Effects of high-intensity interval training on retinal vessel diameters and oxygen saturation in patients with hypertension: A cross-sectional and randomized controlled trial.

INTRODUCTION: Arterial hypertension is a global healthcare burden that affects macrovascular and microvascular structure and function and can promote vascular end-organ damage. This study aimed 1) to evaluate differences in microvascular health between normotensive individuals and patients with arterial hypertension and 2) to assess the effects of short-term high-intensity interval training (HIIT) on microvascular health in the subgroup with arterial hypertension as add-on treatment to antihypertensive medication. METHODS: In the cross-sectional part, central retinal arteriolar (CRAE) and venular diameter equivalent (CRVE), arteriolar-to-venular diameter ratio (AVR), and retinal oxygen saturation (O2-saturation) were investigated in 19 normotensive healthy controls (mean age 56 ± 7 years) and 41 patients with arterial hypertension (mean age 59 ± 7 years). In the subsequent randomized controlled trial (RCT), patients with arterial hypertension were randomized to an intervention group (HIIT 3×/week) or a control group that received standard physical activity recommendations after baseline assessment. Assessments of retinal vessel biomarkers and patients` characteristics were repeated after the intervention period of 8 weeks. RESULTS: In the cross-sectional part, individuals with normal blood pressure (BP) showed lower body mass index (BMI), body fat, 24 h systolic and diastolic BP, higher peak oxygen uptake, wider CRAE (174 ± 17 µm vs. 161 ± 17 µm, p = 0.009), and higher AVR (0.84 ± 0.05 vs. 0.79 ± 0.05, p = 0.003) compared to patients with hypertension. In the RCT, patients with arterial hypertension showed reduced BMI and fasting glucose levels after HIIT and control condition. In addition, the intervention group reduced body fat percentage (27.0 ± 5.5 vs. 25.8 ± 6.1, p = 0.023) and increased peak oxygen uptake (33.3 ± 5.7 vs. 36.7 ± 5.1, p < 0.001). No changes in BP were found in either group. The intervention group showed narrower CRVE (ß -4.8 [95 % CI, -8.85, -0.81] p = 0.020) and higher AVR (0.03 [0.01, 0.04] p < 0.001) after eight weeks of HIIT compared to the control group. No statistically significant changes in retinal O2-saturation were found in either group. CONCLUSION: Short-term HIIT proved to be an effective treatment to ameliorate hypertension-induced retinal microvascular abnormalities in patients with hypertension. Retinal vessel diameters may prove to be a sensitive biomarker to quantify treatment efficacy at the microvascular level, at the earliest possible stage in patients with hypertension.

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation.

BACKGROUND: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. METHODS: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204). MEASUREMENTS AND MAIN RESULTS: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5-190.2] vs. 189.1 [179.4-197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8-0.9] vs. 0.88 [0.8-0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = - 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. CONCLUSION: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. TRIAL REGISTRATION: This study was previously registered at ClinicalTrials ("All Eyes on PCS-Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome". NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552 ). Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com.

Microvascular wall-to-lumen ratio in patients with arterial hypertension: A randomized controlled exercise trial.

BACKGROUND AND AIMS: High blood pressure is one of the main cardiovascular disease risk factors that contribute to vascular remodeling and dysfunction. We aimed to investigate I) group differences of the retinal microstructure between patients with hypertension and healthy individuals and II) the effects of a high-intensity interval training (HIIT) on hypertension-induced microvascular remodeling in patients with hypertension in a randomized controlled trial. METHODS: Arteriolar and venular retinal vessel microstructure including retinal vessel wall (RVW), lumen diameter and wall-to-lumen ratio (WLR) of 41 hypertensive patients, treated with anti-hypertensive medication, and 19 normotensive healthy controls were screened based on high-resolution fundoscopies. Patients with hypertension were randomized to a control group receiving standard physical activity recommendations and an intervention group receiving a supervised and walking-based HIIT for eight weeks. Measurements were repeated after the intervention period. RESULTS: Hypertensive patients showed thicker arteriolar RVW (28.0 ± 7.7mu vs. 21.4 ± 4.4mu, p = 0.003) and higher arteriolar WLR (58.5 ± 14.8 % vs. 42.5 ± 8.2 %, p < 0.001) compared to normotensive controls. The intervention group showed reductions in arteriolar RVW (ß -3.1 (95 % CI, -4.38, -1.78) p < 0.001) and arteriolar WLR (-5.3 (-10.14, -0.39) p = 0.035) compared to the control group. The intervention effects were independent of age, sex, change in blood pressure and change in cardiorespiratory fitness. CONCLUSIONS: HIIT in patients with hypertension improves retinal vessel microvascular remodeling after eight weeks of training. In patients with hypertension, screening retinal vessel microstructure by fundoscopy and monitoring efficacy of short-term exercise treatment are sensitive diagnostic approaches to quantify microvascular health in these patients.

Short-term high-intensity interval training improves micro- but not macrovascular function in hypertensive patients.

INTRODUCTION: Arterial hypertension is a global health burden that affects vascular structure and function. Assessment of endothelial function can improve cardiovascular (CV) risk stratification. Exercise treatment reduces over all CV risk and improves vascular health. However, it is still not clear which part of the vascular bed is most sensitive to exercise treatment in patients with CV risk. This study aimed to investigate the effects of an 8-week walking based and supervised high-intensity interval training (HIIT) on macro- and microvascular endothelial function as add-on therapy in patients with arterial hypertension. METHODS: Forty patients (mean age 58 ± 7 years) treated for arterial hypertension were randomized in the HIIT (3×/week) or control group (CG) receiving standard physical activity recommendations. Arteriolar (aFID) and venular (vFID) flicker light-induced dilatation for retinal microvascular and flow-mediated dilatation (FMD) for macrovascular endothelial function were assessed. In addition, standardized assessments of patients' characteristics were performed before and after 8 weeks. RESULTS: Both groups reduced weight and body mass index but only the HIIT group reduced body fat, visceral fat, and increased peak oxygen uptake after 8 weeks. The control group reduced diastolic blood pressure. No blood pressure changes were found in the HIIT group. Arteriolar FID increased in the HIIT group independently of confounders (pre: 2.40 ± 0.98%, post: 3.19 ± 1.31%, p < 0.001) but not in the control group (pre: 3.06 ± 1.50%, post: 2.90 ± 1.46%, p = 0.280). No changes were found for FMD in either group. CONCLUSION: Arteriolar FID was found to be a sensitive vascular biomarker to assess exercise-induced microvascular improvements even in a short time setting of an 8-week exercise therapy with HIIT. Short-term exercise training affects microvascular endothelial function but not large artery endothelial function. Thus, retinal aFID appears to be a sensitive biomarker to detect short-term exercise efficacy on a vascular level. Dynamic retinal vessel analysis as a diagnostic approach may prove to be an ideal candidate vascular biomarker to monitor treatment effects of exercise in patients with hypertension on top of standard clinical care and may support clinical decision-making in the future.

Microvascular endothelial dysfunction in heart failure patients: An indication for exercise treatment?

BACKGROUND: Endothelial dysfunction represents a diagnostic marker to differentiate disease severity in chronic heart failure (CHF) patients. Retinal vessel phenotyping was applied in CHF patients as it has been acknowledged as a sensitive diagnostic tool to quantify microvascular health and overall cardiovascular risk. METHODS: The central retinal arteriolar (CRAE) and venular diameter equivalents (CRVE) as well as the retinal microvascular function, quantified by arteriolar (aFID) and venular flicker-light induced dilatation (vFID), were analyzed in 26 CHF patients. These data were compared with 26 age- and sex-matched healthy peers. The effects of an exercise intervention on retinal microvascular health in one CHF patient were investigated to demonstrate potentially beneficial effects of exercise treatment in a case report format as proof of concept. RESULTS: CHF patients showed narrower CRAE (170 ± 16 µm vs. 176 ± 16 µm, p = 0.237) and wider CRVE (217 ± 20 µm vs. 210 ± 17 µm, p = 0.152), resulting in a significantly lower arteriolar-to-venular diameter ratio (AVR, 0.79 ± 0.07 vs. 0.84 ± 0.06, p = 0.004) compared to controls. More strikingly, CHF patients showed significantly lower mean aFID (1.24 ± 1.14% vs. 3.78 ± 1.85%, p < 0.001) and vFID (2.89 ± 1.33% vs. 3.88 ± 1.83%, p = 0.033). Twelve weeks of exercise therapy induced wider CRAE (143 ± 1.0 µm vs. 153 ± 0.9 µm), narrower CRVE (183 ± 3.1 µm vs. 180 ± 2.4 µm) and improved aFID (0.67% vs. 1.25%) in a male 78 years old CHF patient. CONCLUSIONS: aFID is a sensitive diagnostic tool to quantify microvascular impairments in CHF patients. Exercise treatment in CHF patients has high potential to improve retinal microvascular health as a marker for vascular regeneration and overall risk reduction, which warrants further examination by randomized controlled trials.

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.

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).

Physical activity and markers of glycation in older individuals: data from a combined cross-sectional and randomized controlled trial (EXAMIN AGE).

BACKGROUND: Advanced glycation end products (AGEs) are protein modifications that are predominantly formed from dicarbonyl compounds that arise from glucose and lipid metabolism. AGEs and sedentary behavior have been identified as a driver of accelerated (vascular) aging. The effect of physical activity on AGE accumulation is unknown. Therefore, we investigated whether plasma AGEs and dicarbonyl levels are different across older individuals that were active or sedentary and whether plasma AGEs are affected by high-intensity interval training (HIIT). METHODS: We included healthy older active (HA, n=38, 44.7% female, 60.1 ± 7.7 years old) and healthy older sedentary (HS, n=36, 72.2% female, 60.0 ± 7.3 years old) individuals as well as older sedentary individuals with increased cardiovascular risk (SR, n=84, 50% female, 58.7 ± 6.6 years old). The SR group was randomized into a 12-week walking-based HIIT program or control group. We measured protein-bound and free plasma AGEs and dicarbonyls by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) at baseline and after the HIIT intervention. RESULTS: Protein-bound AGE Nε-(carboxymethyl)lysine (CML) was lower in SR (2.6 ± 0.5 µmol/l) and HS (3.1 ± 0.5 µmol/l) than in HA (3.6 ± 0.6 µmol/l; P<0.05) and remained significantly lower after adjustment for several potential confounders. None of the other glycation markers were different between HS and HA. HIIT did not change plasma AGEs and dicarbonyls in SR. DISCUSSION: Although lifestyle interventions may act as important modulators of cardiovascular risk, HIIT is not a potent short-term intervention to reduce glycation in older individuals, underlining the need for other approaches, such as pharmacological agents, to reduce AGEs and lower cardiovascular risk in this population.

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.

Endothelial dysfunction in retinal vessels of hemodialysis patients compared to healthy controls.

Endothelial dysfunction is a key factor promoting atherosclerosis and cardiovascular complications. Hemodialysis patients typically show various cardiovascular complications and impaired retinal venular dilation has been described as a risk factor for mortality. Non-invasive retinal vessel analysis provides insight into the microvasculature and endothelial function. Static retinal vessel analysis determines arteriolar and venular vessel diameters and dynamic retinal vessel analysis measures microvascular function by flicker-light induced stimulation, which results in physiological dilation of retinal vessels. We measured 220 healthy individuals and compared them to our preexisting cohort of hemodialysis patients (275 for static and 214 for dynamic analysis). Regarding static vessel diameters, hemodialysis patients and healthy individuals did not significantly differ between vessel diameters. Dynamic retinal vessel analysis showed attenuated dilation of the arteriole of hemodialysis patients with 1.6% vs 2.3% in healthy individuals (p = 0.009). Case-control matching for age (mean 65.4 years) did not relevantly diminish the difference. Hemodialysis patients also exhibited reduced venular dilation after matching for age (3.2% vs 3.8%, p = 0.019). Hemodialysis patients showed microvascular dysfunction compared to healthy individuals when using dynamic retinal vessel analysis. Further studies should focus on dynamic retinal vessel analysis which can add insights into the microvascular function and risk factors in multimorbid patients.

Comparability of childhood blood pressure measurements with two different devices.

INTRODUCTION: Higher blood pressure levels are associated with vascular dysfunction as early as childhood. Here, we aim to compare two blood pressure devices for use in childhood populations within a school setting to screen for elevated blood pressure in children. METHODS: Systolic and diastolic blood pressure, mean arteriolar pressure (MAP) as well as heart rate (HR) were measured with the validated Oscillomate 9002 and Mindray VS-900 in 82 randomly selected children between 10 and 12 years taking part in the EXAMIN YOUTH study in 2020. Measurements were performed after 5 min at rest in a sitting position in the school environment. RESULTS: Both devices showed strong correlations for systolic (r = 0.62, t[80] = 7, p < 0.001) and diastolic blood pressure (r = 0.73, t[80] = 9.52, p < 0.001), MAP (r = 0.75, t[80] = 10.22, p < 0.001) and HR (r = 0.89, t[79] = 17.77, p < 0.001). There was no evidence for a statistically significant difference of both devices for systolic (110 ± 9 mmHg vs. 111 ± 9 mmHg, p = 0.574), diastolic blood pressure (67 ± 9 mmHg vs. 66 ± 9 mmHg, p = 0.301) as well as MAP (81 ± 8 mmHg vs. 80 ± 8 mmHg, p = 0.400) and HR (83 ± 12 BPM vs. 83 ± 11 BPM, p = 0.994). DISCUSSION: Both devices, the older Oscillomate 9002 and the current Mindray VS-900 showed good agreement for the measurement of blood pressure in school children. It therefore appears to be feasible to measure childhood blood pressure with either device or replace one device with another in prospective long-term studies or screening programmes as long as both are validated for use in children.

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

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

Cardiorespiratory fitness and development of childhood cardiovascular risk: The EXAMIN YOUTH follow-up study.

Background: Obesity- and hypertension-related cardiovascular (CV) risk has been shown to originate in childhood. Higher body mass index (BMI) and blood pressure (BP) have been associated with increased large artery stiffness and a lower microvascular arteriolar-to-venular diameter ratio (AVR) in children. This study aimed to investigate the association of cardiorespiratory fitness (CRF) with development of BMI, BP and vascular health during childhood. Methods: In our prospective cohort study, 1,171 children aged 6-8 years were screened for CRF, BMI, BP, retinal vessel diameters and pulse wave velocity using standardized protocols. Endurance capacity was assessed by 20 m shuttle run test. After 4 years, all parameters were assessed in 664 children using the same protocols. Results: Children with a higher CRF at baseline developed a significantly lower BMI (ß [95% CI] -0.09 [-0.11 to -0.06] kg/m2, p < 0.001), a lower systolic BP (ß [95% CI] -0.09 [-0.15 to -0.03] mmHg, p = 0.004) and a higher AVR (ß [95% CI] 0.0004 [0.00004 to 0.0007] units, p = 0.027) after 4 years. The indirect association of CRF with development of retinal arteriolar diameters was mediated by changes in BMI. Conclusion: Our results identify CRF as a key modulator for the risk trajectories of BMI, BP and microvascular health in children. Obesity-related CV risk has been shown to track into adulthood, and achieving higher CRF levels in children may help counteract the development of CV risk and disease not only in pediatric populations, but may also help reduce the burden of CVD in adulthood. Registration: http://www.clinicaltrials.gov/ (NCT02853747).

Retinal vessel diameters and function in cardiovascular risk and disease.

In the last two decades evidence has gradually accumulated suggesting that the eye may be a unique window for cardiovascular risk stratification based on the assessment of subclinical damage of retinal microvascular structure and function. This can be facilitated by non-invasive analysis of static retinal vessel diameters and dynamic recording of flicker light-induced and endothelial function-related dilation of both retinal arterioles and venules. Recent new findings have made retinal microvascular biomarkers strong candidates for clinical implementation as reliable risk predictors. Beyond a review of the current evidence and state of research, the article aims to discuss the methodological benefits and pitfalls and to identify research gaps and future directions. Above all, the potential use for screening and treatment monitoring of cardiovascular disease risk are highlighted. The article provides fundamental comprehension of retinal vessel imaging by explaining anatomical and physiological essentials of the retinal microcirculation leading to a detailed description of the methodological approach. This allows for better understanding of the underlying retinal microvascular pathology associated with the prevalence and development of cardiovascular disease. A body of new evidence is presented on the clinical validity and predictive value of retinal vessel diameters and function for incidence cardiovascular disease and outcome. Findings in children indicate the potential for utility in childhood cardiovascular disease prevention, and the efficacy of exercise interventions highlight the treatment sensitivity of retinal microvascular biomarkers. Finally, coming from the availability of normative data, solutions for diagnostic challenges are discussed and conceptual steps towards clinical implementation are put into perspective.

In-vivo assessment of retinal vessel diameters and observer variability in mice: A methodological approach.

BACKGROUND: Central retinal arteriolar (CRAE) and venular (CRVE) diameter equivalents are predictive for cardiovascular and all-cause mortality in humans. The aim of this study was to investigate the inter- and intraobserver variability for the assessment of CRAE and CRVE in mice using fluorescein contrast enhancement as compared to crude analysis. METHODS: Three high quality images with (F) and without fluorescein (NF) of eight mice (type C57BL) were recorded and analysed by two independent experienced investigators to investigate interobserver variability. In addition, one investigator analysed 20 F and 20 NF images twice to investigate intraobserver variability. The time course of CRAE and CRVE vessel responses after fluorescein injection were recorded in one mouse every 30 seconds for 15 minutes. RESULTS: The interobserver variability was lower in F images compared to NF images for CRAE (r = 0.99, p < 0.001 vs. r = 0.65, p = 0.083) and CRVE (r = 0.99, p < 0.001 vs. r = 0.79, p = 0.019). Intraobserver variability for CRAE (r = 0.99, p < 0.001 vs. r = 0.48, p = 0.032) and CRVE (r = 0.98, p < 0.001 vs. r = 0.86, p < 0.001) were lower in F compared to NF images. Fluorescein injection induced vascular staining mimicking vessel dilation (+14%) followed by a long-lasting stable staining phase well suited for precise measurements. CONCLUSIONS: Measurement variability can be optimized by use of fluorescein as contrast enhancement in mice. Standardization for time of image acquisition after fluorescein injection is advisable. Translation of static retinal vessel analysis into a rodent model has the potential to bridge the research gap between proof of concept studies in animals and clinical studies in humans.

Hypertension and retinal microvascular dysfunction (HyperVasc): protocol of a randomised controlled exercise trial in patients with hypertension.

INTRODUCTION: Hypertension is a global healthcare burden that affects the structure and function of the macrocirculation and microcirculation and induces disease-specific end-organ damage. Vascular biomarkers are essential to timely diagnose this end-organ damage to improve cardiovascular (CV) risk stratification and medical decision making. Exercise therapy is an effective means to improve vascular health and reduce overall CV risk. However, it is still not clear whether high-intensity interval training (HIIT) is recommendable for patients with hypertension to reduce blood pressure, increase cardiorespiratory fitness and ameliorate vascular health. METHODS AND ANALYSIS: The 'Hypertension and retinal microvascular dysfunction' trial will investigate macrovascular and microvascular impairments in hypertensive patients compared with healthy controls to investigate hypertension-induced end-organ damage by using gold-standard methods as well as newly developed unique retinal microvascular biomarkers. In addition, this trial will investigate the reversibility of retinal end-organ damage by assessing the effects of an 8-week supervised and walking based HIIT on blood pressure, cardiorespiratory fitness as well as macrovascular and microvascular health, compared with a control group following standard physical activity recommendations. Primary outcome will be the arteriolar-to-venular diameter ratio. Secondary outcomes will be arteriolar and venular diameters as well as the flicker-light-induced dilation. Further outcomes will be other retinal microvascular biomarkers, flow-mediated dilation of the brachial artery as well as blood pressure, cardiorespiratory fitness, microalbuminuria, hypertensive retinopathy and classical CV risk markers. Analysis of variance and analysis of covariance will be used to investigate group differences between healthy controls and hypertensive patients and training effects in hypertensive patients, respectively. ETHICS AND DISSEMINATION: The Ethics Committee of Northwestern and Central Switzerland approved this study (EKNZ-2021-00086). All participants will give informed consent. TRIAL REGISTRATION NUMBER: NCT04763005.

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 ).

Mortality prediction of retinal vessel diameters and function in a long-term follow-up of haemodialysis patients.

AIM: Retinal vessel diameters are candidate biomarkers of mortality prediction in large population-based studies. We aimed to investigate the predictive value of retinal vessel diameters and flicker-induced retinal arteriolar and venular dilation on all-cause mortality in long-term follow-up of haemodialysis patients. METHODS AND RESULTS: Retinal vessel diameters as well as maximum arteriolar (aMax) and venular dilation (vMax) were investigated in 275 and 214 haemodialysis patients, respectively. Patients were observed in a long-term follow-up for a median period of 73 months. About 36% (76/214) and 41% (113/275) of patients died. Arteriolar and venular diameters were 175 ± 19 and 208 ± 20 µm, respectively. Median aMax and vMax were 1.6 (0.3-3.3) and 3.2 (2.0-5.1)%. Patients within the lowest tertile of vMax showed lower 5-year survival rates compared with the highest tertile (50.6 vs. 82.1%) and also exhibited a higher incidence of infection-related deaths (21.7 vs. 4.0%). Univariate hazard ratio (HR) per standard deviation increase of vMax for all-cause mortality was 0.69 (0.54-0.88) and was even more pronounced for infection-related mortality [HR 0.53 (0.33-0.83)]. Regarding all-cause mortality, multivariate adjustment for eight non-retinal mortality predictors including interleukin-6 did not attenuate the HR relevantly [0.73 (0.54-0.98)]. Arteriolar and venular diameters did not predict all-cause nor cardiovascular and infection-related mortality. CONCLUSIONS: Long-term follow-up of patients on haemodialysis demonstrated the potential of retinal venular dilation capacity for mortality prediction, which was most pronounced for infection-related mortality. In the same cohort, retinal arteriolar and venular diameters showed no predictive value for hard endpoints. Retinal venular dilation but not arteriolar and venular diameters is a valuable diagnostic biomarker for risk prediction in patients with end-stage renal disease and should be considered for monitoring of critically ill patients.