Justin Carrard

Background Measurements of blood sphingolipids have previously been shown to predict cardiometabolic risk beyond traditional biomarkers. However, before these scores can be implemented in clinical practice, it is essential to establish lifespan trajectories and age- and sex-specific values for sphingolipid levels. This cross-sectional study aimed to characterise sphingolipid levels in clinically healthy individuals across the lifespan. Methods Serum sphingolipids from 522 clinically healthy individuals aged 20 to 91 of the COmPLETE-Health study (48% females) were quantified using targeted liquid chromatography-tandem mass spectrometry. Associations between sphingolipids and age were assessed using multiple linear regressions adjusted for sex, cardiorespiratory fitness, and other confounding variables. Descriptive age- and sex-specific sphingolipid quantile curves were modelled using generalised additive models for location, scale, and shape. Results Fourteen of the 21 detected sphingolipids were significantly and positively associated with age in both sexes. Notably, all four sphingolipids included in the Cardiovascular Event Risk Tests (Cer16:0, Cer18:0, Cer24:0, and Cer24:1) increased with age, whereas their respective ratios were not significantly associated with age. Females exhibited significantly higher levels than males for four sphingomyelins, two ceramides, HexCer18:0, and the Cer16:0/Cer24:0 ratio. Age- and sex-specific values across the lifespan (20 to 90 years) are provided as percentiles. Associations between cardiorespiratory fitness and sphingolipid levels varied by species. Conclusions Serum sphingolipid levels depended on age, underscoring the need for age-specific interpretation when assessing cardiometabolic risk using sphingolipid-based scores. Conversely, sphingolipid ratios remained unaffected by age.

In the Research article entitled “A single HIIT session does not alter blood sphingolipid levels in healthy young adults: The SphingoHIIT randomized controlled trial”, the authors identified an error in one of the supplemental files [1]. The raw data file (“SphingoHIIT_raw_data.xlsx”) included participant details that should have been removed. The unnecessary column has now been removed in the supplemental package in the original publication.

Introduction: Physical training stimulates mitochondrial biogenesis and protein synthesis in skeletal muscle. If the training load is too demanding and prolonged, an overtraining syndrome may develop. Reported overtraining symptoms include recurrent respiratory infections, sleep disturbances, with potential alterations at the skeletal muscle level such as soreness, and atrophy. The aim of the present study was to investigate skeletal muscle (mal)adaptations in response to overtraining, using a translational approach combining human data and an in vitro model. Methods: Electrical stimulation was applied to C2C12 myotubes to mimic endurance exercise. For the simulated training (s-T), stimulation was applied once daily for three days. In the simulated overtraining (s-OT), stimulation was applied three times daily for three days. Proteomic analysis, mitochondrial respiration and imaging were performed in the cellular model. In humans, knee extensor neuromuscular function at rest and in response to a standardized exercise was assessed in overtrained vs. well trained athletes. Muscle biopsies were also collected to assess mitochondrial respiration. Results: In s-T, we observed beneficial adaptations, including myotube hypertrophy, increased expression of myosin heavy chain proteins, and enhanced mitochondrial respiration. In contrast, s-OT showed myotube atrophy, reduced myosin heavy chain content, and impaired mitochondrial respiration. Consistent with these respiratory findings, proteomics analysis revealed a decreased abundance of proteins involved in the mitochondrial respiratory chain in s-OT. Interestingly, mitochondria appeared aggregated in s-OT myotubes, suggesting possible impairments in mitochondrial quality control. Live-cell imaging revealed possible autophagy alterations in the s-OT condition but not in s-T. Human data - neuromuscular function and muscle samples - are being processed and results will be presented during the conference. Conclusions: Our in vitro model provides a molecular platform for further investigations of skeletal muscle maladaptations to overtraining. The integrative approach will help to clarify the molecular mechanisms and ameliorate the clinics of muscle maladaptations triggered by excessive exercise in humans.

Rib bone stress injuries (BSIs) are rare in athletes but have been reported in rotational sports, such as tennis or golf. Scapular dyskinesia is a well‐established risk factor for shoulder injury, but its contribution to rib BSI has not previously been described. This case concerns a 25‐year‐old man with longstanding left scapular dysfunction, who developed progressive pain in the left medial scapular region 6 months after starting intensive golf training. Clinical examination revealed marked scapular dyskinesia, raising suspicion of muscle atrophy or peripheral nerve involvement. Shoulder and chest MRI excluded neuromuscular abnormalities but demonstrated nondisplaced BSI of the left posterior fifth and sixth ribs. This case report is the first to suggest scapular dyskinesia as a potential biomechanical risk factor for rib BSI in golf. It emphasizes the need to consider underlying scapular dysfunction when evaluating athletes with atypical thoracic pain.

Mental health and wellbeing are core components of a healthy life. However, emotional stress and mental health problems are on the rise through societies and cause a significant burden of suffering. In the following, we present our watershed framework for optimizing wellbeing and mental health through lifestyle interventions. Emerging evidence also shows that mental health is an important determinant of quality of life. In addition, it may also be a driver of longevity, influencing health outcomes and, ultimately, the overall healthspan. This framework is based on the recognition that mental health is comprised of biological, psychological, and social factors, and that the factors have interdependent relationships amongst them, so that positive changes in one of them can have cascading effects on the others, with the potential to improve the psychological capital of an individual. Our framework consists of nine elements that we consider hallmarks of mental health and wellbeing, structured in three interdependent layers. The first layer is formed by foundational factors, which are essential for wellbeing and mental health, including circadian rhythms and sleep recovery, along with social connections. The second layer, named wellbeing catalysts, encompasses elements of wellbeing that can have powerful positive effects on mental health, including stress resilience, vitality, cardiovascular health, immune health, and the gut-brain axis. The third layer, named as thriving factors, consists of cognitive performance and positive emotions, which are the elements most often associated with a thriving mind. In our framework, we highlight the interactions between the factors and provide a roadmap to structure comprehensive lifestyle interventions aimed at optimizing mental health and wellbeing. Strengthening mental health and wellbeing addresses key biological and behavioral determinants of healthy aging, which are increasingly recognized as critical modulators of longevity trajectories.

Introduction: Sphingolipids and ceramides have been identified as critical drivers of cardiometabolic diseases. Ceramide-based scores were developed, predicting cardiometabolic risk independently of and beyond low-density lipoprotein cholesterol. To date, it remains largely unknown whether exercise can modulate sphingolipid levels. Methods: The SphingoHIIT study was the first parallel randomized controlled trial to investigate the impact of a single session of high-intensity interval training (HIIT; 4 ×4 min at 85–95 % of maximal heart rate) on blood sphingolipid levels. Thirty-six healthy young individuals (aged 20–29 years; 50 % female) were randomly assigned to a HIIT (n = 18) or control group (physical rest, n = 18). Sphingolipid levels were measured from dried blood spots collected over three days before and at five time points after the intervention (2, 15, 30, 60 min, and 24 h). Study conditions were tightly controlled: females were tested during the early follicular phase of their menstrual cycle, and standardized meals were provided for four consecutive days before blood sampling. Results: Forty-seven sphingolipid species were acquired, including 25 ceramides, eight glycosphingolipids, eight sphingomyelins, and six sphingoid bases. After adjusting for sex, body fat mass, cardiorespiratory fitness, and daily physical activity, linear mixed models showed no significant differences in sphingolipid levels between the HIIT and control groups at any post-intervention time point. Conclusion: The present findings suggest that circulating sphingolipids are resilient to an acute bout of intensive exercise, an interesting feature for potential biomarkers of cardiometabolic risk. Future studies should investigate whether regular exercise influences sphingolipid levels and improves cardiometabolic health in different clinical populations.

Coronary artery disease (CAD) remains a leading cause of death worldwide and imposes a substantial socioeconomic burden on healthcare. Improving risk stratification in clinical practice could help to combat this burden. As amino acids are biologically active metabolites whose involvement in CAD remains largely unknown, this study investigated associations between circulating amino acid levels and CAD phenotypes. A high-coverage quantitative liquid chromatography-mass spectrometry approach was applied to acquire the serum amino acids profile of age- and sex-coarsened-matched patients with CAD (n = 46, 66.9 years, 74.7% male) and healthy individuals (n = 120, 67.4 years, 74.7% male) from the COmPLETE study. Multiple linear regressions were performed to investigate associations between amino acid levels and (a) the health status (CAD vs. healthy), (b) the number of affected coronary arteries, or (c) the left ventricular ejection fraction. Regressions were adjusted for age, sex, daily physical activity, sampling, and fasting time. Urea cycle amino acids (ornithine, citrulline, homocitrulline, aspartate, and arginine) were significantly and negatively associated with CAD, the number of affected coronary arteries, and the left ventricular ejection fraction. Lysine, histidine, and the glutamine/glutamate ratio were also significantly and negatively associated with the CAD phenotypes. Overall, patients with CAD displayed lower levels of urea cycle amino acids, highlighting a potential role for urea cycle amino acid profiling in cardiovascular risk stratification.Trial registrationThe study was registered on https://www.clinicaltrials.gov (NCT03986892) on June 5, 2019.

Background: Patients recovering from COVID-19 often present with impaired health and persisting symptoms such as exercise intolerance ⩾3 months post-infection. Uncertainty remains about long-term recovery. We aimed to review studies examining cardiac function, macro- or microvascular function, blood biomarkers and physical activity in adult patients post-COVID-19 and highlight current knowledge gaps. Results: Using echocardiography, persistent cardiac involvement of the left ventricle was observed in a fraction of patients both hospitalized and non-hospitalized. Ventricular dysfunction was often subclinical but may partly contribute to exercise intolerance post-COVID-19. Endothelial dysfunction was seen on micro- and macrovascular levels using retinal vessel imaging methods and brachial artery flow-mediated dilation, respectively. Studies reporting blood biomarkers of disease-specific impairment and endothelial dysfunction yielded upregulated inflammation, hypercoagulability, organ and endothelial damage up to several months after infection. Omics’ scale lipid profiling studies provide preliminary evidence of alterations in several lipid subspecies, mostly during acute COVID-19, which might contribute to subsequent endothelial and cardiometabolic dysfunction. Yet, more robust evidence is warranted. Physical activity may be reduced up to 6 months post-COVID-19. However, studies measuring physical activity more precisely using accelerometry are sparse. Overall, there is growing evidence for long-term multiple organ dysfunction. Conclusion: Research combining all the above methods in the search for underlying mechanisms of post-COVID-19 symptoms is mostly missing. Moreover, studies with longer follow-ups (i.e. ⩾18 months) and well-matched control groups are lacking. The findings may aid the development of rehabilitation regimes for post-COVID-19 syndrome. Condensed This review examined cardiac function, vascular function, blood biomarkers and physical activity in patients post-COVID-19. Evidence suggests long-term dysfunction in multiple organ systems and exercise intolerance due to various factors, including endothelial damage and, in some patients, subclinical ventricular dysfunction. We highlight knowledge gaps for further research to aid post-COVID-19 rehabilitation.

Evidence 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. This 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. The trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.