Association of interleukin-6 and interleukin-18 with cardiovascular disease in older adults: Atherosclerosis Risk in Communities study

Abstract

Aims: Interleukin-6 (IL-6) and interleukin-18 (IL-18), important cytokines implicated in atherosclerosis and inflammaging, were assessed for associations with global cardiovascular disease (CVD), atrial fibrillation (AF), and death in older adults.

Methods and results: Participants from Atherosclerosis Risk in Communities study Visit 5 (mean age 75.4 ± 5.1 years) with IL-6 and IL-18 measurements were included (n = 5672). Cox regression models were used to assess associations of IL-6 and IL-18 with coronary heart disease (CHD), ischaemic stroke, heart failure (HF) hospitalization, global CVD (composite of CHD, stroke, and HF), AF, and all-cause death. Over a median follow-up of 7.2 years, there were 1235 global CVD events, 530 AF events, and 1173 deaths. Higher IL-6 [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.44-1.72 per log unit increase] and IL-18 (HR 1.13, 95% CI 1.01-1.26) were significantly associated with global CVD after adjustment for cardiovascular risk factors. Association between IL-6 and global CVD remained significant after further adjustment for high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT) but was no longer significant for IL-18 after further adjustments. Interleukin-6 was also associated with increased risk for CHD, HF, and AF after adjustment for covariates. Both IL-6 and IL-18 were associated with increased risk for all-cause death independent of cardiovascular risk factors and other biomarkers.

Conclusion: Among older adults, both IL-6 and IL-18 were associated with global CVD and death. The association between IL-6 with CVD appears to be more robust and was independent of hs-CRP, NT-proBNP, and hs-TnT.

Keywords: Ageing; Cardiovascular disease; Inflammation; Interleukin-18; Interleukin-6.

Graphical Abstract

Among older adults in the Atherosclerosis Risk in Communities study, both interleukin-6 and interleukin-18 were associated with global cardiovascular disease (coronary heart disease, ischaemic stroke, and heart failure hospitalization) and death. The association of interleukin-18 with cardiovascular disease appears to be mediated by interleukin-6. Abbreviations: AF, atrial fibrillation; ARIC, Atherosclerosis Risk in Communities; CHD, coronary heart disease; CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; IL-6, interleukin-6; IL-18, interleukin-18.

Figure 1

Association of interleukin-6 and interleukin-18 with risk for global cardiovascular disease, atrial fibrillation, and total death in older adults. Cox regression analysis adjusted for age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive medication use, diabetes, current smoking, lipid-lowering medication use, prevalent global cardiovascular disease, body mass index, and estimated glomerular filtration rate. Abbreviations: AF, atrial fibrillation; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; HF, heart failure; IL-6, interleukin-6; IL-18, interleukin-18.

Figure 2

Associations of (A) tertiles of interleukin-6 and (B) tertiles of interleukin-18 with incident cardiovascular outcome events after Visit 5. Cox regression analysis adjusted for age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive medication use, diabetes, current smoking, lipid-lowering medication use, prevalent global cardiovascular disease, body mass index, and estimated glomerular filtration rate. Abbreviations: AF, atrial fibrillation; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HF, heart failure; IL-6, interleukin-6; IL-18, interleukin-18.