Effects of high-intensity interval training on retinal vessel diameters and oxygen saturation in patients with hypertension: A cross-sectional and randomized controlled trial.

INTRODUCTION: Arterial hypertension is a global healthcare burden that affects macrovascular and microvascular structure and function and can promote vascular end-organ damage. This study aimed 1) to evaluate differences in microvascular health between normotensive individuals and patients with arterial hypertension and 2) to assess the effects of short-term high-intensity interval training (HIIT) on microvascular health in the subgroup with arterial hypertension as add-on treatment to antihypertensive medication. METHODS: In the cross-sectional part, central retinal arteriolar (CRAE) and venular diameter equivalent (CRVE), arteriolar-to-venular diameter ratio (AVR), and retinal oxygen saturation (O2-saturation) were investigated in 19 normotensive healthy controls (mean age 56 ± 7 years) and 41 patients with arterial hypertension (mean age 59 ± 7 years). In the subsequent randomized controlled trial (RCT), patients with arterial hypertension were randomized to an intervention group (HIIT 3×/week) or a control group that received standard physical activity recommendations after baseline assessment. Assessments of retinal vessel biomarkers and patients` characteristics were repeated after the intervention period of 8 weeks. RESULTS: In the cross-sectional part, individuals with normal blood pressure (BP) showed lower body mass index (BMI), body fat, 24 h systolic and diastolic BP, higher peak oxygen uptake, wider CRAE (174 ± 17 µm vs. 161 ± 17 µm, p = 0.009), and higher AVR (0.84 ± 0.05 vs. 0.79 ± 0.05, p = 0.003) compared to patients with hypertension. In the RCT, patients with arterial hypertension showed reduced BMI and fasting glucose levels after HIIT and control condition. In addition, the intervention group reduced body fat percentage (27.0 ± 5.5 vs. 25.8 ± 6.1, p = 0.023) and increased peak oxygen uptake (33.3 ± 5.7 vs. 36.7 ± 5.1, p < 0.001). No changes in BP were found in either group. The intervention group showed narrower CRVE (ß -4.8 [95 % CI, -8.85, -0.81] p = 0.020) and higher AVR (0.03 [0.01, 0.04] p < 0.001) after eight weeks of HIIT compared to the control group. No statistically significant changes in retinal O2-saturation were found in either group. CONCLUSION: Short-term HIIT proved to be an effective treatment to ameliorate hypertension-induced retinal microvascular abnormalities in patients with hypertension. Retinal vessel diameters may prove to be a sensitive biomarker to quantify treatment efficacy at the microvascular level, at the earliest possible stage in patients with hypertension.

Omic-Scale High-Throughput Quantitative LC-MS/MS Approach for Circulatory Lipid Phenotyping in Clinical Research.

Lipid analysis at the molecular species level represents a valuable opportunity for clinical applications due to the essential roles that lipids play in metabolic health. However, a comprehensive and high-throughput lipid profiling remains challenging given the lipid structural complexity and exceptional diversity. Herein, we present an 'omic-scale targeted LC-MS/MS approach for the straightforward and high-throughput quantification of a broad panel of complex lipid species across 26 lipid (sub)classes. The workflow involves an automated single-step extraction with 2-propanol, followed by lipid analysis using hydrophilic interaction liquid chromatography in a dual-column setup coupled to tandem mass spectrometry with data acquisition in the timed-selective reaction monitoring mode (12 min total run time). The analysis pipeline consists of an initial screen of 1903 lipid species, followed by high-throughput quantification of robustly detected species. Lipid quantification is achieved by a single-point calibration with 75 isotopically labeled standards representative of different lipid classes, covering lipid species with diverse acyl/alkyl chain lengths and unsaturation degrees. When applied to human plasma, 795 lipid species were measured with median intra- and inter-day precisions of 8.5 and 10.9%, respectively, evaluated within a single and across multiple batches. The concentration ranges measured in NIST plasma were in accordance with the consensus intervals determined in previous ring-trials. Finally, to benchmark our workflow, we characterized NIST plasma materials with different clinical and ethnic backgrounds and analyzed a sub-set of sera (n = 81) from a clinically healthy elderly population. Our quantitative lipidomic platform allowed for a clear distinction between different NIST materials and revealed the sex-specificity of the serum lipidome, highlighting numerous statistically significant sex differences.

Short-term high-intensity interval training improves micro- but not macrovascular function in hypertensive patients.

INTRODUCTION: Arterial hypertension is a global health burden that affects vascular structure and function. Assessment of endothelial function can improve cardiovascular (CV) risk stratification. Exercise treatment reduces over all CV risk and improves vascular health. However, it is still not clear which part of the vascular bed is most sensitive to exercise treatment in patients with CV risk. This study aimed to investigate the effects of an 8-week walking based and supervised high-intensity interval training (HIIT) on macro- and microvascular endothelial function as add-on therapy in patients with arterial hypertension. METHODS: Forty patients (mean age 58 ± 7 years) treated for arterial hypertension were randomized in the HIIT (3×/week) or control group (CG) receiving standard physical activity recommendations. Arteriolar (aFID) and venular (vFID) flicker light-induced dilatation for retinal microvascular and flow-mediated dilatation (FMD) for macrovascular endothelial function were assessed. In addition, standardized assessments of patients' characteristics were performed before and after 8 weeks. RESULTS: Both groups reduced weight and body mass index but only the HIIT group reduced body fat, visceral fat, and increased peak oxygen uptake after 8 weeks. The control group reduced diastolic blood pressure. No blood pressure changes were found in the HIIT group. Arteriolar FID increased in the HIIT group independently of confounders (pre: 2.40 ± 0.98%, post: 3.19 ± 1.31%, p < 0.001) but not in the control group (pre: 3.06 ± 1.50%, post: 2.90 ± 1.46%, p = 0.280). No changes were found for FMD in either group. CONCLUSION: Arteriolar FID was found to be a sensitive vascular biomarker to assess exercise-induced microvascular improvements even in a short time setting of an 8-week exercise therapy with HIIT. Short-term exercise training affects microvascular endothelial function but not large artery endothelial function. Thus, retinal aFID appears to be a sensitive biomarker to detect short-term exercise efficacy on a vascular level. Dynamic retinal vessel analysis as a diagnostic approach may prove to be an ideal candidate vascular biomarker to monitor treatment effects of exercise in patients with hypertension on top of standard clinical care and may support clinical decision-making in the future.

VascuFit: vascular effects of non-linear periodized exercise training in sedentary adults with elevated cardiovascular risk - protocol for a randomized controlled trial.

BACKGROUND: Early vascular aging (EVA) is increasingly prevalent in the general population. Exercise is important for primary cardiovascular prevention, but often insufficient due to ineffective training methods and a lack of biomarkers suitable to monitor its vascular effects. VascuFit will assess the effectiveness of non-linear periodized aerobic exercise (NLPE) in a non-athletic sedentary population to improve both established and promising biomarkers of EVA. METHODS: Forty-three sedentary adults, aged 40-60 years, with elevated cardiovascular risk will either engage in 8 weeks of ergometer-based NLPE (n = 28) or receive standard exercise recommendations (n = 15). The primary outcome will be the change of brachial-arterial flow-mediated dilation (baFMD) after versus before the intervention. Secondary outcomes will be the change in static vessel analysis (SVA; clinical biomarker of microvascular endothelial function), endomiRs (microRNAs regulating key molecular pathways of endothelial cell homeostasis) and circulating cellular markers of endothelial function (mature endothelial cells, endothelial progenitor cells). Tertiary outcomes will be the change in sphingolipidome, maximum oxygen capacity, and traditional cardiovascular risk factors (blood pressure, triglycerides, cholesterol, fasting glucose, high-sensitivity C-reactive protein). DISCUSSION: We expect an improvement of baFMD of at least 2.6% and significant pre-post intervention differences of SVA and endomiRs as well as of the tertiary outcomes in the intervention group. VascuFit may demonstrate the effectiveness of NLPE to improve endothelial function, thus vascular health, in the general sedentary population. Furthermore, this project might demonstrate the potential of selected molecular and cellular biomarkers to monitor endothelial adaptations to aerobic exercise. TRIAL REGISTRATION: The trial was registered on www. CLINICALTRIALS: gov (NCT05235958) in February 11th 2022.

Lipoprotein Subclasses Independently Contribute to Subclinical Variance of Microvascular and Macrovascular Health.

Lipoproteins are important cardiovascular (CV) risk biomarkers. This study aimed to investigate the associations of lipoprotein subclasses with micro- and macrovascular biomarkers to better understand how these subclasses relate to atherosclerotic CV diseases. One hundred and fifty-eight serum samples from the EXAMIN AGE study, consisting of healthy individuals and CV risk patients, were analysed with nuclear magnetic resonance (NMR) spectroscopy to quantify lipoprotein subclasses. Microvascular health was quantified by measuring retinal arteriolar and venular diameters. Macrovascular health was quantified by measuring carotid-to-femoral pulse wave velocity (PWV). Nineteen lipoprotein subclasses showed statistically significant associations with retinal vessel diameters and nine with PWV. These lipoprotein subclasses together explained up to 26% of variation (R2 = 0.26, F(29,121) = 2.80, p < 0.001) in micro- and 12% (R2 = 0.12, F(29,124) = 1.70, p = 0.025) of variation in macrovascular health. High-density (HDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as triglycerides together explained up to 13% (R2 = 0.13, F(3143) = 8.42, p < 0.001) of micro- and 8% (R2 = 0.08, F(3145) = 5.46, p = 0.001) of macrovascular variation. Lipoprotein subclasses seem to reflect micro- and macrovascular end organ damage more precisely as compared to only measuring HDL-C, LDL-C and triglycerides. Further studies are needed to analyse how the additional quantification of lipoprotein subclasses can improve CV risk stratification and CV disease prediction.

Sports injuries and illnesses at the Lausanne 2020 Youth Olympic Winter Games: a prospective study of 1783 athletes from 79 countries.

OBJECTIVE: To describe the injury and illness characteristics among participating athletes during the Lausanne 2020 Youth Olympic Winter Games (YOG 2020), 9-22 January 2020. METHODS: The daily number of athlete injuries and illnesses were recorded (1) through the reporting of all National Olympic Committee (NOC) medical teams and (2) in the polyclinic and medical venues by the Lausanne 2020 medical staff. RESULTS: In total, 1783 athletes from 79 NOCs were observed. NOC and Lausanne 2020 medical staff reported 228 injuries and 167 illnesses, equating 11.7 injuries and 8.6 illnesses per 100 athletes over the 14-day period. Injury incidence was highest for snowboard slopestyle (39%), bobsleigh (36%), snowboard big air (29%), ski slopestyle (29%), snowboard cross (24%) and ski cross (21%), and lowest for speed skating, snowboard halfpipe and curling (2%-4%). The highest incidence of illness was recorded for curling (21%), ski mountaineering (15%), snowboard halfpipe (13%), bobsleigh (11%), cross-country skiing (10%) and figure skating (10%). Almost one-third of injuries were expected to result in time loss and 17% of illnesses. Most injuries occurred to the knee (12%) and head (11%), and 64% of illnesses affected the respiratory system. Overall, women suffered more injuries and illness than males. CONCLUSION: Overall, injury and illness rates were similar compared with recent YOG. While the rate and characteristics of injury and illness varied between sports, consistent patterns across YOG are emerging. If addressed, changes in highlighted areas of risk could have a positive impact on the health and well-being of these young athletes.

Physical activity is favorably associated with arterial stiffness in patients with obesity and elevated metabolic risk.

OBJECTIVES: Physical activity and cardiorespiratory fitness (CRF) are relevant modifiers of cardiovascular risk. Their independent effects on arterial stiffness have not been assessed in people with obesity. This study aimed to assess the independent effects of light (LPA) and moderate-to-vigorous (MVPA) physical activity and CRF on Pulse wave velocity (PWV). METHODS: Brachial-ankle PWV (baPWV) was measured cross-sectionally in 55 subjects (43.0 ± 13.8 years; 66% women) with moderate cardiovascular risk. Body composition was assessed with bioelectrical impedance-analysis. Daily minutes of LPA and MVPA were measured by accelerometry and CRF (peak oxygen uptake [VO2 peak]) with spiroergometry. Independent effects of LPA, MVPA, and VO2 peak on baPWV were analyzed in an age-, sex-, body fat mass-, and blood pressure-adjusted ANOVA. RESULTS: Every 10 minutes increase of daily MVPA was associated with a 2.8% (0.32m/s [-0.64 to 0.001 m/s], P = .05) reduction of baPWV, whereas LPA and VO2 peak had only a little or no relevant effects on baPWV. CONCLUSIONS: Higher MVPA is associated with lower composite arterial stiffness independent of CRF and the number of metabolic risk factors in patients with obesity and further metabolic risk factors. Thus, lifestyle interventions should aim for an increase in MVPA. BaPWV may improve the monitoring of favorable effects of MVPA, even if an improvement of VO2 peak cannot be obtained.

Effect of an eight-week high-intensity interval training programme on circulating sphingolipid levels in middle-aged adults at elevated cardiometabolic risk (SphingoFIT)-Protocol for a randomised controlled exercise trial.

INTRODUCTION: 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. METHODS: 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. TRIAL REGISTRATION: The trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.

Exercise Science Graduates in the Healthcare System: A Comparison Between Australia and Switzerland.

Physical inactivity (PI) is a leading risk factor for global mortality worldwide, a major preventable cause of non-communicable diseases (NCDs) and a socioeconomic burden for healthcare systems. Fortunately, evidence shows that exercise interventions delivered by qualified exercise science graduates is an effective way to reduce PI, prevent and treat NCDs. This study compares the integration of exercise science graduates, defined as university graduates with degrees in sport and exercise science, in the healthcare systems of Australia, a commonly cited model in this regard, and Switzerland, a country considered to have an effective but costly healthcare system. For both countries, three domains were reviewed: healthcare system, exercise science graduates' education, and roles played by exercise science graduates in healthcare system. Australia formally recognizes specifically trained exercise science graduates (referred to as Accredited Exercise Physiologists) as healthcare professionals. The exercise interventions they deliver, which were shown to be cost-effective and lead to positive health outcomes, are covered by Medicare, the Australian universal health insurance. However, Medicare covers only a maximum of 5 yearly sessions of all allied-health services taken together. Conversely, Switzerland, despite offering university master's degrees that focus on physical activity delivery to clinical populations, does not recognize the respective graduates as healthcare providers. As a result, their services are not covered by the Swiss health insurances. The latter do, however, cover a generous number of services (not formally limited) delivered by other allied-health professionals. In conclusion, Australia makes a better use of exercise science graduates than Switzerland does. Switzerland would benefit from establishing a clinical profession for exercise science graduates, defining competencies that they should acquire and setting their scope of practice. The very restricted number of therapy sessions covered by Medicare might limit the positive impact exercise science graduates have on the Australian healthcare system. Overall, mutual learning between countries can promote development and global recognition of clinical positions for exercise science graduates.

Is healthcare a team sport? Widening our lens on interprofessional collaboration and education in sport and exercise medicine.

Effective interprofessional collaboration (IPC) has great potential to improve healthcare delivery. Therefore, students and trainees in healthcare professions should be prepared for a collaborative workforce through interprofessional education (IPE) settings. However, IPC and IPE are rarely addressed in sport and exercise medicine (SEM), although the field significantly impacts the healthcare system. Hence, we conducted a webinar to promote IPC and IPE in the Swiss SEM community. The lessons resulting from the webinar were: (1) professions involved in SEM should have opportunities to learn, with, from and about other professions in healthcare to achieve mutual respect and understanding; (2) IPC and IPE in SEM may raise awareness, value and recognition of the contributions by exercise scientists in healthcare; (3) IPC and IPE may consider collaborating with a variety of professions not traditionally integrated into healthcare but involved in broader public health and physical activity promotion. In summary, sports and exercise professions should embrace interprofessional approaches to better realise their contribution to healthcare and public health.

Cardiorespiratory Fitness and Endothelial Function in Aging Healthy Subjects and Patients With Cardiovascular Disease.

Background: Individuals with a higher lifelong cardiorespiratory fitness show better vascular health with aging. Studies on fitness-related effects on endothelial function either analyzed samples with a narrow age-range or incompletely assessed endothelial responsiveness. This study aims to assess the impact of cardiorespiratory fitness on the association of brachial-arterial flow-mediated vasodilation (FMD) and low flow-mediated vasoconstriction (L-FMC) with age in healthy adults and patients with cardiovascular diseases. Methods: FMD, L-FMC and V . O2peak were prospectively measured in a population-based sample including 360 healthy adults and 99 patients with cardiovascular disease of European descend. Non-linear models were applied to assess V . O2peak-associated variations in age-related differences of endothelial function independent of classical cardiovascular risk factors. Results: FMD was negatively associated with age in healthy adults (adjusted R2 = 0.27, partial R2 = 0.07, p < 0.001) and in cardiovascular patients (adjusted R2 = 0.29, partial R2 = 0.05, p = 002). L-FMC showed no association with age. In models predicting the change of FMD with higher age, V . O2peak accounted for 2.8% of variation in FMD (χ2(5) = 5.37, p = 0.372, s = 1.43). Thereby, V . O2peak-stratified changes of FMD started to fan out at around 30 years of age in women and 50 years of age in men, with 7-12% lower values at old age with V . O2peak ≤3rd percentile compared to V . O2peak ≥97th percentile) in both, the healthy sample and in cardiovascular patients. Conclusion: The statistical effect of cardiorespiratory fitness on the association of FMD with age independent of classical cardiovascular risk factors was small in both, healthy aging adults as well as patients with cardiovascular diseases. Its clinical significance should be assessed further.

Hypertension and retinal microvascular dysfunction (HyperVasc): protocol of a randomised controlled exercise trial in patients with hypertension.

INTRODUCTION: Hypertension is a global healthcare burden that affects the structure and function of the macrocirculation and microcirculation and induces disease-specific end-organ damage. Vascular biomarkers are essential to timely diagnose this end-organ damage to improve cardiovascular (CV) risk stratification and medical decision making. Exercise therapy is an effective means to improve vascular health and reduce overall CV risk. However, it is still not clear whether high-intensity interval training (HIIT) is recommendable for patients with hypertension to reduce blood pressure, increase cardiorespiratory fitness and ameliorate vascular health. METHODS AND ANALYSIS: The 'Hypertension and retinal microvascular dysfunction' trial will investigate macrovascular and microvascular impairments in hypertensive patients compared with healthy controls to investigate hypertension-induced end-organ damage by using gold-standard methods as well as newly developed unique retinal microvascular biomarkers. In addition, this trial will investigate the reversibility of retinal end-organ damage by assessing the effects of an 8-week supervised and walking based HIIT on blood pressure, cardiorespiratory fitness as well as macrovascular and microvascular health, compared with a control group following standard physical activity recommendations. Primary outcome will be the arteriolar-to-venular diameter ratio. Secondary outcomes will be arteriolar and venular diameters as well as the flicker-light-induced dilation. Further outcomes will be other retinal microvascular biomarkers, flow-mediated dilation of the brachial artery as well as blood pressure, cardiorespiratory fitness, microalbuminuria, hypertensive retinopathy and classical CV risk markers. Analysis of variance and analysis of covariance will be used to investigate group differences between healthy controls and hypertensive patients and training effects in hypertensive patients, respectively. ETHICS AND DISSEMINATION: The Ethics Committee of Northwestern and Central Switzerland approved this study (EKNZ-2021-00086). All participants will give informed consent. TRIAL REGISTRATION NUMBER: NCT04763005.

Diagnosing Overtraining Syndrome: A Scoping Review.

CONTEXT: Overtraining syndrome (OTS) is a condition characterized by a long-term performance decrement, which occurs after a persisting imbalance between training-related and nontraining-related load and recovery. Because of the lack of a gold standard diagnostic test, OTS remains a diagnosis of exclusion. OBJECTIVE: To systematically review and map biomarkers and tools reported in the literature as potentially diagnostic for OTS. DATA SOURCES: PubMed, Web of Science, and SPORTDiscus were searched from database inception to February 4, 2021, and results screened for eligibility. Backward and forward citation tracking on eligible records were used to complement results of database searching. STUDY SELECTION: Studies including athletes with a likely OTS diagnosis, as defined by the European College of Sport Science and the American College of Sports Medicine, and reporting at least 1 biomarker or tool potentially diagnostic for OTS were deemed eligible. STUDY DESIGN: Scoping review following the guidelines of the Joanna Briggs Institute and PRISMA Extension for Scoping Reviews (PRISMA-ScR). LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Athletes' population, criteria used to diagnose OTS, potentially diagnostic biomarkers and tools, as well as miscellaneous study characteristics were extracted. RESULTS: The search yielded 5561 results, of which 39 met the eligibility criteria. Three diagnostic scores, namely the EROS-CLINICAL, EROS-SIMPLIFIED, and EROS-COMPLETE scores (EROS = Endocrine and Metabolic Responses on Overtraining Syndrome study), were identified. Additionally, basal hormone, neurotransmitter and other metabolite levels, hormonal responses to stimuli, psychological questionnaires, exercise tests, heart rate variability, electroencephalography, immunological and redox parameters, muscle structure, and body composition were reported as potentially diagnostic for OTS. CONCLUSION: Specific hormones, neurotransmitters, and metabolites, as well as psychological, electrocardiographic, electroencephalographic, and immunological patterns were identified as potentially diagnostic for OTS, reflecting its multisystemic nature. As exemplified by the EROS scores, combinations of these variables may be required to diagnose OTS. These scores must now be validated in larger samples and within female athletes.

Ideal Life's Simple 7 Score Relates to Macrovascular Structure and Function in the Healthy Population.

BACKGROUND: Cardiovascular health scores, such as Life's Simple 7 from the American Heart Association, and the assessment of arterial properties are independently used to determine cardiovascular risk. However, evidence of their association remains scarce, especially in healthy, middle-aged to older populations. METHODS: A healthy sample of the Swiss population aged 50-91 years as part of the COmPLETE cohort study was included. Carotid intima-media thickness (cIMT), carotid lumen diameter (cLD), carotid distensibility coefficient (DC), flow-mediated dilation (FMD), and brachial-ankle pulse wave velocity (baPWV) were used to determine arterial properties. The Life's Simple 7 cardiovascular health score was calculated using seven categories (body-mass index, cholesterol, systolic blood pressure, hemoglobin A1c, smoking status, physical activity, and diet). In accordance with the American Heart Association, for each category, two points were given for an ideal health metric level, intermediate scores one point, and poor scores zero points. Intermediate and ideal health scores corresponded to a total of 5-9 and 10-14 points, respectively. RESULTS: A total of 280 participants (50.7% male) were included. After adjusting for age and sex, an ideal health score was associated with lower cIMT (-0.038 mm, 95% CI: -0.069 mm--0.007 mm, p = 0.017), lower cLD (-0.28 mm, 95% CI: -0.46 mm--0.11 mm, p = 0.002), and lower baPWV (-0.05 m/s, 95% CI: -0.08 m/s--0.02 m/s, p = 0.003). No differences were found for FMD and DC. CONCLUSIONS: Even in a healthy sample of middle-aged and older adults, individuals with an ideal cardiovascular health score showed more favorable biomarkers of vascular aging than those with an intermediate score. This stresses the relevance of promoting an optimal lifestyle, even among the healthy population.

Investigating the circulating sphingolipidome response to a single high-intensity interval training session within healthy females and males in their twenties (SphingoHIIT): Protocol for a randomised controlled trial.

Introduction: Growing scientific evidence indicates that sphingolipids predict cardiometabolic risk, independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, it remains largely unknown if and how exercise, a simple, low-cost, and patient-empowering modality to optimise cardiometabolic health, influences sphingolipid levels. The SphingoHIIT study aims to assess the response of circulating sphingolipid species to a single session of high-intensity interval training (HIIT). Methods: This single-centre randomised controlled trial (RCT) will last 11 days per participant and aim to include 32 young and healthy individuals aged 20-29 (50% females). Participants will be randomly allocated to the HIIT (n= 16) or control groups (physical rest, n= 16). Participants will self-sample fasted dried blood spots for three consecutive days before the intervention (HIIT versus rest) to determine baseline sphingolipid levels. Dried blood spots will also be collected at five time points (2, 15, 30, 60min, and 24h) following the intervention (HIIT versus rest). To minimise the dietary influence, participants will receive a standardised diet for four days, starting 24 hours before the first dried blood sampling. For females, interventions will be timed to fall within the early follicular phase to minimise the menstrual cycle's influence on sphingolipid levels. Finally, physical activity will be monitored for the whole study duration using a wrist accelerometer. Ethics and dissemination: The Ethics Committee of Northwest and Central Switzerland approved this protocol (ID 2022-00513). Findings will be disseminated in scientific journals and meetings. Trial Registration The trial was registered on www.clinicaltrials.gov (NCT05390866, https://clinicaltrials.gov/ct2/show/NCT05390866) on May 25, 2022.

The Metabolic Signature of Cardiorespiratory Fitness: A Systematic Review.

BACKGROUND: Cardiorespiratory fitness (CRF) is a potent health marker, the improvement of which is associated with a reduced incidence of non-communicable diseases and all-cause mortality. Identifying metabolic signatures associated with CRF could reveal how CRF fosters human health and lead to the development of novel health-monitoring strategies. OBJECTIVE: This article systematically reviewed reported associations between CRF and metabolites measured in human tissues and body fluids. METHODS: PubMed, EMBASE, and Web of Science were searched from database inception to 3 June, 2021. Metabolomics studies reporting metabolites associated with CRF, measured by means of cardiopulmonary exercise test, were deemed eligible. Backward and forward citation tracking on eligible records were used to complement the results of database searching. Risk of bias at the study level was assessed using QUADOMICS. RESULTS: Twenty-two studies were included and 667 metabolites, measured in plasma (n = 619), serum (n = 18), skeletal muscle (n = 16), urine (n = 11), or sweat (n = 3), were identified. Lipids were the metabolites most commonly positively (n = 174) and negatively (n = 274) associated with CRF. Specific circulating glycerophospholipids (n = 85) and cholesterol esters (n = 17) were positively associated with CRF, while circulating glycerolipids (n = 152), glycerophospholipids (n = 42), acylcarnitines (n = 14), and ceramides (n = 12) were negatively associated with CRF. Interestingly, muscle acylcarnitines were positively correlated with CRF (n = 15). CONCLUSIONS: Cardiorespiratory fitness was associated with circulating and muscle lipidome composition. Causality of the revealed associations at the molecular species level remains to be investigated further. Finally, included studies were heterogeneous in terms of participants' characteristics and analytical and statistical approaches. PROSPERO REGISTRATION NUMBER: CRD42020214375.

How Ceramides Orchestrate Cardiometabolic Health-An Ode to Physically Active Living.

Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients' metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as ceramides, were shown to predict cardiometabolic outcomes beyond traditional biomarkers such as cholesterol. Preliminary data showed that physical activity, a potent, low-cost, and patient-empowering means to reduce CMD-related burden, influences ceramide levels. While a single bout of physical exercise increases circulating and muscular ceramide levels, regular exercise reduces ceramide content. Additionally, several ceramide species have been reported to be negatively associated with cardiorespiratory fitness, which is a potent health marker reflecting training level. Thus, regular exercise could optimize cardiometabolic health, partly by reversing altered ceramide profiles. This short review provides an overview of ceramide metabolism and its role in cardiometabolic health and diseases, before presenting the effects of exercise on ceramides in humans.

Endothelial function of healthy adults from 20 to 91 years of age: prediction of cardiovascular risk by vasoactive range.

OBJECTIVES: Brachial arterial low flow-mediated constriction (L-FMC) and flow-mediated dilation (FMD) are ultrasound-based biomarkers that emerge into scientific and clinical practice indicating cardiovascular effects of medical and lifestyle-based treatment beyond classical risk factors. This study is the first to provide reference values and to assess the predictive value of L-FMC, FMD and their composite endpoint vasoactive range (VAR) in healthy adults. METHODS: L-FMC, FMD and VAR were measured in 457 nonsmoking adults of 20-91 years without chronic diseases, medication, with normal heart function and very low cardiovascular risk. Sex-specific percentiles were calculated and predictive ability for elevated cardiovascular risk was assessed using receiver-operating characteristic (ROC) curves. RESULTS: From 20 to 91 years of age, L-FMC increased 86.1 and 105.3%, FMD decreased 63.6 and 47.1% and VAR decreased 58.3 and 55.2% in women and men, respectively. Area under the ROC curves was 0.54 (95% CI = 0.49-0.54) for L-FMC, 0.67 (95% CI = 0.62-0.67) for FMD and 0.72 (95% CI = 0.67-0.72) for VAR (P < 0.001). Discriminatory cut-offs for elevated risk were 0.24% for L-FMC (sensitivity = 0.42, specificity = 0.67), 6.4% for FMD (sensitivity = 0.71, specificity = 0.60) and 6.3% for VAR (sensitivity = 0.62, specificity = 0.73). CONCLUSION: This study demonstrates reduced endothelial function with aging in healthy men and women with very low cardiovascular risk. Percentiles crossed cut-offs for elevated cardiovascular risk between 50 and 55 years in men and 70 and 75 years in women, indicating higher risk for cardiovascular disease in men. VAR showed the highest ability to identify individuals with elevated cardiovascular risk, and should be included in the monitoring and treatment of accelerated vascular aging even in healthy individuals.

Novel CPET Reference Values in Healthy Adults: Associations with Physical Activity.

PURPOSE: Cardiopulmonary exercise testing (CPET) is an important measurement in clinical practice, and its primary outcome, maximal oxygen uptake (V˙O2peak), is inversely associated with morbidity and mortality. The purposes of this study are to provide CPET reference values for maximal and submaximal parameters across the adult age spectrum of a healthy European cohort, to compare V˙O2peak values with other reference data sets, and to analyze the associations between physical activity (PA) levels and CPET parameters. METHODS: In this cross-sectional study, we prospectively recruited 502 participants (47% female) from 20 to 90 yr old. The subjects performed a CPET on a cycle ergometer using a ramp protocol. PA was objectively and continuously measured over 14 d using a triaxial accelerometer. Quantile curves were calculated for CPET parameters. To investigate the associations between CPET parameters and PA levels, linear regression analysis was performed. RESULTS: V˙O2peak values observed in the group of 20-29 yr were 46.6 ± 7.9 and 39.3 ± 6.5 mL·kg⋅min for males and females, respectively. On average, each age category (10-yr increments) showed a 10% lower V˙O2peak relative to the next younger age category. V˙O2peak values of previous studies were on average 7.5 mL·kg⋅min (20%) lower for males and 6.5 mL·kg⋅min (21%) lower for females. There was strong evidence supporting a positive association between the V˙O2peak (mL·kg⋅min) and the level of habitual PA performed at vigorous PA (estimate, 0.26; P < 0.001]. CONCLUSION: Maximal and submaximal CPET reference values over a large age range are novel, and differences to other studies are clinically highly relevant. Objectively measured vigorous-intensity PA showed a strong positive association with higher V˙O2peak and other performance-related CPET parameters, supporting the implementation of higher-intensity aerobic exercise in health promotion.

Metabolic profiling links cardiovascular risk and vascular end organ damage.

BACKGROUND AND AIMS: An untargeted metabolomics approach allows for a better understanding and identification of new candidate metabolites involved in the etiology of vascular disease. We aimed to investigate the associations of cardiovascular (CV) risk factors with the metabolic fingerprint and macro- and microvascular health in an untargeted metabolomic approach in predefined CV risk groups of aged individuals. METHODS: The metabolic fingerprint and the macro- and microvascular health from 155 well-characterized aged (50-80 years) individuals, based on the EXAMIN AGE study, were analysed. Nuclear magnetic resonance spectroscopy was used to analyse the metabolic fingerprint. Carotid-femoral pulse wave velocity and retinal vessel diameters were assessed to quantify macro- and microvascular health. RESULTS: The metabolic fingerprint became more heterogeneous with an increasing number of risk factors. There was strong evidence for higher levels of glutamine [estimate (95% CI): -14.54 (-17.81 to -11.27), p < 0.001], glycine [-5.84 (-7.88 to -3.79), p < 0.001], histidine [-0.73 (-0.96 to -0.50), p < 0.001], and acetate [-1.68 (-2.91 to -0.46), p = 0.007] to be associated with a lower CV risk profile. Tryptophan, however, was positively associated with higher CV risk [0.31 (0.06-0.56), p = 0.015]. The combination of a priori defined CV risk factors explained up to 45.4% of the metabolic variation. The metabolic fingerprint explained 20% of macro- and 23% of microvascular variation. CONCLUSIONS: Metabolic profiling has the potential to improve CV risk stratification by identifying new underlying metabolic pathways associated with atherosclerotic disease development, from cardiovascular risk to metabolites, to vascular end organ damage.