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Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18.

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Autoimmunity: From Bench to Bedside [Internet].

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Chapter 38Cardiovascular involvement in autoimmune diseases

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Autoimmune diseases (ADs) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic factors, gender disparity, environmental triggers, pathophysiological abnormalities and certain subphenotypes which are represent by the autoimmune tautology (1,2). Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, researches in the last three decades have shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors, characterized by lipoproteins metabolism alteration that leads to immune system activation with the consequent proliferation of smooth-muscle cells, narrowing arteries and atheroma formation (3). Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions (4). In recent years, many reports have been focused on the immunologic background of AT, and it is no longer in doubt that shares several autoimmune pathways (5). It is not surprising, to find an accelerated AT in quite a lot of ADs.

Several risk factors have been described since The Framingham Heart Study, known as classic risk factors, which over time conduce to endothelial dysfunction, subclinical AT and Cardiovascular (CV) event manifest. Interestingly, the excessive CV events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to development of premature vascular damage. Sarmiento-Monroy et al. (6,7) previously proposed a classification for non-traditional risk factors in ADs, which divide them into genetic determinants, AD-related and miscellaneous. Therefore, a complex interaction between traditional and disease-specific traits leads to premature AT process in autoimmunity.

All of these pathways may eventually converge into a shared pro-atherogenic phenotype (8). Cardiovascular Disease (CVD) represent a broad spectrum of subphenotypes: hypertension (HTN); Coronary syndromes: angina, Ischemic Heart Disease (IHD), Acute Coronary Syndrome (ACS), Coronary Artery Disease (CAD), Myocardial Infarction (MI); Congestive Heart Failure (CHF); Peripheral Arterial Disease (PAD); Left Ventricular Diastolic Dysfunction (LVDD); cerebrovascular disease (Cerebrovascular Accidents [CVAs]; Transient Ischemic Attacks [TIAs]); thrombosis: Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE); Peripheral Vascular Disease (PVD); and subclinical AT.


Atherosclerosis is a multifactorial, chronic and inflammatory disease that had been traditionally viewed as a lipid-based disorder affecting the vessel walls. Nowadays, this theory had been modified, and it is known that all arms of the immune system take part in atheroma formation. The increased understanding of the mechanisms promoting vascular damage has been recently focus on pro-inflammatory pathways, which appear to play key role in development and propagation of the disease. Thus, some of the mechanisms that drive the atherosclerotic plaque formation, and therefore CVD, are shared with several ADs, although each disease may have particular immunological aberrations that provide specific atherogenic pathways (8). The lesions of AT, the plaque rupture and atherothrombosis resulting in infarction, occur mainly in large and medium sized elastic and muscular arteries and can lead to heart ischemia, brain, or extremities (911).

Cellular immunity and inflammatory markers

AT is characterized by the accumulation of lipid particles, immune system cells [e.g., monocytes/macrophages (Mф) and T lymphocytes], autoantibodies, autoantigens (e.g., vessel walls components), and the multiple production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and Interferon-γ (IFN-γ) in subendothelial regions. All these components leading a gradual thickening of the intima layer, causing a decrease in elasticity, arterial lumen narrowing, blood flow reduction, plaque rupture and finally CV event (9,12). The systemic inflammatory response that characterizes AT also involves acute-phase reactants, such as serum amyloid A, fibrinogen, erythrocyte sedimentation rate (ESR), and C-Reactive Protein (CRP). For instance, CRP can activate complement system and enhance the pro-inflammatory production cytokines, such as interleukin-6 (IL-6) (13). Thus, increased levels of CRP has been shown to be an independent risk factor for CVD (1416). Endothelial dysfunction is the first step leading to AT and had been associated with both, traditional and non-traditional risk factors related to several ADs. For instance, free radicals caused by cigarette smoking and type 2 diabetes mellitus (T2DM) (17), some of them caused or exacerbated by steroid therapy (18), contribute to this process. Other factors involved are angiotensin II high concentrations, which increase smooth-muscle hypertrophy, peripheral resistance and oxidation of low density lipoprotein cholesterol (LDL), as well as elevates plasma homocysteine concentrations (19,20). Several infectious pathogens have been also related with atherosclerotic process, which include C. pneumoniae, M. pneumoniae, H. pylori, Cytomegalovirus, Epstein-Barr virus and Herpes Simplex Virus type 1.

Early in the development of AT, LDL becomes modified (i.e., oxidation, glycation). During this process, reactive aldehydes are produced, which binding to lysine and histidine residues in the ApolipoproteinB (ApoB) component of LDL, and produce immunogenic neoepitopes (21). It is a major cause of injury to the endothelium and underlying smooth muscle (9,12,22,23). Thus, the different forms of injury increase the endothelium adhesiveness regarding leukocytes or platelets, as well as its permeability, with the expression of multiples vascular cell adhesion molecules (VCAM), intercellular adhesion molecules-1 (ICAM-1), selectins and chemokines. In response to these adhesion molecules, monocytes are recruited and differentiated into Mф. Thereby, when LDL particles become trapped in an artery, they can submit progressive oxidation, facilitates the accumulation of cholesterol esters and be internalized by Mф through scavenger receptors pathway (24,25), resulting in the formation of foam cells. Besides their differentiation, Mф are associated with up-regulation of toll-like receptors (TLRs), which enhance a cascade of Mф activation and release of vasoactive molecules such as nitric oxid (NO), reactive oxygen, which increase oxidation and toxicity of lipoproteins, endothelins, eicosanoids, and proteolytic enzymes, all of which lead to the plaque destabilization of and increased risk for rupture (24,25). The foam cells subsequently produce growth factors and cytokines that lead to the proliferation of vascular-smooth-muscle cells and plaques development (8,25). In addition to its ability to injure these cells, modified LDL Cambiar por [i.e., oxidized-LDL (ox-LDL)] is chemotactic for other monocytes and can up-regulate the expression of genes for Mф colony stimulating factor (MCSF) and monocyte chemotactic protein (MCP) derived from endothelial cells. Thus, it may help expand the inflammatory response by several ways: stimulating the replication of monocyte-derived Mф and the entry of new cells into lesions, increasing the bind of LDL to endothelium, transcription of the LDL-receptor gene and attracting more lipoprotein and lymphocytes within artery (23).

After the process is begun, rolling and adherence of monocytes and T cells occur at these sites as result of up-regulation of adhesion molecules on both endothelium and leukocytes. Chemokines may be responsible for chemotaxis and accumulation of Mф in fatty streaks. Activation of monocytes and T cells leads to up-regulation of receptors on their surfaces, such as the mucin-like molecules that bind selectins, integrins that bind adhesion immunoglobulin superfamily molecules and receptors that bind chemoattractant molecules (23,26). T cells, predominantly lymphocyte T helper 1 (Th1) are also recruited to the subendothelial space where they produce cytokines. They appear in the arterial intima as early in 1 year old children in fatty streaks. Th1 are dominating over lymphocytes T helper 2 (Th2) and their anti-inflammatory mediators (i.e., IL-4, 5,10). This kind of reaction is increased in several ADs, which are characterized as being Th1 cell-mediated more than Th2 cell-mediated conditions, with high production of TNF-α, IFN- γ, IL-2, IL-6, IL-17 among others, further to be able to activate T cells, favor smooth muscle cell migration, proliferation and foam cell formation (8,2729). The continuing entry, survival and replication of mononuclear cells in lesions depend on factors such as MCSF and granulocyte–Mф colony-stimulating factor for monocytes and IL-2 for lymphocytes. Therefore, as fatty streaks progress to intermediate and advanced lesions, they tend to form a fibrous cap. The fibrous cap covers a mixture of leukocytes, lipid and debris, which may form a necrotic core, due to inflammatory cytokines such as IFN-γ, which activate Mф and under certain circumstances induce them to undergo programmed cell death, increase proteolytic activity, and lipid accumulation. Those are producing cytokines, such as TNF-α, IL-1, transforming growth factor-β (TGF-β), and growth factors such as platelet-derived growth factor (PDGF) (25), enhancing the inflammatory response and thereby the atherosclerotic process.

Furthermore, activated Mф express human leukocyte antigen (HLA) II such as HLA-DR that allows them to present antigens to T lymphocytes. T cells are activated when they bind antigen processed and presented by Mф. Smooth-muscle cells from the lesions also have class II HLA molecules on their surfaces, presumably induced by IFN-γ and can also present antigens to T cells, such as ox-LDL and heat shock proteins (HSP) 60/65 which can be produced by Mф (25,27). The immune regulatory molecule CD40-ligand and its receptor CD40 are expressed by Mф, T cells, endothelium and smooth muscle. Both are up-regulated in lesions of AT, providing further evidence of immune activation. Furthermore, CD40-ligand induces the release of IL-1β by vascular cells, potentially enhancing the pro-inflammatory response (23). Rupture of the fibrous cap or ulceration of the fibrous plaque can rapidly lead to thrombosis and usually occurs at sites of thinning of the fibrous cap that covers the advanced lesion. Thinning of the fibrous cap is apparently due to the continuing influx and activation of Mф, by activated T cells, which release metalloproteinases and other proteolytic enzymes. These enzymes cause matrix degradation, which promotes plaque instability and can lead to hemorrhage from the vasa vasorum and can result in thrombus formation (30).

Humoral immunity and autoantigens

As ox-LDL is a huge molecule with many potential autoantigens, it is possible that anti-oxidized low-density lipoprotein antibodies (anti-oxLDL) represent a family of auto-antibodies against different autoantigens. In the conventional view, the antigen-antibody reaction is prone to enhance inflammation and results in exacerbation of AT. Thus, the clinical impact of these auto-antibodies might vary. However, reports on elevated anti-oxLDL titers in humans have been detected in patients with early-onset PVD, severe carotid AT, CHF, CAD, MI and death (31,32), suggesting a pro-atherogenic role for this auto-antibodies. Several authors had found elevated levels of these antibodies related to CVD, supporting a key role in the progression of AT (31,33,34).

Beta-2 glycoprotein-1 (β2GPI) is a polypeptide that binds to negatively charged molecules and plays a part in the clearance of apoptotic cells and inhibition of coagulation. It is considered to be the autoantigen in antiphospholipid syndrome (APS). β2GPI is abundantly expressed within the subendothelial regions and in the intima-media layers at the border of human atherosclerotic plaques, and it co-localized with CD4+ T cells (35). Both, IgM and IgG anti-β2GPI levels are elevated in patients with AT and other inflammatory conditions. Immunization with this polypeptide results in accelerated AT in mice (36). Other antibodies with pro-coagulant activity are anti-cardiolipins antibodies (ACLA). β2GPI is the actual autoantigen for most ACLA, as the binding of cardiolipin exposes a cryptic epitope of β2GPI. The association between anti-phospholipid antibodies (APLA), AT and thrombosis can also be seen outside the setting of autoimmunity. Thus, ACLA promote AT by attracting monocytes into the vessel wall, by induction of monocyte adherence to endothelial cells, which is mediated by adhesion molecules such as ICAM-1, VCAM-1 and E-selectin (37). The APLA should be considered as more than a AT marker, as they can enhance AT and are pro-atherogenic (38,39).

HSPs are a family of proteins well conserved across species that may be elevated on endothelial cells and participate in atherosclerotic, inflammatory and autoimmune response. HSP60 is expressed by vascular cells in response to stressful events such as infections, fever, cytokines, oxidative stress and mechanical injury. This and other HSPs perform several functions, including the assembly, intracellular transport, and breakdown of proteins, facilitate refolding of denatured proteins and loading of immunogenic peptides to HLA-I and II. It is assumed that the endogenous HSP60 becomes immunogenic as a consequence of molecular mimicry of HSPs expressed by pathogens such as C. pneumoniae and H. pylori. Likewise, serum of patients with CVD shows high prevalence of antibodies against HSP60 that shares epitopes with cytomegalovirus. Thereby, these antibodies formed against HSP60/65 mediate lysis of stressed endothelial cells in-vitro and are elevated in patients with CVD (35). There are also data showing the existence of oligoclonal T cells within atherosclerotic plaques that can recognize HSP60 specifically, in contrast to T cells more distant from the lesion (21,40).

Rheumatoid arthritis

Rheumatoid Arthritis (RA) is the most common autoimmune arthropathy worldwide. The overall prevalence in developed countries ranges from 0.5 to 1.0% (41). In addition to dyarthrodial joints, RA can damage virtually any organ thus leading to potential extra-articular manifestations (EAMs). CVD is consider an EAM, and represents the major predictor of poor prognosis and main cause of death in this population (6,4244).

There is evidence that vascular damage accrual begins prior to the diagnosis of RA and accelerates as the disease progress. RA patients present with endothelial dysfunction and increased subclinical AT compared to age-matched controls (45). Endothelial function, assessed by brachial artery flow-mediated vasodilation (FMV), also worsens with disease duration (46).

Cardiovascular burden in RA

Many research groups have demonstrated that RA patients are at increased risk of fatal and non-fatal CV events, compared with the general population (47). The CV mortality is higher in RA and life expectancy of patients with RA is three to ten years less than general population (48,49). CVD accounts for 30–50% of all deaths in RA patients (43), and it is known that occurs earlier and 3.6 times more frequently than general population (9,44,50). Thus, CVD is the leading cause of death around the world in RA patients (51,52).

Currently, IHD secondary to AT is the most prevalent cause of death associated with CVD in RA patients (53). Almost all mortality studies have been conducted in populations of European origin, and limited information exists in other ethnic groups. A meta-analysis of 24 RA mortality studies, published between 1970 and 2005, reported a weighted combined all-cause standardized mortality ratio (meta-SMR) of 1.50, with similar increases in mortality risk apparent from the ratios for IHD (meta-SMR 1.59) and for CVA (meta-SMR 1.52) (54). RA patients frequently experience ‘silent’ IHD with no symptoms before a sudden cardiac death. Indeed, sudden cardiac deaths are almost twice as common in patients with RA as in the general population (55). According with above, the Rochester Epidemiology Project (47) showed RA lends a risk for MI than controls of equivalent age and sex. Nicola et al. (56) demonstrated that cumulative incidence of CHF at 30-year follow-up was 34%, compared with 25% in the non-RA cohort.

Recently, Sarmiento-Monroy et al. (6) conducted a systematic literature review of CVD in Latin American (LA) population. A wide range of prevalence for CVD has been reported (13.8–80.6%) for this population. The highest prevalence was indicated by Santiago-Casas et al. (57) in Puerto Rican patients (55.9%). Cisternas et al. (49) evaluated CV risk factors in Chilean RA patients and reported a CVD prevalence of 46.4%. For Brazil (58,59), Colombia (7,42,60,61), and Argentina (62,63), a similar prevalence was reported (47.4, 35.1 and 30.5% respectively). In Mexico, five studies (6468) reported an overall prevalence of 20.9% for CVD in RA patients. However, the mortality in RA patients had been poorly evaluated in this population. Acosta et al. (69) demonstrated a mortality rate of 5.2% in a six-year follow-up. For both, the most frequent cause of death was CVD in 44.7% and 22.2% of the cases, respectively.

Traditional CVD risk factors

General population studies have identified a number of risk factors associated with the development of CVD [e.g., obesity, dyslipidemia, advanced age, T2DM, hyperhomocysteinemia, metabolic syndrome (MetS), sedentary lifestyle, male gender and smoking]. These parameters are often referred to as ‘traditional’ or ‘classic’ CVD risk factors and have also been associated with CVD in RA patients (7075). In a large retrospective cohort study of RA patients, Solomon et al. (76) showed a two to three-fold increase in the Relative Risk (RR) of MI after adjusting by traditional risk factors. Furthermore, the RR for stroke was 1.5 when compared with control groups. Boyer et al. (77), in a recent meta-analysis, confirmed the known association of traditional risk factors for CVD in RA patients. In Colombian population, Amaya-Amaya et al. (7), found that the traditional risk factors including male gender, hypercholesterolemia and abnormal body mass index (BMI) were associated with CVD. These factors, along with age, family history of CVD, and smoking habits were widely related to the high prevalence for CVD. Nevertheless, the increased prevalence of CV events in RA is not fully explained by these classic risk factors. Both non-traditional RA risk factors and traditional risk factors act together to develop CVD (Figure 1).

Figure 1. Traditional and non-traditional risk factors for cardiovascular disease in rheumatoid arthritis.

Figure 1

Traditional and non-traditional risk factors for cardiovascular disease in rheumatoid arthritis. aCVD include a broad spectrum of subphenotypes: stroke/transient ischemic attack, coronary artery disease, myocardial infarction, angina, congestive heart (more...)

Obesitiy. Obesity is associated with the presence of CVD in RA patients (42,66,67,70,78) as in the general population. In particular, abdominal fat is associated with insulin resistance and the evidence shows that, in RA patients, abdominal fat is distributed differently between the visceral and subcutaneous compartments, with visceral fat being more strongly associated with CVD risk than subcutaneous adiposity. Adipose tissue is metabolically active, and, through a network of adipocytokines, regulates not only energy intake and expenditure but also inflammation (79,80). Insulin resistance has consistently been found to be more frequent in RA than general population, and had been related to increased coronary calcification (81). A direct correlation between disease activity in RA and insulin resistance has been demonstrated, where cytokines, especially TNF-α, can directly impede insulin-mediated glucose uptake by skeletal muscle, thus promoting insulin resistance (80,82).

Dyslipidemia. A meta-analysis confirmed that RA is associated with an abnormal lipid pattern, mainly with low levels of high density lipoprotein cholesterol (HDL), high LDL and triglycerides (TGL) levels (48,56,6466,68,69,72,74,76,91). This altered lipid profiles had been related with higher probability of IHD by accelerating AT (42,83). In the large apolipoprotein-related mortality risk (AMORIS) study, the risk of MI was 60% higher in people with RA than in those without it. Total cholesterol (TC) and TGL levels were associated with the development of acute MI in individuals without RA, but not in those with RA (84). Levels of oxidized pro-inflammatory HDL are elevated in RA compared to healthy controls, this phenomenon may promote LDL oxidation and foam cell formation and decrease reverse cholesterol transport (85).

Advance age. It is mostly acknowledged that ‘normal’ or ‘healthy’ ageing of the CV system is distinct from the increasing incidence and severity of CVD with advancing age. Nevertheless, even in the absence of overt coexisting disease (e.g., RA), advanced age is always accompanied by a general decline in organ function, and specifically by alterations in structure and function of the heart and vasculature that will ultimately affect CV performance (86). For this reason, advanced age is considered a strong traditional risk factor and one of the most closely associated with AT in RA patients (30), especially for women over 55 years and men over 45 according to Framingham study (17). In the same way, the immune system of RA patients is subject to accelerated aging probably because of deficiencies in maintaining telomeres and DNA stability leading to excessive T cell apoptosis and increased proliferative pressure (87). A senescent immune system is normally associated with phenotypical and functional changes in cells characterized by a progressive loss of surface molecules such as CD28 and CD27, and the acquisition of cytokine-mediated pro-inflammatory activity and cytolytic functions (9,12,29,30,87).

Family history of CVD. There are several studies in healthy population and RA patients that had demonstrated the association between CV events and the family history of CVD (42,61). This is a non-modifiable risk factor and highlights the genetic features related to other risk factors that are heritable (e.g., HTN, familial hypercholesterolemia), and sometimes, lifestyles into the family.

T2DM. Defects in glucose metabolism are frequently impaired in patients with active RA and may contribute to CVD risk, at least partly related to inflammation. In fact, patients with RA have a similar risk of developing CVD when compared to the same risk in patients with T2DM (42,59,62,65,69). Unfortunately, when there is a coexistence of both diseases, this risk is increased by three times (88). Abdominal obesity, antihypertensive medication, disease activity and use of glucocorticosteroids (GC) affect glucose metabolism in RA patients (89).

Hyperhomocysteinemia. Homocysteine is considered as a biomarker for AT and a risk factor related with CAD and CAVs (81,90), because it contributes to endothelial dysfunction by reducing the availability of endothelium-derived NO (91). In RA patients with PE/DVT it has been found elevated levels of plasma homocysteine (49,65), especially in those receiving methotrexate (MTX). It remains controversy about whether hyperhomocysteinemia is a factitive agent of CV damage or only an epiphenomenon of inflammation (65).

MetS. The development of accelerated AT and increased risk of CVD disease in patients with RA may be influenced by the occurrence of MetS (42,48,59). MetS is characterized for an alteration in production/secretion of pro-inflammatory adipoquines leads to increased activity of RA and accelerating AT (92,93), thus an association between inflammatory activity of RA and MetS has also been suggested. Nevertheless, the frequency of MetS in RA varies according to the criteria used for the assessment [e.g., National Cholesterol Education Program (NCEP); International Diabetes Federation (IDF); Group for the Study of Insulin Resistance; World Health Organization (WHO)]. Da Cunha et al. (59) in a case-control study found MetS associated with disease activity, increased prevalence of waist circumference (WC), blood pressure, and fasting glucose in this RA population when compared to controls, using the NCEP scale.

Sedentary lifestyle. RA patients are less physically active than controls matched for age and sex, as a consequence of pain, stiffness, deformity and impaired mobility (42,67). Using the Paffenbarger physical exercise index, Mancuso et al. (94) found that patients with RA expended fewer kilocalories per week exercising than controls. The difference was mainly attributable to less walking by the RA patients rather than more high-intensity exercise in the controls. Alternatively, a sedentary lifestyle could also be an important cause of impairment of altered lipid pattern (95).

Hypertension. This is common in RA patients and it is known that HTN increases the risk to suffer IHD or CVA with an important impact on mortality (71). HTN is the major determinant of target organ damage in these patients and a link with low-grade inflammation. High CRP can reduce endothelial NO, leading to vasoconstriction, increased endothelin-1, platelet adherence, oxidation and thrombosis; it can also up-regulate angiotensin type 1 receptor expression and thus influence the rennin–angiotensin system (73,96). Multiple other factors may influence blood pressure control in people with RA, including physical inactivity, obesity, specific genetic polymorphisms and several antirheumatic drugs.

Male gender. In general population, CVD is more common in males than females, even a modest increased RR of CVD might translate into a high absolute risk for RA patient (42,60,65,66,68,78).

Smoking. This is a well-known risk factor for the development of CVD in healthy population. In addition, it has been recognized as a potent risk factor for RA development, especially in seropositive patients [i.e., rheumatoid factor (RF) and/or anti-citrullinated peptide antibodies (ACPA)] (42,49,65,67). In a meta-analysis of 4 case–control studies of traditional CVD risk factors in RA, the smoking prevalence was found to be higher in patients than in controls (77). Smokers with RA have a worse prognosis in terms of RF titers, disability, CVD, radiological damage and treatment response (72,87). Interactions are known to occur between smoking, HLA-DR1 shared epitope (SE) alleles, ACPA production, smoking and premature CVD mortality in RA (97).

Non-traditional CVD risk factors

It is known that RA is an independent factor for developing MI (98). Hence, there is an increasing interest in identifying novel risk factors in order to explain the early development of endothelial dysfunction, increased intima-media thickness (IMT) and finally, accelerated AT. This novel risk factors could be categorized into three groups: genetic (e.g., HLA-DRB1 SE alleles), RA-associated (e.g., auto-antibodies, inflammatory markers, high disease activity, long-standing disease and medications), and others (e.g., hypothyroidism, thrombogenic factors) (6,7) (Figure 1).

Genetic determinants. The genetic group includes several polymorphisms at the HLA and non-HLA loci. HLA-DRB1 SE alleles are related to chronic inflammation, more EAMs, high disease activity, endothelial dysfunction, premature death and CVD itself (42,97,99105). Thereby, association between HLA-DRB*0404, and endothelial dysfunction and CV mortality has been described in RA patients (106). Therefore, polymorphisms of HLA-DRB1 can be considered as a predictor of CV events. In Colombian population, Rojas-Villarraga et al. (42) found that being a carrier of a single copy of HLA-DRB1 SE was significantly associated with an increased risk of atherosclerotic plaque in patients with RA. Other authors (97,99), demonstrated that SE alleles, particularly compound heterozygotes, were associated with death from all causes (including CVD), independently of auto-antibody subphenotype.

The non-HLA group includes polymorphisms in endothelin-1 and methylene tetrahydrofolate reductase (MTHFR) genes, TNF-α rs1800629, TRAF1/C5 (TNF receptor-associated factor 1), STAT4 (signal transducer and activator of transcription 4), factor XIIIA, PAI-1 (plasminogen activator inhibitor type-1), TNFR-II (tumor necrosis factor receptor II), ACP1 (acid phosphatase locus 1), VEGFA (vascular endothelial growth factor A), LT-A (lymphotoxin-A), IL-6, LGALS2 (galectin-2), TGF-β, GSTT1 (glutathione S-transferase T1, MBL (mannose-binding lectin), and nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NFKB1)-94ATTG ins/del. All of these genes contributes significantly to increased risk of CVD and showed a potential influence on the course and complications in RA patients (107122).

RA-related factors

The RA-associated risk factors represent a broad spectrum of conditions related with the autoimmune nature of the disease. In fact, RA seems to be an independent risk factor for the development of accelerated AT.

Familial autoimmunity. Familial autoimmunity (FA) is defined as the presence of any AD in first degree relatives (FDRs) of the proband (123,124). This had been associated to presence of atherosclerotic plaque in Colombian patients with RA (42). Amaya-Amaya et al. (7) have replicated the same observation indicating that FA confers additional susceptibility to CVD in RA patients. Conditions related to FA and CVD include radiographic progression, high disease activity and persistent inflammation. El-Gabalawy et al. (125) indicated that levels of multiple cytokines and high sensitivity-CRP are higher in Amerindian patients with RA and their FDRs as compared to individuals from a non-AD. Saevarsdottir et al. (126) showed that familial RA patients had increased frequency of HLA-DR4 as compared with the non-familial RA group. In addition, the mean age at onset of RA was significantly lower in the familial than in the sporadic RA patients and the difference still remained when the DR4 positive and negative subgroups were compared separately.

Glucocorticoids. The use of systemic GC in RA patients has a paradoxical effect. Several studies have reported an increased on CV risk and mortality in RA due to a longer duration of disease and subsequently longer use of GC (127). This can be explained by a chronic systemic pro-inflammatory state that enhances physiopathological changes in the endothelium (42) or due to their potentially deleterious effects. In addition, the effect assessment of GC on CV outcomes is complicated by the potential for confounding factors such as indications due to more severe subphenotypes needing more aggressive treatment with this medication (42,49,57,6163,128). However, GC can reduce the atherosclerotic risk and CVD by suppressing inflammation, which paradoxically may improve glucose tolerance and dyslipidemia (127,129138).

Long duration of disease. Solomon and Sattar et al. (53,139) have found adjusted odds ratios (AOR) of 1.48 for CVD and 2.0 for MI in healthy women, which increases to 3.1 when the disease has more than 10 years of duration. In the same way, disease duration over 10 years was significantly associated with an increased risk of atherosclerotic plaque in Colombian population (42). Other studies found increased carotid atherosclerotic involvement and subclinical AT in patients with long-standing RA when compared with patients of the same age but with shorter disease duration (42,46,61,140153).

Poliautoimmunity. Polyautoimmunity is defined as the presence of more than one AD in a single patient. It was present in average 14–28% in patients with RA, being autoimmune thyroid disease (AITD) the most frequent AD associated (7). Polyautoimmunity was associated with CVD in Colombian population (154).

Auto-antibodies. There are several auto-antibodies associated with CVD in RA, such as RF and ACPA. Immune complexes from RF can be deposited in the endothelium and through inflammatory reactions generate endothelial dysfunction and AT (42,155157). In a cohort of older women, the association with the increase mortality appeared to be restricted to those with RF(+) subphenotype. The widening in the mortality gap between RA subjects and the general population is confined to RF (+) RA subjects and largely driven by CVD (158,159). In fact 0 (+) RA may, like diabetes, act as an independent risk factor for CVD, after controlling inflammatory profiles (160). Similar correlations have been made between ACPA and decreased endothelial dysfunction, presence of atherogenic risk factors and increased IMT, independent of other CV risk factors in RA patients (161,162). Another auto-antibodies related to CVD in RA patients are those directed against to ox-LDL (22,24,163), which are associated with subclinical AT (164). The presence of ACLA, APLA and anti-apolipoprotein A-1 antibodies (anti-ApoA-1) are also associated with early atherosclerotic changes in RA patients (165170). Finally, others auto-antibodies implicated in the atherosclerotic process are anti-phosphorylcholine (anti-PC) and anti-heat shock protein 60/65 (anti-HSP 60/65) (171). Anti-malondialdehyde-modified LDL antibodies (anti-MDA-LDL) may have independent roles in subclinical AT (167,172), meanwhile high levels of anti-modified citrullinated vimentin antibodies (anti-MCV) and LDL-immune complexes are risk factors for increased AT and are associated to inflammation (173).

Chronic pro-inflammatory state. The association of inflammatory pathways with CVD is complex and is composed of several intermediate factors, including dyslipidemia, homocysteinemia, insulin resistance, and endothelial dysfunction (174). However, a pro-inflammatory state is the hallmark of CVD in RA patients (175) since it may accelerate atherogenic processes and microvascular dysfunction (15,176), either by the accentuation of known pathways of plaque formation or by the onset of additional immune mechanisms (177). Markers of chronic inflammation such as CRP, ESR, TNF-α, IL-6, IL-17 and haptoglobin are indicators of endothelial activation and are associated with the increased in carotid IMT the carotid plaque, presence extent of CAD and CV complications (45,61,65,66,105,115,116,171,178188).

High disease activity. It has also been shown that higher activity index is associated with CV events. Therefore, adequate treatment of the disease can reduce CV mortality (18). The lipid profile in RA depends on disease activity. Higher disease activity leads to depressed levels of TC. For instance, disease activity score-28 (DAS28) was a significant predictor of major adverse CV events and mortality, independent of traditional risk factors (42,63,66,171,189,190). van Halm et al. (191) demonstrates that high disease activity, RF (+) and joint destruction conferred, approximately double the risk for CVD.

EAMs. Other non-traditional risk factor related to RA is the presence of EAMs, which are related to the severity, disease activity and endothelial damage and therefore with the risk of developing AT (101). Patients with EAMs are considered to have three times higher risk to develop CVD (61,101). EAMs and long disease duration, even in the absence of traditional clinical CV risk factors, were associated with greater carotid IMT, suggesting an unfavorable CV risk profile (61,101,149). Severe EAMs are associated with an increased risk of CVD events in patients with RA (42,61,63,68,101). In fact, some authors had considered CVD such as a severe EAM of the disease (90,102,192).

Household duties. The association between household duties and CVD is novel and striking and was described recently by Amaya-Amaya et al. (7). Nevertheless, there are few studies about the impact of household duties on RA (193). Employed women are somewhat less physically disabled than their unemployed counterpart (including housework) (194). This factor may correspond to an information bias. In fact, we were unable to determine if this working status was a consequence of RA or was the patient´s choice. Habibet et al. (193) showed that socio-economic status (SES) are highly predictive of homemaking disability in Arabic women with RA and more predictive than the clinical examination. Pincus et al. (195) reported that low educational level (LEL) was a significant risk factor for mortality in RA. In Colombians, household duties are also associated with LEL, low SES and poor access to health services, which could ensure a poor control of the disease, and therefore more systemic involvement.

Rheumatoid cachexia. Rheumatoid cachexia is associated with high levels of LDL, low levels of atheroprotective anti-PC and high frequency of HTN in RA patients (196).

Hypothyroidism. In RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD even after adjustment for other traditional CV risk factors (197,198). McCoy et al. (197) found that Hashimoto’s disease was associated with CVD in patients with RA in a retrospective cohort. Although CVD is linked to the presence of EAMs an increased CV risk is observed within patients with polyautoimmunity. AITD-RA subphenotype were associated when adjusted for potential confounders and variables of clinical interest (199). For more details, see chapter 30.

Thrombogenic factors. The altered levels of von Willebrand factor (66), PAI-1, and tissue type plasminogen (tPA) in patients with RA had also been associated with CVD progression (66,151,170,180,200208), which indicates a status of hypofibrinolysis in these patients (171,180).

Many biomarkers such as osteoprotegerin (OPG) (209), osteopontin (OPN) (210), serum pentraxin-3 (sPTX-3) (211), periodontal disease (200), hepcidin (212), seric uric acid (SUA) (213,214), para-articular bone loss (215), MBL (122,216), and many others (149,150,169,217221) has been related to CVD as well.


CV risk screening and management strategies have been developed for the general population and are based on CV risk score calculators, such as the Framingham score and the Systematic Coronary Risk Evaluation (SCORE) model, but the accuracy of these models has not been adequately evaluated in inflammatory arthritis. The major strategies are to achieve healthy life styles, by means to maintain the control of classical risk factors. Regarding to novel risk factors it is necessary reach an adequate management of the disease. The main goal of the treatment should be reduce the disease activity, and therefore decrease the CV burden (127). Both conventional (222) and biologic disease modifying anti-rheumatic drugs (DMARDs) are used for this purpose. Some studies has shown a greater disease control activity with non-conventional DMARDs, such as anti-TNF agents, which lower CRP and IL-6 levels, increase HDL levels and decrease endothelial dysfunction (223).

Statins and Angiotensin-Converting-Enzyme (ACE) inhibitors. Statins can effectively lower total cholesterol in RA patients and significantly improve CV-related and all-cause mortality when used for primary prevention of vascular events (224). In addition, statins had shown a moderate decrease in disease activity and a significant reduction in TC and LDL in treated RA patients (225). Similarly to statins, ACE inhibitors and angiotensin II blockers may also have a favorable effect on inflammatory markers and endothelial function in RA (226). Hence, these agents are preferred, when antihypertensive agents are indicated (127).

DMARDs. Early and effective antirheumatic treatment, such as MTX, has been shown to be independently associated with a lower CV risk (191,227). This protective effect may be secondary, at least in part, to promotion of reverse cholesterol transport, inhibition of foam cell formation, and important anti-inflammatory effects of this drug (228). Effective treatment may also result in improved physical activity, subsequently leading to a decreased risk of hypertension, obesity and diabetes, all important determinants of CV disease. Studies had reported a lower CV mortality in RA patients using methotrexate, which was ascribed to its anti-inflammatory properties (191).

Antimalarials. The antimalarials (AMs) drugs had been associated with a better CV outcome, improved glycated hemoglobin in patients with T2DM, enhanced glycemic control, improve lipid profiles, decrease thrombosis risk and reduced probability of developing T2DM in patients with RA (191,229,230). Other conventional DMARDs, such as sulfasalazine, is also associated with a reduction in the risk of developing CVD, which strengthens the hypothesis that reducing inflammation is of importance to reduce CVD burden (9,12,191).

Glucocorticosteroids. These drugs should be used prudently to minimize CV risk secondary to their effects on metabolic parameters and blood pressure. Altogether, there is no clear evidence that low-dose of GC contribute significantly to the enhanced CV risk in inflammatory arthritis, in contrast to high doses. Corticosteroids rapidly and effectively suppress inflammation in RA and their use might be justified for short-term in the period between initiation and response to DMARD treatment, although the debate appears not to be settled yet. Therefore, a conservative approach was chosen, recommending the use of the lowest dose for the shortest period possible (127,222).

Biological therapy. Some studies have found no benefit in IHD (despite good anti-inflammatory response) in RA, whereas other reports indicate that anti-TNF shows to be independently associated with a lower CV risk, due to reduce CV events in young patients, improving the lipid profile, insulin resistance, endothelial function, aortic compliance and decrease progression rates of subclinical AT (127,231). Patients treated with tocilizumab, an IL-6 neutralizing antibody, have improvements in insulin sensitivity and lower lipoprotein (a) levels, which contribute to decrease CV risk (232). Finally, data about other biologics are conflicting and preliminary; as such, randomized controlled studies are needed to identify their CV risk reduction role (9,12).

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multiorganic, and chronic disease, with an autoimmune background. Its heterogeneous nature explains the broad spectrum of clinical manifestations (i.e., subphenotypes). SLE occurs most often in young women of child-bearing age, the same population that is at highest relative risk of AT (233,234). Lupus cohorts have documented differences in health status, disease prevalence, treatment outcomes, and healthcare use among different ethnic groups which suggest that minority influence SLE health disparities (235240).

Classically, a bimodal mortality pattern among SLE patients, with an early peak in the first 3 years after diagnosis due to active disease, infections and glomerulonephritis, and later deaths, 4–20 years after SLE diagnosis due to CVD, was described by Urowitz et al. (241). Although overall mortality for SLE patients has improved over the past 30 years, mortality due to CVD has remained equal (242).

Cardiovascular burden in SLE

AT is an accelerated process in SLE patients (50). There is strong epidemiologic evidence that CVD risk among SLE patients compared to the general population is at least doubled (243). Carotid plaque is prevalent in 21% of SLE patients under age 35 and in up to 100% of those over age 65 (244). The increased risk of MI and angina among SLE patients has been well characterized in a number of population-based studies. Most studies reported a 2–10 fold increase in the risk of MI among SLE patients, with a greater increase in RR generally observed in younger patients groups (245250). MI occurs in 6–20% of premenopausal women with SLE (9,12). CVD may account for 3–25% of total mortality in SLE (103,247).

SLE patients have an increased risk of CVA when compared to control populations, similar to that seen for MI and CHF. Ward et al. (247) found the stroke risk was 1.75 times that of age-matched controls. The increased RR diminished with age such that SLE patients over age 65 actually had a somewhat lower overall stroke risk than controls. Mok et al. (251) similarly found a 2-fold increase in the risk of CVAs among all SLE patients over an 8-year period at a single institution in Hong Kong. This risk was 22-fold higher for the youngest group of SLE patients. Bengtsson et al. (250) further corroborated these results in their population-based Swedish study where they demonstrated that the risk of CVA and/or MI in the total SLE population was 1.27 fold higher than the general population, but among women with SLE aged 40–49 it was 8-fold higher over the 7-year follow-up period.

Several research groups have reported prevalence rates in SLE cohorts. In the Systemic Lupus International Collaborating Clinics-Registry for Atherosclerosis (SLICC-RAS) cohort, there were 8 cases of PVD among 1,249 patients during a 2-year period (252). In the Lupus in Minorities: Nature vs. Nurture study (LUMINA), a large multicenter, multiethnic inception cohort, 5.3% of 637 patients developed PVD over a mean follow-up of 4.4 years (253). The average age of this population was young (36.5 years) and PVD predicts either more severe SLE activity or more widespread AT.

In a recent meta-analysis, Schoenfeld et al. (243) showed that epidemiologic data strongly support that SLE patients are at elevated relative risk of CVD. The risks of MI, CHF, CVAs and CVD mortality are all increased among SLE patients compared to general population risks. The variability regarding the relative importance of risk factors for CVD among SLE patients in past epidemiologic studies is likely due in part to different design methods and different patient and comparison groups. Independent predictive risk factors (from multivariate analysis) for CV events had been assessed in five large prospective cohorts of patients with SLE, including Baltimore (254), Pittsburg (246), LUMINA (255), Toronto (256), and SLICC-RAS (252) cohort. The main results are discussed below.

Traditional CVD risk factors

Diverse SLE cohorts had shown the influence of advanced age, dyslipidemia, obesity, HTN, and hyperhomocysteinemia, as classical risk factors for CVD in lupus population (257259). Younger patients with SLE have the greatest RR compared to their healthy counterparts, but the absolute risk of CVD among SLE patients increases with advancing age (243). There is strong epidemiologic evidence that traditional CVD risk factors also elevate CVD risk among SLE patients (Figure 2).

Figure 2. Traditional and autoimmune-related mechanisms of cardiovascular disease in systemic lupus erythematosus and antiphospholipid syndrome.

Figure 2

Traditional and autoimmune-related mechanisms of cardiovascular disease in systemic lupus erythematosus and antiphospholipid syndrome. A complex interaction between traditional and disease-specific traits leads to premature atherosclerosis process. Several (more...)

Amaya-Amaya et al. (260) recently adds further evidence of the high frequency of CVD in 310 consecutive patients with SLE. Their traditional risk factors (i.e., dyslipidemia, smoking), and highlights coffee consumption as a confirmed factor for such a complication in LA population. In addition, they evaluated the state of the art regarding traditional and non-traditional risk factors, as well as CV subphenotypes, and mechanisms underlying accelerated AT in Colombian lupus patients. Out of total of 53 articles that fulfilled eligibility criteria, 40 had interpretable data regarding CVD prevalence, which accounts approximately for 39.2% in Hispanics. This prevalence was similar to that encounter in the analysis of this cohort (36.5%). Several classic CV risk factors such as MetS, obesity, dyslipidemia, HTN, T2DM, sedentary lifestyle, male gender, smoking, advanced age, hyperhomocysteinemia, renal impairment, family history of CVD, and menopausal status were reported. Moreover, several studies were associated with novel risk factors, including ancestry, certain SNPs, SLE per se, poliautoimmunity (154), autoantibodies (e.g., APLA), markers of systemic inflammation (e.g., CRP), SLE disease activity and duration, organ damage, immune cells aberrations, medication (e.g., GC), vasculopathy, lupus nephritis, endogenous dyslipidemia, bone mineral density (BMD), education level, and monthly income. A broad spectrum of CV subphenotypes including HTN, IHD, CAD, ACS, MI, CHF, CVA, thrombosis, PVD, subclinical AT, and mortality due to CVD, were described in LA individuals with SLE.

Obesity. Obesity has not been frequently examined in relation to CVD risk in SLE populations (246,261,262). Only one study in the early 1990s has reported that obesity was correlated with an increased risk of CVD events (RR not reported) (254).

Smoking. Several studies have assessed smoking as an independent risk factor for CV atherosclerotic disease (255,257,261,263265). Gustafsson et al. (264) found that smoking may be the main traditional risk factor promoting increased CV risk in 208 SLE patients. Previously, the same group found that smoking was predictive of MI, stroke, PVD or CV mortality among the same patient population (257). Toloza et al. (255) prospectively followed SLE patients over a median follow-up of 73.8 months and compared those who had a CVD event to those who did not as part of the LUMINA study. Current cigarette use was significantly associated with a 3.7-times increased risk of having a CVD event. In the PROFILE population, another multicenter, multiethnic study population, Bertoli et al. (265) found that smoking acted as an independent risk factor associated with a 2-fold decrease in time to a CV event.

Dyslipidemia. The inflammatory milieu of SLE leads to dysregulation of lipid metabolism pathways, which contributes to the increased risk of atherosclerotic disease among SLE patients (266,267). Five large cohort studies have shown hypercholesterolemia to be a significant risk factor for CVD in SLE patients (246,254,268270).

Advanced age. Older age is a relatively consistent independent predictor of CVD events among SLE patients. Gustafsson et al. (257) found the strongest correlation between age and CV events, with age predicting a 2 to 3-fold increase in CVD events and death.

Hyperhomocysteinemia: Elevated homocysteine levels may act as an independent risk factor for atherosclerotic CVD in general population (91) and among those with SLE. Petri et al. (271) compared homocysteine levels in those patients who had a stroke or thrombotic event versus those who did not over a mean follow-up period of 4.8 years. After adjusting for age, sex, race, obesity, hypercholesterolemia, HTN, T2DM, renal insufficiency and presence of the lupus anticoagulant, homocysteine remained an independent stroke predictor and arterial thrombotic events.

Hypertension. In the Toronto Lupus Cohort, 33% SLE patients were hypertensive compared to 13% of age-matched controls (272). In the Hopkins Lupus cohort, the presence of hypertension or use of antihypertensive medications were independent risk factors for CVD (254). Two recent studies using data from the Toronto Lupus Cohort found that hypertension was associated with 1 to 2-fold risk of CAD among SLE patients (268,270).

Male gender. While most SLE cohorts are comprised predominantly of women, the risk of CVD events, as in the general population, appears higher among men. In each of the 2 large cohort studies, SLICC and LUMINA, male SLE patients had a nearly 4-fold increased risk of experiencing a CVD event compared to females (252,270). Although both studies were comprised of large databases and were well conducted, it should be noted that nearly 90% of the patients were females in both studies. Similarly, in a population-based study by Nikpour et al. (270) males had a nearly 2-fold increased risk of CV events, although again the cohort was comprised of only 10% males.

T2DM. Many of the cohort studies have not examined diabetes as a risk factor (262,265). Those studies that did include this condition had small numbers of patients (261,273).

Hormone replacement therapy. Rojas-Villarraga et al. (274) showed in a recent meta-analysis an association between hormone replacement therapy (HRT) exposure and SLE. This study highlight that identifying individual risk factors that predispose healthy individuals to develop an AD such as SLE, have to be considered with special attention in those who are planning to begin HRT.

Non-traditional CVD risk factors:

It is well known that while traditional CVD risk factors are undoubtedly important in increasing the CVD risk among SLE patients, these do not fully accounts for the elevated risk of CVD in this population. Esdaile et al. (275), evaluate risk factors for CAD in two Canadian lupus cohorts by means of the Framingham multiple logistic regression model, and found a high risk of developing CAD after removing the influence of these risk factors. Thereby, SLE-associated factors play an important role in the premature AT process characteristic of those patients (276,277). Evidence strongly suggests that AT is largely driven by inflammation, active immunological response (278,279), and points to SLE itself as an independent risk factor (280,281) (Figure 2). Several SLE-specific factors, including disease activity and duration, and possibly specific manifestations and therapies (243). Hence, there is an increasing interest in identifying novel risk factors in order to explain the development of accelerated AT in these population.

Genetic determinants. Family and twin studies have repeatedly supported a role for heredity in CAD, particularly when it occurs in relatively young individuals. Several genetic markers have been proposed as predisposing factors for CVD in SLE patients (282284).

SLE-specific factors. The SLE-associated risk factors represent a broad spectrum of conditions related with the autoimmune nature of the disease. In fact, lupus per se seems to be an independent risk factor for the development of accelerated AT (275).

Poliautoimmunity. In patients with SLE and APS, CV risk is even higher, and APLA-induced arterial events are most pronounced, where traditional and non-traditional risk factors are multiplied and AT occurs more prematurely (30,285).

Auto-antibodies. Many studies have tried to determine whether the presence of APLA may be an independent risk factor for CVD among SLE patients. In the LUMINA study, the presence of a positive APLA was significantly associated with 4-times increased risk of having a CVD event over a median of approximately 6 years (255). The presence of APLA was also associated with a greater than 4-fold increased risk of first time MI, stroke or PVD (257,264). Bengtsson et al. (250) found that ACLA IgG predicted a 3-fold increased risk of stroke, but not MI. In a Spanish study by Ruiz-Irastorza et al. (286) the presence of a positive APA was associated with a nearly 3-fold risk of thrombosis or death.

Systemic inflammation. Unlike in the general population, where high sensitivity CRP has clearly been shown to be associated with increased risk of CVD (287), this finding is less consistent among SLE patients. In the LUMINA study (255,273), elevated CRP levels were associated with anywhere between a 1.5 and 3.3 increased CVD risk. However, most of the other large SLE cohorts have not examined CRP in their analyses (246,252,254,261).

SLE disease activity and duration. Several studies have found that disease activity is an important predictor of CVD events. In a recent study, Bengtsson et al. (250) found that a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score predicted both stroke and MI among SLE patients followed over 7 years. Manzi et al. (288) found an inverse relationship between SLE activity and plaque size, and noted that longer disease duration was independently associated with carotid plaque. Nikpour et al. (270) and Touma et al. (268) similarly found that disease activity, as measured by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was predictive of a modest increase risk of CAD during a 6 and 37 year follow-up period, respectively. Mikdashi et al. (96) reported that baseline SLEDAI-2K scores were associated with a 2-fold increased risk of stroke within 8 years. Nevertheless, measures of SLE disease activity, including the SLEDAI, British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Activity Measure (SLAM), used in many of these studies, have been criticized as being insensitive and may not accurately capture systemic inflammation that could drive AT. Disease duration may be of outstanding importance with regard to atherogenesis (103). Von Feldt et al. (289) found disease duration was significantly associated with coronary calcium scores in a cross-sectional cohort. Similarly, Roman et al. (290) found, in multivariate analysis, that longer disease duration and higher Systemic Lupus International Collaborative Clinics damage index (SDI) were independent predictors of carotid plaque in both a cross-sectional and a longitudinal study (291).

Glucocorticoids. Petri et al. (254) demonstrated that longer duration of GC use was independently associated with incident CV events. Nikpour et al. (270) also found that GC use independently predicted a 2-fold increase in the risk of MI, angina and sudden cardiac death, but conflicting data exists regarding the overall risk of GC therapy (246,252,255,261,262,273). Examination of medications and CVD risk is problematic because of the risk of confounding by indication bias. More severely ill phenotypes are more likely to receive GC and other immunosuppressants, while those with milder disease may be more likely to receive hydroxychloroquine (HCQ) alone. In addition, a controversy arises from the dual action of GC, as they are atherogenic (related to exacerbation of multiple traditional risk factors), but, on the other hand, also anti-inflammatory (292294).

Azathioprine. Two studies have reported that azathioprine (AZA) use is an independent risk factor for CVD among SLE patients, predicting 3-fold PVD (253), MI and angina (295). In a study by Touma et al. (268), immunosuppressive medications including AZA were associated with CAD.

Renal disease. The prevalence of CV morbidity and mortality is higher in patients in the general population with chronic kidney disease, and is even more strongly associated with end-stage renal disease (296). Factors that may contribute to this increased risk include HTN (297) and dyslipidemia (298), both of which are frequently seen in patients with proteinuria. Patients with proteinuria also have an increased risk of thrombosis (299). Both proteinuria (300,301) and elevated serum creatinine (302) have been associated with early AT in patients with SLE, and a history of nephritis has been associated with subclinical AT in some studies (289,302).

Endogenous dyslipidemia. Lupus hyperlipidemia pattern include elevated TGL and Very Low-Density Lipoproteincholesterol (VLDL), and decreased HDL and ApoA-1 (103). Lupus nephritis could result in HTN, and the nephrotic syndrome could aggravate this hyperlipidemia (5).

Neuropsychiatric disease. A number of studies have demonstrated a correlation between neuropsychiatric SLE and an increased risk of CV events. In particular, Urowitz et al. (261) found that neuropsychiatric disease predicted an early 4-fold increased risk of CV events. In another large study, Bertoli et al. (265) found that both psychosis and seizure were independent predictors of time to a CVD event.

Miscellaneous. A number of other risk factors have been shown to be predictors of CVD among SLE patients. These include number of years of education, hypovitaminosis D, osteoporosis, absence of thrombocytopenia, some biomarkers (e.g., cystatin C, soluble-VCAM levels), and others (243).


It has been proposed that SLE should be treated as a ‘‘CVD equivalent’’ such as T2DM is, with lower lipid goals, more aggressive aspirin use and potentially more aggressive monitoring (292,303). Recent studies have started to address whether traditional treatment regimens may prevent or slow AT in SLE patients (234).

Antimalarials. There are several new mechanisms of action described for AMs, many of them with beneficial effects in the management of CV risk in patients with SLE (230,304). There is evidence that AMs drugs reduce LDL levels, elevate HDL, and when taken concomitantly with steroids can reduce TC (305). Rekedal et al. (306) showed that HCQ initiation was associated with a significantly greater reduction in HbA1c as compared to MTX initiation among diabetic patients with rheumatic diseases. In addition, beneficial effects of HCQ on thrombosis formation have also been described. Multiple retrospective cohort studies have shown a reduced incidence of thrombotic events and improved overall survival in patients with SLE treated with AMs (307310). Nikpour et al. and Ruiz-Irastorza et al. (270,286), both found that HCQ use conferred a 50–60% decrease in risk of CVD.

Statins. The recent randomized controlled Lupus Atherosclerosis Prevention Study by Petri et al. (311) suggests that atorvastatin did not in fact slow progression of subclinical AT in 200 SLE patients over 2 years. It has been further demonstrated that statins also reduce CD40 levels in vivo and in vitro, and therefore interfere with CD40–CD40 ligand interactions, both in SLE and AT (293).

Other immunosuppressants. As inflammation is one of the targets of therapy in SLE, the several other immunosuppressants and immunomodulatory drugs currently employed in SLE could also be considered such as potential new anti-atherogenic agents. Some data are available for cyclophosphamide (cyclophosphamide) therapy in atheroma. Therefore, multivariable analyses from a recent study revealed that only a few factors are predictors of AT in SLE patients including the use of lesser immunosuppressants such as cyclophosphamide (312). Mycophenolate mofetil (MMF) is able to diminish the plaque formation, as well as the cholesterol arterial content in animal models (313).

Antiphospholipid syndrome

The APS is a pro-thrombotic state that can affect both the venous and arterial circulations. The deep veins of the lower limbs and the cerebral arterial circulation are the most common sites of venous and arterial thrombosis, respectively (314). It is characterized by recurrent thrombotic events, pregnancy loss, and the presence of circulating APLA.

The prevalence of APS ranges from 1.7–6%, and that of APLA reaches to 14% among patients with PVD defined on the basis of clinical outcomes. On the other hand, the prevalence of asymptomatic AT, defined in terms of plaques in ultrasonography, reaches to 15% of patients with APS compared to 9% of SLE patients and 3% of normal controls (315). In the Euro-Phospholipid cohort, that includes 1,000 European patients with APS, MI was the presenting manifestation in 2.8% of the patients, and it appeared during the evolution of the disease in 5.5% of the cohort (316). Therefore, when compared with age and sex matched controls, these patients present an increased risk and a higher prevalence of CVD (317). Cardiac manifestations may be found in up to 40% of patients with APS, but significant morbidity appears in only 4–6% of these patients. Most of these manifestations are explicable on the basis of thrombotic lesions either in the coronary circulation or on the valves (318).

Cardiovascular burden in APS

The clinical spectrum of CVD includes features such as arterial and venous thrombotic events: PAD, valve abnormalities, intracardiac thrombus formation, pulmonary hypertension, ventricular hypertrophy and dysfunction, dilated cardiomyopathy, and myxomas. Therefore, patients with APS could have a significant involvement of the CV system. The heterogeneity of APS clinical manifestations is likely linked to the varied effects that APLA can induce on endothelial cells (319).

Thrombosis. Thrombotic events are the clinical hallmark of APS, occurring in the venous and arterial circulations, with a high recurrence rate (3). Arterial involvement in APS can be expressed as CVA, CAD, and PVD, due to thrombus formation or to AT. Involvement of larger vessels manifests in the form of recurrent thromboembolism, including DVT, cerebral venous thrombosis, PE, whereas involvement of small vessels manifests as thrombotic microangiopathy (320).

Coronary syndromes. AT is one of the main features of APS, and can be the first finding of this entity (3,321). The association between APS and AT probably was suggested for the first time by Shortell et al. (322). Vaarala et al. (285) provided the first evidence that APLA may be involved in AT. As some of thrombotic manifestations occur in the coronary arteries or in the carotid arteries, it is of interest to examine whether APLA are also associated with AT in addition to their relation with thrombosis (5). With regard to recurrent coronary events in post-infarction patients, Bili et al. (323) demonstrated that elevated IgG and IgM APLA at any level are independent risk factors for recurrent cardiac events. Furthermore, patients with both elevated IgG and IgM APLA at any level have the highest risk. This risk was comparable to other known risk factors for recurrent coronary events.

Valvular disease. Apart from AT and CVD, other cardiac manifestations may also be present in these patients. It can include irregular thickening of the valve leaflets due to deposition of immune complexes that may lead to vegetations, and valve dysfunction. APLA are involved in the pathogenesis of Libman–Sacks endocarditis usually associated with SLE (324). These lesions are frequent and may be a significant risk factor for stroke (325). Several studies have demonstrated a positive correlation between the APLA titers and valvular heart disease severity (326,327).

Traditional CVD risk factors

A number of traditional CV risk factors, such as hyperlipidemia, T2DM, smoking, obesity, HTN and sedentary lifestyle have been assessed in APS patients. None of these Framingham risk factors showed any difference between APS patients and the general population (4). The prevalence of traditional risk factors for atheroma among patients with APS and PVD has not been extensively studied (Figure 2).

MetS. Medina et al. (328) showed a high prevalence of MetS in APS patients, similar to that in the general population and other ADs. This study found the most frequent CV risk factors were hypertriglyceridemia, low HDL levels, and visceral obesity. The prevalence of MetS was 17.2% according to WHO, and 37.9% according to IDF criteria.

Non-traditional CVD risk factors

Immuno-inflammatory mechanisms, primarily APLA, have an outstanding role in APS-related vasculopathies (103). APLA includes antibodies directed towards phospholipid moieties, such as cardiolipin or its cofactor β2GPI (anti-β2GPI), as well as lupus anticoagulant (329). These antibodies may induce a pro-inflammatory endothelial phenotype and interfere with pro and anticoagulant reactions by cross-linking membrane-bound proteins, and by blocking different proteins interactions (293) (Figure 2). Increasing evidence suggests that a subset of APLA can also be detected in patients with AT. In fact, patients having APLA and AT may have greater risk for ischemic events than patients with the same degree of AT but without APLA. These autoantibodies have probably been elicited as a consequence of the hypercholesterolemia in AT-prone individuals and autoantibody production could be an epiphenomenon of the disease, simply reflecting the abnormalities in lipid metabolism. However, several studies suggest that APLA can participate in the disease process, in fact, some studies have been associated APLA with mortality in CAD (330,331). Several studies have shown correlation between serum levels of ACLA and anti-β2GPI ACLA and anti-B2GPI, with the incidence and severity of CV events (285,329).

It has been demonstrated that atherosclerotic lesions possesses β2GPI in abundance. β2GPI was distributed both intracellularly and extracellularly and was most commonly present in the subendothelial regions of the atherosclerotic plaque. Therefore, the β2GPI within atherosclerotic regions could be a target for anti-β2GPI that aggravate the atherosclerotic process (332). ACLA and anti-β2GPI may be involved in a number of vascular diseases including CAD and stroke. Veres et al. (329) assessed the presence of APLA in ACS, and found that anti-β2GPI in ACS were associated with previous stroke, but not with HTN or previous MI. Thus, anti-β2GPI may be involved in the thrombotic events underlying ACS.

Soltész et al. (333) in a retrospective analysis of 1,519 APLA positive patients, among them 637 with clinical APS, detected venous thrombotic events more frequently in patients having circulating lupus anti-coagulant in comparison to patients with other types of APLA. In contrast, coronary, carotid and peripheral arterial thrombosis occurred more often in patients with elevated serum levels of IgG or IgM APLA, including ACLA or anti-β2GPI.


The presence of early atheroma in APS underscores the necessity of new therapies for this disorder (293). Although the presence of early atheroma in APS is still a matter of debate, there is increasing evidence for the usefulness of several therapies indicated in AT, which further strengthens this hypothesis (293).

Although the thromboembolic potential of APLA has been well documented, there is still no general consensus on the prophylactic treatment of APLA carriers who have never developed vascular/obstetric manifestations (320). Early diagnosis of APS, thorough examination of the heart, examination od the heart and aggressive control of all traditional risk factors should be performed by lifestyle modifications and pharmacotherapy; probably anti-inflammatory treatment and close follow-up of APS patients may help to minimize CV risk in these individuals (30,324). The APS coagulopathy in these patients requires the careful and judicious use of appropriate anti-aggregant and anti-coagulant therapy (318). There has been a consensus report on the management of cardiac disease in APS (334).

Specifically targeted therapies, exerting anti-inflammatory or immunomodulatory effects become important therapeutic tools in APS. In order to achieve beneficial effects, these drugs should primarily antagonize the pathogenic effects of APLA. Moreover, these treatments should also control atheroma, which is one of the major causes of CV mortality in this pathology (293).

Antimalarials. AMs drugs, may exert evident anti-atherogenic properties (292). In vitro studies suggest that AMs may inhibit platelet aggregation and the thrombogenic effects of APLA (335). Despite these potential benefits, the anti-atherogenic effects of these drugs need to be clinically confirmed. The HCQ also has been associated with decreased levels of TC, TGL, glucose, and also the reduction of blood pressure, with anti-platelet effects as mentioned before.

Statins. These have pleiotropic characteristics, which include anti-atherosclerotic, anti-inflammatory, anti-oxidant, immunomodulatory and anti-thrombotic effects (336). Statins represent a powerful potential therapeutic tool in APS. It has been demonstrated that they prevent endothelial cell activation induced by APLA (337), induce modifications in the cellular and protein composition of atherosclerotic plaques (338), and have various beneficial effects on the endothelium, including improved NO availability and the stimulation of endothelial progenitors (339). Statin therapy significantly reduces the risk of CVD (340), by reducing CRP levels, and preventing endothelial dysfunction (341).

Aspirin. For a number of years, aspirin has been used in secondary prevention in APS patients particularly for its inhibitory effects on platelet aggregation. Aspirin may also have additional effects on the vascular wall (342). Moreover, aspirin may interfere with endothelial NO synthase and stimulate NO production, and is also shown to have an inhibitory effect on endothelial cell activation from inflammatory cytokines by preventing the activation and nuclear translocation of NFkB (343).

Heparin. In addition to their anticoagulant effects, unfractionated heparins and low molecular weight heparins also have anti-inflammatory properties. Thus, heparins may represent another anti-inflammatory therapeutic tool, however, the mechanisms of action responsible for their anti-inflammatory effects are not yet fully understood (344).

CVD in others ADS

It has become evident over the last years that some ADs are characterized by common pathogenetic mechanisms and high rates of morbidity and mortality, mainly CVD-related. The increased CV mortality in the 3 most investigated rheumatic disorders (i.e., RA, SLE, and APS), appears to be sustained by vascular damage secondary to accelerated AT. However, the burden of CV involvement in other ADs appears to be lower and it is characterized by specific risk factors in addition to those shared with the general population.

Sjögren’s syndrome

This is an autoimmune epithelitis that affects the exocrine glands, with a functional impairment that usually presents as persistent dryness of the eyes and mouth (345,346). While sicca complaints in the setting of SS are quiet common, a relatively few number of studies have estimated the population prevalence of SS and its association with CVD. The clinical spectrum extends from an autoimmune exocrinopathy to a systemic involvement with vasculitis and diverse extra-glandular systemic manifestations (40–50%), including CVD, although with lower prevalence (347,348). Chronic systemic inflammation is a risk factor for developing AT, developing AT, but on the contrary to what is expected, the prevalence of CVD associated with AT, such as IHD, PAD and CVA, are not appreciably increased in patients with SS. This probably is characterized by chronic but milder inflammation (349) as Ramos-Casals et al. showed (345).

A recent prospective evaluation showed that CV events occurred in 7.7% of SS patients (350). Recently, Pasoto et al. (351) reported a prevalence of 5%, being the most frequent CVD associated MI, CVA and DVT. On the other hand, Vassiliou et al. (352) evaluated 107 patients with SS by echocardiography, without heart disease and found mainly tricuspid regurgitation, mitral and aortic valves, pulmonary hypertension and increased left ventricular mass. Dyslipidemia has been found as the most significant traditional risk factor linked with SS (353357). Lodde et al. (354) showed a significant difference in the lipid profile (i.e., low HDL) not associated with acute phase reactants, by means with high level of inflammation. Furthermore, he found association between anti-Ro/SSA antibodies (SS-A) and anti-La/SSB antibodies (SS-B) and altered TC levels. In another study, Kang et al. (355) recorded the presence of dyslipidemia as CV compromise and arrhythmias. It has also been reported first-degree heart block, mainly related to the presence of SS-B and low HDL levels (354). It should be noted that the CV risk in patients with SS is increasing with the population affected by the disease (i.e., postmenopausal women) (354,358). Regarding non-traditional risk factors, Perez-De-Lis et al. (358) added to the list of risk factors for CVD in patients with SS the longer duration of the disease, steroid use, elevated CRP, SS-A, thrombocytopenia and severity of the disease (i.e., higher percentage in peripheral neuropathy, gastrointestinal and CNS involvement). By contrast, he also found a protective role of AMs in CVD, since these drugs shown association with lower frequency of HTN, T2DM and dyslipidemia. Vaudo et al. (349) found a high rate of subclinical AT due to changes of the carotid arterial wall, studied by femoral and carotid ultrasonography. This rate is mainly associated with the presence of leukopenia and SS-A antibodies, suggesting that the lack of immune regulation may play an important role in the early development of AT. In the same way, Gofinet et al. (351) observed an relation of APLA with thrombotic events, being the most frequent the lupus anticoagulant, which was significantly associated with APS. By contrast, two studies demonstrated that the APLA in SS are predominantly of the IgA isotype, which are not associated with thromboembolic events in SS (359,360). Increased serum levels of IgG, reflecting B cell hyperactivity of these subjects, were predicted by HDL in Lodde’s study (361). Gerli (356) found that mean levels of serum IgG in SS patients with high-risk HDL levels were higher than the levels found in patients with normal HDL. Both observations suggest an association between hypergammaglobulinaemia and low HDL levels, and may be intriguing to test the hypothesis of the presence of circulating anti-HDL antibodies.

Gerli et al. (357) shown a slight loss of FMV, and lower nitrate mediated vasodilation (NMV) in SS subjects than controls. Patient NMV values were inversely correlated with soluble-VCAM-1 levels. An NMV decrease was confirmed in SS patient subsets with evidence of leukopenia, RF, SS-B and joint involvement. However, patients with joint involvement or parotid enlargement, two of the sites mainly affected by chronic inflammation in SS, had an FMV lower than controls and patients without these clinical features. All these findings suggesting that a functional impairment of the arterial wall may sustain early phases of atherosclerotic damage in SS. A combined effect of disease-related chronic inflammatory and immunologic factors appears to support dysfunction of endothelium and vascular smooth muscle cells, respectively. Finally, the management of CVD in SS patients must be directed toward rigorous intervention of modifiable risk factors as well as non-traditional risk factors, warranting a routine evaluation of autoantibodies and others factors SS-related. So in the future, it is necessary to analyze prospectively the incidence of thrombotic complications and the role of the different risk factors listed in this series for the development of such complications (Table 1).

Table 1. Common and specific mechanisms of CVD in SS and SSc.

Table 1

Common and specific mechanisms of CVD in SS and SSc.

Systemic sclerosis

Systemic sclerosis (SSc) is a chronic disease, characterized by skin fibrosis, microvascular abnormalities and involvement of multiple internal organs. The incidence is approximately 10 cases per one millon persons. There are two major disease presentations: 1) diffuse cutaneous, associated with high risk of early pulmonary fibrosis and acute renal involvement; and 2) limited cutaneous SSc, associated with calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiestasia. Diffuse cutaneous SSc is usually associated with a worse overall prognosis compared with limited cutaneous SSc (362).

It is thought that the vascular involvement is the result of an immune/inflammatory response that activates and injures the vascular endothelium which may increase the risk of coronary AT. The vasculopathy of SSc typically affects the small arteries and capillaries (i.e., microvascular occlusive disease with vasospasm and intimal proliferation in conjunction with cutaneous and parenchymal fibrosis), although macrovascular disease has been demonstrated by carotid ultrasonography, ankle-brachial blood pressure index and peripheral angiography (363,364). Recently, increasing evidence has demonstrated increased atherosclerosis, including coronary artery calcification (CAC), higher prevalence of subclinical CAD and thicker carotid IMT in SSc patients compared with healthy controls, suggesting SSc patients may be exposed to more CV risks (365,366). Patchy fibrosis is the most important feature in the myocardium, especially localized in subendocardial regions, which usually accompanies LVDD (367,368) but it is symptomatic in 10% of the cases (369). Mortality in patients with SE given by CVD is between 20–30% and, despite being similar to general population, it occurs a decade earlier (370). In asymptomatic patients, coronary calcifications were found in approximately 33.3% in diffuse SSc and 40% in limited SSc (371).

There have been reported MI or myocardial perfusion defects with patent coronary arteries, suggesting that the etiology of infarction may be due to microvascular disease rather than coronary AT, while recognizing that the latter is increased in patients with SSc (371,372). Patients with SSc have a reduced coronary flow reserve (373,374), which is associated with higher coronary events (375,376). Other authors have reported ectasia, spasm and coronary artery stenosis (377,378). Arrhythmias and conduction disturbances are characteristic of cardiac involvement in SSc, as hypertrophy and heart failure contractility (368,379) had been reported.

Ultrasonography evaluation is also used to evaluate the carotid arteries, which has proven to be a useful marker for the assessment of subclinical AT and a strong predictor of subsequent MI and CVA (20,373,380). By performing Doppler it has been reported that 64% of the patients with SSc have carotid stenosis, compared with 35% presented in control patients (381).

Regarding the risk factors, it has been described the alteration of lipid profile, given by the increased levels of LDL and lipoprotein A, with a reduction in the fibrinolysis (382). In addition, it has also been found that decreased levels of HDL are related to anti-centromere antibodies positivity (383). According to the presence of antibodies that predispose to develop thrombotic events, there are no conclusive studies on the presence of anti-HSPs65/60. Some authors have found anti-ox-LDL antibodies elevated in limited SSc and cutaneous diffuse SSc. APLA were more found regarding capillary severe compromise (380,384), while anti-HSP 70 have been suggested as a protective factor for CAD (385). Among the non-cardiac alterations, there is the macrovascular involvement, observed by angiography and clinically performed with intermittent claudication (362). Histologically it can be observe fibrosis, thickening and chronic proliferation of the intimal layer as well as transmural lymphocytic infiltrate without evidence of atherosclerotic plaque (362,386) (Table 1).


Atherosclerosis and ADs shares several mechanisms. The excessive CV events observ ed in patients with ADs are not fully explained by classic risk factors. Several novel risk factors contribute to development of premature vascular damage. Therefore, a complex interaction between traditional and disease-specific traits converges into a shared pro-atherogenic phenotype in this population. Until additional research and disease-specific risk prediction tools are available, current evidence supports aggressive treatment of disease activity, and careful screening for and management of modifiable traditional risk factors in patients with ADs. The finding and understanding of complex interactions between predisposing factors will allow us to better describe and assess the broad spectrum of CV subphenotypes in ADs.





anti-cardiolipins antibodies


acid phosphatase locus 1


anti-cyclic citrullinated peptide antibodies


acute coronary syndrome


autoimmune diseases


autoimmune thyroid disease




anti-apolipoprotein A-1 antibodies


anti-beta2 glycoprotein 1 antibodies


anti-modified citrullinatedvimentin antibodies


anti-malondialdehyde-modified LDL antibodies

anti-HSP 60/65/70:

anti-heat shock protein 60/65/70


anti-oxidized low-density lipoprotein antibodies


anti-phosphorylcholine antibodies


adjusted odds ratios


anti-phospholipid antibodies


antiphospholipid syndrome


apolipoprotein B






beta-2 glycoprotein-1


British Isles Lupus Assessment Group


bone mineral density


body mass index


coronary artery calcification


coronary artery disease


congestive heart failure


C-reactive protein




cerebrovascular accident


cardiovascular disease




Disease activity score-28


disease modifying anti-rheumatic drugs


deep vein thrombosis


extra-articular manifestations


erythrocyte sedimentation rate


familial autoimmunity


first degree relatives


flow-mediated vasodilation




Glutathione S-transferase T1




high density lipoprotein cholesterol


human leukocyte antigen


hormone replacement therapy


heat shock proteins




intercellular adhesion molecules


International Diabetes Federation


Interferon- γ


ischemic heart disease




intima-media thickness


Latin American


low density lipoprotein cholesterol


low educational level






Lupus in Minorities: Nature vs. Nurture


left ventricular diastolic dysfunction




mannose-binding lectin


monocyte chemotactic protein


macrophage colony stimulating factor


metabolic syndrome


myocardial infarction


mycophenolate mofetil


methylene tetrahydrofolatereductase




National Cholesterol Education Program


nuclear factor kappa-light-chain-enhancer of activated B cells


Nitrate mediated vasodilation


nitric oxid








peripheral arterial disease


plasminogen activator inhibitor type-1


platelet-derived growth factor


pulmonary embolism


peripheral vascular disease


rheumatoid arthritis


rheumatoid factor


relative risk


SLICC damage index


shared epitope


socioeconomic status


systemic lupus activity measure


systemic lupus erythematosus


Systemic lupus erythematosus disease activity index


Systemic lupus erythematosus disease activity index 2000


Systemic lupus international collaborating clinics score


Systemic Lupus International Collaborating Clinics-Registry for Atherosclerosis


standardized mortality ratio


serum Pentraxin-3


Sjögren’s Syndrome


anti Ro/SSA antibodies


anti La/SSB antibodies


systemic sclerosis




signal transducer and activator of transcription 4


serum uric acid


Systematic Coronary Risk Evaluation


type 2 diabetes mellitus


total cholesterol


transforming growth factor -β




lymphocyte T helper 1


lymphocyte T helper 2


transient ischemic attacks


toll-like receptors

TNF-α :

tumor necrosis factor-α


tumor necrosis factor receptor II


TNF receptor-associated factor 1


tissue type plasminogen


vascular cell adhesion molecules


vascular endothelial growth factor A


very low density lipoprotein cholesterol


waist circumference


World Health Organization


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© 2013 Universidad del Rosario.
Bookshelf ID: NBK459468


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