We now recognize coronary artery disease (CAD) as a significant contributor to morbidity and mortality in various rheumatic diseases. This enlightenment has stemmed from clinical observations in patients as well as from basic research that is providing a better understanding of this connection. Improved understanding of the underlying mechanisms, better ability to assess the cardiovascular risk in these patients, and institution of timely intervention can result in improved outcomes. An ideal risk-assessment model is still needed, and an alliance between preventive cardiology and rheumatology can be immensely useful in comprehensive delivery of care to patients with rheumatic diseases.
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Connection Between Coronary Artery Disease and Rheumatic Disease
What is the connection between CAD and rheumatic diseases?
The inflammatory nature of atherosclerosis has been proved beyond doubt.1 Atherosclerotic affliction of the endothelium and rheumatoid affliction of the synovium can be envisioned as similar inflammatory processes that affect single-cell-thick layers and result from infiltration by cells of the immune system (macrophages, T-cells) as well as transformation and dysfunction of resident cells (endothelial and synovial fibroblasts, respectively). Abnormalities in cadherins, which are transmembrane adhesion proteins, have been proposed to play a role in synovial fibroblast proliferation in rheumatoid arthritis (RA)2 and smooth muscle proliferation in atherosclerosis.3 Identical clonal T-cell subset (CD4+ CD28-) expansion has been observed in the synovium of patients with RA and in the atherosclerotic plaques of patients with unstable angina.4 The initial inciting event in either process is unknown, but ultimately the earliest observed pathology is cellular dysfunction that creates an imbalance in a host of cellular processes that are finely regulated at various levels. Most systemic autoimmune diseases are characterized by inflammation, and this is hypothesized to be the driver fueling accelerated atherosclerosis observed in these diseases (Box 1).
Box 1 Mechanisms of Accelerated Atherosclerosis in Systemic Inflammatory Autoimmune Disease
Direct Effects
Endothelial dysfunction
Antibody mediated endothelial cell damage
Immune complex mediated endothelial cell damage
Cytokine mediated
Prothrombotic milieu
Dysfunctional high-density lipoprotein
Autoantibodies
Indirect Effects
Hypertension
Diabetes/insulin resistance
Renal dysfunction
Increased body mass index
Dyslipidemia
Hyperhomocystinemia
Endothelial dysfunction is the earliest event that signals the development of atherosclerosis. Circulating cytokines that cause endothelial dysfunction accompany systemic inflammation. The normal endothelium is a single-cell-thick semipermeable membrane that has myriad balanced functions (antithrombotic, vasodilator, anti-inflammatory, nonadhesive for platelets, semipermeable). Inflammatory processes disrupt many of these functions. In addition to causing direct effects on the endothelium, inflammation can promote atherosclerosis by indirect mechanisms such as unfavorable alteration of the lipid profile, arterial wall stiffening, and alteration of body-mass index. Tumor necrosis factor α (TNF-α) is a key cytokine in many inflammatory rheumatic diseases such as RA and psoriatic arthritis.
One of the earliest actions of TNF-α discovered was its ability to cause dyslipidemia (hypertriglyceridemia) in patients with Trypanosoma brucei infection.5 This dyslipidemic action of TNF-α is mediated by suppression of lipoprotein lipase in adipocytes6 and also by release of the most active form of the enzyme from the endothelial cell surface.7 TNF-α directly affects endothelium, rendering it a promoter of coagulation and inflammation by altered cell morphology and altered surface expression of molecules.8 Other cytokines commonly released during inflammatory diseases such as interferon-ɣ (INF-ɣ), interleukin-1 (IL-1), and IL-6 also have an adverse effect on the lipid profile, rendering it proatherogenic.
INF-ɣ is also known to inhibit lipoprotein lipase (similar to TNF-α), but it might have an antiatherogenic role as well.9 The resulting lipid profile is hypertriglyceridemia, low total cholesterol, low high-density cholesterol (HDL), and increased oxidized low-density cholesterol (ox-LDL). The dyslipidemia also correlates with the degree of inflammation in various diseases with improvement in atherogenic profile seen after treatment.10
Other mechanisms of accelerated atherosclerosis include hyperhomocysteinemia11 and dysfunctional HDL cholesterol observed in diseases such as systemic lupus erythematosus (SLE) and RA. C-reactive protein (CRP), which is a commonly elevated acute phase reactant in systemic inflammatory autoimmune diseases, might serve as a marker for underlying inflammation, but it also might play a pathogenic role in endothelial damage via complement activation.12 (see Box 1)
Studies of plaque histology in patients with RA have shown extensive involvement of cells of the immune system in plaque formation and potential destabilization resulting in plaque rupture that often underlies precipitation of clinical acute coronary syndromes.13 The presence of T and B lymphocytes in the atherosclerotic plaque might also be the missing link that implicates infection as a causative factor in this disease. In a study of atherosclerotic plaques from two patients who were dying of ischemic heart disease, prominent B lymphocytes were described in the adventitia and within the plaque, suggesting different immune alterations than those observed in traditional atherosclerosis.14
Circulating immune complexes abound in SLE, and these might have a role in myocardial infarction.15 Studies have shown that IFN-ɣ and immune complexes bound to C1q reduce expression of the enzyme cholesterol 27-hydroxylase in human aortic endothelial cells, peripheral blood mononuclear cells, and monocyte-derived macrophages. Immune complexes down-regulate the enzyme only after complement fixation via interaction with the 126-kD C1qRp protein on endothelial cells.16 The CD40 ligand (CD40L) on the T cell that binds CD40 on the macrophage as a costimulatory interaction has also received a lot of attention in atherosclerotic mechanisms in SLE; T cell activation via this mechanism is common to both.17,18 Interestingly, although CD40L plays a role in atherosclerotic plaques, soluble CD40L does not correlate with measures of subclinical atherosclerosis in SLE.19 The presence and titers of antibodies to oxidized LDL (oxLDL) have been shown to be specific for SLE.20 but their exact role in pathogenesis remains to be determined. Insulin resistance as measured by the Homeostasis Model Assessment (HOMA) has been found to be more elevated in patients with RA (correlating with IL-6 and TNF-α levels) than in SLE (correlating with body mass index).21
There is ongoing research to unravel other mechanistic connections between atherosclerosis and systemic autoimmune disease. The main difficulty lies in determining whether the discovered molecule or cell is truly pathogenic, an innocent bystander, or merely an epiphenomenon. To this end, applying principles similar to Koch’s postulates in whole or part may be necessary.