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CARDIAC CONSEQUENCES OF 
THE SYSTEMIC LUPUS ERYTHEMATOSUS 
THERAPY WITH CORTICOSTEROIDS - MORPHOLOGICAL STUDY
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Catalina Arsenescu*, Doina Butcovan**, M Rotar*, GIM Georgescu*
* Dept. of  Medical Cardiology, Cardiology Center Iasi
**   Dept. of  Morfopathology,  UMF “Gr. T. Popa” Iasi
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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.

REFFERENCES 
1. Mogos Gh. LES. In: Mica Enciclopedie de Boli Interne, Ed. Mogos Gh, Editura Stiintifica si Enciclopedica, 1990, pg 601-603
2. Robbins SL, The Heart, In: Pathologic Basis of Disease, Eds., Cotran, Kumar, Robbins,  Ed. W.B. Saunders Company, 1999, pp 544-564 
3. Roberts J, Simon LK. The Heart In: Principles and Practice of Surgical Pathology and Cytopathology, vol II, Eds. Silverberg SG, Ed. Churchill Livingstone 1997, 1362-1370
4. Stanley M. The Heart. In:  Diagnostic Surgical Pathology, Eds. Sternberg SS, Ed. Raven Press, 1944: 1183-1197
5. Olsen E.G.J., Degenerative and Connective-tissue Disorders of the Cardiovascular System, In: The Pathology of the Heart, Eds. Olsen E.G.J., Ed. The Macmillan Press LTD, 1980, 81-92 
6. Virmani R. Disease of the pricardium. In: Atlas of Cardiovascular Pathology, Eds. Virmani, Burke, Farb, Atkinson, Ed. WB Saunders Company 2001, pp 103-106
7. Davies MJ, Pathology of Chronic Acquired AV Block, In: Pathology of Conducting Tissue of the Heart, Eds. MJ Davies, Ed. Butterworth & Co. Ltd, 1871, 63-120
8. Sheppard M.,Cardiomyopathy. In: Practical Cardiovascular Pathology, Eds. Mary Sheppard and M.J. Davies, Ed. Oxford University Press, 1998, 103-149
9. Pomerance A, Connective-Tissue Disorders. In: The Pathology of the Heart, Eds. Pomerance A, Davies MJ, Ed. Blackwell Scientific, 1975, pp 234-341
10. Burke A. Cardiomyopathies In: Cardiovascular pathology, Eds. Virmani, Burke, Farb, Atkinson, Ed. WB Saunders Company 2001, pp 179-231
11. Gallo P, D’Amati. Cardiomyopathies. In: Cardiovascular Pathology, Eds. Silver, Gotlieb, Schoen, Ed. Churchill Livingostone, 2001, 285-318
12. Silver M. Connective-tissue Disorders.In: Pathology of the heart and the great vessels, Eds. Waller BF, Ed. Churchill Livingstone 1998, pg, 191-277 
13. Eduard M. Connective-tissue Disorders. In: Cardiovascular System - vol X, Eds. Symmers WSC. Ed.  Churchill Livingstone, 1995,  pg 43-100.
14.  Egner W: The use of laboratory tests in the SLE diagnosis, J Clin Pathol 2000: 53: 424-432.
15. Jackson M: Lack of specificity for antibodies to double stranded DNA found in four commercial kits. J Clin Pathol 1991; 44: 246-50.
16. Spickett G. SLE. In: Oxford Handbook of clinical Immunology, Oxford University Press 1999, pg 291-297
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