title: Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study.
abstract: Epidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C.
  
  
  
  Serum IF1 levels were measured in 577 male participants with stable CAD (age 45-74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths.
  
  
  
  IF1 levels were positively correlated with HDL-C (r s = 0.40; P < 0.001) and negatively with triglycerides (r s = -0.21, P < 0.001) and CAD severity documented by the Gensini score (r s = -0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38-0.89 and 0.50 (0.28-0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02).
  
  
  
  We investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy.
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.|Université de Toulouse, UMR1048, Toulouse, France.|CHU Toulouse, Toulouse University Hospital, Service de Biochimie, Pôle biologie, Hôpital de Purpan, Toulouse, France.
authors.forename: Annelise
authors.initials: A
authors.lastname: Genoux
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.|Université de Toulouse, UMR1048, Toulouse, France.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Lichtenstein
authors.affiliation: Department of Epidemiology, Health Economics and Public Health, Inserm, Université de Toulouse, CHU Toulouse, UMR1027, Toulouse, France.|CHU Toulouse, Toulouse University Hospital, Fédération de Cardiologie, Toulouse, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Ferrières
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.|Université de Toulouse, UMR1048, Toulouse, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Duparc
authors.affiliation: Department of Epidemiology, Health Economics and Public Health, Inserm, Université de Toulouse, CHU Toulouse, UMR1027, Toulouse, France.
authors.forename: Vanina
authors.initials: V
authors.lastname: Bongard
authors.affiliation: Department of Epidemiology, Health Economics and Public Health, Inserm, Université de Toulouse, CHU Toulouse, UMR1027, Toulouse, France.|CHU Toulouse, Toulouse University Hospital, Fédération de Cardiologie, Toulouse, France.
authors.forename: Paul-Louis
authors.initials: PL
authors.lastname: Vervueren
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.|CHU Toulouse, Toulouse University Hospital, Service de Biochimie, Pôle biologie, Hôpital de Purpan, Toulouse, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Combes
authors.affiliation: CHU Toulouse, Toulouse University Hospital, Fédération de Cardiologie, Toulouse, France.
authors.forename: Dorota
authors.initials: D
authors.lastname: Taraszkiewicz
authors.affiliation: CHU Toulouse, Toulouse University Hospital, Fédération de Cardiologie, Toulouse, France.
authors.forename: Meyer
authors.initials: M
authors.lastname: Elbaz
authors.affiliation: CHU Toulouse, Toulouse University Hospital, Fédération de Cardiologie, Toulouse, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Galinier
authors.affiliation: CHU Toulouse, Toulouse University Hospital, Service de Biochimie, Pôle biologie, Hôpital de Purpan, Toulouse, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nassar
authors.affiliation: Department of Epidemiology, Health Economics and Public Health, Inserm, Université de Toulouse, CHU Toulouse, UMR1027, Toulouse, France.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Ruidavets
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France.|Université de Toulouse, UMR1048, Toulouse, France.|CHU Toulouse, Toulouse University Hospital, Service de Biochimie, Pôle biologie, Hôpital de Purpan, Toulouse, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Perret
authors.affiliation: Institute of Metabolic and Cardiovascular Diseases, I2MC, Inserm, UMR 1048, Toulouse, France. laurent.martinez@inserm.fr.|Université de Toulouse, UMR1048, Toulouse, France. laurent.martinez@inserm.fr.
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Martinez
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000378:metabolism; D003324:Coronary Artery Disease / Q000097:blood*; D003327:Coronary Disease / Q000097:blood*; D005060:Europe; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D011379:Prognosis; D011506:Proteins / Q000032:analysis*; D018570:Risk Assessment; D012307:Risk Factors; D000097795:ATPase Inhibitory Protein
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D011506:Proteins; D000097795:ATPase Inhibitory Protein
keywords: ATP synthase; Biomarker; Cholesterol; F1-ATPase; High density lipoprotein, HDL; Inhibitory Factor 1, IF1