Abstract
PurposeInflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients.MethodsWe examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry.ResultsIRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (ρ, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA).ConclusionThe independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies.
Highlights
Inflammatory rheumatic diseases (IRD), such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), are associated with increased cardiovascular (CV) risk, which is not fully explained by traditional CV factors
This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG)
Circulating Terminal Complement Complex (TCC) was significantly higher in IRDCAD (SLE: 1.4(0.85–1.75) and RA: 1.3(0.9–1.55) CAU/ml) when compared to IRDNo coronary artery disease (CAD) or non-IRDCAD; there was no difference between IRDNo CAD and non-IRDCAD
Summary
Inflammatory rheumatic diseases (IRD), such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), are associated with increased cardiovascular (CV) risk, which is not fully explained by traditional CV factors. It is notable that systemic inflammation, and inflammation within the vessel wall, including the deep vascular and perivascular layers, may play an essential role in atheroma formation and destabilization. C3 is known to be associated with subclinical measures of CVD such as vascular stiffness.[3,4,5,6] In animal models, vascular complement deposition associated with vascular stiffness is likely due to complement binding directly to the elastin and collagen fibers within the vascular wall.[7, 8] The potentially pathogenic role of complement in the development of CVD is highlighted in a C4-deficient patient with well-preserved elastic arteries despite aging and a medical condition associated with vascular stiffness.[9]
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