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Abstract Background Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. Methods We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. Results Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. Conclusions Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. Trial registration clinicaltrials.gov (NCT02752113).

Abstract In patients with type 2 diabetes mellitus (T2DM) arterial stiffness is associated with increased cardiovascular and total mortality. Little is known about determinants of arterial stiffness in clinical routine. Identification of potential determinants of arterial stiffness will help to address treatment targets for patients in the early state of T2DM. This is a cross-sectional analysis of arterial stiffness in 266 patients in the early stage of T2DM who did not have cardiovascular or renal complications. Parameters of arterial stiffness such as central systolic blood pressure (cSBP), central pulse pressure (cPP) and pulse wave velocity (PWV) were measured with the SphygmoCor System (AtCor Medical). We investigated the influence of parameters of glucose metabolism, lipid status, body constitution, blood pressure (BP) and inflammation on the stiffness parameters using multivariate regression analysis. The study cohort consisted of male and female patients aged 61 ± 8 years with mean diabetes duration of 6.4 ± 5.1 years, mean HbA1c 7.1 ± 0.9%, mean cSBP 121 ± 12 mmHg, mean cPP 44 ± 10 mmHg and mean PWV 8.9 ± 1.8 m/s. Multiple regression analysis identified waist circumference (WC) (beta = 0.411, p = 0.026), LDL-cholesterol (beta = 0.106, p = 0.006), systolic office BP (beta = 0.936, p

Abstract Aims Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin–angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin‐converting enzyme–angiotensin II–angiotensin‐1 receptor axis (Ang I–ACE–Ang II receptor axis) is predominantly angiotensin II (Ang‐II) induced and promotes vasoconstriction. In contrast, the angiotensin‐converting‐enzyme‐2–angiotensin‐(1‐7)–Mas axis (Mas‐axis) is mediated by the metabolites angiotensin‐1‐7 (Ang‐(1‐7)) and angtiotensin‐1‐5 (Ang‐(1‐5)) and exerts cardioprotective effects. Methods We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II–III) in a randomized placebo‐controlled clinical trial ‘Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)’. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC‐MS/MS‐based approach) in 72 patients from ELSI. We compared RAS parameters after 1‐month and 3‐months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin‐receptor‐blocking (ARB) or angiotensin‐converting‐enzyme‐inhibitor (ACEI) co‐medication. Results Empagliflozin medication induced a significant rise in Ang‐II [68.5 pmol/L (21.3–324.2) vs. 131.5 pmol/L (34.9–564.0), P = 0.001], angiotensin‐I (Ang‐I) [78.7 pmol/L (21.5–236.6) vs. 125.9 pmol/L (52.6–512.9), P

Hypertension remains the leading treatable global cause of mortality due to high incidence and poor control rates despite of safe and effective drug therapy. Animal studies do not support functional nerve regrowth after RF-RDN and accordingly clinical evidence verify that RDN leads to durable BP reduction. Renal denervation is safe, as up to 36 months after the procedure, there are no statistically significant difference in procedure-related adverse events, deterioration of renal function and adverse cardiovascular outcome Renal denervation is efficient in reducing BP in patients with no drug therapy, independently of the number of antihypertensive drugs and phenotype of patient. This sustained and safe reduction in BP observed up to 36 months after RDN could be associated with lower rates of renal and cardiovascular events.

Abstract Background Vascular remodelling of large arteries increases afterload of the left ventricle. The aim of this study was to analyse whether vascular remodelling and function under laboratory and 24‐hour ambulatory conditions is impaired in patients with chronic heart failure (CHF) independently of cardiovascular risk factors. Methods and results In this monocentric cross‐sectional observational study, 105 patients with CHF and an ejection fraction ≤49% (CHF+) were compared to 118 subjects without CHF (CHF−). After adjustment for age, gender, arterial hypertension, hyperlipidaemia, type 2 diabetes, obesity and smoking, vascular function and structure parameters, as assessed by pulse wave analysis (SphygmoCor) and the UNEX EF device, respectively, between the CHF+ and the CHF− group differed for resting pulse wave velocity (PWV) (P = 0.010), 24‐h ambulatory PWV (P = 0.011), central systolic blood pressure (cSBP) (P =

Abstract Background Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. Main body This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. Conclusion With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.

Abstract Background After initiating cardioprotective agents, a fall of estimated glomerular filtration rate (eGFR) has been reported in several studies. Our goal was to evaluate the accuracy of change of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR in patients with type 2 diabetes (T2D) after short-term pharmacological intervention with angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, gliptin or sodium-glucose cotransporter-2 inhibitor. Methods We analyzed 190 patients with T2D in the early stage of the disease, having no overt renal impairment by CKD-EPI equation. In each patient, we measured GFR (mGFR) by applying the constant infusion input clearance technique with sinistrin (Inutest; Fresenius, Linz, Austria) at baseline and after short-term (4–12 weeks) pharmacological intervention with cardioprotective agents (ramipril, telmisartan, linagliptin, metformin, empagliflozin) that potentially lead to an alteration of renal function. Simultaneously, a standardized analysis of serum creatinine was performed and eGFR was estimated by the CKD-EPI equation. Results Average mGFR was 111 ± 20 ml/min/1.73m2, whereas eGFR was lower with 93 ± 13 ml/min/1.73m2. The ratio eGFR/mGFR in relation to mGFR was almost curvilinear, showing an underestimation of renal function by eGFR in the upper normal range. At baseline only 80 patients (42%) lay within ± 10% of mGFR and the concordance correlation coefficient (CCC) was extremely low (− 0.07). After short-term pharmacological intervention changes in eGFR and mGFR correlated with each other (r = 0.286, p

Introduction: In experimental myocardial infarction with reduced ejection fraction causing overt congestive heart failure, the control of renal sympathetic nerve activity (RSNA) by the cardio-renal baroreflex was impaired. The afferent vagal nerve activity under these experimental conditions had a lower frequency at saturation than that in controls. Hence, by investigating respective first neurons in the nodose ganglion (NG), we wanted to test the hypothesis that after myocardial infarction with still-preserved ejection fraction, the cardiac afferent nerve pathway is also already impaired.Material and methods: A myocardial infarction was induced by coronary artery ligature. After 21 days, nodose ganglion neurons with cardiac afferents from rats with myocardial infarction were cultured. A current clamp was used to characterize neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e.,

Abstract Background In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on l-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. Methods Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. Results Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p

Abstract Background Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p

Abstract Aims Impairment of vascular function contributes to the progression of chronic heart failure (HF) by increasing the afterload. Treatment with selective sodium‐glucose cotransporter 2 (SGLT2) inhibitors improves the prognosis of HF, but the precise mechanisms remain unclear. The aim of this study was to analyse the effect of empagliflozin on vascular function in patients with HF. Methods and results In an investigator initiated, double‐blind, randomized, placebo‐controlled, parallel‐group, clinical study, patients with HF NYHA II‐III and an ejection fraction of 49% or less were randomized 2:1 to receive empagliflozin 10 mg once daily or placebo for 3 months. A total of 74 patients (15% female), aged 66 ± 9 years, with a mean ejection fraction of 39 ± 8% and a median NTproBNP of 558 pg/mL (IQR 219–1051 pg/mL), were included. Vascular parameters such as central systolic blood pressure (cSBP), central pulse pressure (cPP), forward (FPH), and reflected pressure pulse height (RPH) decreased under resting conditions after 1 and 3 months (1 month: cSBP −6.4 ± 8.3 mmHg, P

Abstract Background Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. Methods Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. Results Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p

Abstract 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.

Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. Conclusion: The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

Abstract Aims Congestive heart failure (CHF) and impaired renal function are two often co‐existing medical conditions and associated with adverse cardiovascular outcome. The aim of the current study was to assess renal and intraglomerular haemodynamics by constant infusion input clearance technique in subjects with CHF. Methods and results The group of subjects with CHF consisted of 27 individuals with HFpEF and 27 individuals with HFrEF and were compared with 31 healthy controls. Subjects underwent renal clearance examination to measure glomerular filtration rate (GFR) and renal blood and plasma flow (RBF and RPF) and to calculate intraglomerular haemodynamics such as resistances of the afferent (RA) and efferent arterioles (RE) as well as intraglomerular pressure (Pglom). Measured GFR was lower in CHF subjects (68.1 ± 10.1 mL/min/1.73 m2) compared with controls (83.6 ± 13.4 mL/min/1.73 m2, Padj

Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s−1 cm−5, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s−1 cm−5, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.

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.

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

Abstract A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Milan, Italy, discussed the potential impact and long-term benefits of early active management of cardiovascular disease (CVD) risk in patients with hypertension, and potential barriers to this strategy. Hypertension often aggregates with other cardiovascular risk factors, exponentially increasing morbidity and mortality. While effective therapies to treat hypertension exist, a substantial number of patients still experience major cardiovascular events. Two major issues account for these disappointing results: interventions initiated too late in the disease trajectory and lack of effective translation of the research findings into daily clinical practice. Results from genetic studies suggest that lifetime exposure to lower blood pressure (BP) and cholesterol levels due to protective gene mutations, can provide greater cardiovascular benefits than middle-/late-age interventions. Clinical guidelines suggest adding statins to BP-lowering therapies for further cardiovascular benefits in most hypertensive patients; however, real-world data show that physicians’ compliance with these recommendations and patients’ adherence to BP- and lipid-lowering treatments remain poor, resulting in poor risk factor control and an increased risk of adverse outcomes. The use of single-pill combinations (SPC) can partially mitigate these issues, as they are associated with increased patient adherence and improved BP control. Treatment with SPC has been recommended in the European Hypertension Guidelines, but optimization of the total CVD risk may need adoption of more ambitious treatment strategies aimed to deliver single pills that control multiple CVD risk factors. Amlodipine, perindopril and atorvastatin have been shown to improve BP and lipid levels to a great extent when given separately, and this combination has also been shown to improve cardiovascular outcomes. Overall, early intervention in patients with hypertension with use of an effective, high-intensity cardiovascular risk reduction regimen and attention to medication adherence through reducing pill burden are likely to result in optimal outcomes.

Abstract Background Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness. Methods Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial (http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis. Results As previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p

Introduction: The high burden of left ventricular (LV) abnormalities in patients with advanced chronic kidney disease (CKD) is well established. However, less is known about the prevalence, patterns, and determinants of LV abnormalities in patients with early CKD. Methods: We examined LV structure in 290 patients with a median estimated glomerular filtration rate (eGFR) of 51 ml/min per 1.73 m2 by magnetic resonance imaging (MRI). We explored associations with clinical and hemodynamic parameters, hydration (bioimpedance), endothelial function, inflammation (including C-reactive protein and tumor necrosis factor−α and its soluble receptors) and mineral bone disease (MBD) markers (including vitamin D, parathyroid hormone, α-klotho and fibroblast growth factor−23). Results: Normal geometry was found in 56% of patients, dilation in 4%, concentric remodeling in 10%, and LV hypertrophy in 29%. Linear regression analysis revealed that greater LV mass was independently associated with male sex, greater body mass index (BMI), and higher 24-hour systolic blood pressure (24-hour SBP). Concentric remodeling was independently associated with age, male sex, higher 24-hour SBP, and greater hemoglobin levels. Surprisingly, neither hydration status, nor endothelial function, nor any of the inflammatory or MBD parameters added significantly to these models. Conclusion: Abnormal LV structure was found in almost one-half of the patients. Reducing BMI and 24-hour SBP and avoiding high hemoglobin concentrations appear to be the key factors to prevent abnormal LV remodeling in patients with mild-to-moderate CKD. Key words: chronic kidney disease, hypertension, kidney diseases, left ventricular hypertrophy, mineral metabolism

Abstract 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

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

Abstract Aim Patients with type-2 diabetes mellitus (T2DM) are at high risk of cardiovascular events, accentuated in the presence of hypertension. At present, it is unclear to what extent the guidelines for the management of T2DM, advocating reduction in HbA1c levels to below target levels, are being adhered to in clinical practice. Methods DIALOGUE was a prospective, observational, non‐interventional registry performed across multiple centres in Germany. Patients aged 18 years or older who had T2DM and hypertension for whom the treating physician considered blood glucose lowering medication as inadequate and/or not safe/tolerable and chose to add a further oral drug or switch drug treatment were included. Patients were assigned a treatment target HbA1c value (≤ 6.5% [strict]; > 6.5 to ≤ 7.0% [intermediate]; > 7.0 to ≤ 7.5% [lenient]). Results 8568 patients with T2DM and hypertension were enrolled. 6691 (78.1%) had 12-month follow-up. Patients who were assigned a strict HbA1c treatment target (n = 2644) were younger, had shorter diabetes duration, and less comorbidity in comparison to those with intermediate (n = 2912) or lenient targets (n = 1135). Only 53.1% of patients achieved their HbA1c treatment target (46.2% [strict], 56.8% [intermediate], 59.4% [lenient]). There was little sign of treatment intensification for patients that had not achieved their HbA1c target. Conclusions Achievement of treatment targets was poor, leaving many patients with sub-optimal blood glucose levels. The apparent reluctance of physicians to intensify antidiabetic drug therapy is alarming, especially considering the evidence pointing to an association of hyperglycaemia and microvascular complications in patients with T2DM.

Abstract 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.

Background: following the publication of SYMPLICITY HTN-3 the field of renal of denervation was put on hold. Although SYMPLICITY HTN-3 was well-designed and sham-controlled trial it failed to show any meaningful reduction in office or 24 h ambulatory blood pressure. The procedure was however safe and allowed research to continue. Although several pitfalls of the study have been pointed out, incomplete renal denervation was also implicated. Since then, a great deal of basic and clinical research took place and will be briefly commented on in this article. Methods and results: Before and after SYMPLICITY-HTN-3, numerous uncontrolled, single or unblinded studies have shown substantial office BP reduction ranging from −7.7 to −32 mmHg and ambulatory BP ranging from −2.2 to 10.2 mmHg. Average weighted office systolic BP reduction was −20.8 mmHg and weighted average 24 h ambulatory BPM reduction was −7.8 mmHg. National and international registries have shown similar BP reductions, but results remained unconvincing due to lack of reliable sham controls. In recent years, 5 well-designed sham – controlled studies (beyond, SYMPLICITY-HTN-3) have been published. Of those studies two were single center and three were multicenter international studies. Four studies used single tip or multi-electrode, radiofrequency catheters and one used focused ultrasound. The three multicenter studies reported positive-placebo subtracted results and established BP reductions measured both in the office and by ambulatory monitoring. No serious adverse events were reported. Conclusions: It can therefore be concluded that the latest sham controlled studies established efficacy and safety of renal denervation.

Background Renal denervation has no validated marker of procedural success. We hypothesized that successful renal denervation would reduce renal sympathetic nerve signaling demonstrated by attenuation of α‐1‐adrenoceptor‐mediated autotransfusion during the Valsalva maneuver. Methods and Results In this substudy of the Wave IV Study: Phase II Randomized Sham Controlled Study of Renal Denervation for Subjects With Uncontrolled Hypertension, we enrolled 23 subjects with resistant hypertension. They were randomized either to bilateral renal denervation using therapeutic levels of ultrasound energy (n=12) or sham application of diagnostic ultrasound (n=11). Within‐group changes in autonomic parameters, office and ambulatory blood pressure were compared between baseline and 6 months in a double‐blind manner. There was significant office blood pressure reduction in both treatment (16.1±27.3 mm Hg, P

BackgroundOptions for interventional therapy to lower blood pressure (BP) in patients with treatment‐resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH. Methods and ResultsThe randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment‐resistant hypertension (office systolic BP ≥140 mm Hg, average daytime ambulatory BP ≥135/85 mm Hg, and treatment with ≥3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177±18 mm Hg versus 169±17 mm Hg, P=0.163) and 24‐hour ambulatory systolic BP (159±16 mm Hg versus 154±11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: −29±21 mm Hg versus ISH: −22±31 mm Hg, P=0.445) and 24‐hour ambulatory systolic BP (CH: −14±20 mm Hg versus ISH: −13±15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction ≥10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932). ConclusionsOur data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24‐hour ambulatory systolic BP in patients with combined and isolated systolic hypertension. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498.

BackgroundAdherence 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 ResultsEighty 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). ConclusionsNonadherence 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 RegistrationURL: https://www.clinicaltrials.gov. Unique identifiers: NCT00888433, NCT01442883 and NCT01687725.