Prof. Dr. med. Arno Schmidt-Trucksäss

Overnutrition, reduced energy expenditure and chronic inflammation stimulate triglyceride storage. Once the triglyceride stores are saturated, lipids in excess are redirected to form sphingolipids. However, sphingolipid accumulation drives complex molecular alterations, which promote peripheral insulin resistance and atherosclerosis. Failure to manage this sphingolipid overload eventually results in diabetes mellitus and coronary artery diseases. In the last decade, these pathophysiological findings found resonance in milestone clinical studies. In primary prevention, a score combining the blood level of four sphingolipids outperformed the 2019 SCORE of the European Society of Cardiology in terms of cardiovascular risk prediction. The same score predicted cardiovascular mortality beyond low-density lipoprotein cholesterol in secondary prevention. Remarkably, sphingolipids are not limited to cardiovascular risk prediction, as they were shown to predict diabetes mellitus onset ten years before the disease was diagnosed. While the utility of sphingolipid profiling to stratify cardiometabolic risk is well-established, little is known about therapeutic modalities to lower sphingolipid levels. If circulating sphingolipids are to be measured in clinical practice, providing patients with evidence-based sphingolipid-lowering interventions is essential. As exercise is a powerful means to prevent and treat cardiometabolic diseases, exercise interventions are ideal candidates for mitigating sphingolipid levels in a cost-effective, safe, and patient-empowering manner. This 2-arm, monocentric, randomised controlled trial explores 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. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to verify patients' fitness has improved. 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. Classical biomarkers of cardiometabolic health (total cholesterol, low- and high-density density lipoprotein cholesterol, triglycerides, glycated haemoglobin, and the homeostatic model assessment for insulin resistance) and retinal vessel diameters, a novel surrogate of microvascular health, will also be assessed pre-and post-intervention. This study will inform clinicians whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels.

Background

There is growing evidence that even low-intensity physical activity (e.g., walking at a “normal” pace) produces substantial health benefits. Walking is “universally accessible”, even for mobility-limited and chronically ill older people. To date, little consideration has been given to the environment and individual preferences of older people when promoting walking. A personalized approach based on geographic information systems (GIS) could help address the problem of low long-term adherence to walking programs.

Objective

MOBITEC-Routes aims to investigate the effects of an individualized GIS-based intervention on walking, physical activity, physical function, life space, participation in social activities, and quality of life.

Methods

In the target group of chronically ill, mobility limited older people (aged 65 years and older), the experimental intervention will be compared with a control intervention in a randomized controlled trial.

Outlook

If successful, the personalized GIS-based approach can be easily implemented in preventive health promotion.

Growing scientific evidence shows that specific sphingolipids, known as ceramides, predict cardiovascular risk beyond traditionally used biomarkers such as lipoproteins and triglycerides. Mechanistically, ceramides have been shown to promote foam cell formation, vascular inflammation, peripheral insulin resistance, and ultimately atherosclerosis. Currently, however, it remains unclear if and how physical activity, a simple, low-cost, and patient-empowering mean to optimise cardiometabolic health, can mitigate sphingolipid levels. The SphingoHIIT study aims to assess how certain circulating sphingolipid species respond to a single session of high-intensity interval training (HIIT). We hypothesise that circulating sphingolipid levels will be temporarily increased following a single HIIT session. This risk category A study will last 11 days and include 32 healthy participants aged between 20 and 29 years (50% of females). Participants will be randomly allocated either to the intervention group (n= 16) or the control group (n= 16). Blocked randomisation will be used to reduce bias and achieve balance in the allocation of participants to both groups, as commonly done when the sample size is small. Following an assessment of inclusion and exclusion criteria, a maximal cardiopulmonary exercise testing will be performed to determine peak oxygen uptake and peak heart rate. A washout period of five days will then be carried out before participants start to self-sample fasted dried blood spots to determine baseline levels of sphingolipids. After three days of sampling, participants will undergo a single HIIT session. Dried blood spots will be collected at five additional fixed time points (2min, 15min, 30min, 60min, and 24h) following the HIIT session. To minimise the dietary influence, participants will be asked to solely consume the provided individualised, pre-packaged meals starting one day before the first dried blood sampling.

Additionally, for the duration of the whole study, participants will wear a wrist accelerometer to track their physical activity. The SphingoHIIT study is expected to provide novel knowledge regarding the effect of an acute bout of physical exercise on sphingolipid levels. The results of this study will be published in a peer-reviewed journal and will be presented at scientific conferences.