Advertisement

High-sensitivity troponins for outcome prediction in the general population: a systematic review and meta-analysis

Published:January 07, 2022DOI:https://doi.org/10.1016/j.ejim.2022.01.012

      Abstract

      Background

      High-sensitivity (hs) assays allow to measure cardiac troponin T and I (cTnT/I) even in healthy individuals. The higher hs-cTn values, the higher the ongoing cardiomyocyte damage, and then reasonably the risk of developing symptomatic cardiac disease.

      Methods

      We retrieved all studies evaluating the prognostic value of hs-cTnT or I in the general population. We calculated pooled hazard ratio (HR) values for all-cause and cardiovascular death, cardiovascular events and heart failure (HF) hospitalization.

      Results

      We included 24 studies for a total of 203,202 subjects; 11 studies assessed hs-cTnT and 14 hs-cTnI. One standard deviation (SD) increase in baseline hs-cTn was associated with a 23% higher risk of all-cause death (HR 1.226, 95% CI 1.083-1.388, p<0.001, I2=88.5%); all these studies measured hs-cTnI. In an exploratory analysis on 3 studies with 25,760 subjects, hs-cTn predicted cardiovascular death (HR 1.822, 95% CI 1.241-2.674, p=0.002, I2=87.2%). After synthesizing 9 studies with 58,565 subjects, hs-cTn predicted cardiovascular events (HR 1.328, 95% CI 1.167-1.513, p<0.001, I2=93.8%). Both hs-cTnT (HR 1.627, 95% CI 1.145-2.311, p<0.001) and hs-cTnI (HR 1.260, 95% CI 1.115-1.423, p<0.001; p for interaction <0.001). Furthermore, in 10 studies with 61,467 subjects, hs-cTn predicted HF hospitalization (HR 1.493, 95% CI 1.368-1.630, p<0.001, I2=76.6%). Both hs-cTnT (HR 1.566, 95% CI 1.303-1.883, p<0.001) and hs-cTnI (HR 1.467, 95% CI 1.321-1.628, p<0.001) were associated with HF hospitalization (p for interaction <0.001).

      Conclusions

      hs-cTn values hold strong prognostic value in subjects from the general population, predicting the risk of all-cause and cardiovascular mortality, cardiovascular events, and HF hospitalization.

      Keywords

      Background

      Cardiac troponin T (cTnT) and I (cTnI) are both sensitive and specific indicators of myocardial injury most commonly used to diagnose acute coronary syndrome
      • Collet JP
      • Thiele H
      • Barbato E
      • et al.
      2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
      . From 2005 onwards, new generations of immunoassay methods with progressively better analytical performance allowed the accurate detection of cTnT and cTnI not only in patients with cardiac or extra-cardiac diseases, but even in apparently healthy subjects
      • Clerico A
      • Aimo A
      • Passino C.
      The pathophysiological and clinical relevance of combined measurement of natriuretic peptides and cardiac troponins for risk prediction of incident heart failure in community-dwelling individuals.
      • Clerico A
      • Giannoni A
      • Prontera C
      • Giovannini S.
      High-sensitivity troponin: a new tool for pathophysiological investigation and clinical practice.
      • Clerico A
      • Ripoli A
      • Zaninotto M
      • et al.
      Head-to-head comparison of plasma cTnI concentration values measured with three high-sensitivity methods in a large Italian population of healthy volunteers and patients admitted to emergency department with acute coronary syndrome: A multi-center study.
      • Clerico A
      • Zaninotto M
      • Padoan A
      • et al.
      Evaluation of analytical performance of immunoassay methods for cTnI and cTnT: From theory to practice.
      . Detectable low troponin concentrations may reflect an ongoing cardiomyocyte damage, and correlate with the prevalence of cardiovascular risk factors, metabolic disorders, and cardiac hypertrophy or dysfunction
      • Sinning C
      • Keller T
      • Zeller T
      • et al.
      Association of high-sensitivity assayed troponin I with cardiovascular phenotypes in the general population: the population-based Gutenberg health study.
      ,
      • de Lemos JA
      • Drazner MH
      • Omland T
      • et al.
      Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
      . Measuring circulating troponin through a high-sensitivity (hs) assay might then predict the progression of cardiac damage to symptomatic HF, as well as other clinical manifestations such as adverse cardiovascular events and mortality. Several studies evaluated this point, and were globally evaluated in two meta-analyses whose study search was performed back in 2016
      • van der Linden N
      • Klinkenberg LJJ
      • Bekers O
      • et al.
      Prognostic value of basal high-sensitive cardiac troponin levels on mortality in the general population: A meta-analysis.
      ,
      • Willeit P
      • Welsh P
      • Evans JDW
      • et al.
      High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants.
      . As many studies have been published in the last years (see Table 1), we deemed it useful to reappraise the prognostic value of hs-cTn in the general population.
      Table 1Characteristics of selected studies.
      First Author, year, ref.Troponin T/IAssayPopulation settingCohortPatient nAge (mean/ median) (years)Men (%)Diabetes (%)Hypertension (%)eGFR (mL/min/1.73 m2)Prior HF (%)Known CV disease (%)hs-TnT/hs-TnI (mean/median) (ng/L)
      Blankenberg, 201626IARCHITECT i2000SR10 prospective population-based studiesBiomarCaRE74,738525254294N/AN/AN/A
      Brouwers, 201422TElecsys Troponin T Gen 5 STATHF-free subjectsPREVEND8,569495011482073
      De Lemos, 20107TElecsys Troponin T Gen 5 STATParticipants aged 30-65 yearsDallas Heart Study3,546414412349948N/A
      De Filippi, 201023TElecsys Troponin T Gen 5 STATCommunity-dwelling adults aged ≥65 years without prior HFCardiovascular Health Study4,22171401851N/A0N/AN/A
      Eggers, 201324TElecsys Troponin T Gen 5 STATElderly menUppsala Longitudinal Study of Adult Men87271100117475N/A408
      Eggers, 201627IARCHITECT i2000SRElderly individualsProspective Investigation of the Vasculature in Uppsala Seniors1,01670501172794153
      Everett, 201121TElecsys Troponin T Gen 5 STATFemale health professionals ≥45 years, diabeticWomen's Health Study512560100465400N/A
      Everett, 201121 (2nd subgroup)TElecsys Troponin T Gen 5 STATFemale health professionals ≥45 years, non-diabeticWomen's Health Study5645700174700N/A
      Everett, 201528IARCHITECT i2000SRParticipants without CV diseaseJUPITER12,956666405673003
      Ford, 201614IARCHITECT i2000SRMen with raised LDLc and no history of MIWest of Scotland Coronary Prevention Study3,31855100116N/AN/A0? (no history of MI)4
      Jia, 201917IARCHITECT i2000SRParticipants aged 54 to 74 years without baseline CV diseaseARIC8,121634315448705
      Lyngbakken, 201629IARCHITECT i2000SRSubjects free from known CHD at baselineHUNT9,1144745241N/A003
      McKie, 201430IPrototype hs assay on the Dimension Vista® 1500 SystemResidents aged ≥45 years, no history of HFOlmsted County1,8436248728810N/A3
      McQueen, 201313TElecsys Troponin T Gen 5 STATSubjects ≥55 years with vascular disease or diabetes with at least one other cardiovascular risk factor, without HF or systolic dysfunctionHOPE2,94166773542N/A0N/A6
      Neumann, 201431IARCHITECT i2000SRPopulation-based cohort without a history of CV eventsFINRISK7,8994850545N/A003
      Nguyen, 202025TElecsys Troponin T Gen 5 STATAsymptomatic individualsMESA5,5846248441278007
      Pandey, 201832IARCHITECT i2000SRAfrican Americans without HFJackson Heart Study3,9875336205498006
      Saunders, 201118TElecsys Troponin T Gen 5 STATGeneral populationARIC9,6986236123582N/A0N/A
      Thorsteinsdottir, 201612IARCHITECT i2000SROlder community dwellersAGES-Reykjavik576477421279N/AN/A0N/A
      Wang, 201233IErenna hsTnI, SingulexFramingham cohortFramingham Heart Study342869471228N/AN/A61
      Welsh, 201919TElecsys Troponin T Gen 5 STATMen aged 40- 59 years from 1 general practiceBritish Regional Heart Study3,85269100731N/A01812
      Welsh, 201920IARCHITECT i2000SRGeneral populationGS:SFHS19,50147423872N/AN/A3
      Welsh, 201920TElecsys Troponin T Gen 5 STATGeneral populationGS:SFHS19501474238N/AN/AN/A2
      Zeller, 2013
      • Zeller T
      • Tunstall-Pedoe H
      • Saarela O
      • et al.
      High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort.
      IARCHITECT i2000SRGeneral populationScottish Heart Health ExtendedCohort15340495027N/AN/A0? (history of MI and ischaemic or haemorrhagic stroke excluded)N/A
      Zhu, 201735IARCHITECT i2000SRGeneral populationBusselton Health Study3,939524362068N/A182
      AGES-Reykjavik, Age, Gene/Environment Susceptibility–Reykjavik Study; ARIC, Atherosclerosis Risk in Communities Study; BiomarCaRE, Biomarkers for Cardiovascular Risk Assessment in Europe; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GS:SFHS, Generation Scotland Scottish Family Health Study; HF, heart failure; HOPE, Heart Outcomes Prevention Evaluation; hs-TnT/I, high-sensitivity troponin T/I; HUNT, Nord-Trøndelag Health Study; JUPITER, Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin; LDLc, low-density lipoprotein cholesterol; MESA, Multi-Ethnic Study of Atherosclerosis; MI, myocardial infarction; N/A, not available; PREVEND, Prevention of Vascular and Renal End-stage Disease.

      Methods

      Systematic review

      This systematic review and meta-analysis was registered on PROSPERO (ID: CRD42021272399) and conducted according to the Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement
      • Moher D
      • Shamseer L
      • Clarke M
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      (see Supplemental material). The data collected are available upon request.
      Articles on hs-cTnT or hs-cTnI for outcome prediction in the general population were searched on the PubMed and Web of Science databases on August 15, with the following keywords: “troponin AND (prognosis OR outcome OR survival OR cardiovascular OR predictive) AND (healthy OR population OR community)”. Reference lists of relevant original research papers and review articles were also manually searched. We included studies meeting the following criteria:
      • 1)
        original research articles,
      • 2)
        papers in English,
      • 3)
        assessment of human subjects from the general population or from population subsets at higher risk of cardiovascular disease (such as diabetic or elderly individuals),
      • 4)
        a baseline evaluation through hs-assays for cTnT and/or cTnI,
      • 5)
        a prospective follow-up with the evaluation of at least one of the following endpoints: all-cause death, adverse cardiovascular events (regardless of their specific definition), or HF hospitalization.
      When multiple studies were conducted on the same populations and did not provide additive information for this analysis, only the largest one was considered. Eligible articles were selected independently by 2 Authors (AA and GP); controversies were solved through discussion with a third Author (AC). The flowchart of study selection is provided in Supplemental Figure 1, and the main characteristics of selected studies are reported in Table 1.

      Meta-analysis

      Data extraction and quality assessment

      Two authors (AA and GP) independently extracted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for the 4 most commonly available endpoints, i.e., all-cause death, cardiovascular death, cardiovascular events (defined as reported in Supplemental Table 1), and HF hospitalization. We retained HRs from the most extensively adjusted models (Supplemental Table 1). We also retrieved the main characteristics from study populations. We used the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) system to quantify the certainty of evidence on the association between hs-cTn and outcomes in the general population, as previously suggested
      • Guyatt GH
      • Oxman AD
      • Vist GE
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      . Five domains were considered, including risk of bias, consistency of effect, imprecision, indirectness and publication bias
      • Guyatt GH
      • Oxman AD
      • Vist GE
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      .

      Data synthesis and statistical analysis

      We performed a meta-analysis of available individual studies separately for the association between baseline hs-cTn and all-cause death, cardiovascular death, cardiovascular events, and HF hospitalization. We pooled together all studies reporting effect estimates for 1 standard deviation (SD) increase in continuous untransformed or log-transformed hs-cTn values. For 3 studies
      • Thorsteinsdottir I
      • Aspelund T
      • Gudmundsson E
      • et al.
      High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
      ,
      • McQueen MJ
      • Kavsak PA
      • Xu L
      • Shestakovska O
      • Yusuf S.
      Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.
      ,
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      we calculated indirectly the effect size by assuming that the estimate corresponding to the comparison of the 4th to the 1st quartile approximated the interquartile range and, thus was equal to 1.35 of the SD of the continuous biomarker. We used the I2-statistic as well as visual checks of Forest plots to infer about heterogeneity among eligible studies and employed random-effects models for all analyses. We opted for the inverse variance method with the Sidik-Jonkman two-step heterogeneity estimator as a more robust approach in case of low number of synthesized studies
      • Veroniki AA
      • Jackson D
      • Viechtbauer W
      • et al.
      Methods to estimate the between-study variance and its uncertainty in meta-analysis.
      . To increase confidence in our results, we also applied the Hartung and Knapp correction to the overall estimate of CIs
      • IntHout J
      • Ioannidis JP
      • Borm GF.
      The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.
      . The effect size and CIs of individual studies as well as pooled estimates were visualised with Forest plots. We sought to explore heterogeneity among studies by: a) conducting sensitivity analyses in elderly subjects or stratifying subjects according to the average of mean/median ages across studies (58 years); b) categorizing studies according to the use of hs-cTnT or hs-cTnI assays; c) excluding studies employing hs-cTnI assays other than ARCHITECT i2000SR; d) applying pre-specified random-effects meta-regression to assess the contribution of continuous study moderators (age, prevalence of male sex, diabetes, and estimated glomerular filtration rate [eGFR]) to the overall heterogeneity. Finally, we investigated possible publication bias by funnel plots of precision and by regression tests (i.e., the Egger test and the Begg and Mazumdar test). For cardiovascular death we did not perform meta-regression analyses and publication bias diagnostics due to low number of studies that could be pooled (n=3). Statistical analysis was conducted with Stata v16.0 (StataCorp, College Station, Texas, USA). All tests were 2-tailed, and the level of statistical significance was set at p<0.05.

      Results

      Literature search

      Summary of the screening summary and concise results of the literature search are illustrated in the flow-chart of this systematic review (Supplemental Figure 1). We initially retrieved 2,042 articles and identified 230 to be evaluated in full-text format. At the final step, 24 studies were included in the quantitative synthesis (Table 1).

      Study characteristics

      The 24 studies were carried out on 23 cohorts, with 2 studies evaluating the prognostic value of hs-cTnT and hs-cTnI in the Atherosclerosis Risk in Communities Study (ARIC)
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      ,
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      . Furthermore, both hs-cTnT and hs-cTnI were evaluated in the Generation Scotland Scottish Family Health Study (GS:SFHS)
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      ,
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      , and an analysis on the Women's Health Study considered separately diabetic and non-diabetic women
      • Everett BM
      • Cook NR
      • Magnone MC
      • et al.
      Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
      . When removing the smallest ARIC study
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      and one of the 2 GS:SFHS cohorts
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      ,
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      , the total number of subjects was 203,202. Eleven studies assessed hs-cTnT
      • de Lemos JA
      • Drazner MH
      • Omland T
      • et al.
      Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
      ,
      • McQueen MJ
      • Kavsak PA
      • Xu L
      • Shestakovska O
      • Yusuf S.
      Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.
      ,
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      ,
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      ,
      • Everett BM
      • Cook NR
      • Magnone MC
      • et al.
      Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
      • Brouwers FP
      • van Gilst WH
      • Damman K
      • et al.
      Clinical risk stratification optimizes value of biomarkers to predict new-onset heart failure in a community-based cohort.
      • deFilippi CR
      • de Lemos JA
      • Christenson RH
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      • Nguyen K
      • Fan W
      • Bertoni A
      • et al.
      N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
      , all of them using the Elecsys Troponin T Gen 5 STAT assay. Fourteen studies evaluated hs-cTnI
      • Thorsteinsdottir I
      • Aspelund T
      • Gudmundsson E
      • et al.
      High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
      ,
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      ,
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      ,
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      ,
      • Blankenberg S
      • Salomaa V
      • Makarova N
      • et al.
      Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium.
      • Eggers KM
      • Kempf T
      • Larsson A
      • et al.
      Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.
      • Everett BM
      • Zeller T
      • Glynn RJ
      • Ridker PM
      • Blankenberg S.
      High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
      • Lyngbakken MN
      • Røsjø H
      • Holmen OL
      • et al.
      Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
      • McKie PM
      • AbouEzzeddine OF
      • Scott CG
      • et al.
      High-sensitivity troponin I and amino-terminal pro–B-type natriuretic peptide predict heart failure and mortality in the general population.
      • Neumann JT
      • Havulinna AS
      • Zeller T
      • et al.
      Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
      • Pandey A
      • Keshvani N
      • Ayers C
      • et al.
      Association of Cardiac Injury and Malignant Left Ventricular Hypertrophy With Risk of Heart Failure in African Americans: The Jackson Heart Study.
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      • Sinning C
      • Keller T
      • Zeller T
      • et al.
      Association of high-sensitivity assayed troponin I with cardiovascular phenotypes in the general population: the population-based Gutenberg health study.
      • Zhu K
      • Knuiman M
      • Divitini M
      • et al.
      High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort.
      , measured in all studies through the Architect i2000SR assay except for 2 studies employing the Erenna Singulex assay
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      or a prototype assay
      • McKie PM
      • AbouEzzeddine OF
      • Scott CG
      • et al.
      High-sensitivity troponin I and amino-terminal pro–B-type natriuretic peptide predict heart failure and mortality in the general population.
      . Four studies evaluated only elderly individuals
      • Thorsteinsdottir I
      • Aspelund T
      • Gudmundsson E
      • et al.
      High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
      ,
      • deFilippi CR
      • de Lemos JA
      • Christenson RH
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      ,
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      ,
      • Eggers KM
      • Kempf T
      • Larsson A
      • et al.
      Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.
      , 3 studies only male individuals
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      ,
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      ,
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      , and 1 only female subjects
      • Everett BM
      • Cook NR
      • Magnone MC
      • et al.
      Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
      . In this last study, the prognostic value of hs-cTnT was evaluated separately in women with or without diabetes
      • Everett BM
      • Cook NR
      • Magnone MC
      • et al.
      Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
      . The prevalence of known cardiovascular disease ranged from 0% in 9 studies
      • Thorsteinsdottir I
      • Aspelund T
      • Gudmundsson E
      • et al.
      High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
      ,
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      ,
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      ,
      • Everett BM
      • Cook NR
      • Magnone MC
      • et al.
      Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
      ,
      • Nguyen K
      • Fan W
      • Bertoni A
      • et al.
      N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
      ,
      • Everett BM
      • Zeller T
      • Glynn RJ
      • Ridker PM
      • Blankenberg S.
      High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
      ,
      • Lyngbakken MN
      • Røsjø H
      • Holmen OL
      • et al.
      Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
      ,
      • Neumann JT
      • Havulinna AS
      • Zeller T
      • et al.
      Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
      ,
      • Pandey A
      • Keshvani N
      • Ayers C
      • et al.
      Association of Cardiac Injury and Malignant Left Ventricular Hypertrophy With Risk of Heart Failure in African Americans: The Jackson Heart Study.
      to 40% in a single study
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      . The mean of available hs-cTnT values was 6 ng/L, and the mean of hs-cTnI was 3 ng/L. Other variables are reported in Table 1. Thirteen studies reported data on all-cause death
      • de Lemos JA
      • Drazner MH
      • Omland T
      • et al.
      Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
      ,
      • Thorsteinsdottir I
      • Aspelund T
      • Gudmundsson E
      • et al.
      High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
      ,
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      ,
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      ,
      • Blankenberg S
      • Salomaa V
      • Makarova N
      • et al.
      Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium.
      • Eggers KM
      • Kempf T
      • Larsson A
      • et al.
      Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.
      • Everett BM
      • Zeller T
      • Glynn RJ
      • Ridker PM
      • Blankenberg S.
      High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
      ,
      • Neumann JT
      • Havulinna AS
      • Zeller T
      • et al.
      Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
      ,
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      ,
      • Zhu K
      • Knuiman M
      • Divitini M
      • et al.
      High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort.
      , 8 on cardiovascular death
      • McQueen MJ
      • Kavsak PA
      • Xu L
      • Shestakovska O
      • Yusuf S.
      Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.
      ,
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      ,
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      ,
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      ,
      • deFilippi CR
      • de Lemos JA
      • Christenson RH
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      ,
      • Blankenberg S
      • Salomaa V
      • Makarova N
      • et al.
      Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium.
      ,
      • Everett BM
      • Zeller T
      • Glynn RJ
      • Ridker PM
      • Blankenberg S.
      High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
      ,
      • Zhu K
      • Knuiman M
      • Divitini M
      • et al.
      High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort.
      , 16 on cardiovascular events
      • Thorsteinsdottir I
      • Aspelund T
      • Gudmundsson E
      • et al.
      High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
      ,
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      ,
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      ,
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      • Everett BM
      • Cook NR
      • Magnone MC
      • et al.
      Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
      ,
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      • Nguyen K
      • Fan W
      • Bertoni A
      • et al.
      N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
      • Blankenberg S
      • Salomaa V
      • Makarova N
      • et al.
      Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium.
      • Eggers KM
      • Kempf T
      • Larsson A
      • et al.
      Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.
      • Everett BM
      • Zeller T
      • Glynn RJ
      • Ridker PM
      • Blankenberg S.
      High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
      • Lyngbakken MN
      • Røsjø H
      • Holmen OL
      • et al.
      Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
      ,
      • Neumann JT
      • Havulinna AS
      • Zeller T
      • et al.
      Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
      ,
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      • Sinning C
      • Keller T
      • Zeller T
      • et al.
      Association of high-sensitivity assayed troponin I with cardiovascular phenotypes in the general population: the population-based Gutenberg health study.
      • Zhu K
      • Knuiman M
      • Divitini M
      • et al.
      High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort.
      , and 13 on HF hospitalization
      • Jia X
      • Sun W
      • Hoogeveen RC
      • et al.
      High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      ,
      • Brouwers FP
      • van Gilst WH
      • Damman K
      • et al.
      Clinical risk stratification optimizes value of biomarkers to predict new-onset heart failure in a community-based cohort.
      ,
      • deFilippi CR
      • de Lemos JA
      • Christenson RH
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      ,
      • Nguyen K
      • Fan W
      • Bertoni A
      • et al.
      N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
      ,
      • Lyngbakken MN
      • Røsjø H
      • Holmen OL
      • et al.
      Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
      ,
      • Neumann JT
      • Havulinna AS
      • Zeller T
      • et al.
      Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
      • Pandey A
      • Keshvani N
      • Ayers C
      • et al.
      Association of Cardiac Injury and Malignant Left Ventricular Hypertrophy With Risk of Heart Failure in African Americans: The Jackson Heart Study.
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      ,
      • Zhu K
      • Knuiman M
      • Divitini M
      • et al.
      High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort.
      ; the prognostic value of hs-cTnT or I was most commonly reported as increase in risk for each standard deviation (SD) of log-transformed biomarker value
      • Welsh P
      • Papacosta O
      • Ramsay S
      • et al.
      High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
      ,
      • Welsh P
      • Preiss D
      • Hayward C
      • et al.
      Cardiac Troponin T and Troponin I in the General Population.
      ,
      • Eggers KM
      • Al-Shakarchi J
      • Berglund L
      • et al.
      High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
      ,
      • Nguyen K
      • Fan W
      • Bertoni A
      • et al.
      N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
      ,
      • Eggers KM
      • Kempf T
      • Larsson A
      • et al.
      Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.
      ,
      • Lyngbakken MN
      • Røsjø H
      • Holmen OL
      • et al.
      Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
      • McKie PM
      • AbouEzzeddine OF
      • Scott CG
      • et al.
      High-sensitivity troponin I and amino-terminal pro–B-type natriuretic peptide predict heart failure and mortality in the general population.
      • Neumann JT
      • Havulinna AS
      • Zeller T
      • et al.
      Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
      • Pandey A
      • Keshvani N
      • Ayers C
      • et al.
      Association of Cardiac Injury and Malignant Left Ventricular Hypertrophy With Risk of Heart Failure in African Americans: The Jackson Heart Study.
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      (Supplemental Table 1). Numerical values of 1 SD across the different studies are reported in Supplemental Table 2.

      Association of high sensitivity troponin with outcomes

      All-cause death

      Based on published data, a pooled assessment of the relationship between hs-cTn and the incidence of all-cause death could be examined in 7 studies with 42,769 subjects. We found that 1-SD increase in baseline hs-cTn was associated with 23% higher risk of all-cause death (pooled HR: 1.226, 95% CI 1.083-1.388, p<0.001) (Fig. 1). Substantial heterogeneity was observed (I2=88.5%).
      Fig. 1
      Fig. 1Pooled estimates for baseline high-sensitivity cardiac troponin (hs-cTn) and the incidence of all-cause death.
      Diamonds and their width represent pooled hazard ratios (HRs) and their 95% confidence intervals (CIs), respectively. Pooled estimates are derived from a random-effects model with the Hartung and Knapp correction to address the small number of studies. Studies in red evaluated elderly subjects only.
      All studies measured hs-cTnI. After excluding the studies employing assays other than the ARCHITECT i2000SR
      • McKie PM
      • AbouEzzeddine OF
      • Scott CG
      • et al.
      High-sensitivity troponin I and amino-terminal pro–B-type natriuretic peptide predict heart failure and mortality in the general population.
      ,
      • Wang TJ
      • Wollert KC
      • Larson MG
      • et al.
      Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
      , the HR was 1.280 (95% Ci 1.091-1.501, p=0.002, n=5 studies, I2=90.2%).

      Cardiovascular death

      In an exploratory analysis on 3 studies with 25,760 subjects, hs-cTn significantly predicted cardiovascular death across the follow-up period (pooled HR per 1-SD increase: 1.822, 95% CI 1.241-2.674, p=0.002, I2=87.2%) (Fig. 2).
      Fig. 2
      Fig. 2Pooled estimates for baseline high-sensitivity cardiac troponin (hs-cTn) and the incidence of cardiovascular death.
      See legend to Fig. 1 for further details.
      Because of the small number of studies (n=3), no subgroup analysis was conducted according to assay type. We just excluded the studies employing assays other than the ARCHITECT: HR=1.552, 95% Ci 1.391-1.731, p<0.001, n=2 studies, I2=0 %.

      Cardiovascular events

      After synthesizing 9 studies with 58,565 subjects, hs-cTn was associated with the occurrence of cardiovascular events (pooled HR per 1-SD increase: 1.328, 95% CI 1.167-1.513, p<0.001, I2=93.8%) (Fig. 3). When the analysis was stratified by troponin subtype, both hs-cTnT (pooled HR per 1-SD increase: 1.627, 95% CI 1.145-2.311, p<0.001, n=2 studies) and hs-cTnI (pooled HR per 1-SD increase: 1.260, 95% CI 1.115-1.423, p<0.001, n=7 studies) predicted the incidence of cardiovascular events, with a greater magnitude for hs-cTnT (p for interaction <0.001) (Supplemental Figure 2). After excluding the 2 studies not employing the ARCHITECT i2000SR assays, the HR for hs-cTnI was 1.285 (95% CI 1.118-1.477, p<0.001, n=6 studies, I2=91.8 %; p for interaction <0.001).
      Fig. 3
      Fig. 3Pooled estimates for baseline high-sensitivity cardiac troponin (hs-cTn) and the incidence of cardiovascular events.
      See legend to Fig. 1 for further details. Studies in red evaluated elderly subjects only.

      Heart failure hospitalization

      In 10 studies with 61,467 subjects, hs-cTn predicted HF hospitalization (pooled HR per 1-SD increase: 1.493, 95% CI 1.368-1.630, p<0.001, I2=76.6%) (Fig. 4).
      Fig. 4
      Fig. 4Pooled estimates for baseline high-sensitivity cardiac troponin (hs-cTn) and the incidence of heart failure (HF) hospitalization.
      See legend to Fig. 1 for further details.
      Both hs-cTnT (pooled HR per 1-SD increase: 1.566, 95% CI 1.303-1.883, p<0.001, n=3 studies) and hs-cTnI (pooled HR per 1-SD increase: 1.467, 95% CI 1.321-1.628, p<0.001, n=7 studies) were associated with the occurrence of HF, although hs-cTnT demonstrated a higher effect size (p for interaction <0.001). After excluding the 2 studies not using the ARCHITECT i2000SR assay, the HR for hs-cTnI was 1.489 (95% Ci 1.418-1.565, p<0.001, n=5 studies, I2=0%; p for interaction=0.471).

      Subgroup analyses

      Beyond the hs-cTn assay, we stratified patients based on their age.
      For all-cause mortality, studies with a mean/median age <58 years had a HR of 1.169 (95% CI 1.049-1.302, p=0.005, n=3 studies I2=68.7%), and those ≥58 years a HR of 1.265 (95% CI 1.025-1.561, p=0.028, n=4 studies, I2=91.3%), with a borderline significant p for interaction (0.049).
      In the 2 studies that recruited elderly subjects, hs-cTn was still related to cardiovascular death (pooled HR per 1-SD increase: 2.01, 95% CI 1.129-3.561, p=0.018, I2=85.9%). In studies with mean/median age <58 years, the HR was 1.552 (95% CI 1.391-1.731, p<0.001, n=2 studies, I2=0%), while only 1 study had a mean/median age ≥58 years.
      As for cardiovascular events, when the analysis was restrained to elderly subjects, the direction and magnitude of the association did not change considerably (pooled HR per 1-SD increase: 1.502, 95% CI 1.183-1.908, P<0.001, I2=82%, n=3 studies)
      • McQueen MJ
      • Kavsak PA
      • Xu L
      • Shestakovska O
      • Yusuf S.
      Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.
      ,
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      ,
      • Lyngbakken MN
      • Røsjø H
      • Holmen OL
      • et al.
      Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
      . Studies with a mean/median age <58 years had a HR of 1.251 (95% CI 1.181-1.325, p<0.001, n=4 studies, I2=48.8%), and those ≥58 years a HR of 1.383 (95% CI 1.091-1.753, p=0.007, n=5 studies, I2=94.3%), with a p for interaction of 0.015.
      With respect to the prediction of HF hospitalization, analysis in elderly subjects showed a pooled HR of 1.826 (95% CI 1.392-2.396, p<0.001, I2=0%, n=2 studies)
      • McQueen MJ
      • Kavsak PA
      • Xu L
      • Shestakovska O
      • Yusuf S.
      Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.
      ,
      • Ford I
      • Shah AS
      • Zhang R
      • et al.
      High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
      . Studies with a mean/median age <58 years had a HR of 1.489 (95% CI 1.418-1.565, p<0.001, n=5 studies, I2=0%), and those with a mean/median age ≥58 years a HR of 1.452 (95% CI 1.254-1.680, p<0.001, n=5 studies, I2=79.1%), with a p for interaction of 0.522.

      Meta-regression analyses

      We then performed meta-regression analyses to examine the effect of age, prevalence of male sex, diabetes, and eGFR on pooled estimates. We did not identify any variable that affected the magnitude of the association between hs-cTn and the incidence of all-cause death, cardiovascular events or HF development (p >0.1 for all analyses).

      Publication bias and grading of evidence

      Funnel plots for the association between hs-cTn and all-cause mortality or cardiovascular events were rather symmetrical; the funnel plot for HF hospitalization was rather asymmetrical at its right bottom, implying either potential publication bias or absence of negative studies. However, statistical tests for small-study effect did not raise any concern with respect to publication bias (p >0.1 with either Egger's or Begg and Mazumdar test for all 3 outcomes). According to the GRADE system, a moderate level of certainty was found for the association between hs-cTn and the risk of outcomes (Supplemental Table 3).

      Discussion

      The scope of this study was to estimate the prognostic value of hs-troponin values in the general population, and mostly within normal limits. This meta-analysis provides a robust confirmation that both hs-cTnI and hs-cTnT are reliable predictors of cardiovascular risk in the general population. In particular, a pooled analysis of all studies showed that the risk of all-cause death, cardiovascular death, cardiovascular events and HF hospitalization increases on average by 23%, 82%, 33% and 49%, respectively, for each SD increase in biomarker levels. However, considering that not all studies evaluated the 4 outcomes, the prognostic values of hs-cTnT and hs-cTnI could be separately compared only for 2 endpoints, namely cardiovascular events and HF hospitalization. Both biomarkers emerged as strong predictors. Interestingly, hs-cTnT emerged as more predictive than hs-cTnI for the prediction of cardiovascular events, while hs-cTnT and hs-cTnI were similarly predictive of HF hospitalization. Due to the large heterogeneity in study design and follow-up duration, further evidence is needed to confirm that there are significant differences between the relative prognostic value of hs-cTnI vs. hs-cTnT. hs-cTnT and hs-cTnI are cardiac-specific biomarkers with a very low index of individuality, which is defined as the ratio of the within-subject variation to the between-subject variation, i.e., the variation between the biological set-points. hs-cTnT and hs-cTnI have an index of individuality of about 0.3 because of a low intra-individual variability (8-10%) and an inter-individual variability of 40-50%
      • Clerico A
      • Giannoni A
      • Prontera C
      • Giovannini S.
      High-sensitivity troponin: a new tool for pathophysiological investigation and clinical practice.
      ,
      • Clerico A
      • Zaninotto M
      • Padoan A
      • et al.
      Evaluation of analytical performance of immunoassay methods for cTnI and cTnT: From theory to practice.
      ,
      • Clerico A
      • Zaninotto M
      • Passino C
      • et al.
      Evidence on clinical relevance of cardiovascular risk evaluation in the general population using cardio-specific biomarkers.
      ,
      • Clerico A
      • Padoan A
      • Zaninotto M
      • Passino C
      • Plebani M.
      Clinical relevance of biological variation of cardiac troponins.
      . By contrast, the other cardiac-specific biomarkers B-type natriuretic peptide (BNP) and N-terminal pro-BNP have both intra- and inter-individual variabilities about 40-60%, and then a much higher index of individuality. In other words, slightly different hs-Tn values across serial measurements are more likely to reflect changes in the severity of cardiac damage than slightly different BNP or NT-proBNP levels. A low index of individuality (<0.6) actually plays an important clinical role, especially when biomarker cut-offs are taken into account for clinical decision, as in the case of hs-cTn cut-offs for the diagnosis of myocardial infarction
      • Clerico A
      • Giannoni A
      • Prontera C
      • Giovannini S.
      High-sensitivity troponin: a new tool for pathophysiological investigation and clinical practice.
      ,
      • Clerico A
      • Zaninotto M
      • Passino C
      • et al.
      Evidence on clinical relevance of cardiovascular risk evaluation in the general population using cardio-specific biomarkers.
      • Clerico A
      • Padoan A
      • Zaninotto M
      • Passino C
      • Plebani M.
      Clinical relevance of biological variation of cardiac troponins.
      • Farmakis D
      • Mueller C
      • Apple FS.
      High-sensitivity cardiac troponin assays for cardiovascular risk stratification in the general population.
      . We may add that hs-cTnT and hs-TnI assays may detect even very low circulating levels of troponins, which is particularly important when evaluating subjects from the general population
      • Ndreu R
      • Musetti V
      • Masotti S
      • et al.
      Evaluation of reproducibility of the cTnT immunoassay using quality control samples.
      • Musetti V
      • Masotti S
      • Prontera C
      • et al.
      Evaluation of reference change values for a hs-cTnI immunoassay using both plasma samples of healthy subjects and patients and quality control samples.
      • Clerico A
      • Masotti S
      • Musetti V
      • et al.
      Evaluation of 99th percentile and reference change values of the hs-cTnI method using ADVIA Centaur XPT platform: A multicenter study.
      .
      Another important point is the influence of age on the prognostic value of hs-cTn. Considering that the mean/median ages of studied populations vary greatly among the 24 selected studies, from 41 to 71 years, we divided the studies in two age groups according to the average of mean/median ages in all studies (58 years). In agreement with epidemiological data (34), studies with a mean/median age ≥58 years showed a greater risk of all-cause death than those with a mean/median age <58 years, with an increase in risk by 27% for each SD increase in log-transformed hs-cTn vs. a 17% increase. A greater difference was also found for cardiovascular events (38% for age ≥58 years vs. 25% for age <58 years). Conversely, no significant difference emerged for HF hospitalization between the two age groups.
      Overall, this meta-analysis confirms the finding from individual studies that hs-Tn levels hold strong prognostic significance, and that this applies to several endpoints, from all-cause death to HF hospitalization. Clinical studies should then evaluate the cost-effectiveness of a hs-cTn-based screening strategy in the general population, or in specific subsets such as elderly individuals, to identify subjects at higher risk of cardiovascular events.
      An intrinsic limitation of meta-analyses of aggregated data is the pooled assessment of studies that had heterogeneous designs and assessed different endpoints. Furthermore, several studies expressed the relationship between hs-cTn and outcomes in terms of difference between categories, such as the lowest vs. highest hs-cTn quartiles. Individual subject meta-analyses would be useful to quantify more precisely the prognostic value of hs-cTn (either single or repeated values, or values higher than 99th percentile upper reference limit), to search for prognostic cut-offs and the influence of factors such as age, sex, chronic kidney disease or other comorbidities.
      In conclusion, hs-cTn values hold strong prognostic value in subjects from the general population, predicting the risk of all-cause and cardiovascular mortality, cardiovascular events, and HF hospitalization. Screening programs of cardiovascular risk stratification and prevention strategies incorporating hs-cTn require further investigation to define the optimal target populations, timing of measurement, and preventive interventions.

      Conflicts of interest

      Dr Georgiopoulos was supported by a training grant from the European Association of Cardiovascular Imaging (EACVI).

      Appendix. Supplementary materials

      References

        • Collet JP
        • Thiele H
        • Barbato E
        • et al.
        2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
        European heart journal. 2021; 42: 1289-1367
        • Clerico A
        • Aimo A
        • Passino C.
        The pathophysiological and clinical relevance of combined measurement of natriuretic peptides and cardiac troponins for risk prediction of incident heart failure in community-dwelling individuals.
        European journal of heart failure. 2021; 23: 403-405
        • Clerico A
        • Giannoni A
        • Prontera C
        • Giovannini S.
        High-sensitivity troponin: a new tool for pathophysiological investigation and clinical practice.
        Advances in clinical chemistry. 2009; 49: 1-30
        • Clerico A
        • Ripoli A
        • Zaninotto M
        • et al.
        Head-to-head comparison of plasma cTnI concentration values measured with three high-sensitivity methods in a large Italian population of healthy volunteers and patients admitted to emergency department with acute coronary syndrome: A multi-center study.
        Clinica chimica acta; international journal of clinical chemistry. 2019; 496: 25-34
        • Clerico A
        • Zaninotto M
        • Padoan A
        • et al.
        Evaluation of analytical performance of immunoassay methods for cTnI and cTnT: From theory to practice.
        Advances in clinical chemistry. 2019; 93: 239-262
        • Sinning C
        • Keller T
        • Zeller T
        • et al.
        Association of high-sensitivity assayed troponin I with cardiovascular phenotypes in the general population: the population-based Gutenberg health study.
        Clinical research in cardiology: official journal of the German Cardiac Society. 2014; 103: 211-222
        • de Lemos JA
        • Drazner MH
        • Omland T
        • et al.
        Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
        Jama. 2010; 304: 2503-2512
        • van der Linden N
        • Klinkenberg LJJ
        • Bekers O
        • et al.
        Prognostic value of basal high-sensitive cardiac troponin levels on mortality in the general population: A meta-analysis.
        Medicine. 2016; 95: e5703
        • Willeit P
        • Welsh P
        • Evans JDW
        • et al.
        High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants.
        J Am Coll Cardiol. 2017; 70: 558-568
        • Moher D
        • Shamseer L
        • Clarke M
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Systematic reviews. 2015; 4: 1
        • Guyatt GH
        • Oxman AD
        • Vist GE
        • et al.
        GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
        BMJ (Clinical research ed). 2008; 336: 924-926
        • Thorsteinsdottir I
        • Aspelund T
        • Gudmundsson E
        • et al.
        High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
        Clinical chemistry. 2016; 62: 623-630
        • McQueen MJ
        • Kavsak PA
        • Xu L
        • Shestakovska O
        • Yusuf S.
        Predicting myocardial infarction and other serious cardiac outcomes using high-sensitivity cardiac troponin T in a high-risk stable population.
        Clinical biochemistry. 2013; 46: 5-9
        • Ford I
        • Shah AS
        • Zhang R
        • et al.
        High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
        Journal of the American College of Cardiology. 2016; 68: 2719-2728
        • Veroniki AA
        • Jackson D
        • Viechtbauer W
        • et al.
        Methods to estimate the between-study variance and its uncertainty in meta-analysis.
        Research synthesis methods. 2016; 7: 55-79
        • IntHout J
        • Ioannidis JP
        • Borm GF.
        The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.
        BMC medical research methodology. 2014; 14: 25
        • Jia X
        • Sun W
        • Hoogeveen RC
        • et al.
        High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
        Circulation. 2019; 139: 2642-2653
        • Saunders JT
        • Nambi V
        • de Lemos JA
        • et al.
        Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
        Circulation. 2011; 123: 1367-1376
        • Welsh P
        • Papacosta O
        • Ramsay S
        • et al.
        High-Sensitivity Troponin T and Incident Heart Failure in Older Men: British Regional Heart Study.
        Journal of cardiac failure. 2019; 25: 230-237
        • Welsh P
        • Preiss D
        • Hayward C
        • et al.
        Cardiac Troponin T and Troponin I in the General Population.
        Circulation. 2019; 139: 2754-2764
        • Everett BM
        • Cook NR
        • Magnone MC
        • et al.
        Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
        Circulation. 2011; 123: 2811-2818
        • Brouwers FP
        • van Gilst WH
        • Damman K
        • et al.
        Clinical risk stratification optimizes value of biomarkers to predict new-onset heart failure in a community-based cohort.
        Circulation Heart failure. 2014; 7: 723-731
        • deFilippi CR
        • de Lemos JA
        • Christenson RH
        • et al.
        Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
        Jama. 2010; 304: 2494-2502
        • Eggers KM
        • Al-Shakarchi J
        • Berglund L
        • et al.
        High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men.
        American heart journal. 2013; 166: 541-548
        • Nguyen K
        • Fan W
        • Bertoni A
        • et al.
        N-terminal Pro B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin as Markers for Heart Failure and Cardiovascular Disease Risks According to Glucose Status (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
        The American journal of cardiology. 2020; 125: 1194-1201
        • Blankenberg S
        • Salomaa V
        • Makarova N
        • et al.
        Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium.
        European heart journal. 2016; 37: 2428-2437
        • Eggers KM
        • Kempf T
        • Larsson A
        • et al.
        Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.
        Clinical chemistry. 2016; 62: 485-493
        • Everett BM
        • Zeller T
        • Glynn RJ
        • Ridker PM
        • Blankenberg S.
        High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
        Circulation. 2015; 131: 1851-1860
        • Lyngbakken MN
        • Røsjø H
        • Holmen OL
        • et al.
        Gender, High-Sensitivity Troponin I, and the Risk of Cardiovascular Events (from the Nord-Trøndelag Health Study).
        The American journal of cardiology. 2016; 118: 816-821
        • McKie PM
        • AbouEzzeddine OF
        • Scott CG
        • et al.
        High-sensitivity troponin I and amino-terminal pro–B-type natriuretic peptide predict heart failure and mortality in the general population.
        Clinical chemistry. 2014; 60: 1225-1233
        • Neumann JT
        • Havulinna AS
        • Zeller T
        • et al.
        Comparison of three troponins as predictors of future cardiovascular events–prospective results from the FINRISK and BiomaCaRE studies.
        PloS one. 2014; 9: e90063
        • Pandey A
        • Keshvani N
        • Ayers C
        • et al.
        Association of Cardiac Injury and Malignant Left Ventricular Hypertrophy With Risk of Heart Failure in African Americans: The Jackson Heart Study.
        JAMA cardiology. 2019; 4: 51-58
        • Wang TJ
        • Wollert KC
        • Larson MG
        • et al.
        Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.
        Circulation. 2012; 126: 1596-1604
        • Sinning C
        • Keller T
        • Zeller T
        • et al.
        Association of high-sensitivity assayed troponin I with cardiovascular phenotypes in the general population: the population-based Gutenberg health study.
        Clinical research in cardiology: official journal of the German Cardiac Society. 2014; 103: 211-222
        • Zhu K
        • Knuiman M
        • Divitini M
        • et al.
        High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort.
        Heart. 2018; 104: 895-903
        • Clerico A
        • Zaninotto M
        • Passino C
        • et al.
        Evidence on clinical relevance of cardiovascular risk evaluation in the general population using cardio-specific biomarkers.
        Clinical chemistry and laboratory medicine. 2020; 59: 79-90
        • Clerico A
        • Padoan A
        • Zaninotto M
        • Passino C
        • Plebani M.
        Clinical relevance of biological variation of cardiac troponins.
        Clinical chemistry and laboratory medicine. 2021; 59: 641-652
        • Farmakis D
        • Mueller C
        • Apple FS.
        High-sensitivity cardiac troponin assays for cardiovascular risk stratification in the general population.
        European heart journal. 2020; 41: 4050-4056
        • Ndreu R
        • Musetti V
        • Masotti S
        • et al.
        Evaluation of reproducibility of the cTnT immunoassay using quality control samples.
        Clinica chimica acta; international journal of clinical chemistry. 2019; 495: 269-270
        • Musetti V
        • Masotti S
        • Prontera C
        • et al.
        Evaluation of reference change values for a hs-cTnI immunoassay using both plasma samples of healthy subjects and patients and quality control samples.
        Clinical chemistry and laboratory medicine. 2019; 57: e241-e243
        • Clerico A
        • Masotti S
        • Musetti V
        • et al.
        Evaluation of 99th percentile and reference change values of the hs-cTnI method using ADVIA Centaur XPT platform: A multicenter study.
        Clinica chimica acta; international journal of clinical chemistry. 2019; 495: 161-166
        • Zeller T
        • Tunstall-Pedoe H
        • Saarela O
        • et al.
        High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort.
        European heart journal. 2014; 35: 271-281

      Linked Article