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Definition and management of arterial hypertension in children and adolescents are uncertain, due to different positions of current guidelines. The European Society of Cardiology task-force, constituted by Associations and Councils with interest in arterial hypertension, has reviewed current literature and evidence, to produce a Consensus Document focused on aspects of hypertension in the age range of 6-16 years, including definition, methods of measurement of blood pressure, clinical evaluation, assessment of hypertension-mediated target organ damage, evaluation of possible vascular, renal and hormonal causes, assessment and management of concomitant risk factors with specific attention for obesity, and anti-hypertensive strategies, especially focused on life-style modifications. The Consensus Panel also suggests aspects that should be studied with high priority, including generation of multi-ethnic sex, age and height specific European normative tables, implementation of randomized clinical trials on different diagnostic and therapeutic aspects, and long-term cohort studies to link with adult cardiovascular risk. Finally, suggestions for the successful implementation of the contents of the present Consensus document are also given. ispartof: EUROPEAN HEART JOURNAL vol:43 issue:35 pages:3290-3301 ispartof: location:England status: published

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 ).

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention., European Journal of Preventive Cardiology, 29 (17), ISSN:2047-4873, ISSN:2047-4881

Supplemental Material, sj-pdf-1-chc-10.1177_13674935221078368 for Effects of a cluster-randomized exercise intervention on cardiovascular health in preschoolers by Alice Minghetti, Oliver Faude, Lars Donath and Henner Hanssen in Journal of Child Health Care

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.

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 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 and aims Participation in exhaustive endurance sports competitions continues to be popular. Questions about the cardiovascular side effects of prolonged excessive exercise persist. Our study aimed to elucidate the acute effects of marathon running on arterial stiffness (AST) and to detect the role of body composition, fitness status, and inflammation. Methods Body composition was investigated in lean and obese recreational runners taking part in a marathon race. Fitness levels were determined in advance by a symptom-limited treadmill test to obtain the individual anaerobic threshold. Carotid to femoral pulse wave velocity (PWV), systolic and diastolic blood pressures (BP), and inflammatory markers (TNF-alpha, IL-6, hsCRP) were measured before 2 hours and 24 hours after a marathon race. Results A total of 47 male runners with a wide range of body mass index (BMI) and fitness levels took part in the study. Baseline PWV was independent of body composition. Marathon running induced an acute PWV drop from 8.5 m/s to 7.9 m/s within the first two hours after the race (P < 0.05). Body composition and not physical fitness predicted the PWV differences postmarathon (P > 0.05). Changes in BP, heart rate, or inflammatory markers were not associated with PWV postmarathon. Conclusions Though not evident at baseline, marathon running was associated with a reduced attenuation of central arterial stiffness in overweight and obese runners. The reduced responsiveness and attenuation of PWV with higher BMI, independent of hemodynamic changes and systemic inflammation, may represent masked vascular dysfunction in overweight and obese runners.

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

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

Study data – further outcomes. (DOCX 49 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 In light of demographic and societal changes as well as increasing inactivity within the last decades, the intergenerational exercise setting has been gaining attraction as it possesses the potential to becoming an innovative strategy to promote physical activity in children and seniors. Nevertheless, the effects of such intergenerational exercise programs on physical and psychosocial health have not been examined yet. Aim This PhD project aimed to examine the effects of an intergenerational exercise intervention on physical and psychosocial health-outcomes in preschool children and residential seniors. In this regard, the effects of the exercise setting were compared to peer-group exercise and control conditions in both generations. Furthermore, specific research on the relationship between various health outcomes and physical activity in children and seniors were evaluated. Methods The Generations on the Move Study is a five-armed controlled trial with a 25-week physical exercise training intervention and pre- and post-intervention assessments. Six kindergartens with 68 healthy children and five senior homes with 47 residential seniors from Basel-Stadt and surroundings participated in this study. The kindergartens and senior homes were assigned either to an intergenerational (IG), a peer (PG) or a control group (CON). Children were assessed in gross motor skills (TGMD-2), jump performance, handgrip strength as well as micro- and macrovascular health. Social-emotional skills were assessed by kindergarten teachers with a questionnaire (KOMPIK). Seniors performed the Short Physical Performance Battery (SPPB), including gait speed. Central hemodynamics as well as arterial stiffness were also examined. Questionnaires assessing psychosocial wellbeing (SF-36; FES; AQoL-8) were filled in with staff. IG and PG received one comparable exercise session a week lasting 45 minutes for 25 weeks. The training sessions were conducted in the respective institutions, whereby IG children were accompanied to their partnering residence home. Both CON groups received no intervention and were asked to uphold daily habits. Measurements were performed before and after the intervention. Between group differences were calculated using linear regression models. Results Children: Our analyses show at least moderate improvements of IG over CON in most main physical performance parameters (0.45

In recent decades, cardiovascular mortality has reduced significantly. Among others, improved treatment options for cardiovascular disease (CVD) and a reduction of smoking since the 1960s have contributed to this decline.1 In many countries, smoking in public areas is prohibited. However, western dietary habits, including foods high in sugar, salt and fat, and lack of exercise are still persistent, leading to obesity, diabetes and hypertension. Yet, despite numerous guidelines on prevention and treatment of CVD with medication and lifestyle management, the incidence of CVD is still increasing in many countries, fuelled by rising obesity levels, sedentary lifestyles and increased longevity.2 In particular in the southern hemisphere CVD is on the increase, with high rates of obesity, diabetes and hypertension.3 Demographics are changing in low and middle income countries, fuelling the rise of chronic diseases and a persistent burden of infectious diseases overwhelming the limited health care resources.4 In western countries survival after CVD events has successfully improved; however, at the price of more patients living with chronic CVDs.5 These developments will lead to an increased demand on healthcare services now and in the years ahead for both the prevention and the management of CVD. The organisation and continuity of care through the various layers of the different national healthcare systems is challenging and calls for close collaboration between hospital specialists, general practitioners (GPs) and other primary care workers in the battle against CVD. GPs are key in identifying patients at risk of CVD and providing individualised, risk stratified preventive care

Background: Cardiovascular disease is the leading cause of mortality worldwide. Cardiovascular risk factors, such as obesity and hypertension often manifest in childhood. Both of these cardio-vascular risk factors track into adulthood and are independent predictors for cardiovascular disease events later in life. To date there are no prospective studies on the association of microvascular health with the development of blood pressure in children. Furthermore the association of changes in physical activity behavior on microvascular and macrovascular health in childhood are poorly understood. Aims: The aims of my PhD project were four-fold: 1) to analyze the association of retinal arteriolar diameters at baseline with blood pressure development over 4 years. 2) to analyze the as-sociation of changes in physical activity and fitness with development of body mass index (BMI), blood pressure and retinal vessel diameters over 4 years. 3) to systematically sum-marize and meta-analyze the association of BMI, blood pressure, physical activity and fit-ness with large artery pulse wave velocity (PWV). 4) to analyze the association of changes in BMI, blood pressure, physical activity and fitness as well as retinal vessel diameters with large artery PWV as outcome after 4 years of follow-up. Methods: My PhD is based on the Sportcheck Follow-up study. This prospective school-based cohort study included 262 prepubertal children, who were screened for the above mentioned CV risk factors and retinal vessel diameters at baseline (aged 6-8 years) and at follow-up (aged 10-12 years) using standardized protocols. PWV was measured by an oscillometric device and implemented at follow-up. Cardiorespiratory fitness was objectively assessed by a 20m shuttle run and physical activity was assessed by use of questionnaires. To achieve my third aim, a systematic literature search through the databases PubMed, Web of Science, Embase and the Cochrane Register of Controlled Trials was conducted. Only school and population-related cross-sectional data were included. Results: Our results demonstrated that children with narrower arteriolar vessel diameters at baseline developed a higher systolic blood pressure at follow-up. Elevated blood pressure at base-line was related to narrower arteriolar vessel diameters at follow-up. Children, who achieved a higher cardiorespiratory fitness level over the 4 years reduced their weight and subsequently developed wider arteriolar vessel diameters at follow-up. An increase in sed-entary behavior from baseline to follow-up was associated with narrower arteriolar vessel diameters in children with elevated or high systolic blood pressure at baseline. The results of the meta-analysis showed that a higher BMI and blood pressure is associated with high-er PWV in children. On the other hand a higher cardiorespiratory fitness level was inversely related to PWV. Furthermore increased blood pressure and narrower arteriolar vessel di-ameters over 4 years were related to higher PWV at follow-up. In contrast, children with increased vigorous physical activity from baseline to follow-up had a lower PWV at follow-up. Conclusions: Arteriolar narrowing was predictive for accelerated blood pressure progression. In turn, a higher initial blood pressure was associated with subsequent development of microvascular impairments. The findings postulate a bivariate temporal relationship between microvascu-lar health and blood pressure. Children, who achieved an increased cardiorespiratory fit-ness performance, reduced weight and improved microvascular phenotype. A reduction in sedentary behavior by even 10 min a day can ameliorate microvascular health in children with increased systolic blood pressure. The results from the meta-analysis suggest that a higher childhood BMI and blood pressure are related to impaired arterial stiffness, whereas higher cardiorespiratory fitness performance is associated with favorable arterial stiffness. Additionally increased vigorous physical activity over 4 years seems to decelerate the pro-cess of arterial stiffness in childhood. Based on our findings, we suggest that the assess-ment of vascular biomarkers from different vascular beds can optimize cardiovascular risk stratification. Our findings also highlight the potential of promoting physical activity and fit-ness, especially in children with increased cardiovascular risk to prevent the development of small and large vessel disease.

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.

OBJECTIVE The prevalence of obesity and physical inactivity in children are increasing globally. The study aimed to investigate the association of obesity and cardiorespiratory fitness (CRF) with patterns of lung function in young children. METHODS In this cross-sectional study, lung function, body mass index (BMI), blood pressure (BP) and CRF (shuttle run stages) were measured in an unselected cohort of 1246 children aged 7.2 ± 0.4 years. All parameters and lung function, such as the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC), were assessed by standardized procedures for children. Statistical models were applied for systematic adjustment of potential confounders. RESULTS Obese children had significantly higher FEV1 (Coef. (95% CI) (1.57 (1.50; 1.64) L) and FVC (1.75 (1.67; 1.83) L) compared to normal weight children (1.38 (1.37; 1.40) L; (1.53 (1.51; 1.54) L, respectively). However, with each unit increase of BMI, FEV1/FVC decreased (-0.003 (-0.005; -0.001)) due to a disproportional increase in FVC compared to FEV1. Per stage increase of CRF, FEV1 (0.017 (0.008; 0.025) L) and FVC increased (0.022 (0.012; 0.031) L)). In obese children, higher CRF was independently associated with higher FEV1/FVC (0.03 (0.5E-4; 0.06)) due to a higher increase of FEV1 over FVC with increasing fitness. CONCLUSIONS The decrease of FEV1/FVC with increasing BMI suggests that childhood obesity is associated with an imbalance of ventilation and airway flow. In children with obesity, higher CRF is associated with an improved FEV1/FVC ratio. Physical exercise programs may have the potential to improve patterns of lung function in children with obesity.

Background: Cardiovascular disease (CVD) has its origin early in life and is the number one cause of death worldwide. Obesity is a main predictor of the pathophysiological development of hypertension and cardiometabolic disease. Insufficient physical activity and fitness lead to overweight and obesity from childhood until adulthood. Advanced glycation end products (AGEs) accumulate in adults with micro- and macrovascular complications. Therefore, the association of cardiovascular risk factors such as childhood obesity, high blood pressure and physical inactivity with cardiometabolic health need to be investigated in a systems physiology approach. Aims:We aimed to investigate the association of obesity, high blood pressure, physical activity and fitness with micro- and macrovascular health in young children. Furthermore, we aimed to examine whether AGEs are related to cardiovascular risk factors early in life. Methods: First, we conducted a systematical review and meta-analysis in over 5000 children to investigate the association of body mass index (BMI), blood pressure and physical fitness with retinal vessel diameters. An electronic literature search was performed throughout the databases of PubMed, EMBASE, Ovid, Web of Science and the Cochrane Register of Controlled Trials. In a cross-sectional approach, over 1000 children (aged 7.2±0.4 years) were screened for BMI, blood pressure, retinal arteriolar (CRAE) and venular diameters (CRVE), pulse wave velocity (PWV) and subcutaneous AGEs. A shuttle run and a 20-m sprint test were performed to assess physical fitness parameters in children. Physical activity was reported by questionnaires. Based on data from the population-based German KiGGS Study and according to the American Academy of Pediatrics guidelines, blood pressure was categorised in children with normal, high-normal blood pressure and hypertension. Results: Our results showed that CRAE and PWV were associated with obesity and high blood pressure. Low physical fitness and physical inactivity (screen time) in childhood were determinants for unfavourable micro- and macrovascular health, but not independent of BMI and blood pressure. Moreover, physical fitness and screen time were independently associated with a higher accumulation of subcutaneous AGEs. Conclusions: Our study showed that obesity and high blood pressure are associated with vascular alterations already in young children. We found a beneficial association of physical fitness with vascular health and AGEs. Future primary prevention programs will have to address the improvement of physical activity and fitness to promote cardiometabolic health in children. Cardiovascular risk stratification using different vascular screening tools may be important to help recognize subclinical changes in children at risk. Long-term follow-up studies are needed to clarify whether early cardiovascular changes are predictive for the development of cardiometabolic disease later in life.

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.

In team sports such as football, ice hockey or basketball, athletes benefit from the body’s ability to tolerate high loads during start and stop movements, changes of direction, and tackles during competition. Likewise, in individual sports, such as track-and field or cross-country skiing, maximum performance is only possible with optimally trained and optimally controlled muscles. The strength of the abdominal and back muscles is widely considered crucial, as it is responsible for a high stability of the trunk during movement. The stability of the trunk is not only considered the basis of a high performance in specific sports discipline, but can also contribute to reduced back pain and risk of injuries to the lower extremities and, in general, to fewer overuse injuries. Therefore, a considerable amount of time in training is devoted in order to improve trunk strength in sports. A considerable number of tests, then, is typically applied in order to evaluate trunk muscle strength in athletes. But, surprisingly, the relevance and comparability of the measured values are poorly understood. Therefore, this study on some central aspects of the interrelation of trunk muscle strength and sports performance sets out to highlight the contribution made to the improvement of the athletes' performance in a wide range of sports and to the prevention of sports injuries. This thesis seeks to critically access the methodological presumptions which underlie and have guided the existing scholarship, and the experimental research, on the role of trunk muscles in sports. It will do so by using different methodological perspectives in its discussion and by making use of a set of new investigations and tests. In particular, the quantification of the activity of the trunk muscles in different movements will be discussed as well as measurements which try to determine the strength of the trunk muscles. Finally, this study aspires to contribute to a better overall understanding of the interrelation of trunk muscle strength and athletic performance on the one hand and to preventive training on the other hand. In four studies presented in this thesis, different methodological approaches are used to that end: electromyographic measurements for the determination and analysis of muscle activation as well as different methods of strength assessment for the differentiation of various strength qualities. The differentiation of the strength qualities allows the description of various aspects of trunk strength, such as maximum strength and strength endurance, which relate to essential athletic performance parameters such as sprint, change of direction or balance. The performance in the strength of the abdominal and back muscles is measured with laboratory and field methods in different movements. The findings are not only used to re-address the discussions on the comparability and reliability of different measuring methods but also seek to advance our understanding of the degree of activity of trunk muscles and the influence of trunk strength on basic performance parameters in sport. In the first study, a field test method which is frequently used in Switzerland (Bourbon test: prone plank, side plank, Sorensen test) is compared with a laboratory procedure (isometric trunk flexion, extension, lateral flexion, rotation test) in a group of high-level soccer players. This study aims to compare different assessment methods. No relevant correlation between the performance in the field test (time to failure) and the maximum isometric force measurements (Pearson's correlation: -.14< r

Background Insufficient physical activity and physical fitness are associated with cardiovascular diseases and back pain in adults. But cardiovascular risk factors and risk factors for back pain can be detected earlier in life. Aims Therefore, the aim of this dissertation study was to examine associations between physical fitness, physical activity behaviour, anthropometrics and retinal vessel diameters, as a risk factor of cardiovascular disease, and spinal flexibility or spinal posture, as risk factors for back pain, in a cohort of Swiss children aged 6 to 8 years. Further, the influence of parental education, household income and nationality on physical fitness, retinal vessel diameters and risk factors for back pain was analysed. Additionally, through the Sportcheck project the physical fitness skills of all first-graders of the canton Basel-Stadt could be classified in order to arrange performance-linked additional physical education lessons. The goal was to increase children’s physical activity, knowing that the motivation is higher when children are having a similar level in physical education classes. Methods Therefore, 1314 children conducted a 20 m shuttle run test, a 20 m sprint, a jumping sidewards and a balancing backwards test. Also height and weight were measured and the body mass index (BMI) calculated. The optional measurements of retinal vessel diameters, using a Static Retinal Vessel Analyzer, were completely conducted in 391 children. Measurements of spinal flexibility and spinal posture, using a hand-held computer-assisted electromechanical device, the MediMouse, were performed in 395 children. Additional proxy-reported questionnaires about physical activity behaviour, parental education, household income and nationality were completed by 340 children. Results It was found that cardiorespiratory fitness and indoor activity had a positive influence on retinal vessel health. Physically fit children had a more flexible spinal inclination and pelvic tilt than their peers. Boys with a high level of cardiorespiratory fitness had additionally more often a normal spinal posture. Parental education level, household income and migrant background were negatively related to the physical fitness levels and anthropometrics of the schoolchildren. Moreover, children from less educated parents and with a migrant background were spending more time in front of a screen than their peers. By the use of the physical fitness tests 351 (27%) children were recommended for the movement promotion class and 140 (11%) first-graders for the talent promotion program Talent Eye. The remaining 823 (62%) children were recommended for an additional physical sports lesson. Compared to the year before 43 more children registered for movement promotion classes (2012/2013: 11 children, 2013/2014: 54). Conclusions In conclusion physical fitness showed a beneficial association with cardiovascular and back health and is related to parental education level, household income and migrant background of first-graders. On the basis of the Sportcheck study the physical fitness level of first-graders of Basel-Stadt could be classified for additional physical education lessons. Besides, more children registered for movement promotion classes. Future follow-ups will analyse whether on the basis of the Sportcheck children will be more active in the long-term.

Die Extrembelastung Marathonlaufen führt zu einer Dilatation der retinalen Arteriolen und Venolen. Direkt nach Belastung steigt die AVR durch eine stärkere arterioläre Dilatation an. Im Follow-up einen Tag nach Marathon zeigt sich eine signifikant erhöhte AVR, die durch eine stärkere reaktive venuläre Konstriktion in der Regenarationsphase zu erklären ist. Untersuchung der Anpassung der Mikrozirkulation auf eine extreme Akutbelastung (Marathonlaufen) zeigte eine starke Abhängigkeit der Gefäßdurchmesser von der Marathonzeit und von dem Blutdruck (zentral und peripher). The extreme strain of marathon running causes a dilation of the retinal arterioles and venules. The AVR goes up immediately after the marathon strain due to greater arteriolar dilation. In the follow-up one day after the marathon a significantly higher AVR was found, which can be explained by greater reactive venular constriction during the regeneration phase. The study of the adaptation of the microcirculation to extreme acute strain (marathon running) showed a high dependency of the vascular diameters on the time in the marathon and the blood pressure (central and peripheral).

Die Arbeit untersuchte die retinale Mikrozirkulation bei Kindern nach 6 Monaten Intervention, auf Zusammenhänge mit Adipositas und körperlicher Aktivität sowie auf Zusammenhänge mit Veränderungen des Blutdrucks und der Laborparameter des metabolischen Syndroms. Zu Beginn zeigten sich schwache negative Korrelationen zwischen AVR und Sitzzeit sowie zwischen CRVE und Aktivität. Nach 6 Monaten zeigten sich in der Interventionsgruppe schwache Zusammenhänge zwischen Veränderungen der retinalen Mikrozirkulation und Veränderungen von Blutdruck, HDL und Nüchternglukose. This paper investigated the retinal microcirculation of children after 6 months of intervention, for correlations with obesity and physical activity as well as for correlations with changes of bloodpressure and of laboratory parameters of the metabolic syndrome. At the beginning a weak correlation between AVR and sedentary behaviour as well as between CRVE and activity was seen. After 6 months in the intervention group appeared a weak correlation between changes of the retinal microcirculation and changes of bloodpressure, HDL and fasting glucose.

Die Arbeit beschreibt die retinale Mikrozirkulation von 578 Schulkindern im Alter von 10 bis 13 Jahren im Hinblick auf Adipositas und metabolische Risikofaktoren. Mittels einer stati­schen retinalen Gefäßanalyse wurden die Gesamtdurchmesser der Arteriolen und Venolen sowie deren Ver­hält­nis erhoben und ihr Zu­sammenhang mit anthropometrischen Daten, dem Metabolischen Syndrom, niedriggradi­ger Entzün­dung (hsCRP) und der Elastizität großer Gefäße (Augmentationsin­dex) untersucht. Adipositas ging mit Veränderungen der retinalen Gefäßweiten einher, ebenso der Blut­druck, das hsCRP und der Augmen­tationsindex. Serumlipide und Nüchternglukose besaßen dage­gen keinen unabhän­gigen Einfluss. Die Ergebnisse stellen einen Hinweis auf frühe strukturelle Ver­änderungen durch Adipo­sitas im Kindesalter dar. The examination included 578 school children aged 10-13 years from secondary schools in Munich, Germany. Diameters of retinal vessels and the arteriolar-to-venular ratio were measured using a static vessel-analyser. The objective was to reveal their relation to anthropometric data, components of the metabolic syndrome, low-grade inflammation (high sensitive c-reactive protein, hsCRP) and macrovascular elasticity (augmentation index, AIX). Obesity, as well as blood pressure, hsCRP and AIX, were associated with alterations of retinal vessel proportions. In contrast, serum lipides and fasting glucose had no independent influence. These data provide evidence that obesity could cause early retinal microvascular alterations in childhood.

Die Doktorarbeit untersuchte die myokardiale Belastung von Marathonlaufen. Bei 28 Probanden wurden vor und nach dem Marathon kardiale Biomarker bestimmt und eine Echokardiographie sowie eine hochauflösende kardiale Magnetresonanztomographie (cMRT) durchgeführt. In der Studie zeigten sich keine Hinweise für strukturelle Myokardschäden nach Marathonbelastung. Änderungen der Herzwandbewegung im cMRT deuten auf eine passagere ventrikuläre Dysfunktion infolge der Marathonbelastung. The thesis analysed the myocardial stress after running a marathon. Cardiac biomarkers were measured in 28 male runners before and after a marathon as well as an echocardiographic and high-resolution cardiac magnetic resonance imaging (cMRI). The results of the study didn‘t provide any indications of myocardial necrosis after the physical stress of a marathon. Alterations of the myocardial movement, presentable in cMRI, are indicative of being a transient ventricular dysfunction in consequence of the stress after a marathon run.