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Cardiac Involvement in Systemic Sclerosis

Article in Romanian journal of internal medicine = Revue roumaine de médecine interne · December 2012

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 Cardiac Involvement in Systemic Sclerosis

RALUCA BALAJ1, LAURA POANTA1, SIMONA REDNIC2

1
Internal Medicine Dept., “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
2
Rheumatology Dept., “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

Primary myocardial involvement is common in systemic sclerosis and affects the prognosis of
the disease when it is clinically evident. The exact mechanism leading to the myocardial fibrosis in
systemic sclerosis remains unknown. Its detection depends, at least in part, on the sensitivity of the
diagnostic methods used.
The aim of this review is to analyze the types and mechanism of abnormalities in the heart in
scleroderma and also summarize the diagnostic methods recommended for the most prevalent ones.
The available literature describes the most frequent cardiovascular abnormalities in systemic sclerosis
patients to be: myocardial dysfunction, pericarditis, rhythm and, most frequent, conduction
abnormalities, pulmonary arterial hypertension.
Key points regarding screening, diagnosis, and treatment remain to be determined more
accurately. Novel diagnostic techniques and multicenter studies should improve our understanding of
organ involvement in scleroderma, which will hopefully ultimately result in improved outcomes.
Key words: systemic sclerosis, cardiac involvement.

Systemic sclerosis (SSc) is a generalized
disorder of the connective tissue characterized clinically
by thickening and fibrosis of the skin (scleroderma)
and by distinctive forms of involvement of internal
organs, notably the heart, lungs, kidneys, and
gastrointestinal tract. There are two main forms of
SSc: 1) the limited cutaneous form (lSSc), charac-
terized by restricted skin disease, mild visceral
involvement, and a high prevalence of anticentromere
antibodies (ACA); and 2) the diffuse cutaneous
form (dSSc), characterized by widespread skin
disease, severe visceral involvement, high prevalence
of anti-topoisomerase I antibodies (Scl-70), and
rapid evolution.
The heart is a major organ affected by sclero-
derma and the presence of cardiac involvement
generally associates a poor prognosis. A growing
body of evidence suggests that vascular system
impairment may be the primary cause that could
lead to cardiac disease [1–3] and that myocardial
lesions are manifestations of focal ischemic injury
resulting from abnormal vasoreactivity, with or
without structural vascular disease.
Pathologic series have noted patchy myocardial
fibrosis in as many as 81% of patients with
systemic sclerosis [1]. As in large retrospective
clinical analyses [4], many studies have suggested
that myocardial involvement is a significant and
maybe the principal determinant of survival in
systemic sclerosis. Clinically, however, myocardial
involvement is less confidently detected, and early
presentations or even main symptoms are frequently
attributed to concomitant lung, pericardial, or renal
disease.
Cardiac involvement can generally be divided
into direct myocardial effects and the indirect effect
of other organ involvement (i.e. pulmonary hyper-
tension, renal crisis). Direct myocardial disease
includes myositis, cardiac failure, cardiac fibrosis,
coronary artery disease, conduction system abnor-
malities, and pericardial disease.
Prevalence and prognosis
The presence of cardiac involvement in SSc
is often underestimated due to the occult nature of
the signs and symptoms and reports of the
prevalence of cardiac disease vary depending on
the methods used. Recent studies suggest that
clinical evidence of myocardial disease may be
seen in 20% to 25% of patients with SSc [5–7].
Autopsy studies have observed myocardial fibrosis
and pericardial disease to be most prevalent, but as
any other autopsy study this likely represents patients
with more advanced disease [8]. Other modalities
of study in living patients have been used as well.
With thallium scintigraphy the estimated prevalence
of clinical cardiac involvement in SSc is much
higher [9]. Other modalities, like single photon
emission computed tomography (SPECT) thallium

ROM. J. INTERN. MED., 2012, 50, 4, 269–274

270 Raluca Balaj et al.
imaging, have noted changes in nearly all SSc
patients tested, but the clinical implications of these
defects remain uncertain. In addition to thallium
and MRI studies, echocardiography has been used
to screen SSc patients for asymptomatic cardiac
abnormalities. In a study of 54 patients, 69% were
found to have an abnormality by echocardiogram
[10]; the most common of which were elevated
right ventricular systolic pressure (RVSP), pericardial
effusion, increased RV dimension, and left atrial
enlargement. In addition to structural defects, twenty-
four–hour ECG ambulatory monitoring has been
used to detect arrhythmias and conduction system
abnormalities in SSc patients with or without
symptoms [11][12].
Several lines of evidence suggest that both
cutaneous subtypes could associate cardiac invol-
vement [13]. However, an Italian epidemiological
study suggested that heart involvement might be
more prevalent in the diffuse subtype (32%) than in
the limited form (23%) [14]. Such an association
has been confirmed recently in a study that focused
on depressed LVEF and reported on more than
7000 patients [15].
The presence of clinical cardiac involvement
in SSc is a harbinger of a poor prognosis. Medsger
and Masi [16] showed that clinical cardiac disease
in SSc was associated with a 70% mortality at
5 years. Certainly the presence of pulmonary
arterial hypertension is a poor prognostic sign and
is associated with a higher mortality rate in patients
with SSc than idiopathic PAH as shown in the
Johns Hopkins Cohort from 2001–2005 [17][18].
In general, higher risk findings in patients with SSc
include the presence of clinical heart failure, poor
RV function, pulmonary arterial hypertension, low
cardiac index, high right atrial pressure, and
documented ventricular arrhythmia.
Cardiac manifestations
Myocardial fibrosis is the hallmark of cardiac
involvement in SSc, resulting in ventricular inter-
stitial remodeling and myocardial dysfunction.
Depressed myocardial contractility is supposed to
be specific. However, its existence and prevalence
is still a matter of debate, as most studies have
reported a low prevalence of reduced LVEF [19–
21]. One French multicentre study, which included
570 patients, reported a 1.4% prevalence of left
ventricular systolic dysfunction [19]. Other authors
have reported a low prevalence of depressed LVEF
at rest, although up to 46% of patients had left
ventricular dysfunction when LVEF was also
2
measured during exercise. More recently, the
EUSTAR registry provided robust estimates of the
prevalence of left ventricular dysfunction [22].
The presence of diastolic dysfunction in
patients with SSc has been demonstrated extensively
[19–21]. However, the distinction between patho-
logical findings and age-related changes or other
confounding factors may be hard to ascertain. In
the largest study, the authors reported the presence
of diastolic abnormalities in 101 of 570 patients
(17.7%) [19]. C. Meune et al. found in their study
that 30 of 100 (30%) patients had definite abnormal
left ventricular filling [23]. In other study, Edoardo
Rosato et al. detected abnormal E/A ratio at DE in
24 of 67 patients (35.8%), while abnormal E/A at
TDE was observed in 41 of 67 (61%) [24]. Using
gated myocardial perfusion single photon emission
computed tomography scans, Nakajima et al. [25]
found that diastolic dysfunction was present in
more than half of patients with scleroderma, even
in the absence of myocardial ischemia, and it
correlated with the severity of cutaneous disease.
Overall, the prevalence of diastolic dysfunction
was increased compared with age- and sex-
matched controls [23] and ranged from 17 to 60%.
Several echocardiographic studies in SSc-
PAH showed RV diastolic dysfunction is common
even in the presence of normal systolic pulmonary
artery pressure, as estimated from maximum velocity
of tricuspid regurgitation [30]. To answer the
question as to whether this abnormal RV filling
pattern could be related to the effects of the disease
per se, or to associated pulmonary vasculopathy,
Huez et al. [30] performed tissue Doppler exami-
nations at rest and during exercise in SSc patients
with normal systolic pulmonary artery pressure and
age-matched healthy controls. The results showed a
consistent pattern of altered RV diastolic function
that was correlated to the acceleration time of
pulmonary arterial flow and to the slope of multi-
point pulmonary artery pressure-flow plots, suggesting
latent pulmonary hypertension as a major cause.
Primary pulmonary arterial hypertension is
assumed to be rare, but it is one of the most severe
complications of SSc. In one of the largest series,
the French ITINERAIR cohort, its prevalence was
7.85% [26]. Other series reported similar results,
and its prevalence ranges from 8 to 12% overall,
according to various series [27].
Resting electrocardiographic abnormalities
including atrial and ventricular arrhythmias and
conduction disturbances are encountered in nearly
50 percent of patients [28]. Ambulatory electro-
cardiographic features include a high prevalence of
3 Cardiac Involvement in Systemic Sclerosis
both supraventricular and ventricular tachy-
arrhythmias, with the latter associated strongly
with both overall mortality and the syndrome of
sudden death [29].
Pericarditis is well recognized as a complication
of systemic sclerosis [1][6]. It is particularly seen
in the context of severe diffuse cutaneous systemic
sclerosis and is probably most frequently encountered
in patients with established or imminent sclero-
derma renal crisis. Echocardiographic studies often
reveal small haemodynamically insignificant
effusions in scleroderma patients [20]. Therapeutic
pericardiocentesis is only occasionally required.
Prior studies using echocardiography as well
as studies on autopsy samples have suggested a
relatively minor valvular involvement in SSc [6].
Nodular thickening of the mitral valve was shown
in 38% of their autopsy subjects with SSc [1].
Shortening of the chordae tendinae of the mitral
valve has been noted as well as mitral and tricuspid
valve vegetations some autopsy samples [1][31].
Nodular thickening of the mitral and aortic valves
with regurgitation and mitral valve prolapse have
also been noted [32][33].
SSc patients often show angiographically
normal epicardial coronary arteries and normal LV
function, despite decreased coronary flow and
resistance reserve. This is believed to result from
fixed, structural abnormalities of the small coronary
arteries and arterioles. Sulli et al. demonstrated that
the coronary flow reserve (CFR) is often reduced in
SSc patients, and that CFR was lower in patients
with dSSc than in those affected by lSSc [34].
Assessment of heart involvement
MRI is an accurate and reliable technique to
diagnose heart involvement in SSc and to analyse
precisely its mechanisms, including inflammatory,
microvascular and fibrotic components. As it is
non-invasive, quantitative and highly sensitive,
MRI appears as a method of choice to determine
the natural history of untreated patients or
accurately to monitor the effects of treatment.
Moreover, it could provide powerful prognosis
factors in both groups. Compared to echocardio-
graphy, MRI appears to provide additional
information by visualising myocardial fibrosis and
inflammation. Also, MRI enables the precise
analysis of different patterns of heart involvement
in SSc by differentiating morphological, functional,
perfusion and delayed contrast enhancement
abnormalities. Patients with limited cutaneous SSc
had roughly the same MRI abnormalities as those
271
with diffuse cutaneous SSc, and RV dilatation was
not specific for PAH [35]. The high frequency of
heart abnormalities observed on cardiac MRI is
consistent with necropsy studies which showed that
approximately 80% of patients with SSc had
histological lesions of heart involvement.
Taken together, these results suggest that
such alterations are clinically underestimated and
that MRI is highly sensitive. Yet the clinical signi-
ficance of MRI abnormalities remains to be
established.
When cardiomyopathy is suspected, con-
ventional echocardiography is often the first
method used in order to evaluate LV and RV
function. The routinely used values, such as end-
diastolic diameter, fractional shortening, and LVEF,
are load-dependent and do not reflect the
contractile state of the myocardium.
Tissue Doppler echocardiography is a new,
less load-dependent method that enables the direct,
reliable measurement of regional myocardial
systolic and diastolic abnormalities. Tissue Doppler
derived peak systolic velocities and strain as well
as two dimensional strain and TAPSE are useful
tools to determine early right ventricular systolic
dysfunction in patients with SSc without Doppler
signs of pulmonary arterial hypertension.
Two-dimensional strain is a new Doppler
independent approach for calculation of strain,
strain rate, tissue velocity, and displacement. It is
based on speckle tracking analysis in B-Mode and
therefore angle independent. Right ventricular
isovolumetric acceleration (IVA), derived by
pulsed TDE at lateral tricuspid annulus, has the
highest predictive power with the best area under
the curve for detection of early systolic dys-
function. This parameter has a low inter- and
intraobserver variability and may be used as an
accurate, non-invasive parameter for assessment of
RV systolic function in patients with SSc
especially to detect early systolic disturbances. An
IVA < 3.0 m/s2 predicted SSc patients with 100%
sensitivity and 91% specificity [36].
Screening for biological markers of possible
cardiac dysfunction can be beneficial. One in-
creasingly common example of these surrogate
measures is B-type natriuretic peptide (BNP),
which is secreted from cardiomyocytes in response
to atrial or ventricular wall stretch. Plasma con-
centrations of BNP correlate with the risk of death
and cardiovascular events and N-terminal portion
of pro-BNP (NT-pro-BNP) can be measured in
clinical practice. Annual evaluation of NT-pro-
BNP can be a useful addition to standard screening
272 Raluca Balaj et al.
practice for patients with SSc, as myocardial
involvement may be primary, due to pulmonary or
systemic hypertension or resulting from conventional
cardiac diseases that are typically more common
among a middle-aged patient population.
Recently a new non-invasive Doppler method
has been validated based on advanced ultrasound
technology (second harmonic) and special contrast
agent [37] – determination of coronary flow
reserve. A suboptimal ultrasound window, a major
concern in any ultrasound approach, does not
reduce the feasibility of this evaluation if the
appropriate combination of ultrasound technology
(second harmonic technology) and echo-contrast
agent is used. In their study, Sulli et al. [34] found
that a reduced coronary flow reserve value should
be considered an indirect sign of heart involvement
in scleroderma.
The investigation of myocardial perfusion
and microcirculation may also be considered for
some SSc patients. Single photon emission computed
tomography was proposed a few years ago for the
assessment of myocardial perfusion abnormalities
and possibly for distinguishing reversible ischaemia
from irreversible lesions. However, this procedure
is limited in quantitative studies and has been
replaced progressively by cardiac magnetic resonance
imaging, as it allows the identification of small
subendocardial perfusion defects, myocarditis
(especially in patients with myositis) and the
morphological evaluation of fibrotic myocardium
compared with viable tissue.
Using tissue Doppler echocardiography and
surface ECG, Ilknur Can et al. [38] showed delayed
electromechanical coupling in both left and right
atria in patients with scleroderma. There was also a
delay in interatrial contraction.
These parameters (P wave duration, P wave
dispersion (Pd) and electromechanical coupling
measured by tissue Doppler echocardiography),
easily obtained at the clinical setting, can be used
for the evaluation of the patients with scleroderma.
All in all, Doppler-echocardiography together
with clinical evaluation should be considered for
routine cardiac assessment. Given the broad avail-
ability and sensitivity of pulsed TDE, it is
Afectarea cardiacă primară este frecventă în sclerodermie, influenţând şi
prognosticul bolii când este evidentă clinic. Mecanismul exact prin care apare
fibroza miocardică în sclerodermie nu este complet cunoscut. Evidenţierea
suferinţei cardiace depinde, cel puţin în parte, de sensibilitatea metodelor de
diagnostic utilizate.
4
recommended to be be included in all cardiac
evaluations in routine practice.
Conclusion
Cardiac manifestations of SSc can affect all
structures of the heart, and may result in pericardial
effusion, arrhythmias, conduction system defects,
valvular impairment (in rare cases), myocardial
ischaemia, myocardial hypertrophy and heart failure
[13]. These primary myocardial manifestations –
those without systemic or pulmonary hypertension
and without significant pulmonary or renal disease-
likely result from the underlying vascular
pathology of SSc, i.e. the characteristic vascular
lesions and fibrosis that impair microcirculation
and myocardial function, respectively. The early
myocardial manifestations of SSc are often non-
specific, making evaluation of susceptible patients
problematic. Patients with cardiac alterations may
therefore remain undiagnosed, potentially enabling
the disease to progress silently. Early diagnosis is
therefore very important. In the majority of SSc
patients, however, cardiac manifestations may
remain subclinical. Individuals who develop clinically
apparent myocardial manifestations are recognized
to be at greater risk of clinical deterioration, and
monitoring of myocardial involvement represents
an important aspect of their disease management.
The overall mortality in SSc resulting from cardiac
complications is relatively low in comparison with
manifestations such as interstitial lung disease and
pulmonary arterial hypertension.
The poor prognosis associated with clinically
apparent cardiac manifestations does, however,
necessitate consideration of future research. The
most pressing issues are the current paucity of
detailed information in respect of the natural
history of cardiac involvement and the lack of
high-quality observational data, which are required
to plan appropriate trials.
Large-scale prospective observational registries
linking the known abnormalities on echocardio-
graphy, serum markers and functional testing to the
subsequent development of overt cardiac disease
are urgently required.
5 Cardiac Involvement in Systemic Sclerosis 273

Scopul acestui referat este de a trece în revistă tipurile şi mecanismele

afectării cardiace în sclerodermie, şi de a sumariza metodele de diagnostic
recomandate pentru cele mai des întâlnite dintre ele. Literatura de specialitate
disponibilă arată că cele mai frecvente tipuri de afectare cardiacă în sclerodermie
sunt: disfuncţia miocardică, pericardita, tulburările de ritm şi mai ales de
conducere, hipertensiunea arterială pulmonară.
Punctele cheie legate de screeningul, diagnosticul şi tratamentul bolii
cardiace din sclerodermie sunt încă studiate. Noile metode de diagnostic analizate
şi studiile multicentrice în curs ar putea să ducă la o mai bună înţelegere a
afectării pluriorganice din sclerodermie, ameliorând, astfel, şi prognosticul bolii.

Corresponding author: Laura Poanta, “Iuliu Hatieganu” UMF, Cluj-Napoca

E-mail: laurapoanta@yahoo.com, mobile: 0040745146850

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Received October 5, 2012

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