Relation between waist circumference and the renal hemodynamic in healthy individuals.

BACKGROUND AND AIMS: Obesity has been shown to be an independent risk factor for the development of CKD. Little is known about pathways of interaction of visceral fat mass estimated by waist circumference (WC) and metabolic factors with the renal and intraglomerular hemodynamic profile in healthy, non-obese individuals. METHODS AND RESULTS: The study population of this post-hoc analysis in 80 healthy individuals, who participated in a randomized, controlled clinical trial (www. CLINICALTRIALS: gov: NCT02783456) was divided into two groups based on median of WC (high WC and low WC group). Renal hemodynamic profiles were analyzed using steady state input clearance (infusion of para-amino-hippuric acid and inulin). Intraglomerular pressure (IGP) and resistances of the afferent (RA) and efferent (RE) arterioles were calculated (Gomez equation). The analysis included healthy, non-smoking individuals, aged 27 ± 9 years with median WC of 84.75 ± 9 cm. Glomerular filtration rate (GFR) (110 ± 15 vs. 127 ± 16 ml/min/m2, p < 0.001), renal plasma flow (RPF) (620 ± 109 vs. 700 ± 104 ml/min, p = 0.001) and IGP (36.7 ± 2.3 vs. 38.5 ± 3.1 mmHg, p = 0.003) were lower in the high WC compared to the low WC group. Patients in the high WC group showed higher renal vascular resistance (RVR) (85 ± 19 vs. 70 ± 12 mmHg/(ml/min), p < 0.001), higher RA (4034 ± 1177 vs. 3069 ± 786 dyn∗s/cm5, p < 0.001) and higher RE (2283 ± 339 vs. 2118 ± 280 dyn∗s/cm5, p = 0.021) compared to the low WC group. Individuals in the high WC group showed higher leptin levels (p = 0.003) and higher HOMA-IR (p = 0.024) compared to the low WC group. CONCLUSION: Increased WC in healthy young individuals was associated with reduced GFR and RPF likely mediated by increased RVR.

Determinants of arterial stiffness in patients with type 2 diabetes mellitus: a cross sectional analysis.

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 < 0.001) and diabetes duration (beta = 0.233, p = 0.043) as potential determinants of cSBP. cPP was determined by sex (beta = 0.330, p = 0.008), age (beta = 0.383, p < 0.001), systolic office BP (beta = 0.370, p < 0.001) and diabetes duration (beta = 0.231, p = 0.028) whereas for PWV the following determinants could be identified: age (beta = 0.405, p < 0.001), systolic office BP (beta = 0.421, p < 0.001) and diabetes duration (beta = 0.073, p = 0.038). In addition to the known parameters age, sex and systolic office BP serum LDL-cholesterol, WC and diabetes duration have been identified as determinants of arterial stiffness in patients with T2DM. Treatment of patients in the early stage of T2DM should focus on these clinical parameters to prevent progression of arterial stiffness and as a consequence reduce cardiovascular mortality.Trial registration: The patients included in the analysis participated in one of the following clinical trials NCT02752113 (registered 26.4.2016), NCT02383238 (09.03.2015), NCT02471963 (15.06.2015), NCT01319357 (21.03.2011) ( http://www.clinicaltrials.gov ).

Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure.

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 < 0.001], Ang-(1-7) [3.0 pmol/L (3.0-15.0) vs. 10.1 pmol/L (3.0-31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0-22.9) vs. 9.9 pmol/L (2.8-36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2-750.6) vs. 568.2 pmol/L (164.7-1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0-14.1) vs. 15.0 pmol/L (3.0-31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8-46.6) vs. 36.4 pmol/L (11.1-90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0-60.8) vs. 26.4 pmol/L (10.7-63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0-20.7) vs. 10.5 pmol/L (3.0-50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0-8.4) vs. 2.8 pmol/L (2.0-6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment). CONCLUSIONS: Our data indicate that empagliflozin might lead to an activation of both the Ang I-ACE-Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I-ACE-Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.

Is vascular remodelling in patients with chronic heart failure exaggerated?

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 = <0.001), 24-h ambulatory cSBP (P = <0.001), resting central augmentation index (P = 0.002), and brachial intima-media thickness (P = 0.022). In CHF+ patients, higher levels of NT-proBNP, taken as a marker for the severity of CHF, were related to a higher PWV (r = 0.340, P = <0.001), a higher cSBP (r = 0.292, P = 0.005), and a trend to higher central pulse pressure (cPP) (r = 0.198, P = 0.058), higher 24-h brachial PP (r = 0.322, P = 0.002), and 24-h total peripheral resistance (s = 0.227, P = 0.041) after full adjustment for covariates. CONCLUSIONS: In CHF+ patients we observed augmented vascular remodelling and functional impairment compared with CHF- patients independently of cardiovascular risk factors, age, and gender, and the extent of vascular remodelling and impairment was related to the severity of CHF.

Change of renal function after short-term use of cardioprotective agents in patients with type 2 diabetes is not accurately assessed by the change of estimated glomerular filtration rate: an observational study.

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 < 0.001). For example, for a given mGFR of 111 ml/min/1.73m2, a change of mGFR by ± 10% corresponded to ± 11 ml/min/1.73m2, but the confidence interval of eGFR was 25 ml/min/1.73m2. The CCC was low (0.22). CONCLUSION: The agreement between eGFR by CKD-EPI and mGFR is modest and the change of renal function after short-term pharmacological intervention is not accurately and precisely reflected by the change of eGFR in patients with T2D in the early stage of their disease.

[Renal denervation : Really an alternative to reducing blood pressure?] / Renale Denervation : Wirklich eine Alternative zu Blutdrucksenkern?

Since the current guidelines were published in 2018, a total of 5 sham-controlled high-quality studies evaluating renal denervation have been conducted and the results were published. These five studies clearly confirmed the efficacy and safety of renal denervation, which correspond to the knowledge of the Clinical Consensus Conference. Thus, an update of the guidelines for the treatment of arterial hypertension regarding the clinical significance of renal denervation is urgently necessary. For this reason, the position paper of the working group of the European Society of Hypertension on the current state of renal denervation was reviewed. An approval of this procedure can soon be expected. In Germany there is a diagnosis-related group (DRG) for the reimbursement of renal denervation, which was suspended due to the erroneous Symplicity 3 study. This DRG should be revived in practice by a structured process of the implementation of renal denervation. It will then be a joint task of treating physicians and specialists in certified centers to identify eligible patients. In the future, antihypertensive treatment will consist of three pillars: lifestyle measures, pharmacotherapy and interventional treatment. These three treatment options should not be regarded as competitive (which is better) but alternative (patient preference) and additive (the aim is blood pressure control). It is the task of the treating physician to provide the patient with the ideal treatment concept. Clearly, renal denervation will not replace antihypertensive pharmacotherapy; however, it can lead to a reduction of the drug burden and increase of patient adherence to medication. It represents an option of modern antihypertensive treatment and will also become increasingly more important in special patient groups.

The influence of aircraft noise exposure on the systemic and renal haemodynamics.

AIMS: Epidemiological studies found a link between aircraft noise exposure and increased incidence of arterial hypertension and cardiovascular disease, but the underlying pathophysiological mechanisms are not fully understood. Clinical studies have shown that mental stress affects the systemic and renal haemodynamic, but no such study was performed with noise exposure as stress factor. We analysed systemic and renal effects of 25 min standardized aircraft noise in a sham controlled clinical study including 80 healthy men and 34 male patients with hypertension. METHODS AND RESULTS: Systemic haemodynamic parameters were measured using electrocardiography and impedance cardiography. The renal haemodynamic was assessed using steady state input clearance with infusion of para-aminohippuric acid and inulin for glomerular filtration rate and renal plasma flow, respectively. In the systemic circulation of hypertensive patients, there was an increase in total peripheral resistance (TPR) (1420 ± 387 vs. 1640 ± 516 dyn·s·cm-5, P = 0.001) and a decrease in cardiac index (CI) (2.9 ± 0.8 vs. 2.6 ± 0.8 L/(min·m2, P < 0.001) 25 min after the start of noise exposure, which was not present during sham procedure (P = 0.10, P = 0.86). In healthy individuals a procedure induced increase in TPR and decrease in CI was present after noise (TPR: 995 ± 239 vs. 1106 ± 308 dyn·s·cm-5, P = 0.001, CI: 3.6 ± 0.7 vs. 3.3 ± 0.9 L/(min·m2, P < 0.001) and sham application (TPR: P = 0.002, CI: P < 0.001). However, in healthy individuals changes in TPR (P = 0.450) and CI (P = 0.605) from baseline until 25 min after the start of the intervention did not differ between noise and sham exposure. In the renal circulation of hypertensive patients and healthy individuals the response did not differ between noise and sham procedure. CONCLUSIONS: In hypertensive but not healthy men we observed a systemic vasoconstrictive response after aircraft noise exposure accompanied by a decrease in CI. No significant changes were observed in the renal circulation. Our results suggest that male hypertensive patients are more susceptible for noise-induced changes of vascular resistance in the systemic circulation.

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.

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine.

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 < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. CONCLUSIONS: In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016.

Association of Noise Annoyance with Measured Renal Hemodynamic Changes.

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.

Detection of Changes in Renal Blood Flow Using Arterial Spin Labeling MRI.

BACKGROUND: Alteration in kidney perfusion is an early marker of renal damage. The purpose of this study was to evaluate if changes in renal blood flow (RBF) could be detected using MRI with arterial spin labeling (ASL) technique. METHODS: RBF as assessed by cortical (CRBF), medullary, and total renal blood flow (TRBF) were measured by MRI with arterial spin labeling (ASL-MRI) using flow-sensitive alternating inversion recovery true fast imaging with steady-state precession sequence. In 11 normotensive healthy individuals (NT) and 11 hypertensive patients (HT), RBF was measured at baseline and after both feet were covered with cold ice packs (cold pressor test) that activates the sympathetic nervous system. In another experiment, RBF was measured in 10 patients with CKD before and after a pharmacological intervention. We compared RBF measurements between the 3 study populations. RESULTS: A significant reduction in CRBF (p = 0.042) and a trend in TRBF (p = 0.053) were observed in response to the activation of the sympathetic nervous system. A trend toward reduction of CRBF (p = 0.051) and TRBF (p = 0.059) has been detected after pharmacological intervention. TRBF was significantly lower in patients with HT and CKD patients compared to NT individuals (NT vs. HT, p = 0.014; NT vs. CKD, p = 0.004). TRBF was lower in patients with CKD compared to HT (p = 0.047). CONCLUSION: Our data indicate that both acute and short-term changes in RBF could be detected using ASL-MRI. We were able to detect differences in RBF between healthy and diseased individuals by needing only small sample size per group. Thus, ASL-MRI offers an advantage in conducting clinical trials compared to other technologies.

Dependency of flow-mediated vasodilatation from basal nitric oxide activity.

BACKGROUND: Flow-mediated vasodilatation (FMD) has become one of the most widely assessed parameters to analyse endothelial and vascular function in cardiovascular medicine. The degree of contribution of nitric oxide (NO) to FMD is inconclusive and varies widely depending on the device used. In this study, we used a semi-automatic ultrasound device to analyse to what extent basal NO activity contributes to FMD of the brachial artery. METHODS: FMD was assessed with the UNEX EF device in a cross-over single blinded randomized study at baseline and then during infusion of either a NO-synthase-inhibitor (NG-monomethyl-L-arginine (L-NMMA)) or saline. The analysis was repeated after 1 week with the alternative infusion of L-NMMA or saline. All measurements were analysed both automatically and by a technician manually. RESULTS: In total, 25 healthy men subjects completed the study. Diastolic blood pressure and heart rate significantly changed during infusion of L-NMMA. Infusion of L-NMMA reduced FMD significantly (-37%, p = 0.002). Saline solution had no effect on FMD (+14%, p = 0.392). Change in FMD was significantly different between the groups (ΔFMDL-NMMA vs. ΔFMDsaline , p = 0.032). There was a statistically significant correlation between automatically analysed results and those obtained by an experienced technician (FMDsaline : r = 0.822, p < 0.001; FMDL-NMMA : r = 0.645, p = 0.007). CONCLUSION: The influence of NO on FMD is approximately 40% if assessed using the UNEX EF. Prior to use FMD as a marker of endothelial dysfunction, we should explore different methods including various duration of forearm ischaemia to increase NO dependency of FMD.

Renal and intraglomerular haemodynamics in chronic heart failure with preserved and reduced ejection fraction.

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  < 0.001) as was Pglom (Padj  < 0.001). Total renal vascular resistance (RVR) was higher in CHF subjects (87.3 ± 20.1 vs. 73.8 ± 17.1 dyn × s/cm5 , Padj  < 0.001) mediated by an increased resistance at the afferent site (3201 ± 1084 vs. 2181 ± 796 dyn × s/cm5 , Padj  < 0.001). Comparing HFpEF and HFrEF subjects, RA was higher in HFrEF subjects. The severity of CHF assessed by NT-proBNP revealed an inverse association with renal perfusion (RPF r = -0.421, P = 0.002, RBF r = -0.414, P = 0.002) and a positive relation with RVR (r = 0.346, P = 0.012) at the post-glomerular site (RE : r = 0.318, P = 0.022). CONCLUSIONS: Renal function assessed by measured GFR is reduced and renal vascular resistance at the preglomerular, afferent site is increased in HFpEF and, to greater extent, in HFrEF. Our data indicate a close cardiorenal interaction in CHF.

Combination of empagliflozin and linagliptin improves blood pressure and vascular function in type 2 diabetes.

AIMS: Preserved vascular function represents a key prognostic factor in type 2 diabetes mellitus (T2DM), but data on vascular parameters in this patient cohort are scarce. Patients with T2DM often need more than one drug to achieve optimal glucose control. The aim of this study was to analyse the efficacy of two combination therapies on vascular function in subjects with T2DM. METHODS AND RESULTS: This prospective, randomized study included 97 subjects with T2DM. Subjects were randomized to either the combination therapy empagliflozin (E) 10 mg with linagliptin (L) 5 mg once daily or metformin (M) 850 or 1000 mg twice daily with insulin glargine (I) once daily. At baseline and after 12 weeks, subjects had peripheral office and 24-h ambulatory blood pressure (BP) measurement and underwent vascular assessment by pulse wave analysis under office and ambulatory conditions. Office, 24-h ambulatory and central BP as well as pulse pressure (PP) decreased after 12 weeks of treatment with E + L, whereas no change was observed in M + I. There were greater decreases in 24-h ambulatory peripheral systolic (between-group difference: -5.2 ± 1.5 mmHg, P = 0.004), diastolic BP (-1.9 ± 1.0 mmHg, P = 0.036), and PP (-3.3 ± 1.0 mmHg, P = 0.007) in E + L than M + I. Central office systolic BP (-5.56 ± 1.9 mmHg, P = 0.009), forward pressure height of the pulse wave (-2.0 ± 0.9 mmHg, P = 0.028), 24-h ambulatory central systolic (-3.6 ± 1.4 mmHg, P = 0.045), diastolic BP (-1.95 ± 1.1 mmHg, P = 0.041), and 24-h pulse wave velocity (-0.14 ± 0.05m/s, P = 0.043) were reduced to a greater extent with E + L. CONCLUSION: Beyond the effects on glycaemic control, the combination therapy of E + L significantly improved central BP and vascular function compared with the classic combination of M + I. CLINICALTRIALS.GOV: NCT02752113.

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial.

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 < 0.001), central pulse pressure (39.1 ± 10.2 vs 41.9 ± 10.7 mmHg, p = 0.027) forward (27.1 ± 5.69 vs 28.7 ± 6.23 mmHg, p = 0.031) as well as reflected wave amplitude (18.9 ± 5.98 vs 20.3 ± 5.97 mmHg, p = 0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta = - 0.259, p = 0.054), sex (beta = 0.292, p = 0.040) and change in systolic 24-h ambulatory blood pressure (beta = 0.364, p = 0.019), the change of hsCRP (beta = 0.305, p = 0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta = 0.347, p = 0.017) on arterial stiffness parameters was found. CONCLUSION: Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms. Trial registration http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered.

A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation.

BACKGROUND: The sodium-glucose cotransporter 2 inhibitor, dapagliflozin, has been shown to improve diabetic control and reduce blood pressure in patients with type 2 diabetes mellitus. Its effects on micro- and macrovascular structure and function have not yet been reported. METHODS: This was a prospective, single-centre, placebo-controlled, double-blind, randomised crossover phase IIIb study conducted between March 2014 and February 2015. After a 4-week run-in/washout phase, patients (N = 59) received 6 weeks of either dapagliflozin 10 mg or placebo once daily. They then underwent a 1-week washout before crossing over to the other treatment. Changes in retinal capillary flow (RCF) and arteriole remodelling were evaluated using scanning laser Doppler flowmetry, while micro- and macrovascular parameters in the systemic circulation were assessed using pulse wave analysis. RESULTS: Six weeks of dapagliflozin treatment resulted in improvements in diabetes control, including blood glucose and insulin resistance, and reduced office and 24-h ambulatory blood pressure values. RCF decreased from 324 AU at baseline to 308 AU after treatment with dapagliflozin (p = 0.028), while there was little difference after the placebo (318 AU; p = 0.334). Furthermore, the arteriole remodelling that was seen after the placebo phase was not evident after the dapagliflozin phase. Central systolic and diastolic blood pressure values were significantly lower after 6 weeks of dapagliflozin, by 3.0 and 2.2 mmHg, respectively (p = 0.035 and 0.020, respectively vs. baseline). CONCLUSIONS: Six weeks of dapagliflozin treatment resulted in numerous beneficial effects. In addition to achieving superior diabetes control and blood pressure, parameters associated with the early stages of vascular remodelling were also improved. Trial registration http://www.clinicaltrials.gov (NCT02383238).

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 manidipine vs. amlodipine on intrarenal haemodynamics in patients with arterial hypertension.

AIMS: Intraglomerular pressure is one of the main drivers of progression of renal failure. Experimental data suggest that there are important differences between calcium channel blockers (CCBs) in their renal haemodynamic effects: manidipine reduces, whereas amlodipine increases intraglomerular pressure. The aim of this study was to investigate the effects of manidipine and amlodipine treatment on intragomerular pressure (P(glom)) in patients with mild to moderate essential hypertension. METHODS: In this randomized, double-blind, parallel group study, hypertensive patients were randomly assigned to receive manidipine 20 mg (n = 54) or amlodipine 10 mg (n = 50) for 4 weeks. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant-infusion input-clearance technique with p-aminohippurate (PAH) and inulin. P(glom) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the model established by Gomez. RESULTS: P(glom) did not change in the manidipine group (P = 0.951), whereas a significant increase occurred in the amlodipine group (P = 0.009). There was a significant difference in the change of P(glom) by 1.2 mmHg between the manidipine and amlodipine group (P = 0.042). In both treatment arms, R(A) was reduced (manidipine P = 0.018; amlodipine P < 0.001). The reduction of R(A) was significantly more pronounced with amlodipine compared with manidipine treatment (P < 0.001). R(E) increased in both treatment arms (manidipine P = 0.012; amlodipine P = 0.002), with no difference between the treatment arms. Both CCBs significantly reduced systolic and diastolic blood pressure (BP) (both P < 0.001). However, amlodipine treatment resulted in a significantly greater decrease of BP compared with manidipine (P < 0.001). CONCLUSIONS: In accordance with experimental data after antihypertensive treatment of 4 weeks, intraglomerular pressure was significantly lower with the CCB manidipine than with amlodipine, resulting and explaining their disparate effects on albuminuria.