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Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease including coronary heart disease, peripheral arterial disease, ischaemic stroke, and calcific aortic valve stenosis. Clinical trials of specific and potent Lp(a)-lowering drugs are currently underway. However, in clinical practice, widespread assessment of Lp(a) is still lacking despite several guideline recommendations to measure Lp(a) at least once in a lifetime in all adults to identify those at high or very high risk due to elevated levels. The present review provides an overview of key findings from observational and genetic Lp(a) studies, highlights the main challenges in observational Lp(a) studies, and proposes a minimum set of requirements to enhance the quality and harmonize the collection of Lp(a)-related data. Adherence to the recommendations set forth in the present manuscript is intended to enhance the quality of future observational Lp(a) studies, to better define thresholds for increased risk, and to better inform clinical trial design. The recommendations can also potentially assist in the interpretation and generalization of clinical trial findings, to improve care of patients with elevated Lp(a) and optimize treatment and prevention of cardiovascular disease., Competing Interests: Conflict of interest: P.R.K. reports talks and consultancies sponsored by the Physicians’ Academy for Cardiovascular Education, Silence Therapeutics, Novartis, and the PCSK9 Forum. R.D.G.N. reports consultancies and talks sponsored by Amgen, Novartis, and Pfizer. S.N. reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from AbbVie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics. The author receives no personal remuneration for participation in these trials. U.L. reports receiving institutional research grants from Abbott, Amgen, Bayer, and Novartis as well as lecture or consultant honoraria from Abbott, Amgen, Novartis, Sanofi, and Novo Nordisk. A.H. reports consultancies and talks sponsored by Novo Nordisk, Novartis, Bayer, and AstraZeneca. M.C.-S. and C.A. are employees of Novartis. B.G.N. reports consultancies and talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea Therapeutics, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, Ultragenyx, and Esperion., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes., Methods: PCSK9 was measured with a previously described ELISA., Results: In 81 healthy middle-aged Caucasian men, the PCSK9 concentration was significantly associated with the concentrations of total cholesterol (r = 0.42; P < 0.0001), LDL cholesterol (r = 0.34; P = 0.01), and triglycerides (r = 0.25; P = 0.02). In p.R46L carriers, mean (SD) concentrations of PCSK9 were 15% lower than in RR individuals [65.5 microg/L (21.6 microg/L) vs 77.5 microg/L (18.2 microg/L); P = 0.03]. In patients with the p.D374Y variant (n = 7), the mean PCSK9 concentration was significantly lower than in the combined group of patients with an LDLR (low density lipoprotein receptor) mutation (n = 25), an APOB [apolipoprotein B (including Ag(x) antigen)] variant encoding p.R3527Q (n = 6), or no detectable mutation (n = 14) [96.4 microg/L (42.5 microg/L) vs 151.6 microg/L (69.6 microg/L); P = 0.02]. Two of the 14 patients with no mutation had PCSK9 concentrations below the mean for p.D374Y carriers; sequencing of the PCSK9 gene and promoter revealed no mutations. Among 409 FH patients, we identified 6 carriers of the promoter variant -287G>A (1.5%), a frequency similar to that (1.0%) previously reported for 2772 healthy men in the UK. In neither group was the -287G>A variant associated with differences in lipid traits., Conclusions: The loss-of-function p.R46L variant is associated with the expected lower concentrations of circulating PCSK9; the gain-of-function p.D374Y mutation is also associated with lower concentrations, presumably because of the higher affinity of this variant for the LDL receptor and its more rapid clearance. In treated FH patients, a low plasma PCSK9 concentration does not appear to be a useful screening tool for identifying novel PCSK9 mutations.