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Background: UMOD (uromodulin) has been linked to hypertension through potential activation of Na + -K + -2Cl - cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction., Methods: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897)., Results: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m 2 ), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P <0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P =0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P =0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group ( P =0.004 for difference in trajectories)., Conclusions: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897., Competing Interests: I.S. Mackenzie is a member of the British Heart Foundation Clinical Studies Committee. The other authors report no conflicts.

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).)

Competing Interests: Disclosures None.

Introduction: Hypertension is the leading modifiable risk factor for cardiovascular disease and is implicated in half of all strokes and myocardial infarctions. One-third of the adults in Scotland have hypertension yet only a quarter of them have their blood pressure (BP) controlled to target (<140/90 mm Hg). Empowering patients to have a better understanding of their condition and becoming actively involved in the monitoring and management of hypertension may lead to improved patient satisfaction, improved BP control and health outcomes and reduction in the use of primary/secondary care hypertension clinics., Methods and Analysis: OPTIMA-BP is a randomised parallel group pilot study comparing the use of home BP monitoring accompanied by access to the web-based cardiovascular educational portal (Kvatchii) and home BP monitoring (HBPM) alone in 200 patients with hypertension attending the Glasgow Blood Pressure Clinic, Queen Elizabeth University Hospital, Glasgow. Consented participants will be asked to complete surveys on lifestyle factors, medication adherence, quality of life and hypertension knowledge, understanding and home monitoring. The intervention group will be asked to complete a survey to help evaluate the Kvatchii portal. At 6 and 12 months, the surveys will be repeated via the CASTOR EDC. Both groups will input their HBPM results at 2-month intervals into a CASTOR-EDC survey. OPTIMA-BP will follow-up with participants over 12 months with the study running over 24 months. The primary outcome is HBPM systolic BP area under the curve between baseline and 6 months ETHICS AND DISSEMINATION: OPTIMA-BP was approved by the North of Scotland Research Ethics Committee 2 (22/NS/0095). Current protocol version 1.2 date 6 June 2023. Written informed consent will be provided by all study participants. Study findings will be submitted to international peer-reviewed journals and will be presented at national and international scientific meetings., Trial Registration Number: ClinicalTrials.gov: NCT05575453. Registered 12 October 2022. https://clinicaltrials.gov/ct2/show/NCT05575453., Competing Interests: Competing interests: SP is a Professor of Cardiovascular Genomics and Therapeutics at the University of Glasgow and an Honorary NHS Consultant Physician who works in the Glasgow Blood Pressure Clinic. SP is a cofounder and director of Kvatchii Limited and developed the education portal. There are no other competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca 2+ channels in resistance vessels, leading to vasodilation and a reduction in blood pressure. Various meta-analyses show that dihydropyridines are relatively safe and effective in reducing hypertension. The use of dihydropyridines has recently been called into question as these drugs appear to activate store-operated Ca 2+ entry in fura-2-loaded nonexcitable cells, trigger vascular remodeling, and increase heart failure, leading to the questioning of their clinical use. Given that hypertension is the dominant "silent killer" across the globe affecting ∼1.13 billion people, removal of Ca 2+ channel blockers as antihypertensive agents has major health implications. Here, we show that amlodipine has marked intrinsic fluorescence, which further increases considerably inside cells over an identical excitation spectrum as fura-2, confounding the ability to measure cytosolic Ca 2+ . Using longer wavelength Ca 2+ indicators, we find that concentrations of Ca 2+ channel blockers that match therapeutic levels in serum of patients do not activate store-operated Ca 2+ entry. Antihypertensive Ca 2+ channel blockers at pharmacological concentrations either have no effect on store-operated channels, activate them indirectly through store depletion or inhibit the channels. Importantly, a meta-analysis of published clinical trials and a prospective real-world analysis of patients prescribed single antihypertensive agents for 6 mo and followed up 1 yr later both show that dihydropyridines are not associated with increased heart failure or other cardiovascular disorders. Removal of dihydropyridines for treatment of hypertension cannot therefore be recommended., Competing Interests: A.B.P. holds the position of Executive Editor for Function and is blinded from reviewing or making decisions for the manuscript., (Published by Oxford University Press on behalf of American Physiological Society 2023.)

Background Machine learning (ML) is pervasive in all fields of research, from automating tasks to complex decision-making. However, applications in different specialities are variable and generally limited. Like other conditions, the number of studies employing ML in hypertension research is growing rapidly. In this study, we aimed to survey hypertension research using ML, evaluate the reporting quality, and identify barriers to ML's potential to transform hypertension care. Methods and Results The Harmonious Understanding of Machine Learning Analytics Network survey questionnaire was applied to 63 hypertension-related ML research articles published between January 2019 and September 2021. The most common research topics were blood pressure prediction (38%), hypertension (22%), cardiovascular outcomes (6%), blood pressure variability (5%), treatment response (5%), and real-time blood pressure estimation (5%). The reporting quality of the articles was variable. Only 46% of articles described the study population or derivation cohort. Most articles (81%) reported at least 1 performance measure, but only 40% presented any measures of calibration. Compliance with ethics, patient privacy, and data security regulations were mentioned in 30 (48%) of the articles. Only 14% used geographically or temporally distinct validation data sets. Algorithmic bias was not addressed in any of the articles, with only 6 of them acknowledging risk of bias. Conclusions Recent ML research on hypertension is limited to exploratory research and has significant shortcomings in reporting quality, model validation, and algorithmic bias. Our analysis identifies areas for improvement that will help pave the way for the realization of the potential of ML in hypertension and facilitate its adoption.

Background: Individuals with CKD are at a higher risk of cardiovascular morbidity and mortality. Acidosis is positively correlated with CKD progression and elevated systolic BP. Sodium bicarbonate is an efficacious treatment of acidosis, although this may also increase systolic BP. In this systematic review and meta-analysis, we summarize the evidence evaluating systolic BP and antihypertensive medication change (which may indicate systolic BP change) in response to sodium bicarbonate therapy in individuals with CKD., Methods: Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Cochrane Central Register of Controlled Trials, and World Health Organization (WHO) trials registry databases were searched for randomized control trials where sodium bicarbonate was compared with placebo/usual care in CKD stage G1-5 non-dialysis-dependent populations. Random effects meta-analyses were used to evaluate changes in systolic BP and BP-modifying drugs after sodium bicarbonate intervention., Results: Fourteen randomized control trials (2110 individuals, median follow-up 27 [interquartile range 97] weeks, mean age 60 [SD 10] years, mean systolic BP 136 [SD 17] mm Hg, mean eGFR 38 [SD 10] ml/min, mean serum bicarbonate 22 [SD 4] mmol/L) were eligible for inclusion. Meta-analysis suggested that sodium bicarbonate did not influence systolic BP in individuals with CKD stage G1-5. Results were consistent when stratifying by dose of sodium bicarbonate or duration of intervention. Similarly, there was no significant increase in the use of antihypertensive medication or diuretics in individuals taking sodium bicarbonate, whereas there was a greater decrease in antihypertensive medication use in individuals taking sodium bicarbonate compared with controls., Conclusions: Our results suggest, with moderate certainty, that sodium bicarbonate supplementation does not adversely affect systolic BP in CKD or negatively influence antihypertensive medication requirements., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of American Society of Nephrology.)

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The exclusive expression of uromodulin in the kidneys has made it an intriguing protein in kidney and cardiovascular research. Genome-wide association studies discovered variants of uromodulin that are associated with chronic kidney diseases and hypertension. Urinary and circulating uromodulin levels reflect kidney and cardiovascular health as well as overall mortality. More recently, Mendelian randomization studies have shown that genetically driven levels of uromodulin have a causal and adverse effect on kidney function. On a mechanistic level, salt sensitivity is an important factor in the pathophysiology of hypertension, and uromodulin is involved in salt reabsorption via the NKCC2 (Na + -K + -2Cl - cotransporter) on epithelial cells of the ascending limb of loop of Henle. In this review, we provide an overview of the multifaceted physiology and pathophysiology of uromodulin including recent advances in its genetics; cellular trafficking; and mechanistic and clinical studies undertaken to understand the complex relationship between uromodulin, blood pressure, and kidney function. We focus on tubular sodium reabsorption as one of the best understood and pathophysiologically and clinically most important roles of uromodulin, which can lead to therapeutic interventions.

Background: Association studies have identified several biomarkers for blood pressure and hypertension, but a thorough understanding of their mutual dependencies is lacking. By integrating two different high-throughput datasets, biochemical and dietary data, we aim to understand the multifactorial contributors of blood pressure (BP)., Methods: We included 4,863 participants from TwinsUK with concurrent BP, metabolomics, genomics, biochemical measures, and dietary data. We used 5-fold cross-validation with the machine learning XGBoost algorithm to identify features of importance in context of one another in TwinsUK (80% training, 20% test). The features tested in TwinsUK were then probed using the same algorithm in an independent dataset of 2,807 individuals from the Qatari Biobank (QBB)., Findings: Our model explained 39·2% [4·5%, MAE:11·32 mmHg (95%CI, +/- 0·65)] of the variance in systolic BP (SBP) in TwinsUK. Of the top 50 features, the most influential non-demographic variables were dihomo-linolenate, cis-4-decenoyl carnitine, lactate, chloride, urate, and creatinine along with dietary intakes of total, trans and saturated fat. We also highlight the incremental value of each included dimension. Furthermore, we replicated our model in the QBB [SBP variance explained = 45·2% (13·39%)] cohort and 30 of the top 50 features overlapped between cohorts., Interpretation: We show that an integrated analysis of omics, biochemical and dietary data improves our understanding of their in-between relationships and expands the range of potential biomarkers for blood pressure. Our results point to potentially key biological pathways to be prioritised for mechanistic studies., Funding: Chronic Disease Research Foundation, Medical Research Council, Wellcome Trust, Qatar Foundation., Competing Interests: Declaration of interests T. D. S is a co-founder and shareholder of Zoe Global. All other authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hypertension is the biggest contributor to the global cardiovascular burden with evidence for ethnic differences in treatment response and outcomes. Under-representation of ethnic minorities in clinical research is well known, and despite wide-ranging public engagement events by the Glasgow Blood Pressure Clinic team, there was a lack of participation of ethnic minorities in both engagement activities and clinical trials conducted by them. This study aims to explore the awareness and knowledge of hypertension and the facilitators and barriers to participation in hypertension clinical research among South Asian (SA) and African (AFR) communities in Glasgow., Methods: A survey questionnaire was co-developed with representatives from South Asian (SA) and African (AFR) patients and community members in Glasgow to understand awareness and knowledge of hypertension and enablers and barriers to participation in clinical research. The survey was distributed to adults (aged > 18) years of SA or AFR ancestry at public engagement events at venues that were frequently visited by these two communities in Glasgow., Results: The survey response rate was 337 (67.4%) consisting of 242 (71.8%) South Asian (SA) and 56 (16.9%) African (AFR) respondents. Thirty-nine questionnaires were excluded because of incompletion. Most of the respondents were not born in the UK and were in the 35-53-year group (AFR 29 (51%), SA 113 (47%)). The proportion living in the most deprived (SIMD 1) and least deprived (SIMD 5) was respectively 26 (12.4%) and 34 (16.2%) for SA and 20 (42.6%) and 2 (4.3%) for AFR. There was a considerable recognition that treatment needs to be ethnicity-specific (SA/AFR = 107 (48%)/23 (45.1%)) and that current cardiovascular disease treatment guidelines were not tailored for different ethnicities 84 (38.5%)/23 (45.1%). The key enablers encouraging research participation are enhanced health information, conducting aspects of their clinical research visits/appointments at a location they frequently visited and allowing a family member to accompany them. Barriers included concerns about the use of personal information and side effects of the new treatment., Conclusion: Our survey confirmed enablers and barriers to ethnic minority participation in research. We find improving and evolving awareness and beliefs among the ethnic minority population including community leaders. Thus, continual review of researchers' beliefs and attitudes is also essential to ensure engagement activities keep up with these changing perceptions., (© 2022. The Author(s).)

A true discrepancy between the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on cardiovascular (CV) outcomes remains unclear. This study performed two-sample Mendelian randomization (MR) using genetic instruments that exclusively predict SBP, DBP or both to dissect the independent effect of SBP and DBP on a range of CV outcomes. Genetic predisposition to higher SBP and DBP was associated with increased risk of coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Genetically proxied SBP exclusively was associated with CAD (OR 1.18, 95% CI: 1.03-1.36, per 10 mmHg), stroke (1.44[1.28-1.62]), ischemic stroke (1.49[1.30-1.69]), HF (1.41[1.20-1.65]), AF (1.28[1.15-1.43]), and T2DM (1.2[1.13-1.46]). Genetically proxied DBP exclusively was associated with stroke (1.21[1.06-1.37], per 5 mmHg), ischemic stroke (1.24[1.09-1.41]), stroke small-vessel (1.35[1.10-1.65]) and CAD (1.19[1.00-1.41]). Multivariable MR using exclusive SBP and DBP instruments showed the predominant effect of SBP on CAD (1.23[1.05-1.44], per 10 mmHg), stroke (1.39[1.20-1.60]), ischemic stroke (1.44[1.25-1.67]), HF (1.42[1.18-1.71]), AF (1.26[1.10-1.43]) and T2DM (1.31[1.14-1.52]). The discrepancy between effects of SBP and DBP on outcomes warrants further studies on underpinning mechanisms which may be amenable to therapeutic targeting.

Introduction: COVID-19 may lead to long-term endothelial consequences including hypertension, stroke and myocardial infarction. A pilot study 'COVID-19 blood pressure endothelium interaction study', which found that patients with normal blood pressure (BP) at the time of hospital admission with COVID-19 showed an 8.6 mm Hg higher BP ≥12 weeks after recovery, compared with a group without COVID-19. The 'LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure'(LOCHINVAR) study is designed to provide definitive evidence of the long-term impact of COVID-19 on BP., Methods and Analysis: The LOCHINVAR study is an observational clinical phenotyping study comparing longitudinal BP change between individuals with and without COVID-19 infection. 150 participants (30-60 years) with no history of hypertension and not on BP lowering medications will be recruited to the study to attend three visits (baseline, 12 months, 18 months). Cases will be patients who were admitted to the Queen Elizabeth University Hospital (QEUH), Glasgow, UK, with suspected/confirmed COVID-19 until 31 December 2021 and who were alive at discharge. Controls will be those who have never had confirmed COVID-19 infection. All participants will undergo clinical and vascular phenotyping studies which will include 24-hour ambulatory BP monitoring systolic BP (ABPM SBP), brachial flow-mediated dilatation urine and blood samples to assess the renin-angiotensin system, vascular inflammation and immune status. The primary outcome is the change in systolic 24-hour ABPM (ABPM SBP) between the cases and controls. Sample size was calculated to detect a mean difference of 5 mm Hg ABPM SBP at 80% power., Ethics and Dissemination: The protocol of this study has been approved by the West of Scotland Research Ethics Committee 5 (21/WS/0075), Scotland, UK. Written informed consent will be provided by all study participants. Study findings will be submitted to international peer-reviewed hypertension journals and will be presented at international scientific meetings., Trial Registration Number: NCT05087290., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Aims: Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease., Methods and Results: Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5-11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7-114.3, P = 0.02)., Conclusion: Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Objectives: Glycosylation of immunoglobulin G (IgG) is an important regulator of the immune system and has been implicated in prevalent hypertension. The aim of this study is to investigate whether the IgG glycome begins to change prior to hypertension diagnosis by analysing the IgG glycome composition in a large population-based female cohort with two independent replication samples., Methods: We included 989 unrelated cases with incident hypertension and 1628 controls from the TwinsUK cohort (mean follow-up time of 6.3 years) with IgG measured at baseline by ultra-performance liquid chromatography and longitudinal BP measurement available. We replicated our findings in 106 individuals from the 10 001 Dalmatians and 729 from KORA S4. Cox regression mixed models were applied to identify changes in glycan traits preincident hypertension, after adjusting for age, mean arterial pressure, BMI, family relatedness and multiple testing (FDR < 0.1). Significant IgG-incident hypertension associations were replicated in the two independent cohorts by leveraging Cox regression mixed models in the 10 001 Dalmatians and logistic regression models in the KORA cohort., Results: We identified and replicated four glycan traits, incidence of bisecting GlcNAc, GP4, GP9 and GP21, that are predictive of incident hypertension after adjusting for confoundes and multiple testing [hazard ratio (95% CI) ranging from 0.45 (0.24-0.84) for GP21 to 2.9 (1.5-5.68) for GP4]. We then linearly combined the four replicated glycans and found that the glycan score correlated with incident hypertension, SBP and DBP., Conclusion: Our results suggest that the IgG glycome changes prior to the development of hypertension., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hypertension is a significant risk factor for cardiovascular disease and mortality worldwide. The kidney is a major regulator of blood pressure and electrolyte homeostasis, with monogenic disorders indicating a link between abnormal ion transport and salt-sensitive hypertension. However, the association between salt and hypertension remains controversial. Thus, there is continued interest in deciphering the molecular mechanisms behind these processes. Uromodulin (UMOD) is the most abundant protein in the normal urine and is primarily synthesized by the thick ascending limb epithelial cells of the kidney. Genome-wide association studies have linked common UMOD variants with kidney function, susceptibility to chronic kidney disease and hypertension independent of renal excretory function. This review will discuss and provide predictions on the role of the UMOD protein in renal ion transport and hypertension based on current observational, biochemical, genetic, pharmacological and clinical evidence., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cardiovascular disease remains the primary cause of mortality globally, being responsible for an estimated 17 million deaths every year. Cancer is the second leading cause of death on a global level with roughly 9 million deaths per year being attributed to neoplasms. The two share multiple common risk factors such as obesity, poor physical exercise, older age, smoking and there exists rare monogenic hypertension syndromes. Hypertension is the most important risk factor for cardiovascular disease and affects more than a billion people worldwide and may also be a risk factor for the development of certain types of cancer (e.g. renal cell carcinoma (RCC)). The interaction space of the two conditions becomes more complicated when the well-described hypertensive effect of certain antineoplastic drugs is considered along with the extensive amount of literature on the association of different classes of antihypertensive drugs with cancer risk/prevention. The cardiovascular risks associated with antineoplastic treatment calls for efficient management of relative adverse events and the development of practical strategies for efficient decision-making in the clinic. Pharmacogenetic interactions between cancer treatment and hypertension-related genes is not to be ruled out, but the evidence is not still ample to be incorporated in clinical practice. Precision Medicine has the potential to bridge the gap of knowledge regarding the full spectrum of interactions between cancer and hypertension (and cardiovascular disease) and provide novel solutions through the emerging field of cardio-oncology. In this review, we aimed to examine the bidirectional associations between cancer and hypertension including pharmacotherapy., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Left ventricular hypertrophy (LVH) is a well-known target organ damage. Concentric hypertrophy is the strongest predictor of increased risk of cardiovascular events, but the predictive value of individual echocardiographic parameters remains unclear.The aim of this study was to search for echocardiographic and hemodynamic variables associated with concentric and eccentric remodeling and their association with long-term cardiovascular outcomes., Methods: Patients with echocardiography performed within 1 year prior to the initial clinic visit were included into the study. Logistic regression and multivariable Cox-proportional hazards were calculated according to several risk factors and variables. Additionally, cubic spline interpolation was used., Results: We observed 690 patients for 10 years. There was a total of 177 major adverse cardiac and cerebrovascular events (MACCE) and 90 deaths over a 10-year period. Left ventricular concentric hypertrophy is associated with worse outcomes than eccentric hypertrophy in hypertensive subjects. Interestingly, different echocardiographic parameters contributed to risk depending on type of hypertrophy. In concentric hypertrophy, relative wall thickness provides linear prediction of risk for all-cause mortality (ACM) and composite endpoint. Systolic blood pressure is a significant predictor of MACCE. Blood pressure variability also showed significant predictive value for MACCE and ACM., Conclusions: These data indicate risk stratification based on LVH need to consider different measures based on the type of remodeling., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Hypertension remains the largest modifiable cause of mortality worldwide despite the availability of effective medications and sustained research efforts over the past 100 years. Hypertension requires transformative solutions that can help reduce the global burden of the disease. Artificial intelligence and machine learning, which have made a substantial impact on our everyday lives over the last decade may be the route to this transformation. However, artificial intelligence in health care is still in its nascent stages and realizing its potential requires numerous challenges to be overcome. In this review, we provide a clinician-centric perspective on artificial intelligence and machine learning as applied to medicine and hypertension. We focus on the main roadblocks impeding implementation of this technology in clinical care and describe efforts driving potential solutions. At the juncture, there is a critical requirement for clinical and scientific expertise to work in tandem with algorithmic innovation followed by rigorous validation and scrutiny to realize the promise of artificial intelligence-enabled health care for hypertension and other chronic diseases.

The known genetic architecture of blood pressure now comprises >30 genes, with rare variants resulting in monogenic forms of hypertension or hypotension and >1,477 common single-nucleotide polymorphisms (SNPs) being associated with the blood pressure phenotype. Monogenic blood pressure syndromes predominantly involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, with a smaller fraction caused by neuroendocrine tumours of the sympathetic and parasympathetic nervous systems. The SNPs identified in genome-wide association studies (GWAS) as being associated with the blood pressure phenotype explain only approximately 27% of the 30-50% estimated heritability of blood pressure, and the effect of each SNP on the blood pressure phenotype is small. A paucity of SNPs from GWAS are mapped to known genes causing monogenic blood pressure syndromes. For example, a GWAS signal mapped to the gene encoding uromodulin has been shown to affect blood pressure by influencing sodium homeostasis, and the effects of another GWAS signal were mediated by endothelin. However, the majority of blood pressure-associated SNPs show pleiotropic associations. Unravelling these associations can potentially help us to understand the underlying biological pathways. In this Review, we appraise the current knowledge of blood pressure genomics, explore the causal pathways for hypertension identified in Mendelian randomization studies and highlight the opportunities for drug repurposing and pharmacogenomics for the treatment of hypertension.

Background: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy., Methods: The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160)., Results: The study should conclude August 2021., Conclusions: If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension., Clinical Trials Registration: https://clinicaltrials.gov/ct2/show/NCT03354897., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10 -8 ), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Purpose: To investigate the blood pressure (BP)-lowering effects of statins by conducting a systematic review and meta-analysis of placebo-randomized controlled trials (RCTs)., Method: We conducted a meta-analysis of placebo RCTs reporting antihypertensive effects of statins therapy. We only included RCTs that did not allow for concomitant antihypertensive therapy, or clearly stated that antihypertensive therapy was fixed throughout the study period., Results: Our meta-analysis included 46 placebo RCTs, including 53 group comparisons and a total of 49,087 participants (24,589 participants in the statin groups and 24,498 participants in the placebo group). Subgroup analysis, based on use of concomitant antihypertensive, was performed. The meta-analysis showed that statin reduced systolic BP by - 1.6 mmHg (95% CI: - 2.50 to - 0.60), and diastolic BP by - 0.96 mmHg (95% CI: - 1.36 to - 0.56). Although the presence of concomitant antihypertensive therapy diluted the BP lowering effect of statins, it remained statistically significant and independent of the lipid-lowering activity. Furthermore, the BP -lowering effect of the statins was independent of the dose or type of statin (p > 0.05)., Conclusion: Our results strengthen the evidence for pleiotropic effects of statins on BP that are independent of their lipid-lowering activity, supporting their beneficial role in hypertensive patients with dyslipidemia.

The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Concerns exist regarding the potential increased cardiovascular risk from lowering diastolic blood pressure (DBP) in hypertensive patients. We analyzed 30-year follow-up data of 10 355 hypertensive patients attending the Glasgow Blood Pressure Clinic. The association between blood pressure during the first 5 years of treatment and cause-specific hospital admissions or mortality was analyzed using multivariable adjusted Cox proportional hazard models. The primary outcome was a composite of cardiovascular admissions and deaths. DBP showed a U-shaped association (nadir, 92 mm Hg) for the primary cardiovascular outcome hazard and a reverse J-shaped association with all-cause mortality (nadir, 86 mm Hg) and noncardiovascular mortality (nadir, 92 mm Hg). The hazard ratio for the primary cardiovascular outcome after adjustment for systolic blood pressure was 1.38 (95% CI, 1.18-1.62) for DBP <80 compared with DBP of 80 to 89.9 mm Hg (referrant), and the subdistribution hazard ratio after accounting for competing risk was 1.33 (1.17-1.51) compared with DBP ≥80 mm Hg. Cause-specific nonfatal outcome analyses showed a reverse J-shaped relationship for myocardial infarction, ischemic heart disease, and heart failure admissions but a U-shaped relationship for stroke admissions. Age-stratified analyses showed DBP had no independent effect on stroke admissions among the older patient subgroup (≥60 years of age), but the younger subgroup showed a clear U-shaped relationship. Intensive blood pressure reduction may lead to unintended consequences of higher healthcare utilization because of increased cardiovascular morbidity, and this merits future prospective studies. Low on-treatment DBP is associated with increased risk of noncardiovascular mortality, the reasons for which are unclear.

Objectives: To assess whether a history of major depressive disorder (MDD) in middle-aged individuals with hypertension influences first-onset cardiovascular disease outcomes., Design: Prospective cohort survival analysis using Cox proportional hazards regression with a median follow-up of 63 months (702 902 person-years). Four mutually exclusive groups were compared: hypertension only (n=56 035), MDD only (n=15 098), comorbid hypertension plus MDD (n=12 929) and an unaffected (no hypertension, no MDD) comparison group (n=50 798)., Setting: UK Biobank., Participants: UK Biobank participants without cardiovascular disease aged 39-70 who completed psychiatric questions relating International Classification of Diseases-10 Revision (ICD-10) diagnostic criteria on a touchscreen questionnaire at baseline interview in 2006-2010 (n=134 860)., Primary and Secondary Outcome Measures: First-onset adverse cardiovascular outcomes leading to hospital admission or death (ICD-10 codes I20-I259, I60-69 and G45-G46), adjusted in a stepwise manner for sociodemographic, health and lifestyle features. Secondary analyses were performed looking specifically at stroke outcomes (ICD-10 codes I60-69 and G45-G46) and in gender-separated models., Results: Relative to controls, adjusted HRs for adverse cardiovascular outcomes were increased for the hypertension only group (HR 1.36, 95% CI 1.22 to 1.52) and were higher still for the comorbid hypertension plus MDD group (HR 1.66, 95% CI 1.45 to 1.9). HRs for the comorbid hypertension plus MDD group were significantly raised compared with hypertension alone (HR 1.22, 95% CI 1.1 to 1.35). Interaction measured using relative excess risk due to interaction (RERI) and likelihood ratios (LRs) were identified at baseline (RERI 0.563, 95% CI 0.189 to 0.938; LR p=0.0116) but not maintained during the follow-up., Limitations: Possible selection bias in UK Biobank and inability to assess for levels of medication adherence., Conclusions: Comorbid hypertension and MDD conferred greater hazard than hypertension alone for adverse cardiovascular outcomes, although evidence of interaction between hypertension and MDD was inconsistent over time. Future cardiovascular risk prediction tools may benefit from the inclusion of questions about prior history of depressive disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

Risk factors for hypertension consist of lifestyle and genetic factors. Family history and twin studies have yielded heritability estimates of BP in the range of 34-67%. The most recent paper of BP GWAS has explained about 20% of the population variation of BP. An overestimation of heritability may have occurred in twin studies due to violations of shared environment assumptions, poor phenotyping practices in control cohorts, failure to account for epistasis, gene-gene and gene-environment interactions, and other non-genetic sources of phenotype modulation that are suspected to lead to underestimations of heritability in GWAS. The recommendations of hypertension guidelines in major countries consist of the following elements: weight reduction, a healthy diet, dietary sodium reduction, increasing physical activity, quitting smoking, and moderate alcohol consumption. The hypertension guidelines are mostly the same for each country or region, beyond race and culture. In this review, we summarize gene-environmental interactions associated with hypertension by describing lifestyle modifications according to the hypertension guidelines. In the era of precision medicine, clinicians who are responsible for hypertension management should consider the gene-environment interactions along with the appropriate lifestyle components toward the prevention and treatment of hypertension. We briefly reviewed the interaction of genetic and environmental factors along the constituent elements of hypertension guidelines, but a sufficient amount of evidence has not yet accumulated, and the results of genetic factors often differed in each study.

Background: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a "black versus white" approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia., Study Design: The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure., Conclusion: AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. OHF is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Terho Lehtimäki (TL) is employed by Fimlab Ltd. Ozren Polašek (OP) is employed by Gen‐info Ltd. There are no patents, products in development, or marked products to declare. All the other authors have declared no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Purpose of Review: Hypertension is recognised as the biggest contributor to the global burden of disease, but it is controlled in less than a fifth of patients worldwide, despite being relatively easy to detect and the availability of inexpensive safe generic drugs. Blood pressure is regulated by a complex network of physiologic pathways with currently available drugs targeting key receptors or enzymes in the top pathways. Major advances in the dissection of both monogenic and polygenic determinants of blood pressure regulation and variation have not resulted in rapid translation of these discoveries into clinical applications or precision medicine., Recent Findings: Uromodulin is an example of a novel gene for hypertension identified from genome-wide association studies, currently the basis of a clinical trial to reposition loop diuretics in hypertension management. Gene-editing studies have established a genome-wide association studies (GWAS) SNP in chromosome 6p24, implicated in six conditions including hypertension, as a distal regulator of the endothelin-1 gene around 3000 base pairs away. Genomics of aldosterone-producing adenomas bring to focus the paradox in genomic medicine where availability of cheap generic drugs may render precision medicine uneconomical. The speed of technology-driven genomic discoveries and the sluggish traditional pathways of drug development and translation need harmonisation to make a timely and early impact on global public health. This requires a directed collaborative effort for which we propose a hypertension moonshot to make a quantum leap in hypertension management and cardiovascular risk reduction by bringing together traditional bioscience, omics, engineering, digital technology and data science.

Background: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension., Methods: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081., Findings: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r 2 =0·13, p<0·0001) and plasma renin (r 2 =0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001)., Interpretation: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension., Funding: British Heart Foundation and UK National Institute for Health Research., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches., Methods and Results: We performed a 1-year, double-blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg or hydrochlorothiazide 12.5-25 mg crossing over at 8 weeks), or initial combination (losartan 50-100 mg plus hydrochlorothiazide 12.5-25 mg). In phase 2 (weeks 17-32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33-52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7-6.0 mm Hg) less over 32 weeks ( P <0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: -0.4 to 2.8 mm Hg], P =0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events., Conclusions: Initial combination therapy can be recommended for patients with BP >150/95 mm Hg., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach., (Copyright © 2017 the American Physiological Society.)

A complex network of interacting pathways involving renal, neural, endocrine, vascular and other mechanisms controls the main determinants of blood pressure - cardiac output and total peripheral resistance. Multiple genes within each of these systems contribute to the specialized functions regulating blood pressure. The monogenic forms of blood pressure dysregulation have provided valuable insights into blood pressure regulation and expanded our understanding of both the mechanisms and the treatment of hypertension. Genome wide association studies have identified over 100 single nucleotide polymorphisms associated with blood pressure phenotypes and have identified plausible novel pathways of BP regulation and putative drug targets., (Copyright © 2017. Published by Elsevier Ltd.)

The dicarboxylic acid hexadecanedioate is associated with increased blood pressure (BP) and mortality in humans and feeding it to rats raises BP. Here we aim to characterise the molecular pathways that influence levels of hexadecanedioate linked to BP regulation, using genetic and transcriptomic studies. The top associations for hexadecanedioate in a genome-wide association scan (GWAS) conducted on 6447 individuals from the TwinsUK and KORA cohorts were tested for association with BP and hypertension in the International Consortium for BP and in a GWAS of BP extremes. Transcriptomic analyses correlating hexadecanedioate with gene expression levels in adipose tissue in 740 TwinsUK participants were further performed. GWAS showed 242 SNPs mapping to two independent loci achieving genome-wide significance. In rs414056 in the SCLO1B1 gene (Beta(SE) = -0.088(0.006)P = 1.65 x 10-51, P < 1 x 10-51), the allele previously associated with increased risk of statin associated myopathy is associated with higher hexadecanedioate levels. However this SNP did not show association with BP or hypertension. The top SNP in the second locus rs6663731 mapped to the intronic region of CYP4Z2P on chromosome 1 (0.045(0.007), P = 5.49x10-11). Hexadecanedioate levels also correlate with adipose tissue gene-expression of the 3 out of 4 CYP4 probes (P<0.05) and of alcohol dehydrogenase probes (Beta(SE) = 0.12(0.02); P = 6.04x10-11). High circulating levels of hexadecanedioate determine a significant effect of alcohol intake on BP (SBP: 1.12(0.34), P = 0.001; DBP: 0.70(0.22), P = 0.002), while no effect is seen in the lower hexadecanedioate level group. In conclusion, levels in fat of ADH1A, ADH1B and CYP4 encoding enzymes in the omega oxidation pathway, are correlated with hexadecanedioate levels. Hexadecanedioate appears to regulate the effect of alcohol on BP.

Functional genomics requires an understanding of the complete network of changes within an organism by extensive measurements of moieties from mRNA, proteins, and metabolites. Metabolomics utilizes analytic chemistry tools to profile the complete spectrum of metabolites found in a tissue, cells, or biofluids using a wide range of tools from infrared spectroscopy, fluorescence spectroscopy, NMR spectroscopy, and mass spectrometry. In this protocol, we outline a procedure for performing metabolomic analysis of urine samples using liquid chromatography-mass spectrometry (LC-MS). We outline the advantages of using this approach and summarize some of the early promising studies in cardiovascular diseases using this approach.

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10 - 8 ) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10 -5 ) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10 - 4 ). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment., Competing Interests: Conflicts of interest/Disclosures None., (© 2016 American Heart Association, Inc.)

Major depressive and bipolar disorders predispose to atherosclerosis, and there is accruing data from animal model, epidemiological, and genomic studies that commonly used antihypertensive drugs may have a role in the pathogenesis or course of mood disorders. In this study, we propose to determine whether antihypertensive drugs have an impact on mood disorders through the analysis of patients on monotherapy with different classes of antihypertensive drugs from a large hospital database of 525 046 patients with follow-up for 5 years. There were 144 066 eligible patients fulfilling the inclusion criteria: age 40 to 80 years old at time of antihypertensive prescription and medication exposure >90 days. The burden of comorbidity assessed by Charlson and Elixhauser scores showed an independent linear association with mood disorder diagnosis. The median time to hospital admission with mood disorder was 847 days for the 299 admissions (641 685 person-years of follow-up). Patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had the lowest risk for mood disorder admissions, and compared with this group, those on β-blockers (hazard ratio=2.11; [95% confidence interval, 1.12-3.98]; P=0.02) and calcium antagonists (2.28 [95% confidence interval, 1.13-4.58]; P=0.02) showed higher risk, whereas those on no antihypertensives (1.63 [95% confidence interval, 0.94-2.82]; P=0.08) and thiazide diuretics (1.56 [95% confidence interval, 0.65-3.73]; P=0.32) showed no significant difference. Overall, our exploratory findings suggest possible differential effects of antihypertensive medications on mood that merits further study: calcium antagonists and β-blockers may be associated with increased risk, whereas angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be associated with a decreased risk of mood disorders., Competing Interests: Conflicts of Interest: None declared, (© 2016 The Authors.)

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention., Competing Interests: Conflict of interests N. P. has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. S. K. has received Research Grant-Merck, Bayer, Aegerion; SAB-Catabasis, Regeneron Genetics Center, Merck, Celera; Equity-San Therapeutics, Catabasis; Consulting-Novartis, Aegerion, Bristol Myers-Squibb, Sanofi, AstraZeneca, Alnylam. P. Sever has received research awards from Pfizer Inc. A. Malarstig and M. Uria-Nickelsen are full time employees of Pfizer. D. Reily and M. Hoek are full time employees of Merck and co Inc. M.J. Caulfield is Chief Scientist for Genomics England a UK Government company. The authors declare no competing financial interest.

Albuminuria is associated with increased risk of cardiovascular disease and target organ damage in patients with diabetes mellitus. In nondiabetic hypertensive patients, the threshold at which microalbuminuria (MAU) increases risk is unclear and there is evidence that cardiovascular risk may be increased in individuals with MAU levels lower than the usual recommended screening thresholds. We compared two definitions of MAU (on the basis of three early morning urine samples) in a cohort of hypertensive patients attending two specialist clinics in Scotland: conventional (MAU(C)) albumin-to-creatinine ratio (ACR) >2.5-25 mg mmol(-1) in males or >3.5-25 mg mmol(-1) in females; and low-grade (MAU(L)) ACR 1.2-2.5 in males or 1.7-3.5 mg mmol(-1) in females. Of the 1059 subjects screened, 786 (74%) were nondiabetic, with estimated glomerular filtration rate ⩾30 ml min(-1) per 1.73 m(2) and without gross proteinuria (low-risk subset). The average age was 58±15 years, body mass index 30±6 kg m(-2) and 46% were males. The prevalence of MAU(C) was 11% and 9.5% in the overall and low-risk subset, respectively, whereas MAU(L) prevalence was 11.1% and 10% respectively. The prevalence of cardiovascular disease was higher (24%) with albuminuria (both MAU(C) and MAU(L)) compared with 14% among those without albuminuria. The use of MAU(L) doubled the number of hypertensive subjects with increased cardiovascular risk who can be targeted for more rigorous risk reduction strategies. Consideration should be given to reducing the current threshold for MAU.

Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These "favorable adiposity" alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m(2) [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic -0.859 mmHg [-1.099, -0.618]; P = 3E-12 and diastolic -0.394 mmHg [-0.534, -0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (-0.004 cm [95% CI -0.005, -0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: Hypertension and diabetes mellitus (DM) frequently cluster together and synergistically increase cardiovascular risk. Among those who develop DM during treatment for hypertension (new-onset diabetes, NOD), it is unclear whether NOD reflects a separate entity associated with increased risk or merely reflects accelerated presentation of DM., Methods and Results: We analysed data on 15 089 hypertensive patients attending the Glasgow Blood Pressure Clinic. The date at first hospital encounter either with diagnosis of diabetes or prescription of anti-hyperglycaemic medication were considered as the onset of diabetes. Cox proportional hazard models (including propensity score matching) were employed to study associations between diabetes status, early and late NOD (diagnosis <10 years or >10 years from first clinic visit) and cause-specific mortality. There were 2516 patients (16.7%) with DM, of whom 1862 (12.3%) had NOD [early NOD = 705 (4.6%); late NOD = 1157 (7.6%)]. The incidence rate of NOD was 8.2 per 1000 person-years. The total time at risk was 239 929 person-years [median survival: 28.1 years (inter-quartile range: 16.2-39.9)]. Compared with non-diabetic individuals, prevalent DM [hazard ratio (HR) = 1.8, 95% confidence interval (CI): 1.4-2.2] and time varying NOD status (HR: 1.09, 95% CI: 1.06-1.17) were associated with increased adjusted all-cause mortality. Early NOD (HR: 1.39, 95% CI: 1.2-1.6) was associated with increased in mortality risk, but not late NOD (HR: 0.92, 95% CI: 0.83-1.01). Results were consistent in the propensity score matched analyses., Conclusion: Although 1-in-8 hypertensive patients develop NOD, mortality is increased only in the 1-in-20 who develop early NOD. Further studies are warranted to determine if early identification of such individuals should provide an alert for intensification of therapeutic interventions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Allopurinol lowers blood pressure in adolescents and has other vasoprotective effects. Whether similar benefits occur in older individuals remains unclear. We hypothesized that allopurinol is associated with improved cardiovascular outcomes in older adults with hypertension. Data from the United Kingdom Clinical Research Practice Datalink were used. Multivariate Cox-proportional hazard models were applied to estimate hazard ratios for stroke and cardiac events (defined as myocardial infarction or acute coronary syndrome) associated with allopurinol use over a 10-year period in adults aged >65 years with hypertension. A propensity-matched design was used to reduce potential for confounding. Allopurinol exposure was a time-dependent variable and was defined as any exposure and then as high (≥300 mg daily) or low-dose exposure. A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were studied. Allopurinol use was associated with a significantly lower risk of both stroke (hazard ratio, 0.50; 95% confidence interval, 0.32-0.80) and cardiac events (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87) than nonexposed control patients. In exposed patients, high-dose treatment with allopurinol (n=1052) was associated with a significantly lower risk of both stroke (hazard ratio, 0.58; 95% confidence interval, 0.36-0.94) and cardiac events (hazard ratio, 0.65; 95% confidence interval, 0.46-0.93) than low-dose treatment (n=980). Allopurinol use is associated with lower rates of stroke and cardiac events in older adults with hypertension, particularly at higher doses. Prospective clinical trials are needed to evaluate whether allopurinol improves cardiovascular outcomes in adults with hypertension., (© 2016 American Heart Association, Inc.)

Background: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control., Methods: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12·5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete., Findings: Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0·55 mmol/L [95% CI -0·96 to -0·14]; p=0·0093) and in the combination group than in the hydrochlorothiazide group (-0·42 mmol/L [-0·84 to -0·004]; p=0·048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0·0068). Hyperkalaemia was reported in seven (4·8%) patients in the amiloride group and three (2·3%) patients in the combination group; the highest recorded potassium concentration was 5·8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups., Interpretation: The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic., Funding: British Heart Foundation and National Institute for Health Research., (Copyright © 2016 Brown et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood., Methods and Results: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day., Conclusions: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate., (© 2015 American Heart Association, Inc.)

Background: Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure., Methods: In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081., Findings: Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion., Interpretation: Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition., Funding: The British Heart Foundation and National Institute for Health Research., (Copyright © 2015 Williams et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)