Antiphospholipid syndrome and rheumatic fever: a case spanning three decades of changing concepts and common immunological mechanisms

We present a case of primary antiphospholipid syndrome (APS), initially diagnosed as acute rheumatic fever, resulting in severe mitral valve incompetence. This case raises questions of the specificity of the Jones diagnostic criteria for rheumatic fever in a population where it is infrequently encountered. There are similarities in clinical, pathological and echocardiographic presentations between rheumatic fever and APS, in addition to common immunological mechanisms. Our case highlights the possibility that rather than rheumatic fever being primarily responsible for her recurrent attacks of chorea and arthritis, the streptococcal infections in our patient occurred either in the setting of underlying antiphospholipid antibodies ('second hit' phenomenon), or may have triggered the development of pathogenic antibodies (molecular mimicry), subsequently leading to the clinical evolution of APS. During the three decades of our patient and her recurrent problems, there has been an evolving knowledge of the mechanisms of APS and rheumatic fever, allowing us to extend our understanding beyond symptoms and syndromes, to a better realization of the underlying immunological relationship between the two.     

Cardiac and cerebral manifestations of antiphospholipid syndrome

We describe cardiac and cerebral manifestations in 27 patients with the antiphospholipid syndrome and give a review of the literature. PATIENTS AND METHODS: We studied 27 patients with either cardiac, cerebral or both manifestations, who also were diagnosed with the antiphospholipid syndrome (APS). All patients fulfilled the proposed classification criteria for the APS according to the Scientific Standardisation Committee of the International Society of Thrombosis and Haemostasis (1). Three patients died. RESULTS: Eighteen of the 27 patients had coronary artery disease with either thrombotic coronary occlusions, high grade stenosis or complete vessel occlusion. In three patients the left main artery was involved. Ten patients had involvement of the left anterior descending artery (LAD), 6 patients of the circumflex artery (RCX) and 5 patients had involvement of the right coronary artery (RCA). As valvular lesions have been described in association with the APS it should be noted that in 16 cases there was mitral- and/or aortic valve disease and in 3 cases tricuspid valve disease. Four patients underwent mitral- and/or aortic- and/or tricuspid valve replacement. 7 patients presented with a history of cerebrovascular involvement; 5 of these patients had cerebral infarction, one patient recurrent cerebral bleeding under oral anticoagulation and another patient presented with cognitive disorders. Three of the 7 patients had a prior history of myocardial infarction, whereas 3 patients underwent mitral or aortic valve replacement. CONCLUSION: The frequent occurrence of coronary disease, cardiac valvular disease and cerebral disease in patients diagnosed with APS may suggest a causative relationship between the presence of PL antibodies and vascular disease.     

Cardiovascular abnormalities of the antiphospholipid antibody syndrome

The antiphospholipid antibody syndrome (APS) may present with serious cardiovascular complications which should be recognised by the cardiologist. The authors report a series of 6 cases of APS diagnosed after thrombotic events and the finding of antiphospholipid antibodies. The APS was primary in 5 cases and associated with tuberculous lymphadenitis in 1 case. There was cardiac involvement in 5 patients with pericardial effusion in 3 cases, complicated by tamponade as the presenting sign of primary APS in the other 2, valvular disease in one case (moderate mitral stenosis with aortic valve disease) and pulmonary embolism in one case. Five patients developed recurrent deep vein thrombosis of the legs. One patient had a transient ischaemic cerebral attack.     

Aortic and Mitral Valve Stenosis with Regurgitation: Not Due to Rheumatic Heart Disease

The patient is a 13‐year‐old Mexican–American immigrant who had no previous medical care. Upon arrival to the United States she was diagnosed with severe mitral valve stenosis and regurgitation. In addition she had severe aortic stenosis with mild to moderate aortic valve regurgitation, which was thought to be rheumatic heart disease. On the basis of the clinical and echocardiographic findings she was taken to the operating room for both mitral and aortic valve replacement. Her operation was complicated by the discovery that her aorta was completely calcified, as were her coronary arteries, mitral valve and aortic valve. She underwent aortic and mitral valve replacement as well as replacement of her aortic arch. Her coronary arteries were patch augmented and reimplanted into the newly created ascending aorta. Based on the pathologic examination of the surgical tissue a diagnosis of Gaucher disease was made. (Echocardiography 2011;28:E24‐E27)     

Successful balloon mitral valvotomy in rheumatic mitral stenosis with Ebstein's anomaly

The association of Ebstein's anomaly of tricuspid valve with rheumatic mitral stenosis is extremely rare. The case is presented of a young female who had been admitted with progressive dyspnea secondary to severe rheumatic mitral stenosis with moderate pulmonary hypertension, along with Ebstein's anomaly of tricuspid valve. The patient underwent successful balloon mitral valvotomy, using the Inoue technique, with a marked improvement in her symptoms.     

Quadrivalvular heart disease: transition from congenital pulmonary stenosis to rheumatic disease

The case is reported of a 36-year-old male patient suffering from congenital pulmonary stenosis who previously had undergone pulmonary balloon valvuloplasty. During the past nine years, he had experienced recurrent attacks of rheumatic fever that gradually damaged all four heart valves. The patient underwent aortic, mitral and pulmonary valve replacement with tricuspid valve annuloplasty and pulmonary artery reconstruction. Histologically, all heart valves--including the pulmonary--had similar changes that corresponded to chronic rheumatic disease.     

Clinical significance of anti-phosphatidylserine-prothrombin complex antibodies in antiphospholipid syndrome

We clarified the clinical significance of IgG anti-phosphatidylserine-prothrombin complex (PS-PT) antibodies in the antiphospholipid syndrome (APS). The study population consisted of 122 patients with SLE and lupus-like disease. IgG anti-PS-PT antibodies were detected in 44% of 59 patients according to the diagnostic criteria by Harris and Hughes. This frequency was significantly (p < 0.005) higher than the 14% seen in patients without APS. IgG anti-PS-PT antibodies were strongly (p < 0.005) associated with thrombosis. In addition, IgG anti-PS-PT antibodies were positive in 64% of IgG beta2-GPI dependent anti-cardiolipin antibody negative APS patients under the Sapporo criteria. The above findings indicate that IgG anti-PS-PT antibodies as well as beta2,-GPI dependent anti-cardiolipin antibodies should be examined in the diagnosis of APS.     

Kingella endocarditis and meningitis in a patient with SLE and associated antiphospholipid syndrome

We describe a patient with SLE and antiphospholipid syndrome who presented with severe headache and fever. Lumbar puncture analyses indicated meningitis. Kingella kingae was isolated from her blood cultures. A large mobile vegetation was seen on her mitral valve. The association between SLE, Libman-Sacks endocarditis and bacterial endocarditis is discussed.     

Double heart valve replacement disclosing antiphospholipid syndrome]

In patients with systemic lupus erythematosus (SLE) heart valve lesions are usually discovered at echocardiography; their haemodynamic repercussions are uncommon, and valve replacement is exceptional. We report the case of a woman who had undergone aortic and mitral valve replacement before antiphospholipid antibodies were found associated with 4 ARA criteria of SLE. Histopathological examination confirmed the diagnosis of Libman-Sachs specific endocarditis. The presence of antiphospholipid antibodies leads to a discussion of their role in the physiopathology of the heart valve lesions and vascular accidents that occurred in this patient. The overlap observed between the diagnostic criteria of SLE and those of primary antiphospholipid syndrome is discussed. Heart valve lesions may be one of the modes of access to the antiphospholipid syndrome.     

Mitral valve prolapse in patients with prior rheumatic fever

It is known that rheumatic heart disease frequently results in isolated mitral regurgitation without concomitant mitral stenosis, especially in countries with a high prevalence of rheumatic fever. However, more recent surgical pathologic data also have demonstrated a high incidence of mitral valve prolapse in cases of rheumatic heart disease, which suggests that rheumatic fever may be a cause of mitral valve prolapse. To determine whether this association of mitral valve prolapse and rheumatic heart disease is present in a stable clinic population, we studied 30 patients who had an apical systolic murmur and a well-documented history of rheumatic fever with dynamic auscultation, two-dimensional echocardiography, and pulsed Doppler examinations. Twenty of the 30 patients (67%) had findings on physical examination consistent with isolated mitral regurgitation and 25 patients (84%) had mitral regurgitation by Doppler examination. Echocardiography demonstrated mitral valve prolapse in 24 patients (80%), whereas only one of the total study group had echocardiographic findings consistent with mitral stenosis. We conclude that (1) the presence of an isolated systolic murmur in patients with a history of rheumatic fever frequently represents pure mitral regurgitation secondary to mitral valve prolapse and (2) postinflammatory changes in valvular tissue resulting from rheumatic fever may be the etiology of mitral valve prolapse in these patients.     

Chorea in a pregnant woman with rheumatic mitral stenosis

Chorea gravidarum is a rare movement disorder of pregnancy with a broad differential diagnosis. Although often a benign condition, it may indicate underlying acute rheumatic fever, antiphospholipid antibody syndrome or a hypercoagulable state. However, now that rheumatic fever is rare in western countries, chorea gravidarum occurs most commonly in patients with chronic rheumatic heart disease. Heightened awareness of chorea gravidarum and the morbidity of the often associated rheumatic heart disease, particularly in immigrants from developing countries, is essential for early diagnosis and effective management. A case of chorea gravidarum in a woman with rheumatic mitral stenosis is described. The diagnostic approach, pathophysiology and management of this rare condition are discussed.     

Endovascular Therapy for Rheumatic Mitral and Aortic Valve Disease: Review Article

Rheumatic heart disease remains a major cause of significant mortality and morbidity in the developing world. Rheumatic mitral and aortic stenosis are the two most common valvular sequelae of acute rheumatic fever. Open surgical procedures with either valve replacement or surgical commissurotomy have largely been replaced by percutaneous commissurotomy and balloon valvuloplasty for selected patients since the early 1980s. The purpose of our review is to examine the literature for any recent advancement in procedural techniques of balloon valvuloplasty for selected patients with rheumatic mitral and or aortic stenosis. Our search indicates that, in general, the volume of recent publications on this important topic is rather scanty with no major changes in the fundamentals of procedural techniques and or primary indications for balloon valvuloplasty of a rheumatic valve stenosis. Percutaneous balloon valvuloplasty/commissurotomy remains the main stay of therapy for rheumatic valvular stenosis in selected patients with favorable valve anatomy.     

Heart valve involvement in systemic lupus erythematosus: an echocardiographic study]

The purpose of this study was to evaluate the spectrum of morphologic and functional cardiac involvement in a selected population of patients with systemic lupus erythematosus (SLE) by means of echocardiography. Thirteen patients (2 male and 11 female) affected by SLE, mean age 41.9 years (range, 21-64), underwent M-Mode, two-dimensional and Doppler echocardiography. Eleven patients had renal disease and 3 of them were undergoing dialysis. One patient had findings of active disease. Six patients had systemic hypertension. None had a history suggestive of rheumatic fever or infective endocarditis. At echocardiographic study nine patients demonstrated findings of valvular involvement. These alterations were defined, according to the echocardiographic features, in two types: vegetation (verrucous Libman-Sacks endocarditis) and thickening. Vegetations were present in 6 patients, involving the mitral valve in all six and the aortic valve in three. The mitral valve vegetations were more frequent on the subannular portion of the posterior leaflet. Seven patients had valvular thickening: involvement of both mitral and aortic valve was present in five, and isolated mitral or aortic valve lesions in the remaining two patients. Combined valvular vegetation and thickening were observed in 4 patients. Eight patients had mild valvular dysfunction on Doppler examination: five isolated mitral regurgitation, two combined mitral and aortic regurgitation and one combined mitral stenosis and regurgitation. In agreement with previous reports, our study shows that valvular involvement in SLE is relatively frequent. Echocardiography can identify additional patterns of valvular lesions different from the known "verrucous Libman-Sacks endocarditis". The degree of valvular dysfunction is not important.     

Anti-cardiolipin antibody from a patient with antiphospholipid syndrome (APS) recognizes only an epitope expressed by cardiolipin/beta 2-glycoprotein-I (beta 2GPI) complex and induces APS

OBJECTIVE: As the antiphospholipid syndrome (APS) is characterized by antibodies which bind negatively charged phospholipids either directly or mainly through different target epitopes located on the beta-2-glycoprotein-I (beta 2GPI) molecule, the aim of this study is to describe an additional target epitope for anti-cardiolipin binding. METHODS: The binding characteristics of affinity purified anti-cardiolipin antibodies from a patient with monoclonal gammopathy associated with clinically overt APS were studied; inhibition studies were also carried out. These antibodies were used for the active induction of experimental APS. RESULTS: The affinity purified anti-cardiolipin antibodies were found to bind a target epitope created by the complex of cardiolipin/beta 2GPI, while not reacting with a complex composed by another phospholipid (phosphatidylserine/beta 2GPI), as confirmed by direct binding and competition assays. Immunization of naive mice with this unique affinity purified anti-cardiolipin antibody resulted in the induction of experimental APS (thrombocytopenia, prolonged coagulation timed and fetal resorptions). The anti-cardiolipin/beta 2GPI injected mice developed high titers of mouse anti-cardiolipin/beta 2GPI antibodies with the same binding characteristics as the human antibody which was used for disease induction. CONCLUSION: APS is a unique syndrome that is characterized by a diversity of pathogenic anti-phospholipid antibodies which may explain the diversity of clinical manifestations reported in patients.     

Influence of surgery on the natural history of rheumatic mitral and aortic valve disease

The rate of survival, the evolution of functional cardiac status and the incidence of major complications during a 5 year period were studied in 410 patients with rheumatic mitral or aortic valve disease, of whom 200 were treated medically and 210 by surgery. The 5 year survival rates in patients with various types of rheumatic mitral valve disease were similar (45 percent for those with mitral stenosis and 46 percent for those with mitral insufficiency or mixed mitral insufficiency and stenosis). The survival rate in patients with aortic valve disease was somewhat more favorable (64 percent).Mitral valvulotomy had the most positive influence on mortality. The 85 percent 5 year survival rate of patients who underwent this procedure was significantly higher than that of patients with medically treated mitral stenosis. In patients submitted to mitral and aortic valve replacement, the survival rate was also improved in comparison with data in the corresponding medically treated groups, but to a lesser degree (70 percent for aortic valve replacement and 60 percent for mitral valve replacement). In all surgically treated groups, initial operative mortality was the primary determinant of the rate of survival at the end of 5 years.Survivors of all surgical groups had appreciable improvement in cardiac functional classification and a remarkable reduction in the incidence of heart failure and atrial fibrillation. The incidence of infectious endocarditis was significantly reduced after mitral valvulotomy, as compared with the incidence in patients with medically treated mitral stenosis. Mitral and aortic valve replacement did not reduce the incidence of infectious endocarditis. The incidence of thromboembolic phenomena was favorably influenced by mitral valvulotomy and aortic valve replacement, but not by mitral valve replacement.     

Severe, non-infectious mitral valve endocarditis after mitral valve reconstruction in a 32-year old female with primary antiphospholipid syndrome

BACKGROUND: A 32-year old female with primary antiphospholipid syndrome presented 8 months after mitral valve reconstruction with progressive exertional dyspnea and echocardiographically demonstrable critical mitral stenosis and regurgitation. Tachycardia, weight loss, sleep disturbances and increasing nervosity led to the diagnosis of concomitant hyperthyroidism. After the patient stopped the oral anticoagulation by herself, a 'catastrophic antiphospholipid syndrome' with multiple microthromboembolic events in several organs developed rapidly within a few weeks. Severe respiratory failure was observed 14 days after admission at our hospital because of a pulmonary edema. TREATMENT: Removal of the annuloplasty ring and alloplastic mitral valve replacement with a 25 mm bilifleat valve. Postoperatively, the patient was placed on oral anticoagulation. Several pre- and postoperative plasmaphereses lowered the level of antiphospholipid antibodies. The patient additionally underwent radioiodtherapy 5 months postoperatively. RESULTS: While hemodynamics and diuresis remained sufficient, ventilatory support with tracheostomy was necessary for 16 postoperative days to achieve stable respiration. Thirty months later, the patient is well and without further cardiac and neurological dysfunction. CONCLUSION: Secondary cardiac valve operations on patients with primary antiphospholipid syndrome may be successfully performed within a multidisciplinary approach. Oral anticoagulation remains the treatment of choice to prevent further thromboembolic events.     

Indications for surgical replacement of the mitral valve. With particular reference to common and uncommon causes of mitral regurgitation.

Mitral valve replacement is considered when there is severe mitral stenosis, severe mitral insufficiency or a combination of the two. Ordinarily, surgical replacement is considered only for patients who are in functional classes III or IV and do not respond to medical management. Patients with symptomatic mitral stenosis should be treated with mitral commissurotomy whenever possible. Patients selected for commissurotomy should have a pliable valve, no other major valve dysfunction, sinus rhythm, no systemic embolism and good left ventricular function. Early operation is not ordinarily required. Mitral insufficiency may require mitral valve replacement in six rather common settings: rheumatic disease, rupture of mitral chordae tendineae, postinfarction rupture of a papillary muscle, intractable infective endocarditis, floppy mitral valve and malfunction of a prosthetic valve. Rupture of mitral chordae tendineae can usually be recognized from the history, physical examination, echocardiogram and angiocardiogram. Severe left ventricular papillary muscle dysfunction is usually due to cardiac infarction, and occurs within the first 9 days of infarction. When only a papillary muscle tip is ruptured the patient may survive long enough for a mitral valve replacement. In infective endocarditis, operation is more often needed because of congestive heart failure than because of refractory infection. Evidence of mitral stenosis or insufficiency in a patient with a previously implanted prosthetic valve usually indicates an urgent need for study and early operation. Uncommon causes of mitral incompetence that may require valve replacement are endocardial fibroelastosis, Marfan's syndrome, calcified mitral anulus, osteogenesis imperfecta, methysergide-induced heart disease and carcinoid heart disease.     

Prosthetic valve endocarditis caused by Streptococcus constellatus infection complicated with perivalvular abscess: serial observation by transesophageal echocardiography: a case report

A 61-year-old man was admitted to an associated hospital because of fever. He had undergone aortic valve and mitral valve replacement 6 years ago, because of rheumatic aortic valve stenosis, and mitral valve stenosis and regurgitation. He had prosthetic valve endocarditis caused by a rare Streptococcus constellatus infection complicated by multiple organ failure and systemic embolism. We considered that surgical treatment was difficult, and continued antibiotic treatment. The inflammatory reaction and fever improved. Prosthetic valve endocarditis is often difficult to identify and treat. Streptococcus constellatus infection is characterized by destruction and formation of abscess. We followed up the patient by transesophageal echocardiography, and observed the course of change of the paravalvular abscess around the aortic valve from echogenic to echolucent.     

Postpartum spontaneous colonic perforation due to antiphospholipid syndrome

The antiphospholipid syndrome （APS） is a multi-systemic disease being characterized by the presence of antiphos- pholipid antibodies that involves both arterial and venous systems resulting in arterial or venous thrombosis, fetal loss, thrombocytopenia, leg ulcers, livedo reticularis, cho- rea, and migraine. We document a previously unreported case of a 37-year-old female in whom APS was first manifested by infarction and cecal perforation following cesarean section. At laparotomy the underlying cause of colonic perforation was not clear and after resection of the affected bowel an ileo-colostomy was performed. The diagnosis of APS was established during post-operative hospital stay and the patient was commenced on warfa- rin. Eventually, she made a full recovery and had her sto- ma reversed after 4 mo. Pregnancy poses an increased risk of complications in women with APS and requires a more aggressive approach to the obstetric care. This should include full anticoagulation in the puerperium and frequent doppler ultrasound monitoring of uterine and umbilical arteries to detect complications such as pre- eclampsia and placental insufficiency.     

Anticardiolipin antibodies in acute rheumatic fever.

Recent reports describe the association of antiphospholipid antibodies (aPL) with chorea or severe heart valve lesions in systemic lupus erythematosus, lupus-like disease, or the primary antiphospholipid antibody syndrome. We conducted a case series and a case-control investigation of patients with rheumatic fever with Sydenham chorea or other manifestations of rheumatic fever for anticardiolipin antibodies (aCL) during the acute attack and disease remission. Eighty percent of patients were positive for aCL during the rheumatic fever attack vs 40% when inactive (p = 0.035); IgG and IgM aCL increased significantly with disease activity. Individuals with or without Sydenham chorea were equally positive for aCL (76 and 83%, respectively). A significant association was found between IgM aCL and carditis: All patients with valvulitis had IgM aCL (100%) vs 37% of patients without valvular involvement (p = 0.02). aPL may play a role in the pathogenesis of some clinical manifestations of acute rheumatic fever.