Associations of Serially Measured Pcsk9, Ldlr and Mpo with Clinical Outcomes in Heart Failure

Abstract

Aim: To investigate the temporal evolution of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor (LDLR) and myeloperoxidase (MPO) in relation to clinical outcome in chronic heart failure (CHF). Methodology & results: Trimonthly blood sampling was performed during a median follow-up of 2.2 (IQR 1.4–2.5) years in 263 CHF patients. Seventy patients reached the primary end point (PE) (cardiovascular death, heart transplantation, left ventricular assist device implantation or HF-hospitalization). MPO level was independently associated with the PE; the adjusted (for clinical factors) hazard ratio (aHR) per standard deviation difference in MPO was 1.71 (95% CI: 1.23–2.43) at any time during follow-up. PCSK9 level (HR: 1.45 [1.04–2.06]) and LDLR (HR: 0.66 [0.49–0.87]) were statistical significantly associated with the PE but only in unadjusted analyses. Slope of temporal MPO evolution (aHR: 1.34 [1.12–1.76] per 0.1 standard deviation/year difference in slope) and LDLR (aHR: 0.78 [0.61–0.90]) however, were associated with PE. Conclusion: Temporal patterns of MPO and LDLR are independently associated with clinical outcome in CHF, which illustrates the importance of assessing temporal evolutions. Clinical trial registration information: registered in ClinicalTrials.gov, number NCT01851538 . https://clinicaltrials.gov/ct2/show/NCT01851538 .

Proteome-wide mendelian randomization investigates potential associations in heart failure and its etiology: emphasis on PCSK9

“…This aligns with previously published proteome-wide MR studies [ 46 – 48 ]. Consistent with our findings, a clinical observational study that adjusted for confounding factors, including age, sex, and diabetes, also reported no association between PCSK9 and all-cause HF [ 15 ]. Additionally, meta-analyses and a recent randomized controlled trial (RCT) study, which provide higher-level clinical evidence, consistently concluded that the use of PCSK9 inhibitors did not significantly affect all-cause HF [ 17 – 19 ].…”

“…Circulating PCSK9 has emerged as a potential therapeutic target for HF [ 50 , 51 ]. However, recent studies have presented conflicting findings [ 15 , 17 – 19 ]. Although previous two-sample MR studies based on GWAS of lipid traits or eQTL of PCSK9 have provided support for the association between PCSK9 and all-cause HF [ 24 – 26 ], our study found no evidence of the correlation between circulating PCSK9 and the risk of all-cause HF.…”

“…These findings suggest the potential of PCSK9 as a viable therapeutic target for HF. Conversely, another observational study found no association between PCSK9 and HF after adjusting for confounding factors [ 15 ]. The conflicting clinical finding raised concerns about the use of PCSK9 inhibitors in HF [ 16 ].…”