Interleukin-18 and the risk of future cardiovascular disease among initially healthy women

Abstract

Objective: Elevated levels of interleukin (IL)-18 have been implicated in the development of atherosclerosis in animals. Data in humans are less clear, and data in women are particularly scarce.

Methods and results: In a prospective nested case-control study of initially healthy women, we measured baseline plasma IL-18 levels in 253 participants who subsequently developed cardiovascular disease (CVD) and in 253 healthy age- and smoking-matched controls. IL-18 levels were higher at baseline among those who developed CVD (274.1pg/mL versus 233.8pg/mL, P<0.001), and were associated with future CVD (relative risk (RR) for highest versus lowest quartile 2.53; 95% CI, 1.47-4.35, P<0.001). While that risk was attenuated after adjustment for traditional cardiovascular risk factors (RR 1.60; 95% CI, 0.77-3.34, P=0.13), those with IL-18 levels at or above a threshold of the 90th percentile (442pg/mL) remained at elevated risk after adjustment (RR 2.40; 95% CI, 1.05-5.56, P=0.04). Levels of IL-18 above this threshold modify the fully adjusted risk of future CVD conferred by elevated levels of total cholesterol (P(interaction)=0.02).

Conclusions: In this population of apparently healthy women, IL-18 levels associate with increased risk of cardiovascular disease, but that risk is attenuated in models adjusting for traditional cardiovascular risk factors. Very high levels of IL-18 interact with hypercholesterolemia to alter CVD risk.

Trial registration: ClinicalTrials.gov NCT00000479.

Figures

Figure 1

Natural logarithm normalized concentrations of interleukin (IL)-18 in picograms per milliliter (pg/mL) for 253 cases and age- and smoking-status matched controls.

Figure 2

Fully adjusted relative risk of future cardiovascular disease in initially healthy women according to baseline levels of interleukin (IL)-18 and either (a) total cholesterol or (b) high-sensitivity C-reactive protein (hsCRP). High levels of IL-18 were defined as those falling above the 90th percentile in control subjects (442 pg/mL), while high levels of total cholesterol and hsCRP were those falling above the median in the control population (5.52 mmol/L and 2.3 mg/L, respectively). Formal tests of interaction between total cholesterol and IL-18 were significant in age and smoking adjusted models (Pinteraction =0.02) and in models adjusted for age, current smoking, diabetes (yes/no), blood pressure (Framingham categories), body mass index (kg/m2), parental history of myocardial infarction before the age of 60, hormone therapy, high-density lipoprotein cholesterol (mg/dL), and randomized treatment assignment (Pinteraction =0.024). Formal tests of interaction between hsCRP and IL-18 were significant in age and smoking adjusted models (Pinteraction=0.01), but fell short of statistical significance (Pinteraction =0.125) in models adjusted for age, smoking, diabetes, blood pressure, body mass index, parental history of myocardial infarction before the age of 60, hormone therapy, total cholesterol, high-density lipoprotein cholesterol and treatment assignment.