Università degli Studi della Campania "Luigi Vanvitelli", Piazza Luigi Miraglia 2, 80138, Naples, Italy; Mediterranea Cardiocentro, 80122, Naples, Italy.
IRCCS MultiMedica, Via Fantoli 16/15, 20138, Milan, Italy.
Atherosclerosis. 2023 Aug;378:117180. doi: 10.1016/j.atherosclerosis.2023.06.971. Epub 2023 Jun 29.
Preclinical evidence suggests that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors hold anti-inflammatory properties independently of their ability to lower LDL-cholesterol (C). However, whether PCSK9 inhibitors exert anti-inflammatory effects within the atherosclerotic plaque in humans is unknown. We explored the impact of PCSK9 inhibitors, used as monotherapy, compared with other lipid-lowering drugs (oLLD) on the expression of inflammatory markers within the plaque, assessing also the subsequent incidence of cardiovascular events.
In an observational study, we recruited 645 patients on stable therapy for at least six months and undergoing carotid endarterectomy, categorizing patients according to the use of PCSK9 inhibitors only (n = 159) or oLLD (n = 486). We evaluated the expression of NLRP3, caspase-1, IL-1β, TNFα, NF-kB, PCSK9, SIRT3, CD68, MMP-9, and collagen within the plaques in the two groups through immunohistochemistry, ELISA, or immunoblot. A composite outcome including non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality was assessed during a 678 ± 120 days follow-up after the procedure.
Patients treated with PCSK9 inhibitors had a lower expression of pro-inflammatory proteins and a higher abundance of SIRT3 and collagen within the plaque, a result obtained despite comparable levels of circulating hs-CRP and observed also in LDL-C-matched subgroups with LDL-C levels <100 mg/dL. Patients treated with PCSK9 inhibitors showed a decreased risk of developing the outcome compared with patients on oLLD, also after adjustment for multiple variables including LDL-C (adjusted hazard ratio 0.262; 95% CI 0.131-0.524; p < 0.001). The expression of PCSK9 correlated positively with that of pro-inflammatory proteins, which burden was associated with a higher risk of developing the outcome, independently of the therapeutic regimen.
The use of PCSK9 inhibitors is accompanied by a beneficial remodelling of the inflammatory burden within the human atheroma, an effect possibly or partly independent of their LDL-C lowering ability. This phenomenon might provide an additional cardiovascular benefit.
临床前证据表明，前蛋白转化酶枯草溶菌素 9（PCSK9）抑制剂具有抗炎特性，且不依赖于降低 LDL-胆固醇（C）的能力。然而，PCSK9 抑制剂是否在人类动脉粥样硬化斑块中发挥抗炎作用尚不清楚。我们探讨了单独使用 PCSK9 抑制剂与其他降脂药物（oLLD）对斑块内炎症标志物表达的影响，并评估了随后发生心血管事件的情况。
在一项观察性研究中，我们招募了 645 名接受颈动脉内膜切除术且稳定治疗至少六个月的患者，根据是否单独使用 PCSK9 抑制剂（n=159）或 oLLD（n=486）进行分组。我们通过免疫组织化学、ELISA 或免疫印迹法评估两组斑块内 NLRP3、半胱氨酸天冬氨酸蛋白酶-1（caspase-1）、白细胞介素 1β（IL-1β）、肿瘤坏死因子-α（TNFα）、核因子-κB（NF-kB）、PCSK9、SIRT3、CD68、基质金属蛋白酶 9（MMP-9）和胶原的表达。在手术后 678±120 天的随访期间评估非致命性心肌梗死、非致命性卒中和全因死亡率的复合结局。
接受 PCSK9 抑制剂治疗的患者斑块内促炎蛋白表达水平较低，SIRT3 和胶原含量较高，尽管循环 hs-CRP 水平相当，且在 LDL-C<100mg/dL 的 LDL-C 匹配亚组中也观察到这一结果。与接受 oLLD 治疗的患者相比，接受 PCSK9 抑制剂治疗的患者发生该结局的风险降低，即使在调整 LDL-C 等多个变量后也是如此（调整后的危险比 0.262；95%置信区间 0.131-0.524；p<0.001）。PCSK9 的表达与促炎蛋白的表达呈正相关，其负担与发生该结局的风险增加相关，而与治疗方案无关。
PCSK9 抑制剂的使用伴随着人类动脉粥样硬化斑块内炎症负担的有益重塑，这一效应可能部分独立于其降低 LDL-C 的能力。这一现象可能提供额外的心血管获益。
