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Corresponding Author: Alberto Aimo, MD, Institute of Life Sciences, Scuola Superiore Sant'Anna; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Piazza Martiri della Libertà 33. 56124 Pisa, Italy
Footnotes
⁎ These Authors equally contributed.
Affiliations
Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, ItalyFondazione Toscana Gabriele Monasterio, Pisa, Italy
Department of Clinical Therapeutics, National and Kapodistrian University of Athens, GreeceSchool of Biomedical Engineering and Imaging Sciences, King's College London, UK
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.
Cardiac troponin T (cTnT) and I (cTnI) are both sensitive and specific indicators of myocardial injury most commonly used to diagnose acute coronary syndrome
. 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
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
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
. 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
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
. 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
. 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/I
Assay
Population setting
Cohort
Patient n
Age (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, 201626
I
ARCHITECT i2000SR
10 prospective population-based studies
BiomarCaRE
74,738
52
52
5
42
94
N/A
N/A
N/A
Brouwers, 201422
T
Elecsys Troponin T Gen 5 STAT
HF-free subjects
PREVEND
8,569
49
50
1
14
82
0
7
3
De Lemos, 20107
T
Elecsys Troponin T Gen 5 STAT
Participants aged 30-65 years
Dallas Heart Study
3,546
41
44
12
34
99
4
8
N/A
De Filippi, 201023
T
Elecsys Troponin T Gen 5 STAT
Community-dwelling adults aged ≥65 years without prior HF
Cardiovascular Health Study
4,221
71
40
18
51
N/A
0
N/A
N/A
Eggers, 201324
T
Elecsys Troponin T Gen 5 STAT
Elderly men
Uppsala Longitudinal Study of Adult Men
872
71
100
11
74
75
N/A
40
8
Eggers, 201627
I
ARCHITECT i2000SR
Elderly individuals
Prospective Investigation of the Vasculature in Uppsala Seniors
1,016
70
50
11
72
79
4
15
3
Everett, 201121
T
Elecsys Troponin T Gen 5 STAT
Female health professionals ≥45 years, diabetic
Women's Health Study
512
56
0
100
46
54
0
0
N/A
Everett, 201121 (2nd subgroup)
T
Elecsys Troponin T Gen 5 STAT
Female health professionals ≥45 years, non-diabetic
Women's Health Study
564
57
0
0
17
47
0
0
N/A
Everett, 201528
I
ARCHITECT i2000SR
Participants without CV disease
JUPITER
12,956
66
64
0
56
73
0
0
3
Ford, 201614
I
ARCHITECT i2000SR
Men with raised LDLc and no history of MI
West of Scotland Coronary Prevention Study
3,318
55
100
1
16
N/A
N/A
0? (no history of MI)
4
Jia, 201917
I
ARCHITECT i2000SR
Participants aged 54 to 74 years without baseline CV disease
ARIC
8,121
63
43
15
44
87
0
5
Lyngbakken, 201629
I
ARCHITECT i2000SR
Subjects free from known CHD at baseline
HUNT
9,114
47
45
2
41
N/A
0
0
3
McKie, 201430
I
Prototype hs assay on the Dimension Vista® 1500 System
Residents aged ≥45 years, no history of HF
Olmsted County
1,843
62
48
7
28
81
0
N/A
3
McQueen, 201313
T
Elecsys Troponin T Gen 5 STAT
Subjects ≥55 years with vascular disease or diabetes with at least one other cardiovascular risk factor, without HF or systolic dysfunction
HOPE
2,941
66
77
35
42
N/A
0
N/A
6
Neumann, 201431
I
ARCHITECT i2000SR
Population-based cohort without a history of CV events
High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort.
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
(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
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
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
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
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)
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
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
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
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
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
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
. 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
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
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
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
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
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
; 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
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
(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. 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.
, 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. 2Pooled estimates for baseline high-sensitivity cardiac troponin (hs-cTn) and the incidence of cardiovascular death.
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. 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.
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)
. 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)
. 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%
. 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
. 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
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
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).
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
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
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
High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals.
The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.
Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
Sensitive cardiac troponin T assay and the risk of incident cardiovascular disease in women with and without diabetes mellitus: the Women's Health Study.
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
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
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
High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort.
Troponins are proteins essential for the contraction of the myocardium and currently cardiac troponin I and cardiac troponin T are used as blood biomarkers to assess myocardial injury1,2.
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