In our analysis, cTnT measured with a new high-sensitivity assay had strong associations with CHD, mortality, and HF in a general population of middle-aged to older adults without CVD. The new assay detected cTnT in 66.5% of these individuals, the vast majority of whom had levels that would have been undetectable by the currently available, clinically used 4th-generation assay. Only 65 individuals (<1% of the ARIC population) had cTnT levels ≥0.03 μg/L (i.e., detectable using the currently used assay), consistent with reported detectable levels in <1% of the general population5
and 4.1% of the elderly population.6
Prior studies using this hs-cTnT assay have reported associations with adverse cardiovascular outcomes in individuals with chronic HF9
and stable CHD,10
and we now extend the findings to a general population aged 54–74 years. Among the outcomes tested, associations were strong with fatal CHD, all-cause mortality, and HF hospitalization. Of the CHD outcomes, the association with fatal CHD was strongest, and associations with nonfatal CHD events, including MI and revascularization, were weaker. However, relatively few fatal CHD events occurred; hence, when all CHD events were considered together, the association was weaker than with all-cause mortality and HF. Metrics of risk prediction, including AUC, NRI, and IDI, were also more robust for mortality and HF than for CHD (). In exploratory analyses, improvements in risk prediction for CHD, mortality, and HF when cTnT was added to risk prediction models were similar to those provided by NT-proBNP and larger than those for hs-CRP. In summary, our findings suggest that cTnT may be an important marker in the prediction of hard CHD, mortality, and HF.
Our results are concordant with those of 2 other population studies, the Cardiovascular Health Study (CHS)16
and the Dallas Heart Study (DHS),17
which were published after submission of this report; all 3 studies used the same assay. The ARIC results are most similar to those of CHS (average age ~10 years older than ARIC), in which 66% of participants had detectable cTnT with the new assay.16
Although overall only 25% of DHS participants had detectable levels, >50% were aged <50 years; 56% of participants aged 60–65 had detectable levels.17
All 3 studies found strong associations with mortality. The younger age and greater number of ARIC participants may have contributed to the larger NRI for mortality and HF than in CHS. The prevalence of detectable cTnT with the high-sensitivity assay is clearly distinct from the “sensitive” troponin I assay used by Blankenberg et al., which detected levels in <2% of population cohorts.8
The weaker association observed with nonfatal CHD events seems counter to findings in patients with acute coronary syndromes, in whom elevated cTnT level is a strong marker for risk for future MI.18,19
However, small elevations in cTnT had no association with short-term risk for MI in asymptomatic individuals with stable CHD10
; this, taken together with our findings, suggests that the risk from low detectable cTnT levels in asymptomatic subjects may be mediated through mechanisms other than or in addition to atherothrombosis. These mechanisms, which are not fully understood, may result from troponin release from cardiac myocytes due to asymptomatic ischemia, coronary microvascular dysfunction, apoptosis, or subclinical cardiac structural or functional abnormalities. Troponin I levels measured with a highly sensitive assay increased with reversible ischemia detected by nuclear perfusion imaging,20
supporting the notion that subclinical ischemia could induce troponin release. However, in another study that used the hs-cTnT assay, cTnT levels did not change with exercise- or pharmacological stress–induced ischemia,21
again suggesting that factors other than ischemia contribute significantly to the risk associated with cTnT. Coronary microvascular dysfunction, which occurs in hypertension, diabetes, and LVH, is another potential cause for elevated circulating troponin levels22
and may mediate, in part, the associations observed with HF events. Troponin is eliminated from the circulation via renal clearance; therefore, as glomerular filtration declines, troponin levels may increase. While this was true in ARIC, the associations with outcomes remained strong even after adjustment for eGFR. Therefore, the mechanisms underlying elevated troponin levels may be several, and it is unclear which mechanisms are related to the outcomes observed in our study.
Clinical and Therapeutic Implications
The strength of the associations between cTnT and the various outcomes has several potential implications. First, troponin levels above 99th
percentile values have been recommended for diagnosis of MI.1
percentile value for cTnT in our study (0.03 μg/L) was far higher than that published by the manufacturer (0.014 μg/L), and 7% of the ARIC population had levels ≥0.014 μg/L. Januzzi et al.23
reported (using the manufacturer-determined 99th
percentile cutpoint) that the high-sensitivity assay had a lower positive predictive value (38%) than the conventional assay (67–72%), suggesting that false positives were higher with the high-sensitivity assay. If the 99th
percentile identified in a population study such as ARIC were used, the estimated predictive value may be different. The diagnostic criteria may need to be revised to include both absolute cTnT level and rise and fall in cTnT level when the high-sensitivity assay is used.24
Conversely, undetectable cTnT with the new assay may have superior negative predictive value, which will need further study.
cTnT modestly improves CHD risk prediction, and therapies such as statin and/or aspirin could hypothetically be considered for individuals reclassified as higher risk with cTnT. However, although statins reduce CHD events in patients with traditional risk factors such as hypertension,25
statins have not shown benefit in some high-risk populations such as patients with HF26
or end-stage renal disease.27
Furthermore, a recent study in individuals with diabetes suggested that cTnT levels did not change significantly with either intensive or standard risk factor management.28
The stronger association of cTnT with death and HF than with CHD suggests that this biomarker predicts structural heart disease events to a greater extent than atherosclerotic events. Therefore, strategies aimed to prevent CHD may have smaller effects than strategies aimed to prevent progression of structural heart disease. As HF prevalence and incidence continue to increase, markers such as cTnT may conceivably identify high-risk individuals and allow early initiation of preventive strategies. Better understanding of the adverse mechanisms/process(es) that cTnT marks or mediates may be useful in targeting therapies, but ultimately clinical trials will be needed to examine if risk can be modified.
Validated mortality and HF risk prediction models have not yet been developed in ARIC; therefore, we added BMI, creatinine, and LVH to the ACRS for use as the base model. However, AUCs were greater for both mortality (0.719) and HF (0.749) than for all CHD (0.715). We do not know if cTnT would have added to risk prediction with the addition of other biomarkers or clinical variables including echocardiography (which was not available) to the ACRS.
cTnT measured with a novel highly sensitive cTnT assay was detectable in the majority of middle-aged individuals without prevalent CVD. Even slight elevations were strongly associated with death, especially CHD death, and HF hospitalization. Although there was an association between cTnT and MI, it was less pronounced than that for the other endpoints assessed. Whether the risk for CHD, mortality, and HF hospitalization associated with measurable cTnT in individuals without prior CVD is modifiable is unknown and requires further study.