Sex-Specific Associations of Established and Emerging Cardiac Biomarkers with All-Cause Mortality in Older Adults: The ActiFE Study Dhayana Dallmeier, 1,2 Michael Denkinger, 3,4 Richard Peter, 5,6 Kilian Rapp, 7 Allan S. Jaffe, 8 Wolfgang Koenig, 1* and Dietrich Rothenbacher, 5 for the ActiFE Study Group † BACKGROUND: N-terminal pro B-type natriuretic peptide (NT-proBNP) has strong prognostic value for all-cause mortality in the general population. High-sensitivity as- says now allow detection of cardiac troponins even in asymptomatic populations. We examined the association between NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and hs-cTnI and all-cause mortality in older adults. METHODS: We conducted a longitudinal cohort study [Activity and Function in the Elderly in Ulm (ActiFE Ulm)] including 1506 community-dwelling adults 65 years old with NT-proBNP, hs-cTnT, and hs-cTnI mea- sured at baseline. We evaluated the associations between log-transformed biomarker concentrations and 4-year to- tal mortality, accounting for possible confounders, with Cox proportional hazards models. RESULTS: We observed 125 deaths among 1422 partici- pants (median follow-up 4 years). We detected effect modification by sex for all biomarkers (all P values 0.05) expressed as hazard ratio (HR) for death per 1-unit increment of ln(biomarker concentration) in women (n = 618, 37 deaths) compared with men (n = 804, 88 deaths): HR 2.97 (95% CI 2.04 – 4.33) vs 1.73 (1.40 –2.13) for NT-proBNP; 3.67 (2.31–5.81) vs 2.15 (1.61–2.87) for hs-cTnT; and 3.32 (2.13–5.18) vs 1.92 (1.55–2.38) for hs-cTnI. Among 777 participants with undetectable hs-cTnT (5 ng/L), hs-cTnI remained as- sociated with all-cause mortality in age- and sex-adjusted analysis. CONCLUSIONS: NT-proBNP, hs-cTnT, and hs-cTnI were independently associated with all-cause mortality in older adults. The strength of these associations varied between men and women, emphasizing the need for ad- ditional sex-specific research among older people. © 2014 American Association for Clinical Chemistry In most countries, life expectancy continues to increase. However, living longer is also associated with the grow- ing manifestation of comorbidities, with prevalences as high as 80% and 50% for 1 and 2 comorbidities, respec- tively (1). In this context, cardiovascular disease still re- mains 1 of the 2 leading causes of death among people 65 years old (2). Predicting those at risk might allow for the development of preventive strategies. Biomarkers such as the natriuretic peptides and cardiac troponin measured by high-sensitivity assays have that potential. B-type natriuretic peptide (BNP) 9 (active form) and N-terminal pro-BNP (NT-proBNP) (inactive form with longer half-life) are released from the ventricular myocar- dium in the settings of volume and/or pressure overload. BNP has a cardioprotective effect, improving myocardial relaxation and counteracting vasoconstriction, sodium retention, and antidiuretic effects of the activated renin– angiotensin–aldosterone system (3). Both have been identified as good markers for myocardial hemodynamic 1 Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany; 2 Department of Epidemiology, Boston University School of Public Health, Boston, MA; 3 Agaplesion Bethesda Clinic Ulm, Geriatric Center Ulm/Alb-Donau, Ulm, Germany; 4 Institute of Molecular Medicine and Stem Cell Research, 5 Institute of Epide- miology and Medical Biometry, and 6 Institute of the History, Philosophy, and Ethics of Medicine, Ulm University, Ulm, Germany; 7 Clinic for Geriatric Rehabilitation, Robert- Bosch Hospital, Stuttgart, Germany; 8 Mayo Clinic College of Medicine, Division of Car- diovascular Diseases, Rochester, MN. * Address correspondence to this author at: Department of Internal Medicine II, Cardiol- ogy, University of Ulm Medical Center, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Fax +49-731-500-45021; e-mail wolfgang.koenig@uniklinik-ulm.de. Received August 11, 2014; accepted November 4, 2014. Previously published online at DOI: 10.1373/clinchem.2014.230839 © 2014 American Association for Clinical Chemistry † In addition to the authors, the ActiFE Ulm study group consists of K. Scharffetter- Kochanek, Department of Dermatology and Allergology; H. Geiger, Institute Molecular Medicine and Stem Cell Research; A. Lukas, Agaplesion Bethesda Clinic; M. Riepe, Divi- sion of Gerontopsychiatry, Department of Psychiatry and Psychotherapy II; J.M. Stein- acker, Department of Sports and Rehabilitation Medicine; A. Ludolph, C. von Arnim, Department of Neurology; G. Nagel, G. Weinmayr, Institute of Epidemiology and Medical Biometry. All institutes are located at Ulm University. 9 Nonstandard abbreviations: BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro- BNP; cTnT, cardiac troponin T; hs, high-sensitivity; ActiFE Ulm, Activity and Function in the Elderly in Ulm; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; LOD, limit of detection; BMI, body mass index; HR, hazard ratio; LV, left ventricular. Clinical Chemistry 61:2 389–399 (2015) Lipids, Lipoproteins, and Cardiovascular Risk Factors 389 Downloaded from https://academic.oup.com/clinchem/article/61/2/389/5611376 by guest on 22 June 2022