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Background —Accumulation of LDL within the arterial wall appears to play a crucial role in the initiation and progression of atherosclerotic plaque. The dynamic sequence of this event has not been fully elucidated in humans. Methods and Results —In 7 patients with previous transient ischemic attack or stroke and critical (>70%) carotid stenosis, autologous native [ 125 I]-labeled LDL or [ 125 I]-labeled human serum albumin were injected 24 to 72 hours before endarterectomy. Carotid specimens obtained at endarterectomy were analyzed by autoradiography and immunohistochemistry. Autoradiographic study showed that LDL was localized prevalently in the foam cells of atherosclerotic plaques, whereas the accumulation in the lipid core was negligible. Immunohistochemistry revealed that foam cells that had accumulated radiolabeled LDL were mostly CD68 positive, whereas a small number were α-actin positive. No accumulation of the radiotracer was detected in atherosclerotic plaques after injection of radiolabeled human serum albumin. In 3 patients treated for 4 weeks with vitamin E (900 mg/d), an almost complete suppression of radiolabeled LDL uptake by macrophages was observed. Conclusions —This study shows that circulating LDL rapidly accumulates in human atherosclerotic plaque. The prevalent accumulation of LDL by macrophages provides strong support to the hypothesis that these cells play a crucial role in the pathogenesis of atherosclerosis.

Background Urinary 8‐iso‐ PGF 2α, a marker of oxidative stress, is influenced by the activation of NOX 2. It is unclear if platelets 8‐iso‐ PGF 2α contribute to urinary 8‐iso‐ PGF 2α. Methods and Results In a cross‐sectional study, platelet, urinary, and serum 8‐iso‐ PGF 2α were determined in subjects with downregulation (X‐linked chronic granulomatous disease [ X‐CGD ], n=25) and upregulation (type II diabetic patients [T2D], n=121) of NOX 2 and 153 controls matched for sex and age. In diabetic patients (n=18), the above variables were repeated before and after 7 days treatment with 100 mg/day aspirin or 100 mg/day aspirin plus 40 mg/day atorvastatin. In vitro study was performed to see the contribution of blood cells to serum 8‐iso‐ PGF 2α. Compared with controls, X‐CGD patients had lower platelet, serum, and urinary 8‐iso‐ PGF 2α values; conversely, diabetic patients had higher values of 8‐iso‐ PGF 2α compared with controls. Urinary 8‐iso‐ PGF 2α significantly correlated with both platelet and serum 8‐iso‐ PGF 2α in the 2 cohorts. A parallel increase of platelet, serum, and urinary 8‐iso‐ PGF 2α by aspirin and a parallel decrease by aspirin plus atorvastatin were detected in the interventional study. In vitro study demonstrated that platelets contribute to 37% of serum 8‐iso‐ PGF 2α and that only 13% of it is of extravascular origin. Conclusions The study suggests that NOX 2 contributes to the formation of 8‐iso‐ PGF 2α in both platelets and urine. The direct correlation between platelet and urinary 8‐iso‐ PGF 2α suggests that, at least partly, urinary 8‐iso‐ PGF 2α reflects platelet 8‐iso‐ PGF 2α production. Analysis of serum 8‐iso‐ PGF 2α may represent a novel tool to investigate the production of 8‐iso‐ PGF 2α by blood cells including platelets. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT01250340 .