Postischemic Microcirculatory Blood Flow Correlates Negatively and Independently With Plasma C-Reactive Protein in Longstanding Type 1 Diabetes Free

Moderately increased plasma C-reactive protein (CRP), an acute phase protein produced by the liver and an exquisitely sensitive marker of inflammation, is associated with an increased risk of cardiovascular disease (1). It is not known how systemic inflammation leads to atherosclerosis, but experimental (2) and clinical (3) studies have suggested that it may do so by causing endothelial dysfunction, a process central to the development of atherosclerosis.

Reactive hyperemia (RH) is an endothelium-dependent, physiological, and probably protective response to tissue ischemia that is reduced in patients with atherosclerosis or risk factors for atherosclerosis. The forearm vascular bed, which is readily accessible and rarely affected by atheromatous change, is a useful site to study RH using noninvasive techniques. A close relationship has been shown between coronary endothelial function and RH in the human forearm (4).

To further investigate the relationship between inflammation and endothelial dysfunction, we have studied RH and circulating CRP in 50 subjects (28 men), all of whom had type 1 diabetes for at least 25 years. Urinary albumin/creatinine ratio (ACR), total and HDL cholesterol, and HbA_1c were all measured as previously described (5). CRP was measured by enzyme-linked immunosorbent assay (ELISA) (within-assay coefficient of variation 8%). Forearm RH was measured using the method of Tagawa et al. (6).

The patients had a mean age of 47 ± 2 years and a mean BMI of 27 ± 1 kg/m². Mean total and HDL cholesterol were 5.5 ± 0.2 and 1.4 ± 0.1 mmol/l, respectively. Mean systolic and diastolic blood pressure were 136 ± 3 and 75 ± 2 mmHg, respectively. Eight patients had microalbuminuria (ACR >3 mg/mmol), and three had established nephropathy (urinary albumin excretion rate >300 mg/24 h).

Mean baseline forearm bloodflow (FBF) was 2.8 ± 0.2 ml · 100 ml⁻¹ · min⁻¹ and did not correlate with any measured variable. Mean peak FBF was 7.6 ± 0.5 ml · 100 ml⁻¹ · min⁻¹. Peak FBF was higher in men and correlated negatively with BMI (r = −0.31, P < 0.05) and log CRP (r = −0.38, P < 0.02). To determine whether the relationship between CRP and RH was independent of other variables, stepwise linear regression analysis was performed. Possible predictor variables were entered into the model if a significant bivariate relationship was observed between the measure of RH and the predictor variable. This analysis revealed CRP to be the only independent predictor of peak bloodflow (β = −0.135, P < 0.02). The findings were not altered when patients with microalbuminuria or nephropathy were excluded from analysis.

Although the cross-sectional nature of this study does not permit a cause-effect relationship to be determined, the negative relationship between RH and CRP is consistent with the hypothesis that inflammation contributes to endothelial dysfunction in diabetic patients. Schalwijk et al. (7) recently studied CRP in a similar population of long-standing type 1 diabetic subjects and demonstrated increased CRP as compared with a well-matched control population. By assessing the glycation pattern of α-1-acid glycoprotein, they demonstrated that this effect represented a chronic rather than acute hepatic inflammatory response. Furthermore, in concordance with our findings, they also demonstrated an inverse relationship between CRP and plasma markers of endothelial function.

These observations have potentially important therapeutic implications. Data from the Cholesterol and Recurrent Events (CARE) study have demonstrated that hydroxymethylglutaryl (HMG) CoA reductase inhibitors reduce CRP independently of their effects on plasma lipids (8). It is conceivable that these or other agents, which reduce CRP, might improve endothelial function and reduce development of vascular disease in diabetes.

In summary, CRP correlates negatively and independently with forearm RH in patients with longstanding type 1 diabetes. Prospective studies are warranted to determine whether inflammation precedes endothelial dysfunction and whether therapeutic strategies that reduce inflammation would also reduce development of vascular disease in diabetes.