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CARDIAC CONSEQUENCES OF
THE SYSTEMIC LUPUS ERYTHEMATOSUS
THERAPY WITH CORTICOSTEROIDS
- MORPHOLOGICAL STUDY
...
Catalina Arsenescu*, Doina Butcovan**,
M Rotar*, GIM Georgescu*
* Dept. of Medical Cardiology, Cardiology
Center Iasi
** Dept. of Morfopathology,
UMF “Gr. T. Popa” Iasi
...
CARDIAC CONSEQUENCES OF THE SYSTEMIC LUPUS ERYTHEMATOSUS THERAPY WITH
CORTICOSTEROIDS – MORPHOLOGICAL STUDY (Abstract): It is presented the case
of a fifty years old women, diagnosed 3 years ago with systemic lupus erythematosus,
following prednison and cyclophosphamid therapy. She was admitted in our
hospital for right decompensated heart disease and the presence of an apical
right ventricular mass occluding part of the right ventricular cavity.
The endomyocardial biopsy was made for clearyfing the nature of this mass.
After processing the specimen, the histological study evidentiated
an organizing apical thrombotic mass formed in a large right ventricular
cavity in conditions of pulmonary hypertention. There are mentioned literature
data on the systemic lupus erythematosus lesions. There are shown data
concerning the adverse effects of the systemic lupus erythematosus drug
therapy, as well. In these circumstances, we demonstrated histologicaly,
that the both conditions could alter the heart morphology. Key words: SYSTEMIC
LUPUS ERYTHEMATOSUS, ENDOCARDIAL FIBROSIS;
INTRODUCTION
Systemic lupus erythematosus
(SLE) is a chronic inflammatory disease of connective tissue, affecting
the skin and various internal organs (systemic disease) (1-5). Often
the kidney and heart are affected by progressive attacks of inflammation
followed by the formation of scar tissue (fibrosis) (6-10). Could be associated
with cardiac blocks due to damage to the conducting system (11-13). SLE
is an autoimmune disease where autoantibodies are frequently targeted against
intracellular
antigens of the cell nucleus (double and single stranded DNA-dsDNA). Regarded
as an autoimune disease it can be diagnosed by the presence of abnormal
antibodies in the blood stream (14-16). The disease is treated with corticosteroids
or immunosuppresive drugs. Monitoring of lupus patients gives an indicator
of current activity of disease, and the frecquency of monitoring is dependent
not only by disease activity but also by the type of drugs being used,
as well, due to cytoxicity (16).
MATERIAL AND METHODS
The endocardial specimen obtained
through endomyocardial biopsy was histologicaly evaluated at CCI in 2002;
it was assessed by gross and histologic means, as recommended by Virmani
(2). The three obtained pieces were placed in 10% buffered formaldehide
fixative, and processed for light microscopic study. Histologic sections
were stained with hematoxilin-eosin and elastic Van Gieson. For morphological
specimen evaluation, the patient's history and file was reviewed and the
following informations was recorded: age, gender, pertinent clinical diagnosis,
the cardiac functional state (assessed by electrocardiography and echocardiography),
and the results of histological examination was performed on endocardial
tissue.
RESULTS AND DISCUSSIONS
A female patient of 49 years
old, diagnosed 3 years ago with pericardial effusion and SLE, for which
was treated with PDN and CP until december 2001, presented, at admission
in our center from ferbruary 2002, cardiac failure signs predominantly
from the right side of the heart. The echocardiografic investigation evidentiated
a normal size and function of the left ventricle, a mitral incompetence,
a dilated right atrium and a right ventricle having a particular apical
appearance, where is occupied by a mass with irregular homogenity; there
was also a slight amount of pericardial fluid placed esspecially adjacent
to the right ventricle without constriction signs. The clinical picture
revealed various symptoms permitting the SLE diagnosis on the basis
of identifying of 4 out of 11 clinical SLE diagnostic criteria: serozitis
(pericarditis), neurological disease, endocarditis, and Raynaud phenomenon,
and was sustained by a rising titre of ANA ds DNA (and no evidence of complement
comsumption corresponding with the disease activity) (16). After medication
the clinical heart failure signs were removed, rising the question receiving/about
the restriction of the right ventricular cavity; which is the cause? Immediately
after a complete investigation of the patient for searching the cause of
the cardiomyopathy it was decided a morfological evaluation through endocardiobiopsy,
obtaining 3 small pieces of 3 mm length, which were necessary for histological
procedure; microscopicaly, we are studied the specimen architecture, cellular
components, and the presence of thrombi.
Microscopicaly, we observed the folloing
findings: (1) The three cardiac pieces had involved only the endocardium,
due to the absence from specimens of the myocardial cells; (2) The thickened
endocardium presented an evident stratification consisting of irregular
layers resulted from an ongoing fibrous organization of delicate fibrin
deposits or thrombi. It is evident that an unknown stimulus creates conditions
for continuing fibrin deposition (fig. 1)
which are organized, resulting firstly, an immature fibrous tissue formation
with an appearance of myxomatous tissue, composed by fibroblasts and a
rich extracellular matrix (fig. 2) ,
and than with producing in a secondary step of a mature fibrous tissue
consisting from few cells and many collagen fibers (fig. 3)
as a result of a process of maturation of the previous young tissue.
The question is: which is the stimulus
inducing the thrombi formation in a large cardiac cavities from the right
side of the heart? For answering is necessary a preview in the patient
history. It is any relation with SLE diagnosed few years ago and with the
correspondent therapy indicated for cure? It could be possible.
SLE is the most common connective tissue disorder and
may affect any organ in the body (1, 2, 3, 4). Systemic lupus erythematosus
(SLE), an autoimune disease, affects women more frequently than men, as
in our case, the cardiovascular involvemnt being an important cause of
death (5, 6), where the heart may also be affected secondary by systemic
or pulmonary hypertension (9). Morphoclinical evaluation of the patient
revealed a significant cardiac involvement reffering to the pericardium,
myocardium and endocardium in various ways.
Virmani (6, 10) noted the SLE
as a cause of acute pericardial effusions in 20-42% of cases, and represents
only 4% of causes of chronic pericarditis with pericardial effusions with
or without drug relation, as well. Silver (11, 12) considers that, in SLE,
the pericardium is the most commonly involved tissue and appreciated that
pericarditis or pericardial effusion develops in more than 30% of affected
individuals; he also noted that if cardiac tamponade occurs occasionally,
the constriction is rare. Cervera (12) also observed pericardial effusons
at 27% of patients with SLE, founding acute, subacute and chronic inflammation
of the serosal membranes, as well. He noted that in the acute phase, the
mezsothelium is covered by fibrinous exudate that gradually becomes thicker
and opaque, leading in time to partial or complete obliteration of the
pericardial cavity, but constrictive pericarditis was appreciated as a
rare complication in SLE.
Using indium -111-antimyosin
Fab imaging, Morguet (12) demonstrated myocardial involvement in patients
with SLE, and Fye (11) showed that clinical features of myocarditis may
correlate with myositis. We didn’t identify myocardial mononuclear inflammation
in our case because of no myocyte presence on cardiac biopsy.
Silver (12) appreciated that the mortality rate from
ischemic heart disease in SLE patients is estimated to be nine times higher
than expected. As well as Silver, we also evidentiated the presence of
cardiac ischemic risk factors such as hypertension and hyperlipidemia at
our patient, her coronary artery disease correlating with the duration
of SLE and steroid use, and Spence (12) considered that corticosteroids
accelerate atherosclerosis in SLE patients. This affirmation was sustained
by Roberts (11) who revealed in a group of 21 women with SLE, and ages
between 16 and 36 years, over 75% cross-sectional area narowing by
atherosclerosis of one or more coronary arteries in 10 of them. In proper
cases, Wilson (12) noted that the most myocardial infarcts occuring in
young SLE patients are caused by coronary atherosclerotic disease, and
only few cases are the result of coronary vasculitis, and some are related
by SLE drugs. As well as the others pathologists (9,13), Olsen (5) considers
that the association between SLE, atherosclerosis (ATS) and myocardial
infarction is very well documented, and SLE in the absence of ATS may also
affect the myocardium through lupus arteritis lesions.
Roberts (12) evidentiated that
cardiac conduction tissue may show scarring or inflamation, as well, luminal
narrowing of the SA and AV node arteries being a common feature in these
cases. From Davies observation results (7), since there is a considerable
amount of collagen connective tissue in the conduction system, it is not
surprising to find that SLE affects the conduction system to varying degrees
and may be associated with AV block or other arrhythmias. Davies (7) demonstrated
histolgicaly the complete replacement of the AV node by granulation tissue
in lupus.
Libman and Sachs reported (12)
endocardial lesions at autopsy in four patients with SLE. They consisted
of thrombotic vegetations involving any of the four cardiac valves plus
the atrial and ventricular endocardium. They observed that vegetations
were also present on the ventricular mitral valve surface, extending from
there to the left ventricular endocardium, toward papillary muscles. Some
valves were also thickened with fibrous tissue. Roberts (12) suggested,
that with modern therapy for SLE, the valve lesions, of nonbacterial thrombotic
endocarditis type, seen at autopsy, could show more evidence of healing,
with fibrosis and valvular distortion resulting in regurgitation. As well
Roberts, we consider that the thickening of the mitral valve could be a
consequence of organization of the endocardial lesions.
We also appreciate that the
right cardiac failure, secondary to pulmonary hypertension, registered
in our case, could create right cardiac stasis and conditions for apical
ventricular thrombus formation. Through the organization of the thrombus
could result the apical right ventricular endocardial mass consisting from
fibrotic tissue in diferrent stages of organization as demonstrated on
endocardial biopsy.
The pleuropulmonary manifestations
(e.g., pleuritis with or without pleural effusion) occur in 50% of cases,
affirmed Edward (13). More serious lesions in the lung include acute or
chronic lupus pneumonitis and pulmonary hypertension. Edwards considers
that the pulmonary hypertension, that occurs in about 14% of patients with
SLE, is caused by lupic vasculitis. Apart from pleuritis and interstitial
fibrosis following interstitial pneumonitis, Olsen (5) revealed on necroptic
specimens, that the pulmonary vessels presented a necrotising arteritis
and thrombotic oclusion similar to those found in the kidney at SLE patients.
Slavin (12) observed in a study,
that cyclophosphamide (CP) can induce cardiomyopathy; the signs and symptoms
of cyclophosphamide cardiotoxicity appeared within 10 days after iniation
of therapy, and part of patients died with congestive cardiac failure.
The patients were affected if the drug dosage exceeded 1,55 g/m per day.
Clinically, this drug’s toxic effect is acute in onset and not the result
of cumulative dosage. As well as Buja (12), we appreciated that, also in
our case, not the dosage but the combination therapy for SLE disease, and
SLE disease per se, could alter the myocardium. Cardiactoxicity is marked
by cardiomegaly, microvascular fibrin thrombi, pulmonary vascular congestion,
increased end-diastolic volume, and pericardial effusions. Ferrans (12)
described that the adverse effects of high doses of CP appears secondary
to capillary endothelial damage. This leads to blood extravasation, interstitial
edema, fibrin deposition, and foci of necrosis in the adjacent myocardium,
characterized structurally by extensive contraction bands, myofibrillar
lysis. These lesions heal by fibrosis. The drug may also cause a fibrinous
pericarditis.
Amstrong (12) reviewed the adverse
effects of corticosteroid therapy on the cardiovascular system, because
the corticosteroids (CS) have a significant influience on the metabolism
with disturbance of it, with secondary involvement of various organs. They
also were present in our case, consisting from hypercholesterolemia, obesity,
osteoporosis, peptic ulcer and diabetes mellitus.
CONCLUSIONS
We can conclude that the clinical
picture of this case was the result of complex pathogenic admixture between
SLE disease and medication adverse effects. For that a significant importance
is the continuing clinical and lab monitoring of the patients treated for
SLE for early identifying of other vital involved organs, the adverse effects
of the used drugs, and the permanent communication with the patients for
rapid adresability to specialists in such cases.
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