Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis—The IMPROVE Study

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Abstract

(1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: the IMPROVE study enrolled 3703 European subjects (54–79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: in the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all p < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) ( p = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) ( p < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both p < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: in subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries.

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Most cited references 45

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STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT

J. Martin Bland, DouglasG. Altman (1987)

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Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.

Jonathan C. Cohen, Eric Boerwinkle, Thomas H. Mosley … (2006)

A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol. Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors. Copyright 2006 Massachusetts Medical Society.

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PCSK9: a convertase that coordinates LDL catabolism.

D. Horton, Helen H. Hobbs, Aileen C. Cohen (2009)

The identification and characterization of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) have provided new insights into LDL metabolism and the causal role of LDL in coronary heart disease (CHD). PCSK9 is a secreted protease that mediates degradation of the LDL receptor by interacting with the extracellular domain and targeting the receptor for degradation. Individuals with loss-of-function mutations in PCSK9 have reduced plasma levels of LDL cholesterol and are protected from CHD; these observations have validated PCSK9 as a therapeutic target and suggested new approaches for the treatment and prevention of CHD.

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Author and article information

Contributors

Giuseppina Basta: Role: Academic Editor

Journal

Journal ID (nlm-ta): Biomedicines

Journal ID (iso-abbrev): Biomedicines

Journal ID (publisher-id): biomedicines

Title: Biomedicines

Publisher: MDPI

ISSN (Electronic): 2227-9059

Publication date (Electronic): 19 July 2021

Publication date Collection: July 2021

Volume: 9

Issue: 7

Electronic Location Identifier: 841

Affiliations

[1 ]Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy; daniela.coggi@ 123456ccfm.it (D.C.); beatrice.frigerio@ 123456ccfm.it (B.F.); alice.bonomi@ 123456ccfm.it (A.B.); daniela.sansaro@ 123456ccfm.it (D.S.); alessio.ravani@ 123456ccfm.it (A.R.); palma.ferrante@ 123456ccfm.it (P.F.); manuela.damigella@ 123456ccfm.it (M.D.); fabrizio.veglia@ 123456ccfm.it (F.V.); nicolo.capra@ 123456ccfm.it (N.C.); mauro.amato@ 123456ccfm.it (M.A.)

[2 ]Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy; massimiliano.ruscica@ 123456unimi.it (M.R.); chiara.macchi@ 123456unimi.it (C.M.)

[3 ]Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, 35122 Padova, Italy; nicola.ferri@ 123456unipd.it (N.F.); mariagiovanna.lupo@ 123456gmail.com (M.G.L.)

[4 ]Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, 70100 Kuopio, Finland; kai.savonen@ 123456uef.fi

[5 ]Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, 70210 Kuopio, Finland

[6 ]Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, 17177 Stockholm, Sweden; angela.silveira@ 123456ki.se (A.S.); rona.strawbridge@ 123456glasgow.ac.uk (R.J.S.); bruna.gigante@ 123456ki.se (B.G.)

[7 ]Karolinska University Hospital, Solna, 17177 Stockholm, Sweden

[8 ]Kuopio Campus, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland; sudhir.kurl@ 123456uef.fi

[9 ]Assistance Publique-Hopitaux de Paris, Service Endocrinologie-Metabolisme, Groupe Hôspitalier Pitie-Salpetriere, Unités de Prévention Cardiovasculaire, 75651 Paris, France; philippe.giral@ 123456aphp.fr

[10 ]Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; matteo.pirro@ 123456unipg.it

[11 ]Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8RZ, UK

[12 ]Health Data Research, Glasgow G12 8RZ, UK

[13 ]Department of Medicine, University Medical Center Groningen, Groningen and Isala Clinics Zwolle, 9700 RB Groningen, The Netherlands; a.j.smit@ 123456umcg.nl

[14 ]Maria Cecilia Hospital, 48033 Cotignola, Italy; etremoli@ 123456gvmnet.it

[15 ]Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, 20129 Milan, Italy

Author notes

[* ]Correspondence: damiano.baldassarre@ 123456unimi.it or damiano.baldassarre@ 123456ccfm.it ; Tel.: +39-02-58002253

[†]

The IMPROVE Study Group is part of the Consortium Agreement of the IMPROVE study.

Author information

Beatrice Frigerio https://orcid.org/0000-0002-2539-0733

Massimiliano Ruscica https://orcid.org/0000-0002-0195-7061

Nicola Ferri https://orcid.org/0000-0001-8898-7441

Daniela Sansaro https://orcid.org/0000-0001-8403-4520

Alessio Ravani https://orcid.org/0000-0003-4894-7685

Manuela Damigella https://orcid.org/0000-0002-8496-8101

Fabrizio Veglia https://orcid.org/0000-0002-9378-8874

Nicolò Capra https://orcid.org/0000-0003-1974-2015

Maria Giovanna Lupo https://orcid.org/0000-0002-4236-4414

Chiara Macchi https://orcid.org/0000-0002-5919-989X

Angela Silveira https://orcid.org/0000-0003-2063-4935

Rona Juliette Strawbridge https://orcid.org/0000-0001-8506-3585

Mauro Amato https://orcid.org/0000-0002-0118-5719

Damiano Baldassarre https://orcid.org/0000-0002-2766-8882

Article

Publisher ID: biomedicines-09-00841

DOI: 10.3390/biomedicines9070841

PMC ID: 8301759

PubMed ID: 34356905

SO-VID: 1d832b7d-604a-4f74-a6bd-a9035ba93d6d

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis—The IMPROVE Study

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Abstract

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Journal of Circulating Biomarkers

Most cited references 45

STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT

Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.

PCSK9: a convertase that coordinates LDL catabolism.

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