβ receptors 1 and 2
(TGFBR1 and TGFBR2, respectively) were recently found in association with a continuum of clinical features. On the mild end, the
mutations were found in association with a presentation similar to
that of Marfan syndrome or with familial thoracic aortic aneurysm
2036 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
FIGURE 88–3. Scheme of development of cardiovascular complications
in the Marfan syndrome. Source: From Roberts WC, Honig HS. The
spectrum of cardiovascular disease in the Marfan syndrome: a clinicomorphologic study of 18 necropsy patients and comparison to 151
previously reported necropsy patients. Am Heart J 1982;104:115–135.
Reproduced with permission of the publisher and authors.
FIGURE 88–4. Left: Photomicrograph of the
wall of the ascending aorta from a normal subject. Right: A similar histologic study (Movat
stains) of the wall of an ascending aortic aneurysm in a 35-year-old woman with the Marfan
syndrome. Note the virtual absence of elastic ﬁbers. Source: From Roberts WC, Honig HS.
The spectrum of cardiovascular disease in the
Marfan syndrome: a clinico-morphologic study
of 18 necropsy patients and comparison to
151 previously reported necropsy patients. Am
Heart J 1982;104:115–135. Reproduced with
permission of the publisher and authors.
and dissection,23,24 and, on the severe end, they are associated with a
complex phenotype in which aortic dissection or rupture commonly
occurs in childhood.25 This complex phenotype is characterized by
the triad of hypertelorism; a biﬁd uvula, cleft palate, or both; and
generalized arterial tortuosity with widespread vascular aneurysm
and dissection. Previously described in 10 families, the phenotype
has been classiﬁed as the Loeys-Dietz syndrome.
The disease is caused by heterozygous mutations in the genes encoding TGFBR1 and TGFBR2. Loeys et al.26 undertook the clinical
and molecular characterization of 52 affected families. Forty
probands presented with typical manifestations of the Loeys-Dietz
syndrome. In view of the phenotypic overlap between this syndrome
and vascular Ehlers-Danlos syndrome, the investigators screened an
additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or
the craniofacial features of the Loeys-Dietz syndrome.
A mutation in TGFBR1 or TGFBR2 was found in all probands
with typical Loeys-Dietz syndrome (type I) and in 12 probands
presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz
syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death: 26.0
years) and a high incidence of pregnancy-related complications (in
6 to 12 women). Patients with Loeys-Dietz syndrome type I, as
compared with those with type II, underwent cardiovascular surgery earlier (mean age: 16.9 years vs. 26.9 years) and died earlier
(22.6 years vs. 31.8 years). There were 59 vascular surgeries in the
cohort, with 1 death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from
vascular Ehlers-Danlos syndrome.
Mutations in either TGFBR1 or TGFBR2 predispose patients
to aggressive and widespread vascular disease. The severity of the
clinical presentation is predictive of the outcome. Genotyping of
patients presenting with symptoms like those of vascular EhlersDanlos syndrome may be used to guide therapy, including the use
and timing of prophylactic vascular surgery.
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
2037
FIGURE 88–5. Congenital ﬂoppy mitral valve and ﬂoppy tricuspid valve in a 2-day-old boy who had long toes and ﬁngers, a high-arched palate, and
a grade 3/6 precordial systolic murmur typical of mitral regurgitation. The heart was enlarged (top left ), and he died of congestive cardiac failure. At
necropsy, the intima of the ascending aorta (Ao) was wrinkled (right ), suggesting that the underlying media was abnormal at this early stage. Shown
here are the opened aorta, aortic valve, and left ventricle (LV). A, anterior mitral leaﬂet. Bottom left: Opened left atrium (LA), mitral valve, and LV. The mitral leaﬂets are considerably elongated in both longitudinal and transverse dimensions. The left atrium is dilated. Source: From Roberts WC, Honig HS.
The spectrum of cardiovascular disease in the Marfan syndrome: a clinico-morphologic study of 18 necropsy patients and comparison to 151 previously
reported necropsy patients. Am Heart J 1982;104:115–135. Reproduced with permission of the publisher and author.
Affected patients have a high risk of aortic dissection or rupture at
any early age and at aortic diameters that ordinarily would not be
predictive of these events. Surgical intervention is generally successful, and this characteristic distinguishes patients with the Loeys-Dietz
syndrome from those with vascular Ehlers-Danlos syndrome, a differential diagnosis often considered in patients with mutations in
TGFBR1 and TGFBR2. The importance of careful clinical and molecular characterization to identify patients and families at risk for arterial dissection and rupture cannot be overemphasized, because it allows the use of a structured approach to intervention and leads to
informed counseling regarding the risk of recurrence, concerns related to pregnancy, and guidelines for clinical management.
EHLERS-DANLOS SYNDROME
EDS is a heterogeneous group of several disorders of connective tissue that are characterized primarily by skin fragility, easy bruising,
“cigarette paper” scars, skin hyperextensibility, multiple ecchymoses,
and joint hypermobility.1 Because of the complexity of previous classiﬁcations, in 1997 a new simpliﬁed classiﬁcation divided EDS into
6 clinical types27: (1) classical, (2) hypermobility, (3) vascular, (4) kyphoscoliosis, (5) arthrochalasia, and (6) dermatosparaxis.
The numerous types of the EDS have different clinical manifestations, modes of inheritance, and natural history (see Chap. 81). In
vascular type III EDS, the heart, heart valves, great vessels, and larger
conduit arteries may be involved. Cardiovascular abnormalities in the
EDS include spontaneous rupture of the aorta or large arteries, coronary or intracranial aneurysms, arteriovenous ﬁstulae, mitral and tricuspid valve prolapse, dilatation of the aortic root, ectasia of the sinuses of Valsalva, aortic regurgitation, renal artery aneurysms,
systemic arterial hypertension, and myocardial infarction.28–30
PSEUDOXANTHOMA ELASTICUM
PXE is a rare heritable disorder that is characterized by the progressive
accumulation of mineral precipitants within elastic ﬁbers, particularly
2038 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
TABLE 88–1
Task Force 4 Recommendations for Athletes with
Marfan Syndrome
1. Athletes with Marfan syndrome can participate in low
and moderate static/low dynamic competitive sports
(classes IA and IIA) if they do not have one or more of
the following:
(a) An aortic root dilatation (i.e., transverse dimension
40 mm or greater in adults, or more than 2 standard
deviations from the mean for body surface area in
children and adolescents; z-score of 2 or more);
(b) Moderate-to-severe mitral regurgitation;
(c) Family history of dissection or sudden death in a
Marfan relative.
It is recommended, however, that these athletes have an
echocardiographic measurement of aortic root dimension repeated every 6 months, for close surveillance of
aortic enlargement.
2. Athletes with unequivocal aortic root dilatation (transverse dimension 40 mm or greater in adults or greater
than 2 standard deviations beyond the mean for body
surface area in children and adolescents; z-score of 2 or
more), prior surgical aortic root reconstruction, chronic
dissection of aorta or other artery, moderate-to-severe
mitral regurgitation, or family history of dissection or sudden death can participate only in low-intensity competitive sports (class IA).
3. Athletes with Marfan syndrome, familial aortic aneurysm
or dissection, or congenital bicuspid aortic valve with
any degree of ascending aortic enlargement (as deﬁned
in 1 and 2 above) also should not participate in sports
that involve the potential for bodily collision.
SOURCE: From Maron BJ. Heart disease and other causes of sudden death
in young athletes. Curr Probl Cardiol 1998;23:477–529 with permission.
those of the skin, Bruch’s membrane, and blood vessels. It is transmitted either as an autosomal recessive or as an autosomal dominant
trait.1,31 The estimated prevalence is 1 in 160,000 (see Chap. 81).
The elastic ﬁber changes cause skin, eye, gastrointestinal, and
cardiovascular manifestations. The skin lesions have been described as resembling a “plucked chicken.” Typically, there are yellow macules or papules that produce a rough, cobblestone texture
and are maximal in the ﬂexures of the lateral neck, axillae, antecubital fossae, groins, and popliteal spaces. They may form redundant folds of skin.1 The retinal changes include mottled peau
d’orange hyperpigmentation, angioid streaks, and an increased incidence of retinal hemorrhage and disk drusen. Angioid streaks,
caused by breaks in the Bruch membrane behind the retina, are
present in 85 percent of patients with PXE and usually develop after the second decade of life. They can be found in numerous
other conditions, including Marfan syndrome, EDS, Paget disease, and sickle cell anemia, although PXE is the most common.
It is now recognized that a mutation in the gene ABCC6
(R1141X) is associated with an increased incidence of coronary artery disease (CAD) in patients with PXE. In a study of 441 patients a signiﬁcant odds ratio for a coronary event was 4.23.31
There may be calciﬁc deposits in the media of medium-size arteries. Both vascular deposits similar to Mönckeberg arteriosclerosis and intimal plaques similar to typical atherosclerotic plaques
occur in the coronary, cerebral, gastrointestinal, renal, and peripheral arteries. Angina pectoris and myocardial infarction may occur.
Infrequent but fairly speciﬁc lesions in PXE are calciﬁc deposits
in the mural endocardium of the cardiac ventricles, atria, and
atrioventricular valves. Both mitral stenosis and MVP have been
described in PXE. Surgery to remove mural endocardial calciﬁc
deposits has been performed with fair results. Bleeding may occur
in the gastrointestinal system, uterus, joints, and urinary bladder
and may be prevented by avoiding aspirin. Coronary artery bypass
surgery arterial grafts should not be used because of possible calciﬁcation of the internal elastic laminae.
OSTEOGENESIS IMPERFECTA
Osteogenesis imperfecta, also known as brittle bone disease because
of susceptibility to sustain fractures from mild trauma, is a rare
heritable disorder of connective tissue. The gene prevalence of osteogenesis imperfecta is calculated as 4 to 5 per 100,000 persons;
it is inherited in an autosomal dominant fashion with variable
penetrance. More than 80 different mutations have been identiﬁed in the genes for either of the two chains that form type I collagen, which is the major structural protein of the extracellular
matrix of bone, skin, and tendon. There is a wide variation in its
clinical severity, from some forms that are lethal in the perinatal
period to other forms that may not be detected.32 Most manifestations of osteogenesis imperfecta are bony, ocular, otologic, cutaneous, and dental. The bony changes may result in short stature, in
utero fractures, severe osteoporosis, and severe bone fragility, with
repeated fractures and bowing of long bones. The ocular and otologic changes include blue sclerae, angioid streaks in the retina,
and hearing loss. Cutaneous and dental changes result in easy
bruising and occasional dentinogenesis imperfecta. An increased
risk of bleeding may also be present. A major advance in the treatment of bone manifestations of osteogenesis imperfecta is the use
of cyclic administration of biphosphonates.33
The cardiovascular manifestations include aortic regurgitation,32 aortic root dilatation,32 aortic dissection, and mitral regurgitation.34 Mitral valve repair and reconstruction are occasionally
feasible for patients with severe mitral regurgitation, although
most patients require valve replacement. Mitral valve replacement
or any cardiac surgery is difﬁcult because of weakness and friability
of the tissues and poor wound healing. In addition, some patients
have increased bleeding despite normal preoperative coagulation
tests and bleeding times.35
ANNULOAORTIC ECTASIA
Annuloaortic ectasia, a pear-shaped enlargement of the sinus and
the proximal tubular portions of the ascending aorta, is often part
of Marfan syndrome, where it usually results in aortic regurgitation, partial or complete ascending aortic tears, or both. In some
patients, annuloaortic ectasia is familial and no other stigmata of
Marfan syndrome are present. The genetic and molecular changes
in these patients are not established. Microscopically, there is severe loss of elastic ﬁbers in the media of the ascending aorta.
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
FAMILIAL ANEURYSMS
Various types of familial aneurysms involving cardiovascular structures have been reported, including familial aortic dissection, familial aneurysms of the ventricular septum, familial aneurysms of
the carotid arteries, and familial intracranial aneurysms. At this
time, it is not established that these are heritable disorders of connective tissue.
HOMOCYSTINURIA
See Chap. 51.
NONHERITABLE CONNECTIVE TISSUE DISEASES
The acquired or nonheritable autoimmune or connective tissue
diseases are a subset of the arthritides and rheumatic disorders.
These disorders are systemic in nature, are commonly linked by a
diffuse abnormality of vasculature, and are characterized by inﬂammatory lesions in skin, joints, muscles, and connective tissue
linings such as pleura and pericardium. Involvement of the kidneys, brain, and heart is usually responsible for the fatal and most
serious consequences. Speciﬁc acquired connective tissue diseases
that may have major cardiac involvement include SLE, polyarteritis nodosa, giant cell arteritis, RA, ankylosing spondylitis, polymyositis and dermatomyositis, systemic sclerosis, and, possibly,
syphilis (Table 88–2). Although certain immunogenetic factors
have been identiﬁed, their etiology remains uncertain.
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE is found worldwide and affects all races, is more common
among blacks, Asians, Hispanic Americans and females of childbearing age, and is usually more severe in blacks than in whites.
SLE is more common among females than among males; in patients younger than 40 years of age, the female-to-male ratio is
about 8:1. In pediatric and older patients, the female-to-male ratio
is 2:1. In the United States, the annual incidence of SLE is about 8
per 100,000 persons, and the prevalence is approximately 1 per
2,000 persons. The following genes of the human leukocyte antigen (HLA) are associated with an increased risk for SLE: HLA-B8,
HLA-DR2, HLA-DR3, HLA-DR5, HLA-DR7, HLA-DQ, and
2039
null alleles at the C2 and/or C4 loci. Genetic deﬁciencies of the
complement system—that is, deﬁciencies of C1q, C2, C4, and
C8—predispose individuals to SLE and SLE-like disorders. Homozygous C4a deﬁciency is present in 80 percent of people with
SLE irrespective of the ethnic background.36
The inﬂammatory process of SLE involves multiple organ systems, including skin, joints, kidneys, brain, heart, and virtually all
serous membranes. Its clinical presentation is varied and depends
on the organ systems involved. Fever, arthritis and arthralgias, skin
rashes (see Fig. 12–21), and pleuritis are common early signs of
SLE.
The immunologic abnormalities of SLE have been well characterized and enable it to be diagnosed despite the diversity of clinical
presentations. Typical serologic abnormalities include the presence
of antinuclear antibodies (ANAs), positive serum anti-DNA antibodies, positive anti-Smith antibodies, positive anti-ribonucleoprotein (anti-RNP) antibodies, and a falsely reactive Venereal Disease
Research Laboratory (VDRL) test. Low C3 and C4 serum complement levels are usually markers of disease activity, especially of renal
disease. Other connective tissue diseases, such as rheumatoid arthritis and scleroderma, may present with normal or elevated complement levels. Disseminated infections usually present with elevated
complement levels. Low C3 and C4 complement levels have been
described in gram-negative sepsis. Careful interpretation of abnormal serologic test is always of extreme importance. ANA testing is
very sensitive for SLE but lacks speciﬁcity. It is estimated that 8 percent of the normal population may have a positive ANA test, with a
positive result being more frequent in the elderly, patients with
Hashimoto thyroiditis, hepatitis C, hepatitis B, primary biliary cirrhosis, leukemia, lymphoma, melanoma, lung cancer, kidney cancer,
ovary cancer, and breast cancer. Idiopathic pulmonary ﬁbrosis, multiple sclerosis, polymyositis, Sjögren syndrome, scleroderma, and
rheumatoid arthritis may also present with a positive ANA test. Certain patients with SLE are more likely to have elevated levels of antiphospholipid antibody (aPL), particularly those with recurrent
venous thrombosis, thrombocytopenia, recurrent fetal loss,
hemolytic anemia, livedo reticularis, leg ulcers, arterial occlusions,
transverse myelitis, or pulmonary hypertension.37 Cardiac abnormalities may occur more frequently in patients with increased aPL
or anticardiolipin antibody titers.38
Although it may have an acute, fulminating course, SLE most
often is characterized by a chronic course marked with exacerba-
TABLE 88–2
Primary Cardiac Manifestations of the Nonhereditary Connective Tissue Diseases
DISEASE
PERICARDIUM
MYOCARDIUM
ENDOCARDIUM
(VALVES)
CORONARY
ARTERIES
Systemic lupus erythematosus
Systemic sclerosis
Polyarteritis nodosa
Ankylosing spondylitis
Rheumatoid arthritis
Polymyositis/dermatomyositis
++
+
+/–
0
++
++
+
++
+
+/–
+
++
++
0
0
++
+
+/–
+
++
++
0
+
+/–
+, may be involved, but less frequently; ++, major site of involvement; +/–, rarely involved; 0, not involved.
2040 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
tions and remissions; the 10-year survival rate exceeds 80 percent.
Nephritis and seizures decrease survival approximately twofold.39
When patients die of SLE, it is most often in the setting of acute
renal failure, central nervous system disease, associated infection,
infective endocarditis, or coronary artery disease.
Cardiac Involvement
Approximately 25 percent of patients with SLE have cardiac involvement.40–42 In addition to the valvular thickening or verrucae
and mitral or aortic regurgitation (or occasional stenosis), there
may be pericardial thickening and/or effusion, left ventricular regional or global systolic or diastolic dysfunction, or evidence of
pulmonary hypertension. Either valvular regurgitation or stenosis
as a consequence of SLE can require valve replacement. It is unclear whether cardiac abnormalities are signiﬁcantly more frequent
in patients with elevated titers of aPL.40–42 In general, valve disease
in SLE is frequent but apparently independent of the presence or
absence of aPL.
Pericarditis
SLE may cause a pancarditis with abnormalities of pericardium,
endocardium, myocardium, and coronary arteries. Pericardial involvement is the most frequent, as observed clinically, by echocardiography, or at autopsy.40 Pericardial effusions occur at some
point in more than half of the patients with active SLE. Signs of
active or acute pericardial disease may precede (approximately 5
percent) the other clinical signs of SLE.40 In most SLE patients,
the pericardial involvement is clinically silent and, when present,
runs a benign course. Pericardial tamponade may occur and
should be considered in patients with unexplained signs of venous
congestion. On rare occasions, SLE pericardial disease may lead to
pericardial constriction or to acute cardiac tamponade. Although
the size of the pericardial effusion usually is not sufﬁciently large
to allow aspiration, serologic studies of the pericardial ﬂuid can be
useful in diagnosing pericardial effusions because of SLE.
The most common type of pericardial disease in SLE is the
presence of diffuse or focal adhesions or ﬁbrinous deposits.36 The
pericardial ﬂuid in SLE may be consistent to either an exudate or
transudate. The mean white blood cell count, is 30,000 cells/mL;
usually the neutrophil percentage is 98 percent.43 Presence of low
complement levels, ANA, and lupus erythematosus cells has also
been reported.
In patients with long-standing SLE who are treated with antiinﬂammatory agents, the frequency of pericardial abnormalities is
no different than in patients who are not receiving these agents.
However, at autopsy the involvement is less extensive and more
likely to be ﬁbrous rather than ﬁbrinous. SLE patients with ﬁbrinous pericardial disease, particularly those with severe debilitation
or renal failure, are at increased risk for purulent pericarditis,
which is usually fatal.
Endocarditis and Valve Disease
The cardiovascular lesion of SLE that has received the most attention is the atypical verrucous endocarditis ﬁrst described by Libman
and Sacks in 1924,44 long before SLE was recognized as a systemic
disease. The lesions, as they were ﬁrst described and subsequently attributed to SLE, consist almost entirely of ﬁbrin, and although they
may occur on both surfaces of any of the four cardiac valves, they are
now most frequently found on the left-sided valves, particularly the
ventricular surface of the posterior mitral leaﬂet (Fig. 88–6). These
verrucae are similar histologically to those of nonbacterial thrombotic noninfective endocarditis, the valve lesion that occurs most
frequently in patients with debilitating illnesses or cancer, except
that occasionally hematoxylin bodies, considered the histologic
counterpart of lupus erythematosus cells, may be found within Libman-Sacks lesions. Although valvular verrucae in SLE (LibmanSacks lesions) are usually clinically silent, they can be dislodged and
embolize, and can also become infected, producing infective endocarditis.42 It is prudent to recommend antibiotic prophylaxis against
infective endocarditis when patients with SLE undergo procedures
that may be associated with bacteremia (see Chap. 85).
FIGURE 88–6. An example of Libman-Sacks endocarditis in systemic lupus erythematosus. A and B. The left atrium (LA) and left ventricle (LV) are
open. B and C. Fibroﬁbrinous verrucae, present on the undersurface of the posterior leaﬂet (P) of the mitral valve, are often clinically silent. A, anterior
leaﬂet of mitral valve; CA, left circumﬂex coronary artery; CT, chorda tendineae; P-M, posteromedial papillary muscle. Hematoxylin and eosin (H&E)
stain, × 8. Source: From Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy:
a study of 36 necropsy patients. Am J Med 1975;58:243–264. Reproduced with permission from the publisher and the author.
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
2041
Echocardiographically, SLE has a characteristic appearance,
with leaﬂet thickening and valve masses (see Chap. 16). The
end-stage or healed form of the verrucous endocarditis of SLE is
a ﬁbrous plaque. In some instances, if the thrombotic lesions are
extensive enough, their healing may be accompanied by focal
scarring and deformity of the underlying valve tissue. This
healed form of SLE “endocarditis” may cause valvular dysfunction, particularly mitral and/or aortic regurgitation.45 Verrucous
endocarditis is associated with the presence of the antiphospholipid syndrome.
Myocarditis
It is unclear whether inﬁltration of the myocardial interstitium
with acute and/or chronic inﬂammatory cells and focal myocardial
necrosis (i.e., myocarditis) occurs as a natural part of SLE, unassociated with antiinﬂammatory drug therapy (glucocorticoid treatment). Several reports describe clinical features consistent with
myocarditis, but actual visualization of interstitial myocardial inﬂammatory cells with associated myoﬁber necrosis has not been
demonstrated histologically. Hemodynamic and echocardiographic studies, however, have shown abnormalities in both systolic and diastolic ventricular function in some SLE patients.
T1 spin-echo and T2 relaxation time cardiac MRI is being studied extensively in patients with SLE, and its use for the diagnosis
of myocarditis is promising, but standards are still lacking (see
Chap. 21). A recent case series of 11 consecutive patients with
SLE reported an increased relaxation time by cardiac MRI (index
of soft-tissue signal). Clinical improvement correlated very well
with improvement of the parameters by MRI.46
Whether these abnormalities result from an autoimmune attack
on the myocardium or from the effects of systemic arterial hypertension, coronary artery disease, or coexisting pericardial disease is
unclear.
Coronary Artery Disease
Both fatal and nonfatal acute myocardial infarction and sudden
coronary death (without demonstrable infarction) from CAD may
occur early in the course of SLE, particularly among young
women. In a landmark report by Manzi et al., the incidence of
myocardial infarction in women with SLE (third and fourth decades of life) was found to be increased by 50-fold when compared
to patients from the Framingham cohort. Two-thirds of the coronary events occurred in women younger than 55 years of age.
Older age at the lupus diagnosis, longer disease duration, and the
use of steroids, as well as hypercholesterolemia and postmenopausal status, were more common in the patients with coronary
events (Fig. 88–7).47
Studies of hearts in patients with fatal SLE have demonstrated a
high incidence of CAD in patients who received treatment with
glucocorticoids for more than 2 years.48,49 Accelerated CAD is increasingly recognized as a leading cause of morbidity and mortality
among young women with SLE who receive long-term glucocorticoid administration.48,49
Although the causes of this premature CAD are uncertain, both
glucocorticoid treatment and aPL have been incriminated. It has
been speculated that SLE itself may induce an underlying vasculopathy that may facilitate premature atherogenesis from long-term
FIGURE 88–7. Comparison of rates of myocardial infarction in women
with systemic lupus erythematosus (SLE) versus patients from the Framingham cohort. Rate ratio in the 35- to 44-year-old age group was 52.43
times higher in women with SLE (95 percent conﬁdence interval 21.6–
98.5). Source: Data from Manzi S, Meilahn EN, Rairie JE, et al. Agespecific incidence rates of myocardial infarction and angina in women
with systemic lupus erythematosus: comparison with the Framingham
study. Am J Epidemiol 1997:145:408–415.
glucocorticoid treatment. Premature coronary artery atherosclerosis
determined by electron-beam computed tomography (coronary artery calciﬁcation) has been reported in patients with SLE.50
In one study, the presence of elevated aPL antibodies in patients with SLE correlated with left ventricular (global or segmental) dysfunction, verrucous valvular (aortic or mitral) thickening,
and global valvular (mitral or aortic) thickening and dysfunction,
as well as mitral and aortic regurgitation. Coronary thrombi may
occur in patients with active lupus. Acute myocardial infarction
may occur in the presence of angiographically normal coronary
arteries. SLE also may cause coronary aneurysm; aPL antibodies
are known to promote platelet aggregation and to be associated
with the presence of a clotting tendency, the so-called lupus anticoagulant syndrome.40,41
Inﬂammation (arteritis) of the wall of the sinus node artery in
association with scarring of both sinus and atrioventricular nodes
may account for some of the rhythm and conduction disturbances
seen in these patients.
Pregnancy and the Neonatal Lupus Syndrome
Neonatal lupus erythematosus is a rare disorder that arises when
the so-called anti-Ro, or Sjögren (SSA), autoantibodies—mostly
immunoglobulin G (IgG)—are formed and circulate in pregnant
patients, cross the placenta, and cause a lupus-like syndrome in
newborns with the appearance of a skin rash and transient cytopenias from passively acquired maternal autoantibodies. Because the
half-life of IgG antibodies is approximately 21 to 25 days, the neonatal lupus syndrome in newborn babies is self-limiting; it usually
resolves in 3 to 6 months when all of the IgG-containing anti-Ro
maternal autoantibodies have been cleared from the neonate’s circulation. An unfortunate exception is complete congenital heart
block, which may require the implantation of a pacemaker. Once
complete heart block occurs, it is usually irreversible. One neonate
with ﬁrst-degree heart block at birth that resolved 6 months later
has been described. Antibodies to the Ro (SSA) ribonucleoprotein
2042 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
complexes are present in more than 85 percent of sera from mothers of infants with complete congenital heart block. A recent study
found that the presence of complete heart block is strongly dependant on a speciﬁc antibody proﬁle to Ro 52-kd; this may be a useful tool to identify pregnant women who are at risk of delivering
babies with a complete heart block.51 In many patients, antibodies
reactive to the La (SSB) antigen, as well as the U1RNP protein
particle, are found in association with anti-Ro (SSA) antibodies.
In most cases, the neonatal lupus syndrome is a benign disorder,
and most babies of mothers with anti-Ro (SSA), anti-La (SSB), or
anti-U1RNP antibodies do not develop neonatal lupus. A pregnant woman with SLE with positive anti-Ro, anti-La, or anti-RNP
antibodies has a less than 3 percent risk of having a child with neonatal lupus and congenital heart block. The risk that this patient might
have an infant with neonatal lupus syndrome but without congenital
heart block may be as high as 1 in 3. The neonatal lupus syndrome
mediated by the presence of maternal anti-Ro antibodies can occur in babies of mothers who do not have overt SLE, who may or
may not meet criteria for a diagnosis of SLE, and who may or may
not have a positive test for ANA.52
Neonatal lupus syndrome with congenital heart block can be
diagnosed by the appearance of fetal bradycardia around week 23
of gestation.52 The cardiac damage with conduction abnormalities
in a neonate may result from binding of the passively transferred
pathogenic anti-Ro antibodies to Ro (SSA)/La (SSB) antigens
present in the fetal heart. All mothers of neonates with complete
congenital heart block have been HLA-DR3 positive. If a mother
is HLA-DR3 positive and has circulating IgG anti-Ro antibodies,
her neonate is at risk regardless of the neonate’s HLA-DR status.
Other cardiac abnormalities reported in neonatal lupus syndrome include right bundle-branch block, second-degree atrioventricular block, 2:1 atrioventricular block, patent ductus arteriosus,
patent foramen ovale, coarctation of the aorta, tetralogy of Fallot,
atrial septal defect, hypoplastic right ventricle, ventricular septal
defect, dysplastic pulmonic valve, mitral and tricuspid regurgitation, pericarditis, and myocarditis. Most of these patients eventually have a pacemaker inserted.
Pregnant women with SLE should have a serum anti-Ro (SSA)
antibody determination as early in pregnancy as possible. Prenatal
treatment of established congenital heart block has consisted of
the administration of prednisone or dexamethasone and plasmapheresis from week 23 on, although heart block has persisted in
most cases.52 It is unclear whether aggressive antiinﬂammatory
therapy, in an effort to diminish the generalized fetal insult and to
lower the titers of circulating anti-Ro (SSA) antibodies, makes a
difference in fetal cardiac outcome. Fetal echocardiography is useful in following the progression of the disease and also in helping
to identify decreased left ventricular contractility, increased cardiac
size, tricuspid regurgitation, and pericardial effusion.
Neither dexamethasone nor plasmapheresis has had much success in reversing intrauterine third-degree heart block. Glucocorticoids, however, may be helpful in suppressing an associated inﬂammatory response producing pleuropericardial effusions or
ascites in the fetus. Close monitoring of the clinical course in the
prospective mother is also essential because of the risk of exacerbation of the SLE. If fetal bradycardia is present, an intrauterine therapeutic approach for as long as possible is recommended to allow
for fetal maturation to occur. Ultrasound images can be useful for
assessing the degree of cardiac dysfunction present. Following delivery, the neonatologist should be prepared to have a cardiac pacemaker implanted. Otherwise, all of the other clinical and laboratory features of the neonatal lupus syndrome should slowly and
gradually disappear over the ﬁrst few months of the baby’s life. In
one study, one-third of the children with autoantibody-associated
congenital heart block died in the early neonatal period53; most
survivors required a pacemaker.
Women with SLE who are anti-Ro positive should be closely
monitored during pregnancy, as should mothers of previous babies
born with congenital complete heart block. Pregnant patients
should be reminded that congenital complete heart block is rare
and that the neonatal cutaneous lupus syndrome is benign and
transient. The long-term prognosis of mothers of children born
with congenital heart block is generally fairly good. In these mothers, the risk of congenital heart block in children of subsequent
pregnancies is low. Newborns of mothers with SLE who have a
normal pulse rate are unlikely to have signiﬁcant abnormalities in
atrioventricular conduction.
A higher incidence of clinical evidence of myocarditis and conduction defects is found in adult anti-Ro-positive patients with
SLE than it is in patients who are anti-Ro negative or in healthy
controls.52 The role of the anti-Ro antibody in inducing heart
blocks in adult patients with SLE is unclear.
Secondary Effects on the Heart
Most of the clinically signiﬁcant cardiac problems occurring in patients with SLE are secondary. Systemic arterial hypertension is
common in patients with SLE, particularly those with renal disease and long-standing glucocorticoid therapy, in whom it is a major cause of cardiac enlargement and heart failure.40 Pulmonary
hypertension is also common, approaching 50 percent in a 5-year
followup study. Uremic pericarditis may occur, of course, in patients with severe renal failure. Premature or accelerated atherosclerosis is increasingly recognized in young women with SLE who
are receiving long-term glucocorticoid treatment.40
Therapy
Therapy of cardiovascular SLE is the treatment of the underlying disease and includes nonsteroidal antiinﬂammatory drugs
(NSAIDs), glucocorticoids, and, in severe cases, cytotoxic agents
such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Systemic arterial hypertension, congestive heart failure, and
arrhythmias should be treated with standard therapeutic measures.
SLE-induced valve disease can require valve replacement.40,54 Pericardial tamponade may require either high-dose steroids (prednisone 1 mg/kg), pericardiocentesis, or placement of a pericardial
window, but recurrent effusions or pericardial thickening may develop. A mild to moderate pericardial effusion can be treated with
NSAIDs or prednisone at a dose of 20 to 40 mg/d. Premature cardiovascular events from accelerated atherosclerosis may result in
sudden death or myocardial infarction. The antimalarial agent hydroxychloroquine lowers serum cholesterol levels in patients with
SLE and may decrease myocardial ischemic damage. An antimalarial such as hydroxychloroquine may be beneﬁcial as a prophylactic agent to prevent premature or accelerated atherosclerosis in
young women with SLE who are receiving long-term treatment
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
with glucocorticoids. Although there are no studies documenting
beneﬁt, low-dose aspirin and hydroxychloroquine are often used
in SLE patients receiving long-term glucocorticoid therapy.
2043
shorten survival, especially in older patients. Lymphocytic inﬁltrates of the CD8-positive type may occur in the pericardium of
patients with rheumatoid pericardial disease, suggesting that these
cells may play a role in the development of the pericardial disease
(see Chap. 84).
RHEUMATOID ARTHRITIS
RA is the most common connective tissue disease. Its prevalence is
1.5 percent in males and 2.5 percent in females. It is characterized
by its deforming erosions of the joints; these erosions result from
chronic synovial inﬂammation and proliferation. Joint symptoms
dominate its course, and symmetric involvement of the hands and
wrists is most common. Other joints of the upper and lower extremities and the temporomandibular and sternoclavicular joints
also may be affected. The most common systemic or extraarticular
manifestations of RA include subcutaneous rheumatoid nodules,
weight loss, anemia of chronic inﬂammation, and serositis. Less
frequently, pneumonitis and a necrotizing vasculitis occur in patients with severe long-standing disease. Contrary to prior epidemiologic studies, new data support increased mortality in RA.55
A prospective cohort study comparing the incidence of myocardial infarction and cerebrovascular events between RA patients
and non-RA patients with known CAD found that the RA patients had a greater incidence of vascular events and mortality.56
Atherosclerosis also appears to occur at an accelerated rate in
RA. There is a strong correlation between the presence of inﬂammatory biochemical markers and carotid atherosclerotic plaques.57
Coronary artery calciﬁcation determined by electron-beam computed tomography or multislice CT is signiﬁcantly higher in patients with RA than in healthy individuals. The presence of coronary artery calciﬁcations is highly dependent on disease duration.
Patients with RA who smoke and have an elevated erythrocyte
sedimentation rate have a higher incidence of coronary artery calciﬁcation.58 In a population-based retrospective study of patients
followed for 46 years, a signiﬁcant excess risk of congestive heart
failure (CHF) (hazard ratio [HR] 1.87; 95 percent conﬁdence interval [CI] 1.47–2.39) was found in patients with RA.59 CHF,
rather than ischemic heart disease, contributes to the excess overall
mortality among patients with RA.60
Pericardial Involvement
Although cardiac involvement is uncommon in RA, it does exist
in a variety of forms. A diffuse, nonspeciﬁc ﬁbroﬁbrinous pericarditis occurs in approximately 50 percent of patients with RA; it
is usually clinically silent and is overshadowed by pleuritis or joint
pain.53 The pericardial disease tends to be benign, but sizable effusions can occur and require pericardiocentesis; however, pericardial constriction rarely necessitates pericardiectomy. Constrictive
pericarditis occurred in 4 of 47 patients with RA whose cases were
followed over a 10-year period. The histopathologic ﬁndings after
pericardiectomy were consistent with chronic ﬁbrosing pericardial
disease. In another report, RA patients with constrictive pericarditis had a longer disease course, more severe disease, worse functional class, and more extraarticular features when compared with
RA patients without cardiac constriction. The presenting clinical
features of cardiac constriction included dyspnea, edema, chest
pain, and pulsus paradoxus. Chronic, symptomatic pericarditis
may require glucocorticoid therapy. RA pericardial disease may
Myocardial and Endocardial Involvement
Rarely, rheumatoid nodules focally inﬁltrate the heart, including
the myocardium and the four cardiac valves (Fig. 88–8).53 These
nodules may produce no symptoms, but, if extensive enough or
strategically located, they can compromise cardiac function. A
rheumatoid nodule may extend from the mural endocardium into
a chamber to present as an intracavitary mass. Rheumatoid nodules developing within the valve leaﬂets may result in mild valvular
regurgitation; if the nodule becomes necrotic, perforation of the
leaﬂet can occur and lead to severe valvular regurgitation. The incidence of such valvular inﬁltration has been estimated at 1 to 2
percent in autopsy studies of patients with RA. Although distinctly uncommon, arrhythmias and conduction disturbances, including complete heart block, and congestive heart failure can also
result from RA involvement of the heart. One echocardiographic
study of 39 patients with RA detected left ventricular abnormalities in 25 percent of the patients.
Therapy
Methotrexate appears to reduce cardiovascular mortality.61 However, other traditional disease-modifying antirheumatic drugs such
as sulfasalazine, azathioprine, and hydroxychloroquine do not.
The outcome of patients with rheumatoid arthritis has improved dramatically since the introduction of the antitumor necrosis factor (TNF) α blockers. They are now approved for the
treatment of early RA. However, they should not be used in patients with New York Health Association (NYHA) class III or IV
heart failure (see Table 88–2) because of the potential risk of worsening the CHF.62 The treatment of cardiac constriction from
rheumatoid pericardial disease may include a trial of a high-dose
intravenous glucocorticoid (e.g., methylprednisolone) and/or surgical therapy. Pericardiocentesis should be performed only as a lifesaving procedure. An uncomplicated asymptomatic pericardial effusion does not require any treatment.
ANKYLOSING SPONDYLITIS
Ankylosing spondylitis is the prototypical example within the group
of the seronegative spondyloarthropathies. It is characterized by a
progressive inﬂammatory lesion of the spine, leading to chronic
back pain, deforming dorsal kyphosis, and, in its advanced stage, fusion of the costovertebral and sacroiliac joints with immobilization
of the spine. This condition is much more frequent in men than it is
in women (9:1), generally ﬁrst occurring early in life but with a
chronic progressive course of 20 to 30 years. The HLA-B27 histocompatibility antigen is found in 90 percent of whites and in 50
percent of black patients with ankylosing spondylitis. A spondyloarthropathy associated with an HLA-B27 is seen frequently in patients with reactive arthritis (formerly called Reiter syndrome),
Crohn disease, ulcerative colitis, and psoriatic arthritis.
2044 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
treatment with anti-TNFα drugs is now
the standard of care. Patients with longstanding disease tend to be less responsive. Whether the natural history of the
disease could be improved with early
anti-TNFα therapy is unknown.64
The inﬂammatory lesion of the heart
generally runs a clinically silent course
until aortic regurgitation develops. Not
infrequently, however, the aortic regurgitation of ankylosing spondylitis may become severe enough to warrant aortic
valve replacement (see Chap. 75).
CARDIOVASCULAR
SYPHILIS
Although traditionally not considered to
be a connective tissue disorder, cardiovascular syphilis has histologic features
nearly identical to those of ankylosing
spondylitis, and spirochetes have never
FIGURE 88–8. Rheumatoid arthritis. A. A tricuspid valve (TV) inﬁltrated by rheumatoid nodules. B. A mibeen identiﬁed in the aorta of a patient
tral valve inﬁltrated by rheumatoid nodules. In addition, granulomas are present within the left ventricular (LV)
with cardiovascular syphilis.
wall. LA, left atrium; PML, posterior mitral leaﬂet; RV, right ventricle. Hematoxylin and eosin (H&E) stain:
The distribution of the lesions, howA, × 12; B, × 65. Source: From Roberts WC, Dangel JC, Bulkley BH. Nonrheumatic valvular cardiac
ever, is distinctly different in these two
disease: a clinicopathologic survey of 27 different conditions causing valvular dysfunction. Cardiovasc
Clin. Copyright 1973 by F.A. Davis Company; used by permission of F.A. Davis Company.
conditions.53 In cardiovascular syphilis,
the process is usually limited to the tubular portion of the ascending aorta (i.e., that portion up to the oriCardiac Involvement
gin of the innominate artery). Because the process as a rule does
Cardiovascular disease in ankylosing spondylitis, seen typically in
not extend into the wall of aorta behind the sinuses of Valsalva,
patients with severe peripheral joint involvement and long-standaortic regurgitation is infrequent in syphilis. Exactly what percenting disease, takes the form of a sclerosing inﬂammatory lesion that
age of patients with cardiovascular syphilis develop aortic regurgiis generally limited to the aortic root area. The inﬂammatory protation is unclear, but it is probably less than 15 percent and only
cess, which extends immediately above and below the aortic valve,
those patients in whom the process extends into the wall of aorta
63
typically causes aortic regurgitation (Fig. 88–9). As the inﬂambehind the sinuses of Valsalva. In syphilis, the process never inmatory process extends below the aortic valve, it can inﬁltrate the
volves the aortic valve cusps and never extends below (caudal to)
basal portion of the mitral valve (which is contiguous with the aorthe aortic valve. In contrast, in ankylosing spondylitis, the process
tic valve) and cause mitral regurgitation. Extension of the inﬂamalways involves basal portions of the aortic valve cusps and always
matory lesion into the cephalad portion of the ventricular septum,
extends into the membranous ventricular septum, the basal porimmediately caudal to the aortic valve, accounts for the associated
tion of the anterior mitral leaﬂet, or both. Thus, because the proconduction disturbances. Ventricular diastolic dysfunction may
cess in syphilis never extends below the aortic valve, bundle
also occur.
branch or complete heart block and mitral regurgitation never deThe major clinical manifestation of ankylosing spondylitis is
velop in cardiovascular syphilis. Cardiovascular syphilis characteraortic regurgitation, which occurs in approximately 5 percent of
istically involves the entire tubular portion of the aorta, which
patients with this condition. Among patients with signs of
may become either diffusely or focally dilated. In contrast, in
spondylitis for 10 years, only 2 percent have clinical evidence of
ankylosing spondylitis, the process involves only the proximal 1
aortic regurgitation; by 30 years, that number increases ﬁvefold.
cm of the tubular portion of the ascending aorta and then usually
Ankylosing spondylitis may be associated with aortic root inﬂamin the areas of the aortic valve commissures. Accordingly, aneumatory lesions, as may other seronegative spondyloarthropathies
rysms of the tubular portion of the ascending aorta do not occur
such as Reiter syndrome and psoriatic arthropathy.
in ankylosing spondylitis. Syphilitic aneurysms can become so
large that they burrow into the sternum or compress adjacent
Therapy
structures such as the right atrium, superior vena cava, or pulmonary trunk. Rupture into the adjacent structures or into the periDrug therapy for ankylosing spondylitis used to be directed primarily at relief of the back pain and discomfort. NSAIDs and
cardial sac may also occur.
methotrexate, in addition to physical therapy, remain the ﬁrst line
Histologically, the aortic lesions in both cardiovascular syphilis
of therapy. Glucocorticoids do not have a role in the treatment of
and ankylosing spondylitis are characterized by extensive thickenankylosing spondylitis except for the treatment of uveitis. The
ing by ﬁbrous tissue of the adventitia, with collections of plasma
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
2045
cess are diffuse vascular lesions. Functionally, the vascular disorder is characterized by Raynaud phenomenon, which
is a prominent feature of systemic sclerosis. Raynaud disease of the digits is
present in almost all patients with systemic sclerosis and is the ﬁrst clinical
symptom in most. Structurally, the vascular lesions show intimal and adventitial
thickening of small- and medium-size
vessels, including arterioles. The underlying pathophysiology of scleroderma that
links structure and function is a
Raynaud-type phenomenon of visceral
vasculature that leads to focal vascular lesions and parenchymal necrosis and ﬁbrosis. This concept is supported by ﬁndings in the heart, the lungs and kidneys.
The underlying cause of the vascular disease in systemic sclerosis and the role of
the immune system in its pathophysiology remain unclear. Systemic sclerosis
may be related to increased activity of endothelial cells, mast cells, and ﬁbroblasts,
perhaps under the inﬂuence of immigrant cells, such as T cells, macrophages,
or platelets.
FIGURE 88–9. Diagram showing the characteristic features of ankylosing spondylitis of the heart. The
Like most connective tissue diseases,
aorta and aortic valve are opened, showing the thickening of the aorta in the vicinity of the aortic valve
systemic
sclerosis may have a variable
commissures and the thickening of the anterior mitral leaﬂet. The small diagrams at the bottom of the ﬁgure show the thickening in the wall of the aorta behind the sinuses extending below the aortic valve into
clinical expression. Some patients may
the membranous ventricular septum and anterior mitral leaﬂet. In the patient whose heart was portrayed
have skin involvement predominantly;
by this diagram, there was also some thickening in the posterior mitral leaﬂet.
others have minimal skin abnormalities
but severe visceral disease that may therefore evade diagnosis. Limited scleroderma (formerly called
cells and some lymphocytes within these tissues. The vasa vasorum
CREST syndrome) is most of the time a more benign form of
are larger than normal, their walls are thickened, and their lumens
scleroderma that presents with relatively mild skin changes limited
may be severely narrowed. The inﬂammatory inﬁltrates are located
to the face and ﬁngers, calcinosis, Raynaud phenomenon, esophprimarily in the perivascular locations. The media is thinner than
ageal dysmotility, sclerodactyly, and telangiectasia. Patients with
normal and contains scars that are generally located transversely to
limited scleroderma have a high incidence of pulmonary hypertenthe long axis of the aorta. Within the scars, elastic ﬁbers may be
sion. Overlap syndromes are seen when a patient with typical feaabsent. The overlying intima is thickened, and the intimal process
tures of systemic sclerosis also has features of SLE, polymyositis, or
has the “tree bark” appearance of typical atherosclerotic plaques.
RA. Although systemic sclerosis may run a long and benign
Patients with cardiovascular syphilis, with or without associated
course, the involvement of inner organs, such as kidney, lung, and
aortic regurgitation, usually live into their 70s or 80s.
cardiovascular system, is associated with increased morbidity and
mortality.
SYSTEMIC SCLEROSIS (SCLERODERMA)
Systemic sclerosis, which was ﬁrst identiﬁed more than two centuries ago, is characterized by its striking skin manifestations;
hence the name scleroderma. In 1943, when Weiss et al.65 described a pattern in the cardiac dysfunction of nine patients with
scleroderma and correlated these changes with abnormalities in
the heart at autopsy in two patients, they recognized that the cardiac disease was a manifestation of an underlying primary vascular disorder.
Systemic sclerosis is characterized by ﬁbrous thickening of the
skin and ﬁbrous and degenerative alterations of the ﬁngers and of
certain target organs, particularly the esophagus, small and large
bowels, kidneys, lung, and heart. Central to this degenerative pro-
The Cardiovascular System
Cardiovascular disease in patients with systemic sclerosis can be a
result of either a primary involvement of the heart by the sclerosing disease or a secondary involvement from disease of the kidney
or lungs.
PRIMARY SYSTEMIC SCLEROSIS OF
THE HEART
Myocardial involvement is a major determinant of survival in systemic sclerosis. When the heart is involved directly by sclero-
2046 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
A
C
B
FIGURE 88–10. Systemic sclerosis. A: Cross-section through the dilated right (RV) and left (LV) ventricle of a patient with cardiac systemic sclerosis. Marked ﬁbrous scarring of both ventricles is especially evident in the ventricular septum (arrow). B: Photomicrograph
of myocardium showing replacement ﬁbrosis with patent intramural
coronary arteries (arrows). C: Higher-power magniﬁcation showing
contraction-band necrosis of many ﬁbers surrounding the areas of
scar. Hematoxylin and eosin (H&E) stain, × 45 and × 60. Source:
From Bulkley BH. Progressive systemic sclerosis: cardiac involvement.
Clin Rheum Dis 1979;5:131. Reproduced with permission from the
publisher and author.
derma, a myocardial ﬁbrosis occurs that bears no direct relation to
large- or small-vessel occlusions or other anatomic abnormalities.
Fibrosis tends to be patchy, involving all levels of the myocardium
unpredictably and the right ventricle as often as the left. Focal
patchy myocardial cell necrosis may also be evident, and at autopsy over three-quarters of patients with myocardial systemic
sclerosis have foci of necrosis. The type of necrosis is myoﬁbrillar
degeneration, or contraction-band necrosis (Fig. 88–10). This lesion is characteristic of myocardium that is subjected to transient
occlusion followed by reperfusion. This could occur with vascular
spasm and also may be induced experimentally by exposing myocardium to high concentrations of catecholamine. Thus, the morphologic characteristics of the myocardial lesions of primary cardiac systemic sclerosis are very similar to the ones seen in Raynaud
phenomenon. There is increased incidence of scleroderma renal
crisis during cold weather months. Thus, it is likely that the major
visceral manifestations of systemic sclerosis in the heart, lungs, and
kidneys are related to the vascular spasm that is evident and readily
detectable in the digits. Changes that are comparable to the necrosis and scarring of the ﬁngertips can also develop in the viscera.
Current evidence suggests that the vascular system and particularly the smaller arteries and arterioles are the primary target organ
of systemic sclerosis. Also the cardiac sclerosis of scleroderma may
be a consequence of focal, intermittent, and progressive ischemic
injury.
Several functional studies suggest that microvascular spasm occurs in patients with cardiac scleroderma. Transient perfusion defects identiﬁed by thallium-201 radionuclide imaging in the setting of patent coronary arteries also have been identiﬁed in
patients with systemic sclerosis and symptomatic cardiac disease.66
Clinical Manifestations
The clinical features of myocardial systemic sclerosis include
biventricular congestive heart failure, atrial and ventricular arrhythmias, myocardial infarction, angina pectoris, and sudden cardiac death.67 These clinical manifestations reﬂect the underlying
conditions of myocardial necrosis and ﬁbrosis and may at times
mimic ischemic heart disease caused by CAD. If the myocardial
injury is extensive enough, hypodynamic ventricles, a syndrome
resembling idiopathic dilated cardiomyopathy (see Chap. 29) may
be simulated. Patients with systemic sclerosis may have cardiac involvement but no cardiac symptoms.68 One study examined 18
systemic sclerosis patients by electrocardiography (ECG), ambula-
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
tory ECG, radionuclide ventriculography, myocardial scintigraphy, and echocardiography and found a high rate of cardiac abnormalities, including ventricular tachyarrhythmias, supraventricular
tachycardias, depressed left or right ventricular function, and reversible myocardial perfusion abnormalities. In other studies of
patients with limited scleroderma, noninvasive cardiac techniques
such as Doppler echocardiography and thallium-201 perfusion
scintigraphy after a cold-stress test or radionuclide ventriculography have found a number of cardiovascular abnormalities, such as
mild mitral regurgitation, thickening of papillary muscles, abnormal left and right ventricular diastolic function, and systolic pulmonary arterial hypertension.69,70
Skeletal muscle myositis can complicate systemic sclerosis, and
such patients may have an increased likelihood of developing myocarditis, heart failure, and symptomatic arrhythmias, and often die
suddenly.70 Accordingly, it has been suggested that serum creatine
kinase with myocardial band fractionation and studies of left ventricular function be undertaken in patients with systemic sclerosis
who have skeletal myositis. Autopsy studies suggest that up to 50
percent of patients with systemic sclerosis have increased myocardial scar tissue and that up 30 percent of patients have extensive
disease. Some clinical evidence of cardiac abnormalities may occur
in approximately 40 percent of patients with systemic sclerosis.
Pericardial and Endocardial Disease
Pericardial involvement may occur in approximately 20 percent of
patients with systemic sclerosis. Although the pericardial involvement is a result of renal failure in as many as two-thirds of patients,
some develop a ﬁbroﬁbrinous or ﬁbrous pericarditis for which no
other cause is evident. Exudative pericardial effusions may accompany scleroderma pericardial disease and can be massive.71 Most
cases of pericardial effusion in scleroderma have a benign course.
Rarely, pericardial tamponade may occur and may precede cutaneous thickening. Rarely, constrictive pericardial disease may result
from the pericardial sclerosis. Mitral regurgitation is common in patients with systemic sclerosis.72 Tricuspid regurgitation occurs in patients with very dilated right ventricular cavities.
2047
menger syndrome and primary pulmonary hypertension. Arterial
vasospasm is believed to be a major component of systemic sclerosis pulmonary hypertension, and the association is supported by
angiographic studies. That Raynaud phenomenon of the digits accompanies idiopathic pulmonary hypertension in about one-third
of patients suggests that vascular hyperreactivity may be a common link between this disease and scleroderma (see Chap. 71).
Pulmonary hypertension portends a poor prognosis. Sudden
unexpected death occurs, and hypotension and death can occur
precipitously in the setting of what would appear to be relatively benign procedures such as pericardiocentesis or cardiac
catheterization.
Treatment
No uniform therapy is effective for the cardiovascular disease of
systemic sclerosis. Treatment consists of standard therapy for congestive heart failure and arrhythmias.72 Malignant ventricular arrhythmias in systemic sclerosis seemingly have responded well to
insertion of an implantable cardioverter deﬁbrillator (see Chap.
46). Captopril improves myocardial perfusion.73 Unlike Raynaud
disease secondary to lupus, the beneﬁcial response to nifedipine
when it is associated with scleroderma is marginal. Prazosin and
hydralazine have been used with mixed results. There is growing
experience with the use of angiotensin receptor blockers and their
use is reasonable if there is no contraindication. The role of sympathectomy for severe Raynaud disease refractory to medical
treatment is highly controversial; most patients obtain only temporary relief of their symptoms. Avoiding cool temperatures is
mandatory. The use of continuous intravenous infusion of
epoprostenol74 or the inhaled prostacyclin analogue iloprost75
have improved dramatically the symptoms and mortality caused
by pulmonary hypertension (see Chap. 71). A study with the oral
endothelin-receptor antagonist bosentan showed promising results.76 The use of d-penicillamine, which until recently was standard therapy, has not been proven to be efﬁcacious.
The use of high-dose glucocorticoids should be avoided in scleroderma and doses of prednisone higher than 30 mg daily have been
associated with an increased risk of normotensive renal failure.
Secondary Cardiovascular Disease
Ventricular hypertrophy and congestive heart failure may be associated with long-standing systemic arterial hypertension and renal
disease. Uremic pericarditis may occur. Pulmonary hypertension
with marked right ventricular hypertrophy and right-sided heart
failure may result from long-standing severe pulmonary scleroderma. Mortality as a consequence of scleroderma renal crisis and
malignant hypertension has dramatically decreased with the use of
angiotensin-converting enzyme inhibitors.
Pulmonary Hypertensive Disease
Although the pulmonary ﬁbrosis of scleroderma had been known
for years, the recognition of a pulmonary hypertensive lesion independent of parenchymal disease evolved later. Such patients tend
to develop rapidly progressive dyspnea and right-sided heart failure in the setting of clear lungs. Morphologically, the pulmonary
arterial lesions show the range of advanced alterations (medial and
intimal thickening and plexiform lesions) as seen in the Eisen-
POLYMYOSITIS AND DERMATOMYOSITIS
These idiopathic autoimmune inﬂammatory myopathies are rare
in the United States, with an estimated annual incidence of about
5 to 10 new patients per million. The clinical features include a
typical heliotrope rash in dermatomyositis (DM), with periorbital
edema (see Chap. 12) and proximal muscle weakness present in
both polymyositis (PM) and DM. Typical laboratory ﬁndings reﬂect the presence of muscle breakdown from the inﬂammatory
process. Creatine kinase, myoglobulin, and serum aldolase levels
are commonly elevated during acute states. The former is more
sensitive in those patients who present with normal, or mildly increased, creatine kinase levels. The so-called anti-Jo-1 antibody, directed against histidyl-tRNA (transfer ribonucleic acid) synthetase,
is detectable in the serum of 20 percent of patients with PM/DM.
Its presence has been correlated with erosive arthritis, Raynaud
phenomenon, interstitial lung disease, and excess mortality, mostly
as a result of respiratory failure. Another marker of disease severity
2048 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
is the anti–signal-recognition-particle (anti-SRP) antibody. Typical
electromyogram changes include shortwave potentials, low-amplitude polyphasic units, and increased spontaneous activity with
muscle ﬁbrillation. A positive skeletal muscle biopsy of a proximal
muscle such as the deltoid is often conﬁrmatory.
In addition to skeletal muscle involvement, up to 40 percent of
patients may have cardiac abnormalities. A small study of 16 autopsied patients with PM/DM suggests a poor correlation between
the degree of skeletal involvement and myocarditis; however, in a
study of 55 patients with PM, Behan et al. reported mild diffuse
myocarditis, severe inﬂammation, or ﬁbrosis of the cardiac conduction system in 70 percent of the patients. Also, anti-SSA (antiRo) antibody, which is classically associated with an increased risk
of infant cardiac conduction abnormalities in the neonatal lupus
syndrome, was present in 69 percent of patients with evidence of
cardiovascular involvement.
Myocarditis leading to congestive heart failure is an uncommon
but severe manifestation of PM/DM. Contrast enhancement and
hypokinesia detected by cardiac MRI is reduced after treatment
with corticosteroids and immunosuppressive therapy.77
The role of gadolinium-diethylenetriaminepentaacetic acid
(DTPA)–enhanced MRI appears promising in diagnosing myocarditis in polymyositis (see Chap. 21).
Although coronary arteritis has been reported in few case reports, there are no controlled studies showing evidence of increased incidence of CAD in PM/DM. Glucocorticoids represent
the mainstay of therapy. The usual practice is to begin treatment
with 40 to 80 mg/d of oral prednisone or its equivalent. Methylprednisolone boluses of 500 to 1000 mg/d for 3 days is reserved
for severe and acute cases. Azathioprine (Imuran) and methotrexate are used mostly as steroid-sparing agents. Intravenous immunoglobulin given in monthly boluses is an expensive therapy that
is reserved for patients with severe disease (neuromuscular respiratory involvement, dysphagia) and poor response to conventional
immunosuppressive therapy. Response can be seen as early as 2
weeks, but typically best effects are seen only after 3 months.
POLYARTERITIS NODOSA
Polyarteritis nodosa is an uncommon disease with an annual incidence that ranges from 4.6 to 9.0 per 100,000. Polyarteritis nodosa affects predominantly males with a male-to-female sex ratio
of 2:1.77
Polyarteritis nodosa is characterized by segmental necrotizing
inﬂammation of the medium- to small-size arteries, resulting in
dysfunction of multiple organ systems. The commonly involved
organs are the skin, kidneys, and gastrointestinal tract. Polyarteritis nodosa rarely involves the central nervous system, eyes, testes,
and heart. Lungs are usually spared. A variety of cutaneous lesions
may occur: livedo reticularis, palpable purpura, ulcerations, infarcts of distal digits, and nodules. Evidence of glomerulonephritis
ranges from low-grade proteinuria to malignant hypertension and
acute renal failure.
There is a recognized association between polyarteritis nodosa
and hepatitis B infection. Hepatitis B surface antigen has been
found in 15 percent of the patients. Laboratory tests are nonspeciﬁc and reﬂect mainly an inﬂammatory state. Common ﬁndings
are elevated erythrocyte sedimentation rate, normochromic ane-
mia, thrombocytosis, and low albumin. Typically, rheumatoid factor and ANA are not present and complement levels are decreased
only in 5 percent of the cases. A subset of patients with microscopic polyarteritis nodosa have antineutrophil cytoplasmic antibodies directed against myeloperoxidase. The ﬁnal clinical diagnosis of polyarteritis nodosa rests on the combination of multisystem
disease and biopsy evidence of active arteritis of medium-size vessels. In polyarteritis nodosa, mesenteric vessel angiograms may
show aneurysmal dilatation that mimics mycotic aneurysm in infective endocarditis.
Cardiac Involvement
The heart and coronary arteries are infrequent targets of polyarteritis nodosa. Most often this involvement is a vasculitis of the distal
subepicardial coronary arteries just as they penetrate the myocardium (Fig. 88–11). The lesions are characterized by inﬂammatory
inﬁltrates in the media and adventitia and occasionally by necrosis
of the full thickness of the vessel wall, with prominent involvement
of the surrounding perivascular connective tissue (Fig. 88–11). The
lumens of the involved vessels may contain thrombi, and the walls
may be aneurysmal. The latter is responsible for the nodular appearance of the arteries deemed characteristic of this disorder. An
even later stage of the vasculitis process is evident as the lesions
heal, ﬁrst showing the formation of granulation tissue and subsequently ﬁbrous tissue replacement of the original components of
the artery. In this healing phase, intimal proliferation leading to
coronary artery luminal narrowing is evident.
The CAD of polyarteritis nodosa may lead to myocardial infarction. The myocardial necrosis and subsequent replacement ﬁbrosis tend to be focal and patchy throughout the left ventricular
wall. This is in contrast to the large areas of grossly visible, regional, subendocardial, or transmural necrosis typically seen in the
myocardial infarction caused by CAD (see Chap. 57).
Conduction system abnormalities have been identiﬁed in the
heart of patients with polyarteritis nodosa. The size and location
of the sinoatrial node and atrioventricular node arteries make
them prime targets for polyarteritis. Atrial and ventricular conduction disturbances may be a primary manifestation of polyarteritis
nodosa, despite minimal involvement of vessels elsewhere in the
heart.
Other cardiac abnormalities seen in patients with polyarteritis
nodosa are those that are likely secondary to the underlying systemic arterial hypertension and renal disease. Cardiomegaly and
left ventricular hypertrophy most often represent secondary cardiac manifestations of this disease. Similarly, pericardial disease
may develop in a patient with polyarteritis nodosa, but this is most
often a consequence of renal insufﬁciency.
Clinical Manifestations of Cardiac Disease
Despite the dramatic involvement of coronary arteries that may
accompany polyarteritis nodosa, the most frequent cardiovascular
abnormalities seen in patients with polyarteritis nodosa are unrelated to the coronary arteries per se. Systemic arterial hypertension
occurs in approximately 90 percent of these patients and, in combination with chronic renal failure, is the most likely cause of congestive heart failure, which may develop in up to 60 percent of patients. Those with polyarteritis nodosa also may develop acute
CHAPTER 88 • The Connective Tissue Diseases and the Cardiovascular System
2049
The use of warfarin remains controversial; lowdose aspirin, however, is usually recommended.
GIANT CELL (CRANIAL,
TEMPORAL,
GRANULOMATOUS)
ARTERITIS
Temporal arteritis is a systemic inﬂammatory
vasculitis of unknown etiology that primarily
involves extracranial vessels, especially branches
of the external carotid artery, but can involve almost any artery in the body including the aorta.
Giant cell arteritis occurs almost exclusively in
patients older than 55 years of age. Common
symptoms include headaches, scalp tenderness,
jaw claudication, visual disturbances including
blindness and diplopia, weight loss, anemia,
A
and, in approximately 50 percent of patients,
musculoskeletal symptoms attributable to polymyalgia rheumatica. Uncommon presentations
of giant cell arteritis include fever of unknown
origin, chest pain from aortitis or myocardial infarction, aortic aneurysm, peripheral gangrene,
peripheral neuropathies, and large-vessel involvement with limb claudication, aortic regurgitation, or stroke. Typical physical ﬁndings include tenderness of the temporal or occipital
arteries, nodulations of the artery, a pulseless artery, and a tender scalp.
Most giant cell arteritis patients have a greatly
elevated erythrocyte sedimentation rate. The
only speciﬁc diagnostic test is a temporal artery
biopsy that demonstrates granulomatous arterial
inﬂammation with disruption of the internal
elastica lamina. Giant cells need not be present.
B
Unfortunately, the positive yield for giant cell
arteritis in unilateral temporal artery biopsies is
FIGURE 88–11. Polyarteritis nodosa. Examples of the necrotizing vasculitis affecting the extramural and intramural coronary arteries in polyarteritis. A. Extramural coronary arteries.
no greater than 60 percent, and a contralateral
B. Intramural coronary arteries. The intramural artery shows a necrotizing arteritis with inﬂambiopsy may be necessary.
mation involving the full thickness of the vessel. Hematoxylin and eosin (H&E) stain: top, × 7;
Because the occurrence of skip lesions in hisbottom, × 22.
tologic samples is well known in giant cell arteritis, ideally a 5-cm section of artery should be
myocardial infarction, which poses the diagnostic question of
examined. Angiography is generally not helpful in diagnosis or in
whether the myocardial injury is caused by coronary arteritis with
selecting a biopsy site. A negative or inconclusive biopsy report
secondary thrombosis or to atherosclerosis.
should not prompt the clinician to stop the steroids if the clinical
picture is consistent with giant cell arteritis. High-dose prednisone
(1 mg/kg) should be started promptly. Not starting steroids until
Therapy
the temporal artery biopsy report is available, may result in serious
Polyarteritis nodosa has a poor prognosis. Treatment of the heart
complications including visual loss.
disease in polyarteritis nodosa is directed at the speciﬁc cardiac
dysfunction. Glucocorticoids are still the initial mainstay of therCHURG-STRAUSS SYNDROME
apy. Early use of cyclophosphamide in severe disease with inChurg-Strauss syndrome, or allergic granulomatosis and angiitis,
volvement of major organs has been associated with decreased
is a systemic vasculitis that develops in the setting of allergic rhinimortality.
tis, asthma, and eosinophilia. Sinusitis and pulmonary inﬁltrates
Case reports of improvement of hepatitis B virus-related polyarmay cause confusion with Wegener granulomatosis; the absence of
teritis nodosa with concomitant immunosuppressive and antiviral
cavitating pulmonary nodules or the presence of gastrointestinal
therapy are encouraging.78
2050 PART 15 • Miscellaneous Conditions and Cardiovascular Disease
involvement is often a helpful distinguishing feature. Peripheral
neuropathy, cutaneous involvement, and renal disease are common clinical ﬁndings.
Pathologic studies show inﬂammatory lesions rich in eosinophils with intra- and extravascular granuloma formation. The major morbidity and mortality of Churg-Strauss syndrome result
from cardiac involvement which is the cause of death in 48 percent of the cases. Eosinophilic endomyocarditis, coronary vasculitis, valvular lesions and pericarditis are the typical cardiovascular
manifestations of Churg-Strauss syndrome.79,80
This may be associated with left ventricle dilatation and a reduced ejection fraction, as well as mitral regurgitation, which may
require valve replacement. Left ventricular systolic function may
improve signiﬁcantly with glucocorticoid therapy.81,82 Intravenous
immunoglobulin infusion is reserved for severe disease unresponsive to steroids.
ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
The aPL syndrome is deﬁned by the presence of aPLs in moderate
titers on two or more occasions 12 weeks apart and less than 5
years prior to a venous or arterial thrombotic event or unexplained
recurrent fetal losses after the 10th week of pregnancy.83–88
Livedo reticularis, nonhealing leg ulcers, thrombocytopenia and
Coombs-positive hemolytic anemia may be also present. Clinically, the terms anticardiolipin syndrome, antiphospholipid syndrome, and lupus anticoagulant syndrome are usually considered
equivalent, although some individuals may have one antibody but
not the other. A false-positive Venereal Disease Research Laboratory test may also be detected in patients with aPL syndrome;
aPLs, however, may be present in asymptomatic individuals. Often, anticardiolipin antibodies cross-react with β2-glycoprotein 1
(B2GP1) antibodies. The mechanisms whereby anticardiolipin or
aPLs promote intravascular thrombosis remain uncertain, but recent data suggest an important roll of complement activation.89
The presence of a prolonged activated partial thromboplastin
time should prompt the clinician to rule out the presence of aPL.
These antibodies may react with lipid antigens on endothelial
cells and/or platelets. The precise nature of the antigen recognized by B2GP1-dependent anticardiolipin antibodies is under
active investigation. SLE is present frequently in patients with
aPL syndrome.
An increased incidence of aortic or mitral regurgitation in association with the primary aPL syndrome also has been reported in
patients with SLE who have aPLs.90,91
The term catastrophic antiphospholipid antibody syndrome is
now used to classify a subset of patients with thrombosis of the
small vasculature (microangiopathy) and involvement of at
least three major organs. The mortality in this case approaches
50 percent.92,93
Therapy depends on the clinical setting. Patients with positive
aPLs but without evidence of thrombosis or recurrent fetal loss
should be given low-dose aspirin only. Patients with aPL syndrome
who have had thrombotic events or habitual abortions should be
anticoagulated for life. Anticoagulation and antithrombotic therapy in these patients has included unfractionated heparin, lowmolecular-weight heparin, warfarin.
The intensity of the anticoagulation is still controversial. A recent study showed no signiﬁcant difference in the recurrence of
thrombotic events in a group of patients treated with high-level
anticoagulation (international normalized ratio [INR] 3.1 to 4.0)
versus low-level anticoagulation (INR 2.0 to 3.0). The high-level
anticoagulation group had a signiﬁcantly higher incidence of hemorrhagic events. Because this study did not include patients with
history of recurrent thrombosis and was not powered to assess differences in patients with arterial thrombosis, the treatment in
those cases remains controversial.94
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