We congratulate Rubin et al. (1) on their recent paper entitled “Chronic Hyperglycemia and Subclinical Myocardial Injury.” In a large community-based cohort of 9,661 participants without clinically evident coronary artery disease (CAD), the authors demonstrated that chronic hyperglycemia, as reflected by serum baseline glycated hemoglobin (HbA_1c), is independently associated with high-sensitivity cardiac troponin T (hs-cTnT), an established marker of increased cardiovascular risk. This association was present both in subjects with and without diabetes mellitus. The authors suggest that a number of factors may contribute to this association, including hyperglycemia-mediated microvascular dysfunction, oxidative stress, advanced glycation endproducts, myocardial fibrosis, and subclinical atherosclerotic disease.

Herewith, we would like to underscore the importance of silent atherosclerotic disease in those with diabetes, in whom typical symptoms of cardiac ischemia are usually masked, even in subjects with relevant CAD. Studying consecutive patients who underwent coronary computed tomography angiography (CCTA) for suspected CAD, we previously reported that hs-cTnT above the 99th percentile is present in ∼23% of patients with stable CAD and is related to plaque composition, in particular to noncalcified plaque burden and vascular remodeling (2). In 168 consecutive patients (21 [12.5%] with diabetes mellitus), we found that those with diabetes exhibit both increased hs-cTnT levels (9.8 ± 6.3 pg/ml vs. 14.5 ± 7.7 pg/ml; p = 0.002) and noncalcified plaque burden (12.1 ± 20.2 mm³ vs. 32.1 ± 28.6 mm³; p = 0.0001) compared with patients without diabetes. Using multivariate regression analysis, the observed associations of diabetes with hs-cTnT and noncalcified plaque burden both remained independent after consideration of age, sex, and other atherogenic risk factors (r = 0.24, p = 0.007, and r = 0.26, p = 0.002, respectively).

In patients with acute coronary syndromes, atherosclerotic plaque rupture with subsequent vessel occlusion causes irreversible myocardial damage. Milder forms of plaque rupture with subsequent microembolization of atherothrombotic burden into the coronary circulation, however, may occur in patients with stable CAD or even in presumably healthy subjects. Thus, more than a decade ago, healed plaque destruction was observed in postmortem studies (3), whereas angioscopy studies demonstrated that silent plaque rupture is present in ∼20% of patients with stable CAD (4). Especially in diabetic patients, plaque rupture is expected to remain subclinical, so that the presence of increased plaque burden and troponin leakage in the absence of unstable angina is not surprising. Furthermore, such plaque microembolization and subsequent micronecrosis may subsequently result in the release of alarmin cytokines by stressed cardiomyocytes (5). This may then elicit systemic proinflammatory responses, again contributing to vascular remodeling processes and microvascular dysfunction, thus possibly being part of a vicious circle that encompasses silent plaque rupture, systemic inflammation, and myocardial injury. To confirm this hypothesis, the detection by gadolinium-positive myocardial fibrosis within the perfusion bead of coronary vessels with increased noncalcified plaque burden will be decisive in future biomarker and multimodality imaging studies. Rubin et al. (1) should be commended for their comprehensive analysis because their study represents an important contribution in the area of ischemic heart disease, considering hs-cTnT as a phenotype for increased cardiovascular risk in those with asymptomatic diabetes. Now, future studies are warranted to test whether hs-cTnT and other biomarkers can be used as therapeutic targets in stable CAD.