Effect of lifestyle interventions on carotid arterial structure - The DR's EXTRA study.

No lifestyle-based interventions with medium-term duration on carotid atherosclerotic have been performed so far. We aimed to investigate whether guideline-based dietary and physical activity interventions slow the progression of atherosclerotic changes in the general elderly population. 1410 Finnish men and women from a representative population sample were randomly assigned to one of six groups in the four-year intervention study: 1) reference, 2) aerobic training, 3) resistance training, 4) Nordic Diet, 5) aerobic training + Nordic Diet, 6) resistance training + Nordic Diet. The primary outcome was mean common carotid artery intima-media thickness (cIMT). The lumen diameter of the common carotid artery (cLD) was also analyzed. 567 men and 565 women aged 57 to 78 years were included. None of the intervention groups significantly slowed cIMT progression compared to the reference group. A subgroup analysis showed that men in the diet group had significantly smaller cIMT progression than in the reference group (-0.078 mm, 95% CI: -0.146 to -0.009, p = 0.02) and no significant increase in cIMT (p = 0.23). No other group showed a slowed cIMT progression. Among guideline-based lifestyle interventions, only diet leads to a significantly smaller progression of cIMT in older men of a representative population sample. No other lifestyle intervention contributed to a slowing of the progression of structural carotid markers. It must be questioned whether the guideline-based recommendations for a lifestyle change that were in place until recently are adequate to decelerate the atherosclerotic process.

Association of blood pressure, obesity and physical activity with arterial stiffness in children: a systematic review and meta-analysis.

Central pulse wave velocity (cPWV) is a biomarker for cardiovascular (CV) risk and a predictor for CV events in adulthood. Alterations of arterial stiffness have also been associated with CV risk in childhood. The study aimed to systematically review and meta-analyze the association of blood pressure (BP), body mass index (BMI), and cardiorespiratory fitness (CRF) with cPWV in children. Literature search was through the databases PubMed, Web of Science, Embase and the Cochrane Register of Controlled Trials. Twenty-two articles were included in the systematic review and eight articles in the meta-analysis. Higher systolic and diastolic BP were associated with higher cPWV (pooled estimated effect size (ES) 0.02 (95% CI: 0.012-0.027; P < 0.001), and ES 0.02 (95% CI: 0.011-0.029; P < 0.001); respectively). Higher BMI correlated with higher cPWV (ES 0.025 (95% CI: 0.013-0.038; P < 0.001)). CRF was inversely associated with cPWV (ES -0.033 (95% CI: -0.055 to -0.011; P = 0.002)). In children, higher BP and BMI are already related to increased cPWV, and enhanced CRF may be a preventive strategy to counteract development of CV disease later in life. IMPACT: This meta-analysis suggests that elevated blood pressure and body mass index in childhood correlate with increased central pulse wave velocity. Children with higher cardiorespiratory fitness appear to have favorably lower arterial stiffening. Elevated blood pressure and altered arterial stiffness originate early in life and childhood risk stratification as well as timely initiation of exercise treatment may help counteract development of manifest cardiovascular disease later in life.

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.

Psychometric properties of the MOBITEC-GP mobile application for real-life mobility assessment in older adults.

Aim of this study was to test the reliability and validity of the life-space measures and walking speed delivered by the MOBITEC-GP app. Participants underwent several supervised walking speed assessments as well as a 1-week life-space assessment during two assessment sessions 9 days apart. Fifty-seven older adults (47.4% male, mean age= 75.3 (±5.9) years) were included in the study. The MOBITEC-GP app showed moderate to excellent test-retest reliability (ICCs between 0.584 and 0.920) and validity (ICCs between 0.468 and 0.950) of walking speed measurements of 50 meters and above and of most 1-week life-space parameters, including life-space area, time spent out-of-home, and action range. The MOBITEC-GP app for Android is a reliable and valid tool for the assessment of real-life walking speed (at distances of 50 metres and above) and life-space parameters of older adults. Future studies should look into technical issues more systematically in order to avoid invalid measurements.

Methodological aspects for accelerometer-based assessment of physical activity in heart failure and health.

BACKGROUND: For valid accelerometer-assessed physical activity (PA) data, several methodological aspects should be considered. We aimed to 1) visualize the applicability of absolute accelerometer cut-offs to classify PA intensity, 2) verify recommendations to measure PA over 7 days by examining inter-day variability and reactivity, 3) examine seasonal differences in PA, and 4) recommend during which 10 h day period accelerometers should be worn to capture the most PA in patients with heart failure (HEART) and healthy individuals (HEALTH). METHODS: Fifty-six HEART (23% female; mean age 66 ± 13 years) and 299 HEALTH (51% female; mean age 54 ± 19 years) of the COmPLETE study wore accelerometers for 14 days. Aim 1 was analyzed descriptively. Key analyses were performed using linear mixed models. RESULTS: The results yielded poor applicability of absolute cut-offs. The day of the week significantly affected PA in both groups. PA-reactivity was not present in either group. A seasonal influence on PA was only found in HEALTH. Large inter-individual variability in PA timing was present. CONCLUSIONS: Our data indicated that absolute cut-offs foster inaccuracies in both populations. In HEART, Sunday and four other days included in the analyses seem sufficient to estimate PA and the consideration of seasonal differences and reactivity seems not necessary. For healthy individuals, both weekend days plus four other days should be integrated into the analyses and seasonal differences should be considered. Due to substantial inter-individual variability in PA timing, accelerometers should be worn throughout waking time. These findings may improve future PA assessment. TRIAL REGISTRATION: The COmPLETE study was registered at clinicaltrials.gov ( NCT03986892 ).

Changes in physical activity behavior and development of cardiovascular risk in children.

The study aimed to investigate the association of changes in physical activity, screen time, and cardiorespiratory fitness (CRF) with development of body mass index (BMI), blood pressure (BP), and retinal microvascular health in children over four years. In 2014, 391 children aged 6-8 years were screened, and thereof 262 children were reexamined after four years following standardized protocols. Retinal arteriolar (CRAE) and venular diameters were measured by a retinal vessel analyzer. CRF was objectively assessed by a 20 m shuttle run, physical activity, and screen time by use of a questionnaire. Children who achieved higher CRF levels reduced their BMI (ß [95% CI] -0.35 [-0.46 to -0.25] kg/m2 per stage, P ≤ .001) and thereby developed wider CRAE (ß [95% CI] 0.25 [0.24 to 0.48] µm per stage, P = .03) at follow-up. Moreover, children with elevated or high systolic BP at baseline, but lower levels of screen time during the observation period, had wider CRAE at follow-up (ß [95% CI] -0.37 [-0.66 to -0.08] µm per 10 min/d, P = .013). Change in CRF was not directly associated with better microvascular health at follow-up. However, an increase of CRF over four years was associated with a reduced BMI and consequently wider retinal arterioles at follow-up. In children with elevated or high systolic BP, a reduction of screen time significantly improved retinal microvascular health as a primary prevention strategy to promote childhood health and combat development of manifest CV disease later in life.

Retinal endothelial function in cardiovascular risk patients: A randomized controlled exercise trial.

The aim of this study was to investigate, for the first time, the effects of high-intensity interval training (HIIT) on retinal microvascular endothelial function in cardiovascular (CV) risk patients. In the randomized controlled trial, middle-aged and previously sedentary patients with increased CV risk (aged 58 ± 6 years) with ≥ two CV risk factors were randomized into a 12-week HIIT (n = 33) or control group (CG, n = 36) with standard physical activity recommendations. A blinded examiner measured retinal endothelial function by flicker light-induced maximal arteriolar (ADmax) and venular (VDmax) dilatation as well as the area under the arteriolar (AFarea) and venular (VFarea) flicker curve using a retinal vessel analyzer. Standardized assessments of CV risk factors, cardiorespiratory fitness, and retinal endothelial function were performed before and after HIIT. HIIT reduced body mass index, fat mass, and low-density lipoprotein and increased muscle mass and peak oxygen uptake (VO2peak). Both ADmax (pre: 2.7 ± 2.1%, post: 3.0 ± 2.2%, P = .018) and AFarea (pre: 32.6 ± 28.4%*s, post: 37.7 ± 30.6%*s, P = .016) increased after HIIT compared with CG (ADmax, pre: 3.2 ± 1.8%, post: 2.9 ± 1.8%, P = .254; AFarea, pre: 41.6 ± 28.5%*s, post: 37.8 ± 27.0%*s, P = .186). Venular function remained unchanged after HIIT. There was a significant association between ∆-change VO2peak and ∆-changes ADmax and AFarea (P = .026, R2  = 0.073; P = .019, R2  = 0.081, respectively). 12-weeks of HIIT improved retinal endothelial function in middle-aged patients with increased CV risk independent of the reduction in classical CV risk factors. Exercise has the potential to reverse or at least postpone progression of small vessel disease in older adults with increased CV risk under standard medication. Dynamic retinal vessel analysis seems to be a sensitive tool to detect treatment effects of exercise interventions on retinal microvascular endothelial function in middle-aged individuals with increased CV risk.

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.

P value functions: An underused method to present research results and to promote quantitative reasoning.

Null hypothesis significance testing has received a great amount of attention in recent years in the light of the reproducibility crisis of science. Recently, there have been calls to retire the dichotomization of study results into "significant" or "not significant" depending on whether the P value crosses some threshold or not. Ways of improving the interpretation of P values and confidence intervals are therefore needed. We illustrate the use of P value functions, which display confidence limits and P values for any confidence level for a parameter. P value functions accessibly display a wealth of information: point estimate for the parameter, one-sided and two-sided confidence limits at any level, and one-sided and two-sided P values for any null and non-null value and the counternull value. Presenting several recent examples from the literature, we show how P value functions can be applied to present evidence and to make informed statistical inferences without resorting to dichotomization. We argue that P value functions are more informative than commonly used summaries of study results such as single P values or confidence intervals. P value functions require minimal retraining, are easily interpreted, and show potential to fix many of the common misinterpretation of P values and confidence intervals. To facilitate the adoption of P value functions, we released an R package for creating P value functions for several commonly used estimates.

Functional aging in health and heart failure: the COmPLETE Study.

BACKGROUND: Cardiovascular (CV) diseases including heart failure are the leading causes of morbidity, with age being the primary risk factor. The combination of age-related organic functional impairment and reduced physical fitness can drastically impact an individual's healthspan. One's lifespan can potentially be prolonged by the preservation or improvement of physical fitness. However, it remains unclear as to which biomarkers are most suitable for distinguishing between healthy aging and the impaired organ function associated with heart failure. Therefore, a comprehensive assessment of the components of physical fitness and CV function will be performed to identify the most important factors contributing to aging in relation to both health and disease. METHODS: This cross-sectional investigation will consist of two parts: COmPLETE-Health (C-Health) and COmPLETE-Heart (C-Heart). C-Health will examine the aging trajectories of physical fitness components and CV properties in a healthy population sample aged between 20 and 100 years (n = 490). Separately, C-Heart will assess the same markers in patients at different stages of chronic heart failure (n = 80). The primary outcome to determine the difference between C-Health and C-Heart will be cardiorespiratory fitness as measured by cardiopulmonary exercise testing on a bicycle ergometer. Secondary outcomes will include walking speed, balance, isometric strength, peak power, and handgrip strength. Physical activity as a behavioural component will be assessed objectively via accelerometry. Further, CV assessments will include pulse wave velocity; retinal, arterial, and venous diameters; brachial and retinal arterial endothelial function; carotid intima-media thickness; and systolic and diastolic function. The health distances for C-Health and C-Heart will be calculated using the methodology based on statistical (Mahalanobis) distance applied to measurements of quantitative biomarkers. DISCUSSION: This research seeks to identify physical fitness and CV biomarkers that best resemble underlying CV risk with age. Further, it will examine which physical fitness markers are impaired most in heart failure. The presented integrative approach could define new recommendations for diagnostic guidance in aging. Ultimately, this study is expected to offer a better understanding of which functional characteristics should be specifically targeted in primary and secondary prevention to achieve an optimal healthspan.

Validation of automatic wear-time detection algorithms in a free-living setting of wrist-worn and hip-worn ActiGraph GT3X.

BACKGROUND: Wrist-worn accelerometers are increasingly used in epidemiological studies to record physical activity. The accelerometer data are usually only analyzed if the convention for compliant wear time is met (i.e. ≥ 10 h per day) but the algorithms to detect wear time have been developed based on data from hip-worn devices only and have not been tested in a free-living setting. The aim of this study was to validate the automatic wear time detection algorithms of one of the most frequently used devices in a free-living setting. METHODS: Sixty-eight adults wore one ActiGraph GT3X+ accelerometer on the wrist and one on the hip and additionally recorded wear times for each device separately in a diary. Monitoring phase was during three consecutive days in a free-living setting. Wear time was computed by the algorithms of Troiano and Choi and compared to the diary recordings. RESULTS: Mean wear time was over 1420 min per day for both devices on all days. Lin's concordance correlation coefficient for the wrist-worn wear time was 0.73 (0.60; 0.82) when comparing the diary with Troiano and 0.78 (0.67; 0.86) when comparing the diary with Choi. For hip-worn devices the respective values were 0.23 (0.13; 0.33) for Troiano and 0.92 (0.88; 0.95) for Choi. Mean and standard deviation values for absolute percentage errors for wrist-worn devices were - 1.3 ± 8.1% in Troiano and 0.9 ± 7.7% in Choi. The respective values for hip-worn devices were - 17.5 ± 10% in Troiano and - 0.8 ± 4.6% in Choi. CONCLUSIONS: Hip worn devices may be preferred due to their higher accuracy in physical activity measurement. Automatic wear-time detection can show high errors in individuals, but on a group level, type I, type II, and total errors are generally low when the Choi algorithm is used. In a real-life setting and participants with a high compliance, the algorithm by Choi is sufficient to distinguish wear time from non-wear time on a group level.

MOBIlity assessment with modern TEChnology in older patients' real-life by the General Practitioner: the MOBITEC-GP study protocol.

BACKGROUND: Mobility limitations in older adults are associated with poor clinical outcomes including higher mortality and disability rates. A decline in mobility (including physical function and life-space) is detectable and should be discovered as early as possible, as it can still be stabilized or even reversed in early stages by targeted interventions. General practitioners (GPs) would be in the ideal position to monitor the mobility of their older patients. However, easy-to-use and valid instruments for GPs to conduct mobility assessment in the real-life practice setting are missing. Modern technologies such as the global positioning system (GPS) and inertial measurement units (IMUs) - nowadays embedded in every smartphone - could facilitate monitoring of different aspects of mobility in the GP's practice. METHODS: This project's aim is to provide GPs with a novel smartphone application that allows them to quantify their older patients' mobility. The project consists of three parts: development of the GPS- and IMU-based application, evaluation of its validity and reliability (Study 1), and evaluation of its applicability and acceptance (Study 2). In Study 1, participants (target N = 72, aged 65+, ≥2 chronic diseases) will perform a battery of walking tests (varying distances; varying levels of standardization). Besides videotaping and timing (gold standard), a high-end GPS device, a medium-accuracy GPS/IMU logger and three different smartphone models will be used to determine mobility parameters such as gait speed. Furthermore, participants will wear the medium-accuracy GPS/IMU logger and a smartphone for a week to determine their life-space mobility. Participants will be re-assessed after 1 week. In Study 2, participants (target N = 60, aged 65+, ≥2 chronic diseases) will be instructed on how to use the application by themselves. Participants will perform mobility assessments independently at their own homes. Aggregated test results will also be presented to GPs. Acceptance of the application will be assessed among patients and GPs. The application will then be finalized and publicly released. DISCUSSION: If successful, the MOBITEC-GP application will offer health care providers the opportunity to follow their patients' mobility over time and to recognize impending needs (e.g. for targeted exercise) within pre-clinical stages of decline.

Association of cardiorespiratory fitness with retinal vessel diameters as a biomarker of cardiovascular risk.

OBJECTIVE: We aimed to investigate the association of retinal microvascular health with cardiorespiratory fitness (VO2peak) and cardiovascular risk factors. METHODS: In a population of 260 obesity-enriched participants we investigated the association of retinal vessel diameters with cardiorespiratory fitness (CRF), body mass index (BMI) and blood pressure (BP). Retinal vessel imaging was performed by use of a fundus camera and a semi-automated processing software, calculating the central retinal arteriolar (CRAE) and venular equivalent (CRVE) as well as the arteriolar-to-venular diameter ratio (AVR). RESULTS: Participants had a mean age of 45.8 ±â€¯12.5 years and a BMI of 35.8 ±â€¯6.8 kg/m2. 45% of patients were diagnosed with hypertension, 26% with diabetes and 30% with dyslipidemia. Increasing VO2peak was independently associated with lower CRVE (ß = -0.600; CI -1.141, -0.060; p = 0.030). Higher BMI and mean arterial pressure were independently associated with narrower CRAE (ß = -0.492; CI -0.909, -0.076; p = 0.021 and ß = -0.268; CI -0.471, -0.066; p = 0.009, respectively) and lower AVR (ß = -0.002; CI -0.003, -0.000; p = 0.026 and ß = -0.001; CI -0.002, -0.000; p = 0.001, respectively). CONCLUSIONS: Higher cardiorespiratory fitness is associated with beneficial retinal microvascular health. Higher BMI and BP were associated with an impairment of retinal microvascular health. Exercise is known for its potential to improve body composition and reduce BP but may also prove to be an efficient therapy to counteract small vessel disease in cardiometabolic disease.

Associations of daily levels of PM10 and NO2 with emergency hospital admissions and mortality in Switzerland: Trends and missed prevention potential over the last decade.

BACKGROUND: In most regions of the world, levels and constituents of the air pollution mixture have substantially changed over the last decades. AIMS: To evaluate if the effects of PM10 and NO2 on daily emergency hospital admissions and mortality have changed during a ~10 year period in Switzerland; to retrospectively estimate prevention potential of different policy choices. METHODS: Thirteen Poisson-regression models across Switzerland were developed using daily PM10 and NO2 levels from central monitors and accounting for several temporal and seasonal confounders. Time trends of effects were evaluated with an interaction variable. Distributed lag models with 28 days exposure window were used to retrospectively predict missed prevention potential for each region. RESULTS: Overall, emergency hospitalizations and mortality from any medical cause increased by 0.2% (95% Confidence Interval [95% CI]: 0.01, 0.33) and 0.2% (95% CI: -0.1, 0.6) for a 10 µg/m(3) increment of PM10, and 0.7% (95% CI: 0.1, 1.3) for NO2 and mortality. Over the study period, the association between respiratory emergencies and PM10 changed by a factor of 1.017 (95% CI: 1.001, 1.034) and by a factor of 0.977 [95% CI: 0.956, 0.998]) for respiratory mortality among the elderly for NO2. During the study period, abatement strategies targeting a 20% lower overall mean would have prevented four times more cases than abating days exceeding daily standards. CONCLUSION: During the last decade, the short term effects of PM10 and NO2 on hospitalizations and mortality in Switzerland have almost not changed. More ambitious strategies of air pollutant reduction in Switzerland would have had non negligible public health benefits.

Accelerometer Metrics: Healthy Adult Reference Values, Associations with Cardiorespiratory Fitness, and Clinical Implications.

PURPOSE: Accelerometer-assessed physical activity (PA) can be summarized using cut-point-free or population-specific cut-point-based outcomes. We aimed to 1) examine the interrelationship between cut-point-free (intensity gradient (IG) and average acceleration (AvAcc)) and cut-point-based accelerometer metrics, 2) compare the association between cardiorespiratory fitness (CRF) and cut-point-free metrics to that with cut-point-based metrics in healthy adults aged 20 to 89 yr and patients with heart failure, and 3) provide age-, sex-, and CRF-related reference values for healthy adults. METHODS: In the COmPLETE study, 463 healthy adults and 67 patients with heart failure wore GENEActiv accelerometers on their nondominant wrist and underwent cardiopulmonary exercise testing. Cut-point-free (IG: distribution of intensity of activity across the day; AvAcc: proxy of volume of activity) and traditional (moderate-to-vigorous and vigorous activity) metrics were generated. The "interpretablePA" R-package was developed to translate findings into clinical practice. RESULTS: IG and AvAcc yield complementary information on PA with both IG ( P = 0.009) and AvAcc ( P < 0.001) independently associated with CRF in healthy individuals (adjusted R2 = 73.9%). Only IG was independently associated with CRF in patients with heart failure ( P = 0.043, adjusted R2 = 38.4%). The best cut-point-free and cut-point-based model had similar predictive value for CRF in both cohorts. We produced age- and sex-specific reference values and percentile curves for IG, AvAcc, moderate-to-vigorous PA, and vigorous PA for healthy adults. CONCLUSIONS: IG and AvAcc are strongly associated with CRF and thus indirectly with the risk of noncommunicable diseases and mortality, in healthy adults and patients with heart failure. However, unlike cut-point-based metrics, IG and AvAcc are comparable across populations. Our reference values provide a healthy age- and sex-specific comparison that may enhance the translation and utility of cut-point-free metrics in clinical practice.

Intensity or volume: the role of physical activity in longevity.

AIMS: To investigate how physical activity (PA) volume, intensity, duration, and fragmentation are associated with the risk of all-cause and cardiovascular disease mortality. To produce centile curves for PA volume and intensity representative of US adults. METHODS: This study is based on the observational 2011-2014 National Health and Nutrition Examination Survey (NHANES). Adults (age ≥20) with valid accelerometer, covariate, and mortality data were included. Average acceleration (AvAcc), intensity gradient (IG), and total PA served as proxies for volume, intensity, and duration of PA, respectively. Weighted Cox proportional hazard models estimated associations between outcome and PA metrics. RESULTS: In 7518 participants (52.0% women, weighted median age 49), there were curvilinear inverse dose-response relationships of all-cause mortality risk (81-month follow-up) with both AvAcc (-14.4% [95% CI -8.3 to -20.1%] risk reduction from 25th to 50th percentile) and IG (-37.1% [95% CI -30.0 to -43.4%] risk reduction from 25th to 50th percentile), but for cardiovascular disease mortality risk (N=7016, 82-month follow-up) only with IG (-41.0% [95% CI -26.7 to -52.4%] risk reduction from the 25th to 50th percentile). These relationships plateau at AvAcc: ∼35-45 mg and IG: -2.7 to -2.5. Associations of PA with all-cause and cardiovascular disease mortality are primarily driven by intensity and secondary by volume. Centile curves for volume and intensity were generated. CONCLUSION: Intensity is a main driver of reduced mortality risk suggesting that the intensity of PA rather than the quantity matters for longevity. The centile curves offer guidance for achieving desirable PA levels for longevity.

This study shows that the distribution of the intensity of physical activity accumulated across the day may be more important for mortality reduction than the quantity (volume), underscoring the relevance of integrating physical activity of higher intensity into daily routines for health optimisation.Higher physical activity intensity is more closely associated with reduced mortality risk than physical activity volume, particularly for cardiovascular disease mortality.We provide initial evidence suggesting health benefits when accumulating intense physical activity in continuous bouts rather than sporadically across the day.

Subcutaneous advanced glycation end products, cardiovascular risk factors and vascular health during childhood development in a Swiss population.

Background: Skin-derived advanced glycation end products (sAGEs) have been associated with cardiovascular (CV) risk and mortality in adults. We hypothesize that cardiorespiratory fitness (CRF), body mass index (BMI) and vascular health are associated with development of sAGEs during childhood. Methods: In our prospective cohort study, 1171 children aged 6-8 years were screened for sAGEs, BMI, retinal arteriolar diameters (CRAE) and pulse wave velocity (PWV), using standardized procedures. To determine CRF a 20 m shuttle run was performed. After four 4 years, all parameters were assessed in 675 children using the same protocols. Results: Higher initial CRF levels were significantly associated with lower sAGEs (ß [95 CI] -0.02 [-0.03 to -0.002] au, p = 0.022) levels at follow-up, although they showed a greater change from baseline to follow-up (ß [95 CI] 0.02 [0.002 to 0.03] au, p = 0.027). Moreover, individuals with higher sAGEs at baseline showed narrower CRAE (ß [95% CI] -5.42 [-8.76 to -2.08] µm, p = 0.001) at follow-up and showed a greater change in CRAE (ß [95% CI] -3.99 [-7.03 to -0.96] µm, p = 0.010) from baseline to follow-up. Conclusion: Exercise and higher CRF may help mitigate the formation of AGEs during childhood, thereby reducing the risk for development of CV disease associated with AGEs-induced damage. Preventive strategies may need to target CRF early in life to achieve improvement of CV risk factors and may counteract the development of CV disease later in life.

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.

Bivariate relation of vascular health and blood pressure progression during childhood.

BACKGROUND AND AIMS: Hypertension is a major risk factor for the development of cardiovascular disease (CVD) in adulthood. High blood pressure (BP) is associated with subclinical vascular impairments as early as childhood. We aimed to assess the association of retinal microvascular diameters and large artery pulse wave velocity (PWV) with progression of childhood BP. METHODS: In our prospective Basel cohort study, 1171 children aged 6-8 years were screened for BP, body mass index, retinal vessel diameters and PWV using standardized protocols. After 4 years, all parameters were assessed in 749 children using the same protocols. RESULTS: Children with narrower central retinal arteriolar diameters (CRAE) and higher PWV at baseline developed higher systolic BP after 4 years (ß [95% CI] 0.6 [0.072 to 1.164] mmHg per 10 µm decrease, p = 0.026 and ß [95% CI] 0.6 [0.331 to 0.838] mmHg per 0.1 m/s increase, p < 0.001, respectively). Children with increased systolic BP at baseline developed narrower CRAE and higher PWV at follow-up (ß [95% CI] -3.3 [-4.43 to -2.09] µm per 10 mmHg increase, p < 0.001 and ß [95% CI] 0.13 [0.10 to 0.16] m/s per 10 mmHg increase, p < 0.001, respectively). CONCLUSIONS: Retinal arteriolar diameter and PWV independently predict progression of childhood BP, while initial BP is linked to development of micro- and macrovascular impairments, describing a bivariate temporal relationship between vascular health and BP. Childhood may present a window of opportunity for initiation of primary prevention strategies for the treatment of high BP to help prevent manifestation of CVD later in life.