High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants

Abstract

Background: High-sensitivity assays can quantify cardiac troponins I and T (hs-cTnI, hs-cTnT) in individuals with no clinically manifest myocardial injury.

Objectives: The goal of this study was to assess associations of cardiac troponin concentration with cardiovascular disease (CVD) outcomes in primary prevention studies.

Methods: A search was conducted of PubMed, Web of Science, and EMBASE for prospective studies published up to September 2016, reporting on associations of cardiac troponin concentration with first-ever CVD outcomes (i.e., coronary heart disease [CHD], stroke, or the combination of both). Study-specific estimates, adjusted for conventional risk factors, were extracted by 2 independent reviewers, supplemented with de novo data from PROSPER (Pravastatin in Elderly Individuals at Risk of Vascular Disease Study), then pooled by using random effects meta-analysis.

Results: A total of 28 relevant studies were identified involving 154,052 participants. Cardiac troponin was detectable in 80.0% (hs-cTnI: 82.6%; hs-cTnT: 69.7%). In PROSPER, positive associations of log-linear shape were observed between hs-cTnT and CVD outcomes. In the meta-analysis, the relative risks comparing the top versus the bottom troponin third were 1.43 (95% confidence interval [CI]: 1.31 to 1.56) for CVD (11,763 events), 1.67 (95% CI: 1.50 to 1.86) for fatal CVD (7,775 events), 1.59 (95% CI: 1.38 to 1.83) for CHD (7,061 events), and 1.35 (95% CI: 1.23 to 1.48) for stroke (2,526 events). For fatal CVD, associations were stronger in North American studies (p = 0.010) and those measuring hs-cTnT rather than hs-cTnI (p = 0.027).

Conclusions: In the general population, high cardiac troponin concentration within the normal range is associated with increased CVD risk. This association is independent of conventional risk factors, strongest for fatal CVD, and applies to both CHD and stroke.

Keywords: biomarker; cardiovascular disease; coronary heart disease; primary prevention; stroke; systematic review.

Graphical abstract

Figure 1

PROSPER: hs-cTnT Associations With CVD Outcomes After multivariable adjustment, models were stratified according to treatment arm; the group with undetectable high-sensitivity cardiac troponin T (hs-cTnT) values was used as the reference group. The median hs-cTnT concentrations (ranges) in quartiles of detectable hs-cTnT were 4 ng/l (3 to 4), 6 ng/l (5 to 7), 9 ng/l (8 to 11), and 16 ng/l (12 to 1,840). Sizes of data markers are proportional to the inverse of the variance of the hazard ratios. CHD = coronary heart disease; CI = confidence interval; CVD = cardiovascular disease. PROSPER = Pravastatin in Elderly Individuals at Risk of Vascular Disease Study.

Figure 2

Detectable Cardiac Troponin Concentrations The percentage of participants with detectable cardiac troponin concentrations was categorized by mean age and assay type per included study. The red line and gray area represent the line of best fit and 95% confidence interval, respectively, with individual studies being weighted according to their number of participants. ADVANCE = Atherosclerotic Disease, Vascular Function and Genetic Epidemiology Study; AGES-Reykjavik = Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC = Atherosclerosis Risk in Communities Study; BiomarCaRE = Biomarkers for Cardiovascular Risk Assessment in Europe; BRHS = British Regional Heart Study; BRUN = Bruneck Study; CHS = Cardiovascular Health Study; DHS = Dallas Heart Study; FHS = Framingham Heart Study; FINRISK97 = FINRISK 1997 Survey; hs-cTnT = high-sensitivity cardiac troponin T; HUNT2 = Nord-Trondelag Health Study 2; JUPITER = Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin Trial; MFS = MIDSPAN Family Study; MHS = Minnesota Heart Study; PIVUS = Prospective Investigation of the Vaculature in Uppsala Seniors Study; PROSPER = Pravastatin in Elderly Individuals at Risk of Vascular Disease Study; ULSAM = Uppsala Longitudinal Study of Adult Men; WHS = Women’s Health Study; WOSCOPS = West of Scotland Coronary Prevention Study.

Figure 3

Combined Adjusted Relative Risk for CVD Outcomes Study-specific relative risks were pooled by using random effects meta-analysis and compared in the top third versus the bottom third of cardiac troponin concentration. Abbreviations as in Figure 1.

Central Illustration

Troponin and Risk of CVD Outcomes In assessing the association of cardiac troponin concentration and CVD outcomes, we identified 28 relevant studies. Thirds of cardiac troponin concentration were defined within each study separately. Study-specific relative risks for first-ever CVD outcomes were pooled by using a random effects meta-analysis, demonstrating that high cardiac troponin levels in the normal range are associated with increased CVD event risk. The distribution graph is illustrative and cardiac troponin distributions were not normally distributed. CHD = coronary heart disease; CVD = cardiovascular disease.