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

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

Untargeted sequencing of circulating microRNAs in a healthy and diseased older population.

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 ).

Personalized exercise prescription in the prevention and treatment of arterial hypertension: a Consensus Document from the European Association of Preventive Cardiology (EAPC) and the ESC Council on Hypertension.

Treatment of hypertension and its complications remains a major ongoing health care challenge. Around 25% of heart attacks in Europe are already attributed to hypertension and by 2025 up to 60% of the population will have hypertension. Physical inactivity has contributed to the rising prevalence of hypertension, but patients who exercise or engage in physical activity reduce their risk of stroke, myocardial infarction, and cardiovascular mortality. Hence, current international guidelines on cardiovascular disease prevention provide generic advice to increase aerobic activity, but physiological responses differ with blood pressure (BP) level, and greater reductions in BP across a population may be achievable with more personalized advice. We performed a systematic review of meta-analyses to determine whether there was sufficient evidence for a scientific Consensus Document reporting how exercise prescription could be personalized for BP control. The document discusses the findings of 34 meta-analyses on BP-lowering effects of aerobic endurance training, dynamic resistance training as well as isometric resistance training in patients with hypertension, high-normal, and individuals with normal BP. As a main finding, there was sufficient evidence from the meta-review, based on the estimated range of exercise-induced BP reduction, the number of randomized controlled trials, and the quality score, to propose that type of exercise can be prescribed according to initial BP level, although considerable research gaps remain. Therefore, this evidence-based Consensus Document proposes further work to encourage and develop more frequent use of personalized exercise prescription to optimize lifestyle interventions for the prevention and treatment of hypertension.

Body Composition and Physical Fitness Affect Central Hemodynamics in Young Children.

Objective: Central hemodynamics are related to cardiovascular (CV) outcomes in adults, but associations with childhood CV risk remain unclear. The study aimed to investigate the association of obesity, physical activity, and fitness with parameters of central pulse wave reflection in young prepubertal children. Methods: In this cross-sectional study, 1,324 primary school children (aged 7.2 ± 0.4 years) were screened for parameters of pulse wave reflection such as augmentation index (AIx), central pulse pressure (CPP), body mass index (BMI), and cardiorespiratory fitness (CRF) by standardized procedures for children. Results: The mean AIx and AIx@75 were 22.2 ± 7.7 and 29.2 ± 9.2%, respectively. With each unit increase in BMI, AIx [-0.226 (-0.328; -0.125)%] and AIx@75 [-0.444(-0.660; -0.229)%] decreased, whereas peak forward pulse wave increased (p < 0.001). Increasing BMI was associated with higher CPP, but did not remain significant after adjustment for CRF and heart rate. One unit increase in CRF was associated with lower AIx@75 [-0.509(-0.844; -0.173)%, p = 0.003] and lower reflection magnitude [RM: -0.559 (-0.890; -0.227), p = 0.001], independent of body weight and height. Girls had significantly higher AIx, AIx@75, peak backward pulse wave, and RM compared with boys. Conclusion: Childhood obesity was associated with higher CPP but lower augmentation of the reflected pulse wave in children. Assessment of central blood pressures appears to be a valuable asset to childhood CV risk screening. The validity of augmentation indices during childhood development and the association with early vascular aging in children need to be verified in long-term follow-up studies. Physical activity and fitness have the potential to improve vascular hemodynamics in susceptible children and, thus, counteract vascular aging. Trial registry: ClinicalTrials.gov: Exercise and Arterial Modulation in Youth. Identifier: NCT02853747; URL: https://clinicaltrials.gov/ct2/show/NCT02853747.

Domains of Physical Activity in Relation to Stiffness Index in the General Population.

Background Regular exercise training represents an important modifier of arterial stiffness (AS). Therefore, sex-specific relations between domains of physical activity (PA; commuting, domestic, and leisure-time PA, including active sport and occupational PA) with AS were investigated. Methods and Results Stiffness index by digital photoplethysmography was investigated in 12 650 subjects from the GHS (Gutenberg Health Study). Self-reported PA was evaluated by the "Short Questionnaire to Assess Health-Enhancing Physical Activity" and reported as activity score peer week, being a combined measure of duration, frequency, and intensity of PA. Multivariable linear regression analysis demonstrated strong beneficial effects of repetitive activities, such as active commuting or leisure-time PA-related walking on AS in men, but not in women. Lower AS associated with endurance training was also found among men and premenopausal women. In contrast, intense occupational PA was related to stiffer vessels in men (P<0.0001) and women (P=0.0021) in a fully adjusted model. Combination of both, performing endurance training and having stiffness index values below median, resulted in the best survival. In contrast, subjects with elevated stiffness index at baseline without any endurance activities demonstrated the worst survival. Conclusions In this population representative sample, a differential impact of domains of self-reported PA on AS was demonstrated. Our data strengthen the importance of regular endurance PA to induce a reduction of AS, which, in turn, may improve cardiovascular prognosis. We also report deleterious effects of intense occupational PA on stiffness index, a finding that needs further confirmation by larger prospective trials.

Metabolic profiling links cardiovascular risk and vascular end organ damage.

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

Socioeconomic Status and Parental Lifestyle Are Associated With Vascular Phenotype in Children.

Background/Aims: Socioeconomic barriers and lifestyle conditions affect development of cardiovascular disease in adults, but little is known about the association of parental lifestyle and education with childhood health. We aimed to investigate the association of socioeconomic status (SES), migration background, parental physical activity (PA) and smoking status with micro-and macrovascular health in children. Methods: In 2016/2017, 833 school children (aged 7.2 ± 0.4 years) in Basel (Switzerland) were screened for retinal arteriolar-to-venular ratio (AVR), pulse wave velocity (PWV), SES, migration background and parental PA as well as smoking status. Results: High parental PA levels were associated with a favorable higher AVR (p = 0.020) and lower PWV (p = 0.035), but not independent of parental smoking status. Children with parents who smoked had a higher PWV [4.39 (4.35-4.42) m/s] compared to children with non-smoking parents [4.32 (4.29-4.34) m/s, p = 0.001]. Children of parents with a low household income had a higher PWV [4.36 (4.32-4.41) m/s] compared to children of parents with a high household income [4.30 (4.26-4.34) m/s, p = 0.033]. Low parental educational level was associated with a lower AVR [0.86 (0.85-0.88)] compared to children with highly educated parents [AVR:0.88 (0.87-0.88), p = 0.007; PWV: 4.33 (4.30-4.35) m/s, p = 0.041]. Children with a European background showed a higher AVR [0.88 (0.87-0.88)] compared to non-European children [AVR: (0.86 (0.85-0.87), p = 0.034]. Conclusion: Parental PA is associated with better macro- and microvascular childhood health. However, the positive association is lost when parental smoking is considered in the analysis. Socioeconomic factors seem to associate with subclinical vascular alterations in children. Primary prevention programs should focus on including parental lifestyle interventions and educational programs to reduce the burden of lifestyle-associated barriers in order to improve cardiovascular health during lifespan. Clinical Trial Registration: ClinicalTrials.gov Exercise and Arterial Modulation in Youth, https://clinicaltrials.gov/ct2/show/NCT02853747, NCT02853747.

Physical activity and exercise improve retinal microvascular health as a biomarker of cardiovascular risk: A systematic review.

BACKGROUND AND AIMS: Physical activity (PA) and fitness are important modulators of vascular ageing and may therefore help expand individual health span. We aimed to systematically review the association of PA and fitness, as well as the effects of exercise interventions on the new microvascular biomarkers retinal arteriolar (CRAE) and venular (CRVE) diameters and the retinal flicker light-induced dilatation (FID) in children and adults. METHODS: PubMed, Ovid, The Cochrane, EMBASE and Web of Science were searched. 805 studies were found, and 25 full-text articles analysed. Twenty-one articles were included in this systematic review. RESULTS: Higher PA levels were associated with narrower CRVE in children and adults. Physical inactivity was associated with wider CRVE in both age groups. Combined aerobic and motor skill training in school settings lead to wider CRAE in children. Aerobic exercise interventions in adults with or without CV risk factors induced wider CRAE and narrower CRVE. Studies on the effect of exercise on FID are scarce. In a twelve-week randomized controlled trial, high-intensity interval training significantly improved FID in older patients with CV risk factors. CONCLUSIONS: Higher PA and fitness levels were associated with improved retinal microvascular health in children and adults. Short-term exercise interventions in healthy children and adults, as well as CV risk patients, improved retinal microvascular structure and function. Exercise has the potential to counteract microvascular remodelling and development of small vessel disease during lifespan. Retinal vessel analysis can differentiate the beneficial effects of exercise on target microvascular organ damage.

Physical activity may drive healthy microvascular ageing via downregulation of p66Shc.

BACKGROUND: Narrower retinal arterioles and wider venules are linked to adverse cardiovascular outcomes. The mitochondrial adaptor p66Shc is a major source of ageing-induced generation of reactive oxygen species. Promoter DNA methylation inhibits p66Shc gene transcription. This cross-sectional study was designed to investigate the link between physical activity, retinal vessel diameters and p66Shc expression in active and sedentary ageing subjects. DESIGN/METHODS: Altogether 158 subjects were included in the study (mean age 59.4 ± 7.0 years). Thirty-eight subjects were healthy active, 36 were healthy sedentary and 84 were sedentary with ≥2 cardiovascular risk factors. Retinal arteriolar and venular diameters were measured by means of a retinal vessel analyser. As a marker of oxidative stress, plasma 3-nitrotyrosine was determined by enzyme-linked immunosorbent assay. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by real-time quantitative polymerase chain reaction and methylated-DNA capture (MethylMiner Enrichment kit) coupled with quantitative polymerase chain reaction, respectively. RESULTS: Wider retinal arterioles (179 ± 14 vs 172 ± 11 and 171 ± 14 µm; p < 0.05 and narrower venules (204 ± 17 vs 209 ± 11 and 218 ± 16 µm; p < 0.001) were observed in healthy active subjects compared with healthy sedentary subjects and sedentary subjects with ≥2 cardiovascular risk factors, respectively. Furthermore, healthy active subjects had blunted p66Shc expression and lower 3-nitrotyrosine plasma levels compared with healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors. Accordingly, hypomethylation of p66Shc promoter observed in healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors was not found in healthy active subjects. CONCLUSION: Long-term physical activity-induced DNA methylation of p66Shc may represent a putative mechanistic link whereby active lifestyle promotes healthy microvascular ageing.

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

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

High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized controlled trial (EXAMIN AGE).

AIMS: Impairments of retinal vessel diameter are associated with major adverse cardiovascular (CV) events. Promoter DNA methylation is a repressor of the mitochondrial adaptor p66Shc gene transcription, a key driver of ageing-induced reactive oxygen species. The study aimed to investigate whether high-intensity interval training (HIIT) affects retinal microvascular phenotype as well as p66Shc expression and oxidative stress in ageing subjects with increased CV risk from the EXAMIN AGE cohort. METHODS AND RESULTS: Eighty-four sedentary subjects (mean age 59.4 ± 7.0 years) with ≥2 CV risk factors were randomized into either a 12-week HIIT or standard physical activity recommendations. Retinal arteriolar and venular diameters were measured by use of a retinal vessel analyser. As a marker of oxidative stress plasma 3-nitrotyrosine (3-NT) level was determined by ELISA. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by RT-qPCR and methylated-DNA capture (MethylMiner Enrichment Kit) coupled with qPCR, respectively. High-intensity interval training reduced body mass index, fat mass, low-density lipoprotein and increased muscle mass, as well as maximal oxygen uptake (VO2max). Moreover, HIIT restored microvascular phenotype by inducing retinal arteriolar widening (pre: 175 ± 14 µm vs. post: 181 ± 13 µm, P = 0.001) and venular narrowing (pre: 222 ± 14 µm vs. post: 220 ± 14 µm, P = 0.007). After HIIT, restoration of p66Shc promoter methylation (P = 0.034) reduced p66Shc gene expression (P = 0.037) and, in turn, blunted 3-NT plasma levels (P = 0.002). CONCLUSION: High-intensity interval training rescues microvascular dysfunction in ageing subjects at increased CV risk. Exercise-induced reprogramming of DNA methylation of p66Shc gene may represent a putative mechanistic link whereby exercise protects against age-related oxidative stress. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ct2/show/NCT02796976).

Exercise and Arterial Stiffness in the Elderly: A Combined Cross-Sectional and Randomized Controlled Trial (EXAMIN AGE).

INTRODUCTION: Arterial stiffness (AST) is a main determinant of cardiovascular (CV) mortality. Long-term physical activity (PA) is considered to decrease age-related progression of AST but effects of short-term exercise interventions on AST remain unclear. METHODS: In a combined cross-sectional and interventional study approach, we investigated the effects of long-term PA and short-term high-intensity interval training (HIIT) on AST in an older population. 147 older individuals (mean age 59 ± 7 years) were assigned to three groups according to their PA and CV risk profile and compared: healthy active (HA, n = 35), healthy sedentary (HS, n = 33) and sedentary at risk (SR, n = 79). In addition, SR were randomized to either 12 weeks of HIIT or standard recommendations. Pulse wave velocity (PWV) was measured by applanation tonometry. Cardiorespiratory fitness (CRF) was performed by symptom-limited spiroergometry to determine maximal oxygen uptake (VO2max). RESULTS: Higher CRF was associated with lower PWV (p < 0.001) and VO2max explained 18% of PWV variance. PWV was higher in SR (8.2 ± 1.4 m/s) compared to HS (7.5 ± 1.6 m/s) and HA (7.0 ± 1.1 m/s; p < 0.001). 12 weeks of HIIT did not change PWV in SR. HIIT-induced reduction in systolic BP was associated with a reduction in PWV (p < 0.05). DISCUSSION: SR show higher PWV compared to HS and long-term PA is associated with lower PWV. Reduction of AST following short-term HIIT seems to depend on a concomitant decrease in blood pressure. Our study puts into perspective the effects of long- and short-term exercise on arterial wall integrity as treatment options for CV prevention in an older population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ct2/show/NCT02796976).

Retinal Endothelial Function, Physical Fitness and Cardiovascular Risk: A Diagnostic Challenge.

INTRODUCTION: Dynamic retinal vessel analysis (DVA) is a new non-invasive method to quantify microvascular endothelial dysfunction by flicker light-induced dilatation (FID). FID has been shown to be impaired in type 2 diabetes as well as heart failure. The aim of the study was to analyze FID in healthy active versus healthy sedentary and cardiovascular (CV) risk patients in addition to corresponding static vessel diameters. METHODS: Thirty-one healthy active (HA, mean age 60 ± 8 years), 33 healthy sedentary individuals (HS, 59 ± 7 years) and 76 sedentary patients with increased CV risk (SR, 58 ± 6 years) were included in this cross-sectional study. Group differences in CV risk factors and cardiorespiratory fitness, maximal arteriolar (ADmax) and venular (VDmax) dilatation as well as the arteriolar (AFarea) and venular (VFarea) area under the flicker curve were analyzed. The central retinal arteriolar and venular diameters were used to calculate the arteriolar-to-venular diameter ratio (AVR). RESULTS: HS [ADmax = 3.5 (2.1)%; AFarea = 48.2 (31.9)%∗s] showed higher FID compared to SR [ADmax = 2.7 (1.8)%, p = 0.021; AFarea = 34.5 (26.5)%∗s, p = 0.006] and HA [AFarea = 32.8 (23.1)%∗s, p = 0.029]. HA and SR did not significantly differ. HA had a higher AVR (0.87 ± 0.05) compared to HS (0.83 ± 0.04, p < 0.001) with further deterioration in SR (0.79 ± 0.05, p < 0.001). Interestingly, 28 participants had impaired FID but normal AVR and 43 participants had normal FID but impaired AVR. DISCUSSION: FID can differentiate between sedentary low and high risk individuals. However, FID in healthy active persons (HA) seemed impaired with a concomitant higher AVR. We postulate that lower FID in HA may be explained by predilatated arterioles and a reduced dilatation reserve. We recommend combination of FID with analysis of retinal vessel diameters to differentiate functional non-responders from manifest microvascular endothelial dysfunction and, thereby, improve microvascular risk stratification in a personalized medicine approach. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ ct2/show/NCT02796976).

Influence of body composition and physical fitness on arterial stiffness after marathon running.

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-ɑ, 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.

Exercise, Arterial Crosstalk-Modulation, and Inflammation in an Aging Population: The ExAMIN AGE Study.

Background: Age is a key determinant for the development of cardiovascular disease and higher age coincides with an increased prevalence of obesity and physical inactivity. The study examines the influence of physical activity on aging processes of physiological systems focusing on the mechanisms of vascular aging. Methods/Design: The study consists of two parts. The cross-sectional approach aims at examining the association of physical fitness and cardiovascular risk with large and small artery function in healthy older active (HOA, n = 40) and sedentary (HOS, n = 40) persons as well as older sedentary individuals with increased cardiovascular risk (OSR, n = 80) aged 50-80 years. In the interventional approach, the OSR group is randomized into a 12-week walking-based high intensity interval training (HIIT) group or a control condition, aiming at examining the effects of HIIT on arterial function in diseased older adults. Active lifestyle is defined as >9 metabolic equivalent of task (MET) per week and sedentary as ≤3 MET/week. Inclusion criteria for OSR are overweight or obesity (body mass index ≥30 kg/m2) plus at least one additional cardiovascular risk factor. The primary outcome is arterial stiffness as determined by aortic pulse wave velocity (PWV). The secondary outcomes are retinal arterial and venous diameters. Further cardiovascular assessments include peripheral PWV, central haemodynamics, retinal endothelial function, carotid intima media thickness, cardiac strain and diastolic function as well as autonomic function and inflammation. Physical fitness is measured by a treadmill-based spiroergometry to determine peak oxygen uptake. Discussion: The aim of the study is to demonstrate the importance of and need for specific physical activity programs for seniors to achieve healthier aging as a long-term goal. Vascular function defines disease- and age-related end organ damage and represents the potential to contain health at older age. This research will identify cardiovascular biomarkers that best resemble underlying cardiovascular risk in age and disease. The integrated approach will help define new recommendations for treatment guidance of exercise therapy in an aging population. ClinicalTrials. gov: NCT02796976; registered 02 June 2016 (retrospectively registered).

Retinal Vessel Diameters and Physical Activity in Patients With Mild to Moderate Rheumatic Disease Without Cardiovascular Comorbidities.

Objectives: Low-grade systemic inflammation is responsible for atherosclerotic lesions in patients with rheumatic diseases. Vascular dysfunction is a precursor of atherosclerosis and can be improved by physical activity (PA). Our aim was to asses micro- and macrovascular function as well as PA and cardiorespiratory fitness (CRF) in patients with rheumatic diseases in the absence of cardiovascular (CV) comorbidities compared to controls. Methods: Fifty-one patients without CV comorbidities were compared to 35 controls. Retinal microvascular diameters were assessed using a Retinal Vessel Analyzer. Arterial stiffness (AST) was measured by applanation tonometry. CRF was assessed as peak oxygen consumption and PA was assessed with a questionnaire. Results: Retinal venular diameters were significantly wider in patients [median 221 µm (interquartile range (IQR) 211, 231)] compared to controls [median 215 µm (IQR 196, 223); p = 0.01]. One hour increase of PA per week led to a venular constriction of -0.56 µm (95%CI -1.09, -0.03; p = 0.04). In our patients with low disease activity (median DAS28 1.9; median BASDAI 2.8), no differences in AST were evident compared to controls. The association of PA and CRF with AST was not independent of blood pressure. Conclusions: Patients with rheumatic disease and mild-to-moderate disease activity show an impairment of the retinal microvasculature but not of large artery stiffness. Retinal vessel analysis seems to be a sensitive biomarker to unmask vascular impairments even in the absence of classic CV risk factors. PA may have the potential to counteract the development of small artery disease at early stages of rheumatic disease.

Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.

A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease.

BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.