Cardiac manifestations in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease associated with arterial and venous thrombotic events and recurrent fetal loss. Cardiac manifestations in APS primarily include accelerated atherosclerosis leading to cardiovascular disease. There is increased cardiovascular mortality in APS. Cardiovascular risk is even higher in secondary APS in lupus patients. Several traditional and disease-related, autoimmune-inflammatory risk factors are involved in APS-associated atherosclerosis and its clinical manifestations. Antiphospholipid antibodies (APA), lupus anticoagulant, anti-oxLDL and other antibodies have been implicated in vascular events underlying APS. The primary and secondary prevention of atherosclerosis and CAD in these diseases includes drug treatment, such as the use of statins and aspirin, as well as lifestyle modifications. Apart from atherosclerosis and CVD, other cardiac manifestations may also be present in these patients. Among these conditions, valvular disease including thickening and vegetations is the most common. APA are involved in the pathogenesis of Libman-Sacks endocarditis usually associated with SLE. In addition, ventricular dysfunction, intracardiac thrombi and myxomas, pulmonary hypertension may also exist in APS patients. Early diagnosis of APS, thorough examination of the heart, control of traditional risk factors by lifestyle modifications and pharmacotherapy, probably anti-inflammatory treatment, and close follow-up of APS patients may help to minimize cardiovascular risk in these individuals.     

The antiphospholipid antibody syndrome: A riddle wrapped in a mystery inside an enigma

The antiphospholipid antibody syndrome (APS) is the association of certain clinical features with the presence of antiphospholipid antibodies (APA) in the serum or plasma of affected individuals. APS may be primary or secondary to another disease, typically autoimmune diseases such as systemic lupus erythematosus (SLE).The prototypic clinical features are thrombotic events (venous and arterial) and pregnancy morbidity (recurrent fetal loss, severe preeclampsia, eclampsia, and multiple spontaneous abortions). The term antiphospholipid antibody is a misnomer since it now appears that APA are actually directed against protein phospholipid complexes. APA may also occur secondary to infections however these APA seem to be directed at phopsholipid only and are transient. Particular phospholipid-binding proteins associated with APS include beta 2-glycoprotein I (B2GPI), prothrombin, and annexin V. A recent International Consensus Statement defines Definite APS as the presence of certain clinical findings (either a thrombotic event and/or pregnancy morbidity) and the presence and persistence of laboratory evidence of APA [either the lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL)]. Other clinical features associated with APS include thrombocytopenia, various skin conditions, cardiac valvular diseases, and diverse neurological conditions as outlined in the main text. These other features may be part of APS but require further evidence to establish their pathological and clinical validity. Other laboratory tests of interest include anti-B2GPI, antiprothrombin, and antiphosphatidylserine antibodies. The diagnostic and clinical importance of these additional laboratory tests remains to be determined.APA are estimated to be present in up to 5% of the general population, with the prevalence increasing with age. APA are estimated to be present in 12% or more of patients with thrombosis. ACL are present in 12 to 30% of patients with SLE and LA are present in 15 to 34% of patients with SLE. There is often concordance between LA and ACL however this is not always true. APA (both ACL and LA) are associated with thromboembolic events. Venous thrombosis is more common than arterial thrombosis and a minority of patients have both. LA is more strongly associated with thrombosis than ACL. The estimated yearly incidence of thrombosis in individuals with APA is 1% for those with no history of thrombosis, 4% for those with SLE, and 6% for those with high titer immunoglobulin G (IgG) ACL. The presence of LA, and possibly of medium to high titers of IgG ACL, help identify patients at risk for thrombosis.     

Apoptosis and the antiphospholipid syndrome

The target of many antiphospholipid autoantibodies (APA) has been shown to be a complex between anionic phospholipid (PL) and the plasma protein beta 2-glycoprotein I (beta 2-GPI), but the identity of the natural target(s) and/or immunogen for APA in vivo remains undetermined. The anionic PL of cell membranes represent important potential targets and immunogenes for APA. Although anionic PL are normally absent from the extracellular surface of cell membranes, they redistribute from the inner to the outer leaflet during apoptosis. We and others have shown that beta 2-GPI binds selectively to the surface of apoptotic, but not viable, cells, and that the binding of beta 2-GPI to the surface of apoptotic cells generates an epitope recognized by APA from patients with both primary antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). In this review, we discuss recent findings, which suggest not only that apoptotic cell-bound beta 2-GPI is injected by non-intravenous routes. We also review briefly the potential role of oxidation in generating epitopes responsible for the recognition and induction of APA. Taken together, we believe that the available evidence supports a role for apoptotic cells as far as targets of APA and possible players in the induction of APA.     

Insights into atherosclerosis therapy in antiphospholipid syndrome

The presence of early atheroma in antiphospholipid syndrome (APS) underscores the necessity of new therapies for this disorder. Inflammation plays an essential role in the pathogenesis of both APS secondary to systemic lupus erythematosus and atheroma. Several drugs currently used in APS have also anti-atherogenic properties via their anti-inflammatory effect. Furthermore, in addition to screening and treatment of traditional cardiovascular risk factors, it has been suggested that the introduction of some new medication such as statins in APS patients could be useful. This review assesses the current knowledge in this field and the justification for this new therapeutical approach. Furthermore, these data underscore the necessity for the use of other medication for atherosclerosis in APS patients, such as immunomodulatory drugs, which would be complementary to the anti-thrombotic and anti-platelet therapy.     

Atherosclerosis in primary antiphospholipid syndrome

Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia, but experimental and clinical evidence accumulated over the years suggest that the clinical manifestations of APS go beyond those of a simple hypercoagulable state. Although still a controversial topic, the elevated risk of atherosclerosis in systemic lupus erythematosus seems little accounted for by the presence of antiphospholipid antibodies, whereas premature atherosclerosis has been addressed in few series of patients with primary APS. The available data in primary APS suggest that traditional risk factors for atherosclerosis are less involved in arterial disease, rather antiphospholipid antibodies appear as major players. Their effect on the coagulation system, the vessel wall and on the antioxidant/oxidant balance impairs vascular homeostasis, leading to premature arterial thickening.     

Antiphospholipid Antibodies and Atherosclerosis: Insights from Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome

The issue of atherosclerosis in the antiphospholipid syndrome (APS) is receiving considerable attention within and without the autoimmune settting. Measurement of arterial intima media thickness (IMT) of is an easy and surrogate means of detecting subclinical atherosclerosis. This technique has been applied to patients with systemic lupus erythematosus (SLE) nand primary APS in the attempt to unravel a possible association between antiphospholipid antibodies and premature atherosclerosis. The available data is reviewed in the light of the most recent atherogenic pathways that may differentially account for premature vascular disease in SLE and primary APS.     

Cardiovascular disease in autoimmune rheumatic diseases

Various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis, spondyloarthritis, vasculitis and systemic lupus erythematosus, are associated with premature atherosclerosis. However, premature atherosclerosis has not been uniformly observed in systemic sclerosis. Furthermore, although experimental models of atherosclerosis support the role of antiphospholipid antibodies in atherosclerosis, there is no clear evidence of premature atherosclerosis in antiphospholipid syndrome (APA). Ischemic events in APA are more likely to be caused by pro-thrombotic state than by enhanced atherosclerosis.     

Intravenous immunoglobulin for the secondary prevention of stillbirth in obstetric antiphospholipid syndrome: A case series and systematic review of literature

ObjectiveTo evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) in secondary prevention of pregnancy complications for patients with obstetric antiphospholipid syndrome (APS) and history of stillbirth.MethodsWe described three cases of obstetric APS patients with history of stillbirth treated with IVIg in four pregnancies. In addition, we conducted a systematic literature review on the use of IVIg in obstetric APS with history of stillbirth.ResultsThree patients with obstetric APS and history of stillbirth were treated with prophylactic IVIg, in addition to standard treatment (hydroxychloroquine, low-dose aspirin, low molecular weight heparin, and prednisone), in four pregnancies (three singleton and one twin). All pregnancies resulted in live healthy newborns. Long-term follow-up re-evaluations (24–53 months) did not shown any sign or symptom of active systemic disease, and the children were healthy.The systematic literature review retrieved only three cases of use of IVIg in obstetric APS patients with history of stillbirth. All three cases resulted in live healthy newborns. Only in one case, mild thrombocytopenia occurred during treatment, although this event was unlikely to be related to IVIg.ConclusionOur experience suggests that IVIg as secondary prevention of APS-related stillbirth is associated with good pregnancy and long-term outcomes, with no relevant safety concerns. However, the literature evidence on this topic is limited to few isolated cases, and further studies are needed to clarify which obstetric APS patients may benefit the most from IVIg.     

Endothelial progenitor cell dysfunction in type 1 diabetes: another consequence of oxidative stress?

Endothelial progenitor cells (EPC) have been shown to contribute to neovascularization and vascular maintenance and repair in adults. Recently, the concept has evolved that EPC dysfunction, in patients at risk for cardiovascular disease, may contribute to the development of atherosclerosis and ischemic vascular disease. Particularly, patients with diabetes mellitus are likely to be affected by EPC dysfunction as several studies have shown a reduced number and function of EPC in patients, as well as in preclinical models for type 1 diabetes. Here, we review our current understanding of EPC (dys)function in diabetes and discuss some potential mechanisms underlying their altered properties. Moreover, we provide circumstantial evidence indicating that increased oxidative stress could play a role in the development of EPC dysfunction in type 1 diabetes. Finally, we discuss the potential implication of our findings for EPC-based therapies and the potential impact of pharmacological interventions on the vascular regenerative capacity of EPC.     

Preventing autoimmune and infection triggered atherosclerosis for an enduring healthful lifestyle

Atherosclerosis is a chronic inflammatory disease of the arteries associated with various risk factors that promote lipid abnormalities (i.e., dyslipidemia), development and progression of atherosclerotic lesions, plaque rupture, and vascular thrombosis. Experimental evidence from biochemical and clinical studies support the idea that arterial thrombosis is an autoimmune process resulting from 'autoantibody'-mediated pro-atherogenic mechanisms now seen in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). In addition, it has been shown that persistent infections of Chlamydia pneumoniae (C. pneumoniae), Porphyromonas gingivalis (P. gingivalis), and Helicobacter pylori (H. pylori) cause immune responses (infectious immunity) in their hosts that promote atherogenesis. In this article, we review recent progress in our understanding of immune- and infection-mediated atherosclerosis.     

Systemic Antiphospholipid Syndrome and Atherosclerosis

Atherosclerosis (AT) is a metabolic, systemic inflammatory/immune disease characterized by lipoproteins metabolism alteration that leads to immune/inflammatory system activation with the consequent proliferation of smooth-muscle cells, narrowing arteries and atheroma formation. Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombophilic state and circulating antiphospholipid antibodies (aPL) including anti β2-GPI. Experimental studies and human observations suggest that APS is associated with AT. In fact, innate and adaptive immune responses participate in the pathogenesis of both diseases. Anti-oxLDL, anti-aPL, anti β2GPI, anti-HSP antibodies, among others, has been found in patients with APS and AT. Endothelial dysfunctions, oxidative stress, increase of cell adhesion molecules, active platelets, are common findings in both diseases. Macrophages, dendritic cells, T-cell activation, CD40–CD40 ligand interaction, are considered as pathogenic mechanism of AT and APS. Premature AT may be the first symptom of APS. Thrombophilia, aPL antibodies, and APS may be present in patients with premature AT. An association between AT and venous thrombosis (a clinical hallmark of APS) has been proposed in unselected patients with deep venous thrombosis of the legs without symptomatic AT. Asymptomatic AT, defined in terms of carotid intima media thickness and lumen diameter decrease, was observed in patients with APS. Premenopausal female patients with PAPS have a higher prevalence of cerebrovascular disease in comparison with male patients. Accelerated AT and hormones could be the explanation of these findings. High levels of aCLs, significantly predict the risk of future ischemic stroke in women but not in men. AT is one of the main features of systemic APS and offer opportunities for new treatment strategies.     

Prevention & treatment of obstetrical complications in APS: Is hydroxychloroquine the Holy Grail we are looking for?

Pregnancy morbidity is part of the clinical spectrum of the anti-phospholipid syndrome (APS), with an important social and economical cost. Antiplatelet and anticoagulant agents are effective in preventing the clinical manifestations in the majority of the patients. However, a consistent proportion of the pregnant women present recurrences in spite of the standard therapy. Observational studies and anecdotal reports raised the issue of additional therapeutic strategies in these refractory cases. Among these, anti-malarials (AMs) and in particular hydroxychloroquine (HCQ) are becoming more and more popular in APS as well as in other systemic autoimmune rheumatic conditions. AMs display a pleiotropic activity spanning from immunomodulation effect to anti-inflammatory and anti-thrombotic activities, all of which potentially useful in APS. The well-known safety of HCQ in pregnancy encouraged its use in pregnant women with autoimmune rheumatic disorders including APS and observational reports suggested a protective effect on obstetrical recurrences. Since thrombosis does not seem to be the main pathogenic mechanism in obstetric APS, effectiveness of the treatment with HCQ should be related to other pharmacological effects rather than to the anti-platelet or anti-thrombotic activity of the molecule. Experimental models showed that HCQ may restore some defective biological functions induced by anti-phospholipid antibodies (aPL) on trophoblasts and a recent study reported a protective effect on in vivo aPL-mediated placental and foetal neurodevelopmental abnormalities. Although the rational behind the use of HCQ in obstetric APS is sound, the evidence from the real life is not conclusive and a critical appraisal through clinical trials is mandatory.     

Elevated anti-annexin V antibody levels in antiphospholipid syndrome and their involvement in antiphospholipid antibody specificities

To clarify the involvement of annexin V (ANX) in antiphospholipid antibody (APA) specificities, we studied antiANX antibodies (aANX) using 2 kinds of enzyme-linked immunosorbent assay plates (plain and gamma-irradiated) and anti-beta 2-glycoprotein I antibodies (a-beta 2GPI) in 53 patients with antiphospholipid syndrome (APS). The incidence of aANX IgG-positive results in the autoimmune APS group was significantly higher than that of healthy control subjects. However, we could not demonstrate a significantly higher incidence in the infection- or drug-induced group. Nor could we find an increased incidence of IgM isotype. When the 2 plates were compared, the discrepancies of positivity were demonstrated in both isotypes. We speculated that these discrepancies between the plate surfaces were attributed to the altered antigenicity of ANX. Although positivity of a-beta 2GPI was associated significantly with clinical manifestations, no significant associations were demonstrated between the incidence of aANX-positive results and clinical manifestations. We inferred that the involvement of aANX in the pathogenic mechanism of APS is unlikely.     

Oxidation of LDL and its clinical implication

Oxidative modification of low-density lipoprotein (LDL) is one of the earliest events in atherosclerosis. Oxidized LDL (oxLDL) represents a variety of modification of both lipid and apolipoprotein B (apoB) components by lipid peroxidation. This promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the formation of macrophage foam cells. Recent findings also suggest that oxLDL forms complexes with beta(2)-glycoprotein I (beta(2)GPI) and/or C-reactive protein (CRP) within atherosclerotic lesions and that these complexes appear in the circulation. Autoantibodies (auto-Abs) against oxLDL/beta(2)GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). These autoantibodies significantly correlate with arterial thrombosis. IgG auto-Abs having similar specificity emerge spontaneously in NZWxBXSB F1 mice, which generally are considered to be an animal model of APS, and these mice produce a monoclonal IgG auto-Ab (WB-CAL-1) against oxLDL/beta(2)GPI complexes. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages, which suggests that such IgG auto-Abs are pro-atherogenic. In contrast, IgM anti-oxLDL natural Abs found in the atherosclerosis-prone mice have been proposed to be protective. The presence of such Abs in humans has been documented in many publications but their exact pathophysiological significance remains unclear. In this article, we review recent progress in our understanding of the clinical significance of oxidation of LDL, formation of oxLDL complexes, and Abs in atherosclerotic and/or autoimmune disease.     

Anti-lysobisphosphatidic acid antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus

Lyso(bis)phosphatidic acid (LBPA) is a novel antigenic target in anti-phospholipid syndrome (APS) and antibodies directed against LBPA (aLBPA) have been detected in sera from APS patients. In this study we first evaluated aLBPA in comparison with the most widely used methods (i.e. anticardiolipin [(aCL)-enzyme-linked immunosorbent assay (ELISA)] and antibeta-2-glycoprotein-I antibodies (abeta(2)-GPI-ELISA) utilized to detect antiphospholipid antibodies in patients with primary or secondary APS, systemic lupus erythematosus, chronic HCV infection and healthy subjects. We then assessed the relationship between aLBPA, lupus anticoagulant (LAC) and the main clinical manifestations of APS. Finally, we evaluated the presence of 'pure' (i.e. beta(2)-GPI-independent) aLBPA in patients with APS and controls. The results indicate that aLBPA as well as abeta(2)-GPI display higher specificity but lower sensitivity for APS compared to aCL. Moreover, serum aLBPA correlate closely with aCL and abeta(2)-GPI in APS patients and are strictly associated with LAC positivity. We demonstrate that beta(2)-GPI binds to LBPA with affinity similar to CL, and antibodies able to react with phosholipid-protein complex exist; however, 'pure' aLBPA can also be detected in sera of APS patients. Altogether these data confirm that LBPA may be an antigenic target in APS and that aLBPA are serological markers of APS with similar sensitivity and specificity compared to abeta(2)-GPI. However, the clinical utility of aLBPA detection alone or in combination with aCL and/or abeta(2)-GPI remains to be elucidated in larger and longitudinal studies.     

Is there today a place for corticosteroids in the treatment of scleroderma?

In systemic sclerosis (SSc), the use of corticosteroids (CS) is controversial due to their association with scleroderma renal crisis (SRC). However, patients with very early and early disease, characterised by main inflammatory component, may benefit from CS therapy.The aim of this review is to discuss pros and cons of CS treatment in SSc, providing current evidence about the use of CS in SSc. Moreover, we discuss also the underlying pathogenetic mechanisms that may be the background for the potential harms and efficacy of CS in SSc.     

Arterial stenosis in antiphospholipid syndrome: Update on the unrevealed mechanisms of an endothelial disease

First described in 1983, antiphospholipid syndrome (APS) is an autoimmune condition characterized by the occurrence of recurrent arterial and/or venous thrombosis, and/or pregnancy morbidity, in the setting of persistent presence of antiphospholipid antibodies (aPL). While thrombosis is the most well-known pathogenic mechanism in this disorder, the relevance of some other mechanisms such as arterial stenosis is being increasingly recognized. Arterial stenosis has been first described in the renal arteries in patients with APS, however intracranial and coeliac arteries can also be involved with various and treatable clinical manifestations. The underlying pathophysiology of this stenotic arterial vasculopathy is not fully understood but some recent studies revealed new insights into the molecular mechanism behind this endothelial cell activation in APS. In this review, we discuss these newly discovered mechanisms and highlight the diagnostic and therapeutic modalities of the APS related arterial stenosis.     

Atherosclerosis and antiphospholipid syndrome

Atherosclerosis is an autoimmune/inflammatory disease associated with infectious, inflammatory, and autoimmune factors. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions. Heat-shock protein (hsp), oxidized low-density lipoprotein (LDL), and β2-GPI have been reported to elicit humoral and cellular immune response in both experimental animals and humans. These autoantigens are expressed within atherosclerotic lesions. Immunization with the given autoantigens elicits an immune response that influences lesion progression. Atherosclerosis susceptibility can be transferred by autoantigen-sensitized lymphocytes from immunized animals. Patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have a high risk for atherosclerotic cardiovascular events. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS. Immunological alterations, such as antibodies to oxidized LDL, antiphospholipid antibodies (aPL), antibodies to β-2 Glycoprotein (anti-β2-GPL), anti-prothrombin antibodies, may play a role in premature atherosclerosis in SLE and APS. Paraoxonase (PON1) is an enzyme with antioxidant activity attached to the circulating high-density lipoprotein (HDL) in plasma. Its function is to prevent oxidation of LDL, thereby accounting for the antioxidant properties and the atherosclerotic protective effects of HDL. The relationship between PON1 and aPL has been recently suggested. IgG anti-HDL and IgG anti-β2-GPI antibodies were associated with reduced PON1 activity in patients with SLE and primary APS. The determination of classic and new factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis in SLE and PAPS. Therapeutic strategies, including early control of disease and other risk factors, are essential to reduce morbidity and mortality.     

Cardiovascular involvement in systemic autoimmune diseases

Autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, affect a large number of people in whom one of the leading causes of morbidity and mortality is cardiovascular disease. Cardiovascular disease is associated with the development of accelerated atherosclerosis. It seems to occur at a younger age than in the general population, is often asymptomatic and, in addition to traditional risk factors, also involves specific risk factors as chronic inflammation, the duration and activity of the autoimmune disease, and immunosuppressive therapy. The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. There are various means of detecting morphological cardiac damage: coronary angiography remains the gold standard for diagnosing coronary stenosis, but new, non invasive and more reliable methods have been introduced into clinical practice in order to detect subclinical microcirculation abnormalities.