Role of PCSK9 in the course of ejection fraction change after ST‐segment elevation myocardial infarction: a pilot study

Abstract

Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma low‐density lipoprotein cholesterol. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of postmyocardial infarction left ventricle remodelling and heart failure‐related complications. The aim of this study was to assess the relationship between circulating PCSK9 and 6 month cardiac magnetic resonance imaging‐derived left ventricular ejection fraction (LVEF) after a first ST‐segment elevation myocardial infarction (STEMI). Methods and results We prospectively evaluated 40 patients with a first STEMI, LVEF < 50% and treated with primary percutaneous coronary intervention in which PCSK9 was measured 24 h postreperfusion. All patients underwent cardiac magnetic resonance imaging 1 week and 6 months after STEMI. Baseline characteristics were compared across median values of PCSK9. The association between PCSK9 levels and LVEF at 6 months was evaluated by analysis of covariance. The mean age of the sample was 60 ± 12 years and 33 (82.5%) were male patients. The infarct location was anterior in 27 patients (67.5%), and 9 patients (22.5%) were Killip class ≥ II. The mean 1 week and 6 month LVEF were 41 ± 7% and 48 ± 10%, respectively. The mean PCSK9 was 1.93 ± 0.38 U/mL. Testing the association between serum PCSK9 and 6 month LVEF with analysis of covariance revealed an inverse relationship (r = −0.35, P = 0.028). After multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6 month LVEF (P = 0.002). Conclusions In patients with a first STEMI with reduced ejection fraction at index admission and treated with primary percutaneous coronary intervention, circulating PCSK9 was associated with lower LVEF at 6 months.

Autocrine effects of PCSK9 on cardiomyocytes

“…Recently it was reported that PCSK9 plasma levels are associated with a reduced ejection fraction in patients suffering from ST-segment elevation myocardial infarction [24]. Furthermore a distinct function of cardiomyocyte-derived PCSK9 has only been reported for neonatal mouse cardiomyocytes, where under hypoxic conditions the release of PCSK9 determines autophagy in these cells [9].…”

“…In addition, PCSK9 inhibitors have been shown to improve cardiac function in rats with acute I/R injury when applied prior to ischemia [ 26 ]. Finally a clinical study reports a correlation between high PCSK9 plasma levels and a reduction of left ventricular ejection fraction in patients that suffered from ST-segment elevation myocardial infarction [ 24 ]. These studies demonstrate, similar to our findings, a positive effect of PCSK9 inhibition or genetic deletion on cardiac function after ischemia or I/R injury in vivo [ 9 , 26 ].…”

Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

“…Moreover, PCSK9 inhibitors antagonize the interaction between PCSK9 protein and CD36 receptor on platelet surface, thereby affecting CMVO, the risk of NR, and the following IS extension [223]. Consistently, lower circulating levels of PCSK9 were found to be inversely associated with LVEF at six months since the STEMI event [224].…”

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

“…This suggests that extracellular PCSK9 mediates the effect. Furthermore, ischemia/reperfusion triggers the cardiac and hepatic release of PCSK9 as well as its cardiac expression ( Chandrakala et al, 2012 ; Zhang et al, 2014 ; Minana et al, 2020 ). HIF links ischemia to the upregulation of PCSK9 ( Ding et al, 2018b ).…”