Scanning Laser Doppler Flowmetry Research Articles

Early vascular damage in retinal microcirculation in arterial hypertension: the Czech post-MONICA study.

A total of 398 randomly selected individuals from an urban population aged 25-65 years, residing in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry, with data evaluable in 343 patients. Complete data were available for 342 individuals divided into four groups based on blood pressure and control status of hypertension: normotensive individuals ( n = 213), treated controlled hypertensive individuals ( n = 30), treated uncontrolled hypertensive individuals ( n = 26), and newly detected/untreated hypertensive individuals ( n = 73). There was a tendency to higher wall thickness in treated but uncontrolled hypertensive patients (compared to normotensive and treated controlled hypertensive individuals). WLR was significantly increased in treated but uncontrolled hypertensive patients as well as in individuals with newly detected thus untreated hypertension or in patients with known but untreated hypertension. There was no difference in WLR in treated, controlled hypertensive patients compared with normotensive individuals. Our results show that an increased WLR, reflecting early vascular damage, was found in newly detected individuals with hypertension and in untreated hypertensive patients, reflecting early hypertension-mediated vascular damage. Early initiation of hypertension treatment may be warranted.

Microcirculation in Hypertension: A Therapeutic Target to Prevent Cardiovascular Disease?

Arterial hypertension is a common condition worldwide and an important risk factor for cardio- and cerebrovascular events, renal diseases, as well as microvascular eye diseases. Established hypertension leads to the chronic vasoconstriction of small arteries as well as to a decreased lumen diameter and the thickening of the arterial media or wall with a consequent increased media-to-lumen ratio (MLR) or wall-to-lumen ratio (WLR). This process, defined as vascular remodeling, was firstly demonstrated in small resistance arteries isolated from subcutaneous biopsies and measured by micromyography, and this is still considered the gold-standard method for the assessment of structural alterations in small resistance arteries; however, microvascular remodeling seems to represent a generalized phenomenon. An increased MLR may impair the organ flow reserve, playing a crucial role in the maintenance and, probably, also in the progressive worsening of hypertensive disease, as well as in the development of hypertension-mediated organ damage and related cardiovascular events, thus possessing a relevant prognostic relevance. New non-invasive techniques, such as scanning laser Doppler flowmetry or adaptive optics, are presently under development, focusing mainly on the evaluation of WLR in retinal arterioles; recently, also retinal microvascular WLR was demonstrated to have a prognostic impact in terms of cardio- and cerebrovascular events. A rarefaction of the capillary network has also been reported in hypertension, which may contribute to flow reduction in and impairment of oxygen delivery to different tissues. These microvascular alterations seem to represent an early step in hypertension-mediated organ damage since they might contribute to microvascular angina, stroke, and renal dysfunction. In addition, they can be markers useful in monitoring the beneficial effects of antihypertensive treatment. Additionally, conductance arteries may be affected by a remodeling process in hypertension, and an interrelationship is present in the structural changes in small and large conductance arteries. The review addresses the possible relations between structural microvascular alterations and hypertension-mediated organ damage, and their potential improvement with antihypertensive treatment.

RENAL DENERVATION REDUCES RETINAL ARTERIAL REMODELING IN PATIENTS WITH TREATMENT RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS

Objective: Renal denervation has been shown to be a safe and effective method to lower blood pressure (BP) in patients with uncontrolled treatment resistant hypertension (TRH). Patients with TRH and T2DM typically show hypertrophic arteriolar remodeling, which is associated with the development of early target end-organ damage. By using the retinal vasculature as a mirror of vascular remodeling in the systemic circulation, arteriolar remodeling can be non-invasively assessed with Scanning Laser Doppler Flowmetry (SLDF). In this analysis we assessed the impact of RDN on retinal arteriolar remodeling in patients with TRH and T2DM. Design and method: Retinal arteriolar remodeling was assessed using SLDF together with office and 24-hour ambulatory BP before and 6 as well as 12 months after renal denervation in 22 patients with TRH and T2DM. All patients participated in the investigator initiated study program “Renal Denervation in Treatment Resistant Hypertension” (NCT01687725). SLDF allows confocal measurement of the retinal arteriolar parameters, such as outer (OD) and inner (ID) diameter. Based on ID and OD the following parameters of arteriolar remodeling are derived: retinal arteriolar wall thickness (WT), wall-to-lumen ratio (WLR), and retinal arteriolar crosssectional area (CA). Results: Retinal arteriolar parameters were analysed in 18 male and 4 female patients with 6.5 antihypertensive medications on average. There was a significant reduction of systolic and diastolic 24-hour ambulatory as well office BP 6 as well as 12 months after RDN (table 1). In 77.3% of the patients number of antihypertensive medications was reduced. We found a reduction of hypertrophic retinal arteriolar remodeling and also a reduction of WLR 12 months after RDN (table 1). Of note, no significant changes of retinal arteriolar remodeling were found 6 months after RDN. Conclusions: In very high-risk patients with TRH and T2DM endovascular RDN reduced retinal arteriolar remodeling and retinal wall-to-lumen ratio, a prognostic marker of further end-organ damage. Whereas BP-changes already occurred 6 months after RDN, changes in retinal arteriolar remodelling were observed 12 months after RDN. We conclude that after RDN reversal of arteriolar remodeling happens slowly and requires long-term effective BP control.

Impact of type 1 diabetes and its duration on wall-to-lumen ratio and blood flow in retinal arterioles.

Subclinical damage to both the small and large vessels may contribute to the development and progression of cardiovascular disease. Scanning laser Doppler flowmetry (SLDF), an established method used to measure retinal microcirculation, has been successfully applied in hypertensive and post-stroke patients. Retinal microcirculation was assessed in 158 patients with type 1 diabetes and 38 age-matched healthy controls. The diabetics were divided into 3 groups: group A with diabetes duration <12months, group B with diabetes with 1-10years, and group C >10years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8±4.7years, mean BMI 22.9±4.1). In the univariate analyses, RCF (retinal capillary flow) was significantly higher in group A (297±121 arbitrary units [AU]) vs group B (236±52AU; p=0.007) and group C (236±70AU; p=0.008) and comparable to that of the controls (p=0.46). Additionally, the WLR (Wall-to-Lumen Ratio) was highest in group C compared to the other diabetic subgroups and controls (p=0.001). Multivariate regression analyses including age, BMI, sex, HbA1c, smoking, systolic blood pressure, and diabetes duration as covariates, showed, that only diabetes duration was significantly associated with WLR variations, whereas HbA1c was significantly linked to retinal capillary flow levels. New-onset diabetes is associated with an increase in RCF, which then gradually decreased with the duration of the disease. Structural changes of the retinal arterioles estimated via WLR are evident later in the course of diabetes, especially when the disease duration exceeded 10years.

New Noninvasive Methods to Evaluate Microvascular Structure and Function.

The structural and functional alterations of microvessels are detected because of physiological aging and in several cardiometabolic diseases, including hypertension, diabetes, and obesity. The small resistance arteries of these patients show an increase in the media or total wall thickness to internal lumen diameter ratio (MLR or WLR), often accompanied by endothelial dysfunction. For decades, micromyography has been considered as a gold standard method for evaluating microvascular structural alterations through the measurement of MLR or WLR of subcutaneous small vessels dissected from tissue biopsies. Micromyography is the most common and reliable method for assessing microcirculatory endothelial function ex vivo, while strain-gauge venous plethysmography is considered the reference technique for in vivo studies. Recently, several noninvasive methods have been proposed to extend the microvasculature evaluation to a broader range of patients and clinical settings. Scanning laser Doppler flowmetry and adaptive optics are increasingly used to estimate the WLR of retinal arterioles. Microvascular endothelial function may be evaluated in the retina by flicker light stimulus, in the finger by tonometric approaches, or in the cutaneous or sublingual tissues by laser Doppler flowmetry or intravital microscopy. The main limitation of these techniques is the lack of robust evidence on their prognostic value, which currently reduces their widespread use in daily clinical practice. Ongoing and future studies will overcome this issue, hopefully moving the noninvasive assessment of the microvascular function and structure from bench to bedside.

Temperature Influence on Scanning Laser Doppler Flowmetry in Anesthetized Mice

Temperature Influence on Scanning Laser Doppler Flowmetry in Anesthetized Mice

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes

BackgroundProspective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease. MethodsIn patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles. The structural parameters of retinal arterioles assessed by Scanning Laser Doppler Flowmetry were vessel (VD) and lumen diameter (LD), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was measured with a 3.0 T clinical 23Sodium-Magnetic Resonance Imaging (23Na-MRI) system. ResultsIn patients with type 2 diabetes (N = 52) we observed a significant correlation between muscle sodium content and VD (p = 0.005), WT (p = 0.003), WCSA (p = 0.002) and WLR (p = 0.013). With respect to skin sodium content a significant correlation has been found with VD (p = 0.042), WT (p = 0.023) and WCSA (p = 0.019). Further analysis demonstrated that tissue sodium content of skin and muscle is a significant determinant of hypertrophic vascular remodeling independent of age, gender, diuretic use and 24-hour ambulatory BP. ConclusionWith the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. Trial registrationTrial registration number: NCT02383238Date of registration: March 9, 2015.

Hypertrophic remodelling of retinal arterioles in patients with congestive heart failure.

AimsAnalysis of microvascular parameters in the retinal circulation—known to reflect those in the systemic circulation—allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid‐range ejection fraction.Methods and resultsForty subjects with CHF underwent measurement of retinal capillary flow (RCF), wall‐to‐lumen ratio (WLR), vessel and lumen diameter, wall thickness, and wall cross‐sectional area (WCSA) of retinal arterioles of the right eye by scanning laser Doppler flowmetry (SLDF). Applying a matched pair approach, we compared this group with reference values of age‐matched controls from a random sample in the population of Pilsen, Czech Republic. There was no significant difference in RCF and WLR between the groups (RCF: P = 0.513; WLR: P = 0.106). In contrast, wall thickness and WCSA, indicators of hypertrophic remodelling, were higher in CHF subjects (WT: 15.0 ± 4.2 vs. 12.7 ± 4.2 μm, P = 0.021; WCSA: 4437.6 ± 1314.5 vs. 3615.9 ± 1567.8 μm2, P = 0.014). Similarly, vessel (109.4 ± 11.1 vs. 100.5 ± 14.4 μm, P = 0.002) and lumen diameter (79.0 ± 7.9 vs. 75.2 ± 8.5 μm, P = 0.009) were increased in CHF.ConclusionsIn CHF subjects, we observed hypertrophic remodelling of retinal arterioles indicative of similar changes of small resistance arteries in the systemic circulation. Microvascular structure and function assessed by SLDF may thereby represent a useful, non‐invasive method for monitoring of microvascular damage in patients with CHF and may offer innovative treatment targets for new CHF therapies.

Reference values of retinal microcirculation parameters derived from a population random sample

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Our objective has been to establish reference values for major functional and structural parameters of retinal microcirculation in a randomly selected urban population sample.A total of 398 randomly selected individuals from an urban population aged 25 to 65 years, resident in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry (SLDF), with data evaluable in 343 patients. Of this number, complete data were available for 256 individuals free from manifest cardiovascular disease, diabetes and drug treatment for hypertension and/or dyslipidemia, constituting the reference value population.Juxtapapillary retinal capillary blood flow has increased significantly with age whereas vessel and luminal diameters have decreased. No sex differences in retinal microcirculation parameters have been found. Therefore, reference values for retinal microcirculation parameters have been established by age groups. Unattended automated office systolic BP, after adjusting for age, correlated significantly with wall-to-lumen ratio (WLR) and wall thickness (WT). Moreover, after adjusting for age and mean BP, a positive relationship has been found between carotid femoral pulse wave velocity and WT, WLR and wall cross-sectional area, indicating the interaction between micro- and macro-vasculature.In conclusion, our study is the first to provide reference values of retinal microcirculation parameters in a random Caucasian population sample. Our results have shown that, at the population level, the first structural changes in retinal microcirculation are those in lumen diameters. Of note, a close relationship between BP and vascular remodeling of retinal arterioles and between aortic stiffness and WLR of retinal arterioles suggests an interaction between micro- and macro-vasculature.

The eye — a window to cardiovascular diseases

Microvascular alterations can parallel and even precede development of cardiovascular disease. Ocular bulb, due to transparent anatomical elements provides a unique opportunity to examine microcirculation non-invasively and in vivo by means of scanning laser Doppler flowmetry. This device enables to obtain both structural and functional parameters of retinal microvasculature. Alterations observed in retinal arterioles, i.e. lumen narrowing, increased wall-to-lumen ratio, rarefaction or reduced retinal capillary flow, have been independently associated with cardiometabolic diseases: hypertension, heart failure, coronary artery disease, stroke, chronic kidney disease and diabetes. Therefore, examination of easily accessible retinal microcirculation may provide novel insights into the mechanisms underlying various diseases, serve as a marker of target organ damage and add valuable information to cardiovascular risk stratification.

Longitudinal Study of Functional Reinnervation of the Denervated Skin by Collateral Sprouting of Peptidergic Nociceptive Nerves Utilizing Laser Doppler Imaging.

Restitution of cutaneous sensory function is accomplished by neural regenerative processes of distinct mechanisms following peripheral nerve lesions. Although methods available for the study of functional cutaneous nerve regeneration are specific and accurate, they are unsuitable for the longitudinal follow-up of the temporal and spatial aspects of the reinnervation process. Therefore, the aim of this study was to develop a new, non-invasive approach for the longitudinal examination of cutaneous nerve regeneration utilizing the determination of changes in the sensory neurogenic vasodilatatory response, a salient feature of calcitonin gene-related peptide-containing nociceptive afferent nerves, with scanning laser Doppler flowmetry. Scanning laser Doppler imaging was applied to measure the intensity and spatial extent of sensory neurogenic vasodilatation elicited by the application of mustard oil onto the dorsal skin of the rat hindpaw. Mustard oil induced reproducible and uniform increases in skin perfusion reaching maximum values at 2–4 min after application whereafter the blood flow gradually returned to control level after about 8–10 min. Transection and ligation of the saphenous nerve largely eliminated the vasodilatatory response in the medial aspect of the dorsal skin of the hindpaw. In the 2nd to 4th weeks after injury, the mustard oil-induced vasodilatatory reaction gradually recovered. Since regeneration of the saphenous nerve was prevented, the recovery of the vasodilatatory response may be accounted for by the collateral sprouting of neighboring intact sciatic afferent nerve fibers. This was supported by the elimination of the vasodilatatory response in both the saphenous and sciatic innervation territories following local treatment of the sciatic nerve with capsaicin to defunctionalize nociceptive afferent fibers. The present findings demonstrate that this novel technique utilizing scanning laser Doppler flowmetry to quantitatively measure cutaneous sensory neurogenic vasodilatation, a vascular response mediated by peptidergic nociceptive nerves, is a reliable non-invasive approach for the longitudinal study of nerve regeneration in the skin.

Retinal arterial remodeling in patients with pheochromocytoma or paraganglioma and its reversibility following surgical treatment.

Structural abnormalities in resistance arteries are a hallmark of patients with hypertension. In hypertensive patients with pheochromocytoma or paraganglioma (PPGL), it is still a matter of debate whether structural vascular changes are because of elevated blood pressure (BP) or to toxic effects of elevated circulating catecholamines. Hence, the aim of our study was to assess whether catecholamine excess and/or elevated BP affect the structure of small retinal arteries in patients with catecholamine-producing tumors. The study included 27 patients with PPGL and 27 hypertensive patients. All patients underwent biochemical tests for catecholamine excess, echocardiography and analyses of scanning-laser-Doppler-flowmetry (SLDF) both at baseline and 12 months following surgical resection of PPGL. Baseline retinal arterial diameter, arterial wall thickness and wall cross sectional area (WCSA) were higher in patients with PPGL as compared with subjects without PPGL (arterial diameter: 110 ± 16.5 vs. 99.5 ± 10.8 μm, wall thickness: 16.3 ± 6.0 vs. 13.5 ± 4.0 μm, WCSA: 4953.9 ± 2472.8 vs. 3784.1 ± 1446.3 μm, P < 0.05). Significant correlations were noted between wall thickness and WCSA and echocardiographic parameters assessing diastolic and systolic function of left ventricle. No correlations between retinal parameters, BP level and plasma concentrations of metanephrines were observed. In patients with PPGL, there were postoperative decreases in wall thickness (16.4 ± 15.8 vs. 14.8 ± 4.7 μm; P = 0.011) and WLR (0.42 ± 0.13 vs. 0.37 ± 0.10; P = 0.003) at 12 months after surgical removal of tumors. This is the first study to demonstrate that catecholamine excess is related to thickening of retinal arteries independent of BP and reversible after surgical cure. These data support a role of catecholamines in vascular remodeling in PPGL patients.

Aortic stiffness is not only associated with structural but also functional parameters of retinal microcirculation

ObjectiveThe aim of the study was to test the hypothesis that alterations in large arteries are associated with microvascular remodelling and decreased retinal capillary blood flow. MethodsThe study group comprised of 88 patients with essential hypertension and 32 healthy controls. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of arterial stiffness measurement (carotid-femoral pulse wave velocity), its hemodynamic consequences (central pulse pressure, augmentation pressure, augmentation index) and intima media thickness of common carotid artery. ResultsPulse wave velocity was inversely correlated to mean retinal capillary blood flow in hypertensive patients (R = −0.32, p < 0.01). This relationship remained significant in multivariate regression analysis after adjustment for age, sex, central systolic blood pressure (BP) and body mass index (β = −31.27, p < 0.001). Lumen diameter (LD) of retinal arterioles was significantly smaller in hypertensive then normotensive subjects (79.4 vs. 83.8, p = 0.03). Central and brachial systolic, diastolic and mean BPs were significantly correlated with LD and outer diameter of retinal arterioles. The relationship between LD and central BPs remained significant in multivariate analysis (β = −0.15, p = 0.03 for cSBP; β = −0.22, p = 0.04 for cDBP; β = −0.21, p = 0.03 for cMBP). Moreover, in a subgroup with cardiac damage central and brachial pulse pressure were positively associated with retinal wall thickness, wall cross sectional area, and wall to lumen ratio. ConclusionIn conclusion, the study provides a strong evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters.

Factors associated with non-active retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry in an elderly population: the Thessaloniki Eye Study (TES)

PurposeTo identify factors associated with retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry (Heidelberg retina flowmeter (HRF)) in the Thessaloniki Eye Study (TES).MethodsParticipants of the TES (age...

P4993Tissue sodium concentration emerged as a determinant of hypertrophic vascular remodeling in type 2 diabetes

Abstract Background Studies describe a linkage between greater sodium intake and higher incidence of organ damage and cardiovascular end points. Sodium intake is usually assessed by measuring 24-hour urinary sodium excretion, which is prone to high fluctuation. For the assessment of tissue sodium a new technique (23Na-MRI) has been developed. We analyzed whether tissue sodium is linked to vascular remodeling of small resistance vessels in patients with type-2 diabetes. Methods In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles, since structural changes of resistance vessels (150–300 μm) can be non-invasively and reliably assessed in the retinal circulation by Scanning Laser Doppler Flowmetry (SLDF). Patients with antidiabetic medication were off the therapy (antihypertensives were kept constant) for 4 weeks. The structural parameters of retinal arterioles assessed were outer- and inner diameter (OD &amp; ID), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was assessed non-invasively with a 3.0 T clinical MRI system in each patient. Subject placed their lower legs in the center of a 23Na knee coil and sodium content in skin and muscle (musculus triceps surae) were measured. Results In patients with type 2 diabetes (N=52) we observed a significant correlation between tissue sodium content (muscle and skin) and OD, WT and WCSA and a trend has been noticed between muscle sodium content and ID and WLR. Multiple linear regression analysis demonstrated that tissue sodium content is a significant determinant of hypertrophic vascular remodeling as indicated by increased WT and WCSA, independent of age, gender and 24-hour ambulatory diastolic blood pressure. Correlation coefficients Muscle sodium content (mmol/l) Skin sodium content (mmol/l) OD (μmol) r=0.402, p=0.003 r=0.299, p=0.033 ID (μmol) r=0.265, p=0.058 r=0.202, p=0.154 WT (μm) r=0.402, p=0.003 r=0.313, p=0.026 WLR r=0.247, p=0.078 r=0.171, p=0.230 WCSA (μm2) r=0.417, p=0.002 r=0.322, p=0.021 Conclusion With the novel 23Na-MRI technology, we could demonstrate that high tissue sodium concentration is linked to with hypertrophic vascular remodeling of retinal arterioles. Thus, the reduction of tissue sodium content may emerge as a therapeutic target.

Lumen narrowing and increased wall to lumen ratio of retinal microcirculation are valuable biomarkers of hypertension-mediated cardiac damage

Purpose: In the course of hypertension, left ventricular hypertrophy and diastolic dysfunction develop very often and may progress toward heart failure. The aim of the study was to analyze the relationship between abnormalities of retinal microcirculation and cardiac damage defined as left ventricular hypertrophy and/or diastolic dysfunction.Materials and methods: The study comprised 88 patients with essential hypertension. The group was divided into two subgroups: hypertensives without cardiac damage (n = 55) and with cardiac damage (n = 33). Control group comprised 32 normotensive subjects. Scanning laser Doppler flowmetry was used to evaluate retinal microcirculation. Echocardiography was used to assess cardiac damage.Results: Lumen diameter of retinal arterioles was significantly smaller in patients with cardiac damage vs. controls (77 vs. 84 µm, p = 0.02). Additionally, there was an evident trend with respect to lumen diameter (LD) across all three studied subgroups; i.e.: the smallest dimeters were present in cardiac damage patients, moderate size in hypertensives’ without cardiac damage, and the largest diameters in healthy controls (pfor trend < 0.01). Lumen diameter was inversely correlated with cardiac intraventricular septum diameter (R = –0.25, p = 0.02), left ventricular mass (R = –0.24, p = 0.02), and left atrial volume (R = –0.22, p = 0.04). Wall to lumen ratio was associated with intraventricular septum diameter (R = 0.21, p = 0.044) and left atrial volume (R = 0.21, p = 0.045). In multivariable regression analysis, lumen diameter was independently associated with intraventricular septum diameter (β = –0.05, p = 0.03), left ventricular mass (β = –1.15, p = 0.04), and left atrial volume (β = –0.42, p = 0.047); wall to lumen ratio was independently associated with intraventricular septum diameter (β = 3.67, p = 0.02) and left atrial volume (β = 30.0, p = 0.04).Conclusions: In conclusion, retinal arterioles lumen diameter and wall to lumen ratio were independent biomarkers of cardiac damage. Retinal examination performed by means of scanning laser Doppler flowmetry might be a valuable tool to improve cardiovascular risk stratification of hypertensive patients.

REFERENCE VALUES OF RETINAL MICROCIRCULATION PARAMETERS IN A WHITE POPULATION RANDOM SAMPLE. CZECH POST-MONICA STUDY

Objective: Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Our objective was to establish reference values for major functional and structural parameters of retinal microcirculation in a randomly selected urban population sample.Design and method: A total of 398 randomly selected individuals from an urban population aged 25 to 65 years, resident in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry (SLDF), with data evaluable in 345 patients. Of this number, complete data were available for 257 individuals free from manifest cardiovascular disease, diabetes and drug treatment for hypertension and/or dyslipidemia who made up the reference value population. Results: Retinal capillary blood flow (RCF) increased significantly with age whereas vessel and luminal diameters decreased. No sex differences in retinal microcirculation parameters were found. Reference values by age were established (see Table). A comparison between the reference value population and the diseased population (n = 88) derived from the same population sample found significant differences in age, BMI, BP, HbA1c, pulse wave velocity and prevalence of dyslipidemia, with the latter population consistently showing less favorable values. When comparing retinal parameters, after adj. for age, the only differences were found in vessel (reference value population: 103.5 ± 0.8 vs. diseased population: 107.0 ± 1.5 μm; p = 0.05) and luminal diameters (reference value population: 77.1 ± 0.5 vs. diseased population: 80.1 ± 0.9 μm; p = 0.007), with no differences in wall thickness or wall-to-lumen ratio, thus confirming that, at the population level, the first structural changes in retinal microcirculation are changes in lumen diameters. Conclusions: This is the first study providing reference values of retinal microcirculation parameters in a random white population sample. Our results show that, at the population level, the first structural changes in retinal microcirculation are those in lumen diameters.

EFFECTS OF THE NO SYNTHASE INHIBITOR RONOPTERIN (VAS203) ON MICRO- AND MACROCIRCULATION IN HEALTHY VOLUNTEERS

Objective: The tetrahydrobiopterin-analogue VAS203, an in vivo inhibitor of predominantly the inducible nitric oxide synthase (iNOS), was developed to reduce secondary damage in patients with severe traumatic brain injury. However, its effect on micro- and macrocirculation is less well established. The aim of the present study was to characterize in detail the pharmacological effects of VAS203 on micro- and macrocirculation in humans. Design and method: In this single-centre, double-blind, randomized, placebo-controlled cross-over phase I study 16 healthy male subjects were included. A constant infusion of VAS203 (total 10 mg/kg body weight) or placebo was administered for 6 hours. After a wash-out phase of 28 days the second course with either placebo or VAS203 was applied. Renal hemodynamics were assessed with constant-infusion input-clearance technique with para-aminohippuric acid (PAH) for renal plasma flow (RPF). In addition, we assessed retinal capillary flow, as microvascular parameter by scanning laser Doppler flowmetry (SLDF) at 670 nm and used pulse wave analysis by SphygmoCorTM device for assessment of central systolic pressure, as macrovascular parameter of systemic circulation. Results: Intravenous infusion of VAS203 resulted in a reduction of RPF, but remained unchanged with placebo (Figure), resulting in a significant decrease of RPF with VAS203 compared to placebo (p < 0.0001).In contrast, mean retinal capillary flow (mirroring cerebral circulation) remained preserved at any time-point during as well as up to 2 hours after intravenous infusion of VAS203 (all p > 0.4). Compared to placebo, there was no change of brachial blood pressure due to VAS203 infusion (p > 0.2). In addition, no significant effect of VAS203 infusion on central systolic pressure was observed, indicative of no clinical meaningful effects of VAS203 on systemic circulation (p > 0.1). Conclusions: Our phase I study in humans indicate that a dose of 10 mg/kg body weight VAS203 reduces renal perfusion within a physiological range, but has no other acute effects on assessed parameters of micro- and macrocirculation.

AORTIC STIFFNESS IS NOT ONLY ASSOCIATED WITH STRUCTURAL BUT ALSO WITH FUNCTIONAL PARAMETERS OF MICROCIRCULATION

Objective: The aim of the study was to test the hypothesis if arterial stiffness is linked to reduction of retinal capillary blood flow and development of retinal microvascular remodelling. Design and method: The study group comprised of 88 patients with essential hypertension (n = 88, 54.3 ± 8.3 years, 44.3% were female) and 32 healthy controls. Inclusion criteria were: essential hypertension, age of 40–70 years old. Exclusion criteria were: secondary hypertension, any cardiovascular disease including heart failure, coronary artery disease, arrhythmia, moderate or severe valve disease, history of stroke or transient ischemic attack, chronic kidney disease with eGFR < 60 mml/min/1.73 m2, diabetes mellitus, eye disease, pregnancy. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of measurement of arterial stiffness (by carotid-femoral pulse wave velocity, central pulse pressure, augmentation pressure and augmentation index) and intima media thickness of common carotid artery. Diastolic dysfunction and left ventricular hypertrophy were analysed by echocardiography. Results: Pulse wave velocity was inversely correlated with mean retinal capillary blood flow in a group of hypertensive patients (R = −0.32, p < 0.01). This relationship remained significant in multivariate regression analysis even after adjustment for age, systolic blood pressure and waist to hip ratio (β = −40.275, p < 0.001). Central pulse pressure was positively correlated with retinal wall thickness (R = 0.44, p < 0.05), wall cross sectional area (R = 0.44, p < 0.05) and wall to lumen ratio (R = 0.43, p < 0.05). Brachial pulse pressure was positively correlated with wall thickness (R = 0.43, p < 0.05), wall cross sectional area (R = 0.41, p < 0.05) and wall to lumen ratio (R = 0.47, p < 0.05). In contrast, the relationship between augmentation pressure or augmentation index and structural indicators of retinal remodelling was not observed. Conclusions: In conclusion, the study provides an evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters. Pulse wave velocity was independently associated with retinal capilary flow. Central and brachial pulse pressure were significantly related to retinal wall thickness, wall cross sectional area and wall to lumen ratio.

LUMEN NARROWING OF RETINAL ARTERIOLES IS A VALUABLE BIOMARKER OF CARDIAC DAMAGE

Objective: The aim of the study was to establish the relationship between structural and functional abnormalities of retinal microcirculation and cardiac damage defined as the presence of left ventricle hypertrophy and/or diastolic dysfunction. Design and method: The study consisted of 88 patients with essential hypertension (54.3 ± 8.3 years, 44.3% were female) and 32 healthy subjects. Inclusion criteria were: essential hypertension, age of 40–70 years old. Exclusion criteria were: secondary hypertension, any cardiovascular disease including heart failure, coronary artery disease, arrhythmia, moderate or severe valve disease, history of stroke or transient ischemic attack, chronic kidney disease with eGFR < 60 mml/min/1.73 m2, diabetes mellitus, eye disease, pregnancy. Scanning laser Doppler flowmetry was used to evaluate retinal structure and function. Diastolic dysfunction and left ventricle hypertrophy were analysed by echocardiography. The group was divided into two subgroups: 1. hypertensives without cardiac damage (n = 55); 2. hypertensives with cardiac damage (n = 33). Cardiac damage was defined as the presence of left ventricle hypertrophy and/or diastolic dysfunction. Results: Among all retinal parameters lumen diameter was significantly smaller in patients with cardiac damage versus healthy subjects (77 vs. 83 μm, p < 0.05). Lumen diameter revealed a significant decreasing trend across the groups of controls, patients without cardiac damage and patients with concomitant cardiac damage (84 vs. 81 vs. 77 μm, p trend <0.01). Moreover, in correlation analysis lumen diameter was inversely related to intraventricular septum diameter (r = −0.25 p < 0.05), left ventricular mass (r = −0.23, p < 0.05) and left atrial volume (r = −0.22 p < 0.05). These associations remained significant even after adjustment for age, sex and mean blood pressure in multivariate analysis: intraventricular septum diameter (β = −1.1 p < 0.05), left ventricular mass (β = −0.4, p < 0.05) and left atrial volume (β = −0.05 p < 0.05). The association of lumen diameter with diastolic dysfunction indices apart left atrial volume was not observed. Conclusions: Retinal examination performed by mean of scanning laser Doppler flowmetry is of great value in detecting patients with cardiac damage. Lumen narrowing of retinal arterioles was independently associated with intraventricular septum diameter, left ventricular mass and left atrial volume.