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Abstract A key limitation in assessing the therapeutic impact of non-pharmacological approaches to treating hypertension is the method of reporting outcomes. Reducing the medications required to achieve the same blood pressure may be reported separately to a reduction in the blood pressure without change in medication, and thus lessen the reported beneficial impact of treatment. This study aims to derive a novel scoring system to gauge the therapeutic impact of non-drug treatment of hypertension by utilising a combination of excessive blood pressure and the number of anti-hypertensives into a combined score—the hypertensive index (HTi). The hypertensive index was empirically derived based on the systolic blood pressure and number of antihypertensive drugs, and applied retrospectively to a cohort undergoing intervention for renovascular hypertension. Subgroup and receiver operating characteristic analyses were used to compare the HTi to traditional methods of reporting outcomes. Following intervention (99 patients), 46% had improvement in both medication load and blood pressure, 29% had benefit in blood pressure without reduction in medication load, 15% had reduction in medication load without significant change in blood pressure and 9% showed no benefit in either parameter. The HTi was superior in detecting benefit from intervention compared with measuring blood pressure or medication load alone (AUC 0.94 vs 0.85;0.84). The hypertensive index may be a more sensitive marker of treatment effect than assessing blood pressure measurements alone. The use of such scoring systems in future trial design may allow more accurate reporting of the effects of interventions for hypertension.

Background. In the coronary and the forearm circulations, endothelium-dependent vasomotion is impaired in smokers, but can be augmented by l-arginine or vitamin C. We examined whether smoking similarly affects the renal circulation. Methods. In 20 smokers (age 26 ± 4 years) and in 20 non-smokers (age 28 ± 3 years) changes of renal plasma flow (RPF), glomerular filtration rate (GFR), blood pressure and heart rate in response to the subsequent intravenous infusions of NG-monomethyl-l-arginine (L-NMMA), l-arginine and l-arginine plus vitamin C were studied by use of a constant infusion input clearance technique. Results. Systemic haemodynamic parameters did not differ between smokers and non-smokers during each experimental phase. At baseline, RPF and GFR were similar between the groups. The infusion of L-NMMA led to a similar decrease of RPF, while GFR did not change in either group. During the infusion of l-arginine RPF increased similarly. Finally, the co-infusion of l-arginine plus vitamin C led to a significantly greater increase of RPF (+277 ± 395 vs +79 ± 76 ml/min, P = 0.03) and GFR (+12.1 ± 10.6 vs +3.4 ± 11.2 ml/min, P = 0.02) in smokers as compared to non-smokers. Conclusions. L-NMMA-induced vasoconstriction of the renal vasculature was similar in smokers compared to non-smokers. l-arginine alone induced a similar increase of RPF. The co-infusion of vitamin C and l-arginine led to a greater increase of RPF and GFR in smokers. This might suggest that oxidative stress is increased in the renal vasculature of smokers. [ABSTRACT FROM AUTHOR]

Renal ischaemia due to renal artery stenosis produces two differing responses - a juxtaglomerular hypertensive response and cortical renal dysfunction. The reversibility of renal impairment is not predictable, and thus renal revascularisation is controversial. This study aims to test the hypothesis that the hypertensive response to renal ischaemia reflects viable renal parenchyma, and thus could be used to predict the recovery in renal function. A retrospective analysis was performed of all patients who had renal revascularisation for renal impairment in a defined geographical area (West of Scotland, population 2.4 million) between 2008 and 2024. Clinical records were used to determine the pre-intervention blood pressure, anti-hypertensive medication load and renal function, and post-intervention outcomes. The Hypertensive Index (HTi), a combined measure of systolic blood pressure and antihypertensive drug load, was used as a measure of pre-intervention hypertensive response. 75 patients had intervention for renal impairment over 15 years (68 endovascular, 7 open). Mean pre-intervention serum creatinine of 323 µmol/L was reduced to 191 umol/L at discharge and 182 µmol/L at 6-month follow-up. Refractory hypertension (HTi > 120) was associated with a significant benefit from revascularisation with improved renal function (p = 0.003) and reduced risk of future dialysis (p = 0.001). Renal impairment with no hypertensive response was highly predictive of the need for future dialysis. The hypertensive index is a good predictor of the impact of renal revascularisation on improving renal function with good outcomes in selected patients, and the absence of this is an indicator of chronic non-reversible renal dysfunction., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Conflict of interest: CD is funded by the British Heart Foundation (Centre of Research Excellence Award, reference RE/18/6/34217). All other authors declare no conflict of interest. Ethics statement: All participants provided written informed consent and all study procedures were in concordance with the Declaration of Helsinki, 1975 (revised 2000). Formal ethical approval for this retrospective study was not required as per national legislation produced by the Health Research Authority., (© 2025. The Author(s).)

Competing Interests: Competing interests: None declared.

Background: Renal denervation lowers blood pressure (BP) in patients with uncontrolled hypertension. We conducted an unbiased genomic screen to identify genetic variants that may associate with BP response to renal denervation (RDN)., Methods: Patients (n=268) with uncontrolled resistant hypertension (baseline BP, 166±21/90±15 mm Hg) who underwent endovascular RDN using the Symplicity catheter (Medtronic, Inc, Santa Rosa, CA) were included. Reduction in 24-hour ambulatory systolic BP was assessed at 6 months and divided into 2 groups: above and below the median response of 6.0 mm Hg, taking preintervention 24-hour ambulatory BP and regression to the mean into account. Whole exome sequencing assessing 249 669 variants, was conducted using Illumina NovaSeq technology read on a NovaSeq S4 Flow Cell device., Results: We did not identify individual gene variants associated with BP response following RDN. These findings were confirmed after adjustment for sex and in a sensitivity analysis looking at tertiles of BP response. We also explored specific variants in AGT , ADD1 , ADRB1, ADRB2 , and SCNN1A that have been proposed as potential candidate genes for response and found no association (all P >0.13). Gene ontology analysis of variants across the 2 responder groups highlighted differences in biologic processes such as cell adhesion and molecular function such as protein tyrosine kinase activity., Conclusions: The response to RDN, in terms of 24-hour BP reduction, was not associated with the genetic profile of patients with resistant hypertension. These data do not support the use of a genetic score to identify potential responders to RDN., Competing Interests: F. Mahfoud’s institution (Saarland University) has received scientific support from Ablative Solutions, Medtronic, and ReCor Medical. He has received speaker honoraria and consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. R. E. Schmieder’s institution (University Hospital Erlangen) has received scientific research support from Ablative Solutions, Medtronic, and ReCor Medical. He has received speaker honoraria and consulting fees from Ablative Solutions, Medtronic, and ReCor Medical. The other authors report no conflicts.

Aims: This study aimed to explore the effect of discontinuation of long-term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study., Materials and Methods: An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re-examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin-creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow-up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium., Results: No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI -12, 55; p = 0.28) nor the placebo (5%; 95% CI -13, 26; p = 0.63) group at follow-up. No difference in UACR between the groups was observed at follow-up (relative difference in geometric mean: 11%, 95% CI -26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05)., Conclusions: UACR did not change after discontinuation of long-term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys., (© 2024 John Wiley & Sons Ltd.)

Blood pressure (BP) measurement is a common procedure conducted in various disciplines and is widely available on clinical reports. The diagnosis and management of hypertension require reliable measurement of BP in outpatient clinics. Published studies suggest the standardised method for BP measurement is difficult to apply in routine clinical practice. This study aimed to assess the current practice of BP measurement in outpatient clinics in relevant secondary care clinical specialties across the 15 separate hospital sites of the NHS Greater Glasgow and Clyde region (population 1.2 million) compared to the recommended standardised method. An online questionnaire was developed and disseminated to the supervising clinician of each of 268 regular outpatient clinics. The questionnaire focused on the standardised BP method (patient preparation, environment, and BP measurement technique). The questionnaire was returned for 110 clinics. 73 (66.4%) of the participating clinics measure BP routinely and these formed the basis for further analysis. 3 clinics (4.1%) apply all components of the standardised BP method. 5 (6.9%) clinics deliver advice to patients prior to clinic attendance on how to prepare for BP measurement. 61 (83.6%) of participating clinics have a dedicated quiet environment for BP measurement. 50 (68.5%) clinics always place the cuff on bare upper arm and 63.0% use a cuff size appropriate to upper arm circumference. In a wide range of secondary care out-patient clinic settings, we found that BP measurement rarely adheres to the recommended standards. This has important implications for the quality of treatment decisions that are based on BP measurement., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All methods were performed in accordance with the relevant guidelines and regulations. Ethical approval was granted by the Research Ethics Committee of the University of Glasgow’s College of Medical, Veterinary, and Life Sciences on 11th July 2023 (reference number 200220359). Informed consent was obtained from all participants., (© 2024. The Author(s).)

Purpose: Cardiovascular disease (CVD) is one of the leading causes of death in women, largely underpinned by hypertension. Current guidelines recommend first-line therapy with a RAAS-blocking agent especially in young people. There are well documented sex disparities in CVD outcomes and management. We evaluate the management of patients with newly diagnosed hypertension in a tertiary care clinic to assess male-female differences in investigation and treatment., Methods: Clinic letters of all new patients under the age of 51 attending the Glasgow Blood Pressure Clinic between January and December 2023 were reviewed. The primary outcomes measured were first-line treatment choices, deviations from guideline-recommended treatment, investigations for secondary hypertension, and documentation of female-specific risk factors and family planning advice. Secondary outcomes included clinical characteristics such as systolic and diastolic blood pressure at referral and at the new patient appointment, age at diagnosis, age at first appointment, and the number of antihypertensive drugs prescribed at referral., Results: One hundred and five (59:46, M:F) new patient encounters were reviewed after sixteen exclusions for non-attendance and inappropriate clinic coding. Choice of first line antihypertensive agent did not vary between sexes with no deviation from guideline-recommended medical therapy. Men, however, had more biochemical investigations conducted for secondary causes across all ages. This was greatest in those under 40 years old. There was suboptimal documentation of female-specific risk factors (obstetric and gynaecological history), contraceptive drug history and family planning with 35%, 20%, and 15.6%, respectively., Conclusion: In 2023, women under 51 years of age seen in a tertiary care hypertension clinic received similar first-line treatment to their male peers. However, relevant female-specific histories were suboptimally documented for these patients. Whilst therapeutic approaches in men and women appear to be similar in this clinic, there are opportunities to improve CVD prevention in women, even in a specialised clinic setting.

Purpose of Review: We review the role of uromodulin, a protein exclusively expressed in the kidney, in blood pressure regulation and hypertension., Recent Findings: The last few years have seen a shift of focus from genetic association to mendelian randomisation and uromodulin-salt interaction studies, thus confirming the causal role of uromodulin in blood pressure regulation and hypertension. This work has been complemented by phenome-wide association studies in a wider range of ethnicities. Important recent molecular work elucidated uromodulin trafficking and secretion and provided more insights into the pathophysiological roles of circulating and urinary uromodulin. Uromodulin has a causal role in blood pressure regulation and hypertensin. Recent studies show utility of the uromodulin as a biomarker and a possible precision medicine application based on genetically determined differential responses to loop diuretics., (© 2024. The Author(s).)

Background: This study estimated to what extent the number of measurements of cardiometabolic risk factors (e.g., blood pressure, cholesterol, glycated haemoglobin) were impacted by the COVID-19 pandemic and whether these have recovered to expected levels., Methods and Findings: A cohort of individuals aged ≥18 years in England with records in the primary care-COVID-19 General Practice Extraction Service Data for Pandemic Planning and Research (GDPPR) were identified. Their records of 12 risk factor measurements were extracted between November 2018 and March 2024. Number of measurements per 1,000 individuals were calculated by age group, sex, ethnicity, and area deprivation quintile. The observed number of measurements were compared to a composite expectation band, derived as the union of the 95% confidence intervals of 2 estimates: (1) a projected trend based on data prior to the COVID-19 pandemic; and (2) an assumed stable trend from before pandemic. Point estimates were calculated as the mid-point of the expectation band. A cohort of 49,303,410 individuals aged ≥18 years were included. There was sharp drop in all measurements in March 2020 to February 2022, but overall recovered to the expected levels during March 2022 to February 2023 except for blood pressure, which had prolonged recovery. In March 2023 to March 2024, blood pressure measurements were below expectation by 16% (-19 per 1,000) overall, in people aged 18 to 39 (-23%; -18 per 1,000), 60 to 79 (-17%; -27 per 1,000), and ≥80 (-31%; -57 per 1,000). There was suggestion that recovery in blood pressure measurements was socioeconomically patterned. The second most deprived quintile had the highest deviation (-20%; -23 per 1,000) from expectation compared to least deprived quintile (-13%; -15 per 1,000)., Conclusions: There was a substantial reduction in routine measurements of cardiometabolic risk factors following the COVID-19 pandemic, with variable recovery. The implications for missed diagnoses, worse prognosis, and health inequality are a concern., Competing Interests: NS has consulted for and/or received speaker honoraria from Abbott Laboratories, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. JV was National Clinical Director for Diabetes and Obesity at NHS England from 2013 to September 2023. JH received research grants from Amgen, British Heart Foundation, Health and Care Research Wales, and speaker honorarium from Amgen. CD is the Treasurer of European Council for Cardiovascular Research, Association of Physicians of Great Britain and Ireland, Council Member of the European Society of Hypertension, and the Vice President of Scottish Heart & Arterial disease Risk Prevention (SHARP). All other authors declared no potential conflicts of interests., (Copyright: © 2024 Ho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Gender-affirming hormone therapy (GAHT) is used in individuals with gender identity dysphoria to align an individual's secondary sexual characteristics with their affirmed gender. We conducted a systematic review of the literature to explore the mechanisms regarding the effects of GAHT on the vasculature., Methods: A literature search using PUBMED, Embase, Scopus and Lilacs was performed using search terms for GAHT, cardiovascular disease (CVD) risk and transgender. Studies were screened by two independent reviewers. Comparison to a cohort of transgender individuals naïve or prior to GAHT or a cisgender population was required. Quality assessment was done using the relevant Critical Skills Appraisal Programme checklists., Results: Out of 2,564 potentially eligible studies, 69 studies met the inclusion criteria. Studies provided evidence of beneficial changes in CVD risk profile including reduced haemoglobin and pro-inflammatory markers, and atheroprotective changes in lipids in transgender women. In transgender men there was evidence of negative changes in CVD risk profile including atherogenic changes in lipids and increased haemoglobin, arterial stiffness, and pro-inflammatory markers., Conclusions: There is a paucity of research across non-traditional measures of CVD risk which in combination with heterogeneous study design, loss of follow-up, low sample sizes and lack of diversity in age and ethnicity requires the results to be interpreted with caution. More evidence is required to elucidate the mechanisms behind the increased risk of CVD in the transgender population and determine if GAHT is a contributing factor.

Blacks are more prone to salt-sensitive hypertension than Whites. This cross-sectional analysis of a multi-ethnic cohort aimed to search for proteins potentially involved in the susceptibility to salt sensitivity, hypertension, and hypertension-related complications. The study included individuals enrolled in African Prospective Study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), Flemish Study of the Environment, Genes and Health Outcomes (FLEMENGHO), Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID)-Austria, and Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform Trial (UPRIGHT-HTM). Sequenced urinary peptides detectable in 70% of participants allowed the identification of parental proteins and were compared between Blacks and Whites. Of 513 urinary peptides, 300 had significantly different levels among healthy Black (n = 476) and White (n = 483) South Africans sharing the same environment. Analyses contrasting 582 Blacks versus 1731 Whites, and Sub-Saharan Blacks versus European Whites replicated the findings. COL4A1, COL4A2, FGA, PROC, MGP, MYOCD, FYXD2, and UMOD were identified as the most likely candidates underlying the racially different susceptibility to salt sensitivity, hypertension, and related complications. Enriched pathways included hemostasis, platelet activity, collagens, biology of the extracellular matrix, and protein digestion and absorption. Our study suggests that MGP and MYOCD being involved in cardiovascular function, FGA and PROC in coagulation, FYXD2 and UMOD in salt homeostasis, and COL4A1 and COL4A2 as major components of the glomerular basement membrane are among the many proteins potentially incriminated in the higher susceptibility of Blacks compared to Whites to salt sensitivity, hypertension, and its complication. Nevertheless, these eight proteins and their associated pathways deserve further exploration in molecular and human studies as potential targets for intervention to reduce the excess risk of hypertension and cardiovascular complications in Blacks versus Whites., (© 2024 The Author(s). PROTEOMICS published by Wiley‐VCH GmbH.)

Aims: Biomarkers associated with asymptomatic ventricular dysfunction might improve risk stratification and identify pathways leading to heart failure (HF). We explored the association between proteomic biomarkers and left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and incident HF in three population-based cohorts., Methods and Results: A chip was used to measure 92 protein biomarkers in blood samples from >1500 Malmö Preventive Project (MPP) participants, of whom 514 had LVH (34%), 462 had DD (32.4%) and, over a median follow-up of 13 (11-14) years, 130 developed HF (7.7%). Findings were confirmed in the STANISLAS (n > 1500, 238 participants with LVH, 76 with DD) and HOMAGE case-control (562 cases of incident HF, 871 controls) cohorts. In multivariable logistic or Cox regression analyses adjusted for age, sex and cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with LVH, DD and incident HF in all cohorts: MPP (LVH odds ratio [OR] [95% confidence interval] 1.48 [1.28-1.71]; DD OR 1.71 [1.53-1.92]; HF HR 1.98 [1.66-2.36]); STANISLAS (LVH OR 1.20 [1.02-1.41]; DD OR 1.46 [1.12-1.90]); HOMAGE (HF HR 1.85 [1.62-2.12]). Galectin-4, growth differentiation factor 15 and suppression of tumorigenicity-2 were associated with incident HF in MPP and HOMAGE. A pathway enrichment analysis suggested that inflammation and viral infection were related to incident HF., Conclusion: In conclusion, our study reinforces the role of NT-proBNP as a key biomarker for asymptomatic cardiac dysfunction and incident HF, consistent with its established use in clinical practice. This underscores the value of NT-proBNP for identifying patients at high risk for HF, and provides insights into pathways leading to HF and potential therapeutic targets., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Socioeconomic inequality in infant mortality in the UK is rising. This study aims to identify contributory maternal and pregnancy factors that can explain the known association between area deprivation and infant mortality., Methods: A cohort study was conducted using Clinical Practice Research Datalink (CPRD) primary care data between 2004 and 2019 linked to the Index of Multiple Deprivation (IMD), and infant mortality from the Office for National Statistics death data. Potential maternal and pregnancy contributory factors included: maternal age, prior maternal health conditions, pregnancy lifestyle factors and complications, use of medications during pregnancy, and characteristics of birth. Counterfactual-based decomposition analysis was used to quantify the relative importance of equalising these factors to reduce inequalities in infant mortality., Findings: A total of 392,606 mother-child dyads were included in this study. The overall risk of infant mortality was greatest for individuals in the most deprived quintile (risk ratio 2.13 [95% CI 1.58-2.90]; risk difference 6.6 [3.8-8.8] per 10,000 live births) compared with the least deprived. Four contributory factors were identified as potentially important: preterm birth (Proportion eliminated [PE] 15.25% [95% CI 9.44-24.12%]), smoking during pregnancy (PE 13.61% [95% CI 3.96-80.97%]), maternal age <20 years at childbirth (PE 10.52% [95% CI 2.93-21.35%]) and maternal depression (PE 9.13% [95% CI 4.47-14.93%]). These collectively accounted for more than one-third of the socioeconomic inequality in mortality., Interpretation: Multifactorial interventions targeting maternal mental health, smoking, teenage pregnancy and preterm birth may mitigate a proportion of the effects of socioeconomic inequality but targeting these, alone, will not stem the rise in infant mortality. Structural efforts to reduce socioeconomic inequalities will also be required to prevent these excess infant deaths., Funding: UK Medical Research Council, Scottish Chief Scientist Office, Wellcome Trust., Competing Interests: FH received research funding from Glasgow Children Hospital Charity, Biotechnology and Biological Sciences Research Council, Understanding Children's Trust, and The Swedish Child Neuropsychiatry Science Foundation, consulting fee from the Chinese University of Hong Kong, and personal honorarium from Sage Publications. KM received research funding from CW Maplethorpe Fellowship, European Commission Horizon 2020, National Institute for Health and Care Research UK, Hong Kong Research Grant Council. JC received research funding from Bristol Myers Squibb, CSL-Vifor, British Heart Foundation, and Pharmacosmos, consulting fee from Pharmacosmos, CSL-Vifor, and Biopeutics, personal honorarium from Pharmacosmos and ABBOTT, travel support from Pharmacosmos, participated on advisory boards of Medtronic, ADAPT-CRT, CMR-Guide, PROTECT-HF, and have stocks or stock options in HeartFelt (non-invasive monitoring), Viscardia (synchronous diaphragmatic pacing). CD received research funding from Wellcome Trust. PI received research funding from Hong Kong Health and Medical Research Fund and Hong Kong General Research Fund. ICKW received research grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer and Bristol-Myers Squibb and Takeda, Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, The European Union's Seventh Framework Programme for research, technological development, Research Grants Council Hong Kong and Health and Medical Research Fund Hong Kong; consulting fees from IQVIA and World Health Organization; payment for expert testimony for Appeal Court in Hong Kong; serves on advisory committees for Member of Pharmacy and Poisons Board; is a member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization; is a member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; is the non-executive director of Jacobson Medical in Hong Kong; and is the founder and director of Therakind Limited (UK), Advance Data Analytics for Medical Science (ADAMS) Limited (HK), Asia Medicine Regulatory Affairs (AMERA) Services Limited and OCUS Innovation Limited (HK, Ireland and UK). PW received research funding from Boehringer Ingelheim, Astrazeneca, Roche diagnostics, Novartis, personal honorarium from Novo Nordisk and Raisio. AP received research funding from Wellcome Trust, MRC, CSO, NIHR, Obesity Action Scotland, Health Foundation, and UKPRP., (© 2024 The Author(s).)

Objectives: Hypertension is a common condition worldwide; however, its underlying mechanisms remain largely unknown. This study aimed to identify urinary peptides associated with hypertension to further explore the relevant molecular pathophysiology., Methods: Peptidome data from 2876 individuals without end-organ damage were retrieved from the Human Urinary Proteome Database, belonging to general population (discovery) or type 2 diabetic (validation) cohorts. Participants were divided based on systolic blood pressure (SBP) and diastolic BP (DBP) into hypertensive (SBP ≥140 mmHg and/or DBP ≥90 mmHg) and normotensive (SBP <120 mmHg and DBP <80 mmHg, without antihypertensive treatment) groups. Differences in peptide abundance between the two groups were confirmed using an external cohort ( n  = 420) of participants without end-organ damage, matched for age, BMI, eGFR, sex, and the presence of diabetes. Furthermore, the association of the peptides with BP as a continuous variable was investigated. The findings were compared with peptide biomarkers of chronic diseases and bioinformatic analyses were conducted to highlight the underlying molecular mechanisms., Results: Between hypertensive and normotensive individuals, 96 (mostly COL1A1 and COL3A1) peptides were found to be significantly different in both the discovery (adjusted) and validation (nominal significance) cohorts, with consistent regulation. Of these, 83 were consistently regulated in the matched cohort. A weak, yet significant, association between their abundance and standardized BP was also observed., Conclusion: Hypertension is associated with an altered urinary peptide profile with evident differential regulation of collagen-derived peptides. Peptides related to vascular calcification and sodium regulation were also affected. Whether these modifications reflect the pathophysiology of hypertension and/or early subclinical organ damage requires further investigation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The conflict of interest declaration of authors are compiled into one file that can be found on the ESH website: https://www.eshonline.org/guidelines/2023-guidelines/. ESH received no financial support for the generation of this guidelines.

Surrogate measures of glomerular filtration rate (GFR) continue to serve as pivotal determinants of the incidence, severity, and management of acute kidney injury (AKI), as well as the primary reference point underpinning knowledge of its pathophysiology. However, several clinically important deficits in aspects of renal excretory function during AKI other than GFR decline, including acid-base regulation, electrolyte and water balance, and urinary concentrating capacity, can evade detection when diagnostic criteria are built around purely GFR-based assessments. The use of putative markers of tubular injury to detect "sub-clinical" AKI has been proposed to expand the definition and diagnostic criteria for AKI, but their diagnostic performance is curtailed by ambiguity with respect to their biological meaning and context specificity. Efforts to devise new holistic assessments of overall renal functional compromise in AKI would foster the capacity to better personalize patient care by replacing biomarker threshold-based diagnostic criteria with a shift to assessment of compromise along a pathophysiological continuum. The term AKI refers to a syndrome of sudden renal deterioration, the severity of which is classified by precise diagnostic criteria that have unquestionable utility in patient management as well as blatant limitations. Particularly, the absence of an explicit pathophysiological definition of AKI curtails further scientific development and clinical handling, entrapping the field within its present narrow GFR-based view. A refreshed approach based on a more holistic consideration of renal functional impairment in AKI as the basis for a new diagnostic concept that reaches beyond the boundaries imposed by the current GFR threshold-based classification of AKI, capturing broader aspects of pathogenesis, could enhance AKI prevention strategies and improve AKI patient outcome and prognosis., (© 2024 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

National and international hypertension guidelines recommend that adults with young-onset hypertension (aged <40 years at diagnosis) are reviewed by a hypertension specialist to exclude secondary causes of hypertension and optimise therapeutic regimens. A recent survey among UK secondary care hypertension specialist physicians highlighted variations in the investigation of such patients. In this position statement, the British and Irish Hypertension Society seek to provide clinicians with a practical approach to the investigation and management of adults with young-onset hypertension. We aim to ensure that individuals receive consistent and high-quality care across the UK and Ireland, to highlight gaps in the current evidence, and to identify important future research questions., (© 2024. The Author(s).)

Objectives: To investigate if the effect of cardiac computed tomography (CT) vs. invasive coronary angiography (ICA) on cardiovascular events differs based on smoking status., Materials and Methods: This pre-specified subgroup analysis of the pragmatic, prospective, multicentre, randomised DISCHARGE trial (NCT02400229) involved 3561 patients with suspected coronary artery disease (CAD). The primary endpoint was major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, or stroke). Secondary endpoints included an expanded MACE composite (MACE, transient ischaemic attack, or major procedure-related complications)., Results: Of 3445 randomised patients with smoking data (mean age 59.1 years + / - 9.7, 1151 men), at 3.5-year follow-up, the effect of CT vs. ICA on MACE was consistent across smoking groups (p for interaction = 0.98). The percutaneous coronary intervention rate was significantly lower with a CT-first strategy in smokers and former smokers (p = 0.01 for both). A CT-first strategy reduced the hazard of major procedure-related complications (HR: 0.21, 95% CI: 0.03, 0.81; p = 0.045) across smoking groups. In current smokers, the expanded MACE composite was lower in the CT- compared to the ICA-first strategy (2.3% (8) vs 6.0% (18), HR: 0.38; 95% CI: 0.17, 0.88). The rate of non-obstructive CAD was significantly higher in all three smoking groups in the CT-first strategy., Conclusion: For patients with stable chest pain referred for ICA, the clinical outcomes of CT were consistent across smoking status. The CT-first approach led to a higher detection rate of non-obstructive CAD and fewer major procedure-related complications in smokers., Clinical Relevance Statement: This pre-specified sub-analysis of the DISCHARGE trial confirms that a CT-first strategy in patients with stable chest pain referred for invasive coronary angiography with an intermediate pre-test probability of coronary artery disease is as effective as and safer than invasive coronary angiography, irrespective of smoking status., Trial Registration: ClinicalTrials.gov NCT02400229., Key Points: • No randomised studies have assessed smoking status on CT effectiveness in symptomatic patients referred for invasive coronary angiography. • A CT-first strategy results in comparable adverse events, fewer complications, and increased coronary artery disease detection, irrespective of smoking status. • A CT-first strategy is safe and effective for stable chest pain patients with intermediate pre-test probability for CAD, including never smokers., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Competing Interests: Disclosures None.

Aims: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables., Methods and Results: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m 2 ). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m 2 ). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (p interaction  > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (p interaction  > 0.10)., Conclusion: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p  < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p  < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p  < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p  < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Urbanisation is considered a major contributor to the rising prevalence of hypertension in West Africa, yet the evidence regarding rural-urban differences in the prevalence of hypertension in the region has been mixed. A systematic literature search of four electronic databases: PubMed, Embase, African Journals Online, and WHO's African Index Medicus; and reference lists of eligible studies was carried out. Original quantitative studies describing the rural-urban difference in the prevalence of hypertension in one or more countries in West Africa, and published in English language from the year 2000 to 2021 were included. A random effects meta-analysis model was used to estimate the odds ratio of hypertension in rural compared to urban locations. A limited sex-based random effects meta-analysis was conducted with 16 studies that provided sex-disaggregated data. Of the 377 studies screened, 22 met the inclusion criteria (n = 62,907). The prevalence of hypertension was high in both rural, and urban areas, ranging from 9.7% to 60% in the rural areas with a pooled prevalence of 27.4%; and 15.5% to 59.2% in the urban areas with a pooled prevalence of 33.9%. The odd of hypertension were lower in rural compared to urban dwellers [OR 0.74, 95% CI: 0.66-0.83; p < 0.001]. The pooled prevalence of hypertension was 32.6% in males, and 30.0% in females, with no significant difference in the odds of hypertension between the sexes [OR 0.91, 95% CI: 0.8-1.05, p = 0.196]. Comprehensive hypertension control policies are needed for both rural, and urban areas in West Africa, and for both sexes., (© 2022. The Author(s).)

Blood pressure is regulated by vascular resistance and intravascular volume. However, exchanges of electrolytes and water between intra and extracellular spaces and filtration of fluid and solutes in the capillary beds blur the separation between intravascular, interstitial and intracellular compartments. Contemporary paradigms of microvascular exchange posit filtration of fluids and solutes along the whole capillary bed and a prominent role of lymphatic vessels, rather than its venous end, for their reabsorption. In the last decade, these concepts have stimulated greater interest in and better understanding of the lymphatic system as one of the master regulators of interstitial volume homeostasis. Here, we describe the anatomy and function of the lymphatic system and focus on its plasticity in relation to the accumulation of interstitial sodium in hypertension. The pathophysiological relevance of the lymphatic system is exemplified in the kidneys, which are crucially involved in the control of blood pressure, but also hypertension-mediated cardiac damage. Preclinical modulation of the lymphatic reserve for tissue drainage has demonstrated promise, but has also generated conflicting results. A better understanding of the hydraulic element of hypertension and the role of lymphatics in maintaining fluid balance can open new approaches to prevent and treat hypertension and its consequences, such as heart failure., Competing Interests: None.

Importance: The effectiveness and safety of computed tomography (CT) and invasive coronary angiography (ICA) in different age groups is unknown., Objective: To determine the association of age with outcomes of CT and ICA in patients with stable chest pain., Design, Setting, and Participants: The assessor-blinded Diagnostic Imaging Strategies for Patients With Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE) randomized clinical trial was conducted between October 2015 and April 2019 in 26 European centers. Patients referred for ICA with stable chest pain and an intermediate probability of obstructive coronary artery disease were analyzed in an intention-to-treat analysis. Data were analyzed from July 2022 to January 2023., Interventions: Patients were randomly assigned to a CT-first strategy or a direct-to-ICA strategy., Main Outcomes and Measures: MACE (ie, cardiovascular death, nonfatal myocardial infarction, or stroke) and major procedure-related complications. The primary prespecified outcome of this secondary analysis of age was major adverse cardiovascular events (MACE) at a median follow-up of 3.5 years., Results: Among 3561 patients (mean [SD] age, 60.1 [10.1] years; 2002 female [56.2%]), 2360 (66.3%) were younger than 65 years, 982 (27.6%) were between ages 65 to 75 years, and 219 (6.1%) were older than 75 years. The primary outcome was MACE at a median (IQR) follow-up of 3.5 (2.9-4.2) years for 3523 patients (99%). Modeling age as a continuous variable, age, and randomization group were not associated with MACE (hazard ratio, 1.02; 95% CI, 0.98-1.07; P for interaction = .31). Age and randomization group were associated with major procedure-related complications (odds ratio, 1.15; 95% CI, 1.05-1.27; P for interaction = .005), which were lower in younger patients., Conclusions and Relevance: Age did not modify the effect of randomization group on the primary outcome of MACE but did modify the effect on major procedure-related complications. Results suggest that CT was associated with a lower risk of major procedure-related complications in younger patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02400229.

Background: Pregnancy involves major adaptations in renal haemodynamics, tubular, and endocrine functions. Hypertensive disorders of pregnancy are a leading cause of maternal mortality and morbidity. Uromodulin is a nephron-derived protein that is associated with hypertension and kidney diseases. Here we study the role of urinary uromodulin excretion in hypertensive pregnancy., Methods: Urinary uromodulin was measured by ELISA in 146 pregnant women with treated chronic hypertension (n = 118) and controls (n = 28). We studied non-pregnant and pregnant Wistar Kyoto and Stroke Prone Spontaneously Hypertensive rats (n = 8/strain), among which a group of pregnant Stroke-Prone Spontaneously Hypertensive rats was treated with either nifedipine (n = 7) or propranolol (n = 8)., Results: In pregnant women, diagnosis of chronic hypertension, increased maternal body mass index, Black maternal ethnicity and elevated systolic blood pressure at the first antenatal visit were significantly associated with a lower urinary uromodulin-to-creatinine ratio. In rodents, pre-pregnancy urinary uromodulin excretion was twofold lower in Stroke-Prone Spontaneously Hypertensive rats than in Wistar Kyoto rats. During pregnancy, the urinary uromodulin excretion rate gradually decreased in Wistar Kyoto rats (a twofold decrease), whereas a 1.5-fold increase was observed in Stroke-Prone Spontaneously Hypertensive rats compared to pre-pregnancy levels. Changes in uromodulin were attributed by kidney injury in pregnant rats. Neither antihypertensive changed urinary uromodulin excretion rate in pregnant Stroke-Prone Spontaneously Hypertensive rats., Conclusions: In summary, we demonstrate pregnancy-associated differences in urinary uromodulin: creatinine ratio and uromodulin excretion rate between chronic hypertensive and normotensive pregnancies. Further research is needed to fully understand uromodulin physiology in human pregnancy and establish uromodulin's potential as a biomarker for renal adaptation and renal function in pregnancy., (© 2024. The Author(s).)

Homeostasis of fluid and electrolytes is a tightly controlled physiological process. Failure of this process is a hallmark of hypertension, chronic kidney disease, heart failure, and other acute and chronic diseases. While the kidney remains the major player in the control of whole-body fluid and electrolyte homeostasis, recent discoveries point toward more peripheral mechanisms leading to sodium storage in tissues, such as skin and muscle, and a link between this sodium and a range of diseases, including the conditions above. In this review, we describe multiple facets of sodium and fluid balance from traditional concepts to novel discoveries. We examine the differences between acute disruption of sodium balance and the longer term adaptation in chronic disease, highlighting areas that cannot be explained by a kidney-centric model alone. The theoretical and methodological challenges of more recently proposed models are discussed. We acknowledge the different roles of extracellular and intracellular spaces and propose an integrated model that maintains fluid and electrolyte homeostasis and can be distilled into a few elemental players: the microvasculature, the interstitium, and tissue cells. Understanding their interplay will guide a more precise treatment of conditions characterized by sodium excess, for which primary aldosteronism is presented as a prototype., Competing Interests: Disclosures None.