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)

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 &gt;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 longterm 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

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 )

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

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, R; 2; = 0.073; P = .019, R; 2; = 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

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

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

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.; 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).; Higher CRF was associated with lower PWV (; p; &lt; 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; &lt; 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; &lt; 0.05).; 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.; ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ct2/show/NCT02796976)

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

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.; 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.; 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.; 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

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