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In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing. This trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing. Patients aged 18 to 80 years with reasonably controlled hypertension (≤150/≤90 mm Hg) on stable therapy of ≥1 antihypertensive agent were recruited from 2 centers in London and Thessaloniki. Patients were randomized to receive usual therapy either in the morning (6 am-11 am) or evening (6 pm-11 pm) for 12 weeks when participants crossed over to the alternative timing for a further 12 weeks. Clinic blood pressures and a 24-hour recording were taken at baseline, 12, and 24 weeks and routine blood tests were taken at baseline. The study had 80% power to detect 3 mm Hg difference in mean 24-hour systolic blood pressure (α=0.05) by time of dosing. A 2-level hierarchical regression model adjusted for center, period, and sequence was used. Of 103 recruited patients (mean age, 62; 44% female), 95 patients (92%) completed all three 24-hour recordings. Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am-10 pm) and nighttime (10 pm-7 am) blood pressure levels nor on clinic levels. Stratification by age (≤65/≥65 years) or sex did not affect results. In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01669928.

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.

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.)

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10 -8 ) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10 -8 ). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2)., (Copyright © 2018 American Society of Human Genetics. 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.)

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.

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.

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.

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.

Objectives: This study investigated whether wave reflection measured by wave intensity analysis predicts future cardiovascular events in individuals with hypertension and sought to establish whether this relationship is independent of other cardiovascular risk factors and is associated with evidence of increased load on the left ventricle., Background: Wave reflection may impose an additional load on the left ventricle, and augmentation index, a surrogate of wave reflection, has been reported to predict cardiovascular events in some, but not all studies., Methods: Measurements of brachial and carotid blood pressure (BP) measurement, carotid ultrasound, echocardiography, and blood chemistry analyses were performed on 259 ASCOT (Anglo Scandinavian Cardiac Outcomes Trial) participants approximately 1 year after randomization, and wave intensity analysis was used to calculate wave reflection index (WRI), the ratio of peak forward to peak backward pressure (P(b)/P(f)), and carotid augmentation index (cAI(x)). All participants were followed up for a median period of 5.9 years, accruing 33 cardiovascular events., Results: WRI, P(b)/P(f), and to a lesser extent, cAI(x), were correlated. WRI predicted cardiovascular events (hazard ratio: 2.10; 95% confidence interval: 1.10 to 3.99; p = 0.02) in an unadjusted model. Multivariate analysis showed that this association was independent of BP. P(b)/P(f) and cAI(x) did not significantly predict cardiovascular events. WRI was also positively associated with increased left ventricular mass index and elevated B-type natriuretic peptide adjusted for age and sex, and these associations were independent of BP or other cardiovascular risk factors., Conclusions: Higher wave reflection predicts future cardiovascular events independent of conventional risk factors in people with treated hypertension., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Four simple pragmatic rules are proposed to facilitate the management of essential hypertension in the context of primary care. Rule 1: Abandon diastolic blood pressure measurement and rely on systolic blood pressure values for decisions on treatment thresholds and goals. Rule 2: Assess overall cardiovascular risk by history taking, physical examination and simple investigation (urine dipsticks, serum creatinine, glucose, lipids and ECG). Rule 3: As a generality, apply a systolic threshold of 150 mm Hg for the introduction of drug treatment when repeated measures of blood pressure following a trial of non-pharmacological treatment, remain persistently above this level. This threshold may be reduced to 140 mm Hg for higher risk patients (eg, those with target organ damage or diabetes) or raised to 160 mm Hg for low risk patients and the elderly. Rule 4: Modify therapy if initial drug treatment is ineffective, partially effective or poorly tolerated. If blood pressure does not fall below the treatment threshold, drug dosage should be increased (except diuretics), treatment changed or combinations used to achieve goal pressures.

Black hypertensive persons have been observed to have a greater degree of left ventricular hypertrophy than white hypertensives. However, previous studies have matched groups for blood pressure (BP) measured in the clinic, and it has been demonstrated that black hypertensives have an attenuated nocturnal BP dip. Clinic BPs may thus underestimate mean 24-hour BP in this group. To investigate whether the differences in left ventricular hypertrophy can be accounted for by the greater mean 24-hour BP in black hypertensives, 92 previously untreated hypertensives were studied with 24-hour ambulatory BP monitoring and echocardiography. The 46 black hypertensives (24 men and 22 women) were matched with the 46 white hypertensives for age, gender, and mean 24-hour BP. Despite similar mean 24-hour BPs (blacks, 142/93 mm Hg; whites, 145/92 mm Hg; P=.53/.66), the black group had a smaller mean nocturnal dip than the white group (blacks, 8/8 mm Hg; whites, 16/13 mm Hg; P<.01). In addition, mean left ventricular mass index (LVMI) was greater (blacks, 130 g/m2; whites, 107 g/m2; P<.001). Mean 24-hour systolic BP was significantly related to LVMI in both groups (blacks, r=.45, P<.01; whites, r=.56, P<.01). However, systolic BP dip correlated inversely with LVMI only in the black group (blacks, r=-.30, P<.04; whites, r=.05, P=.76). In a multiple regression model, LVMI was independently related to both mean daytime BP and mean nocturnal BP dip in black subjects but only to mean daytime BP in white subjects. In conclusion, the increased left ventricular hypertrophy observed in black hypertensives compared with white hypertensives is not accounted for by differences in mean 24-hour BP. However, LVMI in black hypertensives appears to be more dependent on nocturnal BP than that in white hypertensives; this, coupled with the attenuated BP dip in black hypertensives, suggests that the BP profile rather than 24-hour BP may be important in determining the differences in left ventricular hypertrophy.

It has been suggested that the deletion polymorphism of the angiotensin-converting enzyme (ACE) genotype may be important in the development of left ventricular hypertrophy (LVH). In order to test this hypothesis we investigated the interaction between blood pressure (BP), LVH and ACE genotype in 86 previously untreated hypertensive patients. Each underwent two-dimensional and Doppler echocardiography and ACE genotyping. There were no significant differences in BP, the parameters of left ventricular structure (including left ventricular mass index) or diastolic function between the three genotype groups. Additionally, there were no significant differences in the relationship between systolic BP and left ventricular mass index among the three genotype groups (II genotype, r = 0.46, P = 0.02; ID genotype, r = 0.42, P = 0.01; DD genotype, r = 0.34, P = 0.10; F = 0.38). In contrast to some previous studies, we have found in this group of previously untreated hypertensive subjects no evidence to suggest that the deletion polymorphism of the ACE genotype is important in the development of LVH.

Vascular structural changes in hypertension are proposed to contribute to raised peripheral resistance. Endogenous polyamines (putrescine, spermidine and spermine) have an essential role in cellular growth and may be required in vascular restructuring. We have previously shown raised polyamines in resistance vessels in response to angiotensin II (angII) infusion in the rat and here we examined whether polyamine depletion influences the hypertensive process. Wistar-Kyoto rats were infused with either angII or saline by osmotic minipump, and maintained on either 2% difluoromethylornithine (DFMO; polyamine synthesis inhibitor) or water for 12 days. AngII significantly increased tail-cuff blood pressure (bp), resistance vessel spermidine and spermine concentration, and media:lumen ratios. DFMO attenuated both the rise in bp (p < 0.05) and vascular spermidine (p < 0.05) in the angII infused rats but vascular structure was apparently unaffected on day 12. In conclusion, raised concentration of resistance vessel spermidine may be a necessary component of the ang II pressor effect.

Aims: To determine the prevalence of cardiovascular risk factors among hypertensives in a cross-sectional survey of hypertensives from 13 general practices in England., Findings: Of 1,948 European hypertensives (systolic blood pressure 150 mmHg and/or diastolic blood pressure > 90 mmHg and/or on treatment for hypertension), 40 to 69 years of age, 53.3% on treatment had controlled blood pressures (systolic blood pressure < 160 mmHg and diastolic blood pressure < 95 mmHg). Electrocardiographic abnormalities and other cardiovascular risk factors were common among these hypertensives, with dyslipidaemia, past or current smoking and lack of physical exercise being present in the majority of those studied. All risk factors except reported diabetes were more prevalent amongst subjects from northern practices, where coronary heart disease rates are higher. Compared with those on no therapy, those receiving diuretics only had significantly higher levels of serum total cholesterol (6.39 mmol/l vs 6.69 mmol/l: p < 0.01), and those receiving beta-blockers only had significantly higher levels of triglycerides (2.32 mmol/l vs 2.64 mmol/ l: p < 0.01), and lower levels of HDL-cholesterol (1.33 mmol/l vs 1.23 mmol/l: p < 0.001)., Conclusion: It is important to consider other cardiovascular risk factors in hypertensives because they are very common and interact with blood pressure (BP) to determine levels of risk. The high proportion of inadequately controlled hypertensives demands a more effective management strategy.

Objective: To demonstrate the magnitude, timing, and cause of changes in blood pressure that occur in migrants from a low blood pressure population on moving to an urban area., Design: A controlled longitudinal observational study of migrants as soon after migration as possible and follow up at three, six, 12, 18, and 24 months after migration. A cohort of controls living in a rural area who were matched for age, sex, and locality were also observed at the same periods., Setting: 35 Villages on the northern shores of Lake Victoria in western Kenya and Nairobi., Participants: 325 Members of the Luo tribe aged 15 to 34 years who had migrated to Nairobi and 267 controls living in villages. The numbers of both groups reduced during follow up such that only 63 migrants and 143 controls were followed up for two years., Main Outcome Measures: A medical questionnaire and three 24 hour diet histories were completed by migrants and controls. Height, weight, pulse, and blood pressure were measured. Three 12 hour overnight urine samples were collected from all participants and analysed for sodium, potassium, and creatinine concentrations., Results: The mean systolic blood pressure of migrants was significantly higher than that of controls throughout the study, and the distribution of blood pressure was shifted to the right compared with controls. The mean diastolic blood pressure of the two groups diverged over time. Blood pressure differences were not due to selective migration. The migrants' mean urinary sodium:potassium ratio was higher than that of controls (p less than 0.001) throughout, and weight and pulse rate were also higher among migrants, although differences diminished with time., Conclusions: Urinary sodium:potassium ratio, pulse rate, and weight are important predictors of increased blood pressure among migrants from a low blood pressure community and may also be implicated in the initiation of essential hypertension.

Changes in blood pressure (BP) and associated factors which occur on migration from a rural to an urban environment are under observation in a longitudinal study. Blood pressures, heart rate (HR), urinary electrolytes, sociological and anthropometric data are recorded at 0, 3, 6, 12, 18 and 24 months following migration and compared with a cohort of age and sex-matched rural based controls. Data from the first 6 months' follow-up reveal that the migrants' BPs are higher and tend to rise compared with controls, in whom BP falls progressively with time. Changes in body weight and dietary electrolytes appear to explain some of the BP differences, while differences in pulse rates between groups suggest that a further mechanism operative through the autonomic nervous system is responsible for some of the elevation of systolic BP shown amongst migrants, particularly on arrival in the urban area.

1. The effects of coitus on heart rate, blood pressure and plasma concentration of noradrenaline were studied in six male rabbits. 2. During coitus, heart rate rose from 228 +/- 6 to 324 +/- 8 beats/min (mean +/- SEM; n = 24). Mean blood pressure rose from 87 +/- 3 to 165 +/- 4 mmHg, and plasma concentration of noradrenaline from 2.07 +/- 0.21 to 5.02 +/- 0.26 nmol/l. The maximum heart rate did not occur until after the peak in blood pressure. 3. Propranolol had no effect on the power expended during coitus, but there was a dose dependent fall in the changes in heart rate, blood pressure and plasma concentration of noradrenaline.

In 10 patients with chronic autonomic failure the clinical features and cardiovascular reflexes were correlated with the pressor responses to intravenous noradrenaline and tyramine. In all patients there was an exaggerated response to noradrenaline but a normal or only mildly exaggerated response to tyramine. Patients with lack of sinus arrhythmia and by implication baroreceptor reflex loss had greater responsiveness to pressor drugs than patients with preservation of this reflex. The responses to tyramine infusions imply that there must be sufficient noradrenaline released at defective sympathetic endings for a pressor response to occur. However, the lack of rise of plasma noradrenaline following tyramine, except in the patients with pure autonomic failure, clearly separates these responses from those of normal subjects. These results can be explained by the presence of lesions of both central and peripheral sympathetic pathways in patients with chronic autonomic failure and multiple system atrophy or Parkinsonism. The peripheral lesion, which is incomplete, may consist of replication of the receptors so causing supersensitivity with a duration of response that is little prolonged. The peripheral defect in the two patients with pure autonomic failure was found to be more complex and the prolonged response in one of these patients suggests the possibility of defective re-uptake or metabolism of noradrenaline. Clearly further study of the defects of sympathetic endings is required, including the use of other techniques such as catecholamine fluorescence. The extreme supersensitive responses underline the need for blood pressure monitoring during pressor drug studies prior to treatment, if the hazards of recumbent hypertension are to be avoided.

A longitudinal study of the effects of migration on blood pressure and related factors is being carried out in members of a black Kenyan population who migrate from a traditional rural community to an urban environment. Data on the first 139 migrants (78 male, 61 female) and 204 control non-migrants (126 male, 78 female) who have been followed up for a period of 6 months are presented. Blood pressure changes rapidly on migration (within the first 2 months); thereafter trends between migrants and controls differ. Significant differences in systolic pressure between migrants and controls are found at all examinations during the 6 month follow-up in both sexes. Diastolic pressure falls in controls but rises in migrants, the greatest difference being seen at the 6 month examination. Migration is associated with a marked increase in dietary sodium and a fall in potassium demonstrated by measurements of urinary electrolyte excretion in 3 X 12 h or 3 X 24 h urine collections. Analysis of covariance shows that the blood pressure differences between migrants and controls are partly explained by urinary sodium/potassium ratios and in some instances by body weight.

We examined the influence of baroreceptor reflex sensitivity (the increase in pulse interval in response to a phenylephrine-induced increase in blood pressure), age, blood pressure, and beta-adrenergic receptor blockade on the variability of blood pressure and heart rate in essential hypertension. Fifty-six subjects were studied before treatment; intra-arterial blood pressure was recorded outside the hospital for 24 hours. Variability was defined (from all beats occurring while subjects were awake) as the standard deviation about the average waking value for mean arterial pressure (MAP) or pulse interval. The correlation (r) between baroreceptor reflex sensitivity and blood pressure variability was -0.47 (p less than 0.0002). Baroreceptor reflex sensitivity was the only independent determinant of blood pressure variability on multiple regression analysis. Thirty subjects were restudied after 5 months of beta-adrenergic receptor blockade. Ambulatory blood pressure was lower during treatment, whereas pulse interval, its variability, and baroreceptor reflex sensitivity were higher. Blood pressure variability was unchanged. The variability of MAP was inversely correlated with baroreceptor reflex sensitivity before (r = -0.42, p less than 0.02) and during (r = -0.45, p less than 0.02) treatment, but it was unrelated to the average ambulatory MAP or to the variability of pulse interval either before or during beta-blockade. Sixteen subjects whose average waking ambulatory blood pressure was 140/90 mm Hg or less were not treated. This group of borderline hypertensive subjects had less variable MAP than did the remaining 40 subjects (12.4 +/- 2.3 [SD] vs 14.5 +/- 2.5 mm Hg; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

115 factory workers (62 white, 53 black) were studied with measurements of blood pressure, plasma noradrenaline concentration, and plasma renin activity. Blood pressure was higher in blacks than in whites. There were no ethnic differences in plasma noradrenaline, which increased with age, but was not related to blood pressure. Mean plasma renin activity was 55% lower in blacks than whites and this difference was not related to differences in sodium intake. There were no associations between renin and noradrenaline, or between renin and blood pressure.

Clinic cuff blood-pressure measurements, obtained on at least three occasions, were compared with mean arterial pressures in 59 patients with borderline or essential hypertension who underwent direct ambulatory monitoring of blood pressure. In 22 patients (group I) mean cuff and ambulatory pressures were similar (+/- 10 mm Hg) while in 32 subjects (group II) cuff pressures were more than 10 mm Hg higher. Groups I and II could not be distinguished on the basis of clinical examination, indices of sympathetic nerve activity, or blood-pressure variability, or by the magnitude of pressure rise during physical or mental exercise. Group II had less cardiovascular target organ damage and better baroreflex sensitivity but there was considerable overlap. There was no reliable way of telling which subjects would have lower ambulatory than cuff pressures. 20 out of 59 subjects classified as hypertensive by cuff measurements had awake ambulatory pressures or less than 140/90 mm Hg.

A relationship between salt intake and blood pressure has been described in cross-sectional studies of several populations. However, serious methodological problems in many studies could have resulted in erroneous results. In the present studies, the blood pressure profiles of a Kenyan tribe have been shown to differ according to environment, being lower in rural and higher in urban communities. Although several factors could explain the observed blood pressure differences, dietary factors, including sodium and potassium intake, could be important determinants of the observed differences. A within-population study of 1,737 rural male subjects was carried out in which it was found that systolic and diastolic pressures correlated positively with urinary sodium/potassium ratios. In this rural group, within subject day-to-day variations in dietary electrolytes are small, as indicated from multiple urinary collections, and are less than those observed in Western societies. We have demonstrated in this rural population that causal samples of urine correlated well with average sodium and potassium excretion over a 7-day period. Preliminary results are reported of a longitudinal study of migrants from a low to a high blood pressure environment and a nonmigrant population. The blood pressure rise consequent to migration was related independently to changes in body weight and urinary electrolytes. The implications of these observations for active intervention studies are discussed.

Blood pressure (BP) and associated factors were determined in 1737 men in a remote Kenyan agricultural community. Systolic BP showed no significant rise with age until after 54 years; diastolic BP showed a small rise with age. Both systolic and diastolic BP correlated with weight independent of age. Systolic and diastolic BP correlated positively with casual urinary sodium/potassium and negatively with potassium/creatinine ratios. Both systolic and diastolic BP correlated significantly with the number of years of education, as did urinary sodium/potassium and sodium/creatinine ratios. Potassium/creatinine ratios were negatively correlated with the number of years of education. Blood pressure and urinary sodium/creatinine ratios were significantly lower in subsistence farmers compared with those in other occupations, and potassium/creatinine ratios were significantly higher. Two pilot studies of Luo tribesmen showed a strong correlation between casual urinary electrolyte ratios and those derived from 24-hour urine samples and a greater variance of sodium excretion between these people than that found within individuals. These results suggest that a relationship between BP and casual urine electrolyte estimations may be identifiable in communities where there is less day-to-day dietary variation. They also suggest that some of the changes in BP associated with urbanization could be mediated by changes in dietary electrolytes.

In 62 untreated patients with essential hypertension, arterial baroreflex sensitivity (BRS) for heart rate, i.e. the change in pulse interval in response to a phenylephrine-induced increase in blood pressure, was compared with (1) haemodynamic changes during mental arithmetic, a reaction time test, isometric and bicycle exercise; (2) plasma noradrenaline (PNA) concentrations at rest, and during bicycle exercise and; (3) the variability of ambulatory intra-arterial blood pressure. Subjects with diminished BRS showed the following responses: (1) higher mean arterial blood pressure (MAP) during all four stimuli; (2) a greater pressor response to cycling; (3) tended to have higher PNA concentrations during bicycle exercise and; (4) greater variation in ambulatory blood pressure. Furthermore, an increased pressor response to the reaction time test and increased ambulatory blood pressure variability was seen in younger subjects with reduced BRS. When subjects were subgrouped according to their WHO stage of hypertension, there were significant inverse relationships between BRS and the pressor responses to mental arithmetic, the reaction time test and cycling, and with ambulatory blood pressure variability only in those subjects without ECG or radiographic evidence of left ventricular enlargement (WHO stage I hypertension; n = 42). None of these correlations were present in subjects with one or both of these clinical findings (WHO stage II; n = 20). Pressor responses to the four laboratory stimuli and ambulatory blood pressure variability were similar in both groups, despite significantly higher arterial pressure and significantly lower BRS in WHO stage II subjects. These results suggest that differing mechanisms may be responsible for the regulation of blood pressure variation in these two groups. The arterial baroreflex can buffer acute changes in blood pressure in subjects with WHO stage I hypertension, but this ability is attenuated with progressive reduction of BRS. With the development of clinically evident cardiac adaptation to hypertension (WHO stage II), the contribution of the arterial baroreflex to the regulation of blood pressure is no longer detectable and the influence of cardiac and somatic afferents to reflex circulatory adjustments to activity may predominate.

Blood-pressure and associated factors were compared in tribal and urban Xhosa people of Southern Africa. In the urban group blood-pressures were high and rose significantly with age whereas in the tribal group they were low and rose little with age. Indices of obesity including weight, skin-fold thickness, and ponderal index were significantly greater in urban dwellers and correlated strongly with arterial pressure. Dietary sodium and urine-sodium/creatinine ratio were significantly higher in the urban people, but there was no within-population relationship between either dietary sodium or urine-sodium/creatinine ratio and blood-pressure. Plasma-noradrenaline, an index of sympathetic activity, was similar in both populations, as was plasma-renin activity. Low plasma-renin was common and may be genetically determined. Diet and obesity may contribute to the rise in arterial pressure that is a consequence of urbanisation.

As part of a longitudinal study of migrants who move from a subsistence farming rural society to Nairobi, blood pressures and associated factors were measured in cross sectional studies of members of the Luo tribe in their traditional rural environment and in the urban environment of Nairobi. Blood pressures in Nairobi correlated with duration of urban residence. In the rural area men showed a negligible rise in blood pressure with age, and both sexes showed a significantly smaller rise than in the urban area. Although mean weights of the rural group were smaller, this did not account for all the urban/rural differences in blood pressures. Nevertheless, mean urinary sodium concentration and sodium ratios (sodium/potassium and sodium/creatinine) were significantly higher in the urban group whereas mean urinary potassium concentration and potassium/creatinine ratio were significantly lower. Perhaps the ratio of sodium to potassium in the diet contributes to the different blood pressure profiles of these two populations.

The cardiovascular and hormonal effects of intravenous saralasin (0.5, 1 and 5 micrograms min-1 kg-1) were assessed in nine tetraplegic patients (with complete cervical spinal cord transaction above the sympathetic outflow) and in six normal subjects. In the tetraplegic patients, saralasin caused an immediate transient pressor response which was not dose-dependent and substantially greater than the pressor response in normal subjects. The pressor response in the tetraplegic patients was not accompanied by a rise in levels of plasma noradrenaline. In the tetraplegic patients, after alpha-adrenoceptor blockade with thymoxamine (1 mg kg-1 h-1), twice the dose of intravenous noradrenaline was needed to induce the same pressor response. The pressor response to saralasin (5 micrograms kg-1 min-1), however, was unaffected by thymoxamine. Saralasin caused minimal changes in levels of plasma renin activity and plasma aldosterone in both groups. There was no relationship between basal plasma renin activity and the pressor response in either group. We therefore conclude that the immediate transient pressor response to saralasin in man is not due to central sympathetic stimulation, is unlikely to be due to peripheral sympathetic activation and is probably the result of intrinsic angiotensin II-like myotropism.

1 Treatment of postural hypotension due to chronic autonomic failure with fludrocortisone increased the pressor sensitivity to intravenous noradrenaline. Fludrocortisone increased the blood pressure in the standing but not the lying position. These effects of fludrocortisone may be the result of increased sensitivity of vascular receptors to noradrenaline. 2 The pressor action of angiotensin II, to which patients were supersensitive, may have involved the stimulation of alpha-adrenoceptors since it was partially antagonised by phentolamine. 3 Saralasin had a marked, paradoxical, pressor effect. This may have been mediated by vascular alpha-adrenoceptors because log dose-response curves of saralasin-induced increases in systolic pressure were shifted to the right in a parallel fashion after phentolamine. 4 Fludrocortisone treatment increased the pressor sensitivity to intravenous saralasin but not to angiotensin-II.

1. Twelve subjects (mean age 46.3 +/- 12.5 years) with mild to moderate hypertension were studied before, during and after bicycle ergometer exercise. 2. Baroreflex sensitivity was determined by the Oxford phenylephrine method; sensitivity at rest was inversely related to intra-arterial pressure and age. Age and resting arterial pressure were not related. 3. Exercise for 5 min at 50 W and 5 min at 75 W raised the mean arterial pressure from 116.4 +/- 18.0 to 150.0 +/- 25.4 mmHg, the heart rate from 73.2 to 126.7 beats/min and the plasma noradrenaline from 541 +/- 142.7 to 1309.8 +/- 543.5 pg/ml (P less than 0.001). 4. The increase in noradrenaline during exercise and the maximum mean pressure achieved were inversely related to resting baroreflex sensitivity (r = -0.68 and -0.77 respectively). Resting values of noradrenaline were not related to baroreflex sensitivity, age, or resting blood pressure. 5. It is possible that the rise in both plasma noradrenaline and arterial blood pressure produced by exercise is controlled by the baroreceptor reflexes; these are less effective in hypertensive subjects and thus the increases in noradrenaline and arterial pressure during exercise are greater in subjects with raised blood pressure.

A longitudinal study has shown that migrants from a remote Kenyan low-blood pressure (BP) community living in an urban environment had significantly higher BPs than a cohort of matched, nonmigrant controls. Selective migration was thought to be the likely explanation for this observation, but the BPs of 90 males studied prior to migration were almost identical to those found in the age-matched rural based controls studied in the low-BP community from which they came (120.9/59.0 mm Hg vs 120.5/60.1 mm Hg). Hence, in view of these premigration data supported by other evidence from the Kenyan Luo Migrant Study, it appears that the higher BP levels of the Luo migrants are not due to selective migration but are consequent upon environmental changes, including changes in electrolyte intake, which occur rapidly after migration.

The blood pressure patterns of three Kenyan communities have been studied: 861 members of the Luo tribe in a rural community, 281 members of the Kamba tribe in a rural community and 310 "urban" Luo living in Nairobi. The slope of linear regression of blood pressure with age was significantly different in each population: rural Luo had the smallest rise with age and urban Luo had the largest rise with age, while the Kamba tribe were in between. The differences could not be accounted for by weight. Urinary electrolyte data showed rural Luo had the lowest sodium ratios (sodium/creatinine, sodium/potassium) and the highest potassium/creatinine ratio: urban Luo had the highest sodium and lowest potassium ratios and rural Kamba had values in between. The differences in blood pressures between the two groups of the same tribe in different environments (rural and urban Luo) were far greater than those between different genetic groups (Kamba and Luo) underlining the importance of environmental factor(s) in the determination of arterial pressure. Furthermore, these data support the theory that the dietary intake of sodium and potassium are the major influential environmental factors affecting blood pressure.