Dilation Of Retinal Arterioles Research Articles

High-intensity interval training in patients with glaucoma (HIT-GLAUCOMA): protocol for a multicenter randomized controlled exercise trial

BackgroundGlaucoma stands as a prominent global cause of irreversible blindness and the primary treatment approach involves reducing intraocular pressure (IOP). However, around one-third of patients exhibit disease progression despite effective IOP reduction. Microvascular endothelial function, chronic inflammation, and oxidative stress are known to affect retinal neuronal networks and have been associated with disease severity and progression. Exercise training has the potential to counteract these mechanisms as add-on treatment to usual care.AimsThe HIT-GLAUCOMA study will investigate the effects of a 6-month high-intensity interval training (HIIT) on intermediate endpoints such as local retinal microvascular and systemic large artery function, inflammation, and oxidative stress as well as clinical endpoints such as visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology.MethodsThe study is a multi-center randomized controlled clinical trial in patients with both normal tension and high-tension primary open angle glaucoma. Across two study centers, 128 patients will be enrolled and randomized on a 1:1 basis into an exercise intervention group and a usual care control group. The primary microvascular endpoints are retinal arteriolar and venular flicker light-induced dilation at 6 months. The primary endpoint in the systemic circulation is brachial artery flow-mediated dilation at 6 months.Anticipated resultsWe hypothesize that exercise therapy will improve retinal microvascular function and thus ocular blood flow in patients with glaucoma. As clinical outcomes, we will investigate the effect of exercise on visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology.DiscussionHIT-GLAUCOMA is a blueprint trial design to study the effect of exercise training on neurodegenerative and cardiovascular diseases. Importantly, patients are also expected to benefit from improvements in general health and cardiovascular co-morbidities. If proven effective, exercise may offer a new add-on treatment strategy to slow glaucoma progression.Clinical Trial Registration NumberThe trial is registered at Clinicaltrials.gov under the identifier NCT06058598 and is currently in the recruitment stage.

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Microvascular Dysfunction and Whole-Brain White Matter Connectivity: The Maastricht Study.

Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (β per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

Biomarkers of microvascular dysfunction and cerebral white matter connectivity: The Maastricht Study

AbstractBackgroundMicrovascular dysfunction may contribute to the development of various cerebral disorders, including cognitive dysfunction, dementia, and certain forms of depression. The suggested mechanism through which microvascular dysfunction contributes to these disorders is by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and cerebral white matter connectivity.MethodWe used cross‐sectional data from The Maastricht Study, a Dutch population‐based cohort (n = 4,326, mean±SD age 59.4±8.6 years, 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers (CRAE and CRVE), a composite score of flicker light‐induced retinal arteriolar and venular dilation response, and a composite score of plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin (sE‐selectin) and von Willebrand factor (vWF)). White matter connectivity was calculated from 3T diffusion MRI to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient and local efficiency) of cerebral white matter connections.ResultA higher endothelial dysfunction composite score was associated with a longer characteristic path length (beta per SD: 0.066 (95% confidence interval: 0.017; 0.114)) after adjustment for sociodemographic, lifestyle and cardiovascular factors, but not with any of the other white matter connectivity measures. All other measures of microvascular dysfunction were not associated with any of the connectivity measures after adjustments.ConclusionThe present study suggests that microvascular dysfunction, as quantified by a set of various measures, is not consistently associated with cerebral white matter connectivity. Only a composite score of plasma biomarkers of endothelial dysfunction was associated with a longer characteristic path length, with a longer characteristic path length being indicative for a topographically less integrated and less efficient cerebral network. Future cross‐sectional and longitudinal studies are needed to further understand the role of microvascular dysfunction in the development of cerebral disorders.

Differential effects of purines and prostaglandins on hypoxia induced dilatation of porcine retinal vessels at different branching level ex vivo

The metabolic pathways leading from hypoxia to retinal vasodilatation can involve effects of both purines and prostaglandins, but the effects of these compounds at different vascular branching levels are unknown. The purpose of the present study was to investigate differential effects of purines and prostaglandins in hypoxia-induced dilatation of retinal arterioles, precapillary arterioles and capillaries ex vivo.Porcine hemiretinas were mounted in a tissue chamber while monitoring temperature, pH, and oxygen tension. The effect of hypoxia on the diameter of larger arterioles, precapillary arterioles and capillaries was studied in the presence of the ecto-nucleotidase inhibitor AOPCP, the nonselective P2 purinoreceptor antagonist PPADS, the A2B adenosine receptor antagonist MRS 1754, the A3 adenosine receptor antagonist MRS 1523, the EP1 receptor antagonist SC-19220, the EP2 receptor antagonist PF-04418948, the EP3 receptor antagonist L-798,106, the EP4 receptor antagonist L-161-982, the prostaglandin synthesis inhibitor ibuprofen, and ibuprofen combined with AOPCP or ATP.Hypoxia-induced dilatation in arterioles was reduced by the A2B adenosine receptor antagonist (p < 0.01) and increased by the EP2 and the EP3 receptor antagonists (p < 0.01 for both comparisons). In precapillary arterioles the dilatation was reduced by the EP2 receptor antagonist (p < 0.04) and increased by the EP1 receptor antagonist (p < 0.03), whereas in capillaries the dilatation was increased by both the A3 adenosine receptor antagonist (p < 0.01), by ibuprofen in combination with the unspecific ecto-nucleotidase inhibitor AOPCP (p = 0.04) and by the prostaglandin EP3 receptor antagonist.Hypoxia-induced dilatation of retinal vessels is influenced by adenosine A2B and A3 receptors, and by the prostaglandin EP1, EP2 and EP3 receptors. The effects mediated by these receptors differ at different branching levels of the resistance vessels.

Dilation of porcine retinal arterioles to nobiletin, a polymethoxyflavonoid: Roles of nitric oxide and voltage-dependent potassium channel

We examined the effects of nobiletin, a polymethoxyflavonoid, on the retinal microvascular diameter to determine if they depend on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to nobiletin. The retinal arterioles dilated in a nobiletin concentration-dependent (100 pM-10 μM) manner and decreased by 50% after endothelial removal. The nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), reduced nobiletin-induced vasodilation comparable to denudation. Blockade of soluble guanylyl cyclase by 1H-[1,2,4] oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) produced a similar inhibitory effect as that by L-NAME. Nobiletin-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor, tetraethylammonium (TEA), and the voltage-gated K (Kv) inhibitor, 4-aminopyridine. Co-administration of L-NAME and TEA almost eliminated nobiletin-induced vasodilation. Nobiletin elicits both endothelium-dependent and -independent dilation of retinal arterioles mediated by NO release and Kv channel activation, respectively.

A pilot study of diabetic retinopathy in a porcine model of maturity onset diabetes of the young type 3 (MODY3)

Diabetic retinopathy (DR) is a leading cause of blindness in the working population. Because novel therapeutic intervention require testing, there is an urgent need for reliable animal models that faithfully replicate DR. Pig eyes have many similarities to human eyes anatomically and physiologically. Thus, attempts have been made to establish porcine models of DR by surgical, pharmaceutical or genetical induction of insulin deficiency, and dietary intervention. A previous study reported a transgenic pig model of maturity onset diabetes of the young type 3 (MODY3) developed signs of severe DR such as hemorrhage and proliferative tissue at the surface of the retina. However, the course of development of DR has not been studied in detail in this model. The purpose of this study was to investigate the early phase of DR in a MODY3. MODY3 and wild-type (WT) pigs underwent fundus photography and fluorescein angiogram (FA) before they developed cataracts. Animals were euthanized at age 1, 4, 7, and 10 months. Whole-mount retina and 10-μm thick paraffinized sections were stained with isolectin B4, and vessel density was determined by MATLAB software. At 4 and 7 months, retinal arterioles were immediately cannulated, and vasomotor action was measured by incubation with bradykinin and sodium nitroprusside. In the MODY3 pigs, fasting blood sugar levels gradually increased up to 500 mg/dL. Vascular tortuosity and yellowish spindle-shaped lesions were confirmed in MODY3 pigs at the age of 7 months; however, no microaneurysms were detected on FA. Compared with age-matched WT pigs, MODY3 pigs showed a significant decrease in blood vessel density in the intermediate and deep vascular plexus at 4 and 7 months of age and a slight decrease in capillary density in the superficial vascular plexus at 7 months of age. In MODY3 pigs, electron microscopy revealed thickening of the capillary basement membrane and leukostasis in the major blood vessels at 10 months of age. Bradykinin-induced dilation of retinal arterioles was diminished in MODY3 pigs as early as 7 months of age. Within 1 year after birth, MODY3 pigs show all typical early vascular lesions of diabetes except for microaneurysm formation. This pilot study suggests that the MODY3 pigs may serve as a suitable DR model to test effects of newly developed compounds on DR.

Retinal microvascular function is associated with the cerebral microcirculation as determined by intravoxel incoherent motion MRI

Background and aimsThe easily accessible retinal vessels provide a unique opportunity to study a proxy for cerebral small vessels. Associations between retinal vessel diameters and macrostructural brain white matter changes have already been demonstrated. Alterations in microvascular function, likely precede these structural abnormalities. We examined whether retinal microvascular function is related to cerebral microvascular properties, assessed by the intravoxel incoherent motion (IVIM) effect in brain MRI. MethodsSeventy participants (age 60 ± 8 years, 41% women) from the population-based Maastricht Study underwent brain IVIM diffusion imaging (3 Tesla) to determine the microvascular measures f (perfusion volume fraction) and D* (pseudo-diffusion of circulating blood). The retinal arteriolar and venular dilation response to flicker light stimulation were measured by a dynamic vessel analyzer. Linear regression analysis was used to investigate associations between retinal vasoreactivity and IVIM measures in white matter hyperintensities (WMH), normal-appearing white matter (NAWM) and cortical gray matter (CGM). ResultsMore retinal arteriolar dilation was significantly associated with stronger pseudo-diffusion (D*) in the NAWM and CGM (β 0.280 [95% CI 0.084–0.475], and β 0.310 [95% CI 0.091–0.528], respectively), but not with the cerebral blood volume fraction (f). No associations were observed between retinal venular dilation response and cerebrovascular IVIM measures. ConclusionsVariations in retinal arteriolar microvascular function and microcirculatory properties in the brain are linked. The retina could serve as a proxy for early detection of brain microvascular dysfunction.

N-Methyl-D-Aspartic Acid Receptor-Mediated Vasodilation Is Attenuated in the Retinas of Diabetic Rats

Purpose Activation of N-methyl-d-aspartic acid (NMDA) receptors enhances nitric oxide (NO) production in retinal neuronal cells, and in turn, NO released from neuronal cells induces glial cell-mediated dilation of retinal arterioles in rats. The purpose of this study was to examine how neuronal cell-dependent, glial cell-mediated vasodilation is impacted in diabetic rat retinas. Methods Diabetes was induced in 6-week-old male Wistar rats by combining streptozotocin injection and D-glucose feeding. Two weeks later, the dilator function of retinal arterioles was assessed. Results Compared with non-diabetic rats, the dilator responses of retinal arterioles induced by intravitreal injection of NMDA and NOR3, an NO donor, were reduced in diabetic rats. Following the blockade of large-conductance Ca2+-activated K+ (BKCa) channels with iberiotoxin, no significant difference in the retinal vasodilator response to NOR3 was observed between non-diabetic and diabetic rats. Intravitreal injection of 14,15-epoxyeicosatrienoic acid, a vasodilatory factor released from glial cells, dilated retinal arterioles, and the response was diminished by diabetes. Conclusion These findings suggest that the impaired BKCa channel function in vascular cells is responsible for the diminished neuronal cell-dependent, glial cell-mediated dilation of retinal arterioles during the early stage of diabetes.

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

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. 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. 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.

Involvement of Gap Junctions in Acetylcholine-Induced Endothelium-Derived Hyperpolarization-Type Dilation of Retinal Arterioles in Rats.

An electrical communication between the endothelial and smooth muscle cells via gap junctions, which provides the signaling pathway known as endothelium-dependent hyperpolarization (EDH), plays a crucial role in controlling the vascular tone. In this study, we investigated the role of gap junctions in the acetylcholine (ACh)-induced EDH-type dilation of rat retinal arterioles in vivo. The dilator response was evaluated by measuring the diameter of retinal arterioles. Intravitreal injection of gap junction blockers (18β-glycyrrhetinic acid and carbenoxolone) reduced the ACh-induced dilation of retinal arterioles. Moreover, the retinal arteriolar response to ACh was attenuated by 18β-glycyrrhetinic acid under treatment with a combination of NG-nitro-L-arginine methyl ester (a nitric oxide (NO) synthase inhibitor; 30 mg/kg) and indomethacin (a cyclooxygenase inhibitor; 5 mg/kg). The NO- and prostaglandin-independent, EDH-related component of ACh-induced dilation of retinal arterioles was prevented by intravitreal injection of iberiotoxin, which inhibits large-conductance Ca2+-activated K+ channels. Furthermore, the combination of 18β-glycyrrhetinic acid and iberiotoxin produced greater attenuation in the EDH-related response than that by the individual agent. Treatment with 18β-glycyrrhetinic acid revealed no significant effect on NOR3 (an NO donor)-induced retinal vasodilator response. These results suggest that gap junctions contribute to the ACh-induced, EDH-type dilation of rat retinal arterioles in vivo.

Extracerebral microvascular dysfunction is related to brain MRI markers of cerebral small vessel disease: The Maastricht Study

BackgroundCerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers.MethodsCross-sectional data of the population-based Maastricht Study was used (n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI.ResultsThe eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010–0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803–1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896–1.242], p value 0.52).ConclusionA compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.

Retinal microvascular function predicts chronic kidney disease in patients with cardiovascular risk factors

Background and aimsEndothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD. MethodsIn a single centre prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR). ResultsFlicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR <90 mL/min/1.73 m2, compared to those with normal renal function (eGFR ≥90 mL/min/1.73 m2) (1.0 [0.4–2.1]% vs. 2.0 [0.8–3.6]%; p < 0.01). In patients with normal renal function, subjects with the lowest FI-RAD responses exhibited the greatest annual decline in eGFR. In uni- and multivariable analysis, among subjects with normal renal function, a 1% decrease in FI-RAD was associated with an accelerated decline in eGFR of 0.10 (0.01, 0.15; p = 0.03) and 0.07 mL/min/1.73 m2 per year (0.00, 0.14; p = 0.06), respectively. FI-RAD was not predictive of CKD progression in subjects with baseline eGFR <90 mL/min/1.73 m2. ConclusionsRetinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD, and serves as an indicator of long-term CKD progression in those with normal renal function.

Improvement of retinal microvascular function after initiation of lipid-lowering therapy with PCSK9 inhibitors – an observational study

Abstract Background Hypercholesterolemia is associated with endothelial dysfunction. While good evidence exists for the beneficial endothelial effects of first-line lipid-lowering drugs (statins), less is known on the new class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This is particularly true for the differential effects on micro- and macrovascular endothelial function and arterial stiffness. Purpose The goal of this study was to study the change in retinal microvascular dysfunction, brachial artery endothelial function and arterial stiffness in high-risk cardiovascular risk patients before and after initiation of PCSK9 inhibitor therapy with alirocumab or evolocumab. Methods In this prospective observational study, cardiovascular high-risk patients with a clinical indication for PCSK9 inhibitors were included for the measurement of retinal microvascular function (flicker light-induced dilatation of retinal arterioles and venules, FIDart and FIDven respectively; retinal arteriovenous ratio, AVR), brachial artery flow-mediated dilatation (FMD) and arterial stiffness (pulse wave velocity, PWV; augmentation index, AI). Measurements were performed at baseline, after 3 months and after 12 months of PCSK9 inhibitor therapy. The primary endpoint was the change in FIDart after 12 months of therapy compared to baseline. Results We recruited 48 patients (mean age 57±11 years, 27% female, 81% coronary artery disease) which began treatment with alirocumab or evolocumab in our lipid outpatient clinic. 6 patients were excluded from the analysis (n=3 stopped due to side effects, n=1 stopped due to new metastatic cancer, n=1 moved abroad, n=1 no retinal vessel analysis possible). LDL cholesterol was reduced from 3.8±1.2 to 1.5±0.8 and 1.8±0.9 mmol/L at 3 and 12 months respectively (all p&amp;lt;0.001). There was no significant change in systolic blood pressure during therapy. The primary endpoint FIDart was significantly increased after 12 months of PCSK9 inhibitor therapy compared to baseline (3.4±2.3 vs. 2.6±1.6%, p=0.01). Among the secondary endpoints, augmentation index improved at 12 months vs. baseline (21±12 vs. 24±9%, p=0.03). No significant change was seen for FIDven, AVR, FMD and PWV after 3 and 12 months of therapy. Conclusion In cardiovascular high-risk patients, PCSK9 inhibition is associated with an improvement of retinal microvascular function and augmentation index after one year of therapy. No effects were seen for macrovascular parameters such as FMD or PWV in our cohort. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Hospital Zurich, AGLA Grant (sponsored by Amgen)

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study

BackgroundWomen with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures.MethodsIn a population-based cohort study of individuals aged 40–75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders.ResultsMen with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: − 0.74% (− 1.22; − 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (− 3.50;4.07) and: − 0.52% (− 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation.ConclusionsOur findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.

Carotid stiffness is associated with retinal microvascular dysfunction-The Maastricht study.

ObjectiveThis study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy.Research design and methodsThis study used cross‐sectional data from the Maastricht Study, a type 2 diabetes‐enriched population‐based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid‐femoral pulse wave velocity with retinal microvascular diameters and flicker light‐induced dilation and adjusted for cardiovascular and lifestyle risk factors.ResultsThe retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light‐induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non‐significantly, but directionally similarly, associated with greater retinal venular flicker light‐induced dilation (0.04 [−0.02; 0.10]). Carotid‐femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light‐induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light‐induced dilation were two‐ to threefold stronger in individuals with type 2 diabetes than in those without.ConclusionIn this population‐based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light‐induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction.

Role of Epoxyeicosatrienoic Acids in Acetylcholine-Induced Dilation of Rat Retinal Arterioles in Vivo.

CYP epoxygenase-derived epoxyeicosatrienoic acids (EETs) contribute to endothelium-dependent hyperpolarization (EDH)-related dilation in multiple vascular beds. The present study aimed to determine the role of EETs in the acetylcholine (ACh)-induced dilation of retinal arterioles in rats in vivo. The vasodilator responses were assessed by determining the change in diameter of the retinal arterioles on images of the ocular fundus. The intravitreal injection of 17-octadecynoic acid (1.4 nmol/eye), an inhibitor of CYP epoxygenase, and 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EE-5(Z)-E; 2 nmol/eye), an antagonist of EETs, reduced the ACh (0.3-10 µg/kg/min)-induced dilation of the retinal arterioles. The EET antagonist attenuated the vasodilator response to ACh under blockade of nitric oxide (NO) synthases and cyclooxygenases with NG-nitro-L-arginine methyl ester (30 mg/kg) plus indomethacin (5 mg/kg). Intravitreal injection of 14,15-EET (0.5 nmol/eye) dilated retinal arterioles and the response was prevented by iberiotoxin, an inhibitor of large-conductance Ca2+-activated K+ (BKCa) channels (20 pmol/eye). These results suggest that ACh stimulates the production of EETs, thereby dilating the retinal arterioles via activation of BKCa channels. CYP epoxygenase-derived EETs may be involved in the EDH-related component of the ACh-induced dilation of the retinal arterioles.

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Retinal Neurovascular Coupling in Diabetes.

Neurovascular coupling, also termed functional hyperemia, is one of the physiological key mechanisms to adjust blood flow in a neural tissue in response to functional activity. In the retina, increased neural activity, such as that induced by visual stimulation, leads to the dilatation of retinal arterioles, which is accompanied by an immediate increase in retinal and optic nerve head blood flow. According to the current scientific view, functional hyperemia ensures the adequate supply of nutrients and metabolites in response to the increased metabolic demand of the neural tissue. Although the molecular mechanisms behind neurovascular coupling are not yet fully elucidated, there is compelling evidence that this regulation is impaired in a wide variety of neurodegenerative and vascular diseases. In particular, it has been shown that the breakdown of the functional hyperemic response is an early event in patients with diabetes. There is compelling evidence that alterations in neurovascular coupling precede visible signs of diabetic retinopathy. Based on these observations, it has been hypothesized that a breakdown of functional hyperemia may contribute to the retinal complications of diabetes such as diabetic retinopathy or macular edema. The present review summarizes the current evidence of impaired neurovascular coupling in patients with diabetes. In this context, the molecular mechanisms of functional hyperemia in health and disease will be covered. Finally, we will also discuss how neurovascular coupling may in future be used to monitor disease progression or risk stratification.

Impaired retinal microvascular function predicts long-term adverse events in patients with cardiovascular disease.

Endothelial dysfunction is a precursor to the development of symptomatic atherosclerosis. Retinal microvascular reactivity to flicker light stimulation is a marker of endothelial function and can be quantified in vivo. We sought to determine whether retinal microvascular endothelial dysfunction predicts long-term major adverse cardiovascular events (MACE). In a single-centre prospective observational study, patients with coronary artery disease (CAD) or cardiovascular risk factors underwent dynamic retinal vessel assessment in response to flicker light stimulation and were followed up for MACE. Retinal microvascular endothelial dysfunction was quantified by measuring maximum flicker light-induced retinal arteriolar dilatation (FI-RAD) and flicker light-induced retinal venular dilatation (FI-RVD). In total, 252 patients underwent dynamic retinal vessel assessment and 242 (96%) had long-term follow-up. Of the 242 patients, 88 (36%) developed MACE over a median period of 8.6 years (interquartile range 6.0-9.1). After adjustment for traditional risk factors, patients within the lowest quintile of FI-RAD had the highest risk of MACE [odds ratio (OR) 5.21; 95% confidence interval (CI) 1.78-15.28]. Patients with lower FI-RAD were also more likely to die (OR 2.09; 95% CI 1.00-4.40, per standard deviation decrease in FI-RAD). In Kaplan-Meier analysis, patients with FI-RAD responses below the cohort median of 1.4% exhibited reduced MACE-free survival (55.5 vs. 71.5%; log-rank P = 0.004). FI-RVD was not predictive of MACE. Retinal arteriolar endothelial dysfunction is an independent predictor of MACE in patients with CAD or cardiovascular risk factors. Dynamic retinal vessel analysis may provide added benefit to traditional risk factors in stratifying patients at risk for cardiovascular events.