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.

Retinal Capillary Rarefaction in Patients with Type 2 Diabetes Mellitus.

PURPOSE: In diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease. METHODS: This cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2. RESULTS: In diabetic patients, ICD was greater (23.2±5.5 vs 20.2±4.2, p = 0.013) and CapA smaller (1592±595 vs 1821±652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1±5.8, p = 0.781) and CapA (1556±649, p = 0.768). CONCLUSION: In the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals.

Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial.

AIMS/HYPOTHESIS: Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. METHODS: In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N G-monomethyl-L-arginine (L-NMMA). RESULTS: Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA1c, although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (-46.8 ± 34 vs -65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident. CONCLUSIONS/INTERPRETATION: Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01835678 FUNDING: : This study was funded by Boehringer Ingelheim.

Improvement in Retinal Capillary Rarefaction After Valsartan Treatment in Hypertensive Patients.

Decreased capillary density influences vascular resistance and perfusion. The authors aimed to investigate the influence of the renin-angiotensin receptor blocker valsartan on retinal capillary rarefaction in hypertensive patients. Retinal vascular parameters were measured noninvasively and in vivo by scanning laser Doppler flowmetry before and after 4 weeks of treatment with valsartan in 95 patients with hypertension stage 1 or 2 and compared with 55 healthy individuals. Retinal capillary rarefaction was determined with the parameters intercapillary distance (ICD) and capillary area (CapA). In hypertensive patients, ICD decreased (23.4±5.5 µm vs 21.5±5.6 µm, P<.001) and CapA increased (1564±621 vs 1776±795, P=.001) after valsartan treatment compared with baseline. Compared with healthy normotensive controls (ICD 20.2±4.2 µm, CapA 1821±652), untreated hypertensive patients showed greater ICD (P<.001) and smaller CapA (P=.019), whereas treated hypertensive patients showed no difference in ICD (P=.126) and CapA (P=.728). Therapy with valsartan for 4 weeks diminished capillary rarefaction in hypertensive patients.

Early Signs of End-Organ Damage in Retinal Arterioles in Patients with Type 2 Diabetes Compared to Hypertensive Patients.

BACKGROUND: Eutrophic and hypertrophic remodeling are major vascular hallmarks for hypertension and diabetes-associated microvascular end-organ damage in peripheral arterioles. The aim of this study is to compare retinal arterioles of diabetic, hypertensive, and healthy individuals. METHODS: Retinal parameters were assessed in 99 patients with T2DM, 158 hypertensive, and 149 healthy individuals. WT and CA of retinal arterioles (80-140 µm) were measured noninvasively and in vivo by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). RESULTS: After adjustment for values differing between the groups (age, BMI, gender, HDL cholesterol and serum creatinine, systolic office BP), patients with T2DM showed no significant difference in WT (14.2 ± 3), and CA (4199 ± 1107) in comparison with hypertensive patients (WT = 13.3 ± 4, p = 0.18, CA = 3862 ± 1546, p = 0.10) and healthy individuals (WT = 13.1 ± 3, p = 0.55, CA = 3864 ± 1216, p = 0.86). However, the subgroup of patients with diabetes duration of more than 60 months showed greater WT (14.9 ± 4, p = 0.04) and CA (4557 ± 1137, p = 0.02) than the hypertensive group and greater WT (p = 0.04) and CA (p = 0.03) than the healthy group, which is consistent with hypertrophic remodeling. CONCLUSION: In the early stage of T2DM no hypertrophic remodeling was seen in retinal arterioles. However, hypertrophic remodeling was found in diabetic patients with more than 60 months duration of disease.

Benefits and Risks of Aliskiren Treatment in Patients With Type 2 Diabetes: Analyses of the 3A Registry.

The authors sought to retrospectively analyze the real-world evidence on aliskiren in diabetic patients with or without concomitant renin-angiotensin system (RAS) blocker use based on the Registry for Ambulant Therapy With RAS Inhibitors in Hypertension Patients in Germany (3A). Of 14,986 patients included, 3772 patients had diabetes and 28.5% received aliskiren, 14.3% received angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), 35.4% received aliskiren plus an ACE inhibitor/ARB, and 10.5% received other drugs. Ambulatory blood pressure (BP) monitoring (baseline BP 148±15.8/84.0±10.9 mm Hg) revealed stronger diastolic BP reduction for aliskiren plus ACE inhibitor/ARB than aliskiren alone in the low (2.8±0.5 vs 0.6±0.6; P=.004) and intermediate (5.9±0.5 vs 4.5±0.5; P=.04) baseline BP groups. There was a lesser ambulatory BP reduction observed for patients receiving non-RAS in the high baseline category for both systolic (12.5±1.8 vs 17.1±1.0; P=.02) and diastolic (6.9±1.0 vs 9.8±0.6; P=.01) BP. In patients with hypertension and type 2 diabetes, aliskiren was beneficial in lowering BP, with no observed increases in major adverse effects compared with RAS-blocking therapy alone.

Reproducibility of Kidney Perfusion Measurements With Arterial Spin Labeling at 1.5 Tesla MRI Combined With Semiautomatic Segmentation for Differential Cortical and Medullary Assessment.

Magnetic resonance imaging with arterial spin labeling (ASL) is a noninvasive approach to measure organ perfusion. The purpose of this study was to evaluate the reproducibility of ASL kidney perfusion measurements with semiautomatic segmentation, which allows separate quantification of cortical and medullary perfusion. The right kidneys of 14 healthy volunteers were examined 6 times on 2 occasions (3 times at each occasion). There was a 10-minute pause between each examination and a 14-day interval between the 2 occasions. Cortical, medullary, and whole kidney parenchymal perfusion was determined with customized semiautomatic segmentation software. Coefficient of variances (CVs) and intraclass correlations (ICCs) were calculated. Mean whole, cortical, and medullary kidney perfusion was 307.26 ±â€Š25.65, 337.10 ±â€Š34.83, and 279.61 ±â€Š26.73 mL/min/100 g, respectively. On session 1, mean perfusion for the whole kidney, cortex, and medulla was 307.08 ±â€Š26.91, 336.79 ±â€Š36.54, and 279.60 ±â€Š27.81 mL/min/100 g, respectively, and on session 2, 307.45 ±â€Š24.65, 337.41 ±â€Š33.48, and 279.61 ±â€Š25.94 mL/min/100 g, respectively (P > 0.05; R²â€Š= 0.60/0.59/0.54). For whole, cortical, and medullary kidney perfusion, the total ICC/CV were 0.97/3.43 ±â€Š0.86%, 0.97/4.19 ±â€Š1.33%, and 0.96/4.12 ±â€Š1.36%, respectively. Measurements did not differ significantly and showed a very good correlation (P > 0.05; R²â€Š= 0.75/0.76/0.65). ASL kidney measurements combined with operator-independent semiautomatic segmentation revealed high correlation and low variance of cortical, medullary, and whole kidney perfusion.

Adherence to Antihypertensive Medication in Treatment-Resistant Hypertension Undergoing Renal Denervation.

BACKGROUND: Adherence to medication has been repeatedly proposed to represent a major cause of treatment-resistant hypertension (TRH); however, treatment decisions such as treating TRH with renal denervation depend on accurate judgment of adherence. We carefully analyzed adherence rates to medication before and after renal denervation and its effect on blood pressure (BP) control. METHODS AND RESULTS: Eighty patients with TRH were included in 2 prospective observational studies that assessed the difference of potential antihypertensive and nephroprotective effects of renal denervation. To compare prescribed with actual medication intake (representing a measure of adherence), we analyzed urine samples collected at baseline and at 6 months after renal denervation for antihypertensive compounds or metabolites (by liquid chromatography-mass spectrometry). In addition to office BP, 24-hour ambulatory BP and central hemodynamics (central systolic pressure, central pulse pressure) were assessed. Informed consent for analyses of urine metabolites was obtained from 79 of 80 patients. Actual intake of all antihypertensive drugs was detected at baseline and at 6 months after renal denervation in 44 (56%) and 52 (66%) patients, respectively; 1 drug was missing in 22 (28%) and 17 (22%) patients, respectively, and ≥2 drugs were missing in 13 (16%) and 10 (13%) patients, respectively. At baseline, 24-hour ambulatory BP (P=0.049) and central systolic BP (P=0.012) were higher in nonadherent patients. Adherence did not significantly change overall (McNemar-Bowker test, P=0.362). An increase in adherence was observed in 21 patients, and a decrease was observed in 11 patients. The decrease in 24-hour ambulatory BP was not different in those with stable adherence 6 months after renal denervation (n=41, -7±13 mm Hg) compared with those with increased adherence (n=21, -10±13 mm Hg) and decreased adherence (n=11, -7±14 mm Hg) (P>0.20). Our study is limited by the relatively small sample size and potentially by the specific health environment of our university center (Northern Bavaria, Germany). CONCLUSIONS: Nonadherence to medication among patients with TRH was relatively low: ≈1 of 6 patients with TRH did not take ≥2 of the prescribed drugs. Adherence pattern did not change significantly after renal denervation and had no impact on the overall observed BP changes, supporting the concept that renal denervation is an effective treatment in patients with TRH. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00888433, NCT01442883 and NCT01687725.

Effect of aliskiren on vascular remodelling in small retinal circulation.

BACKGROUND: In hypertension, changes in small arterial structure are characterized by an increased wall-to-lumen ratio (WLR). These adaptive processes are modulated by the rennin-angiotensin system. It is unclear whether direct renin inhibitors exert protective effects on small arteries in hypertensive patients. METHODS: In this double-blind, randomized, placebo-controlled study (http://www.clinicaltrials.gov: NCT01318395), 114 patients with primary hypertension were randomized to additional therapy with either placebo or aliskiren 300 mg for 8 weeks after 4 weeks of standardized open-label treatment with valsartan 320 mg (run-in phase). Parameter of arteriolar remodelling was WLR of retinal arterioles (80 - 140 µm) assessed noninvasively and in vivo by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). In addition, pulse wave analysis (SphygmoCor, AtCor Medical, Australia) and pulse pressure (PP) amplification were determined. RESULTS: In the whole study population, no clear effect of additional therapy with aliskiren on vascular parameters was documented. When analyses were restricted to patients with vascular remodelling, defined by a median of WLR more than 0.3326 (n = 57), WLR was reduced after 8 weeks by the treatment with aliskiren compared with placebo (-0.044 ±â€Š0.07 versus 0.0043 ±â€Š0.07, P = 0.015). Consistently, after 8 weeks of on-top treatment with aliskiren, there was an improvement of PP amplification compared with placebo (0.025 ±â€Š0.07 versus -0.034 ±â€Š0.08, P = 0.013), indicative of less stiff arteries in the peripheral circulation. CONCLUSION: Thus, our data indicate that treatment with aliskiren, given on top of valsartan therapy, improves altered vascular remodelling in hypertensive patients.

Effects of folic acid on renal endothelial function in patients with diabetic nephropathy: results from a randomized trial.

Endothelial dysfunction has been shown to promote podocyte injury and albuminuria in diabetes, highlighting the importance of the interaction between renal endothelial cells and podocytes. Folic acid (FA) improves nitric oxide synthase (NOS) function and reduces progression of diabetic nephropathy in animal models. We tested whether high-dose FA treatment improves renal endothelial function and albuminuria in human subjects with incipient diabetic nephropathy. Following a double-blind, randomized, cross-over design, 28 patients with Type 2 diabetes and albuminuria were allocated to 4 weeks' treatment with placebo and high-dose FA (5 mg/day). Renal nitric oxide (NO) production determined as the response of renal plasma flow (RPF) to NOS inhibition with NG-monomethyl-L-arginine (L-NMMA) (4.25 mg/kg intravenously), renal oxidant stress as response of RPF to vitamin C infusion (3 mg/kg) and albuminuria were determined after each treatment phase. Neither the reduction in RPF to L-NMMA nor the increase in RPF to vitamin C infusion differed between treatment phases (ΔRPF to L-NMMA: -74±71 ml/min per m2 during placebo compared with -63±56 ml/min per m2 during FA, P=0.57; ΔRPF to vitamin C: +93±118 ml/min per m2 compared with +94±108 ml/min per m2; P=0.70). In line with the lack of effect on the renal endothelium, albuminuria was not affected by FA treatment (110±179 mg/day during placebo compared with 87±146 mg/day during FA; P=0.12). High-dose FA treatment does not improve renal endothelial function and fails to reduce albuminuria in human subjects with diabetic nephropathy. Novel treatment options for oxidant stress and endothelial dysfunction in patients with diabetes are urgently needed.

Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes.

BACKGROUND: Patients with diabetes mellitus are at increased risk for microvascular complications. Early changes in microcirculation are characterized by hyperperfusion (e.g. in the retina and kidney) and increased pulse wave reflection leading to increased aortic pressure. We investigated the effects of the DPP-4-inhibitor saxagliptin on early retinal microvascular changes. METHODS: In this double-blind, controlled, cross-over trial 50 patients (without clinical signs of microvascular alterations) with type-2 diabetes (mean duration of 4 years) were randomized to receive placebo or 5 mg saxagliptin for 6 weeks. Retinal arteriolar structure and retinal capillary flow (RCF) at baseline and during flicker-light exposure was assessed by scanning laser Doppler flowmetry. Central hemodynamics were assessed by pulse wave analysis. RESULTS: Postprandial blood glucose (9.27 ± 0.4 versus 10.1 ± 0.4 mmol/L; p = 0.001) and HbA1c (6.84 ± 0.15 (51 ± 1.6) versus 7.10 ± 0.17% (54 ± 1.9 mmol/mol); p < 0.001) were significantly reduced with saxagliptin treatment compared to placebo. RCF was significantly reduced after treatment with saxagliptin (288 ± 13.2 versus 314 ± 14.1 AU; p = 0.033). This was most pronounced in a subgroup of patients (n = 32) with a fall in postprandial blood glucose (280 ± 12.1 versus 314 ± 16.6 AU; p = 0.011). No significant changes in RCF were seen during flicker-light exposure between placebo and saxagliptin, but the vasodilatory capacity increased two-fold with saxagliptin treatment. Central augmentation pressure tended to be lower after treatment with saxagliptin (p = 0.094), and central systolic blood pressure was significantly reduced (119 ± 2.3 versus 124 ± 2.3 mmHg; p = 0.038). CONCLUSIONS: Our data suggest that treatment with saxagliptin for 6 weeks normalizes retinal capillary flow and improves central hemodynamics in type-2 diabetes. TRIAL REGISTRATION: The study was registered at (ID: NCT01319357).

Poor glycemic control is related to increased nitric oxide activity within the renal circulation of patients with type 2 diabetes.

OBJECTIVE: Experimental studies have shown that glucose releases endothelial nitric oxide (NO) and that NO contributes to renal hyperperfusion in models of diabetes. To examine whether this translates into the human condition, we studied the relationship between glycemic control and renal NO activity in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 113 patients with type 2 diabetes and a wide range of HbA1c concentrations were included. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant infusion input clearance. Functional NO activity in the renal circulation was determined as change of RPF to infusion of the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (4.25 mg/kg). As additional markers, we measured urinary excretion of NO (UNOx) and L-arginine-to-asymmetrical dimethylarginine (ADMA) ratio in plasma. RESULTS: Subjects within the highest tertile of HbA1c concentration had increased RPF (low, medium, and high tertiles 576 ± 17 vs. 585 ± 22 vs. 627 ± 33 mL/min/m(2), P = 0.05 by one-way ANOVA), while GFR was similar across tertiles. The response of RPF to NOS blockade was augmented in subjects with higher HbA1c levels (-55 ± 7 vs. -64 ± 8 vs. -86 ± 8 mL/min, P = 0.04 by one-way ANOVA). Further, L-arginine-to-ADMA ratio and UNOx were increased in subjects with higher HbA1c levels. CONCLUSIONS: In line with experimental evidence, we could demonstrate in humans that poor glycemic control is related to higher NO activity and hyperperfusion of the kidney. The renal NO system may thus be a novel therapeutic target for improving renal hemodynamics in patients with diabetes.

Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies.

The dentate gyrus (DG) plays a pivotal role in the functional and anatomical organization of the hippocampus and is involved in learning and memory formation. However, the impact of structural DG abnormalities, i.e., granule cell dispersion (GCD), for hippocampal seizure susceptibility and its association with distinct lesion patterns in epileptic disorders, such as mesial temporal sclerosis (MTS) remains enigmatic and a large spectrum of pathological changes has been recognized. Here, we propose a clinico-pathological classification of DG pathology based on the examination of 96 surgically resected hippocampal specimens obtained from patients with chronic temporal lobe epilepsy (TLE). We observed three different histological patterns. (1) A normal granule cell layer was identified in 11 patients (no-GCP; 18.7%). (2) Substantial granule cell loss was evident in 36 patients (referred to as granule cell pathology (GCP) Type 1; 37.5%). (3) Architectural abnormalities were observed in 49 specimens, including one or more of the following features: granule cell dispersion, ectopic neurons or clusters of neurons in the molecular layer, or bi-lamination (GCP Type 2; 51%). Cell loss was always encountered in this latter cohort. Seventy-eight patients of our present series suffered from MTS (81.3%). Intriguingly, all MTS patients displayed a compromised DG, 31 (40%) with significant cell loss (Type 1) and 47 (60%) with GCD (Type 2). In 18 patients without MTS (18.7%), seven displayed focally restricted DG abnormalities, either cell loss (n = 5) or GCD (n = 2). Clinical histories revealed a significant association between DG pathology patterns and higher age at epilepsy surgery (p = 0.008), longer epilepsy duration (p = 0.004), but also with learning dysfunction (p < 0.05). There was no correlation with the extent of pyramidal cell loss in adjacent hippocampal segments nor with postsurgical seizure relief. The association with long-term seizure histories and cognitive dysfunction is remarkable and may point to a compromised regenerative capacity of the DG in this cohort of TLE patients.