Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation

Daniele Pastori; Cristina Nocella; Alessio Farcomeni; Simona Bartimoccia; Maria Santulli; Fortunata Vasaturo; Roberto Carnevale; Danilo Menichelli; Francesco Violi; Pasquale Pignatelli; ATHERO-AF Study Group

doi:10.1016/j.jacc.2017.07.743

Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation

J Am Coll Cardiol. 2017 Sep 19;70(12):1455-1462. doi: 10.1016/j.jacc.2017.07.743.

Collaborators

ATHERO-AF Study Group:
Mirella Saliola, Marco Antonio Casciaro, Domenico Ferro, Tommasa Vicario, Fabiana Albanese, Francesco Cribari, Alberto Paladino, Francesco Del Sole, Marta Novo, Vittoria Cammisotto, Paola Andreozzi, Tiziana Di Stefano, Patrizia Iannucci, Elio Sabbatini

Affiliations

¹ I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.
² I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
³ Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.
⁴ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Azienda Ospedaliera Universitaria Policlinico Umberto I, Rome, Italy.
⁶ I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. Electronic address: pasquale.pignatelli@uniroma1.it.

PMID: 28911508
DOI: 10.1016/j.jacc.2017.07.743

Abstract

Background: Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available.

Objectives: This study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B₂ (11-dh-TxB₂), a marker of platelet activation.

Methods: We conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient-years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB₂ (n = 852) were measured. The population was divided into tertiles of PCSK9 for the analysis.

Results: The mean age of patients was 73.5 ± 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB₂ were significantly correlated (Spearman's rho: 0.665; p < 0.001).

Conclusions: Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB₂ suggests PCSK9 as a mechanism potentially implicated in platelet activation.

Keywords: cholesterol; myocardial infarction; platelets; risk factors; stroke.

MeSH terms

Aged
Atrial Fibrillation / complications*
Atrial Fibrillation / urine*
Cardiovascular Diseases / epidemiology*
Cardiovascular Diseases / etiology*
Female
Humans
Incidence
Male
Predictive Value of Tests
Proprotein Convertase 9 / blood*
Prospective Studies
Risk Assessment
Thromboxane B2 / analogs & derivatives*
Thromboxane B2 / urine

Substances

Thromboxane B2
11-dehydro-thromboxane B2
Proprotein Convertase 9