Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population

Abstract

Background The cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community‐dwelling individuals whether a higher plasma interleukin 6 (IL‐6) level is associated with an increased risk of developing new‐onset heart failure (HF) over time, and specifically HFpEF. Methods and Results We performed a case‐cohort study based on the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study, a prospective general population‐based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of ≤40% or >40%, respectively. In Cox proportional hazard regression analyses, IL‐6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02–1.61; P =0.03) after adjustment for key risk factors. Specifically, IL‐6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16–2.19; P =0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75–1.47; P =0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction ≥50%, IL‐6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04–2.06; P =0.03) after adjustment for key risk factors. Conclusions IL‐6 is associated with new‐onset HFpEF in community‐dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL‐6 might be a novel treatment target to prevent HFpEF.

Genetically Determined Inflammatory Biomarkers and the Risk of Heart Failure: A Mendelian Randomization Study

“…The “upstream” proinflammatory biomarkers IL-1 and IL-6 act as important initiators of inflammation and can trigger a cascade of inflammatory mediators, such as CRP and fibrinogen ( 44 ). Although evidence from preclinical and clinical studies suggested that the IL-1-IL-6 signaling pathway led to impaired systolic and diastolic cardiac function ( 45 ), clinical trials choosing these pathways as anti-inflammatory therapeutic targets have reported controversial results. Administration of anakinra, an IL-1 receptor antagonist, yielded beneficial effects on aerobic capacity improvement but did not reduce the length of hospital stay or rehospitalization in HF ( 14 , 46 ).…”

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

“…Recently, novel evidence emerged strengthening the inflammatory paradigm and reinforcing research for anti-cytokine biological therapy in HFpEF (Paulus and Zile, 2021). For example, higher IL-6 levels were demonstrated to be associated with an increased risk of developing HFpEF (Chia et al, 2021) and circulating levels of TNF-α receptor 2 were shown to be increased in association with the degree of diastolic dysfunction in patients with HFpEF but not HFrEF (Putko et al, 2014). Also, (anti-inflammatory) high density lipoprotein cholesterol/(inflammatory) CRP ratio was shown to be a useful marker for prognostication and correlated with echocardiographic parameters in HFpEF patients (Yano et al, 2021).…”

Inflammation in Metabolic Cardiomyopathy

“…High hsCRP, TNF-α, and TGF-β levels increase the susceptibility to cardiac damage in hypertensive patients with the metabolic syndrome, in whom they are independently related to the LV mass index and diastolic LV dysfunction ( 65 ). In accordance, elevated TNF-α and IL-6 independently predict incident HFpEF, the predominant type of HF in obesity and diabetes, but not HF with reduced ejection fraction (HFrEF) ( 266 , 267 ). Subjects with obesity or diabetes account for the majority of the HFpEF patient population in which pathophysiological pathway analyses demonstrated a close link to vascular cell adhesion, leucocyte migration and inflammation ( 268 ).…”