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Non-invasive ultrasound (US) imaging enables the assessment of the properties of superficial blood vessels. Various modes can be used for vascular characteristics analysis, ranging from radiofrequency (RF) data, Doppler- and standard B/M-mode imaging, to more recent ultra-high frequency and ultrafast techniques. The aim of the present work was to provide an overview of the current state-of-the-art non-invasive US technologies and corresponding vascular ageing characteristics from a technological perspective. Following an introduction about the basic concepts of the US technique, the characteristics considered in this review are clustered into: 1) vessel wall structure; 2) dynamic elastic properties, and 3) reactive vessel properties. The overview shows that ultrasound is a versatile, non-invasive, and safe imaging technique that can be adopted for obtaining information about function, structure, and reactivity in superficial arteries. The most suitable setting for a specific application must be selected according to spatial and temporal resolution requirements. The usefulness of standardization in the validation process and performance metric adoption emerges. Computer-based techniques should always be preferred to manual measures, as long as the algorithms and learning procedures are transparent and well described, and the performance leads to better results. Identification of a minimal clinically important difference is a crucial point for drawing conclusions regarding robustness of the techniques and for the translation into practice of any biomarker.

Patients recovering from COVID-19 often report symptoms of exhaustion, fatigue and dyspnoea and present with exercise intolerance persisting for months post-infection. Numerous studies investigated these sequelae and their possible underlying mechanisms using cardiopulmonary exercise testing. We aimed to provide an in-depth discussion as well as an overview of the contribution of selected organ systems to exercise intolerance based on the Wasserman gears. The gears represent the pulmonary system, cardiovascular system, and periphery/musculature and mitochondria. Thirty-two studies that examined adult patients post-COVID-19 via cardiopulmonary exercise testing were included. In 22 of 26 studies reporting cardiorespiratory fitness (herein defined as peak oxygen uptake—VO2peak), VO2peak was VO2peak was notably below normal even in the long-term. Given the available evidence, the contribution of respiratory function to low VO2peak seems to be only minor except for lung diffusion capacity. The prevalence of low lung diffusion capacity was high in the included studies. The cardiovascular system might contribute to low VO2peak via subnormal cardiac output due to chronotropic incompetence and reduced stroke volume, especially in the first months post-infection. Chronotropic incompetence was similarly present in the moderate- and long-term follow-up. However, contrary findings exist. Peripheral factors such as muscle mass, strength and perfusion, mitochondrial function, or arteriovenous oxygen difference may also contribute to low VO2peak. More data are required, however. The findings of this review do not support deconditioning as the primary mechanism of low VO2peak post-COVID-19. Post-COVID-19 sequelae are multifaceted and require individual diagnosis and treatment.

Background: Arterial stiffening is central to the vascular ageing process and a powerful predictor and cause of diverse vascular pathologies and mortality. We investigated age and sex trajectories, regional differences, and global reference values of arterial stiffness as assessed by pulse wave velocity (PWV). Methods: Measurements of brachial-ankle or carotid-femoral PWV (baPWV or cfPWV) in generally healthy participants published in three electronic databases between database inception and August 24th, 2020 were included, either as individual participant-level or summary data received from collaborators (n = 248,196) or by extraction from published reports (n = 274,629). Quality was appraised using the Joanna Briggs Instrument. Variation in PWV was estimated using mixed-effects meta-regression and Generalized Additive Models for Location, Scale, and Shape. Findings: The search yielded 8920 studies, and 167 studies with 509,743 participants from 34 countries were included. PWV depended on age, sex, and country. Global age-standardised means were 12.5 m/s (95% confidence interval: 12.1–12.8 m/s) for baPWV and 7.45 m/s (95% CI: 7.11–7.79 m/s) for cfPWV. Males had higher global levels than females of 0.77 m/s for baPWV (95% CI: 0.75–0.78 m/s) and 0.35 m/s for cfPWV (95% CI: 0.33–0.37 m/s), but sex differences in baPWV diminished with advancing age. Compared to Europe, baPWV was substantially higher in the Asian region (+1.83 m/s, P = 0.0014), whereas cfPWV was higher in the African region (+0.41 m/s, P < 0.0001) and differed more by country (highest in Poland, Russia, Iceland, France, and China; lowest in Spain, Belgium, Canada, Finland, and Argentina). High vs. other country income was associated with lower baPWV (−0.55 m/s, P = 0.048) and cfPWV (−0.41 m/s, P < 0.0001).Interpretation: China and other Asian countries featured high PWV, which by known associations with central blood pressure and pulse pressure may partly explain higher Asian risk for intracerebral haemorrhage and small vessel stroke. Reference values provided may facilitate use of PWV as a marker of vascular ageing, for prediction of vascular risk and death, and for designing future therapeutic interventions. Funding: This study was supported by the excellence initiative VASCage funded by the Austrian Research Promotion Agency, by the National Science Foundation of China, and the Science and Technology Planning Project of Hunan Province. Detailed funding information is provided as part of the Acknowledgments after the main text.

This project aims to conduct a scoping review of the available diagnostic tools for the overtraining syndrome.

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.; FMD, L-FMC and; V; .; O; 2; peak 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; .; O; 2; peak-associated variations in age-related differences of endothelial function independent of classical cardiovascular risk factors.; FMD was negatively associated with age in healthy adults (adjusted R; 2; = 0.27, partial R; 2; = 0.07,; p; < 0.001) and in cardiovascular patients (adjusted R; 2; = 0.29, partial R; 2; = 0.05,; p; = 002). L-FMC showed no association with age. In models predicting the change of FMD with higher age,; V; .; O; 2; peak accounted for 2.8% of variation in FMD (χ; 2; (5) = 5.37,; p; = 0.372,; s; = 1.43). Thereby,; V; .; O; 2; peak-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; .; O; 2; peak ≤3rd percentile compared to; V; .; O; 2; peak ≥97th percentile) in both, the healthy sample and in cardiovascular patients.; 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.

We performed untargeted profiling of circulating microRNAs (miRNAs) in a well characterized cohort of older adults to verify associations of health and disease-related biomarkers with systemic miRNA expression. Differential expression analysis revealed 30 miRNAs that significantly differed between healthy active, healthy sedentary and sedentary cardiovascular risk patients. Increased expression of miRNAs miR-193b-5p, miR-122-5p, miR-885-3p, miR-193a-5p, miR-34a-5p, miR-505-3p, miR-194-5p, miR-27b-3p, miR-885-5p, miR-23b-5b, miR-365a-3p, miR-365b-3p, miR-22-5p was associated with a higher metabolic risk profile, unfavourable macro- and microvascular health, lower physical activity (PA) as well as cardiorespiratory fitness (CRF) levels. Increased expression of miR-342-3p, miR-1-3p, miR-92b-5p, miR-454-3p, miR-190a-5p and miR-375-3p was associated with a lower metabolic risk profile, favourable macro- and microvascular health as well as higher PA and CRF. Of note, the first two principal components explained as much as 20% and 11% of the data variance. miRNAs and their potential target genes appear to mediate disease- and health-related physiological and pathophysiological adaptations that need to be validated and supported by further downstream analysis in future studies.Clinical Trial Registration: ClinicalTrials.gov: NCT02796976 ( https://clinicaltrials.gov/ct2/show/NCT02796976 ).

Additional file 4: Table 2S. Motor imagery: Summary of Findings using modified GRADE.

The purpose of this study is to examine the response of a comprehensive panel of circulating sphingolipids to a single high-intensity interval training (HIIT) session in healthy females and males in their twenties.

Additional file 3: Table 1S. Characteristics of the Included Measurement Tools for Motor Imagery.

Additional file 5: Table 3S. Characteristics of the Included Measurement Tools for Mental Imagery.

Additional file 6: Table 4S. Mental imagery Assessments: Summary of Findings using modified GRADE.

Additional file 1. Example search strategy for web of science.

Additional file 2. COSMIN Risk of Bias checklist.

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). Supplementary Information The online version contains supplementary material available at 10.1186/s12874-021-01350-6.

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.

Background: Metformin is an effective treatment option for type 2 diabetes mellitus, and it is, to this day, the most prescribed oral antiglycaemic drug. Besides its effects mainly on mitochondrial activity, an off-label use came up as a pharmaceutical for subjects with a diagnosis of polycystic ovarian syndrome (PCOS) along with altered steroid hormone homeostasis. Besides these effects, even an influence on mood and social behavior was described, leading to the aim of this case report to elucidate the effects before versus after treatment with metformin on steroid hormones and social behavior. Methods: A female patient with diagnosed PCOS was analyzed three times for steroid hormone levels. The first analysis was performed before treatment; the second, after a period of 71 days with metformin at 2 × 500 mg; and the third, after a total of 144 days with metformin at 2 × 500 mg. Spot urine probes were taken in the morning for a combined gas chromatography–mass spectrometry (GC-MS), and the steroid levels were adjusted for creatinine excretion. A questionnaire on social behavior (Autism Spectrum Questionnaire) was administered before treatment and after 71 days. Results: A decrease in all the steroid hormones measured was detected after 71 and 144 days of treatment with metformin, being more pronounced after 144 days of treatment and highly significant (p < 0.001). Furthermore, in the untreated state, the class of corticosterone metabolites showed increased values compared to the female reference values for TH-11-DH-corticosterone, TH-corticosterone, and 5a-TH-corticosterone. In the class of estrogen metabolites, increased values compared to the reference values were detected for 17b-estradiol; in the class of 11-deoxycortisol metabolites, an increase in TH-11-deoxycortisol was detected. For the class of cortisol metabolites, increased values compared to the reference values were detected for cortisone, TH-cortisone, a-cortolone, b-cortolone, 20b-dihydrocortisone, cortisol, TH-cortisol, 5a-TH-cortisol, a-cortol, 20b-dihydrocortisol, and 6b-OH-cortisol. No increases in androgen metabolites were detected. Interestingly, weight decreased from 93.4 kg to 91.3 kg after 71 days and fell to 82.7 kg after 144 days of treatment. The skeletal muscle mass was 30.1 kg at the first visit, decreasing to 29.9 kg and to 27.5 kg. No significant difference in the social behavior score from baseline to after 71 days of treatment was detected. Discussion: Metformin improved the steroid hormone profiles from levels above the upper reference values to the middle of the reference values after 71 days and to the lower ends of the reference values after 144 days of treatment. This implies not only that metformin has an effect on steroid hormone levels, but in addition that the efficacy of the pharmaceutical seems to depend on the time interval from intake. To summarize, in this patient, steroid hormones were affected but social behavior was not. If no effect of metformin on social behavior exists, this must be supported by further cases.

Supplemental material, sj-docx-2-sph-10.1177_19417381211044739 for Diagnosing Overtraining Syndrome: A Scoping Review by Justin Carrard, Anne-Catherine Rigort, Christian Appenzeller-Herzog, Flora Colledge, Karsten Königstein, Timo Hinrichs and Arno Schmidt-Trucksäss in Sports Health: A Multidisciplinary Approach

Supplemental material, sj-docx-1-sph-10.1177_19417381211044739 for Diagnosing Overtraining Syndrome: A Scoping Review by Justin Carrard, Anne-Catherine Rigort, Christian Appenzeller-Herzog, Flora Colledge, Karsten Königstein, Timo Hinrichs and Arno Schmidt-Trucksäss in Sports Health: A Multidisciplinary Approach

Supplemental material, sj-docx-1-sph-10.1177_19417381211044739 for Diagnosing Overtraining Syndrome: A Scoping Review by Justin Carrard, Anne-Catherine Rigort, Christian Appenzeller-Herzog, Flora Colledge, Karsten Königstein, Timo Hinrichs and Arno Schmidt-Trucksäss in Sports Health: A Multidisciplinary Approach

Supplemental material, sj-docx-3-sph-10.1177_19417381211044739 for Diagnosing Overtraining Syndrome: A Scoping Review by Justin Carrard, Anne-Catherine Rigort, Christian Appenzeller-Herzog, Flora Colledge, Karsten Königstein, Timo Hinrichs and Arno Schmidt-Trucksäss in Sports Health: A Multidisciplinary Approach

Supplemental material, sj-docx-3-sph-10.1177_19417381211044739 for Diagnosing Overtraining Syndrome: A Scoping Review by Justin Carrard, Anne-Catherine Rigort, Christian Appenzeller-Herzog, Flora Colledge, Karsten Königstein, Timo Hinrichs and Arno Schmidt-Trucksäss in Sports Health: A Multidisciplinary Approach

Background: Accurately assessing dietary intake is crucial in understanding how diet affects a person’s health. In large cohorts, paper-based Dietary Assessment Tools (DAT) such as food recalls or food frequency questionnaires have emerged as valid tools with a low burden for participants. Objective: To validate a visually aided DAT for use in studies with Swiss adults against the gold standard of a weighed 7-day food record (7d-FR). Design: Fifty-one subjects (n=24 women, n=27 males) participated in the study and were recruited within two age groups (20- 40y and 50-70 y). Each subject filled out the visually aided DAT, then the 7dFR. The DAT was compared to the 7d-FR for total energy intake, macronutrients, sugar, water, and portions of fruits and vegetables. Pearson correlation and Bland-Altman analyses were used for statistical analyses. Results: Total correlations ranged from 0.288 (sugar, p 0.5, whereas only water and protein reached those values in the young group. Both groups overestimated total calories in kcal (+14.0%), grams of protein (+44.6%), and fats (+36.3%), and portions of fruits and vegetables (+16.0%) but strongly underestimated sugar intake (-50.9%). Conclusions: This DAT showed that all macronutrients and total energy intake were estimated more accurately by the older age group and therefore might be adequate to capture dietary habits in older Swiss adults.

Supplemental material, sj-docx-2-sph-10.1177_19417381211044739 for Diagnosing Overtraining Syndrome: A Scoping Review by Justin Carrard, Anne-Catherine Rigort, Christian Appenzeller-Herzog, Flora Colledge, Karsten Königstein, Timo Hinrichs and Arno Schmidt-Trucksäss in Sports Health: A Multidisciplinary Approach

Background Map-based tools have recently found their way into health-related research. They can potentially be used to quantify older adults’ life-space. This study aimed to evaluate the validity (vs. GPS) and the test-retest reliability of a map-based life-space assessment (MBA). Methods Life-space of one full week was assessed by GPS and by MBA. MBA was repeated after approximately 3 weeks. Distance-related (mean and maximum distance from home) and area-related (convex hull, standard deviational ellipse) life-space indicators were calculated. Intraclass correlations (MBA vs. GPS and test-retest) were calculated in addition to Bland-Altman analyses (MBA vs. GPS). Results Fifty-eight older adults (mean age 74, standard deviation 5.5 years; 39.7% women) participated in the study. Bland-Altman analyses showed the highest agreement between methods for the maximum distance from home. Intraclass correlation coefficients ranged between 0.19 (95% confidence interval 0 to 0.47) for convex hull and 0.72 (95% confidence interval 0.52 to 0.84) for maximum distance from home. Intraclass correlation coefficients for test-retest reliability ranged between 0.04 (95% confidence interval 0 to 0.30) for convex hull and 0.43 (95% confidence interval 0.19 to 0.62) for mean distance from home. Conclusions While acceptable validity and reliability were found for the distance-related life-space parameters, MBA cannot be recommended for the assessment of area-related life-space parameters. peerReviewed

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.

Background Regular physical activity (PA) is an essential component of a successful type 2 diabetes treatment. However, despite the manifest evidence for the numerous health benefits of regular PA, most patients with type 2 diabetes remain inactive, often due to low motivation and lack of PA enjoyment. A recent and promising approach to help overcome these PA barriers and motivate inactive individuals to change their PA behavior is PA-promoting smartphone games. While short-term results of these games are encouraging, the long-term success in effectively changing PA behavior has to date not been confirmed. It is possible that an insufficient incorporation of motivational elements or flaws in gameplay and storyline in these games affect the long-term motivation to play and thereby prevent sustained changes in PA behavior. We aimed to address these design challenges by developing a PA-promoting smartphone game that incorporates established behavior change techniques and specifically targets inactive type 2 diabetes patients. Objective To investigate if a self-developed, behavior change technique-based smartphone game designed by an interdisciplinary team is able to motivate inactive individuals with type 2 diabetes for regular use and thereby increase their intrinsic PA motivation. Methods Thirty-six inactive, overweight type 2 diabetes patients (45-70 years of age) were randomly assigned to either the intervention group or the control group (one-time lifestyle counseling). Participants were instructed to play the smartphone game or to implement the recommendations from the lifestyle counseling autonomously during the 24-week intervention period. Intrinsic PA motivation was assessed with an abridged 12-item version of the Intrinsic Motivation Inventory (IMI) before and after the intervention. In addition, adherence to the game-proposed PA recommendations during the intervention period was assessed in the intervention group via the phone-recorded game usage data. Results Intrinsic PA motivation (IMI total score) increased significantly in the intervention group (+6.4 (SD 4.2; P

International audience; While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required.

Background: Clinical studies revealed age and pathological-related arterial stiffening. Arterial stiffening is associated with a higher risk of cardiovascular disease. Cardio-ankle vascular index (CAVI), which reflects both central elastic and peripheral muscular arterial stiffness, has been applied as a simple noninvasive method to evaluate the risk for cardiovascular events. However, whether it is necessary to standardize the time of the day when performing this measurement is unknown. We aim to examine the effect of daytime on CAVI in individuals with and without heart disease. Methods: We investigated the daytime variation of CAVI using Vasera VS-1500N (Fukuda Denshi; Japan) in 23 healthy young individuals (28.3±4.7yr, HY), 22 healthy elderly individuals (61.1±9.0 yr, HE) and 25 patients with heart disease (63.9±11.5yr, HD). Results: The effect of time on CAVI was shown to be significant in both univariate and multivariate analysis. Age was found as a significant determinant of CAVI (p

Study data – further outcomes. (DOCX 49 kb)

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist. (DOC 121 kb)

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist. (DOC 121 kb)

Background In the last centuries, life expectancy in industrialized nations has doubled. Many people reach an advanced age, but the period of life in which a manifest cardiovascular disease has to be treated, is continuously lengthening. Vascular biomarkers and risk scores are used to determine cardiovascular risk. In recent years, however, there has been a shift toward measures of healthy lifestyle, which are more focused on determining health potential. However, the relationship between lifestyle, especially nutrition and physical activity, and the traditionally used biomarkers is still poorly understood. Aims This PhD project had several aims. The first one was to validate a visually aided dietary assessment tool (DAT). Second, this project aimed at comparing various lifestyle metrics, calculated as a cardiovascular health score, and their influence on the structure and function of large human arteries in both a healthy Swiss (aged 50+ years old) and Finnish (aged 55-74 years old) population. Third, the effects of a 4-year lifestyle-based intervention on carotid structure in the same Finnish population were analyzed, to determine if atherosclerotic progression could be slowed. Methods The DAT was validated against a weighed seven-day food record (7d-FR). Young (20-40 years old) and older (50-70 years old) adults were recruited. The DAT was compared to the 7d-FR for total energy intake, macronutrients, sugar, water, and portions of fruits and vegetables. The Finnish Dose-Responses to Exercise Training (DR’s EXTRA) study was a randomized-controlled trial lasting four years that consisted of six groups: aerobic exercise, resistance exercise, diet, aerobic exercise + diet, resistance exercise + diet, and reference. Carotid intima-media thickness (cIMT), and lumen diameter (cLD) were used as vascular biomarkers to quantify atherosclerotic progression during the intervention and were measured by transcutaneous ultrasound using state-of-the-art wall contour detection techniques. In a cross-sectional approach of the DR’s EXTRA study, adherence to the American Heart Association’s “Life’s Simple 7” cardiovascular health score, consisting solely of modifiable lifestyle metrics, was compared with cIMT and cLD, as well as carotid distensibility. The Life’s Simple 7 score was divided into poor, intermediate, and ideal cardiovascular health. The Swiss cross-sectional Cardiopulmonary Exercise Testing (COmPLETE) study included a healthy sample of the Swiss population. For this PhD project, only a sub-sample aged 50-91 years old was considered. The Life’s Simple 7 were also used to determine cardiovascular health and were compared to arterial properties, namely cIMT, cLD, carotid distensibility coefficient (DC), flow-mediated dilation (FMD), and brachial-ankle pulse wave velocity (baPWV). Results DAT: 51 participants were included. Correlations between the DAT and the 7d-FR ranged from 0.288 (sugar, p

Background Unipolar depression is a debilitating disease and one of the leading causes of global disease burden. Unipolar depression is bidirectionally associated with insomnia and attenuated heart rate variability. Insomnia has a negative effect on disease trajectory across all treatment phases in depression. Attenuated heart rate variability is one of the pathophysiological mechanisms explaining the increased risk of cardiovascular disease in patients with depression. Approximately one-third of the patients do not remit when treated with guideline therapies for depression, i.e., psychotherapy and pharmacotherapy. Moreover, insomnia is one of the most frequent residual symptoms in those who respond or remit. Lastly, guideline therapies do not seem to improve heart rate variability. Therefore, adjuvant therapies to improve depressive and insomnia symptoms and heart rate variability are need. Exercise is a promising auxiliary treatment based on previous research, but multiple knowledge gaps remain. Aims This Ph.D. project aimed to address important knowledge gaps. The first aim was to summarize the existing research concerning the effects of aerobic, resistance, and mind-body exercise on sleep quality in patients with unipolar depression. The second aim was to quantify the effect of a single bout of moderate-intensity aerobic exercise performed in the afternoon on sleep outcomes in patients with unipolar depression. The third aim was to quantify the effect of a single bout of moderate-intensity aerobic exercise performed in the afternoon on mood and adverse effects. The fourth and last aim was to quantify the effect of a single bout of moderate-intensity aerobic exercise performed in the afternoon on nocturnal and pre-sleep arousal. Methods A systematic review with network meta-analysis and a randomized controlled trial were conducted within this Ph.D. project. The systematic review (PROSPERO CRD42019115705) was conducted according to the PRISMA network meta-analysis extension and AMSTAR2 guidelines. A systematic search was conducted in multiple electronic bibliographic databases (PubMed, EMBASE, Cochrane Library, PsycINFO, Sportdiscus, CINHAL, OpenGrey, ProQuest Dissertations & Theses A&I, Clinicaltrials.gov, and WHO International Clinical Trials Registry) from their inception until February 12th, 2020. Randomized controlled trials investigating the effects of regular aerobic, resistance, or mind-body exercise on self- or observer-reported sleep quality in patients with depression were included. Network meta-analysis was conducted, and the network geometry, forest plots, and league tables were reported. The trial (NCT03673397) was a two-arm parallel-group, randomized, outcome assessor-blinded, controlled, superiority trial. It was conducted and reported in compliance with SPIRIT, GRAPH, FAIR, CONSORT, GCP, and GDPR guidelines and directives. The trial took place in the OBERWAID clinic. Patients between 18 and 65 years of age with a primary diagnosis of unipolar depression were included. The intervention was a single 30-minute bout of moderate aerobic exercise. The control group sat and read for 30 minutes. The primary outcome was sleep efficiency measured by polysomnography. Secondary outcomes were other polysomnographic variables, subjective sleep quality, daytime sleepiness, mood states, adverse events, pre-sleep arousal, as well as pre-sleep and nocturnal heart rate variability. Results Publication 1: The effects of aerobic, resistance, and meditative movement exercise on sleep in individuals with depression: protocol for a systematic review and network meta-analysis This publication provides a thorough account of the purpose and methodology of the systematic revie and network meta-analysis. The report adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guideline. Publication 2: The effects of exercise on sleep in unipolar depression: a systematic review and network meta-analysis The network meta-analysis was based on 17 trials with N = 1645 patients randomized to 13 treatments yielding 35 comparisons. The confidence in the mixed (i.e., direct and indirect) evidence was moderate (43% of comparisons), low (39% of comparisons), or very low (18% of comparisons). All exercise types and intensity levels except moderate aerobic exercise improved sleep quality more than passive control. The effects of active control, mind-body exercise, treatment as usual, and vigorous aerobic exercise were similar. Vigorous strength exercise yielded a significantly larger effect on sleep quality than aerobic or mind-body exercise compared to passive control. None of the exercise modes or intensities was significantly less efficacious than treatment as usual. Adding moderate or vigorous aerobic exercise to treatment as usual resulted in slightly larger effect sizes, but these differences were not statistically significant. However, vigorous strength exercise alone or adding mind-body exercise to treatment as usual resulted in significantly larger effects than treatment as usual alone. Publication 3: The acute effects of aerobic exercise on sleep in patients with depression: study protocol for a randomized controlled trial This publication presents the rationale, hypothesis, and procedures of the randomized controlled trial in detail. The publication was written in accordance with the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) statement. Publication 4: The acute effects of aerobic exercise on sleep in patients with unipolar depression: a randomized controlled trial There was no evidence for an effect of allocation on polysomnographic sleep efficiency. This finding was confirmed in all sensitivity analyses (i.e., complete case and per-protocol analysis as well as excluding an influential data point). There was also no evidence that chronotype, expectancy, or credibility altered the effect of allocation. No evidence of a correlation between exercise intensity (i.e., rate of perceived exertion and percent of maximal age-predicted heart rate) and sleep efficiency at follow-up was found. Furthermore, there was no evidence for an effect of allocation on any of the secondary objective or subjective measures of sleep or daytime sleepiness. However, there was a strong effect of allocation on mood immediately post-exercise. This effect was consistent across all subscales, with the intervention group showing decreases in negative and increases in positive mood states. Although there was a trend toward lower symptom severity in the intervention group compared to the control group immediately post-exercise, this effect was non-significant. Publication 5: The acute effects of aerobic exercise on nocturnal and pre-sleep arousal in patients with unipolar depression: a randomized controlled trial There was no evidence for an effect of allocation on root mean square of successive differences of normal-to-normal intervals during the sleep period. All sensitivity analyses confirmed this finding (i.e., only using complete data, excluding patients who smoked, used either beta-blockers, any antidepressant, or only tricyclic antidepressants). Furthermore, no evidence suggested that allocation altered root mean square of successive differences of normal-to-normal intervals in any sleep stage (although N1 was not analyzed due to insufficient data). There was also no evidence to suggest that any of the other heart rate variability parameters were affected by allocation during the sleep period. Lastly, no evidence indicated that pre-sleep root mean square of successive differences of normal-tonormal intervals or pre-sleep somatic and cognitive arousal were altered by allocation. Conclusions The findings of the network meta-analysis confirm the salubrious effects of regular aerobic, resistance, and mind-body exercise for patients with depression. None of the investigated exercise types or intensities lowered subjective sleep quality. Vigorous resistance and mind-body exercise in combination with treatment as usual elicited the most substantial effects. Therefore, these exercise modes might be recommended to target sleep quality in patients with depression specifically. However, the confidence in these findings is low, and thus more research is needed. The results of publications 4 and 5 confirm previous findings, which found no evidence of an adverse effect of acute exercise after 02:00 pm on sleep-related outcomes. The absence of evidence was consistent across all outcomes of sleep, pre-sleep arousal, and heart rate variability. Thus, these findings question the validity of the exercise timing recommendations in sleep hygiene guidelines. Moreover, a single bout of moderate-intensity exercise lasting 30 minutes can be recommended to improve the mood of patients with depression. In summary, regular aerobic, resistance, and mind-body exercise can be recommended as an adjuvant treatment to improve mood and insomnia symptoms in patients with depression.

40812 Before this PhD project started, evidence showed that physical inactivity causes a substantial health and economic burden globally. For Switzerland, there was research available investigating the burden of physical inactivity. However, this research estimated the burden for the entire country without differentiating between sub regions although the prevalence of physical inactivity varies significantly between the French-, German- and Italian-speaking regions. Therefore, this thesis had three aims: 1. Estimating the health and economic burden of physical inactivity in Switzerland and for the French-, German- and Italian-speaking language regions separately 2. Systematically reviewing trial-based economic evaluations of interventions to reduce physical inactivity 3. Developing a health economic model that investigates the cost-effectiveness of physical activity interventions in Switzerland and its three language regions The thesis showed that the burden of physical inactivity in Switzerland is substantial and that the French- and Italian-speaking regions are over-proportionally affected. These two regions distinguish themselves from the German-speaking region by having a higher prevalence of physical inactivity, higher per capita health care spending, and higher disease prevalence. Due to the substantial burden of physical inactivity, interventions aiming to increase physical activity should be considered. In the systematic review we conducted, we found evidence from randomized controlled trials indicating the cost-effectiveness of some physical activity interventions for primary prevention in adults. These interventions were then further evaluated in a cost-effectiveness model built for the Swiss setting. This model showed that Swiss policy makers have cost-effective options of physical activity promotion. We recommend that individualized advice and general practitioner referral be further evaluated as interventions and that decision-making considers the specifics of the Swiss language regions. Furthermore, we judge the cost-effectiveness model to be not only relevant for Switzerland but also for other multicultural countries. Based on similar data availability, our model has the potential to be applied beyond Switzerland, primarily to high-income countries with a comparable background, as a tool to guide societal efforts in primary prevention of physical-inactivity-related diseases.

Background Aging and the changing age demographics potentially represent one of the most critical problems of our time. The shift of the major causes of morbidity towards chronic disease, coupled with changing age demographics, is likely to lead to an epidemic of age-driven chronic disease. Cardiovascular diseases (CVD), which include heart failure (HF), are the leading cause of death worldwide. The prevalence of HF continues to rise over time in sync with the aging population. HF has been defined as a global pandemic, based on the large number of people affected by the syndrome worldwide. Physiological functions decline with age, and these declines often end in a systemic process that contributes to numerous physiological impairments and disease. The ability to perform physical tasks is critical for maintaining overall functional capacity, and physical fitness parameters are biomarkers of health among older adults, predicting quality of life, disability, and mortality. Links between CVD risk factors and limitations in physical fitness have been widely described. Physical fitness markers include measurements of endurance capacity, muscle strength, and neuromuscular coordination. Cardiorespiratory fitness (CRF) and other markers measured by cardiopulmonary exercise testing (CPET) have been described to be highly useful health markers, and VO2peak is even suggested for use as a vital sign in clinical evaluation. Some limitations, however, likely hinder a wider application of CPET including: 1) the evaluation of whether the true individual physiological limit is reached and VO2peak can be determined, 2) the lack of accurate and suitable normative reference values of healthy individuals across the lifespan, 3) submaximal CPET parameters as an alternative in the case VO2peak was not reached. Further, additional physical fitness measurements and their combination to a composite outcome could provide a useful tool for the management of age-related chronic disease such as HF. To date, however, no attempts to combine biomarkers of several physical fitness domains have been performed. Aims The aims of this Ph.D. project were: (1) To review the current evidence of CPET variables for the purpose of risk stratification and management of heart failure with reduced ejection fraction (HFrEF); (2) To design and conduct a study involving a comprehensive assessment of physical fitness components and cardiovascular (CV) function to identify which markers are most highly associated with CV risk with increasing age and which markers are most impaired in HF; (3) To determine data-based and age-dependent cutoffs for maximal exercise criteria for a general population which is free of exercise-limiting chronic conditions; (4) To provide reference values for maximal and submaximal CPET parameters across the adult age spectrum of a healthy European cohort and to analyze the associations between physical activity (PA) levels and CPET parameters; (5) To determine whether VO2-kinetics is a useful marker for risk stratification of HF; and finally (6) to analyze whether a composite measure (health distance, HD) of physical fitness biomarkers can increase discriminative performance between healthy individuals and patients with HF compared to standard clinical biomarkers. Methods In this Ph.D. project, a literature review (publication 1) and one large project including two cross-sectional studies (publication 2-6) were conducted. In the literature review, five widely studied gas exchange variables from CPET (VO2peak, VE/VCO2 slope, exercise oscillatory ventilation (EOV), oxygen uptake efficiency slope (OUES) and PETCO2) were evaluated regarding risk stratification and management of HFrEF based on nine different criteria (proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus and reference values). The literature search was performed for each of the five variables and the nine criteria separately, beginning with a search for systematic reviews using the Cochrane Library. Subsequently, simple search strings were used for electronic literature searches in the Medline and Embase databases. The COmPLETE Project, the project of this Ph.D. Thesis, consists of two parts: COmPLETE-Health and COmPLETE-Heart (study protocol, publication 2). COmPLETE-Health examined physical fitness and CV markers in a healthy population aged between 20 and 90 years. A total number of approximately 490 participants with a valid cardiorespiratory fitness measurement (the primary outcome) were included. Participants were equally distributed over the 7 age decades from 20–30 to 80–90 and by sex (50% female). COmPLETE-Heart examined the same physical fitness and CV markers as COmPLETE-Health in 80 patients at different stages of chronic HF. CRF was assessed by CPET. Secondary outcomes included walking speed, balance, isometric strength, peak power, and handgrip strength. PA as a behavioral component was assessed objectively via accelerometry, and several CV assessments were performed. For publication 3, CPET data from the COmPLETE-Health Study were analyzed involving 274 men and 252 women. All participants underwent a CPET until maximal voluntary exertion using a cycle ergometer. To determine new exhaustion criteria, based on maximal respiratory exchange ratio (RERmax) and age-predicted maximal heart rate (APMHR), one-sided lower tolerance intervals for the tests confirming VO2 plateau status were calculated using a confidence level of 95% and a coverage of 90%. In publication 4, CPET data of the COmPLETE-Health Study were further analyzed. Participant included in the final analysis, had to have reached secondary exhaustion criteria based on age-dependent RER cut-offs during the CPET. PA was objectively and continuously measured over 14 days using a triaxial accelerometer. Quantile curves were calculated for CPET parameters to provide reference data. To investigate the associations between CPET parameters and PA levels, linear regression analysis was performed. In publication 5, the CPET data of both the healthy participants of the COmPLETE-Health Study and the patients with HF of the COmPLETE-Heart Study were analyzed. To achieve comparability, we first created a matched dataset where we matched two healthy participants to every patient with HF according to age and sex (2:1 matching). The CPET was preceded by a 3-minute low-intensity warm-up and followed by a 3-minute recovery bout. VO2-kinetics was calculated from the rest-to-exercise transition of the warm-up bout (on-kinetics), from the exercise-to-recovery transition following ramp test termination (off-kinetics), and from the initial delay of VO2 during the warm-up to ramp-test transition (ramp-kinetics). As in publication 5, both groups—COmPLETE-Health and COmPLETE-Heart—were analyzed in publication 6. Fifty-nine biomarkers in the categories fitness (cardiovascular endurance, muscle strength, and neuromuscular coordination) and general health (anthropometry, vascular and respiratory health and blood testing) were used for the analysis. HDs were computed for all relevant biomarkers and domain-specific subsets as the Mahalanobis distance defined for vectors of biomarker measurements that quantified the deviations of individuals’ biomarker profiles from “optimal” values in the “reference population” (healthy study participants aged less than 40 years). Linear regressions were fitted with HD outcomes and disease status (HF/Healthy) and relevant covariates as predictors. Also were logistic regressions fitted for the disease status as the outcome and sex, age, and age2 as covariates in the base model and the same covariates plus combinations of one or two HDs to compare different models’ performance in predicting HF cases. Results Publication 1: The Role of Gas Exchange Variables in Cardiopulmonary Exercise Testing for Risk Stratification and Management of Heart Failure with Reduced Ejection Fraction (1). This review demonstrated that the evidence supporting the clinical assessment of variables beyond peak VO2 for HF patients with reduced ejection fraction is well established. The five variables: peak VO2 or predicted peak VO2, VE/VCO2 slope, EOV, OUES, and PETCO2 provide evidence for the criteria “proof of concept”, “prospective validation”, and “incremental value”. Based on the results of this review, the combined assessment of peak VO2 or predicted peak VO2, VE/VCO2 slope, and EOV is recommended as part of the clinical examination. Further, because no additional costs are incurred in investigating the OUES and PETCO2, these parameters should also be considered as part of routine analysis. Each of those five variables reflects in part a different pathophysiologic feature of HFrEF, and combining these variables delivers a broader three-dimensional picture of the pathophysiologic process and severity of HFrEF. A multi-variable approach is, therefore, appropriate. Publication 2: Functional Aging in Health and Heart Failure: the COmPLETE Study (2). The COmPLETE study will allow for the investigation and characterization of the physical fitness components of endurance capacity, muscle strength, and neuromuscular coordination in individuals aged 20 to 90 years without chronic diseases and in patients with HF. The age-matched comparison with patients at different stages of HF may provide an estimate of the health distance of different fitness parameters to healthy individuals. Health distance provides a new complex measure of aging-related decline in the adaptive capacity of the organism by comparing the values of the physiological “norms” (COmPLETE-Health) with those with prevalent HF (our example). The study’s results shall provide a better understanding of which functional characteristics should specifically be targeted in primary and secondary prevention to achieve optimal healthspan. Publication 3: New Data-based Cutoffs for Maximal Exercise Criteria Across the Lifespan (3). The analysis of 526 participants aged 20–90 years revealed data-based optimal secondary exhaustion criteria according to tolerance intervals optimizing the evaluation of VO2max. These criteria are for the age group of 20 to 39 years: RERmax ≥ 1.13, APMHR210 ≥ 96%, and APMHR208 93%; for the age group of 40 to 59 years: RERmax ≥ 1.10, APMHR210 ≥ 99%, and APMHR208 92%; and, for the age group of 60 to 69 years: RERmax ≥ 1.06, APMHR210 ≥ 99%, and APMHR208 89%. The proposed cut-off values for secondary criteria reduce the risk of underestimating VO2max. The criteria differ clearly from previously used lower cut-offs and our results show that higher criteria need to be applied. Lower criteria than the ones we suggest would increase false-positive results, assuming participants are exhausted although, in fact, they are not. Publication 4: Novel CPET Reference Values in Healthy Adults: Associations with Physical Activity (4). VO2peak values observed in the group aged 20–29 years were 46.6 ± 7.9 and 39.3 ± 6.5 (mL/kg/min) for males and females, respectively. On average, each age category (10-year increments) showed a 10% lower VO2peak relative to the next younger age category. VO2peak 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 VO2peak (mL/kg/min) and the level of habitual PA performed at vigorous PA (estimate 0.26; p < 0.001]. Publication 5: VO2 Kinetics: An Alternative to Peak VO2 for Risk Stratification and Diagnosis in Heart Failure (5). VO2 off-kinetics demonstrated the highest z-score differences between healthy participants and patients with HF. Furthermore, off-kinetics were strongly associated with VO2peak. In contrast, ramp-kinetics and on-kinetics showed only minimal z-score differences between healthy participants and patients with HF. The best on- and off-kinetic parameters significantly improved a model to predict disease severity. However, there was no significant additional value of VO2-kinetics when VO2peak was part of the model. Publication 6: Composite Measures of Physical Fitness to Discriminate between Healthy Aging and Heart Failure: the COmPLETE Study (6). Nine out of ten calculated HDs showed evidence of group differences between the Healthy and the HF group (p ≤ 0.002), and most models presented a negative estimate of the interaction term age by group (p < 0.05 for eight out of ten HDs). The predictive performance of HF cases of the base model significantly increased by adding HD General health or HD Fitness with an increase in the AUC estimate from 0.63 to 0.89 and 0.84, respectively. HD Cardiovascular endurance alone reached an AUC of 0.88. Further, there is evidence that the combination of HD Cardiovascular endurance and HD General health shows superior predictive power compared to when using HDs alone. Conclusions The results of this thesis provide further knowledge and advances in the assessment of physical fitness, particularly CPET markers for risk stratification and management of chronic diseases such as HF. According to our literature review: a multi-parameter approach including VO2peak, VE/VCO2 slope, and EOV is recommended when assessing HF patients with reduced ejection fraction by CPET. The application of the provided age-dependent exhaustion criteria reduces the risk of underestimating VO2peak and provides a simple, yet effective tool. Further, reference values for maximal and several submaximal CPET parameters over a large age range are novel and differences to other studies are clinically highly relevant. Vigorous-intensity PA showed a strong positive association with higher VO2peak and other performance-related CPET parameters within the healthy cohort. Further, VO2-kinetics can provide an acceptable substitute if VO2peak cannot be determined. VO2 off-kinetics appears to be superior for distinguishing patients with HF and healthy participants compared to VO2 on-kinetics and ramp-kinetics. Finally, when combining several physical fitness biomarkers, a significant difference in HD between healthy individuals and patients with HF can be observed. The application of HD could strengthen a comprehensive assessment of physical fitness and may present an optimal target for interventions to slow the decline of physical fitness with aging and, therefore, to increase healthspan.

Background Cardiovascular (CV) disease remains a major health care burden worldwide. Exercise has a preventive effect on CV disease risk. Risk factors for CV disease include higher age, higher inactivity levels as well as reduced cardiorespiratory fitness. The retinal microcirculation is a valid vascular bed to detect vascular alterations in an early and subclinical stage. Alterations in retinal microvascular phenotype, defined as narrower central retinal arteriolar equivalents(CRAE), wider central retinal venular equivalents (CRVE) as well as reduced flicker light induced dilatation (FID), are associated with increased CV risk. Reactive oxygen species (ROS)production, modulated by DNA methylation of p66Shc, is a key driver for vascular alterations. To date no study exists that investigates the influence of physical activity (PA) or the effect of an exercise intervention on the ageing process of the retinal microcirculation in healthy individuals and patients with increased CV risk. Aims The aims of my PhD project were: 1) to investigate the association of long-term PA or inactivity on retinal microvascular phenotype in healthy older individuals, 2) to investigate the association of CV risk on retinal microvascular phenotype in long-term physical inactive older individuals and 3) to investigate the effects of twelve-weeks HIIT on retinal microvascular phenotype in older CV risk patients. Methods This PhD based on the “Exercise, Arterial Crosstalk-Modulation, and Inflammation in an Ageing Population” study (EXAMIN AGE). This study investigated the exercise effects in a systems physiology approach with a cross-sectional and an interventional study design. In the crosssectional approach 38 healthy active (HA), 36 healthy sedentary (HS) and 84 sedentary individuals at increased CV risk (SR) were included. SR were randomised into a twelve-week high-intensity interval training (HIIT) or a control condition with standard PA recommendations after the baseline assessment. The Retinal Vessel Analyser was used to measure the retinal microvascular phenotype. Enzyme-linked immunosorbent assay kits were used to analyse plasma 3-nitrotyrosine (3-NT) as a marker of oxidative stress. Gene expression of p66Shc and DNA methylation analysis were assessed in mononuclear cells by real-time quantitative polymerase chain reaction and Methylminer quantitative polymerase chain reaction to detect the epigenetic pathway of oxidative stress, one potential mechanism that affect retinal microvascular phenotype. Results Our results demonstrated wider CRAE and narrower CRVE in HA compared to HS resulting in a higher arteriolar-to-venular diameter ratio (AVR). By contrast, SR showed narrower CRAE and wider CRVE compared to HS resulting in a lower AVR compared to HS and HA. HS showed higher FID compared to SR and HA. FID in SR and HA did not significantly differ. A significant correlation between CRVE and maximal oxygen consumption (VO2peak) as well as between AVR and VO2peak were observed. In both sedentary groups, higher p66Shc expression and increased plasma levels of 3-NT were associated with hypomethylation of p66Shc promoter. HIIT reduced body mass index, fat mass, low-density lipoprotein and increased muscle mass and VO2peak. HIIT increased CRAE, decreased CRVE and increased arteriolar FID compared to the control group. A significant association between ΔCRAE and ΔVO2peak, ΔAVR and ΔVO2peak as well as between Δarteriolar FID and ΔVO2peak were observed. HIIT restored promoter methylation, blunting p66Shc expression and 3-NT levels. Conclusion Higher PA seems to be associated with favourable microvascular phenotype compared to sedentary individuals, with a further decline in sedentary individuals with increased CV risk. However, the use of FID seems to be limited in highly active individuals, eventually due to predilated arterioles. Therefore, our recommendation is to combine FID with analysis of retinal vessel diameters to differentiate functional non-responders from manifest microvascular endothelial dysfunction and thereby improve individual microvascular risk stratification. Exercise treatment has the potential to counteract microvascular dysfunction in older patients at increased CV risk. Exercise-induced reprogramming of DNA methylation on p66Shc gene promoter may represent a putative mechanistic link whereby exercise protects against age-related oxidative stress. Retinal vessel analysis seems to be a sensitive tool for detecting longterm PA as well as short-term exercise effects on retinal microvascular health in an ageing population.