Impact of Sex on the Prognostic Value of High-Sensitivity Cardiac Troponin I in the General Population: The HUNT Study Torbjørn Omland, 1,2* James A. de Lemos, 3 Oddgeir L. Holmen, 4 Håvard Dalen, 5,6 Ju  rate ˙S ˇ altyte ˙ Benth, 7,8 Ståle Nygård, 2,9,10 Kristian Hveem, 4 and Helge Røsjø 1,2 BACKGROUND: A new, high-sensitivity assay for cardiac troponin I (hs-cTnI) permits evaluation of the prognostic value of cardiac troponins within the reference interval. Men have higher hs-cTnI concentrations than women, but the underlying pathophysiological mechanisms and prognostic implications are unclear. The aim of this study was to assess the potential impact of sex on the association between hs-cTnI and cardiovascular death. METHODS: By use of the Architect STAT High-Sensitive Troponin assay, we measured hs-cTnI in 4431 men and 5281 women aged 20 years participating in the prospec- tive observational Nord-Trøndelag Health Study (HUNT). RESULTS: hs-cTnI was detectable in 98.5% of men and 94.7% of women. During a mean follow-up period of 13.9 years, 708 cardiovascular deaths were registered. hs- cTnI was associated with the incidence of cardiovascular death [adjusted hazard ratio (HR) per 1 SD in log hs- cTnI 1.23 (95% CI 1.15–1.31)], with higher relative risk in women than men [HR 1.44 (1.31–1.58) vs 1.10 (1.00 –1.20); P interaction  0.001]. This finding was me- diated by both lower risk associated with low hs-cTnI concentrations in women than in men and higher risk associated with high concentrations of hs-cTnI in women than in men. Male sex was associated with a higher risk of cardiovascular death [HR 1.28 (1.11–1.49)], but after adjustment for hs-cTnI, this association disappeared [HR 0.87 (0.75–1.02)]. CONCLUSIONS: The prognostic value of hs-cTnI concen- trations in the general population is stronger in women than in men. Subtle impairment of cardiovascular status may contribute to higher hs-cTnI concentrations in men, reflecting sex-dependent differences in cardiovascular risk. © 2015 American Association for Clinical Chemistry Important differences exist between men and women with respect to the prevalence of risk factors for and the incidence of cardiovascular events. For instance, for a given age, blood pressure is higher in men than in women (1); after puberty, left ventricular mass is greater in men than in women (2); and women generally develop car- diovascular disease at an older age than men (3). The recent introduction of assays with enhanced an- alytic sensitivity allows accurate determination of very low concentrations of circulating cardiac troponins (4, 5 ). The use of these high-sensitivity assays has permit- ted enhanced characterization of the distribution and cross- sectional correlates of cardiac troponin concentrations. One consistent and potentially important observation made in these studies is that circulating concentrations of cardiac troponins are markedly higher in men than in women (6 – 12 ). For instance, for a new, highly sensitive assay for cardiac troponin I (hs-cTnI), 11 the 99th percentile values in a healthy reference population have been reported to be 15 ng/L in women and 36 ng/L in men (13 ). However, the underlying pathophysiological mechanisms and potential prognostic implications of the sex differences in cardiac tro- ponin concentrations are unknown. The objectives of the current study, which uses a novel assay with high analytic sensitivity, were therefore (a) to assess the distribution of 1 Division of Medicine and 8 HØKH Research Centre, Akershus University Hospital, Løren- skog, Norway; 2 Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre and 7 Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 3 Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX; 4 HUNT Re- search Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; 5 Department of Medicine, Levanger Hos- pital, Nord-Trøndelag Health Trust, Levanger, Norway; 6 MI Laboratory and Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; 9 Institute for Experimental Medical Research and 10 Bioinformatics Core Facility, Institute for Medical Informatics, Oslo University Hospital and University of Oslo, Oslo, Norway. * Address correspondence to this author at: Division of Medicine, Akershus University Hospital, NO-1478, Lørenskog, Norway. Fax +47-67-96-88-60; e-mail torbjorn.omland@ medisin.uio.no. Received October 5, 2014; accepted January 27, 2015. Previously published online at DOI: 10.1373/clinchem.2014.234369 © 2015 American Association for Clinical Chemistry 11 Nonstandard abbreviations: hs-cTnI, high-sensitivity cardiac troponin I; HUNT, Nord- Trøndelag Health Study; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; ICD, International Classification of Diseases; AMI, acute myocardial infarction; HR, hazard ratio. Clinical Chemistry 61:4 646–656 (2015) Proteomics and Protein Markers 646