The current hypertension guidelines consistently emphasize the importance of home blood pressure monitoring. In addition to confirming the diagnosis it is possible to identify clinically relevant hypertension phenotypes. A home blood pressure reading of 135/85 mm Hg is considered the threshold for arterial hypertension. Standardized conditions must also be observed for home blood pressure measurement. By documenting the home blood pressure values measured twice in both mornings and evenings over a period of (ideally) 7 days, home blood pressure readings can be assessed quickly and easily. It is essential to ensure that a validated blood pressure monitor is used. The sensor technology built into "smart technologies" allows cuffless detection of (pulse) waveforms and thus estimation of blood pressure. Validation based on a specific protocol is not necessary. Possible sources of error include bias, deviations over time and (varying) environmental conditions. For this reason, cuffless blood pressure measurement is not recommended by current hypertension guidelines. The Apple Watch takes a different approach: instead of blood pressure values it displays the message "possible hypertension." Due to its widespread use we will probably be confronted increasingly more with this issue but greater awareness and more newly diagnosed hypertensive patients can also be expected.

Objective: Long-term follow-up data from the SYMPLICITY 3 trial (Bhatt et al, Lancet, 2022) and the Global Symplicty Register data (Mahfoud et al, JACC, 2020) show a further decrease in BP over time up to 3 years post procedure. Yet these observations lack a mechanistic explanation. A decrease in vascular resistance could possibly explain the observed phenomenon. Scanning Laser Doppler Flowmetry (SLDF) allows the non-invasive assessment of vascular resistance and capillary density by using the retinal vasculature as a mirror of the systemic circulation. Design and method: Retinal parameters were assessed using SLDF together with office and 24-hour ambulatory BP before and 6 as well as 12 months after renal denervation in 63 patients with treatment resistant hypertension (TRH) (NCT01687725). SLDF allows the assessment of retinal capillary flow (RCF), pulsed retinal capillary flow (systolic retinal capillary flow – diastolic retinal capillary flow) (pRCF), retinal vascular resistance, capillary area (CapA) and intercapillary distance (ICD). Results: Mean age of the study cohort was 60±11 years, mean BMI 30.6±4.9 kg/m2. Patients took 5.8 antihypertensive medications on average. There was a significant reduction of systolic and diastolic 24-hour ambulatory as well office BP 6 as well as 12 months after RDN (table 1). There was no significant reduction in the number of antihypertensive medications taken between baseline and 12 months after RDN (5.8vs.5.7 antihypertensive pills, p=0.159). Retinal vascular resistance was reduced 6 months after RDN (table 1), pRCF was reduced 6 as well as 12 months after RDN and capillary density improved 12 months after RDN. Conclusions: In high-risk patients with TRH endovascular RDN improved vascular resistance and reversed capillary rarefaction in the retinal circulation, a prognostic marker of further end-organ damage. The reduction of pRCF indicates a decrease of shear stress on the vascular wall by the pulsed blood flow. Increment of capillary density was observed not already 6 months, but only 12 months after RDN. We conclude that, improvement of capillary rarefaction happens slowly after RDN and requires long-term effective BP control and, that reduction in vascular resistance might explain the prolonged BP reduction after RDN.

ABSTRACT Background Renal denervation (RDN) has emerged as an adjacent option for the treatment of hypertension. This analysis of the Erlanger registry aimed to compare the blood pressure (BP)-lowering effects and safety of RDN in patients with and without chronic kidney disease (CKD). Methods In this single-center retrospective analysis, 47 patients with and 127 without CKD underwent radiofrequency-, ultrasound- or alcohol-infusion-based RDN. Office and 24-h ambulatory BP and estimated glomerular filtration rate (eGFR) were measured at baseline, and after 6 and 12 months. Results A total of 174 patients with a mean age of 59.0 ± 10 years were followed up for 12 months. At baseline, mean eGFR was 55.8 ± 21 mL/min/1.73 m2 in patients with CKD and 87.3 ± 13 mL/min/1.73 m2 in patients without CKD. There was no significant eGFR decline in either of the groups during 12 months of follow-up. In patients without CKD, office systolic and diastolic BP were reduced by –15.3 ± 17.5/–7.9 ± 10.8 mmHg 6 months after RDN and by –16.1 ± 18.2/–7.7 ± 9.6 mmHg 12 months after RDN. In patients with CKD, office systolic and diastolic BP were reduced by –10.7 ± 24.0/–5.8 ± 13.2 mmHg 6 months after RDN and by –15.1 ± 24.9/–5.9 ± 12.9 mmHg 12 months after RDN. Accordingly, in patients without CKD, 24-h ambulatory systolic and diastolic BP were reduced by –7.2 ± 15.8/–4.9 ± 8.8 mmHg 6 months after RDN and by –9.0 ± 17.0/–6.2 ± 9.8 mmHg 12 months after RDN. In patients with CKD, 24-h systolic and diastolic BP were reduced by –7.4 ± 12.9/–4.2 ± 9.9 mmHg 6 months after RDN and by –8.0 ± 14.0/–3.6 ± 9.6 mmHg 12 months after RDN. There was no difference in the reduction of office and 24-h ambulatory BP between the two groups at any time point (all P > .2). Similar results have been found for the 6 months data. With exception of rare local adverse events, we did not observe any safety signals. Conclusion According to our single-center experience, we observed a similar reduction in 24-h, day and night-time ambulatory BP as well as in-office BP in patients with and without CKD at any time point up to 12 months. We conclude that RDN is an effective and safe treatment option for patients with hypertension and CKD.

Impaired endothelial function predicts cardiovascular events. The aim of this study was to analyze the effect of evolocumab on endothelial function in patients with cardiovascular disease. This was a prospective, double-blinded, randomized, controlled, single center study including patients with cardiovascular disease and treated with statins. Patients were consecutively randomized (1:1) to either evolocumab treatment or placebo. All patients underwent examination of endothelial function at baseline, and after 1, 4 and 8 weeks of treatment by a semi-automatic high-resolution ultrasound system (UNEX EF 18G). Parameters of endothelial function were flow-mediated vasodilation (FMD), low flow-mediated vasoconstriction (L-FMC) and vasoactive range (VAR). Hundred three patients with a mean age of 66.2 ± 7.7 years and a mean LDL-cholesterol of 98 ± 19.1 mg/dl completed the study. The change in VAR from baseline to week 8 was significantly different with evolocumab compared to placebo (p = 0.045). Moreover, VAR increased after 8 weeks of treatment with evolocumab compared to baseline (p = 0.034). No change has been noticed in FMD and L-FMC after 8 weeks of treatment with evolocumab. In subgroup analyses, VAR improved in patients with age ≤ 67 years, lower systolic blood pressure (≤ 125 mmHg) and higher baseline LDL-cholesterol (> 95 mg/dl), (p = 0.006, p = 0.049 and p = 0.042, respectively) after 8 weeks of evolocumab treatment. No serious adverse event related to study medication occurred during the study. Our data indicate that endothelial function improved with evolocumab treatment in high-risk patients on statin therapy with preexisting cardiovascular disease. Our results contribute to the mechanistic explanation why lower incidence of the cardiovascular composite endpoint has been demonstrated in the FOURIER study.

The individual impact of arterial hypertension on several hypertension-mediated organ damages (HMODs) varies widely. This chapter mainly addresses HMODs with arterial hypertension being the most important attributable risk factor. HMOD can be detected in an early subclinical (asymptomatic) stage, but once HMOD, even intermediate, has developed, these conditions are by far overwriting any risk prediction from the cardiovascular (CV) risk factor scores. Hence, the specific impact of HMOD is particular in (younger and middle-aged) patients with a probable reclassification of their individual risk estimation. A variety of techniques are available nowadays to diagnose HMOD of the brain, heart, eyes, kidneys, and vasculature in different organs, but with differences in sensitivity and specificity as well as applicability is limited depending on the availability of the various techniques and the reimbursement strategy of the national health care systems. The clinical importance of HMOD is also underlined by the fact that regression of HMOD is clinically a useful tool for evaluation of the efficacy of (more aggressive and immediate) antihypertensive treatment in individual patients. Therefore this chapter also emphasizes the consequences of HMOD regression by antihypertensive treatment, and attempts to establish whether or not changes of HMOD have related prognostic significance.

Objective: Renal denervation has been shown to be a safe and effective method to lower blood pressure (BP) in patients with uncontrolled treatment resistant hypertension (TRH). Patients with TRH and T2DM typically show hypertrophic arteriolar remodeling, which is associated with the development of early target end-organ damage. By using the retinal vasculature as a mirror of vascular remodeling in the systemic circulation, arteriolar remodeling can be non-invasively assessed with Scanning Laser Doppler Flowmetry (SLDF). In this analysis we assessed the impact of RDN on retinal arteriolar remodeling in patients with TRH and T2DM. Design and method: Retinal arteriolar remodeling was assessed using SLDF together with office and 24-hour ambulatory BP before and 6 as well as 12 months after renal denervation in 22 patients with TRH and T2DM. All patients participated in the investigator initiated study program “Renal Denervation in Treatment Resistant Hypertension” (NCT01687725). SLDF allows confocal measurement of the retinal arteriolar parameters, such as outer (OD) and inner (ID) diameter. Based on ID and OD the following parameters of arteriolar remodeling are derived: retinal arteriolar wall thickness (WT), wall-to-lumen ratio (WLR), and retinal arteriolar crosssectional area (CA). Results: Retinal arteriolar parameters were analysed in 18 male and 4 female patients with 6.5 antihypertensive medications on average. There was a significant reduction of systolic and diastolic 24-hour ambulatory as well office BP 6 as well as 12 months after RDN (table 1). In 77.3% of the patients number of antihypertensive medications was reduced. We found a reduction of hypertrophic retinal arteriolar remodeling and also a reduction of WLR 12 months after RDN (table 1). Of note, no significant changes of retinal arteriolar remodeling were found 6 months after RDN. Conclusions: In very high-risk patients with TRH and T2DM endovascular RDN reduced retinal arteriolar remodeling and retinal wall-to-lumen ratio, a prognostic marker of further end-organ damage. Whereas BP-changes already occurred 6 months after RDN, changes in retinal arteriolar remodelling were observed 12 months after RDN. We conclude that after RDN reversal of arteriolar remodeling happens slowly and requires long-term effective BP control.

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 ).

Patients with treatment resistant hypertension (TRH) are known to have elevated sodium (Na) content in muscle and skin. Renal denervation (RDN) emerged as an adjacent therapeutic option in this group of patients. This analysis aimed at evaluating whether tissue Na content predicts blood pressure (BP) response after RDN in patients with TRH. Radiofrequency-device based RDN was performed in 58 patients with uncontrolled TRH. Office and 24-h ambulatory BP were measured at baseline and after 6 months. To assess tissue Na content Na magnetic resonance imaging (Na-MRI) was performed at baseline prior to RDN. We splitted the study cohort into responders and non-responders based on the median of systolic 24-h ambulatory blood pressure (ABP) reduction after 6 months and evaluated the association between BP response to RDN and tissue Na content in skin and muscle. The study was registered at http://www.clinicaltrials.gov (NCT01687725). Six months after RDN 24-h ABP decreased by −8.6/−4.7 mmHg. BP-Responders were characterized by the following parameters: low tissue sodium content in the skin ( p = 0.040), female gender ( p = 0.027), intake of aldosterone antagonists ( p = 0.032), high baseline 24-h night-time heart rate ( p = 0.045) and high LDL cholesterol ( p < 0.001). These results remained significant after adjustment for baseline 24-h systolic BP. Similar results were obtained when the median of day-time and night-time ABP reduction after 6 months were used as cut-off criteria for defining BP response to RDN. We conclude that in addition to clinical factors including baseline 24-h ABP Na-MRI may assist to select patients with uncontrolled TRH for RDN treatment.

Objective: Abdominal adiposity, measured by waist circumference (WC), is associated with increased mortality in patients with hypertension. Little is known about the impact of abdominal obesity on the renal perfusion and function in patients with hypertension. We analyzed whether abdominal adiposity changes renal hemodynamics in 36 patients with uncomplicated hypertension grade 1-2 without other cardiovascular (CV) disease. Design and method: We analysed the renal hemodynamic using steady state input clearance with infusion of para-aminohippuric acid and inulin, respectively. Intraglomerular pressure and resistances of the afferent (RA) and efferent (RE) arterioles were calculated according to the Gomez equation. The study population was divided in into two groups based on median of WC of the total study population. Results: The study cohort consisted of 36 male, non-smoking individuals, aged 36 ± 10 years with mean WC of 96.1 ± 10.4 cm and mean BMI of 27 ± 3.8 kg/m2. True hypertension was confirmed using 24-hour ambulatory blood pressure (BP) measurement. Patients in the high WC group (19 patients) showed mean office BP of 145/ 90 mmHg and mean 24-hour ambulatory BP of 139/ 86 mmHg, whereas patients in the low WC group (17 patients) showed mean office BP of 144/ 88 mmHg and mean 24-hour-ambulatory BP of 140/ 86 mmHg (office BP: p = 0.895/ p = 0.662, 24-hour-ambulatory BP: p = 0.645/ p = 0.918). Renal vascular resistance and RA were higher in the high WC compared to the low WC group, whereas glomerular filtration rate and renal plasma flow were lower in the high WC compared to the low WC group (table 1). Conclusions: Higher WC in young, male patients with hypertension grade 1-2 without other cardiovascular disease was associated with increased renal vascular resistance predominantly at the afferent site leading to reduced glomerular filtration rate.

Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6

Objective: Afferent renal nerve pathways likely play a role in salt sensitive hypertension. We recently reported that high salt diet (HS) impairs these afferent renal pathways in rats. Now we tested the hypothesis that during HS a decrease in sensitivity of renal afferent neurons is prevented by the SGLT2 inhibitor empagiflozin. Design and method: Respective groups of rats were put on HS containing 8% NaCl or a normal diet. Two groups (HS, controls) received empagiflozin 20 mg/kg BW/day orally. Renal neurons were retrogradely labeled with DiI. In culture, labeled dorsal root ganglion neurons (DRG Th11-L2) with renal afferents were investigated electrophysiologically using current clamp mode to assess action potential generation during current injection. Neurons were characterized as tonic highly active ( less than 5 action potentials, AP) and phasic less active neurons (more than 5 AP upon stimulation). Results: In neurons from rats on HS, the relation of tonic highly active neurons to less active phasic neurons shifted consistently towards phasic units (63,8% tonic neurons in controls vs. 42%* on HS, *p < 0.05, z-test). However, continuous treatment with empagiflozin preserved the proportion of tonic neurons as in controls (67,9% on HS with concomitant administration of empagiflozin). In controls, empagiflozin did not affect the proportion of tonic to phasic neurons (63,8% tonic neurons in controls vs. 67,9% on HS & empagliflozin, p = 0.7, z-test). Blood pressure and heart rate were not altered by HS and/or treatment with any chosen dose of empagiflozin. Conclusions: In rats, chronically elevated sodium intake (8% NaCl) reduced the sensitivity and stimulability of renal afferent DRG neurons. Under these circumstances, concomitant treatment with the SGLT2 inhibitor empagiflozin preserved the function of renal afferent DRG neurons. SGLT 2 inhibitors may help to treat dysfunction of renal innervation in cardiovascular disease.

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., <5 APs upon current injection. Cardiac ejection fraction was measured using echocardiography; RSNA was recorded to evaluate the sensitivity of the cardiopulmonary baroreflex. Renal and cardiac histology was studied for inflammation and fibrosis markers.Results: A total of 192 neurons were investigated. In rats, after myocardial infarction, the number of neurons with a tonic response pattern increased compared to that in the controls (infarction vs. control: 78.6% vs. 48.5%; z-test, *p < 0.05), with augmented production of APs (23.7 ± 2.86 vs. 15.5 ± 1.86 APs/600 ms; mean ± SEM, t-test, *p < 0.05). The baseline activity of RSNA was subtly increased, and its control by the cardiopulmonary baroreflex was impaired following myocardial infarction: the fibrosis marker collagen I augmented in the renal interstitium.Discussion: After myocardial infarction with still-preserved ejection fraction, a complex impairment of the afferent limb of the cardio-renal baroreflex caused dysregulation of renal sympathetic nerve activity with signs of renal fibrosis.

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.

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 < 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.

Background: Impaired endothelial function predicts cardiovascular events. The aim of this study was to analyse the effect of evolocumab on endothelial function in patients with cardiovascular disease and on obligatory statin therapy. Methods: This was a prospective, double-blinded, randomized, controlled, single center study (NCT03626831) including patients with cardiovascular disease (diagnosis of coronary artery disease, non-hemorrhagic stroke, transient ischemic attack or symptomatic peripheral artery disease) and treated with statins, similar to the inclusion criteria of the FOURIER study. Patients were consecutively randomized (1:1) to either evolocumab treatment (420 mg was administrated in monthly intervals, twice during the study) or placebo. All patients underwent examination of endothelial function at baseline, and after 1, 4 and 8 weeks of treatment by a semi-automatic high-resolution ultrasound system (UNEX EF 18G; Unex Co., Nagoya, Japan). Endothelial function parameter such as flow-mediated vasodilation (FMD; vasodilator responsiveness), low flow-mediated vasocontriction (L-FMC; vasoconstrictor responsiveness) and vasoactive range (VAR; total vasomotor responsiveness) were measured. Results: 103 patients with a mean age of 66.2 (±7.7) years and a mean LDL-cholesterol of 98.2 (±19.1) mg/dl completed the study. 83.5% of the study population was known to have coronary artery disease. Endothelial function parameter (VAR) increased after 8 weeks of treatment with evolocumab compared to baseline (p = 0.034), whereas there was no significant change at 1 and 4 weeks after treatment. Moreover, an improvement in VAR from baseline at week 8 was found with evolocumab compared to placebo (p = 0.045). In a subgroup analysis, in patients with age < 67 years, lower systolic blood pressure (< 125 mmHg) or higher baseline LDL-cholesterol (> 95 mg/dl), significant evolocumab treatment effect was found in VAR improvement (p = 0.006, p = 0.049 and p = 0.042, respectively) from baseline at week 8. No serious adverse event related to study medication occurred during the study. Conclusion: Our data indicate that endothelial function could be improved with evolocumab treatment in high-risk patients with preexisting cardiovascular disease and on statin therapy. Our results contribute to the mechanistic explanation why lower incidence of the cardiovascular composite endpoint has been demonstrated in the FOURIER study.

Objective:Hypertension management is directed by cuff blood pressure (BP), but this may be inaccurate, potentially influencing cardiovascular disease (CVD) events and health costs. This study aimed to determine the impact on CVD events and related costs of the differences between cuff and invasive SBP.Methods:Microsimulations based on Markov modelling over one year were used to determine the differences in the number of CVD events (myocardial infarction or coronary death, stroke, atrial fibrillation or heart failure) predicted by Framingham risk and total CVD health costs based on cuff SBP compared with invasive (aortic) SBP. Modelling was based on international consortium data from 1678 participants undergoing cardiac catheterization and 30 separate studies. Cuff underestimation and overestimation were defined as cuff SBP less than invasive SBP and cuff SBP greater than invasive SBP, respectively.Results:The proportion of people with cuff SBP underestimation versus overestimation progressively increased as SBP increased. This reached a maximum ratio of 16 : 1 in people with hypertension grades II and III. Both the number of CVD events missed (predominantly stroke, coronary death and myocardial infarction) and associated health costs increased stepwise across levels of SBP control, as cuff SBP underestimation increased. The maximum number of CVD events potentially missed (11.8/1000 patients) and highest costs ($241 300 USD/1000 patients) were seen in people with hypertension grades II and III and with at least 15 mmHg of cuff SBP underestimation.Conclusion:Cuff SBP underestimation can result in potentially preventable CVD events being missed and major increases in health costs. These issues could be remedied with improved cuff SBP accuracy.

Background: Accurate blood pressure (BP) measurement is critical for optimal cardiovascular risk management. Age-related trajectories for cuff-measured BP accelerate faster in women compared with men, but whether cuff BP represents the intraarterial (invasive) aortic BP is unknown. This study aimed to determine the sex differences between cuff BP, invasive aortic BP, and the difference between the 2 measurements. Methods: Upper-arm cuff BP and invasive aortic BP were measured during coronary angiography in 1615 subjects from the Invasive Blood Pressure Consortium Database. This analysis comprised 22 different cuff BP devices from 28 studies. Results: Subjects were 64±11 years (range 40–89) and 32% women. For the same cuff systolic BP (SBP), invasive aortic SBP was 4.4 mm Hg higher in women compared with men. Cuff and invasive aortic SBP were higher in women compared with men, but the sex difference was more pronounced from invasive aortic SBP, was the lowest in younger ages, and the highest in older ages. Cuff diastolic blood pressure overestimated invasive diastolic blood pressure in both sexes. For cuff and invasive diastolic blood pressure separately, there were sex*age interactions in which diastolic blood pressure was higher in younger men and lower in older men, compared with women. Cuff pulse pressure underestimated invasive aortic pulse pressure in excess of 10 mm Hg for both sexes in older age. Conclusions: For the same cuff SBP, invasive aortic SBP was higher in women compared with men. How this translates to cardiovascular risk prediction needs to be determined, but women may be at higher BP-related risk than estimated by cuff measurements.

(1) Background: watching sporting events may trigger cardiovascular events by elevating emotional stress levels. The underlying reasons and specific populations at risk are not well defined. (2) Methods: we conducted a multicenter prospective trial at three German sites during the UEFA Soccer EC 2012 and 2021 comprising 52 healthy participants (noCVD) and 18 patients hospitalized with cardiovascular disease (CVD). Subjects were studied during matches of the German national team (GP) as well as corresponding matches without German participation (noGP). Peripheral and central blood pressure (BP) and parameters of arterial stiffness were measured (Mobil-O-Graph™, I.E.M., Stolberg, Germany) before, during, and after the matches. (3) Results: in terms of CVD, peripheral as well as central BP and heart rate increased significantly during GP as well as noGP matches and remained elevated beyond the end of the matches. Likewise, arterial stiffness parameters and vascular resistance were higher during the matches and remained elevated after the matches. No consistent significant differences were found between GP and noGP matches. (4) Conclusions: this is the first study on real-life changes in hemodynamics during sport-associated emotional stress, with comparison between noCVD and CVD. We found that alterations were profound in CVD and remained elevated even after the matches.

Basal NO emerged as a determinant of the renal hemodynamic response in the combination therapy of empagliflozin and linagliptin, but not in the combination therapy of insulin and metformin.