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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.

Tissue sodium content byPatients with T2DM were compared to those with primary hypertension. Patients with T2DM were off any antidiabetic and hypertensive patients off any antihypertensive therapy for at least 4 weeks. Skin and muscle sodium content was assessed non-invasively with a 3.0 T clinical MRI system (Magnetom Verio, Siemens Health Care, Erlangen, Germany) in each patient.In patients with T2DM (N = 59) we observed significantly greater muscle sodium content (diabetes: 20.6 ± 3.5 vs hypertension: 16.3 ± 2.5 mmol/l, p 0.001) and skin sodium content (diabetes: 24.5 ± 7.2 vs hypertension: 20.6 ± 5.7 mmol/l, p = 0.01) than in those with primary hypertension (N = 33). When potential confounders (age, body mass index, gender, systolic and diastolic blood pressure, estimated glomerular filtration rate) were entered in a covariance analysis, both skin sodium content (p = 0.037) and muscle sodium content (p 0.001) were still clearly elevated.Patients with T2DM have greater skin and muscle sodium content. These are the first known data to demonstrate increased tissue sodium content in patients with T2DM, measured by

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 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.

Background and purpose The optimal choice of antidiabetic medication in patients that need combined therapy is under debate. The aim of this study was to analyze whether beyond glucose control the combination of empagliflozin (E) and linagliptin (L) improves blood pressure (BP) and vascular function in patients with type 2 diabetes (T2DM) as opposed to the combination of metformin (M) and insulin glargine (I). Methods This was a prospective, randomized, controlled, single center study including 101 patients with T2DM, who were randomized 1:1 to E 10–25mg combined with L 5mg once daily or M 850 or 1000mg twice daily combined with I once daily. All patients underwent BP measurement and vascular function analysis by validated systems at baseline and after 12 weeks of treatment. Results In comparison to baseline, office, 24-hour ambulatory BP as well as central blood and pulse pressure (PP) values decreased significantly after 12 weeks of treatment with E+L, whereas there was no change in the M+I group (see table). Twenty-four-hour peripheral systolic (mean difference: −5.2±1.5mmHg, p=0.004) and diastolic BP (−1.9±1.0mmHg, p=0.036), central clinical systolic BP (−5.56±1.9mmHg, p=0.009), forward pressure pulse height (−2.0±0.9mmHg, p=0.028), 24-h central systolic BP (−3.6±1.4mmHg, p=0.045) and 24-h pulse wave velocity (−0.14±0.05m/s, p=0.043) were reduced to a greater extent in the E+L than in the M+I group. Empagliflozin+Linagliptin Metformin+Insulin Baseline 12 weeks p value Baseline 12 weeks p value Peripheral ambulatory BP values 24-h SBP [mmHg] 131.0±10.9 127.0±8.8 Conclusion The combination of E+L significantly improves BP and vascular function in contrast to the combination of M+I. Acknowledgement/Funding This IIS was supported by a research grant from Boehringer Ingelheim International GmBH

BACKGROUND Copeptin, the C-terminal peptide of provasopressin, is released from the neurohypophysis and reflects the activity of the hormone arginine vasopressin in patients with hypertension. Elevated copeptin levels are associated with increased cardiovascular and all-cause mortality. The aim of this study is to compare copeptin levels in patients with treatment-resistant hypertension (TRH) before and 6 months after renal denervation (RDN). METHODS Copeptin was measured in 34 patients with TRH and 30 patients with primary hypertension stage 1 or 2 (HT). In addition, copeptin levels were measured in patients with TRH at 6-month follow-up visit after RDN. RDN was performed by an experienced interventionalist applying at least 4 ablations longitudinally and rotationally within the lengths of each renal artery to cover a full 4-quadrant ablation. RESULTS In patients with TRH 24-hour ambulatory blood pressure (BP) decreased from 154 ± 15/87 ± 12 mm Hg to 146 ± 13/83 ± 7.9 mm Hg after RDN (systolic: P = 0.001, diastolic: P = 0.034). There was no significant change in copeptin levels in these 34 patients with TRH before vs. 6 months after RDN (median 8.4 [interquartile range 3.6–14] vs. 8.5 [4.5–13] pmol/l, P = 0.334). Patients with TRH had higher copeptin levels (P = 0.024) than patients with HT (24-hour ambulatory BP: 142 ± 11/91 ± 8.3 mm Hg, copeptin: 4.2 [2.8–6.3] pmol/l). CONCLUSION Patients with TRH showed 2-fold higher copeptin levels than patients with HT. RDN did not lead to any change of copeptin levels in patients with TRH 6 months after procedure despite significant fall in BP. CLINICAL TRIAL REGISTRATION NCT01318395, NCT01687725

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 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 registrationhttp://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered

Objective: In patients with resistant hypertension, percutaneous placement of an iliac arteriovenous coupler device leads to a reduction of blood pressure (BP) via decreased total vascular resistance and improved arterial compliance. However, long-term efficacy and safety need to be further explored. We report on the first case of 3.5-year follow-up in a patient who underwent implantation of an iliac arteriovenous coupler device. Results: A patient with resistant hypertension was admitted to hospital. Despite treatment with six anti-hypertensive drugs, his BP was poorly controlled. Previously, he had undergone renal denervation, which did not cause a significant BP decrease. Therefore, an arteriovenous coupler device was implanted, leading to an immediate and significant BP decrease. The patient was discharged with an office BP of 122/71 mmHg. After 3 months, there was a sustained BP decrease (−14/9 mmHg), whereas later, it was fluctuant (office BP: 147–173/85–95 mmHg, ABPM: 153–166/81–94 mmHg) probably due to medication non-adherence confirmed by a urinary toxicological screening test. Follow-up right heart catheterization showed changes in hemodynamic parameters related to volume congestion, which were accompanied by progressive dyspnea and weight gain. This was controlled by an optimized diuretic therapy. Additionally, an invasive closure maneuver was performed, leading to an immediate BP increase after closure and a similar decrease after re-opening of the anastomosis, verifying its proper long-term function. Conclusion: The implantation of an iliac arteriovenous coupler device appears to be a promising and effective method to decrease BP and therefore reduce cardiovascular risk in patients with severe, treatment-resistant hypertension.

Background: In a large 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) and 54 subjects without T2DM we assessed urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF), 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]. Results: Compared to subjects without T2DM, patients with type 2 diabetes (duration: mean 63.9 ± 56.4, range 1-271 months) were older (59.8 ± 7.3 vs. 43.4 ± 12.9 years, p Non-T2DM-subjects (n=54)Patients with T2DM (n= 111)Unadjusted p-valueAge- gender- adjusted p-valueAdjusted p-value (potential confounders)ICD (µm)20.8 ± 3.523.9 ± 5.1 Conclusion: These data suggest that at similar blood pressure capillary rarefication in the retinal circulation (ICD), eGFR in the renal circulation and central pulse pressure (cPP) of large arteries are earlier detectable than vascular remodeling of the micro- (WLR, RCF, UACR) and macrocirculation (cSPB) in patients with T2DM. Disclosure R.E. Schmieder: Consultant; Self; AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; Novartis AG. Consultant; Self; Novartis AG. Speaker's Bureau; Self; Servier. D. Kannenkeril: None. M.V. Karg: None. A. Bosch: None. J.M. Harazny: None. C. Ott: None.

From a clinical perspective, type 2 diabetes mellitus might also be regarded as a vascular disease, characterized by increased arterial stiffness. Empagliflozin is a selective sodium-glucose cotransporter 2 inhibitor shown to improve glycemic control after short- and long-term treatment.1 In the EMPA-REG OUTCOME study (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), a prospective randomized double-blind study in patients with type 2 diabetes mellitus with established cardiovascular disease, treatment with empagliflozin reduced the primary combined cardiovascular end point (3P-MACE [3-point major adverse cardiovascular event]), as well as secondary end points of hospitalization because of heart failure, cardiovascular morbidity, total mortality, and renal end points.2 We tested the hypothesis that improvements of vascular function and stiffness are involved in the observed improved cardiovascular and renal outcomes with empagliflozin treatment. In this investigator-initiated prospective, double-blind, randomized, placebo-controlled, crossover, interventional single-center trial, 76 female and male patients (18–75 years of age) with diagnosed type 2 diabetes mellitus were randomized to either empagliflozin 25 mg orally once daily or placebo for 6 weeks, followed by the second 6-week treatment with the other compound (crossover). In 64 patients, any antidiabetic agent was withdrawn 4 weeks before the baseline examination. We analyzed the effects …

Mineralocorticoid receptor antagonists are increasingly used in patients with treatment-resistant hypertension (TRH). There is experimental evidence for blood pressure (BP) independent effects of mineralocorticoid receptor blockade on cardiovascular target organ damage. We hypothesized that low-dose eplerenone (50 mg) will reduce left ventricular mass (LVM) beyond its BP-lowering effects.We performed a randomized, double-blind, placebo-controlled, parallel group study in 51 patients with TRH. Patients were allocated to receive either eplerenone 50 mg or placebo for 6 months, while other antihypertensive agents could be added in both groups to achieve a BP target of less than 140/90 mmHg. LVM was assessed by MRI before and after treatment.Baseline office BP was similar in the eplerenone and the placebo group (166 ± 21/91 ± 15 versus 159 ± 19/94 ± 8 mmHg, n.s.). BP was similarly reduced in the eplerenone versus the placebo group (-35 ± 20/-15 ± 11 versus -30 ± 19/-13 ± 7 mmHg, n.s.). However, LVM was reduced only in the eplerenone group (from 155 ± 33 to 136 ± 33 g, P 0.001), but not in the placebo group (152 ± 32 versus 148 ± 38 g, P = 0.45).Despite similar BP-lowering, only patients with TRH who were allocated to eplerenone experienced a reduction of LVM. Thus, our data suggest that in patients with TRH, mineralocorticoid receptor antagonists should be used preferentially in order to achieve an effective reduction of LVM along with the improvement of BP control.

Objective:Epidemiological evidence suggests a link between noise exposure and increased incidence of arterial hypertension and cardiovascular disease. The kidney as long-term regulator of blood pressure might play a role in the underlying pathophysiological mechanism. The aim of this study is to inv

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)

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. 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 assessed urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF), 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 blood pressure (cSBP) and central pulse pressure (cPP) [assessed by Syphygmocor] both reflecting vascular stiffness of large arteries. Results: Compared to subjects without T2DM, patients with T2DM were older, more females but 24-hour systolic and diastolic BP did not differ between the two groups (129.3 ± 11.4/78.9 ± 8.3 vs. 130.4 ± 10.8/77.4 ± 5.6 mmHg). The analysis adjusted for age, gender and cardiovascular risk factors showed that ICD, cPP were significantly higher and eGFR was significantly lower in patients with T2DM than in subjects without T2DM (Figure). Conclusion: These data suggest that at similar BP capillary rarefication in the retinal circulation (ICD), eGFR in the renal circulation and cPP of large arteries are earlier detectable than vascular remodeling of the micro- (WLR, RCF, UACR) and macrocirculation (cSBP) in patients with T2DM.

Background: The selective sodium-glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin leads to improved cardiovascular, renal and heart failure outcome in secondary prevention. To better understand these effects, we examined vascular function and central hemodynamics. Methods: In this prospective, double-blind, randomized, placebo-controlled, crossover study 76 patients with untreated type 2 diabetes were randomized to empagliflozin 25 mg orally once daily or placebo. After 6 weeks of treatment with either empagliflozin or placebo and 1 week wash-out-phase, patients crossed over to the other treatment. Central hemodynamics and vascular function were assessed by central systolic blood pressure (BP), central pulse pressure, forward and backward wave amplitude under office (Sphygmocor, AtCor, Australia) as well as ambulatory conditions (Mobilograph, IEM, Aachen). Results: Treatment with empagliflozin reduced central systolic BP (114 ± 12 vs. 119 ± 14 mmHg, p < 0.001), central diastolic BP (74.4 ± 6.9 vs. 76.8 ± 8.2 mmHg, p = 0.004) and central pulse pressure (39.5 ± 9.9 vs. 42.2 ± 11 mmHg, p = 0.012) compared to placebo. Forward (p = 0.006) and backward (p = 0.026) reflection amplitude, assessed under office conditions, were also significantly lower with empagliflozin than with placebo. Under ambulatory conditions over 24-hours we also observed lower central systolic (117 ± 9 vs. 119 ± 9 mmHg, p = 0.059) and diastolic (79 ± 7 vs. 81 ± 7 mmHg, p = 0.011) BP after 6 weeks treatment with empagliflozin compared to placebo. Pulse wave velocity under ambulatory conditions was also reduced after 6 weeks with empagliflozin (p = 0.016). Conclusions: Our study demonstrated consistent significant improvements of vascular function and central hemodynamics with empagliflozin under office and ambulatory conditions. Our data support the concept that empagliflozin exerts beneficial effects on cardiovascular and heart failure outcome via improved vascular function.