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Background: The strong relationship between blood pressure (BP) and age is well known. Limited evidence suggests that a steeper age-BP slope may be associated with an increased risk of adverse outcomes. The May Measurement Month campaign enables an investigation of geographic, socioeconomic, and sex differences in age-related BP gradients and their association with public-health outcomes., Methods: Cross-sectional, annual global BP May Measurement Month screening data were analyzed. Average systolic BP and age-related BP slopes across different age groups were calculated to assess regional, socioeconomic, and sex-stratified variations. The association of BP slopes derived from adjusted linear regression models with country-level health metrics was investigated., Results: Age-related systolic BP gradients differed distinctly across global geographic regions, income levels, and between sexes. The steepest age gradients of BP were observed in populations from Africa and Europe. Women had lower BP levels than men at younger ages (20s and 30s) but subsequently experienced more pronounced age-related BP gradients. Geographically divergent age-related BP gradients were significantly associated with major national public health indicators. Globally, steeper age-related BP slopes were associated with poor BP control, increased disability-adjusted life years, and death rates. A steeper population age-BP slope of 1 mm Hg per 10 years was associated with a decrease in life expectancy of 3.3 years in this population (95% CI, -5.1 to -1.4; P =0.0007)., Conclusions: Age-related BP gradients vary considerably across global populations and are associated with variability in BP-related risks and adverse outcomes across regions. Effective public health strategies may require region-specific targeting of adverse BP gradients to improve health outcomes., Competing Interests: A.E. Schutte has received speaker fees from Omron, Medtronic, Aktiia, Servier, Sanofi, and Novartis and is an advisory board member for Skylabs, Medtronic, and Abbott. M.P. Schlaich has received research support from Medtronic, Abbott, and Servier Australia. He serves on scientific advisory boards for Abbott, Boehringer Ingelheim, Servier, Novartis, and Medtronic and has received travel/speaker honoraria from Abbott, Medtronic, Lilly, and AstraZeneca. G.S. Stergiou has received speaker fees from AstraZeneca, Menarini, Omron, and Servier and consulting fees from Huawei, InBody, Microlife, Sanofi-Aventis, Skylabs, Sonion, and Viatris. The other authors report no conflicts.

May Measurement Month (MMM) is a global and national blood pressure (BP) screening campaign initiated by the International Society of Hypertension to improve awareness of BP worldwide. This study reports on the findings of the MMM21 campaign in Australia. Adult participants (≥18 years) were screened through opportunistic sampling across Australia between 1 May and 30 November 2021. Trained volunteers recorded standardized BP measurements from community volunteer participants along with demographic data, lifestyle factors, comorbidities, and history of COVID-19 infection and vaccination. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg and/or taking antihypertensive medication. Data were collated and analysed centrally using the current MMM protocol and presented after the imputation of missing BP readings. A total of 1307 participants were screened in 2021, comprising 652 (49.9%) females and 654 (50.0%) males with a mean age of 48 years (SD 20.1). Of all 1307 participants, 524 (40.1%) had hypertension. Of participants with hypertension, 65.4% were aware and 59.3% were on antihypertensive medication. Of 311 participants on antihypertensive medication, 54.7% had controlled BP. Of all 524 participants with hypertension, 32.5% had controlled BP. The current 2021 data may indicate some progress in creating BP awareness; however, consecutive Australian data obtained since 2017 demonstrated stagnating treatment, and control rates compared with global rates and those in other high-income countries. Concerted efforts from all stakeholders will be required to further improve BP awareness, treatment, and control rates in Australia., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Renal denervation is a recognized adjunct therapy for hypertension with clinically significant blood pressure (BP)-lowering effects. Long-term follow-up data are critical to ascertain durability of the effect and safety. Aside from the 36-month follow-up data available from randomized control trials, recent cohort analyses extended follow-up out to 10 years. We sought to analyze study-level data and quantify the ambulatory BP reduction of renal denervation across contemporary randomized sham-controlled trials and available long-term follow-up data up to 10 years from observational studies., Methods: A systematic review was performed with data from 4 observational studies with follow-up out to 10 years and 2 randomized controlled trials meeting search and inclusion criteria with follow-up data out to 36 months. Study-level data were extracted and compared statistically., Results: In 2 contemporary randomized controlled trials with 36-month follow-up, an average sham-adjusted ambulatory systolic BP reduction of -12.7±4.5 mm Hg from baseline was observed ( P =0.05). Likewise, a -14.8±3.4 mm Hg ambulatory systolic BP reduction was found across observational studies with a mean long-term follow-up of 7.7±2.8 years (range, 3.5-9.4 years; P =0.0051). The observed reduction in estimated glomerular filtration rate across the long-term follow-up was in line with the predicted age-related decline. Antihypertensive drug burden was similar at baseline and follow-up., Conclusions: Renal denervation is associated with a significant and clinically meaningful reduction in ambulatory systolic BP in both contemporary randomized sham-controlled trials up to 36 months and observational cohort studies up to 10 years without adverse consequences on renal function., Competing Interests: Disclosures M.P. Schlaich has received support from a National Health and Medical Research Council Research Fellowship and research support from Medtronic, Abbott, and Servier Australia. He serves on scientific advisory boards for Abbott, Boehringer Ingelheim, Servier, Novartis, and Medtronic. A. Walton is a Proctor for Medtronic and Abbott, is on the Medical Advisory Board of Medtronic, and receives grant support from Medtronic, Abbott, and Edwards. M.D. Esler and G.W. Lambert have received consulting fees and travel and research support from Medtronic. The other authors report no conflicts.

Background: Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis, but cumbersome to assess by gold-standard methodology. Twenty-four-hour average heart rate (HR) and mean arterial pressure (MAP) dipping, taken by ambulatory blood pressure monitoring (ABPM), stratifies patients into high, moderate, and low salt sensitivity index (SSI) risk categories., Objectives: We aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world RDN patient cohort., Methods: Sixty participants had repeat ABPM as part of a renal denervation long-term follow-up. Average time since RDN was 8.9 ± 1.2 years. Based on baseline ABPM, participants were stratified into low (HR < 70 bpm and MAP dipping > 10%), moderate (HR ≥70 bpm or MAP dipping ≤ 10%), and high (HR ≥ 70 bpm and MAP dipping ≤ 10%) SSI risk groups, respectively., Results: One-way ANOVA indicated a significant treatment effect ( P  = 0.03) between low ( n  = 15), moderate ( n  = 35), and high ( n  = 10) SSI risk with systolic BP reduction of 9.6 ± 3.7 mmHg, 8.4 ± 3.5 mmHg, and 28.2 ± 9.6 mmHg, respectively. Baseline BP was not significantly different between SSI Risk groups ( P  = 0.18). High SSI risk independently correlated with systolic BP reduction ( P  = 0.02)., Conclusions: Our investigation indicates that SSI risk may be a simple and accessible measure for predicting the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug naive RDN cohorts., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Herein, we review interventional peripheral neuromodulatory approaches to reduce blood pressure (BP), specifically focusing on catheter-based renal denervation (RDN), as well as the latest data from recent clinical trials underpinning its clinical use. Given the apparent failure of established lifestyle measures and pharmacologic BP-lowering approaches to improve hypertension (HTN) control rates, the past decade has seen remarkable scientific efforts to explore the utility of interventional strategies for BP management. Experimental studies and human clinical trials have demonstrated the crucial role of the sympathetic nervous system in the development and mainenance of HTN - consequently, most recent interventional technologies aimed primarily at modulating neural pathways. Advanced approaches that were rigorously tested in human studies include RDN, endovascular baroreflex amplification, baroreflex activation therapy and cardiac neuromodulation stimulation.Amongst these, RDN is by far the most established technology. With recent robust evidence from clinical trials and real-world data showing the safety and efficacy of both ultrasound and radiofrequency-based approaches, a recent clinical consensus statement of the European Society of Cardiology Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions concludes that RDN represents an ancillary therapeutic option in patients with uncontrolled resistant HTN confirmed by ambulatory blood pressure measurement and in spite of attention to lifestyle changes and optimised pharmacological treatment. Furthermore, RDN could alos be considered for patienst unlikley to adhere to or tolerate long-term antihypertensive drug treatment. Very recent data indicate long-term safety and efficacy up to 10 years. Appropriate implementation of RDN into clinical practice is now warranted.For all other interventions additional data from adequately designed human studies are required to establish their safety and clinical utility for potential future use in routine practice., Competing Interests: Competing interests: MGK has received consulting fees and/or travel and research support from Medtronic. RC is supported by the Australian National Heart Foundation post doc fellowship. CES and SS have been involved in renal denervation studies supported by Medtronic. SS has received consulting fees and/or travel and research support from Medtronic. MS has received consulting fees, and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer and Boehringer-Ingelheim., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Pigment epithelium-derived factor (PEDF) has been recently linked to insulin resistance and is capable of differentiating myocytes to bone. We examined in more detail the intricate signalling of the insulin pathway influenced by PEDF in skeletal myocytes. We tested whether this serpin is also capable of generating de novo bone from adipocytes in vitro and in vivo, and how the anticancer drug doxorubicin links with PEDF and cellular metabolism., Methods and Key Findings: We demonstrate that PEDF can inhibit phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS) in skeletal myocytes. PEDF constitutively activates p42/44 MAPK/Erk, but paradoxically does not affect mitogenic signalling. PEDF did not perturb either mitochondrial activity or proliferation in cells representing mesenchymal stem cells, cardiomyocytes, and skeletal myocytes and adipocytes. PEDF induced transdifferentiation of adipocytes to osteoblasts, promoting bone formation in cultured adipocytes in vitro and gelfoam fatpad implants in vivo. Bone formation in white adipose tissue (WAT) was better than in brown adipose tissue (BAT). The frontline anticancer drug doxorubicin increased levels of PEDF in a human breast cancer cell line, mirroring the in vivo finding where cardiac muscle tissue was stained increasingly for PEDF as the dose of doxorubicin increased in mice. PEDF also increased levels of reactive oxygen species (ROS) and glutathione (GSH) in the breast cancer cell line., Conclusions: PEDF may be used to regenerate bone from adipose tissue in cases of trauma such as fractures or bone cancers. The increased presence of PEDF in doxorubicin-treated tumour cells need further exploration, and could be useful therapeutically in future. The safety of PEDF administration in vivo was further demonstrated in this study.

Cardiometabolic disorders are associated with a substantial loss in quality of life and pose a large burden on healthcare systems worldwide. Overactivation of the sympathetic nervous system has been shown to be a key player in several aspects relating to cardiometabolic disturbances. While diet- and exercise-induced approaches to help reduce weight remains the main strategy to combat metabolic disorders, this is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication side effects and non-adherence in the long term. There is a clear clinical need for complementary therapies to curb the burden of cardiometabolic disease. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. Data from sham-controlled clinical trials demonstrate the feasibility, safety and efficacy of catheter-based renal denervation. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multi-organ neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum including blood pressure, glucose and lipid control., (© 2023. The Author(s).)

Background: Raised blood pressure (BP) remains the single most important modifiable risk factor contributing to cardiovascular and all-cause mortality in Australia and worldwide. May Measurement Month , a global BP measurement and screening campaign initiated by the International Society of Hypertension and carried out in Australia since its inception in 2017, aimed at obtaining standardized BP measurements from members of the community to increase awareness of high BP and its associated risks., Method: Adults participants (≥18 years) were recruited through opportunistic sampling across Australia during the month of May in 2017, 2018 and 2019. Trained volunteers recorded BP readings in a standardized manner and collected data on demographic, lifestyle factors and comorbidities. Hypertension was defined as SBP of at least 140 mmHg, or DBP of at least 90 mmHg, or taking antihypertensive medication. Data were collated centrally and analysis was carried out using regression models to evaluate the associations between BP and participant characteristics., Results: A total of 10 046 participants were screened, of whom 3097 (31.0%) had hypertension, only 48.5% were aware of their condition and 44.4% were taking antihypertensive medication. Of those taking antihypertensive medication, 53.2% were controlled to less than 140/90 mmHg, whereas the remaining 46.8% of participants had BP of at least 140/90 mmHg suggestive of inadequately treated hypertension., Conclusion: Consecutive data obtained over a 3-year period in Australia demonstrated stagnating awareness, treatment and control rates with the latter two being substantially lower than global rates and those in other high-income countries. Concerted efforts from all stakeholders will be required to help overcome the unacceptably poor rates of BP treatment and control in Australia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Recent sham-controlled randomized clinical trials have confirmed the safety and efficacy of catheter-based renal denervation (RDN). Long-term safety and efficacy data beyond 3 years are scarce. Here, we report on outcomes after RDN in a cohort of patients with resistant hypertension with an average of ≈9-year follow-up (FU)., Methods: We recruited patients with resistant hypertension who were previously enrolled in various RDN trials applying radiofrequency energy for blood pressure (BP) lowering. All participants had baseline assessments before RDN and repeat assessment at long-term FU including medical history, automated office and ambulatory BP measurement, and routine blood and urine tests. We analyzed changes between baseline and long-term FU., Results: A total of 66 participants (mean±SD, 70.0±10.3 years; 76.3% men) completed long-term FU investigations with a mean of 8.8±1.2 years post-procedure. Compared with baseline, ambulatory systolic BP was reduced by -12.1±21.6 (from 145.2 to 133.1) mm Hg ( P <0.0001) and diastolic BP by -8.8±12.8 (from 81.2 to 72.7) mm Hg ( P <0.0001). Mean heart rate remained unchanged. At long-term FU, participants were on one less antihypertensive medication compared with baseline ( P =0.0052). Renal function assessed by estimated glomerular filtration rate fell within the expected age-associated rate of decline from 71.1 to 61.2 mL/min per 1.73 m 2 . Time above target was reduced significantly from 75.0±25.9% at baseline to 47.3±30.3% at long-term FU ( P <0.0001)., Conclusions: RDN results in a significant and robust reduction in both office and ambulatory systolic and diastolic BP at ≈9-year FU after catheter-based RDN on less medication and without evidence of adverse consequences on renal function.

Introduction: Elevated nocturnal blood pressure (BP) is closely associated with increased risk of cardiovascular (CV) events. Circulating extracellular vesicles (EVs) have been proposed as a potential CV risk biomarker and shown to correlate with BP. The present study aimed to assess whether a reduction in BP is paralleled by respective changes in EVs., Methods: Fifty-five hypertensive patients (age: 57.7 ± 14.1 years) were included in the study. EVs and BP were assessed at baseline and at 12 weeks follow-up. Interventions to lower BP included advice on life-style modification only or life-style advice combined with additional pharmacotherapy. EVs were evaluated by flow cytometry (CD41+/Annexin V+) and BP by unobserved automated office BP and ambulatory BP monitoring., Results: Nocturnal systolic BP correlated with EV levels at baseline ( P  = 0.01). Multivariable regression models showed that changes in nocturnal systolic BP (adjusted R2  = 0.23; P  = 0.01) and diastolic BP (adjusted R2  = 0.18; P  = 0.02) were associated with respective changes in EV levels. Furthermore, intervention-induced improvement of systolic dipping was associated with a reduction in EVs in the univariate analysis (adjusted R2  = 0.06; P  = 0.03). In contrast, systolic office, 24 h- and daytime-BP did not show significant associations with EVs. Patients whose medication was up-titrated at baseline showed a trend towards lower EV levels at follow-up (absolute change of -1.7 ± 1.3 EV/μl; P  = 0.057)., Conclusions: Circulating platelet-derived EVs were positively associated with nocturnal BP and therapy-induced changes over a 12-week treatment period. EVs may provide an integrated measure of BP changes achieved with pharmacotherapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Elevated circulating platelet-derived extracellular vesicles (EVs) have been reported in conditions associated with thrombotic risk. The present study aimed to assess the relationship between circulating platelet-derived EV levels, cardiovascular risk stratification and vascular organ damage, as assessed by pulse wave velocity (PWV). A total of 92 patients were included in the present analysis. Platelet EV were evaluated by flow cytometry (CD41+/Annexin v+). The cardiovascular risk was determined using the 2021 ESC guideline stratification and SCORE2 and SCORE-OP. PWV was performed as a surrogate to assess macrovascular damage. Risk stratification revealed significant group differences in EV levels (ANOVA, p = 0.04). Post hoc analysis demonstrated significantly higher levels of EVs in the very high-risk group compared with the young participants (12.53 ± 8.69 vs. 7.51 ± 4.67 EV/µL, p = 0.03). Linear regression models showed SCORE2 and SCORE-OP (p = 0.04) was a predictor of EV levels. EVs showed a significant association with macrovascular organ damage measured by PWV (p = 0.01). PWV progressively increased with more severe cardiovascular risk (p < 0.001) and was also associated with SCORE2 and SCORE-OP (p < 0.001). Within the pooled group of subjects with low to moderate risk and young participants (<40 years), those with EV levels in the highest tertile had a trend towards higher nocturnal blood pressure levels, fasting glucose concentration, lipid levels, homocysteine and PWV. Levels of platelet-derived EVs were highest in those patients with very high CV risk. Within a pooled group of patients with low to moderate risk, an unfavourable cardiometabolic profile was present with higher EV levels.

Recent analysis of systolic inter-arm differences in blood pressure from the INTERPRESS-IPD Collaboration suggest an association with increased all-cause mortality, cardiovascular mortality and cardiovascular events. Previous studies have demonstrated associations with other risk parameters. We aimed to reproduce these associations in a cohort of 199 treated, at-risk hypertensive patients with pulse wave velocity (PWV) as a surrogate marker of cardiovascular (CV) damage. Simultaneously measured inter-arm blood pressure (BP) differences, 24 hour ambulatory BP and PWV were measured in 199 treated patients from a tertiary hospital hypertension outpatient clinic. Associations between systolic inter-arm BP difference and PWV were analyzed with uni- and multi-variate regression models. Out of 199 participants, 90 showed an inter-arm BP difference of more than 5 mmHg. The inter-arm difference was not associated with PWV. Furthermore, neither observed single BP measurements nor 24 hour ambulatory BP was associated with inter-arm BP differences. In our clinical patient cohort we failed to observe an association between inter-arm BP differences and PWV. Mode of assessment, study design and the sample characteristics of this treated, hypertensive cohort may have contributed to the negative findings. The limited sample size of the study poses a challenge to the detection of smaller effects in our study., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Hypertension is the most common chronic condition globally, contributing to an increased risk of cardiovascular disease and premature death. Despite advances in treatment options, approximately 10% of patients have resistant hypertension, characterized by elevated blood pressure that does not respond to treatment. The gut microbiome is now increasingly recognized to play a role in the development and pathogenesis of several diseases, including hypertension, although the exact mechanisms remain unclear., Method: The aim of the present study was to investigate circulating levels of short-chain fatty acids, metabolites produced by gut bacteria, in essential ( n  = 168) and resistant hypertensive ( n  = 27) patients, compared with healthy controls ( n  = 38)., Results: Serum acetate was significantly lower in the resistant hypertensive population, compared with both the normotensive controls and those with essential hypertension (748 ± 89 versus 1335 ± 61 and 1171 ± 22 nmol/ml, P  < 0.0001). Acetate was also significantly lower in treated versus untreated hypertensive patients or controls (1112 ± 27 versus 1228 ± 40 and 1327 ± 63 nmol/l, P  < 0.01), with this finding more pronounced with increasing number of antihypertensive therapies. In contrast, propionate was lower and butyrate significantly higher in those with essential hypertension compared with controls (propionate: 25.2 ± 7.5 versus 58.6 ± 7.6 nmol/ml, P  < 0.0001; butyrate: 46.5 ± 3.5 versus 14.7 ± 9.9 nmol/ml, P  < 0.01). A novel and perhaps clinically relevant observation was the significant difference in acetate and propionate levels between patients taking ACE inhibitors or angiotensin-receptor blockers., Conclusion: The present study has highlighted differences in circulating short-chain fatty acids in different hypertensive phenotypes and a possible influence of drug number and class. Although further research is necessary, this may represent a novel therapeutic target, particularly in patients with resistant hypertension., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Influential guidelines currently define hypertension at different thresholds of blood pressure (BP). The global May Measurement Month initiative provides a unique opportunity to estimate the potential consequences of universal lowering of BP thresholds on the prevalence of hypertension based on a large, real-world, patient-level data set., Methods: The average of the second and third of 3 attended BP readings after 5 minutes of rest from 4 021 690 standardized, opportunistic BP screenings in various settings of the 2017 to 2019 May Measurement Month initiatives from 104 countries were analyzed to assess the demographic and phenotypic impact of 3 defined BP thresholds., Results: The age- and sex-standardized median of the relative increase in rate of hypertension with a change of thresholds from ≥140/≥90 to ≥130/≥80 mm Hg was 72.3% (interquartile range, 59.3%-91.3%) among the participating countries. With a change from ≥140/≥90 to ≥120/≥70 mm Hg, the median range was 162.6% (interquartile range, 132.8%-202.6%). The increase in rate of hypertension was most pronounced in low-income (95.3% and 203.9%) and least pronounced in high-income countries (71.6% and 167.1%)., Conclusions: The impact of a universal application of lower BP thresholds for the definition of hypertension would have an enormous impact on the prevalence of hypertension globally with large disparities between countries and substantial heterogeneity of demographic and phenotypic patterns, which should be confirmed in dedicated population studies. While focusing on lower BP targets may constitute an opportunity for early intervention, the potential socioeconomic consequences may pose unsurmountable obstacles for most health care systems worldwide.

Objective: We analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage., Research Design and Methods: In a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes., Results: The CDF was lower in patients with prediabetes than in those with normal glucose metabolism. Moreover, we found a correlation between CDF and HbA1c and glucose levels for the entire cohort. In patients with HbA1c <6.5% (48 mmol/mol), CDF was lower in patients with HOMA for insulin resistance (HOMA-IR) ≥2.5 than in patients with HOMA-IR <2.5., Conclusions: Patients with hypertension and prediabetes display retinal capillary changes, and an association with markers of glucose metabolism exists, even within a nondiabetic HbA1c range., (© 2022 by the American Diabetes Association.)

Elevated office blood pressure (BP) has previously been associated with increased levels of circulating extracellular vesicles (EVs). The present study aimed to assess the relationship between levels of platelet derived EVs, ambulatory BP parameters, and pulse wave velocity as a marker of macrovascular organ damage. A total of 96 participants were included in the study. Platelet-derived extracellular vesicles (pEVs) were evaluated by flow cytometry (CD41+/Annexin v+). BP evaluation included unobserved automated office BP and ambulatory BP monitoring. Carotid-femoral pulse wave velocity (PWV) was measured as a marker of macrovascular damage. pEVs correlated with nocturnal systolic BP (r = 0.31; p = .003) and nocturnal dipping (r = -0.29; p = .01) in univariable analysis. Multivariable regression models confirmed robustness of the association of EVs and nocturnal blood pressure (p = .02). In contrast, systolic office, 24h- and daytime-BP did not show significant associations with pEVs. No correlations were found with diastolic BP. Circulating pEVs correlated with pulse wave velocity (r = 0.25; p = .02). When comparing different hypertensive phenotypes, higher levels of EVs and PWV were evident in patients with sustained hypertension compared to patients with white coat HTN and healthy persons. Circulating platelet derived EVs were associated with nocturnal BP, dipping, and PWV. Given that average nocturnal BP is the strongest predictor of CV events, platelet derived EVs may serve as an integrative marker of vascular health, a proposition that requires testing in prospective clinical trials., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background and Aims: Machine Learning is transforming data processing in medical research and clinical practice. Missing data labels are a common limitation to training Machine Learning models. To overcome missing labels in a large dataset of microneurography recordings, a novel autoencoder based semi-supervised, iterative group-labelling methodology was developed., Methods: Autoencoders were systematically optimised to extract features from a dataset of 478621 signal excerpts from human microneurography recordings. Selected features were clusters with k-means and randomly selected representations of the corresponding original signals labelled as valid or non-valid muscle sympathetic nerve activity (MSNA) bursts in an iterative, purifying procedure by an expert rater. A deep neural network was trained based on the fully labelled dataset., Results: Three autoencoders, two based on fully connected neural networks and one based on convolutional neural network, were chosen for feature learning. Iterative clustering followed by labelling of complete clusters resulted in all 478621 signal peak excerpts being labelled as valid or non-valid within 13 iterations. Neural networks trained with the labelled dataset achieved, in a cross validation step with a testing dataset not included in training, on average 93.13% accuracy and 91% area under the receiver operating curve (AUC ROC)., Discussion: The described labelling procedure enabled efficient labelling of a large dataset of physiological signal based on expert ratings. The procedure based on autoencoders may be broadly applicable to a wide range of datasets without labels that require expert input and may be utilised for Machine Learning applications if weak-labels were available., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Renal denervation (RDN) has been proven in multiple sham-controlled trials to lower blood pressure (BP) in various forms of hypertension. RDN-mediated interruption of sympathetic signaling through its effects on renal blood flow, salt retention, and renin release are likely contributors to the BP-lowering effects. However, the impact of RDN on salt sensitivity in humans has not yet been explored., Methods: We, therefore, investigated the effect of RDN on ambulatory BP monitoring-derived salt sensitivity in a cohort of patients with uncontrolled hypertension on habitual salt intake. RDN was performed in 153 hypertensive patients, who were categorized into low intermediate and high-salt sensitivity groups, based on the ambulatory BP monitoring-derived salt sensitivity index estimated prior to (baseline) and at 3, 6 and 12 months after the procedure as previously described. Crude and adjusted mixed effects ordinal regression models were fitted to test for changes in the proportions of salt sensitivity risk during follow-up., Results: The proportions of individuals in the intermediate and high-salt sensitivity risk group increased after RDN and the odds for being in a higher estimated salt sensitivity risk group at 3, 6 and 12 months follow-up compared with baseline were highly significant during the 12 months follow-up period., Conclusion: Increased salt sensitivity after RDN may represent a compensatory mechanism to maintain renal capacity for adequate salt handling. This novel finding may have implications for patient management after RDN, such as prescription of salt moderation to further optimize RDN-induced BP-lowering efficacy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Accessibility of labelled datasets is often a key limitation for the application of Machine Learning in clinical research. A novel semi-automated weak-labelling approach based on unsupervised clustering was developed to classify a large dataset of microneurography signals and subsequently used to train a Neural Network to reproduce the labelling process., Methods: Clusters of microneurography signals were created with k-means and then labelled in terms of the validity of the signals contained in each cluster. Only purely positive or negative clusters were labelled, whereas clusters with mixed content were passed on to the next iteration of the algorithm to undergo another cycle of unsupervised clustering and labelling of the clusters. After several iterations of this process, only pure labelled clusters remained which were used to train a Deep Neural Network., Results: Overall, 334,548 individual signal peaks form the integrated data were extracted and more than 99.99% of the data was labelled in six iterations of this novel application of weak labelling with the help of a domain expert. A Deep Neural Network trained based on this dataset achieved consistent accuracies above 95%., Discussion: Data extraction and the novel iterative approach of labelling unsupervised clusters enabled creation of a large, labelled dataset combining unsupervised learning and expert ratings of signal-peaks on cluster basis in a time effective manner. Further research is needed to validate the methodology and employ it on other types of physiologic data for which it may enable efficient generation of large labelled datasets., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose of Review: To provide an overview of the associations between elevated blood pressure and lipoprotein (a) and possible causal links, as well as data on the prevalence of elevated lipoprotein (a) in a cohort of hypertensive patients., Recent Findings: Elevated lipoprotein (a) is now considered to be an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Despite this, there are limited data demonstrating an association between elevated lipoprotein (a) and hypertension. Further, there is limited mechanistic data linking lipoprotein (a) and hypertension through either renal impairment or direct effects on the vasculature. Despite the links between lipoprotein (a) and atherosclerosis, there are limited data demonstrating an association with hypertension. Evidence from our clinic suggests that ~ 30% of the patients in this at-risk, hypertensive cohort had elevated lipoprotein (a) levels and that measurement of lipoprotein (a) maybe useful in risk stratification., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Extracellular vesicles (EVs) represent a promising biomarker in several medical areas. Flow cytometry (FC) is one of the most widely-used methods to characterize EVs, providing quantitative information and determination of EV subtypes. EV evaluation represents a challenge as no standardized methods are available to facilitate assessment across different research centers. This is principally because their size falls below the detection limit of most standard flow cytometers and a thorough optimization process is required to ensure instrument-specific sensitivity. We provide an overview of a standardized method to evaluate large EVs using the Attune™ Nxt Acoustic Focusing Flow Cytometer system (Thermo Fisher Scientific)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel glucose-lowering drugs (GLDs) which additionally promote weight loss and blood pressure reduction among other beneficial effects. Areas covered: This review reflects on the extra-glycemic effects of SGLT2 inhibitors and their impact on important clinical endpoints, and provides an overview of data relating to a newer member of the SGLT2 inhibitor class, bexagliflozin. Expert opinion: SGLT2 inhibitors, while consolidating glycemic control as adjunctive therapy, indisputably affect cardio-renal benefits in the T2D population which is prevalently afflicted by heightened cardiovascular risk and a disproportionately increased incidence of unfavorable cardiovascular and renal outcomes. The data from landmark trials demonstrate that beneficial effects of SGLT2 inhibitors extend to non-diabetic patients with chronic kidney disease (CKD) and/or heart failure with reduced ejection fraction (HFrEF). Preliminary findings from the BEST trial suggest that Bexagliflozin's effects reflect those of other licensed drugs in its class. Bexagliflozin has also been shown to be safe and effective in patients with diabetes and CKD stage 3b. If and when approved, it presents physicians with the prospect of an additional therapeutic option in managing patients with type 2 diabetes mellitus (T2D), and conceivably also, nondiabetic patients with established CKD and/or HFrEF.

Introduction: The concept of targeting the renal sympathetic nerves therapeutically to lower blood pressure (BP) is based on their crucial role in regulating both renal and cardiovascular control. These effects are mainly mediated via three major mechanisms including alteration of renal blood flow, renin-release, and Na + retention. Initial surgical approaches applying crude and unselected sympathectomy, while rendering significant BP lowering and cardiovascular event reducing properties, where plagued by side effects. More modern selective catheter-based denervation approaches selectively targeting the renal nerves have been shown to be safe and effective in reducing BP in various forms of hypertension and multiple comorbidities., Areas Covered: This article covers the background relevant for the concept of renal denervation (RDN), the evidence obtained from relevant randomized controlled trials to substantiate the safety and efficacy of RDN, and recently published clinical recommendations., Expert Opinion: Catheter-based RDN is safe and has now been shown in sham-controlled randomized clinical trials to result in clinically meaningful BP lowering in both drug naïve hypertensive patients and those on concomitant antihypertensive therapy. Real world data from a large global registry further supports the clinical utility of RDN. It now seems time to embed renal denervation into routine clinical care.

Background: A nocturnal non-dipping pattern has been associated with hypertension-mediated organ damage (HMOD), morbidity and mortality. Retinal imaging through application of modern technologies including optical coherence tomography angiography (OCT-A) can provide detailed insights into early vascular damage. In this observational study, we investigated the relationship of microscopic vascular density in the retina measured with OCT-A and nocturnal blood pressure (BP) dipping., Methods: Retinal OCT-A and ambulatory BP monitoring (ABPM) data prospectively obtained from 142 patients referred to a tertiary hypertension clinic were analysed with regression models for associations between BP night-time dipping and retinal capillary vascular density in three different zones around the fovea., Results: More pronounced nocturnal SBP and DBP dipping was significantly associated with increased vascular density in the central foveal area of the retina. These associations were robust to adjustment for other available risk factors including mean daytime BP. Parafoveal and whole image vascular density did not show equivalent significant associations with nocturnal BP dipping. The results were reproducible when assessed in a subgroup of patients who had concomitant type 2 diabetes., Conclusion: Foveal vascular density was associated with the nocturnal BP dipping pattern in hypertensive patients. These associations were robust to adjustment of relevant factors such as daytime BP. Our findings highlight the importance of nocturnal BP features reflected in ambulatory BP monitoring in the assessment of HMOD. Whether routine assessment of retinal damage markers may improve risk management of hypertensive patients remains to be determined., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Arterial stiffness is an important predictor of cardiovascular events, independent of traditional risk factors. Stiffening of arteries, though an adaptive process to hemodynamic load, results in substantial increase in the pulsatile hemodynamic forces that detrimentally affects the microcirculation perfusing the vital organs such as the brain, heart and kidneys. Studies have proposed that arterial stiffness precedes and may contribute to the development of hypertension in individuals with obesity. Our study sought to determine the gender-based effects on arterial stiffening in obesity which may predispose to the development of hypertension. We found female sex is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure in obesity. Women had significantly higher carotid-femoral pulse wave velocity (CF-PWV) with higher body mass index (BMI) status (normal: 7.9 ± 2 m/s; overweight: 9.1 ± 2 m/s; obese: 9 ± 2 m/s, p < 0.001), whereas it was similar in males across all BMI categories. The linear association between arterial stiffness and BMI following adjustment for age and brachial systolic and diastolic blood pressure (BP), remained significant in females (β = 0.06; 95% CI 0.01 to 0.1; p < 0.05) but not in males (β = 0.04; 95% CI -0.01 to 0.1; p > 0.05). The mean CF-PWV values increased by 0.1 m/s for every 1 kg/m 2 increase in BMI in the female subjects in the age adjusted linear model, while such effect was not seen in the male subjects. In line with arterial stiffening, the overweight and obese females demonstrated significantly higher systolic brachial BP. (BP difference: ΔBP 9-11 mmHg, p < 0.01) and central systolic pressure (ΔBP 8-10 mmHg, p < 0.05) compared to their lean counterparts, unlike the male subjects. Our results suggest that female gender is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure.

Sympathetic overdrive plays a key role in the perturbation of cardiometabolic homeostasis. Diet-induced and exercise-induced weight loss remains a key strategy to combat metabolic disorders, but is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication intolerance and nonadherence. A clinical need exists for complementary therapies to curb the burden of cardiometabolic diseases. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. The experience from catheter-based renal denervation studies clearly demonstrates the feasibility, safety and efficacy of such an approach. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multiorgan neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum offering a holistic approach., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Automated analysis and quantification of physiological signals in clinical practice and medical research can reduce manual labor, increase efficiency, and provide more objective, reproducible results. To build a novel platform for the analysis of muscle sympathetic nerve activity (MSNA), we employed state-of-the-art data processing and machine learning applications. Data processing methods for integrated MSNA recordings were developed to evaluate signals regarding the overall quality of the signal, the validity of individual signal peaks regarding the potential to be MSNA bursts and the timing of their occurrence. An overall probability score was derived from this flexible platform to evaluate each individual signal peak automatically. Overall, three deep neural networks were designed and trained to validate individual signal peaks randomly sampled from recordings representing only electrical noise and valid microneurography recordings. A novel data processing method for the whole signal was developed to differentiate between periods of valid MSNA signal recordings and periods in which the signal was not available or lost due to involuntary movement of the recording electrode. A probabilistic model for timing of the signal bursts was implemented as part of the system. Machine Learning algorithms and data processing tools were implemented to replicate the complex decision-making process of manual MSNA analysis. Validation of manual MSNA analysis including intra- and inter-rater validity and a comparison with automated MSNA tools is required. The developed toolbox for automated MSNA analysis can be extended in a flexible way to include algorithms based on other datasets., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)