Reduced oxidized LDL in T2D plaques is associated with a greater statin usage but not with future cardiovascular events
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ORIGINAL INVESTIGATION
Cardiovascular Diabetology Open Access
Reduced oxidized LDL in T2D plaques is associated with a greater statin usage but not with future cardiovascular events Pratibha Singh1, Isabel Goncalves1,2, Christoffer Tengryd1, Mihaela Nitulescu1, Ana F. Persson1, Fong To1, Eva Bengtsson1, Petr Volkov3, Marju Orho‑Melander1, Jan Nilsson1 and Andreas Edsfeldt1,2,4*
Abstract Background: Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated ath‑ erosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target. Methods: Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during followup were obtained from national registers. Results: Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expres‑ sion of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p 70% or 2) asymptomatic plaques with a degree of stenosis greater than 80%. All patients included were preoperatively assessed by a neurologist. Two patients underwent carotid endarterectomy on two occasions. Informed consent was given by each patient. The study follows the declaration of Helsinki and was approved by the local ethical committee at Lund University. Plaques were directly snap frozen upon surgical removal. As previously described, a fragment (1 mm) from the most stenotic region of the carotid plaque was kept for histological analysis whereas the rest of the tissue was homogenized [18]. Clinical information and blood samples
Clinical data regarding risk factors and medications were recorded at the time of inclusion. Among the included patients four different types of statin treatments were recorded, which should have been initiated > 1 week prior to surgery. Statin treatments were divided into low, intermediate or high dose accordingly: Simvastatin (10 mg, 20–30 mg, 40 mg), Pravastatin (10 mg, 20 mg, 40 mg), Atorva
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