Arterial stiffness is increased in patients with type 1 diabetes without cardiovascular disease: a potential role of low-grade inflammation

OBJECTIVE

To investigate the relationship between arterial stiffness and low-grade inflammation in subjects with type 1 diabetes without clinical cardiovascular disease.

RESEARCH DESIGN AND METHODS

Sixty-eight patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated. Arterial stiffness was assessed by aortic pulse wave velocity (aPWV). Serum concentrations of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and soluble fractions of tumor necrosis factor-α receptors 1 and 2 (sTNFαR1 and sTNFαR2, respectively) were measured. All statistical analyses were stratified by sex.

RESULTS

Subjects with diabetes had a higher aPWV compared with healthy control subjects (men: 6.9 vs. 6.3 m/s, P < 0.001; women: 6.4 vs. 6.0 m/s, P = 0.023). These differences remained significant after adjusting for cardiovascular risk factors. Men with diabetes had higher concentrations of hsCRP (1.2 vs. 0.6 mg/L; P = 0.036), IL-6 (0.6 vs. 0.3 pg/mL; P = 0.002), sTNFαR1 (2,739 vs. 1,410 pg/mL; P < 0.001), and sTNFαR2 (2,774 vs. 2,060 pg/mL; P < 0.001). Women with diabetes only had higher concentrations of IL-6 (0.6 vs. 0.4 pg/mL; P = 0.039). In men with diabetes, aPWV correlated positively with hsCRP (r = 0.389; P = 0.031) and IL-6 (r = 0.447; P = 0.008), whereas in women with diabetes no significant correlation was found. In men, multiple linear regression analysis showed that the following variables were associated independently with aPWV: age, BMI, type 1 diabetes, and low-grade inflammation (R² = 0.543). In women, these variables were age, BMI, mean arterial pressure, and type 1 diabetes (R² = 0.550).

CONCLUSIONS

Arterial stiffness assessed as aPWV is increased in patients with type 1 diabetes without clinical cardiovascular disease, independently of classical cardiovascular risk factors. In men with type 1 diabetes, low-grade inflammation is independently associated with arterial stiffness.It is well established that type 2 diabetes is a risk factor for cardiovascular disease. However, it is less well known that the relative risk of cardiovascular disease in type 1 diabetes can be as much as 10-fold greater than in the healthy population, especially in women (1), being even greater than in type 2 diabetes (2). Consequently, cardiovascular disease is the major cause of mortality in type 1 diabetes (2). Diabetes results in an accelerated arteriosclerotic process, which is not fully explained by classical cardiovascular risk factors. As a result, the pathophysiological mechanisms underlying cardiovascular events in type 1 diabetes are not completely understood.Arterial stiffness is an early sign of arteriosclerosis (3), and its study would be appropriate for investigating the arteriosclerotic mechanisms long before any cardiovascular event occurs. Arterial stiffness predicts cardiovascular events independently of classical cardiovascular risk factors in several populations (see below). Therefore, it can be assumed that it reflects the deleterious effect of all cardiovascular risk factors (known and unknown) on the arterial wall. The gold standard for measuring central arterial stiffness is aortic pulse wave velocity (aPWV), according to a recent consensus (4). aPWV independently predicts cardiovascular events and mortality in the general population, in the elderly, in hypertensive individuals, in subjects with end-stage renal failure, and in subjects with type 2 diabetes (5).Finally, little is known regarding factors involved in the pathophysiology of arterial stiffness in type 1 diabetes. One of these factors could be low-grade inflammation. High-sensitivity C-reactive protein (hsCRP) is the most established downstream marker of low-grade inflammation and has been reported to be a strong predictor of cardiovascular outcomes (6). The primary proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α are the main inducers for the hepatic synthesis of hsCRP (7). Although there is less evidence in comparison with hsCRP, both of them also have been associated with the prediction of cardiovascular outcomes (8–10). Low-grade inflammation also has been associated with the development of both micro- and macrovascular complications in type 1 diabetes (11). Indeed, low-grade inflammation impairs endothelial function and has been associated with an increase in aPWV in healthy subjects (12), in hypertensive individuals (13), and in subjects with chronic kidney disease (14) or with metabolic syndrome (15). No such evidence exists in type 1 diabetes; however, recently an activation of the TNFα system has been reported in association with an increase in brachial PP, a subrogate marker of arterial stiffness, in normotensive subjects with type 1 diabetes (16).Our main objective was to evaluate aPWV as a measure of arterial stiffness in a group of subjects with type 1 diabetes without clinical cardiovascular disease and to explore its relationship with biomarkers of low-grade inflammation. Because the role of low-grade inflammation in the atherosclerotic process seems to be different in men and women (17), our study was stratified by sex, and the sample size was calculated taking this stratification into account.