Karpouzas George A, Papotti Bianca, Ormseth Sarah R, Palumbo Marcella, Hernandez Elizabeth, Adorni Maria Pia, Zimetti Francesca, Budoff Matthew J, Ronda Nicoletta
Division of Rheumatology, Harbor-UCLA and The Lundquist Institute, Torrance, CA, USA.
Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
J Transl Autoimmun. 2023 Jul 18;7:100209. doi: 10.1016/j.jtauto.2023.100209. eCollection 2023 Dec.
High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events.
Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol.
Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027).
ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.
高密度脂蛋白（HDL）从动脉粥样硬化病变细胞中清除胆固醇，这一功能称为胆固醇流出能力（CEC）。ATP结合盒A1（ABCA1）膜转运蛋白启动胆固醇从巨噬细胞向HDL颗粒的转移。在类风湿关节炎（RA）中，甲氨蝶呤和生物疾病改善药物（bDMARDs）具有抗动脉粥样硬化作用，而皮质类固醇和C反应蛋白（CRP）则具有促动脉粥样硬化作用。我们评估了这些因素对ABCA1-CEC与动脉粥样硬化及心血管事件关系的影响。
对140例RA患者进行计算机断层扫描血管造影评估动脉粥样硬化情况，并在6.9±0.3年后对99例患者进行复查。记录包括急性冠状动脉综合征、中风、心血管死亡、跛行、血管再通和心力衰竭在内的事件。在J774A.1小鼠巨噬细胞中对ABCA1-CEC进行定量，并以流出胆固醇占细胞内胆固醇的百分比表示。
较高的ABCA1-CEC与以下情况相关：（i）仅在CRP>7mg/L（中位数）的患者（p交互作用=0.001）和未使用甲氨蝶呤的患者（p交互作用=0.037）中，基线时钙化斑块更多；仅在未使用bDMARDs的患者中，部分钙化斑块更多（p交互作用=0.029）；（ii）在时间平均CRP低于中位数而非高于中位数的患者中，新钙化斑块较少（p交互作用=0.028）；（iii）在随访期间未暴露于泼尼松而非暴露于泼尼松的患者中，新的总斑块和钙化斑块较少（p交互作用分别为0.034和0.004）；（iv）基线时未使用bDMARDs的患者中新斑块更多，而使用bDMARDs的患者中新斑块较少（p交互作用=0.001）。此外，仅在基线时使用泼尼松的患者中，ABCA1-CEC与更高的心血管风险相关（p交互作用=0.027）。
ABCA1-CEC与基线和时间平均CRP低于中位数且使用bDMARDs的患者动脉粥样硬化减少相关。相反，ABCA1-CEC与CRP较高、使用皮质类固醇、未使用甲氨蝶呤和未使用bDMARDs的患者斑块增加相关。在病情得到良好治疗和控制的情况下，ABCA1-CEC似乎具有抗动脉粥样硬化作用，而在未控制的RA中，其作用可能被掩盖或无法抵消炎症驱动的促动脉粥样硬化状态。
