The present study demonstrates that up to 25% of T2DM patients without clinical evidence of active cardiovascular disease have ongoing subtle myocardial injury/necrosis as detected by an elevated serum level of hs-TnI. An elevated serum hs-TnI level in patients with T2DM, above the gender-specific cut-off value in the control population, was associated with a more than 2-fold increase in the adjusted risk of MACE. Importantly, a normal serum hs-TnI level had an excellent negative predictive value for future adverse cardiovascular outcome in patients with T2DM after up to 4 years of follow-up.
Elevated high sensitivity troponin level suggested myocardial injury that has been shown to be related with arterial stiffening in patients with T2DM . In addition to detect subtle myocardial necrosis, its clinical value has also been shown to provide important prognostic information in various groups of patients. Several studies have demonstrated the predictive value for future cardiovascular events by hs-TnT in the general population [4, 5, 21], patients with stable and unstable angina , acute coronary syndrome  and heart failure . Similarly, hs-TnI has been shown to provide prognostic information in the general population , patients with stable atherosclerotic disease [10, 11] and acute coronary syndrome . Although these studies have consistently demonstrated that high sensitivity troponin can predict future adverse cardiovascular events in different groups of patients, its prognostic value has not been well studied in patients with T2DM. A recent report from the Women Health Study demonstrated that among diabetic women without cardiovascular disease (n = 512), a detectable hs-TnT was associated with total cardiovascular disease (adjusted hazard ratio [HR] = 1.76) and cardiovascular death (adjusted HR = 3.13) . Conversely, another study using elevated hs-TnT above 99th percentile reference could not demonstrate a statistical association with adverse cardiovascular outcome . The contradictory results from these studies may suggest the potentially limited prognostic value of hs-TnT in patients with T2DM. Because of the different biological characteristics , the clinical relevance and strength of detecting myocardial injury between hs-TnT and hs-TnI may differ. Indeed, it has been shown that the prognostic value of hs-TnI may be superior to hs-TnT in a cohort of patients with stable coronary artery disease . The prognostic implication of hs-TnI may thus be more robust than hs-TnT in patients with T2DM.
A prior study demonstrated that a low level of circulatory TnI (9 ng/L to 30 ng/L) was predictive of MACE (death, MI or stroke) in patients with T2DM who underwent elective coronary angiography . Nonetheless no study has evaluated the predictive value for MACE using a high sensitivity assay of TnI (level of detection = 1.2 ng/L). The present study included an expanded and clinically relevant population, consisting of both male and female T2DM patients, with and without underlying cardiovascular disease. Our results demonstrate that elevated hs-TnI independently predicted MACE (adjusted HR = 2.85) in patients with T2DM, and thus provides further evidence that elevated hs-TnI is closely associated with and predictive for future adverse events in patients with T2DM.
In this study, the high prevalence of MACE in T2DM patients with elevated hs-TnI was mainly driven by more frequent heart failure and cardiovascular death. In contrast, an elevated hs-TnI was not associated with future myocardial infarction. Indeed, prior studies have shown that among patients with stable chronic cardiovascular disease, an elevated troponin level better predicts heart failure than ischemic events [2, 4, 5, 7, 11, 21]. In the Framingham Offspring Study, an elevated hs-TnI was independently predictive of death, heart failure and major cardiovascular events, but not coronary heart disease . Similarly, Omland et al. showed that among patients with stable coronary artery disease, an elevated hs-TnI was strongly associated with cardiovascular death and heart failure but only weakly with non-fatal myocardial infarction . Collectively, these findings support the hypothesis that a measurable circulating troponin level reflects chronic myocardial damage/myocardial stress, rather than acute ischemic insult or vascular stress. It can thereby identify an increased risk for pathological cardiac remodeling and subsequent heart failure.
In patients with T2DM, a number of mechanisms might explain the presence of ongoing subtle myocardial injury, including coronary microvascular dysfunction , depletion of endothelial progenitor cells , elevated oxidative stress [9, 28], and advanced glycation end-products . This is further evidenced by a study that showed that chronic hyperglycaemia, as measured by HbA1c, was independently associated with subclinical myocardial injury in subjects without clinically evident coronary artery disease, as assessed by elevated levels of hs-TnT . In addition, this study also showed that the association of HbA1c with hs-TnT extends to subjects below the diagnostic threshold of 6.5%, and suggests that hyperglycaemia-related myocardial injury may begin before the onset of clinically evident diabetes. The circulating troponin detected by these high sensitive assays in patients with T2DM thus represents an intermediate phenotype of subtle myocardial injury, rather than an acute ischemic event.
In patients with T2DM, a number of different cardiovascular investigations, including treadmill testing , computed tomography angiography  and electrocardiogram-gated single photon emission computed tomography  have been shown to provide excellent negative predictive value for future cardiovascular events. Nevertheless their widespread clinical use for risk stratification is limited by the need for an experienced operator; prolonged study duration and prohibitive cost. One of the most intriguing findings of the present report was that a normal hs-TnI had a high negative predictive value for future adverse cardiovascular events in patients with T2DM after up to four years of follow-up. The present study thus suggests that a single serum measurement of hs-TnI provides a simple and inexpensive means to accurately risk stratify patients with T2DM, particularly identifying those at low risk for intermediate-term (>4 years) adverse cardiovascular events.
Interpretation of both hs-TnI and hs-TnT level can be done using a cut-off value either above the level of detection or above the 99th percentile of a reference population . Even within the same study population, the proportion of subjects with detectable hs-TnI is greater than hs-TnT . The present study has shown that >99% of patients with T2DM had a detectable hs-TnI, compared with only 45.5% of diabetic women in the Women’s Health Study using hs-TnT . Further, up to 25% of patients with T2DM had an elevated hs-TnI defined according to the 99th percentile of an age and gender matched reference population. This finding demonstrates that hs-TnI is a sensitive assay to detect subtle myocardial injury, and up to one quarter of stable patients with T2DM had significant myocardial damage. In addition to the prognostic implication, this assay hence can be used as a surrogate for subtle myocardial injury to further study the mechanism of myocardial damage in patients with T2DM.
The present study included only a small study population of patients with T2DM and future study with a larger number of subjects is required to confirm the results. None of the patients received further coronary work-up based on the hs-TnI level alone. Future studies should evaluate the predictive value of significant coronary artery disease in T2DM patients with elevated hs-TnI. The study population is Asian, thus it may not be appropriate to extrapolate the results to other ethnic groups. Finally, only a single measurement of hs-TnI was used for risk stratification. Whether serial measurements of hs-TnI would provide additional information requires further evaluation.