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IntroductionEvidence indicates that sphingolipid accumulation drives complex molecular alterations promoting cardiometabolic diseases. Clinically, it was shown that sphingolipids predict cardiometabolic risk independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, little is known about therapeutic modalities to lower sphingolipid levels. Exercise, a powerful means to prevent and treat cardiometabolic diseases, is a promising modality to mitigate sphingolipid levels in a cost-effective, safe, and patient-empowering manner.MethodsThis randomised controlled trial will explore whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n = 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An 'omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to assess patient fitness changes. Cholesterol, triglycerides, glycated haemoglobin, the homeostatic model assessment for insulin resistance, static retinal vessel analysis, flow-mediated dilatation, and strain analysis of the heart cavities will also be assessed pre- and post-intervention. This study shall inform whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels.Trial registrationThe trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.

ObjectiveThis study compared the robustness of a [Formula: see text]-plateau definition and a verification-phase protocol to day-to-day and diurnal variations in determining the true [Formula: see text]. Further, the additional value of a verification-phase was investigated.MethodsEighteen adults performed six cardiorespiratory fitness tests at six different times of the day (diurnal variation) as well as a seventh test at the same time the sixth test took place (day-to-day variation). A verification-phase was performed immediately after each test, with a stepwise increase in intensity to 50%, 70%, and 105% of the peak power output.ResultsParticipants mean [Formula: see text] was 56 ± 8 mL/kg/min. Gwet's AC1 values (95% confidence intervals) for the day-to-day and diurnal variations were 0.64 (0.22, 1.00) and 0.71 (0.42, 0.99) for [Formula: see text]-plateau and for the verification-phase 0.69 (0.31, 1.00) and 0.07 (-0.38, 0.52), respectively. In 66% of the tests, performing the verification-phase added no value, while, in 32% and 2%, it added uncertain value and certain value, respectively, in the determination of [Formula: see text].ConclusionCompared to [Formula: see text]-plateau the verification-phase shows lower reliability, increases costs and only adds certain value in 2% of cases.