Interleukin-6 in Patients With Heart Failure and Preserved Ejection Fraction

Abstract

Background: Interleukin (IL)-6 is a central inflammatory mediator and potential therapeutic target in heart failure (HF). Prior studies have shown that IL-6 concentrations are elevated in patients with HF, but much fewer data are available in heart failure with preserved ejection fraction (HFpEF).

Objectives: This study aims to determine how IL-6 relates to changes in cardiac function, congestion, body composition, and exercise tolerance in HFpEF.

Methods: Clinical, laboratory, body composition, exercise capacity, physiologic and health status data across 4 National Heart, Lung, and Blood Institute-sponsored trials were analyzed according to the tertiles of IL-6.

Results: IL-6 was measured in 374 patients with HFpEF. Patients with highest IL-6 levels had greater body mass index; higher N-terminal pro-B-type natriuretic peptide, C-reactive protein, and tumor necrosis factor-α levels; worse renal function; and lower hemoglobin levels, and were more likely to have diabetes. Although cardiac structure and function measured at rest were similar, patients with HFpEF and highest IL-6 concentrations had more severely impaired peak oxygen consumption (12.3 ± 3.3 mL/kg/min 13.1 ± 3.1 mL/kg/min 14.4 ± 3.9 mL/kg/min, P < 0.0001) as well as 6-minute walk distance (276 ± 107 m vs 332 ± 106 m vs 352 ± 116 m, P < 0.0001), even after accounting for increases in IL-6 related to excess body mass. IL-6 concentrations were associated with increases in total body fat and trunk fat, more severe symptoms during submaximal exercise, and poorer patient-reported health status.

Conclusions: IL-6 levels are commonly elevated in HFpEF, and are associated with greater symptom severity, poorer exercise capacity, and more upper body fat accumulation. These findings support testing the hypothesis that therapies that inhibit IL-6 in patients with HFpEF may improve clinical status. (Clinical Trial Registrations: Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure [RELAX], NCT00763867; Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction, NCT02053493; Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF, NCT02742129; Inorganic Nitrite to Enhance Benefits From Exercise Training in Heart Failure With Preserved Ejection Fraction [HFpEF], NCT02713126).

Keywords: fat mass; heart failure with preserved ejection fraction; inflammation; interleukin-6; obesity.

FIGURE 1. Comparison of Exercise Capacity by IL-6 Level

As compared with patients with HFpEF and lower IL-6 levels, those with higher IL-6 levels displayed more severe impairments in exercise capacity, reflected both by lower 6MWD and peak VO₂. Data from all 4 included trials, n = 374. 6MWD = 6-minute walk distance; HFpEF = heart failure with preserved ejection fraction; IL = interleukin; VO₂ = oxygen consumption.

FIGURE 2. Comparison of Exercise Capacity and NT-proBNP by IL-6 Level Adjusted for BMI

(A) Linear regression analysis investigating the association between IL-6 levels and BMI. The tertiles of IL-6 relative to BMI-predicted values are represented in green (Tertile 1), orange (Tertile 2), and magenta (Tertile 3). (B) As compared with patients with IL-6 relative to predicted BMI in the lowest tertile, those in the highest tertile had lower peak VO₂ and 6MWD, along with higher NT-proBNP. Data from all 4 included trials, n = 374. BMI = body mass index; NT-proBNP = N-terminal pro–B-type natriuretic peptide; other abbreviation as in Figure 1.

FIGURE 3. Comparison of Symptom Severity and Physical Limitations by IL-6 Level

As compared with patients with lower IL-6, patients with higher IL-6 levels displayed more severe symptoms of fatigue and dyspnea walking during the 2–2–5 treadmill walk test (A, B), and relative to exercise level during the maximal-effort upright cycling cardiopulmonary exercise test (C, D), along with poorer physical limitation scores from the SF-35 and KCCQ-Clinical Summary (CS) scores (E, F). Error bars not included to maximize clarity for C and D; SDs are provided in Table 2 for all distributions. Data from the INABLE trial, n = 52. CS = Clinical Summary; KCCQ = Kansas City Cardiomyopathy Questionnaire; 2–2–5 treadmill walk test = walking test at a gait speed of 2 miles per hour at a 2% grade for 5 minutes; other abbreviations as in Figures 1 and 2.

FIGURE 4. Body Composition, Adiposity, and IL-6

(A) DXA scans from patients with low (left) and high (right) IL-6 levels. (B) Fat mass index and its regional distribution in IL-6 tertiles. Patients with higher IL-6 levels had significantly greater total body fat mass index (kg/m²) compared with lower IL-6 patients. Differences in fat (kg/m²) were also observed within measurements of android/trunk, and lower limb regions between higher and lower IL-6 groups. Data from the INABLE trial, n = 52. DXA = dual-energy x-ray absorptiometry; other abbreviation as in Figure 1.

CENTRAL ILLUSTRATION. IL-6 Levels and Associated Clinical Characteristics in HFpEF

6MWD = 6-minute walk distance; BMI = body mass index; CRP = C-reactive protein; HFpEF = heart failure with preserved ejection fraction; IL = interleukin; NIH = National Institutes of Health; NT-proBNP = N-terminal pro-B-type natriuretic peptide; TNF = tumor necrosis factor; VO₂ = oxygen consumption.