Electron-beam computed tomography (EBCT) is a sensitive tool for the
noninvasive detection of coronary artery calcium, which is an excellent marker of atherosclerotic plaque burden.1 This marker has been exten-
sively studied as a tool to assess cardiovascular risk, and several investigations have established its value as a good predictor of risk. In a number of studies, coronary artery calcium provided incremental prognostic value over traditional risk factors.2,3 Because of its very high cardiovascular complication rate, diabetes mellitus is considered equivalent to established coronary artery disease (CAD); therefore, aggressive preventive measures should be implemented early in its course.4,5
Despite the obviously increased risk, however, not all diabetic patients have an untoward cardiovascular event, and there is wide heterogeneity among these patients. Hence, risk stratification might be of some use, even in this high-risk cohort. The prevalence and extent of coronary artery calcium are increased in diabetic patients, although not ubiquitously for all patients.6-8 One might wonder if this objective measure of coronary atherosclerosis could be useful in identifying patients at higher risk as well as those at lower risk for cardiovascular events.
In a recent analysis, we addressed this question by assessing all-cause mortality
in a large population of CAD-naive individuals with risk factors for atherosclerosis. Nearly 1 in 10 of the subjects studied had diabetes mellitus, and the majority (85%) had type 2 diabetes. The dual aim of the study was to assess the value of coronary artery calcium to predict all-cause mortality in diabetic patients and to compare the cardiovascular risk of coronary artery calcium in diabetic and nondiabetic individuals.
Patients and methods
Asymptomatic patients (n = 10,377) who had undergone EBCT imaging from 1996 to 2000 for the detection of coronary artery calcium were retrospectively identified from a large database. Patients were included in this study if they carried at least one risk factor for cardiovascular disease, such as diabetes mellitus, family history of premature CAD, smoking, hyperlipidemia, or hypertension. They were excluded if they had a history of CAD. Nine hundred three patients had diabetes, defined as a previous diagnosis of diabetes mellitus by a physician or current treatment with insulin or oral hypoglycemic drugs, or both. For each patient, a Framingham risk score was computed.
All participants underwent EBCT with an Imatron C-100 or a C-150 scanner (GE-Imatron, South San Francisco, CA), with rapid acquisition (100 milliseconds) of 30 to 40 contiguous slices, from the carina to the diaphragm. Each tomographic section was 3 mm thick. The scans were electrocardiographically triggered at 60% to 80% of the R-R interval. The presence of a calcified area with a density of 130 Hounsfield units (voxel size, 1.03 mm3) along the length of the
coronary arteries was used as the definition of coronary artery calcification, and a calcium score was calculated according to the method of Agatston and colleagues.9-11
Information on mortality in this cohort was derived from the Nation-
al Death Registry employing the blinded Social Security number of the in-
dividuals studied. Cox proportional hazards models, with and without adjustment for cardiovascular risk factors, were developed to predict all-cause mortality.
The mean follow-up period was 5 ± 3.5 years (range, 2—5 years). Diabetic patients were older and had a higher prevalence of hypertension and smoking (P < .001) than nondiabetic subjects. The mean coronary calcium score (CS) was 281 ± 567 in diabetic patients and 119 ± 341 in nondiabetic subjects (P = .001).
During follow-up, all-cause mortality was higher (c2 = 43; P < .001) in diabetic than in nondiabetic individuals (Figure 1). Mortality rates were higher in diabetic patients with other co-
morbidities (older age, smoking, and hypertension).
Survival was lower with any level of CS (from mild to extensive) in patients with diabetes mellitus than in nondiabetic subjects—with a strong association between diabetes and CS—and was lowest in subjects with a CS above 400 on the screening EBCT scan. Notably, however, the cumulative survival in the absence of coronary artery calcium (CS = 0) was equal and very high (~99% at 5 years) in both groups (Figure 2).
Framingham risk equations were used to estimate the risk of death in the study population. When the CS was added to the Framingham risk score in nondiabetic subjects, the estimation
of risk increased (C-index increase) from 0.61 to 0.70 (P < .001). A similar effect was noted in the diabetic patients (C-index increase from 0.50 to 0.72;
P < .001).
Diabetic patients have greater coronary artery calcium than nondiabetic patients, even when there is no difference in their cardiovascular risk profiles.4,5 Our study showed a strong relationship among extent of coronary artery calcium, diabetes, and all-cause mortality. These findings are in line with those reported in previous investigations conducted with other non-invasive imaging methods, such as nuclear myocardial perfusion imaging and stress echocardiography.12-14 Those studies emphasized that diabetic patients are at higher risk for cardiac events compared with nondiabetic individuals. This suggests that the atherosclerotic burden of diabetic patients is particularly unstable, rendering the individual exquisitely prone to untoward events.
Our study also showed that both diabetic and nondiabetic individuals have an equally low 5-year mortality rate in the absence of coronary artery calcium. Nondetectable coronary artery calcium, that is, absent or minimal atherosclerotic burden, is therefore a good prognostic indicator in the midterm follow-up period, which constitutes an innovative finding and underscores the power of atherosclerosis imaging for the assessment of risk, even in apparently high-risk populations. Imaging of atherosclerotic plaque burden is currently viewed as an excellent screening tool, mostly for intermediate-risk subjects,6 where finding unknown arterial wall disease may help refine risk assessment in the individual patient. There appears to be a role for screening, however, even in high-risk individuals.
The obvious limitation to this study was the lack of data on cardiovascular outcome because the only end point considered was all-cause mortality. Although all-cause mortality does not have the potential diagnostic and interpretative biases seen with other outcome end points, it is limited in its ability to assess the full impact of diabetes mellitus on the cardiovascular system.
The pathophysiology of coronary artery calcification is not completely understood, although the basic process appears to be very similar to bone formation. Experimental studies on cultured rat aortic smooth muscle cells showed that hyperglycemia stimulates the expression of osteopontin, a soluble bone-related protein that plays a key role in vascular remodeling and atherogenesis. Osteopontin is also capable of activating a proatherogenic and prothrombotic cascade through induction of expression of platelet-derived growth factor.15
Vascular calcifications in diabet-
ic patients are localized both in the
intima and the medial layer. Although the intimal calcifications are typical-
ly correlated with the presence of atherosclerotic plaque and its consequences, medial calcification is responsible for reduced arterial elasticity and myocardial compliance, with an attendant high risk of cardiovascular events.16
Because cardiovascular disease in diabetes is highly prevalent, and it is associated with an adverse outcome, an early and accurate diagnosis may ensure a more benign outcome in patients affected by this disease, which is often silent in its course.17 Screen-
ing for cardiovascular disease may afford an opportunity for early and aggressive preventive treatment, a key step in the management of cardiovascular event reduction. Additionally, the identification of a subset of patients
at lower risk is also possible with imaging techniques that quantify the burden of disease.