Oxidized phospholipids (OxPLs) dynamics following acute myocardial infarction (MI): effects of PCSK9 inhibition with evolocumab

Background The peri- and early post-infarction periods are associated with an increased risk for plaque instability and recurrent ischemic events. OxPLs are pro-inflammatory mediators implicated in plaque instability and thrombosis but the trajectory, and the impact of PCSK9 inhibition on the trajectory, are not well characterized. Assessment of these changes may contribute to our understanding of post-MI oxidative stress and associated adverse outcomes. Purpose To investigate the early post-MI trajectories of OxPLs on Lp(a) [OxPL-apo(a)] and OxPLs on apoB-100-containing lipoproteins (OxPL-apoB) and assess the impact of PCSK9 inhibition, particularly across different age groups. Methods A total of 96 participants with NSTEMI (troponin-I >5 ng/ml) or STEMI were randomized to receive placebo (n=48) or 420 mg subcutaneous evolocumab (n=48) within 24 hours of hospital admission. OxPL-apo(a) and OxPL-apoB were measured prior to randomization and at 30 days post-MI. Changes in OxPL levels were analyzed in the overall cohort and stratified by age (≤60 vs. >60 years). Results Demographics and clinical characteristics in the two groups did not differ. The mean age was 59.8 ± 12.08 years, 69% had a NSTEMI, 34% were women, and 33% were Black individuals. In the placebo group, OxPL-apo(a) significantly increased from 52.6 [19.28, 106.5] nmol/L to 61.7 [31.53, 116.9] nmol/L (p=0.01) at 30 days, and OxPL-apoB rose from 6.75 [3.1, 20.98] nmol/L to 8.8 [3.72, 22.98] nmol/L (p=0.004). In contrast, there were no significant increases of either OxPL-apo(a), 49.9 [10.38, 100.4] at baseline and 55.4 [5.4, 109.6] nmol/L at 30 days (p=0.17); or OxPL-apoB 7.4 [3.8, 18.7] at baseline and 9.8 [3.2, 26.2] nmol/L at 30 days (p=0.06) (Figure 1). The effect of evolocumab was primarily driven by the results in the younger patients (≤60 years). In this subgroup, OxPL-apo(a) significantly increased from 56.7 [14.8, 94.7] nmol/L to 64.9 [34.00, 112.8] nmol/L (p<0.01) in the placebo group, compared to no significant change in the evolocumab group, 34.9 [8.7, 92.35] at baseline and 29.95 [3.85, 94.63] nmol/L at 30 days. Similarly, OxPL-apoB increased from 6.8 [1.9, 17.2] nmol/L to 10.6 [3.6, 21.4] nmol/L (p<0.01) in the placebo group and did not change in the evolocumab group, 5.8 [2.875, 12.58] at baseline and 5.6 [1.9, 20.28] nmol/L at 30 days (Figure 2). For those patients >60 years, there were no significant OxPL changes from baseline to 30 days in either group. Conclusion These findings provide novel insights into the early trajectory of OxPLs following an acute MI and suggest a protective role of PCSK9 inhibition in attenuating post-MI oxidative stress. The impact was most marked in the younger patients, highlighting a potential age-dependent effect on oxidative stress modulation.