The important role of autoimmunity in cardiovascular disease

Summary: Inflammation of the blood vessels is the fundamental factor in cardiovascular diseases including heart attack and stroke. Vascular inflammation due to autoimmunity, a widespread phenomenon, is not encompassed by the 'traditional' metabolic risk factors. In the clinic the autoimmune components of vascular disease must be investigated and treated.The authors of a paper published in the clinical journal Mædica observe:

"Inflammation plays a crucial role in atherogenesis either by local cellular mechanisms or humoral consequences...inflammation and endothelial dysfunction are triggered by cardiovascular risk factors: hypercholesterolemia, hypertension, smoking or diabetes. In other cases inflammation precedes atherosclerotic changes that occur in autoimmune diseases, as systemic lupus erythematosus and rheumatoid arthritis. In these diseases atherogenesis is mostly independent from conventional risk factors. Irrespective of its cause systemic inflammation is correlated with cardiovascular events."

They also note:

"The pathogenic mechanisms of autoimmune disorders include an important localized or systemic inflammatory response. This may trigger as an "innocent bystander" reaction a peculiar type of endothelial injury that predisposes to atherogenesis. Many of these diseases are associated with early, accelerated atherosclerosis. This can also be due to concomitant presence of conventional risk factors, but is determined mainly by specific autoimmune and pro-inflammatory mechanisms or by specific medication (i.e. long term systemic corticosteroid use). In these cases atherosclerosis occurs in population subgroups traditionally protected from the atherosclerotic process, as young women that develop systemic lupus erythematosus. Atherothrombosis became the main cause of mortality in autoimmune disorders...Endothelial dysfunction found in early stages of athero genesis in autoimmune diseases is independent from traditional risk factors, depends only on the severity of systemic inflammation."

As stated by the authors of a paper published in The Netherlands Journal of Medicine, autoimmune conditions such as rheumatoid arthritis and SLE have long been known to increase cardiovascular risk:

"Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis and spondyloarthritis, are associated with increased cardiovascular morbidity and mortality, independent of the established cardiovascular risk factors. The chronic inflammatory state, a hallmark of IMIDs, is considered to be a driving force for accelerated atherogenesis."

They discuss autoimmunity and cardiovascular disease using as models RA, psoriatic arthritis and ankylosing spondyloarthritis, SLE and role of innate and adaptive immunity, concluding:

"Over the past two decades it has become increasingly clear that chronic inflammation is an independent risk factor for cardiovascular events, with an impact over and above established risk factors. Since IMIDs are protracted disorders, the focus on adequate cardiovascular prevention in these patients is long overdue. Pathophysiologically, chronic inflammation provides a direct link between IMIDs and accelerated atherogenesis."

A fascinating review article, rich with references to other valuable citations, was published recently in the International Journal of Inflammation that expands on the role of oxidative stress in eliciting an autoimmune response that produces cardiovascular inflammation. The authors state:

"Recently, it has become clear that atherosclerosis is a chronic inflammatory disease in which inflammation and immune responses play a key role. Accelerated atherosclerosis has been reported in patients with autoimmune diseases, suggesting an involvement of autoimmune mechanisms in atherogenesis. Different self-antigens or modified self-molecules have been identified as target of humoral and cellular immune responses in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients, is the major event causing structural modification of proteins with consequent appearance of neoepitopes. Self-molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development."

The authors acknowledge the role of infectious agents as instigators of autoimmune activity, but emphasize the role of modified self-antigens:

"Although infectious agents have been associated with the activation of immune mechanisms, evidence exist that the main antigenic targets in atherosclerosis are modified endogenous structures [12]. Atherosclerotic plaques express autoantigens that are targeted by both IgM and IgG. It is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful antigens [13, 14]. However, studies performed on hypercholesterolaemic mice deficient in different components of innate and adaptive immunity uniformly indicate that the net effect of immune activation is proatherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease."

They go on to discuss the roles of oxidized LDL, heat shock proteins, Beta2-glycoprotein I (β2-GPI), and oxidized hemoglobin as oxidized agents that act as autoantigens eliciting an autoimmune response implicated in atherogenesis and cardiovascular disease, then conclude by stating:

"Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases...In addition to pro-inflammatory properties, self molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development...Modulation of the immune system could represent a useful approach to prevent and/or treat these diseases."

An excellent paper published in the journal Nature Reviews Rheumatology (formerly Nature Clinical Practice Rheumatology) discusses the mechanisms of atherosclerosis in autoimmune diseases. The authors note:

"Many components of the immune system are involved in the pathologic processes underlying the development of atherosclerosis: macrophages that develop into foam cells; T cells; autoantibodies; autoantigens that are components of vessel walls and cholesterol particles; and cytokines that are secreted by cells within atherosclerotic plaques, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, IL-10, tumor-necrosis factor, interferon-gamma and platelet-derived growth factor."

They note evidence for the role of cellular immunity...

"Several autoimmune diseases are characterized as being TYPE 1 T HELPER (TH1) CELL-mediated or TYPE 2 T HELPER (TH2) CELL-mediated conditions. A study in which ApoE-/- mice were treated with pentoxifylline (an inhibitor of the TH1 differentiation pathway) for 12 weeks suggested that atherosclerosis is a TH1-mediated process."

And the participation of humoral immunity is characterized by antibodies to oxidized LDL cholesterol and to heat-shock proteins (HSPs):

"Oxidized LDL (oxLDL) is the type of LDL cholesterol most likely to be taken up by macrophages that develop into foam cells. Increased levels of anti-oxLDL antibodies have been detected in patients with early-onset peripheral vascular disease, severe carotid atherosclerosis, and angiographically verified coronary artery disease (CAD). In addition, raised levels of oxLDL antibodies were found to be predictive of progression of carotid atherosclerosis, MI, and death...it was found that individuals with atherosclerosis had significantly higher levels of anti-HSP65 antibodies than controls."

It has long been known that antiphospholipid antibodies (aPL) and anticardiolipin antibodies (aCL) can be associated with cardiovascular disease, and the authors discuss their relation to arterial intima–media thickness (IMT, pathological thickening of the blood vessel wall). They conclude:

"The complex involvement of the immune system in the pathogenesis of atherosclerosis is most evident in patients with autoimmune diseases, but is also important in the general population. Immunomodulation of atherosclerosis carries great potential for future human therapies...

• Autoimmune rheumatic diseases are characterized by enhanced atherosclerosis, which leads to cardiovascular disease
• Some forms of atherosclerosis can be detected at the preclinical stage
• Both cellular and humoral components of the immune system are involved in the pathogenesis of atherosclerosis
• Classical and nonclassical risk factors for atherosclerosis are associated with accelerated atherosclerosis in autoimmune rheumatic diseases
• Atherosclerosis can be immunomodulated in experimental models in various ways, which include induction of immune tolerance"

The authors of a paper published in the journal Stroke observe that inflammation plays the critical role in arterial plaque destabilization:

"Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder."

Expanding on this...

"...a complex endothelial dysfunction induced by elevated and modified low-density lipoproteins (LDL), free radicals, infectious microorganisms, shear stress, hypertension, toxins after smoking or combinations of these and other factors leads to a compensatory inflammatory response. Endothelial dysfunction is characterized by decreased nitric oxide synthesis, local oxidation of circulating lipoproteins and their entry into the vessel wall. Intracellular reactive oxygen species similarly induced by the multiple atherosclerosis risk factors lead to enhanced oxidative stress in vascular cells and further activate intracellular signaling molecules involved in gene expression. Upregulation of cell adhesion molecules facilitates adherence of leukocytes to the dysfunctional endothelium and their subsequent transmigration into the vessel wall. As outlined in this review, the evolving inflammatory reaction is instrumental in the initiation of atherosclerotic plaques and their destabilization."

The authors summarize the stream of events leading to plaque rupture:

"Inflammation plays an important role in the progression of atherosclerosis and ICA plaque destabilization converting a chronic process into an acute disorder with ensuing thrombo-embolism. During atherosclerosis, T cells and macrophages infiltrate the vessel wall triggered by endothelial dysfunction, and locally interact in a synergistic manner. Autoreactive T cells recognize oxLDL, HSP and shared microbial antigens by molecular mimicry and locally release proinflammatory cytokines. Macrophages on stimulation by T-cell-derived cytokines and transformation into foam cells after uptake of oxLDL secrete MMP predisposing the plaques to subsequent rupture. Plaque-associated macrophages, moreover, are an important cellular source of TF. On plaque rupture TF-rich plaque material gets in contact with the circulation and activates the extrinsic coagulation pathway...Vaccination against modified LDL and HSP can slow development of atherosclerotic plaques. Current therapeutics effective in preventing atherosclerosis and stroke such as statins, ASS [aspirin] and renin-angiotensin system inhibitors may exert part of their effects by modulating inflammatory responses in the vessel wall."

The authors of a review article published in Clinical and Developmental Immunology consider epigenetic mechanisms involved in autoimmune cardiovascular risk. They state:

"Autoimmune diseases (AIDs) have been associated with accelerated atherosclerosis (AT) leading to increased cardio- and cerebrovascular disease risk...many new genes and signalling pathways involved in autoimmunity...have been further detected. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Epigenetic regulatory mechanisms comprise DNA methylation, histone modifications, and microRNA activity, all of which act upon gene and protein expression levels. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development.

In other words, environmental factors that modulate gene expression play a role in 'turning on' autoimmunity that promotes heart attacks and strokes. As the authors note:

"It is widely known that AIDs are the result of interaction between predisposing genetic factors, deregulation of the immune system, and environmental triggering factors."

Of great importance is that these factors can be modified:

"Moreover, epigenetic changes may be reversed. A remarkable example of disease in which epigenetic abnormalities and patterns of inheritance are extremely complex is SLE. The high incidence of twin pairs in which SLE develops in only one of the siblings supports the notion that environmental factors and their involvement in epigenetic modifications could affect the onset of disease."

And there seem to be differences of autoimmune expression depending on the disease and the individual:

"Significant evidence has shown that there is heterogeneity in the characteristics of vasculopathies underlying different autoimmune diseases such as APS, SLE, RA, and pSS. It has been also shown a relevant heterogeneity with respect to inflammatory risk factors. The data presented in this revision further indicated that epigenetic mechanisms also seem to influence inflammation and cardiovascular disease in those autoimmune conditions."

The authors of a paper published in Zeitschrift für Rheumatologie (Journal of Rheumatology) note that EULAR (the European League Against Rheumatism) recommends aggressive cardiovascular risk factor management for rheumatoid arthritis, which would be reasonable extrapolate to other autoimmune diseases:

"Beyond the traditional CV risk factors, chronic systemic inflammation has been shown to be a crucial factor in atherosclerosis development and progression from endothelial dysfunction to plaque rupture and thrombosis. Numerous studies have shown that atherosclerosis is not a passive process characterized by accumulation of lipids in the vessel walls, but rather represents active inflammation of the vasculature...According to the recently published EULAR recommendations for CV risk screening and management in patients with inflammatory arthritis, annual CV risk assessment is recommended for all patients with RA. Any CV risk factors identified should be optimally managed. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower CV risk."

Stroke in young women, particularly in the absence of 'traditional' risk factors such as elevated cholesterol, hypertension, metabolic syndrome and obesity, etc. is a great concern. In a paper published recently in the Canadian Journal of Neurological Sciences the authors state:

"In women ages 15-45 years, an additional set of risk factors are important in the pathogenesis of ischemic stroke. Some of these pertain strictly to women, and relate to exogenous hormones and pregnancy. Various other conditions are more common in women, which include migraine with aura, selected vascular disorders and autoimmune conditions. These differences do have implications for management in both the primary and secondary prevention of stroke in this age group."

Of interest to clinicians is another paper in the same journal drawing attention to the role of the cytokine transforming growth factor-β (TGF-β) in vascular inflammation. The authors investigated polymorphisms of the TGF-β gene in ischemic stroke:

"Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cerebrovascular complications. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with a central role in inflammation. To investigate whether polymorphisms of the TGF-β1 gene can modify the risk of ischemic stroke (IS) in Chinese population, we conduct this hospital-based, case-control study."

They determined the transforming growth factor-β1 genotype in 450 Chinese patients (306 male and 144 female) with ischemic stroke compared to 450 control subjects (326 male and 124 female).

"Subjects carrying 869TT were susceptible to IS (odds ratio [OR] =1.58). Further analysis of IS data partitioned by gender revealed the female-specific association with 869T/C (OR=2.64)."

While the 869TT genotype of the TGF-β1 gene increased the risk of stroke for both sexes, the increase in risk for stroke was 264% for females.The authors of an interesting paper published recently in the Endocrine Journal investigate the association of chronic inflammation in autoimmune thyroiditis with endothelial (vascular) dysfunction:

"Our study aims to investigate the presence of the well known preceding clinical situations of atherosclerosis like endothelial dysfunction and inflammation in subclinical hypothyroidism."

They evaluated 37 patients with subclinical hypothyroidism (29 women, 8 men) in comparison to 23 healthy volunteers (19 women, 4 men) for endothelial dysfunction as measured by brachial artery responses to endothelium-dependent (flow mediated dilation, FMD) and endothelium-independent stimuli (sublingual nitroglycerin (NTG)). They also measured serum TNF-alpha, interleukin-6, and hs-CRP, and estimated insulin resistance by HOMA score. The data make paint an interesting picture:

"There were no significant differences in age, body mass index, waist circumference, HOMA scores. There was a statistically significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the patients with subclinical hypothyroidism and the normal healthy controls...The TSH and LDL, IL-6, TNF-alpha and hs-CRP levels in the patient group were significantly higher than those in control group. A positive correlation was found only between endothelium-dependent vasodilation and TNF-alpha, hs-CRP and IL-6, TSH, total cholesterol, LDL and triglycerides. Neither of the groups were insulin resistant and there was not any difference either in fasting insulin or in glucose levels. We found endothelial dysfunction in subclinical hypothyroidism group."

The vascular inflammation associated with autoimmune thyroiditis stands out in high relief against a background of normal traditional risk factors like BMI, waist circumference and insulin resistance. The authors conclude:

"Our findings suggest that there is endothelial dysfunction and low grade chronic inflammation in SH due to autoimmune thyroiditis. There are several contributing factors which can cause endothelial dysfunction in SH such as changes in lipid profile, hyperhomocysteinemia. According to our results low grade chronic inflammation may be one of these factors."

Finally, in the journal Circulation Research the authors of a commentary  on a study just published in the Journal of Clinical Investigation ask the question "Is Atherosclerosis an Allergic Disease?":

"A new report in the Journal of Clinical Investigation adds to the ever-increasing evidence that immunological mechanisms play an important role in atherogenesis. These new observations suggest involvement of IgE and its FcϵR1α receptor in the promotion of atherosclerosis, and specifically in plaque instability and clinical events."

They further note, importantly...

"In addition, aside from conditions in which there are generalized increases in IgE levels, such as parasitic infections and hyper-IgE syndromes, elevated IgE levels usually reflect allergic-type immune responses."

This is one mechanism by which food and other allergies contribute to the inflammation of cardiovascular disease. The authors conclude:

"The report by Wang et al and other reports describing the potential importance of mast cells to CVD have provided a compelling case to study the role of IgE in inflammatory conditions such as atherosclerosis. It adds to the growing evidence of the importance of immune function in atherogenesis and in particular of the role that immunoglobulins play, both through antigen-specific interactions and antigen-independent regulatory roles."

Bottom line: In clinical management of cardiovascular disease the autoimmune components should be investigated and addressed with a rational treatment strategy.