Interleukin-18 Is a Strong Predictor of Cardiovascular Events in Elderly Men With the Metabolic Syndrome

Abstract

OBJECTIVE -The aim of this study was to investigate the role of inflammatory markers as potential predictors of cardiovascular events in subjects with and without the metabolic syndrome.RESEARCH DESIGN AND METHODS -This was a post hoc analysis from the Diet and Omega-3 Intervention Trial (DOIT), comprising 563 elderly men with (n ϭ 221) and without (n ϭ 342) metabolic syndrome. Circulating inflammatory markers were measured.RESULTS -During 3 years, 68 cardiovascular events were recorded. In the total population, C-reactive protein (CRP) (P Ͻ 0.001), interleukin-18 (IL-18) (P ϭ 0.008), and IL-6 (P ϭ 0.003) were elevated in subjects with events. In subjects with metabolic syndrome, IL-18 was the strongest predictor (adjusted odds ratio 2.9 [95% CI 1.1-7.8]). In subjects without metabolic syndrome, only CRP seemed to be an independent predictor (3.3 [1.5-7.3]). There was a significant interaction between fasting glucose and IL-18 (P ϭ 0.008) and IL-6 (P ϭ 0.024) but not CRP. Elevated fasting glucose (Ͼ6.2 mmol/l) markedly increased the predictive power of inflammatory markers (IL-18: 5.5 [1.4 -21.1], IL-6: 3.5 [1.0 -11.8], and CRP: 3.5 [1.0 -11.9]). For IL-18, there was a stepwise increase in event rate by quartiles of fasting glucose.CONCLUSIONS -IL-18 was an independent predictor of cardiovascular events in subjects with metabolic syndrome and even more so in the presence of elevated fasting glucose. Our findings suggest a mutually potentiating effect of hyperglycemia and inflammation in cardiovascular risk prediction. Diabetes Care 32:486-492, 2009

Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4

“…Overall, these results illustrate that increased circulating concentrations of proand anti-inflammatory cytokines are generally affected by BMI and other potential confounders. This observation did not hold true for IL-10, which was detected in 44% of individuals only, similar to the findings in previous studies [42][43][44][45]. Differences in cytokine concentrations between those with type 2 diabetes and those with both autoimmune diabetes types are not solely explained and influenced by these potential confounders, suggesting a diabetes-type associated immune dysregulation.…”

Adipose tissue expression of interleukin-18 mRNA is elevated in subjects with metabolic syndrome and independently associated with fasting glucose

“…Whereas IL-6 and PAI-1 are thought to at least be partially derived from adipose tissue, not much is known on the source of IL-18 [12]. It has previously been suggested that non-fat cells are the main source of IL-18 in adipose tissue, whereas a recent study found an enhancing eff ect of intermittent high glucose on IL-18 expression in cultured adipocytes [5,13]. However, the exact cellular source remains unknown.…”

“…A pro-infl ammatory eff ect of altered glucose metabolism is discussed [5]. Most clinical studies have focused on hyperinsulinaemia and insulin resistance, whereas most pre-clinical studies have investigated direct eff ects of insulin and advanced glycosylated endproducts (AGE) [14][15][16].…”

“…Th erefore, it has been suggested that infl ammation could be a possible pathogenetic link between CVD and MetS [3]. Amongst others, plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6) have been shown to be independently associated with CVD and interleukin-18 (IL- 18) has recently been shown to predict cardiovascular events in subjects with MetS [4,5]. Furthermore, IL-18 expression in adipose tissue is elevated in obese subjects [6].…”

Interleukin-12 Is Associated With Arterial Stiffness in Healthy Individuals

“…2,3 Elevated serum levels of IL-12 and IL-18 have also been observed in several human disease states including metabolic syndrome, obesity, type 2 diabetes, hypertension, and systemic lupus erythematosus (SLE). [4][5][6][7] Noninvasive measurements of arterial stiffness, including aortic pulse wave velocity (PWV) and augmentation index (AIx), are established surrogate markers of CVD-associated and all-cause mortality in the general population, and may have utility in CVD-risk stratification. 8 IL-18 is independently associated with CVD-related outcomes and also PWV in prospective and cross-sectional studies limited to individuals with CVD risk factors.…”