In this cohort, apparently healthy community-dwelling adults with minimally detectable TnT were at increased risk of death. Elevated NT-proBNP levels also independently predicted death in this cohort. The predictive ability was improved by incorporating both TnT and NT-proBNP, and the prognostic value of each biomarker persisted for years after initial measurement.
Current guidelines recommend that TnT levels >0.03 ng/ml be considered abnormal (38
). However, we have shown that individuals with any detectable TnT level, even those lower than this cut point, have clinical features suggestive of poor health, including higher NT-proBNP levels and poorer renal function. This is in agreement with the findings of Wallace et al. (12
), who also noted that individuals with detectable TnT tended to have significant comorbidity. Importantly, in the present study more than 60% of those with detectable TnT did not have known prior heart disease, and the prognostic ability of TnT was independent of other CHD risk factors. Thus, cardiac TnT probably reflects subclinical heart disease in adults without known CHD. When analysis was limited to the subgroup of participants without prior CHD, the strength of the associations between detectable TnT or elevated NT-proBNP and all-cause mortality was not materially changed, suggesting that TnT and NT-proBNP are predictive even in an apparently heart disease–free population.
The prevalence of detectable TnT in the Rancho Bernardo cohort was 4.1%, higher than the prevalence of 0.7% estimated from the population-based Dallas Heart Study (12
). This difference likely reflects the younger age of the Dallas cohort. Few studies have reported the clinical significance of minimally elevated troponin levels. Wallace et al. (12
) reported that the presence of measurable troponin levels among the 3,557 subjects from the Dallas Heart Study was associated with a high-risk phenotype including underlying heart failure, left ventricular hypertrophy, chronic kidney disease, or diabetes, but did not report on how the presence of a measurable troponin level affected clinical outcomes. The only prior study that has reported minimally detectable troponin levels and outcomes in the general population was based on registry data and included only men; in this study Zethelius et al. (13
) reported that cardiac troponin I predicted death and first CHD event over approximately 10 years of follow-up in 1,203 elderly men, and this association was independent of conventional risk factors.
The association of even minimally elevated TnT levels with mortality suggests that TnT is a marker of subclinical myocardial damage. Plausible mechanisms for the release of detectable TnT in the blood include silent ischemia, microvascular disease, left ventricular strain, impaired subendocardial perfusion, endothelial dysfunction, apoptosis, oxidative stress injury, inflammation, or other undetermined factors leading to microscopic myocardial cell necrosis or cellular membrane leak reflecting increased myocyte permeability (41
). Until more sensitive tests become available, the relatively low prevalence of detectable TnT levels in the community may limit its utility as a screening agent.
In contrast, natriuretic peptides have been shown to predict cardiovascular disease in a variety of settings, including apparently healthy individuals. The NT-proBNP cut point of 450 pg/ml, derived from the recommended decision threshold for older outpatients with shortness of breath, also provided prognostic information in this community-based population of older adults. In the Framingham Offspring Study of 3,346 individuals with a mean age of 58 years, Wang et al. (29
) found a 27% increased risk of death for each 1-SD increment in log BNP levels during 5.2 years of follow-up; higher BNP levels were also associated with increased risk of cardiovascular events, atrial fibrillation, heart failure, and stroke or transient ischemic attack. Kistorp et al. (46
) measured NT-proBNP levels in a community-based cohort of 626 Danish adults (mean age 68 years) and reported a 43% increase in the adjusted risk of death from any cause per 1-SD increase in log NT-proBNP. These results are similar to the 39% increased risk of death per 1-SD increase in log NT-proBNP reported in the present study. Higher NT-proBNP levels were also associated with the first major cardiovascular event in the Danish cohort, in agreement with our finding of increased risk of cardiovascular death in individuals with elevated NT-proBNP.
In the present study, the coexistence of both elevated NT-proBNP and a detectable troponin level was uncommon, but was associated with a 3.2-fold increased risk of death. The effects of NT-proBNP and TnT were independent of each other, which is in accord with their differing pathophysiologic roles. It is likely that each marker identifies a distinct physiology, either of which confers increased risk. It is plausible that the simultaneous presence of subclinical myocardial ischemia and increased left ventricular wall stretch portends an outcome worse than either factor alone. Both NT-proBNP and TnT measurements may prove clinically useful in identifying a high-risk population with subclinical CVD in whom aggressive preventive measures may be warranted. Further studies are needed to evaluate this possibility. Both TnT and NT-proBNP added significantly to risk prediction by the Framingham score, with elevated levels of either marker predicting an increased hazard of death, irrespective of Framingham risk level. Although both biomarkers improved the AUC for prediction of CVD death and all-cause mortality, NT-proBNP raised the AUCs more than TnT. Elevated NT-proBNP is also more prevalent than detectable TnT, and is therefore better suited to screening.
This study has several limitations. Because the Rancho Bernardo Study consists primarily of middle-class to upper-middle-class adults of European ancestry, the results may not be generalizable to other ethnic and socioeconomic groups. Baseline CHD events were based on self-report of prior coronary revascularization or of a physician diagnosis, which could have resulted in misclassification. However, at an earlier Rancho Bernardo study visit, 85% of reported cardiovascular events were confirmed in the 30% subset that had medical records permitting validation. Also, this study had small numbers of individuals with measurable TnT, limiting our ability to identify all important predictors of detectable TnT levels and our power to detect significant associations with CVD mortality after excluding participants with baseline CHD. Nonetheless, we were able to show a significant association for both TnT and NT-proBNP with all-cause mortality even after excluding participants with baseline CHD. In this case both TnT and NT-proBNP remained independent predictors of death.