Relationship between interleukin-6, coronary artery calcium and risk of heart failure: Insights from MESA

This study investigated the joint association of interleukin-6 (IL-6) and coronary artery calcium (CAC) with the risk of heart failure (HF).

Among 6592 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), individuals were categorized into four groups based on CAC (0 vs >0) and IL-6 (cutoff 1.32 pg/mL via Youden's index): low CAC/low IL-6 (reference), low CAC/high IL-6, high CAC/low IL-6, and high CAC/high IL-6. Multivariable Cox models were used to assess the risk of total heart failure (HF), HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF). Compared to the reference group, the hazard ratios (HRs) for total HF were 1.61 (95 % CI, 1.12-2.31) for high IL-6, 1.56 (95 % CI, 1.11-2.20) for high CAC, and 2.00 (95 % CI, 1.43-2.80) when both were elevated (multiplicative interaction p = 0.28). For HFrEF, the risk was significantly higher only when both markers were elevated: HR 2.34 (95 % CI, 1.44-3.81), compared to isolated CAC (1.11; 95 % CI, 0.65-1.87) or IL-6 (1.07; 95 % CI, 0.59-1.95) (multiplicative and additive interaction p = 0.05 and 0.008, respectively). Conversely, for HFpEF, the combined elevation of IL-6 and CAC was associated with a lower risk than either marker alone: HRs 2.13, 2.31, and 2.21, respectively (antagonistic multiplicative interaction, p = 0.02).

Combined elevation of IL-6 and CAC was associated with increased HFrEF risk, with significant additive and multiplicative interactions. For HFpEF, combined elevation conferred less risk than either alone. Inflammation modifies the CAC-HFrEF relationship and merits further study.