High-Resolution Imaging of Cones and Retinal Arteries in Patients with Diabetes Mellitus Type 1 Using Adaptive Optics (rtx1).

(1) Background. Diabetes mellitus (DM), called the first non-infectious epidemic of the modern era, has long-term health consequences leading to a reduced quality of life, long-term disabilities, and high mortality. Diabetic retinopathy (DR) is a neurovascular complication of diabetes and accounts for about 80% cases of vision loss in the diabetic population. The adaptive optics (AO) technique allows for a non-invasive in vivo assessment of retinal cones. Changes in number or morphology of retinal cones may be one of the first indicators of DR. (2) Methods. This study included 68 DM1 patients (17 women) aged 42.11 ± 9.69 years with a mean duration of diabetes of 22.07 ± 10.28 years, and 41 healthy volunteers (20 women) aged 41.02 ± 9.84 years. Blood pressure, BMI, waist circumference, and metabolic control measures were analysed. Cones' morphological parameters were examined with a retinal camera with Imagine Eyes adaptive optics (rtx1). Statistical analysis was carried out with IMB SPSS version 23 software. (3) Results. Neither study group differed significantly in age, BMI, blood pressure, or eyeball length. Intraocular pressure (IOP) was statistically significantly higher in DM1 patients but remained within physiological range in both groups. Analysis of cone parameters showed a statistically significant lower mean regularity of cones (Rmean) in the DM1 group compared to control group (p = 0.01), with the lowest value in the group with DM1 and hypertension (p = 0.014). In addition, DM1 patients tended to have fewer cones. (4) Conclusions. Our study revealed abnormalities in cone and vessel parameters and these abnormalities should be considered as risk factors for the development of DR. Complementing an eye examination with AO facilitates non-invasive in vivo cellular imaging of the retina. Lesions like those detected in the eye may occur in the brain and certainly require further investigation.

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

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Wall-to-lumen ratio (WLR) may represent the earliest step in hypertension-mediated organ damage.Our objective was to compare functional and structural parameters of retinal microcirculation in a randomly selected urban population sample, in hypertensive and normotensive individuals. DESIGN AND METHOD: 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). RESULTS: 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. CONCLUSION: 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.

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

BACKGROUND: 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. METHODS: 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 <12 months, group B with diabetes with 1-10 years, and group C >10 years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. RESULTS: Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8 ± 4.7 years, 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 ± 52 AU; p = 0.007) and group C (236 ± 70 AU; 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. CONCLUSIONS: 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 10 years.

Evaluation of Morphological Changes in Retinal Vessels in Type 1 Diabetes Mellitus Patients with the Use of Adaptive Optics.

INTRODUCTION: Diabetes mellitus contributes to the development of microvascular complications in the eye. Moreover, it affects multiple end organs, including brain damage, leading to premature death. The use of adaptive optics technique allows to perform non-invasive in vivo assessment of retinal vessels and to identify changes in arterioles about 100 µm in diameter. The retinal vasculature may be a model of the cerebral vessels both morphologically and functionally. Aim. To evaluate morphological parameters of retinal arterioles in patients with type 1 diabetes mellitus (DM1). Material and methods. The study included 22 DM1 patients (13 females) aged 43.00 ± 9.45 years with a mean diabetes duration of 22.55 ± 10.05 years, and 23 healthy volunteers (10 females) aged 41.09 ± 10.99 years. Blood pressure, BMI, waist circumference, and metabolic control markers of diabetes were measured in both groups. Vascular examinations were performed using an rtx1 adaptive optics retinal camera (Imagine Eyes, Orsay, France); the vessel wall thickness (WT), lumen diameter (LD), wall-to-lumen ratio (WLR), and vascular wall cross-sectional area (WCSA) were assessed. Statistical analysis was performed with the application of IMB SPSS version 23 software. Results. The DM1 group did not differ significantly in age, BMI, waist circumference, blood pressure, or axial length of the eye compared to the control group. Intraocular pressure (IOP) in both groups was normal, but in the DM1 group it was significantly higher. The DM1 group had significantly higher WT, WLR, and WCSA. These parameters correlated significantly with the duration of diabetes, but not with IOP. Conclusions. The presented study demonstrates the presence of significant morphological changes in retinal vessels in DM1 patients without previously diagnosed diabetic retinopathy. Similar changes may occur in the brain and may be early indicators of cardiovascular risk, but further investigation is required to confirm that.

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

BACKGROUND: Prospective 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. METHODS: In 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. RESULTS: In 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. CONCLUSION: With the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. TRIAL REGISTRATION: Trial registration number: NCT02383238 Date of registration: March 9, 2015.

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

AIMS: Analysis 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 RESULTS: Forty 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. CONCLUSIONS: In 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.

How to measure retinal microperfusion in patients with arterial hypertension.

PURPOSE: Assessment and monitoring of changes in microcirculatory perfusion, perfusion dynamic, vessel structure and oxygenation is crucial in management of arterial hypertension. Constant search for non-invasive methods has led the clinical focus towards the vasculature of the retina, which offers a large opportunity to detect the early phase of the functional and structural changes in the arterial hypertension and can reflect changes in brain vasculature. We review all the available methods of retinal microcirculation measurements including angiography, oximetry, retinal vasculature assessment software, Optical Coherence Tomography Angiography, Adaptive Optics and Scanning Laser Doppler Flowmetry and their application in clinical research. MATERIALS AND METHODS: To further analyse the applicability of described methods in hypertension research we performed a systematic search of the PubMed electronic database (April 2020). In our analysis, we included 111 articles in which at least one of described methods was used for assessment of microcirculation of the retina in hypertensive individuals. RESULTS: Up to this point, the methods most commonly published in studies of retinal microcirculation in arterial hypertension were Scanning Laser Doppler Flowmetry followed shortly by Optical Coherence Tomography Angiography and retinal vasculature assessment software. CONCLUSIONS: While none of described methods enables the simultaneous measurement of all microcirculatory parameters, certain techniques are widely used in arterial hypertension research, while others gain popularity in screening.

Relationship Between Ubiquitin-Specific Peptidase 18 and Hypertension in Polish Adult Male Subjects: A Cross-Sectional Pilot Study.

BACKGROUND Arterial hypertension (HT) is a leading cause of cardiac hypertrophy and heart failure. Ubiquitin-specific peptidase 18 (USP18) has been recently described as a factor that prevents myocardial dysfunction. The present study measured serum USP18 levels in normotensive (n=29), isolated diastolic hypertensive (n=20), and systolic-diastolic hypertensive (n=30) male participants and correlated these results with biochemical parameters that are included in routine assessments of patients with hypertension. MATERIAL AND METHODS Seventy-nine men, aged 24 to 82 years (mean=50.8±11.4 years), were included in the study. None of the participants had ever been treated for HT. Blood and urine parameters were assessed using routine techniques. Serum USP18 levels were measured by enzyme-linked immunosorbent assay. RESULTS The means and 95% confidence intervals (CIs) of USP18 levels in the HT(-), iDHT(+), and HT(+) groups were 69.3 (22.1-116.5) pg/ml, 90.1 (29.0-151.3) pg/ml, and 426.7 (163.1-690.3) pg/ml, respectively. In the HT(+) group, the mean serum USP18 level was 6.2-times higher than in the HT(-) group (p=0.014) and 4.7-times higher than in the iDHT(+) group (p=0.19). The partial correlation analysis that was adjusted for risk factors of arteriosclerosis indicated that USP18 levels were correlated with systolic blood pressure, pulse pressure, and heart rate. CONCLUSIONS This preliminary study found that serum USP18 levels were significantly higher in drug-naive male participants with arterial hypertension compared with normotensive controls. USP18 exerts cardiovascular-protective effects. Elevations of USP18 levels may indicate a counterregulatory process that is engaged during increases in pressure in the left ventricle.

Retinal neurodegeneration in patients with end-stage renal disease assessed by spectral-domain optical coherence tomography.

Spectral-domain optical coherence tomography (SD-OCT) represents a reliable tool for retinal layer volume and thickness measurement. The aim of this study was to evaluate retinal changes indicating neurodegenerative processes in patients with end-stage renal disease (ESRD) compared to healthy controls. This was a cross-sectional, single-center study comprising 32 ESRD patients and 38 controls. Sectoral retinal nerve fiber layer (RNFL) thickness and retinal layer volumes were obtained by SD-OCT. Age- and gender-adjusted retinal layer volumes such as total retinal volume (p = 0.037), ganglion cell layer volume (GCL, p = 0.003), ganglion cell layer - inner plexiform layer volume (GCL-IPL, p = 0.005) and inner retinal layer volume (IRL, p = 0.042) of the right eye were lower in ESRD patients. Inner plexiform layer volume of both eyes (IPL, right eye: p = 0.017; left eye: 0.044) was reduced, as was RNFL thickness in the temporal superior sector (right eye: p = 0.016). A subgroup analysis excluding patients with diabetes revealed that GCL (p = 0.014) and GCL-IPL volume of the right eye (p = 0.024) and temporal superior sector of the RNFL scan (p = 0.021) in ESRD patients were still significantly thinner. We observed a decrease in several retinal layer volumes and temporal RNFL thickness indicative of retinal neurodegenerative processes in patients with ESRD.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 ±â€Š16.5 vs. 99.5 ±â€Š10.8 µm, wall thickness: 16.3 ±â€Š6.0 vs. 13.5 ±â€Š4.0 µm, WCSA: 4953.9 ±â€Š2472.8 vs. 3784.1 ±â€Š1446.3 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 ±â€Š15.8 vs. 14.8 ±â€Š4.7 µm; P = 0.011) and WLR (0.42 ±â€Š0.13 vs. 0.37 ±â€Š0.10; P = 0.003) at 12 months after surgical removal of tumors. CONCLUSION: 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.

OBJECTIVE: The 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. METHODS: The 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. RESULTS: Pulse 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 (ß = -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 (ß = -0.15, p = 0.03 for cSBP; ß = -0.22, p = 0.04 for cDBP; ß = -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. CONCLUSION: In conclusion, the study provides a strong evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters.

Evidence of neurodegeneration in individuals with only mildly elevated blood pressure.

OBJECTIVE: Initiation of antihypertensive drug treatment in low-risk individuals with grade 1 hypertension is under debate. The aim of this study was to examine the impact of mildly elevated blood pressure (BP) on early neurodegenerative processes independent of ageing. METHODS: Sixty-two individuals were included in this study: 25 young (aged <40 years) and 37 older (aged ≥40 years) individuals at low cardiovascular risk and grade 1 hypertension at most. Macular retinal layer volumes of both eyes were determined by SD-OCT. Total retinal volume but also each inner retinal layer volume separately including retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL-IPL were measured in each individual. RESULTS: Retinal layer volumes were lower among older individuals compared with young individuals (RNFL right eye: P = 0.037/left eye: P = 0.021; GCL and GCL-IPL: both eyes P < 0.001; IPL right eye: P = 0.005/left eye: P = 0.002; total retinal volume: both eyes P = 0.002) and there was an inverse correlation between retinal layer volumes and age. Partial correlation analysis, excluding age as a cofactor, revealed an inverse association between retinal layer volumes and DBP. In multiple regression analysis, DBP was identified as a determinant of retinal neurodegenerative processes. CONCLUSION: In the current study, we observed an inverse association between retinal neurodegenerative processes and DBP, suggesting that BP-lowering therapy by early antihypertensive drug-treatment might be beneficial to avoid early neurodegeneration.

Epidemiological Survey and Retrospective Analysis of Salmonella Infections between 2000 and 2017 in Warmia and Masuria Voivodship in Poland.

Background and Objectives: Salmonellosis is a major foodborne bacterial infection throughout the world. Epidemiological surveillance is one of the key factors to reduce the number of infections caused by this pathogen in both humans and animals. The first outcome measure was the prevalence of non-typhoid Salmonella (NTS) infections between 2000 and 2017 among the population of the predominantly agricultural and touristic Polish region of Warmia and Masuria (WaM). The second outcome measure was the comparison of the NTS hospitalization rate of all registered NTS cases, an investigation of the monthly reports of infections, and the exploration of the annual minimal and maximal NTS infection number in WaM in the above-mentioned time period. The last outcome was a comparison of the prevalence of NTS infections in the region and in its administrative districts by considering both rural and urban municipalities three years before and three years after the accession of Poland into the European Union (EU) in 2004. Materials and Methods: The total number of infections and hospitalizations in the 19 districts of the WaM voivodship in Poland was registered monthly between 2000⁻2017 by the Provincial Sanitary-Epidemiological Station in Olsztyn, Poland. Results: Between 2000 and 2017, the number of diagnosed salmonellosis cases decreased significantly in WaM; the decrease was higher in urban districts than in rural ones, and the ratio of hospitalizations and the total number of NTS cases increased significantly across all districts. The lowest number of cases was reported in the winter months and was stable from 2007, whereas the highest number was reported in the summer months with a higher tendency of outbreaks. Conclusion: The falling number of salmonellosis cases in 2000⁻2017 in WaM reflects the general trend in Poland and Europe. The decrease of NTS infections in WaM is related to the accession of Poland into the EU.

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 (ß = -0.05, p = 0.03), left ventricular mass (ß = -1.15, p = 0.04), and left atrial volume (ß = -0.42, p = 0.047); wall to lumen ratio was independently associated with intraventricular septum diameter (ß = 3.67, p = 0.02) and left atrial volume (ß = 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.

Early vascular parameters in the micro- and macrocirculation in type 2 diabetes.

BACKGROUND: Diabetes converts from a metabolic disorder into a predominantly vascular disease, once its duration extends over several years or/and when additional cardiovascular risk factors such as hypertension coexist. In a cross-sectional analysis we analyzed various vascular parameters in the renal, retinal and systemic circulation, with the goal to identify which vascular parameter of early organ damage is the earliest that can be clinically detected. METHODS: In 111 patients with type 2 diabetes (T2DM) (off any anti-diabetic medication for at least 4 weeks) and 54 subjects without T2DM we compared various parameters of early vascular remodeling in the same patient: urinary albumin creatinine ratio ([UACR], early morning spot urine) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF) and intercapillary distance (ICD) as parameters of capillary rarefaction, wall-to-lumen ratio (WLR) of the retinal arterioles [all assessed by Scanning Laser Doppler Flowmetry], and central systolic pressure (cSBP) and central pulse pressure (cPP) [measured by pulse wave analysis, Syphygmocor] both reflecting vascular stiffness of large arteries. RESULTS: Compared to subjects without T2DM, patients with T2DM (diabetes duration: median 48 months, interquartile range 24-88 months) were older (59.8 ± 7.3 vs 43.4 ± 12.9 years, p < 0.001), more females (33.3 vs 20.4%, p < 0.001), but 24-h systolic and diastolic blood pressure did not differ between the two groups. The analysis adjusted for age, gender and cardiovascular risk factors revealed that ICD (23.9 ± 5.1 vs 20.8 ± 3.5 µm, p value = 0.001) and cPP (41.8 ± 11.7 vs 34.8 ± 10.6 mmHg, p value < 0.001) were significantly higher and eGFR (91.7 ± 9.9 vs 95.9 ± 17.3 ml/min/1.73 m2, p value < 0.001) was significantly lower in patients with T2DM than in subjects without T2DM. CONCLUSION: These data suggest that at similar blood pressure capillary rarefaction in the retinal circulation (ICD), decreased eGFR in the renal circulation and increased central pulse pressure (cPP) of large arteries are earlier detectable than other vascular remodeling parameters of the micro- (WLR, RCF, UACR) and macrocirculation (cSBP) in patients with T2DM. Trial registration Trial registration number: NCT02471963, Date of registration: June 15, 2015, retrospectively registered; Trial registration number: NCT01319357, Date of registration: March 21, 2011, retrospectively registered; Trial registration number: NCT02383238, Date of registration: March 9, 2015, retrospectively registered; Trial registration number: NCT00152698, Date of registration: September 9, 2005, prospectively registered; Trial registration number: NCT00136188, Date of registration: August 26, 2005, prospectively registered.

Retinal capillary and arteriolar changes in patients with chronic kidney disease.

RATIONALE: Premature cardiovascular disease is a leading cause of death in patients with chronic kidney disease (CKD). In animal models CKD has been shown to cause renal and extrarenal vascular remodeling and capillary rarefaction, but data in humans with CKD are sparse. Retinal arteriolar wall-to-lumen ratio (WLR) is an established marker of early end-organ damage and there is evidence that arteriolar and capillary changes in the retinal circulation mirror those in the general and in particular the cerebrovascular microcirculation. OBJECTIVE: The aim of this study was to compare retinal capillary density and arteriolar structure between patients with CKD and healthy individuals. METHODS: We compared 76 patients with CKD stage 3+ or proteinuria >500 mg/g creatinine in the presence of a normal GFR from the German Chronic Kidney Disease cohort to 53 healthy control subjects, who participated in clinical trials during 2007 and 2015 in our Clinical Research Center. Retinal vascular parameters were measured non-invasively in vivo by scanning laser Doppler Flowmetry (SLDF, Heidelberg Engineering, Germany). Capillary rarefaction was assessed by intercapillary distance. RESULTS: Patients with CKD showed greater WLR (0.403 ±â€¯0.11 vs 0.351 ±â€¯0.11, p = 0.010) and greater wall thickness (WT) (15.1 ±â€¯4.1 vs 13.5 ±â€¯3.8, p = 0.026) compared to healthy individuals. Intercapillary distance (ICD) (22.4 ±â€¯5.7 vs 20.2 ±â€¯4.1, p = 0.008) was greater in the CKD group compared to the healthy control group. After adjustment for differences in clinical characteristics of the groups (age, gender, BMI, serum cholesterol) WLR (p = 0.046), WT (p = 0.025) and ICD (p = 0.003) remained significantly different between the two groups. There was a correlation between serum phosphate level and WLR in the CKD group (r = 0.288, p = 0.013). CONCLUSION: Patients with moderately severe CKD show retinal signs of end-organ damage indicated by an increased wall-to-lumen ratio and capillary rarefaction.

Retinal vascular resistance in arterial hypertension.

PURPOSE: Retinal microcirculation represents an easily accessible, non-invasive, in-vivo possibility to assess early microvascular changes. In addition to the assessment of functional (e.g. retinal capillary flow, RCF) and retinal arteriolar structural parameters (e.g. wall-to-lumen-ratio, WLR) we now suggest a new parameter reflecting the resistance in small retinal arterioles (RVR). MATERIAL AND METHODS: In 45 normotensive (NT) subjects and 123 patients with hypertension stage 1 (HT) we assessed RCF, WLR, arteriolar diameter, lumen diameter and wall cross section area in the retinal circulation by using scanning laser Doppler flowmetry (SLDF). Mean arterial pressure (MAP) was measured immediately before the SLDF measurement and retinal vascular resistance was calculated (RVR = MAP/RCF). In a separate study the test-retest reliability was determined in 6 volunteers from our clinical staff by assessing RVR three times within six weeks. RESULTS: The analysis of the volunteers revealed a coefficient of variation for RVR of 7.75 ± 2.11% and Cronbach´s alpha was 0.90. WLR, a marker of vascular remodeling did not differ between NT and HT. In contrast, RCF and inner diameter of the retinal arterioles (ID) were significantly lower (RCF: p = .045 and ID: p = .001) in the HT group than in the NT group and RVR was significantly higher in the HT group than in the NT group (p < .001). In both groups we found no correlation of RVR with age, but a significant correlation of RVR with WLR (NT: r = 0.34, p = .006; HT: r = 0.25, p = .01), indicating that the RVR reflects vascular remodeling in the retinal circulation. CONCLUSION: Our data showed an increased retinal vascular resistance in hypertensive patients compared to non-hypertensive patients prior to the occurrence of structural retinal vascular remodeling. The correlation between RVR and WLR indicates that RVR is a reliable, non-invasive and early-sensitive marker of vascular remodeling in early hypertension.

Retinal capillary rarefaction in patients with untreated mild-moderate hypertension.

BACKGROUND: Microvascular rarefaction influences peripheral vascular resistance, perfusion and metabolism by affecting blood pressure and flow pattern. In hypertension microvascular rarefaction has been described in experimental animal studies as well as in capillaroscopy of skin and biopsies of muscle tissue in patients. Retinal circulation mirrors cerebral microcirculation and allows non-invasive investigations. We compared capillary rarefaction of retinal vessels in hypertensive versus normotensive subjects. METHODS: In this study retinal capillary rarefaction in 70 patients with long time (more than 67 month of disease duration) and 64 patients with short time hypertension stage 1 or 2 has been compared to 55 healthy control subjects, who participated in clinical trials in our Clinical Research Center ( www.clinicaltrials.gov : NCT01318395, NCT00627952, NCT00152698, NCT01319344). Retinal vascular parameters have been measured non-invasively and in vivo in perfusion image by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). Capillary rarefaction was assessed by capillary area (CapA) (in pixel-number) and intercapillary distance (ICD) (in µm). Additionally retinal capillary flow (RCF) was measured. RESULTS: ICD was greater in the long time hypertensive group compared to healthy individuals (24.2 ± 6.3 µm vs 20.1 ± 4.2 µm, p = 0.001) and compared to short time hypertensive patients (22.2 ± 5.2 µm, p = 0.020). Long time hypertensive patients showed less CapA compared to healthy people (1462 ± 690 vs 1821 ± 652, p = 0.005). Accordingly, RCF was significantly lower in the long time hypertensive group compared to the healthy control group (282 ± 70 AU vs 314 ± 60 AU, p = 0.032). Our data indicate a lower level of retinal capillary density in hypertensive patients, especially in those with long time hypertension. CONCLUSION: Patients with hypertension stage 1 or 2 showed retinal capillary rarefaction in comparison to healthy normotensive subjects. Retinal capillary rarefaction was intensified with duration of disease.