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Diets low in seafood omega-3 polyunsaturated fatty acids (PUFAs) are very prevalent. Such diets have recently been ranked as the sixth most important dietary risk factor-1.5 million deaths and 33 million disability-adjusted life-years worldwide are attributable to this deficiency. Wild oily fish stocks are insufficient to feed the world's population, and levels of eicosapentaenoic acid and docosahexaenoic acid (DHA) in farmed fish have more than halved in the last 20 years. Here we report on a double-blinded, controlled trial, where 161 healthy normotensive adults were randomly allocated to eat at least three portions/week of omega-3-PUFA enriched (or control) chicken-meat, and to eat at least three omega-3-PUFA enriched (or control) eggs/week, for 6 months. We show that regular consumption of omega-3-PUFA enriched chicken-meat and eggs significantly increased the primary outcome, the red cell omega-3 index (mean difference [98.75% confidence interval] from the group that ate both control foods, 1.7% [0.7, 2.6]). Numbers of subjects with a very high-risk omega-3 index (index < 4%) were more than halved amongst the group that ate both enriched foods. Furthermore, eating the enriched foods resulted in clinically relevant reductions in diastolic blood pressure (- 3.1 mmHg [- 5.8, - 0.3]). We conclude that chicken-meat and eggs, naturally enriched with algae-sourced omega-3-PUFAs, may serve as alternative dietary sources of these essential micronutrients. Unlike many lifestyle interventions, long-term population health benefits do not depend on willingness of individuals to make long-lasting difficult dietary changes, but on the availability of a range of commonly eaten, relatively inexpensive, omega-3-PUFA enriched foods.

Objective: The aim of this study was to determine the effect of polypill-based care on the achievement of 2016 European Society of Cardiology (ESC) guideline targets for blood pressure (BP), low-density lipoprotein (LDL) cholesterol and antiplatelet therapy., Methods: We conducted an individual participant data meta-analysis of three randomised clinical trials that compared a strategy using a polypill containing aspirin, statin and antihypertensive therapy with usual care in patients with a prior cardiovascular disease (CVD) event or who were at high risk of their first event. Overall, the trials included 3140 patients from Australia, England, India, Ireland, the Netherlands and New Zealand (75% male, mean age 62 years and 76% with a prior CVD event). The primary outcome for this study was the proportion of people achieving ESC guideline targets for BP, LDL and antiplatelet therapy., Results: Those randomised to polypill-based care were more likely than those receiving usual care to achieve recommended targets for BP (62% vs 58%, risk ratio (RR) 1.08, 95% CI 1.02 to 1.15), LDL (39% vs 34%, RR 1.13, 95% CI 1.02 to 1.25) and all three targets for BP, LDL and adherence to antiplatelet therapy (the latter only applicable to those with a prior CVD event) simultaneously (24% vs 19%, RR 1.27, 95% CI 1.10 to 1.47) at 12 months. There was no difference between groups in antiplatelet adherence (96% vs 96%, RR 1.00, 95% CI 0.98 to 1.01). There was heterogeneity by baseline treatment intensity such that treatment effects increased with the fewer the number of treatments being taken at baseline: for patients taking 3, 2 and 0-1 treatment modalities the RRs for reaching all three guideline goals simultaneously were 1.10 (95% CI 0.94 to 1.30, 22% vs 20%), 1.62 (95% CI 1.09 to 2.42, 27% vs 17%) and 3.07 (95% CI 1.77 to 5.33, 35% vs 11%), respectively., Conclusions: Polypill-based therapy significantly improved the achievement of all three ESC targets for BP, LDL and antiplatelet therapy compared with usual care, particularly among those undertreated at baseline., Competing Interests: Competing interests: Support for the submitted work: RW is funded by an NHMRC early career fellowship. The authors have received grants from several research charities and national funding agencies for research on cardiovascular polypills, and from Dr Reddy’s Laboratories for coordination of the SPACE programme (www.spacecollaboration.org). The polypills used in the SPACE trials were manufactured and supplied by Dr Reddy’s Laboratories free of charge. Some authors received funding from Dr Reddy’s Laboratories to attend investigator meetings related to the polypill (VS, RW, AP, ST, NR, AW and AR). George Health Enterprises, the social enterprise arm of The George Institute for Global Health (employer of some coauthors) has received investment for the development of fixed dose combination therapy containing statin, aspirin and blood pressure lowering medications., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

Creation of a central iliac arteriovenous anastomosis using a novel nitinol coupler device results in an immediate, significant reduction of blood pressure (BP). We present efficacy and safety findings at 12 months post-coupler insertion. This open-label, multicenter, prospective, randomized trial enrolled patients with a baseline office systolic BP ≥140 mm Hg and average daytime ambulatory BP ≥135/85 mm Hg. Subjects were randomly allocated to coupler implantation and continuing previous pharmacotherapy or to maintain previous treatment alone. At 12 months, 39 patients who had coupler therapy were included in the intention-to-treat analysis. Office-based systolic BP reduced by 25.1±23.3 mm Hg (baseline, 174±18 mm Hg; P <0.0001) post-coupler placement, and office diastolic BP reduced by 20.8±13.3 mm Hg (baseline, 100±13 mm Hg; P <0.0001). Mean 24-hour ambulatory BP reduced by 12.6±17.4/15.3±9.7 mm Hg ( P <0.0001 for both). In a prespecified subset of patients who failed to respond adequately to prior renal denervation, coupler therapy led to highly significant reduction in office systolic/diastolic BP (30.7/24.1 mm Hg) and significant reduction in 24-hour ambulatory systolic/diastolic BP (12.4/14.4 mm Hg) at 12 months (n=9). After coupler therapy, 14 patients (33%) developed ipsilateral venous stenosis; all were treated successfully with venous stenting. These findings confirm the importance of arterial mechanics in the pathophysiology of hypertension and support the clinical use of a central iliac arteriovenous anastomosis., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498., (© 2017 American Heart Association, Inc.)

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

Background: Options for interventional therapy to lower blood pressure (BP) in patients with treatment-resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH., Methods and Results: The randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment-resistant hypertension (office systolic BP ≥140 mm Hg, average daytime ambulatory BP ≥135/85 mm Hg, and treatment with ≥3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177±18 mm Hg versus 169±17 mm Hg, P=0.163) and 24-hour ambulatory systolic BP (159±16 mm Hg versus 154±11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: -29±21 mm Hg versus ISH: -22±31 mm Hg, P=0.445) and 24-hour ambulatory systolic BP (CH: -14±20 mm Hg versus ISH: -13±15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction ≥10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932)., Conclusions: Our data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24-hour ambulatory systolic BP in patients with combined and isolated systolic hypertension., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

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.

Objective: Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors., Design: An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde)., Methods: Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling., Results: There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04)., Conclusion: Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group., (© 2016 European Society of Endocrinology.)

Background: Blood pressure (BP) is highly heritable, but our understanding of the genetic causes underlying variations in BP is incomplete. In this study, we explored whether novel loci associated with BP could be identified using a genecentric approach in 3 community-based cohorts with accurate BP measurements., Methods and Results: Genotyping of 1857 single nucleotide polymorphisms (SNPs) in 91 ion channel genes was performed in a discovery cohort (n=358). Thirty-four SNPs associated with BP traits (P≤0.01) were followed up in an independent population (n=387); significant SNPs from this analysis were looked up in another independent population (n=1010) and meta-analyzed. Repeated clinic and ambulatory measurements were available for all but the discovery cohort (clinic only). Association analyses were performed, with systolic, diastolic, and pulse pressures as quantitative traits, adjusting for age and sex. Quantile-quantile plots indicated that the genecentric approach resulted in an inflation of association signals. Of the 29 SNPs taken forward from the discovery cohort, 2 SNPs were associated with BP phenotypes with the same direction of effect, with experiment-wide significance, in follow-up cohort I. These were rs2228291, in the chloride channel gene CLCN2, and rs10513488, in the potassium channel gene KCNAB1. Both associations were subsequently replicated in follow-up cohort II., Conclusions: Using a genecentric design and 3 well-phenotyped populations, this study identified 2 previously unreported, biologically plausible, genetic associations with BP. These results suggest that dense genotyping of genes, in pathways known to influence BP, could add to candidate-gene and Genome Wide Association studies in further explaining BP heritability., (© 2014 American Heart Association, Inc.)

Excess blood pressure remains the most important risk factor for cardiovascular and renal disease. Poly pharmacy has been proved safe and effective under clinical trial circumstances; however, the majority of patients fail to sustain pharmaceutical persistence and adherence. The opportunity to offer patients a treatment or device in addition or perhaps instead of drug therapy alone may significantly broaden the options for patients and allow greater success in hypertensive therapy. In this review, we examine the potential of a fixed-volume central arterial-venous anastomosis to reduce blood pressure in hypertensive patients, review possible mechanisms by which the anastomosis may reduce blood pressure, and consider the unique clinical trial opportunities posed by this therapy.

Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial., (© 2014 American Heart Association, Inc.)

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke., Methods: A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings., Results: The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18)., Conclusions: We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

Dietary salt intake is associated with high brachial blood pressure (BP) and increased risk of cardiovascular disease. We investigated whether changes in dietary salt intake are associated with changes in central BP and wave reflection in healthy volunteers. Ten healthy normotensive male volunteers (22-40 yr) participated in a 6-wk double-blind randomized crossover study to compare a low-dietary salt intake (60-80 mmol sodium/day) with a high-salt intake (low salt intake supplemented with 128 mmol sodium/day) on central BP and wave reflection. Brachial and carotid BP, carotid blood flow velocity, forward (P(f)) and backward (P(b)) pressure, wave intensity, body weight, and urinary electrolyte excretion were measured at the end of each crossover period. High salt intake significantly increased carotid systolic BP [98 (SD 11) vs. 91 mmHg (SD 13), P < 0.01] and increased wave reflection [ratio of backward to forward pressure (P(b)/P(f)) 0.13 (SD 0.02) vs. 0.11 (SD 0.03), P = 0.04] despite only small effects on brachial BP [114 (SD 9) vs. 112 mmHg (SD 6), P = 0.1]. Urinary sodium excretion and body weight were also increased following high salt intake. High salt intake disproportionately increases central BP compared with brachial BP as a result of enhanced wave reflection. These effects may contribute to the adverse effect of high dietary salt intake on the risk of cardiovascular disease.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk., Competing Interests: The authors have declared that no competing interests exist.

Background: Studies of knockout and transgenic mice have demonstrated key roles for genes encoding components of the renin angiotensin system in blood pressure regulation. However, whether polymorphisms in these genes contribute to the cause of essential hypertension in humans is still a matter of debate., Methods and Results: We performed an experiment with dense tagging single-nucleotide polymorphism coverage of 4 genes encoding proteins that control the overall activity of the cascade, namely renin, angiotensinogen, angiotensin-converting enzyme, and angiotensin-converting enzyme 2, in 2 Irish populations. Both clinic and 24-hour ambulatory blood pressure measurements were available from population I (n=387), whereas just clinic blood pressure was measured in population II (n=1024). Of the 23 polymorphisms genotyped, only a single renin gene polymorphism, REN-5312C/T, showed consistent statistically significant associations with elevated diastolic pressures. Carriage of one REN-5312T allele was associated with the following age- and sex-adjusted increments in diastolic pressures (mean [95% CI]): population I, clinic, 1.5 mm Hg (0.3 to 2.8); daytime, 1.4 mm Hg (0.4 to 2.4); night-time, 1.3 mm Hg (0.4 to 2.3), and population II, clinic, 1.1 mm Hg (0.1 to 2.1). Haplotypic analyses and multivariate stepwise regression analyses were in concordance with individual single-nucleotide polymorphism analyses., Conclusions: The REN-5312T allele had been shown previously to result in increased in vitro expression of the renin gene. We have now shown, in 2 independent populations, that carriage of a REN-5312T allele is associated with elevated diastolic blood pressure. These data provide evidence that renin is an important susceptibility gene for arterial hypertension in whites.

Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after > or =4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.

Hypertensive patients with low-baseline plasma renin activity (PRA) are known to respond best to natriuretic drugs, and those with high PRA respond best to renin-angiotensin system (RAS) blockade. However, there has been recent speculation that blood pressure (BP)-lowering responses to the renin inhibitor, aliskiren, might also be blunted in some patients with medium-to-high baseline PRA. It has been suggested that treatment resistance in these patients may result from excessive reactive increases in renin secretion, such that aliskiren's blockade of PRA is overwhelmed. In order to test for evidence in support of this hypothesis, we conducted a reanalysis of original data from three published clinical trials of aliskiren. When aliskiren was administered as a monotherapy, or in combination with other blockers of the RAS, changes in PRA were closely correlated with baseline PRA. Patients with low-baseline PRA demonstrated small reductions or rises in PRA, rather than patients with medium-to-high baseline PRA. We confirmed that ambulatory BP-lowering responses to full dose aliskiren monotherapy were greatest and least among patients with high- and low-baseline PRA, respectively. However no such association was demonstrated during aliskiren combination therapy. With either monotherapy or combination therapy, no patient with a baseline PRA >0.65 ng/ml/h was observed to have a rise in both PRA and BP. We conclude, therefore, that there is only evidence for one type of resistance to aliskiren--as with all blockers of the RAS, lesser BP-lowering responses to aliskiren occur in those with the least renin to block.

Background: Statins reduce the risk of cardiovascular events in people with hypertension. This benefit could arise from a beneficial effect of statins on central aortic pressures and hemodynamics. The Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA) study, an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy, investigated this hypothesis in a prospective placebo-controlled study of treated patients with hypertension., Methods and Results: CAFE-LLA recruited 891 patients randomized to atorvastatin 10 mg/d or placebo from 5 centers in the United Kingdom and Ireland. Radial artery applanation tonometry and pulse-wave analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits over 3.5 years of follow-up. Atorvastatin lowered low-density lipoprotein cholesterol by 32.4 mg/dL (95% confidence interval [CI], 28.6 to 36.3) and total cholesterol by 35.1 mg/dL (95% confidence interval, 30.9 to 39.4) relative to placebo. Time-averaged brachial blood pressure was similar in CAFE-LLA patients randomized to atorvastatin or placebo (change in brachial systolic blood pressure, -0.1 mm Hg [95% CI, -1.8 to 1.6], P=0.9; change in brachial pulse pressure, -0.02 mm Hg [95% CI, -1.6 to 1.6], P=0.9). Atorvastatin did not influence central aortic pressures (change in aortic systolic blood pressure, -0.5 mm Hg [95% CI, -2.3 to 1.2], P=0.5; change in aortic pulse pressure, -0.4 mm Hg [95% CI, -1.9 to 1.0], P=0.6) and had no influence on augmentation index (change in augmentation index, -0.4%; 95% CI, -1.7 to 0.8; P=0.5) or heart rate (change in heart rate, 0.25 bpm; 95% CI, -1.3 to 1.8; P=0.7) compared with placebo. The effect of statin or placebo therapy was not modified by the blood pressure-lowering treatment strategy in the factorial design., Conclusions: Statin therapy sufficient to significantly reduce cardiovascular events in treated hypertensive patients in ASCOT did not influence central aortic blood pressure or hemodynamics in a large representative cohort of ASCOT patients in CAFE-LLA.

Objectives: Increased arterial stiffness is associated with the development of cardiovascular disease and may even predict its development at an early stage. Increased pulse pressure is seen as a marker of increased arterial stiffness and can be readily measured by ambulatory blood pressure monitoring. We propose another surrogate measure of arterial stiffness derived from ambulatory blood pressure monitoring that may predict cardiovascular mortality over and above pulse pressure, namely, the dynamic relationship between diastolic and systolic blood pressure over 24 h--the ambulatory arterial stiffness index., Methods: Using all blood pressure readings over the 24-h period from 11 291 (5965 women; mean age 54.6 years) patients referred for ambulatory blood pressure monitoring to a blood pressure clinic, diastolic blood pressure was plotted against systolic blood pressure, and the regression slope was calculated; ambulatory arterial stiffness index was defined as one minus this regression slope., Results: Both ambulatory arterial stiffness index and pulse pressure were higher in women (0.42 vs. 0.40 and 57.0 vs. 55.3 mmHg, respectively). For the entire group, the correlation between ambulatory arterial stiffness index and pulse pressure was 0.5., Conclusions: Ambulatory arterial stiffness index is a new measure that is readily available from ambulatory blood pressure monitoring and may provide added prognostic information for cardiovascular outcome.

Objectives: We hypothesized that one minus the slope of diastolic on systolic blood pressure in individual 24-h ambulatory blood pressure recordings (ambulatory arterial stiffness index) might reflect arterial stiffness and predict cardiovascular mortality., Methods: In volunteers and a population recruited in China, we studied concordance between ambulatory arterial stiffness index and established indexes of arterial stiffness. We assessed the predictive value of ambulatory arterial stiffness index in relation to cardiovascular outcome in Irish hypertensive patients., Results: In 166 healthy volunteers, aged 22-83 years, the correlation coefficient between ambulatory arterial stiffness index and pulse wave velocity was 0.51 (P<0.001). In 348 randomly recruited Chinese, the correlations between ambulatory arterial stiffness index and both the central and peripheral systolic augmentation indexes were significantly stronger than those for 24-h ambulatory pulse pressure, particularly in study participants younger than 40 years. Among normotensive participants, the 95th percentile of the ambulatory arterial stiffness index was 0.55 in 234 Chinese and 0.57 in 1617 Europeans enrolled in the International Database on Ambulatory Blood Pressure Monitoring. The upper boundary of the 95% prediction interval of the ambulatory arterial stiffness index in relation to age ranged from 0.53 at 20 years to 0.72 at 80 years. In 11 291 patients enrolled in the Dublin Outcome Study, both ambulatory arterial stiffness index and 24-h ambulatory pulse pressure significantly predicted cardiovascular mortality. Ambulatory arterial stiffness index was a strong predictor of fatal stroke in normotensive participants, whereas pulse pressure better predicted heart attack in hypertensive patients., Conclusion: Ambulatory arterial stiffness index is a novel measure of arterial stiffness, which can be readily determined from ambulatory blood pressure recordings and which independently predicts cardiovascular mortality.

Background: Different blood pressure (BP)-lowering drugs could have different effects on central aortic pressures and thus cardiovascular outcome despite similar effects on brachial BP. The Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of 2 different BP lowering-regimens (atenolol+/-thiazide-based versus amlodipine+/-perindopril-based therapy) on derived central aortic pressures and hemodynamics., Methods and Results: The CAFE study recruited 2199 patients in 5 ASCOT centers. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and hemodynamic indexes on repeated visits for up to 4 years. Most patients received combination therapy throughout the study. Despite similar brachial systolic BPs between treatment groups (Delta0.7 mm Hg; 95% CI, -0.4 to 1.7; P=0.2), there were substantial reductions in central aortic pressures with the amlodipine regimen (central aortic systolic BP, Delta4.3 mm Hg; 95% CI, 3.3 to 5.4; P<0.0001; central aortic pulse pressure, Delta3.0 mm Hg; 95% CI, 2.1 to 3.9; P<0.0001). Cox proportional-hazards modeling showed that central pulse pressure was significantly associated with a post hoc-defined composite outcome of total cardiovascular events/procedures and development of renal impairment in the CAFE cohort (unadjusted, P<0.0001; adjusted for baseline variables, P<0.05)., Conclusions: BP-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics despite a similar impact on brachial BP. Moreover, central aortic pulse pressure may be a determinant of clinical outcomes, and differences in central aortic pressures may be a potential mechanism to explain the different clinical outcomes between the 2 BP treatment arms in ASCOT.

We hypothesized that 1 minus the slope of diastolic on systolic pressure during 24-hour ambulatory monitoring (ambulatory arterial stiffness index [AASI]) might reflect arterial stiffness. We compared AASI with established measures of arterial stiffness and studied its distribution in Chinese and European populations. We used 90207 SpaceLabs monitors and the SphygmoCor device to measure AASI, central and peripheral pulse pressures, the central (CAIx) and peripheral (PAIx) systolic augmentation indexes, and aortic pulse wave velocity. In 166 volunteers, the correlation coefficient between AASI and pulse wave velocity was 0.51 (P<0.0001). In 348 randomly recruited Chinese subjects, AASI correlated (P<0.0001) with CAIx (r=0.48), PAIx (r=0.50), and central pulse pressure (r=0.50). AASI increased with age and mean arterial pressure but decreased with body height. Both before and after adjustment for arterial wave reflections by considering height and heart rate as covariates, AASI correlated more (P<0.0001) closely with CAIx and PAIx than 24-hour pulse pressure. Among normotensive subjects, the 95th percentile of AASI was 0.55 in Chinese and 0.57 in 1617 Europeans enrolled in the International Database on Ambulatory Blood Pressure Monitoring. The upper boundary of the 95% prediction interval of AASI in relation to age ranged from 0.53 at 20 years to 0.72 at 80 years. In conclusion, AASI is a new index of arterial stiffness that can be easily measured under ambulatory conditions. Pending additional validation in outcome studies, normal values of AASI are probably <0.50 and 0.70 in young and older subjects, respectively.

We hypothesized that the dynamic relation between diastolic and systolic blood pressure over 24 hours provides a measure of arterial stiffness and might, therefore, predict cardiovascular mortality over and above pulse pressure. At baseline, while not on antihypertensive medication, 11 291 patients (mean age, 54.6 years; 5965 women) underwent ambulatory blood pressure monitoring. Using all of the blood pressure readings, we plotted diastolic against systolic blood pressure from each individual and calculated the regression slope. The ambulatory arterial stiffness index (AASI) was defined as 1 minus this regression slope. Over a median follow-up of 5.3 years, 566 cardiovascular deaths occurred, including 151 from stroke and 358 from cardiac disorders. Before and after adjustment for other cardiovascular risk factors, AASI and pulse pressure significantly predicted total cardiovascular mortality. AASI was a stronger predictor than pulse pressure for stroke (mutually adjusted relative hazard ratios for 1 SD increase, 1.21 versus 1.04; P=0.02 versus 0.66) with the opposite trend for cardiac mortality (relative hazard ratios, 1.03 versus 1.21; P=0.63 versus 0.002). In subjects with normal daytime ambulatory blood pressure (<135/<85 mm Hg), AASI was more predictive than pulse pressure of cardiovascular mortality (1.26 versus 0.96; P=0.04 versus 0.70) and of stroke mortality (1.81 versus 1.12; P=0.007 versus 0.58), whereas neither independently predicted cardiac mortality (1.11 versus 0.89; P=0.47 versus 0.40). AASI is a novel measure of arterial stiffness, which can be readily determined from ambulatory blood pressure recordings and which independently predicts cardiovascular mortality, even in normotensive subjects.

The article discusses the research that explores that novel loci connected with blood pressure (BP) could be identified using genecentric approach in community-based cohorts with acute measurements of BP. It states that the genotyping of 1857 single nucleotide polymorphism in 91 ion channel genes was performed. It mentions the identification of two unreported biologically plausible and genetic associations with BP.

Renin catalyzes the rate-limiting step of the renin-angiotensin system. A T allele variant at position -5312 within a distal enhancer region has been reported to increase in vitro renin gene transcription. Among 387 White bank employees, ambulatory blood pressures were higher in 133 -5312T allele carriers than in 254 CC homozygotes-mean differences [99% confidence interval] between carriers and homozygotes for daytime and night-time systolic/diastolic pressure were 2.5[0.4,4.6]/1.7[0.2,3.2] and 2.4[0.5,4.4]/1.5[0.1,2.9] respectively. Ambulatory pressure estimates for the only common renin haplotype including the -5312T variant (-5312T, 5090C, 5912A, 9479A, 10194G), were statistically significantly higher than estimates for all other haplotypes. Among 259 White hypertensive participants in a randomized double-blind clinical trial comparing a renin antagonist, aliskiren, with an angiotensin receptor blocker, losartan, plasma renin activity did not differ with renin -5312C/T genotype. Nocturnal blood pressure reductions with losartan 100 mg daily were significantly greater in -5312T allele carriers than in CC homozygotes (mean[standard error]; -12.9[3.7]/-7.9[2.4] versus -7.1[2.5]/-4.2[1.6]) whereas with aliskiren 150 and 300 mg daily, lesser reductions were observed in -5312T allele carriers than in CC homozygotes (-5.4[2.0]/-4.1[1.3] versus -10.1[1.4]/-6.5[1.1]; P<0.03 for treatmentxgenotype interaction for night-time systolic and diastolic pressures). Hence, the -5312 renin C/T enhancer polymorphism does contribute to blood pressure variation in Whites and also appears to predict responses to inhibition of the renin-angiotensin system. These findings suggest that genotyping at this locus may aid in the identification of susceptibility to hypertension and in the selection of optimal therapy for individual hypertensive patients. [ABSTRACT FROM AUTHOR]

Since renin catalyses the first and rate-limiting step of the renin-angiotensin system (RAS) cascade, interruption of the generation of angiotensin II (Ang II) by renin inhibitors at this highly specific initial step of the cascade has long been a therapeutic goal. The early development of renin inhibitors was hampered by problems with bioavailability and high costs of synthesis. However, more recently a potent non-peptidic inhibitor of renin, aliskiren, with acceptable oral bioavailability, has been synthesised. Aliskiren effectively reduces Ang II levels in normal volunteers and has been shown to lower blood pressure (BP) in patients with mild-to-moderate hypertension.Renin inhibitors would be expected to have similar, but not identical effects to those of the established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of Ang II production may be more effective with renin inhibition than with angiotensin-converting enzyme (ACE) inhibition.Furthermore, because renin has high specificity for only one substrate, angiotensinogen, side-effects would be expected to be less frequent. It is currently unclear whether blockade of Ang II type 1 (AT1) receptors, leaving other Ang II receptors (AT2, AT3 and AT4) unblocked, is preferable to the reduction in plasma and tissue Ang II levels achieved with either ACE or renin inhibition.Pharmacological suppression of the RAS, through ACE inhibition, or blockade of AT1, β-adrenoceptor or mineralocorticoid receptors, has been proven to reduce morbidity and mortality in patients with hypertension, diabetes mellitus, atherosclerosis, heart failure and nephropathy. While, to date, aliskiren has only been shown to reduce BP, it appears likely that orally-active renin inhibitors could prove useful in the management of a wide range of cardiovascular pathologies. [ABSTRACT FROM PUBLISHER]

Aim: The use of fixed-dose combination (FDC) pills, frequently called polypills, containing aspirin, a statin and blood pressure (BP) lowering medication may improve medication adherence and consequently reduce cardiovascular risk. Carotid intima-media thickness (CIMT) and CIMT progression have been used as surrogate measures of cardiovascular risk. This study evaluated the effect of a polypill-based treatment strategy compared to usual care on CIMT progression. Methods: A study nested within the UMPIRE trial was performed to assess whether a polypill-based treatment strategy reduces CIMT progression compared to usual care. The study was a randomized, open label, blinded endpoint clinical trial in participants with established cardiovascular disease or at equivalent high risk (estimated five year cardiovascular risk of ≥15%). Two versions of the polypill were available. These contained aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide. The choices of polypill version and the components of usual care were made at the discretion of the physician. (http://clinicaltrials.gov/show/NCT01326676). Results: In total 296 participants in the polypill group and 290 participants in the usual care group had both a baseline and follow-up CIMT scan. Allocation to a polypill compared to usual care resulted in similar levels of low-density lipoprotein (LDL)-cholesterol (mean difference: 0.0 mmol/L; 95%-confidence interval (CI): -0.1 to 0.1; p=0.41) and systolic BP (mean difference -1.7 mmHg; 95%-CI:-4.5 to 1.1; p=0.23) after a median follow-up duration of 1.00 year [IQR: 0.93 to 1.04 year]. The annualized rate of change in common CIMT in the polypill-based treatment strategy group (6.56 μm/year; standard error (SE): 4.76 μm/year) did not differ significantly from the rate of change in the usual care group (10.72 μm/year; SE: 4.76 μm/year; mean difference: -4.2 μm/year; 95%-CI: -17.0 to 8.7; p=0.53). Conclusion: This study demonstrated that a polypill-based cardiovascular treatment strategy compared to usual care did not reduce the rate of progression of common CIMT during a one year follow-up interval in a well-treated population with cardiovascular disease. Importantly, CIMT progression was not adversely effected by the polypill-based treatment strategy. [ABSTRACT FROM AUTHOR]

Background Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension. Methods We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov, number NCT01642498. Findings 83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting. Interpretation Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension. INSET: Panel: Research in context.. [ABSTRACT FROM AUTHOR]

Aims To conduct a prospective, individual participant data (IPD) meta-analysis of randomised controlled trials comparing a polypill-based approach with usual care in high risk individuals. Methods and results Three trials comparing polypill-based care with usual care in individuals with CVD or high calculated cardiovascular risk contributed IPD. Primary outcomes were self-reported adherence to combination therapy (anti-platelet, statin and ≥ two blood pressure (BP) lowering agents), and difference in mean systolic BP (SBP) and LDL-cholesterol at 12 months. Analyses used random effects models. Among 3140 patients from Australia, England, India, Ireland, New Zealand and The Netherlands (75% male, mean age 62 years), median follow-up was 15 months. At baseline, 84%, 87% and 61% respectively were taking a statin, anti-platelet agent and at least two BP lowering agents. At 12 months, compared to usual care, participants in the polypill arm had higher adherence to combination therapy (80% vs. 50%, RR 1.58; 95% CI, 1.32 to 1.90; p < 0.001), lower SBP (− 2.5 mmHg; 95% CI, − 4.5 to − 0.4; p = 0.02) and lower LDL-cholesterol (− 0.1 mmol/L; 95% CI, − 0.2 to 0.0; p = 0.04). Baseline treatment levels were a major effect modifier for adherence and SBP (p-homog < 0.0001 and 0.02 respectively) with greatest improvements seen among those under-treated at baseline. Conclusions Polypill therapy significantly improved adherence, SBP and LDL-cholesterol in high risk patients compared with usual care, especially among those who were under-treated at baseline. [ABSTRACT FROM AUTHOR]

Abstract: The ADVANCE Retinal Measurements (AdRem) Study is a large intervention study evaluating the effects of target driven intensive glucose control and placebo controlled blood pressure lowering on retinal vascular changes. AdRem is a sub-study of the ADVANCE Study (Action in Diabetes and Vascular disease), a 2×2 factorial randomized controlled trial with an ACE inhibitor–diuretic combination (perindopril-indapamide) and a gliclazide MR-based regimen in patients with type 2 diabetes mellitus. The AdRem study is based on seven-field stereoscopic retinal photographs of both eyes. These are taken within 3 months after randomization in ADVANCE (baseline), at the biennial and at the final visit. The primary outcome is progression of two or more steps in ETDRS classification. Secondary outcomes include progression of retinal vascular lesions and distortion of retinal vascular geometry. Retinal photographs are made on film and digitized at a central laboratory. The AdRem study uses fully digitized quality control and grading. Between August 2002 and January 2004 1978 patients were included in the AdRem study, from 39 centers in 14 countries. Approximately 85% comply with the strict AdRem quality requirements. Publication of the results is expected in early 2008. The AdRem study is designed to provide reliable evidence on the effects of intensive glucose control and blood pressure lowering on both diabetic retinopathy and abnormalities of retinal vasculature in patients with type 2 diabetes mellitus. [Copyright &y& Elsevier]