title: Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes.
abstract: OBJECTIVE
  Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD).
  
  
  RESULTS
  In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32-2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08-3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42-1.53; P = 0.51) of subclinical CVD (Pinteraction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure.
  
  
  CONCLUSIONS
  Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA scheng3@partners.org.
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, Boston University, Boston, MA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Enserro
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Department of Biostatistics, Boston University, Boston, MA, USA Sections of Preventive Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Xanthakis
authors.affiliation: Department of Biostatistics, Boston University, Boston, MA, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sullivan
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Department of Cardiology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Department of Radiology, New England Medical Center, Boston, MA, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Polak
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wolf
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Pulmonary Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
authors.affiliation: Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Boston, MA, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA Sections of Preventive Medicine, Boston University School of Medicine, Boston, MA, USA Department of Cardiology, Boston University School of Medicine, Boston, MA, USA Department of Epidemiology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
mesh_terms: D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001944:Breath Tests; D002248:Carbon Monoxide / Q000032:analysis* / Q000097:blood; D002318:Cardiovascular Diseases / Q000175:diagnosis* / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D015415:Biomarkers; D002248:Carbon Monoxide
keywords: Carbon monoxide; Cardiovascular outcomes; Subclinical vascular disease