Relation of platelet C4d with all-cause mortality and ischemic stroke in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with significant morbidity, including premature cardiovascular disease, and mortality. Platelets bearing complement protein C4d (P-C4d) were initially determined to be specific for diagnosis of SLE and were later found to be associated with acute ischemic stroke in non-SLE patients. P-C4d may identify a subset of SLE patients with a worse clinical prognosis. This study investigated the associations of P-C4d with all-cause mortality and vascular events in a lupus cohort. A cohort of 356 consecutive patients with SLE was followed from 2001 to 2009. Primary outcome was all-cause mortality. Secondary outcomes were vascular events (myocardial infarction, coronary artery bypass graft, percutaneous coronary transluminal angioplasty, ischemic stroke, venous thromboembolism, pulmonary embolism, or other thrombosis). P-C4d was measured at study baseline. Seventy SLE patients (19.7%) had P-C4d. Mean follow-up was 4.7 years. All-cause mortality was 4%. P-C4d was associated with all-cause mortality (hazard ratio 7.52, 95% confidence interval (CI) 2.14-26.45, p = 0.002) after adjusting for age, ethnicity, sex, cancer, and anticoagulant use. Vascular event rate was 21.6%. Patients with positive P-C4d were more likely to have had vascular events compared to those with negative P-C4d (35.7 vs. 18.2%, p = 0.001). Specifically, P-C4d was associated with ischemic stroke (odds ratio 4.54, 95% CI 1.63-12.69, p = 0.004) after adjusting for age, ethnicity, and antiphospholipid antibodies. Platelet-C4d is associated with all-cause mortality and stroke in SLE patients. P-C4d may be a prognostic biomarker as well as a pathogenic clue that links platelets, complement activation, and thrombosis.

Relative contributions of age and atherosclerosis to vascular stiffness.

To determine the relative contributions of aging and atherosclerosis to vascular stiffness, we studied aortic stiffness, plaque, and elastin in 8-, 16-, 25-, and 34-week-old male ApoE-KO and C57BL/6J control mice (N = 48). Stiffness increased gradually in both strains up to 25 weeks (p < 0.05), and dramatically between 25 and 34 weeks in ApoE-KO (p < 0.001). Aging ApoE-KO demonstrated increased plaque (p = 0.02), medial thickening (p < 0.001), and severe elastin fragmentation (p < 0.001). We conclude that the contribution of aging to vascular stiffness is relatively minor compared with the influence of atherosclerosis. However, the effect of atherosclerosis on stiffness is significant only with advanced stages of plaque formation.