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(Circulation. 1996;93:1579-1587.)
© 1996 American Heart Association, Inc.

Articles

Heart Valve Involvement (Libman-Sacks Endocarditis) in the Antiphospholipid Syndrome

Maja Hojnik, MD; Jacob George, MD; Lea Ziporen, MSc; Yehuda Shoenfeld, MD

From the Department of Medicine "B" and Research Unit of Autoimmune Diseases, Sheba Medical Center (affiliated with Sackler Faculty of Medicine, Tel-Aviv University), Tel-Hashomer, Israel.

Correspondence to Yehuda Shoenfeld, MD, Department of Medicine "B," Sheba Medical Center, Tel-Hashomer 52621, Israel.

	Abstract

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
Abstract The antiphospholipid syndrome (APS) is defined by the presence of anti-phospholipid antibodies (aPLs) and venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The syndrome can be either primary or secondary to an underlying condition, most commonly systemic lupus erythematosus (SLE). Echocardiographic studies have disclosed heart valve abnormalities in about a third of patients with primary APS. SLE patients with aPLs have a higher prevalence of valvular involvement than those without these antibodies. Valvular lesions associated with aPLs occur as valve masses (nonbacterial vegetations) or thickening. These two morphological alterations can be combined and are thought to reflect the same pathological process. Both can be associated with valve dysfunction, although such association is much more common with the latter alteration. The predominant functional abnormality is regurgitation; stenosis is rare. The mitral valve is mainly affected, followed by the aortic valve. Valvular involvement usually does not cause clinical valvular heart disease. The presence of aPLs seems to further increase the risk for thromboembolic complications, mainly cerebrovascular, posed by valve lesions. Superadded bacterial endocarditis is rare but may be difficult to distinguish from pseudoinfective endocarditis. The current therapeutic guidelines are those for APS in general. Secondary antithrombotic prevention with long-term, high-intensity oral anticoagulation is advised. The efficacy of aspirin, either alone or in combination, is yet to be assessed. Corticosteroids are not beneficial and may even facilitate valve damage. Immunosuppressive agents should only be used for the treatment of an underlying condition. Current data suggest a role for aPLs in the pathogenesis of valvular lesions. aPLs may promote the formation of valve thrombi. These antibodies may also act by another mechanism, as indicated by the finding of subendothelial deposits of immunoglobulins, including anti-cardiolipin antibodies, and of colocalized complement components in deformed valves from patients with APS.

Key Words: antibodies • pathology • rheumatic heart disease • valves

	Introduction

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
Antiphospholipid syndrome has been defined as venous or arterial thrombosis, recurrent fetal loss, or thrombocytopenia accompanied by an increased level of aPLs.^{1 2} The spectrum of clinical manifestations appearing in patients with aPLs is, however, much wider and more diverse, encompassing neurological disorders (chorea, transverse myelopathy, atypical migraine, epilepsy, subtle cognitive deficits, and amaurosis fugax),^{3 4} obstetric complications (different degrees of fetal distress, pregnancy-induced hypertension, and preeclampsia),⁵ valvular heart disease,⁶ and cutaneous features (livedo reticularis, leg ulcers, gangrene, skin nodules, and superficial macules resembling vasculitis).⁷ APS is termed secondary when it occurs in the context of another defined autoimmune disease or malignancy or as a drug-induced condition. In the absence of an underlying disorder, the syndrome is classified as primary.⁸ Increased levels of aPLs are common in infections but are not regularly associated with APS.^{9 10} It is becoming increasingly recognized that APS is primary in about half of the patients, whereas it is secondary in the rest, mainly to SLE.¹¹

The term aPL designates a heterogeneous group of immunoglobulins (IgG, IgM, and, rarely, IgA) detectable by two kinds of tests: (1) solid phase immunoassays, typically ELISA, with phospholipids used as the coating antigens, or (2) phospholipid-dependent coagulation tests, by virtue of the ability of some aPLs to impair in vitro coagulation reactions, thereby prolonging clotting time. Some aPLs also yield false-positive reactions in the standard (nontreponemal) tests for syphilis. aPLs determined by the conventional ELISA test with negatively charged phospholipid cardiolipin are termed aCLs, whereas those identified in the coagulation tests are labeled LAs.^{12 13}

Until the 1990s, aPLs in patients with autoimmune diseases (autoimmune aPLs) have generally been thought to be directed against negatively charged phospholipids.^{1 13} This paradigm was challenged by the observation that certain phospholipid-binding plasma proteins involved in hemostasis are necessary for the detection of aPLs. ß₂-Glycoprotein I, also called apolipoprotein H, has been found to be required for the binding of autoimmune aCLs in ELISA tests^{14 15 16} and for a subset of LAs to express their in vitro anticoagulant activity.^{17 18 19} Much controversy has been generated regarding whether aPLs recognize complex epitopes consisting of both phospholipid and protein, protein alone, or neoepitopes or cryptic epitopes exposed on either component on their mutual interaction. Recent data strongly support the hypothesis that ß₂-glycoprotein I, bound to anionic phospholipid or synthetic surfaces, represents the pathophysiologically relevant target for aCLs.^{20 21 22} By analogy, subsets of LAs were shown to be directed toward phospholipid-bound human prothrombin,^{23 24 25} protein C,²⁴ or protein S.²⁴ Furthermore, evidence has been provided that certain LAs recognize prothrombin immobilized in the absence of phospholipids.^{25 26} There are also preliminary data that some LAs react specifically with coagulation factor X and that kininogen is a protein cofactor in the antibody binding to phosphatidylethanolamine.²⁷

In summary, recent investigations suggest that aPLs in autoimmune patients are directed against phospholipid-protein complexes or phospholipid-bound plasma proteins and may even be viewed as part of a broader family of autoantibodies with immunologic specificity for various phospholipid-binding plasma proteins involved in hemostatic reactions.²⁷ The role of phospholipids appears to be both in vitro and in vivo in providing the surface on which proteins, on attachment, become available for antibody binding. This may be because of an increase in the local concentration of the protein targets²¹ and/or a conformational change of the proteins that exposes neoepitopes or cryptic epitopes recognized by the antibodies.^{20 27}

Table 1 lists the phospholipid-binding plasma proteins identified to date as antigenic targets and summarizes the reactivity of their respective antibodies in the standard detection assays for aPL. Three points should be noted: (1) Antibodies determined in either of the two antiphospholipid assays are heterogeneous. The anticardiolipin ELISA detects antibodies to cardiolipin-bound ß₂-glycoprotein I as well as to cardiolipin (phospholipid-specific antibodies), which are typically found in infections. The LA tests detect antibodies to phospholipid-bound ß₂-glycoprotein I or prothrombin but generally do not detect phospholipid-specific antibodies. (2) There is only a partial overlap between the antigenic specificities of antibodies measured by anticardiolipin and LA assays. (3) Antibodies to protein C and protein S that are potentially of clinical importance are not detected by the antiphospholipid assays currently in clinical use. This information, together with the fact that autoantibodies to phospholipid-binding plasma proteins occur in various combinations, helps explain what has been known for years: an individual patient may have only aCLs, only LAs, or both types of aPL simultaneously that may either appear to be a single antibody population or distinct and physically separable.^{28 29}

View this table: [in this window] [in a new window]   Table 1. Detection of Autoantibodies to Phospholipid-Binding Plasma Proteins in Standard Assays for aPL

There is convincing evidence that aPLs at moderate or high titers are associated with an increased risk for thrombosis at virtually any vascular site.^{30 31} Diverse pathophysiological effects of aPLs have been proposed to explain the related clinical manifestations, commonly implicating hypercoagulability of the blood as the central pathogenic mechanism.³² Whether these antibodies are a cause, a consequence, or a coincidence is still debatable. Data provided by both spontaneous³³ and induced animal models of APS^{34 35} substantiate a pathogenic role for aPLs. Recently, an in vivo experimental model of aPL-mediated thrombosis has also been described.³⁶

As alternatives to the specific antigens or physiological effectors of aPLs, a number of immunologic and biological cross-reactive substances have been reported, such as the glycosaminoglycans heparin and heparan sulfate,³⁷ vascular heparan sulfate proteoglycan,³⁸ placental anticoagulant protein I,³⁹ and oxidized LDL, which is an established atherogenic factor.^{40 41 42} In addition to various antigenic specificities and biological effects of aPLs and other risk factors that differ among individuals, this could be a further explanation for the clinical complexity and heterogeneity of APS. It also suggests an involvement of aPLs in pathological processes not previously envisioned in connection with these autoantibodies.

This review will focus on cardiac valve abnormalities that occur in patients with aPLs, as well as their prevalence, morphological types, clinical significance, and the mechanisms proposed to explain their development. Additionally, treatment and prevention of potential clinical complications will be discussed.

	Historical Background

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
Libman-Sacks endocarditis was originally described in 1924 in four patients with atypical sterile verrucose lesions of the valvular and mural endocardium.⁴³ The lesions, pathologically distinct from endocarditis of other etiologies, were believed to be characteristic of SLE.^{44 45 46 47} Libman-Sacks vegetations were found in 35% to 65% of lupus patients in early autopsy studies but routinely were clinically silent and of minor hemodynamic importance.^{46 47 48} Subsequent postmortem series showed smaller incidence and size of vegetations.^{49 50 51} The introduction of echocardiographic diagnostic techniques, however, revealed a frequent occurrence in SLE of thickened, functionally impaired cardiac valves that were prone to hemodynamic deterioration.^{52 53 54} It has been postulated that the two morphological types of valvular lesions represent different stages of the same pathological process. The shift in valve pathology has been ascribed to steroid therapy and generally longer survival of patients with SLE, presumably allowing the more frequent emergence of fibrosed, malfunctioning valves as the end-stage or healed form of Libman-Sacks endocarditis.^{49 53}

The association between Libman-Sacks endocarditis and aPLs was first noted in 1985 in a young woman with SLE and LAs.⁵⁵ Similar observations in four patients with SLE and one with primary APS soon followed.^{56 57 58} In 1989, four groups^{59 60 61 62} highlighted a probable role of aPLs in the pathogenesis of valvular heart disease in patients with SLE. Those authors had already anticipated that valve lesions constituted part of the APS.

	Evidence for an Association Between aPLs and Heart Valve Lesions

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
aPLs in Patients With SLE and Heart Valve Involvement
Data from larger echocardiographic studies that assessed the frequency of valvular abnormalities (morphological and/or functional) among SLE patients in relation to the presence of aPLs are given in Table 2. By use of transthoracic two-dimensional and Doppler echocardiography, several studies^{63 64 65 66} showed a significantly higher prevalence of valvular defects in SLE patients with aPLs than in those without these antibodies. In one study,⁶⁷ which used the transesophageal Doppler technique, valvular affection was common in both aPL-positive and aPL-negative patients and the incidences did not differ (Table 2). The presence of aPLs, determined as IgG, IgM, or IgA aCLs and LAs, was found to be associated with mitral or aortic verrucose valvular thickening, global valvular thickening and dysfunction, and mitral and aortic regurgitation.⁷⁰ Valvular involvement has been shown to be influenced both by SLE disease duration and IgG aCLs. It is of interest that the duration of SLE also affected myocardial function, whereas the aCLs were related only to the endocardial damage.⁷¹

View this table: [in this window] [in a new window]   Table 2. Frequency of Heart Valve Abnormalities in Patients With SLE With or Without aPL

aPLs in Patients With Heart Valve Involvement in the Absence of SLE
The evaluation of sizable series of patients with primary APS by two-dimensional and Doppler echocardiography revealed a 32% to 38% prevalence of valvular defects.^{69 72 73 74} The frequency of valvular lesions differed in two other studies (10% and 60%).^{67 68} However, each of those studies included only 10 patients with primary APS. By contrast, valvular abnormalities were detected in 0% to 4% of healthy control subjects.^{68 73 74 75} Results from larger studies of patients with primary APS are presented in Table 3.

View this table: [in this window] [in a new window]   Table 3. Frequency of Valvular Involvement in Patients With Primary APS and Control Subjects in Different Studies

Data on the prevalence of aPLs in patients with isolated valvulopathy are limited. A cohort of 87 patients presenting with hemodynamically important mitral and/or aortic regurgitation due to valvular causes were examined for the presence of IgG and IgM aCLs. Increased IgG aCLs were detected in 30% of the patients and none of the normal control subjects. All patients with IgM-class aCLs had simultaneously elevated IgG aCLs, and there was no difference in the frequency of IgM aCLs between patients and control subjects. The patients had no systemic disease, nor were they receiving any treatment that could potentially affect aCL production.⁷⁵

Comments
Results of clinical studies suggest a link between aPLs and heart valve lesions. Approximately one third of patients with primary APS exhibit valvular abnormalities, which is considerably more than in the general population. The differences between studies in the prevalence of valvular defects observed among SLE patients with and without aPLs could be due in part to different methods of aPL detection as well as variances in echocardiographic techniques and interpretation of results. Patient characteristics probably influenced the estimated prevalences markedly. SLE is a complex and protean disease, and factors such as the presence of other antibodies and immunologic disturbances, duration of active disease, and immunomodulatory and antithrombotic therapy may all influence the expression of endocardial lesions. Recently, a significantly higher prevalence of valvular involvement was observed in patients with APS secondary to SLE than in primary APS patients. SLE-related factors that promote endocardial damage could account for such a distinction.⁶⁹

Similar to the established relationship between aCL isotype and clinical manifestations of APS, IgG aCLs appear to be more specific for valve affection than the IgM class.^{63 67 68 70 71 75} In addition, numerous patients with valvular disease were reported in whom LA was the only type of aPL detected.^{55 57 73 74 76} It should, however, be noted that aCLs and LAs may represent some of the same antibodies, ie, antibodies to phospholipid-bound ß₂-glycoprotein I (Table 1). In both primary and secondary APS, the probability of developing a valvulopathy seems to be increased with higher levels of circulating aPLs. For instance, in a study of 93 patients with SLE, at least one valvular abnormality was present in 50% of patients with high aCL levels, 37% of those with moderately increased aCLs, and only 14% of those without elevated aCLs.⁶⁴

The common lack of pathological confirmation of echocardiographic findings limits assessment of the sensitivity and accuracy of these diagnostic techniques. Cases have been reported of valves that were found to be pathologically altered on gross examination yet had been interpreted as normal by echocardiography.^{57 66 76} In spite of the new sophisticated echocardiographic methods, it may well be that the prevalence of valvular abnormalities is indeed underestimated. On the other hand, there is an appreciable chance of ascertainment artifact due to patient selection bias, as many of the studies were conducted in cardiology units.

	Morphological and Functional Types of aPL-Associated Valve Abnormalities and Their Histological Appearance

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
Valvular abnormalities in patients with APS, either primary or secondary to SLE, appear to be similar in both form and location to those previously described in patients with SLE in general. Two morphological echocardiographic patterns can be discerned: valve masses (vegetations) and valvular thickening. These two morphological alterations can be combined and both can be associated with valve dysfunction, although the latter is much more common. The predominant functional abnormality is regurgitation, whereas stenosis is rarely seen. The mitral valve is mainly affected, followed by the aortic valve.^{63 64 65 66 67 68 69 72 73 74 76} Involvement of the tricuspid or pulmonary valve was seldom identified.^{65 68 73 77}

Libman-Sacks valvular lesions, as described in early pathological studies, are sterile fibrofibrinous vegetations that may develop anywhere on the endocardial surface of the heart but with a propensity for the left valves, particularly the ventricular surface of the mitral valve. They are typically sessile, wartlike, and small, varying from pinhead size to 3 to 4 mm (Fig 1).^{43 44 45 46 47 48 49 50 51} Similar verrucose valvular lesions have been identified on valves from patients with APS, either primary or secondary to SLE.^{57 59 70 76 78} Echocardiographically, vegetations appeared as valve masses of varying size and shape with irregular borders and echodensity, firmly attached to the valve surface and exhibiting no independent motion (Fig 2).^{64 67} Whereas in previous postmortem studies, vegetations were seen mostly near the valve tips, recent echocardiographic data showed their predominant location on the proximal or middle portion of the leaflets or cusps.^{64 67 72}

View larger version (112K): [in this window] [in a new window]   Figure 1. Verrucose lesion of the mitral valve from a patient with APS secondary to SLE.

View larger version (134K): [in this window] [in a new window]   Figure 2. Parasternal long-axis echocardiogram from a patient with primary APS demonstrating a vegetation on the mitral valve (arrow).

Libman-Sacks valve lesions are microscopically characterized by fibrin deposits at various stages of fibroblastic organization and neovascularization and by a variable extent of inflammation with mononuclear cell infiltration. In the presteroid era, inflammatory changes seemed to be more florid, at times associated with focal necrosis and scattering of hematoxylin bodies, which were thought to be a histological counterpart to the lupus erythematosus cells.^{43 44 45 46 47 48 49 50 51} These changes were not reported in contemporary studies.^{57 70 76 77 78 79 80 81}

The end-stage or healed form of Libman-Sacks verrucose endocarditis is a fibrous plaque, sometimes with focal calcification.^{43 44 45 46 47 48 49 50 51} If the lesions are extensive enough, their healing may be accompanied by marked scarring, thickening, and deformity of the valve, which most likely leads to valve dysfunction.^{43 44 45 46 47 48 49 50 51 53}

Two peculiar changes of the valves from patients with primary APS were reported, each one in a single patient: myxoid aortic valve degeneration⁷⁴ and a thrombus over a histologically normal mitral valve.⁸²

Information on the histopathological appearance of valvular lesions in patients with APS derives from anecdotal reports of individual cases. Systematic studies comparing lesioned valve tissue from patients with and without aPLs, either in the setting of SLE or without an underlying disease, are clearly lacking. One study⁷⁹ attempted this but involved valve specimens deformed because of various etiologies, which certainly complicated the assessment.

	Clinical Implications of Valvular Lesions Associated With aPLs

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
In the majority of studied patients with aPLs, valvular involvement was of minor hemodynamic significance and did not cause clinically overt valvular heart disease. However, cases of extensive valve deformity and dysfunction that even required surgical replacement or repair have been reported, both in secondary^{57 59 63 64 66 70} and primary APS.^{73 74 77}

Valvular lesions may present with other clinical complications before signs or symptoms of valve dysfunction develop. Many case reports and larger series have highlighted a frequent concomitant occurrence of valve abnormalities, thromboembolic events, and aPLs.^{55 56 57 58 59 70 72 73 75 76 82 83 84 85} Most common in those patients were cerebrovascular ischemic events, manifested as stroke or transient ischemic attacks. In the past, Libman-Sacks vegetations were thought to be infrequently dislodged, although embolisms from such lesions were described in patients with SLE.^{86 87} aPLs are known to be associated with an increased risk of thromboembolic complications.^{1 2 3 4 11 30 31} Thus, both valvular disease and aPLs can independently contribute to a greater likelihood of embolic events. The risk posed by their simultaneous presence in either patients with SLE or those without an underlying disorder awaits assessment.

In one study⁷⁵ of patients with mitral and/or aortic regurgitation and no evidence of SLE, focal ischemic cerebral events occurred in 8 patients, including 7 of 26 with elevated IgG aCLs and only 1 of 60 who were negative for aCL. The mean age of patients at the time of ischemic cerebral complications was 49 years (range, 28 to 63 years), and the mean age of the entire study group was 52 years (range, 29 to 78 years).⁷⁵ Echocardiographic analysis performed among 72 patients with aPLs and cerebral ischemia in the retrospective study by the Antiphospholipid Antibodies in Stroke Study Group⁸⁸ disclosed mitral valve abnormalities in 22.2%, aortic valve abnormalities in 2.8%, cardiac wall abnormalities in 9.7%, and thrombi in 4.2%. The mean age of the entire study group at the time of the index cerebrovascular event was 45.8 years (SD=17 years).⁸⁸ These data suggest the use of echocardiography to detect a potential cardiogenic source of emboli in patients who suffer from embolisms and have aPLs.

Although superadded infective endocarditis does not appear to be a common complication of aPL-associated valvular lesions, such lesions may serve as a substrate for microbial colonization.⁸⁹ Diagnostic and therapeutic problems may, however, arise in the case of so-called pseudoinfective endocarditis, which has been reported in patients with SLE⁹⁰ as well as primary APS.⁹¹ Such patients present with the following clinical and laboratory features: fever, cardiac murmurs, echocardiographic pattern of valve vegetations, splinter hemorrhages, moderately to highly increased aPLs, and repeatedly negative blood cultures. The serological markers of SLE disease activity may be present. Measurement of C reactive protein, aPL level, and white blood cell count may assist in the differential diagnosis of true infective endocarditis.⁹²

	Possible Pathogenetic Mechanisms

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
The pathogenesis of Libman-Sacks endocarditis has generally been assumed to involve the formation of fibrin-platelet thrombi on the altered valve, the organization of which leads to valve fibrosis, distortion, and subsequent dysfunction.^{57 58 79} It has been supposed that aPLs mediate valvular damage merely by promoting thrombus formation on the injured valve endothelium rather than by playing a more direct pathogenetic role.^{54 79 92} There is evidence that subpopulations of aPLs or some other immunoglobulins in the sera of patients with APS bind to endothelial cells.^{93 94} This binding could be directed to cell-membrane phospholipids⁹⁵ or mediated by phospholipid-binding plasma proteins, such as ß₂-glycoprotein I, that adhere to or are expressed on the endothelial surface.^{96 97} Various biological effects of aPLs have been demonstrated in vitro that could account for an increased endothelial cell procoagulant activity. These include interference with production and/or release of prostacyclin (prostaglandin I₂), enhanced production of platelet activating factor, increased tissue factor activity, inhibition of plasminogen activator release, increase of plasminogen activator inhibitor, and interference with the endothelium- and thrombomodulin-dependent protein C/S system. The thrombogenic potential of aPL may also be exerted by interfering with the functions of platelets, monocytes, and plasma proteins involved in blood coagulation and fibrinolysis.^{13 32 96 98}

However, the initial insult to the valve, eliciting the pathogenetic sequence of events, has not yet been identified. Immunologic injury, possibly mediated by the immune complex, has been postulated. Deposits of immunoglobulins and complement were found within the vessel walls in the zone of neovascularization of verrucose valvular lesions from two patients with SLE, implying a role of circulating immune complexes in the growth of valve vegetations.⁹⁹ Bidani et al¹⁰⁰ demonstrated granular deposits of immunoglobulins and complement components in the endocardial stroma, along the edges of valve leaflets and in vegetations on the valves from an SLE patient. Neither of these studies^{99 100} addressed the question of the antigenic specificity of deposited immunoglobulins. Recently, Ziporen et al¹⁰¹ evaluated by immunohistochemical methods cardiac valves derived from both patients with secondary APS and those with primary APS. Deposits of immunoglobulins and colocalized complement components were observed in macroscopically or microscopically altered valves. The pattern of deposition was alike in all the valves, appearing as a distinct, subendothelial, ribbonlike layer along the surface of valve leaflets or cusps (Fig 3). This finding seemed to be specifically related to the APS, as it was not seen in any of the normal or altered control valves. Using an anti-idiotypic antibody to human aCL, they¹⁰¹ were able to identify aCLs in the immunoglobulin deposits. An anticardiolipin specificity of deposited antibodies was further confirmed by elution of immunoglobulins from the valve tissue. It is as yet unknown whether the subendothelial deposition of aCL was a primary event due to a specific antigen-antibody interaction or secondary to another initiating insult.

View larger version (121K): [in this window] [in a new window]   Figure 3. Section of the aortic valve from a patient with APS secondary to SLE stained with mouse monoclonal antibody S2.9 that identifies a common idiotype on human aCLs. Note a distinct, stained, linear layer of deposited aCLs. The binding of the S2.9 anti-idiotypic antibody (anti-aCL) was visualized by use of a fluorescein isothiocyanate–conjugated second antibody. The same linear pattern of staining in the subendothelial stroma of the valve was seen for human immunoglobulins (predominantly of the IgG isotype) and complement components (C1q, C3c, and C4). The staining pattern was alike in all deformed valves from patients with APS with either immunofluorescence or the immunoperoxidase method.101

Findings in the lesioned valve tissue from patients with APS seem to be peculiar compared with those usually encountered in the syndrome. The characteristic histopathological lesion in APS is thrombotic vascular occlusion without signs of inflammation.^{102 103} Inflammatory changes were observed in the affected valves from patients with secondary^{57 59 66 70} as well as primary APS.^{76 78 81 101} Furthermore, immune complexes have not been implicated in the pathogenesis of other clinical phenomena related to aPLs. Interestingly, Pope et al⁷⁶ noted decreased total complement levels with low C3 and C4 in 11 of 14 patients with APS and valvular heart disease, even though only 3 of those 11 patients met the diagnostic criteria for SLE and the others were considered to have the primary form of the syndrome.

Taken together, the above data suggest that aPLs play a pathogenic role in the development of valvular lesions rather than being elicited by the antigens exposed in the damaged valve tissue or merely being an epiphenomenon. Thrombotic tendency may not be the only mechanism whereby aPLs may mediate valve damage. At present, there is no explanation for an apparently selective vulnerability of the endocardium to the action of aPLs. The anatomic, cellular, and molecular locations of the initial injury, whether or not it is caused by aPLs, remain to be clarified, as well as which additional risk factors compound valve damage or provide a second hit that leads to morphological and clinical expression of the lesion.

Therapeutic Considerations
Until the actual role of aPLs in the pathogenesis of valvular lesions is unambiguously defined and possible targeted therapy is validated, the general therapeutic guidelines for APS should be followed. These have been aimed at either lowering blood hypercoagulability (antithrombotic therapy) or aPL levels (immunosuppression). Immunosuppressive agents have not given long-term benefit in APS and should only be used if required for the treatment of an underlying condition (eg, SLE).¹⁰⁴ Antithrombotic agents (anticoagulants, vitamin K antagonists, heparin, and antiplatelet agents) have proved efficacious, and consensus is gradually being reached on the optimal doses of these agents.

Antithrombotic therapy is certainly indicated as a secondary prevention in patients with aPL-associated valvular disease who have already experienced a thromboembolic event. In the recent large, controlled study by Khamashta et al,¹⁰⁵ high-intensity oral anticoagulant therapy (producing an INR3) proved to be more effective than low-intensity anticoagulation (INR<3) in preventing further venous and arterial thrombotic events associated with aPLs, yet it entailed an acceptable risk of complications, including bleeding. The results of two other larger therapeutic trials essentially paralleled this conclusion.^{106 107} As patients with APS are prone to repeated thrombotic episodes, especially in the first few months after withdrawal of oral anticoagulants, long-term, possibly lifelong anticoagulation is required in the presence of persistently elevated aPL titers.^{105 106 107}

In the study by Khamashta et al¹⁰⁵ on the secondary prevention of aPL-associated thromboses, low-dose aspirin (75 mg daily), either alone or in combination with warfarin, yielded no therapeutic benefit after adjustment for other risk factors for thrombosis. This observation is similar to that of Rosove and Brewer.¹⁰⁷ Still, the use of aspirin and other antiplatelet agents, especially in the prevention of arterial thrombosis, remains to be validated.¹⁰⁸ Whether the presence of high titers of aPLs in patients with echocardiographically documented or even clinically manifest valvular disease is an indication for therapeutic intervention also awaits appraisal.

There is no evidence that treatment with corticosteroids can prevent valvular damage. Although the inflammatory reaction may be dramatically suppressed, the basic disease process and tissue injury are not altered by steroid therapy. In fact, steroids may facilitate healing of valvular vegetations, which may result in marked scarring and deformity of the valve, thereby most likely leading to valve dysfunction.^{49 53} New antithrombotic agents and plausible, better-targeted therapies have yet to be evaluated in terms of their efficacy and safety.^{109 110}

It is prudent that patients with features of pseudoinfective endocarditis receive antibiotics. Anticoagulants should be instituted to reduce the risk of thromboembolic complications.⁹²

	Conclusions

Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
Data provided by clinical and immunopathological studies support an association between aPLs and heart valve lesions. They also imply that aPLs play a pathogenetic role in endocardial damage. Basic and randomized, prospective, controlled clinical studies are needed to further define the role of aPLs in cardiac valve disease, elucidate its natural history, and establish optimal treatment and prevention of the disease and its potential clinical sequelae.

	Selected Abbreviations and Acronyms

 

aCL = anti-cardiolipin antibody aPL = anti-phospholipid antibody APS = antiphospholipid syndrome INR = international normalized ratio LA = lupus anticoagulant SLE = systemic lupus erythematosus

	Acknowledgments

 
This work was supported in part by the S. Burton Fund for Research in Autoimmunity. Dr. Hojnik was supported by the Ministry of Science and Technology of Slovenia (grant No. C3-0562-353-94/IV).

Received September 5, 1995; revision received October 26, 1995; accepted November 5, 1995.

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Top Abstract Introduction Historical Background Evidence for an Association... Morphological and Functional... Clinical Implications of... Possible Pathogenetic Mechanisms Conclusions References

 
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