University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Brigham and Women's Hospital, Boston, Massachusetts; TIMI Study Group, Boston, Massachusetts.
Am Heart J. 2022 Jan;243:147-157. doi: 10.1016/j.ahj.2021.08.022. Epub 2021 Sep 8.
p38 mitogen activated kinase (MAPK) mediates the response to pro-inflammatory cytokines following myocardial infarction (MI) and is inhibited by losmapimod.
LATITUDE-TIMI 60 (ClinicalTrials.gov NCT02145468) randomized patients with MI to losmapimod or placebo for 12 weeks (24 weeks total follow-up). In this pre-specified analysis, we examined outcomes based on MI type [ST-segment elevation MI (STEMI) (865, 25%) and non-STEMI (2624, 75%)].
In patients with STEMI, inflammation, measured by hs-CRP, was significantly attenuated with losmapimod at 48 hours (P <0.001) and week 12 (P = 0.01). Losmapimod lowered NT-proBNP in patients with STEMI at 48 hours (P = 0.04) and week 12 (P = 0.02). The effects of losmapimod on CV death (CVD), MI, or severe recurrent ischemia requiring urgent coronary artery revascularization at 24 weeks [MACE] differed in patients with STEMI (7.0% vs 10.8%; HR 0.65, 95%CI 0.41 - 1.03; P= 0.06) and NSTEMI (11.4% vs 8.5%; HR 1.30, 95%CI 1.02 - 1.66; P = 0.04; p[int] = 0.009). CVD or HHF among patients with STEMI were 5.6% (losmapimod) and 8.3% (placebo) (HR 0.66; 95%CI 0.40 - 1.11; P = 0.12) and in NSTEMI were 4.8% (losmapimod) and 4.4% (placebo) (HR 1.09; 95%CI 0.76 - 1.56) in patients with NSTEMI.
Patients with STEMI treated with losmapimod had an attenuated inflammatory response. Our collective findings raise the hypothesis that mitigating the inflammatory response may result in different outcomes in patients with STEMI and NSTEMI. While the difference in outcomes is exploratory, these findings do support separate examination of patients with STEMI and NSTEMI and increased emphasis on heart failure in future investigation of modulators of inflammation in MI.
p38 丝裂原活化蛋白激酶（MAPK）介导心肌梗死后（MI）对促炎细胞因子的反应，并被 losmapimod 抑制。
LATITUDE-TIMI 60（ClinicalTrials.gov NCT02145468）将 MI 患者随机分为 losmapimod 或安慰剂治疗 12 周（总随访 24 周）。在本预先指定的分析中，我们根据 MI 类型[ST 段抬高 MI（STEMI）（865，25%）和非 ST 段抬高 MI（NSTEMI）（2624，75%）]检查了结果。
在 STEMI 患者中，hs-CRP 测量的炎症在 losmapimod 治疗 48 小时（P <0.001）和 12 周（P=0.01）时显著减轻。在 STEMI 患者中，losmapimod 在 48 小时（P=0.04）和 12 周（P=0.02）时降低了 NT-proBNP。在 24 周时，losmapimod 对 STEMI 患者的心血管死亡（CVD）、MI 或需要紧急冠状动脉血运重建的严重复发性缺血（MACE）的影响不同[7.0%对 10.8%；HR 0.65，95%CI 0.41 - 1.03；P=0.06]和 NSTEMI（11.4%对 8.5%；HR 1.30，95%CI 1.02 - 1.66；P=0.04；p[int]=0.009）。STEMI 患者中 CVD 或 HHF 分别为 5.6%（losmapimod）和 8.3%（安慰剂）（HR 0.66；95%CI 0.40 - 1.11；P=0.12）和 NSTEMI 患者中分别为 4.8%（losmapimod）和 4.4%（安慰剂）（HR 1.09；95%CI 0.76 - 1.56）。
接受 losmapimod 治疗的 STEMI 患者炎症反应减弱。我们的综合研究结果提出了一个假设，即减轻炎症反应可能导致 STEMI 和 NSTEMI 患者的结果不同。虽然结果的差异是探索性的，但这些发现确实支持对 STEMI 和 NSTEMI 患者进行单独检查，并在 MI 中炎症调节剂的未来研究中更加关注心力衰竭。
