In a community-based population of almost 10,000 individuals without clinically evident CHD, chronic hyperglycemia was independently associated with subclinical myocardial injury, as assessed by elevated levels of hs-cTnT in both persons with and without diabetes.
Elevated troponin levels have been previously associated to cardiovascular events(11
). Using conventional assays, troponin can be detected in 0.7% of the population(20
) and is associated with myocardial infarction and death(11
). In contrast, the novel high-sensitivity troponin assay allows for the detection of troponin at levels far below previous detection limits. We observed that hs-cTnT was present in 66.3% of the ARIC population without clinically evident CHD. The 99th
percentile value for hs-cTnT in our study (30 ng/L) was considerably higher than that reported by the manufacturer (14 ng/L) in a healthy population aged 20–70 years. Firm reference ranges for this assay have not yet been established.
Others have recently shown in both ARIC(17
) and other(15
) cohorts that troponin levels measured with the highly sensitive assay independently predict cardiovascular events. In ARIC, hs-cTnT levels above the 99th
percentile were associated with all-cause mortality (OR 3.69, 95% CI 3.21, 4.88)(17
). Also of interest, minimally elevated levels of hs-cTnT (3 to 5 ng/L) were associated with all-cause mortality (OR 1.37, 95% CI 1.14, 1.65).
Numerous studies have demonstrated associations between hyperglycemia and macrovasular and microvascular complications(2
). The use of this high sensitivity assay allowed for the detection of minimally elevated troponin levels thought to represent subclinical cardiac injury(18
). Although hyperglycemia is traditionally thought to be associated to cardiovascular events via atherosclerosis, our results suggest that hyperglycemia may contribute to cardiovascular events by alternate mechanisms.
A potential mechanism by which hyperglycemia induces myocardial injury is hyperglycemia-mediated coronary microvascular dysfunction(21
). Other mechanisms include oxidative stress(21
), advanced glycation end-products(23
) and myocardial fibrosis(25
). Diabetic subjects have increased oxidative stress(26
) and administration of antioxidant vitamin C has been shown to improve endothelial dysfunction in diabetics(27
). Finally, hyperglycemia may also be associated with myocardial damage through silent atherosclerotic disease and as others have shown, up to 12% of asymptomatic diabetic subjects had coronary artery stenosis greater than 75%(28
While some have demonstrated associations of hyperglycemia with subclinical CVD using imaging modalities(8
), to our knowledge we are the first to demonstrate an association between hyperglycemia and early subclinical myocardial injury. Recent studies using this new highly sensitive assay for cTnT suggest that the association with cardiac outcomes is mediated by mechanisms independent of atherosclerosis(14
). While left ventricular mass was independently associated with detectable levels of hs-cTnT, coronary artery calcium –a marker of coronary atherosclerosis- was not(16
). Hs-cTnT had a stronger association with total mortality and heart failure than to CHD(17
). Furthermore, the association with non-fatal CHD was even weaker than for fatal CHD, again suggesting that hs-cTnT is related to outcomes by mechanisms other than atherosclerosis. Nevertheless, due to the observational nature of these investigations, the non-atherosclerotic mechanisms remain unclear.
Our results suggest that HbA1c performs better as a marker of subclinical myocardial damage compared to fasting glucose and are consistent with the growing body of literature demonstrating that HbA1c is an important marker of cardiovascular risk(4
). Our data support new recommendations for the use of HbA1c for the diagnosis of diabetes and identification of persons at high risk for development of complications(7
Our study has important limitations: Measurements of HbA1c and hs-cTnT were not available at the same visit. Although in sensitivity analysis we excluded persons with any history of clinical CHD at visit 4 and incident CHD in the 6 months following hs-cTnT measurement, we cannot rule out the possibility that a number of subjects had elevated troponin levels at the baseline visit. While elevated hs-cTnT levels have now been associated with increased CVD(15
), whether clinical management should be modified on the basis of chronically elevated levels of troponin is unknown. Because we excluded persons that died or developed CHD between visit 2 and visit 4 and HbA1c is associated with both elevated troponin levels and mortality, there is a possibility that this resulted in selection bias. This would tend to underestimate the true association. Although we adjusted for known risk factors for CHD, we cannot exclude the possibility of residual confounding in this observational study. There were 679 people excluded from our analysis (<10% of the study sample) due to missing data. Nonetheless, this represents one of the largest community-based studies of HbA1c and hs-cTnT. Additional major strengths of this study include the large sample of persons with and without diabetes, including a large number of African Americans, rigorous measurement of cardiovascular risk factors, and our ability to exclude clinical CHD cases utilizing comprehensive and adjudicated surveillance data for clinical events.
In conclusion, in this community-based study of persons without clinically evident CHD, HbA1c was associated with hs-cTnT in a graded fashion. Our findings suggest that hyperglycemia contributes to myocardial injury beyond its effects on development of clinical atherosclerotic coronary disease.