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J Am Coll Cardiol. 2017 Oct 24;70(17):2128-2136. doi: 10.1016/j.jacc.2017.08.057.

The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis.

Author information

1
Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (CIBERCV), Autonomous University of Barcelona, Barcelona, Spain. Electronic address: abayesgenis@gmail.com.
2
Cardiology Department, Hospital Clínico Universitario, Instituto de Investigación Sanitaria, Valencia, Spain; Departamento de Medicina, Universitat de València, València, Spain; CIBERCV, Madrid, Spain.
3
INSERM, Centre d'Investigation Clinique Plurithématique, INSERM U1116, Université de Lorraine, Centre Hospitalier Régional Universitaire de Nancy, French Clinical Research Infrastructure Network and Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France.
4
INSERM, Centre d'Investigation Clinique Plurithématique, INSERM U1116, Université de Lorraine, Centre Hospitalier Régional Universitaire de Nancy, French Clinical Research Infrastructure Network and Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France; Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal.
5
Division of Cardiology and Metabolism-Heart Failure, Cachexia & Sarcopenia, Department of Cardiology, and Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany; Department of Cardiology and Pneumology, University Medicine Göttingen, and DZHK (German Center for Cardiovascular Research), Göttingen, Germany.
6
National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, United Kingdom.
7
University of Bergen, Stavanger University Hospital, Stavanger, Norway.
8
National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Heart Failure Unit, Athens University Hospital Attikon, Athens, Greece.
9
School of Medicine Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, University of Dundee, Ninewells Hospital & Medical School, Dundee, United Kingdom.
10
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom.
11
Department of Heart Diseases, Wroclaw Medical University, Poland and Cardiology Department, Military Hospital, Wroclaw, Poland.
12
Department of Cardiology, University of Groningen, Groningen, the Netherlands.
13
Department of Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.
14
Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
15
Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (CIBERCV), Autonomous University of Barcelona, Barcelona, Spain.

Abstract

BACKGROUND:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression.

OBJECTIVES:

The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF).

METHODS:

The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores.

RESULTS:

This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance.

CONCLUSIONS:

The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

KEYWORDS:

LDLR; PCSK9; heart failure; low-density lipoprotein receptor; proprotein convertase subtilisin/kexin type 9

PMID:
29050560
DOI:
10.1016/j.jacc.2017.08.057
[Indexed for MEDLINE]
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