IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

BACKGROUND: Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-l blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. METHODS AND RESULTS: Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo2), ventilatory efficiency (VE/Vco2 slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo2 or VE/Vco2 slope between groups at baseline. Peak Vo2 was not changed after 12 weeks of anakinra (from 13.6 [11.8–18.0] to 14.2 [11.2–18.5] mL-kg−1-min−1, P=0.89), or placebo (14.9 [11.7–17.2] to 15.0 [13.8–16.9] mL-kg−1-min−1, P=0.40), without significant between-group differences in changes at 12 weeks (−0.4 [95% CI, −2.2 to +1.4], P=0.64). VE/Vco2 slope was also unchanged with anakinra (from 28.3 [27.2–33.0] to 30.5 [26.3–32.8], P=0.97) or placebo (from 31.6 [27.3–36.9] to 31.2 [27.8–33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, −1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline (P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). CONCLUSIONS: Treatment with anakinra for 12 weeks failed to improve peak Vo2 and VE/Vco2 slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: .

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

“…It is indeed noteworthy that although canagliflozin patients tended to have lower RER at follow‐up this did not negatively affect the peak VO 2 , as it is was not reduced from baseline. It is possible that in this cohort of HFrEF patients with obesity and deconditioning, a treatment that improves cardiac function may fall short in improving peak VO 2 due to supervening secondary limitation to maximal aerobic capacity 25 …”

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

“…In two small clinical studies in HFrEF patients, anakinra treatment improved indicators of systolic function [80]. In a small group of patients with HFpEF and elevated hsCRP, treatment with anakinra reduced NT-proBNP, but failed to improve indicators of cardiorespiratory fitness [81]. Moreover, in patients with rheumatoid arthritis, treatment with anakinra improved indicators of left ventricular and vascular function [76,82].…”

The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

“…Anakinra blunted the acute inflammatory response associated with ST‐segment elevation and acute MI and numerically lowered the incidence of HF . In HFPEF, anakinra treatment for 14 days significantly reduced the systemic inflammatory response and improved the aerobic exercise capacity of patients with HFPEF and elevated plasma CRP levels, whereas treatment with anakinra for 12 weeks in a group of obese patients with HFPEF failed to improve peak Vo 2 . This emphasizes the importance of the duration of treatment and the patient cohort when considering treatment therapies and their efficacy.…”