From the Division of Cardiovascular Medicine (P.L., B.M.E.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Preventive Medicine (B.M.E.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):538-545. doi: 10.1161/ATVBAHA.118.310958.
Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA (lipoprotein-associated phospholipase A), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.
许多措施可以控制动脉粥样硬化的血脂危险因素。然而，即使血脂异常得到了很好的控制，其他风险源仍然存在。因此，我们必须超越血脂来解决剩余风险。生活方式措施应构成心血管风险控制的基础。许多针对氧化的药物干预措施已被证明令人失望。一项大型计划测试了脂蛋白相关磷脂酶 A (LpPLA) 的抑制作用，最终进行了两项大型临床试验，但均未达到主要终点。各种抗氧化剂在临床试验中均未显示出获益。许多实验室和临床研究表明，炎症途径与动脉粥样硬化事件的发病机制有关。p38 MAPK（丝裂原活化蛋白激酶）抑制剂 losmapimod 和白细胞黏附分子 P 选择素抑制剂在试验中并未改变不良事件。尽管观察性研究前景看好，但小剂量甲氨蝶呤并未降低炎症标志物或改变心血管结局在 CIRT（心血管炎症减少试验）中。四项正在进行的大规模研究将确定秋水仙碱在二级预防中降低复发性事件的能力。CANTOS（Canakinumab Anti-inflammatory Thrombosis Outcomes Study）表明，一种中和白细胞介素-1β的抗体可降低二级预防中的复发性心血管事件。CANTOS 的成功表明，从 NLRP3（NOD 样受体家族，pyrin 结构域包含蛋白 3）炎性体通过白细胞介素-1β到白细胞介素-6 的途径是一个有吸引力的靶点，超越了脂质治疗，以进一步研究和临床开发，以解决尽管我们在二级预防中提供了最佳的现有护理，但仍然存在不可接受的风险负担。
