Exercise-induced changes in left ventricular strain are affected by interleukin-6 activity: An exploratory analysis of a randomised-controlled trial in humans with abdominal obesity.

Whilst the exercise-induced myokine interleukin-6 (IL-6) plays a beneficial role in cardiac structural adaptations, its influence on exercise-induced functional cardiac outcomes remains unknown. We hypothesised that IL-6 activity is required for exercise-induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12 weeks' high-intensity exercise or no exercise in combination with IL-6 receptor inhibition (IL-6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by -5.4% [95% CI: -9.1% to -1.6%] (P = 0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (-4.8% [95% CI: -7.4% to -2.2%]; P < 0.0004) to the exercise + IL-6i group (-1.1% [95% CI: -3.8% to 1.6%]; P = 0.42), the exercise + placebo group changed -3.7% [95% CI: -7.4% to -0.02%] (P = 0.049) more than the exercise + IL6i group. However, the interaction effect between exercise and IL-6i was insignificant (4.5% [95% CI: -0.8% to 9.9%]; P = 0.09). Similarly, the exercise + placebo group improved LV global circumferential strain by -3.1% [95% CI: -6.0% to -0.1%] (P = 0.04) more compared to the exercise + IL-6i group, yet we found an insignificant interaction between exercise and IL-6i (4.2% [95% CI: -1.8% to 10.3%]; P = 0.16). There was no effect of IL-6i on exercise-induced changes to volume rates. This study underscores the importance of IL-6 in improving LV GLS in individuals with abdominal obesity suggesting a role for IL-6 in cardiac functional exercise adaptations.

Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial.

INTRODUCTION: The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. METHODS AND ANALYSIS: 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals. TRIAL REGISTRATION NUMBERS: Eudra-CT: 2021-b005287-21 and NCT05215509.