BACKGROUND:Besides the usual characterization of metabolic syndrome as a cluster of markers arbitrarily defined by thresholds, it is unclear to which extent these markers as continuous traits are correlated with each other in the general population. The present study aimed to explore these correlations across a wide array of biological, social and behavioral characteristics. METHODS:The cross-sectional analyses were performed in a large population-based French cohort (CONSTANCES) of 159,476 adults in whom blood glucose, low-density lipoproteins (LDL) and high-density lipoproteins (HDL), triglycerides, body mass index, waist and hip circumferences, systolic and diastolic blood pressures were measured at the time of recruitment between 2012 and 2021. Correlations between each pair of continuous marker distributions were assessed by calculating raw and partial correlation coefficients (r). RESULTS:The same pattern of partial correlations is observed with little variation in all groups of sex, age, individual and parental histories of cardiovascular disease, diagnosis of metabolic syndrome, social position, work environment, lifetime unemployment exposure, smoking, non-moderate alcohol consumption, leisure-time physical inactivity and diet quality. This pattern is composed of strong and expected intercorrelations between systolic and diastolic blood pressures (r ranging from 0.62 to 0.74), between body mass index and waist (r from 0.50 to 0.63) and hip (r from 0.58 to 0.70) circumferences and between waist and hip circumferences (r from 0.07 to 0.19). It also includes intercorrelations of systolic blood pressure with waist (r from 0.10 to 0.21) and hip (r from -0.07 to -0.12) circumferences and with blood glucose (r from 0.09 to 0.15), those of triglycerides with blood glucose (r from 0.07 to 0.16), LDL (r from 0.24 to 0.33), HDL (r from -0.20 to -0.29) and waist circumference (r from 0.07 to 0.15), and finally those of waist and hip circumferences with blood glucose (r from 0.09 to 0.17 and from -0.08 to -0.13) and HDL (r from -0.12 to -0.24 and from 0.08 to 0.18). CONCLUSIONS:These results show that metabolic syndrome markers are correlated with each other whatever the biological, social or behavioral characteristics of individuals. They suggest that it makes sense to systematically consider these markers all together rather than separately in terms of etiology, prevention and treatment of metabolic diseases and cardiovascular risk in the general population.

Clinical practice guidelines for patients with diabetes recommend using blood pressure (BP) and atherosclerotic cardiovascular disease (ASCVD) risk to guide antihypertensive treatment. While this approach directs treatment to patients who should receive a large ASCVD risk reduction, its effect on other outcomes is uncertain. The aim of this study was to assess the contributions of systolic blood pressure level (SBP) and predicted 10-year ASCVD risk using Pooled Cohort risk equations to the prediction of major macrovascular disease, death and major microvascular disease in patients with diabetes. Data came from 7426 individuals with type 2 diabetes (T2D) without macrovascular disease at baseline in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The risk for major macrovascular events and death increased progressively across ASCVD risk categories. Compared to participants with 10-year predicted ASCVD risk <20% and SBP <130 mmHg, the hazard ratios (HRs) (95% confidence intervals (CIs)) associated with SBP ≥150 mmHg and 10-year predicted ASCVD risk <20%, 20–34% and ≥35% were 1.01 (0.58, 1.77), 1.90 (1.28, 2.84) and 2.82 (1.98, 4.01) for major macrovascular disease, respectively, and 0.83 (0.42, 1.62), 1.79 (1.13, 2.82) and 3.29 (2.22, 4.88) for death, respectively. The risk for major microvascular disease increased with BP regardless of ASCVD risk; HRs for SBP ≥150 mmHg and 10-year predicted ASCVD risk <20%, 20–34% and ≥35% vs. ASCVD risk <20% and SBP <130 mmHg were 1.52 (1.08,2.13), 1.47 (1.10, 1.96) and 1.23 (0.94, 1.60), respectively. ASCVD risk in addition to SBP improved the estimation of major macrovascular events and death but not major microvascular events among individuals with T2D.

Objective It is unclear whether retirement age can modify the association of working conditions with health and mortality in retirees who are no longer exposed to these conditions. Methods The present study investigated this issue in a cohort of 13,378 French workers in whom self-rated health and mortality were measured over 15 years after statutory retirement. The analyses were also performed in homogenous clusters of workers differentiated on the basis of working conditions, social position, birth and retirement years. Results Bad working conditions before retirement, which were assessed using a global score combining 25 different occupational exposures, were associated with higher rates of suboptimum self-rated health and mortality in retirees after adjusting for retirement age, social position, demographics and health status before retirement. These rates were also substantially higher in the cluster of workers characterized by bad working conditions in comparison to other clusters. In contrast, retirement age was not associated with self-rated health or mortality after adjusting for working conditions, social position, demographics and health status before retirement. Likewise, no association of retirement age with self-rated health or mortality was found in any cluster of workers and no interactions were observed with any of these clusters. Conclusion These results suggest that bad working conditions before retirement have long-term detrimental effects on health and mortality in retirees and that retirement age does not modulate these effects. Improving work environment rather than modifying retirement age should be prioritized to promote health and reduce mortality not only in workers but also in retirees.

Objective: Improving the efficiency of hypertension management has driven treatment indications to be based on cardiovascular disease risk calculations instead of blood pressure or cholesterol management. The aim of this study was to explore the relationship between ten-year risk of atherosclerotic cardiovascular disease (ASCVD) and systolic blood pressure (SBP) in individuals with type 2 diabetes and describe the characteristics of individuals according to their ASCVD risk and SBP cross-classification. The secondary aim was to model the association of ASCVD risk and SBP at study baseline with clinical outcomes (major macrovascular, major microvascular and death). Design and method: This current study used 7,426 individuals from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) randomised clinical trial, that were free from macrovascular disease at baseline. ASCVD risk and SBP were categorised into approximate thirds, reflecting clinically meaningful cut points, defined as intermediate risk: ASCVD < 20 or SBP < 130, high risk: ASCVD 20 -34 or SBP 130–149, and very high risk: ASCVD > = 35 or SBP > = 150. Individuals were cross-classified according to their ASCVD and SBP categories. Characteristics of individuals among the categories were summarised using descriptive statistics. Cox proportional hazards models were fitted to model the association of ASCVD and SBP cross-classification with clinical outcomes. Results: There was a high proportion of women for ASCVD < 20 across the three sequential SBP categories (67.3%, 80.3% and 87.6%). Mean age increased through increasing ASCVD risk categories, in all risk categories the mean age was highest for SBP < 130 and lowest for SBP > = 150. The risk of death increased as ASCVD increased; though there was no significant association of SBP within the ASCVD categories. The risk of major macrovascular events increased sequentially through the combined effect of ASCVD and SBP (see figure). The highest risk of major microvascular events was for SBP > = 150 across all ASCVD categories. Conclusions: The cross-classification of ASCVD and SBP yielded varying associations with death, major macrovascular and major microvascular events, thus indicating that using ASCVD and /or SBP as predictors produces a non-uniform pattern for adverse clinical outcomes.

Bibliometric analysis, a powerful tool for assessing trends in research output, was employed to analyze the evolution of hypertension research over a 20-year period. The analysis was based on 90 308 original articles and a citation analysis. The use of bibliometric as a potential tool for shaping research policy at the institution or country level was also explored. The number of published hypertension articles increased by 43.5% over the 20-year period. By contrast, the increase in the number of articles in all medical disciplines was 96%, and in the cardiovascular field was 64%. Of the 6 countries producing the largest number of articles, the United States was consistently the major contributor. There was a slight decrease from Japan, a slight increase from the United Kingdom, and relatively stable output from Germany and Italy over the study period. Output from China showed the strongest growth. The trends in Specialization Index and Category Normalized Citation Impact varied by country. In Russia, Poland, and Brazil, increases in output were greater for hypertension research than for medical research in general. The United Kingdom and Denmark had greater hypertension research output than the other countries. VOSviewer analysis showed an intensification of collaborations between countries and a shift, over 10 years, from 3 clusters towards 2 clusters. Such analysis may help to shape research policy at the country level and can be similarly performed for institutions. Historical changes in hypertension research can be monitored over decades if the same channels continue to be used for communication of scientific results.

This study examined the dose-response characteristics of aprocitentan, a dual endothelin A/endothelin B receptor antagonist, in patients with essential hypertension. In a randomized, double-blind, parallel study design, eligible patients with a sitting diastolic blood pressure (BP) of 90–109 mm Hg received aprocitentan 5, 10, 25, or 50 mg, placebo, or lisinopril 20 mg as a positive control once daily for 8 weeks. Multiple automated office BP readings were obtained with patients resting unattended (unattended automated office BP) at baseline, weeks 2, 4, and 8. Ambulatory BP was monitored for 24 hours at baseline and week 8. After a single-blind placebo run-in period, 490 eligible patients were randomized to the double-blind phase, with 409 patients completing 8 weeks of therapy per protocol. Aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office BP from baseline to week 8 (placebo-corrected decreases: 7.05/4.93, 9.90/6.99, and 7.58/4.95 mm Hg, respectively, P ≤0.014 versus placebo), compared with an unattended automated office BP reduction of 4.84/3.81 mm Hg with lisinopril 20 mg. For patients with valid ambulatory BP, aprocitentan 10, 25, and 50 mg significantly decreased placebo-corrected 24-hour BP by 3.99/4.04, 4.83/5.89, and 3.67/4.45 mm Hg, respectively. Incidence of adverse events was similar in the aprocitentan groups (22.0%–40.2%) and the placebo group (36.6%). Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, an increase in estimated plasma volume, but no change in weight versus placebo. These findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603809.

Objective: Hypertension, a major cardiovascular risk factor, may reach a global prevalence of 1.56 billion by 2025. Much research has been conducted in this field, but few bibliometric studies have been performed. We aimed to analyse the changes in scientific output relating to hypertension over the past two decades. Methods: We analysed, via PubMed and Web of Science, the scientific output relating to hypertension from 1997 to 2016. Quantitative (number of publications) and citation (top 1 and 10%) analyses were performed for output globally and by major countries/regions, with a particular focus on the European Union. Results: In total, 100 789 articles relating to hypertension were identified in Web of Science. The number of publications increased by 52.7% (3989 in 1997, 6092 in 2016). Of the 100 789 articles, 38% had authors from the European Union, 32.1% had authors from the USA, and 26.7% had authors from Asia, with a marked increase in contributions from China over the period analysed. Articles appeared in more than 400 journals and were cited nearly 2 556 000 times. The relative weights of different research fields have also changed over time. Conclusion: Combined use of PubMed and Web of Science enabled robust bibliometric analysis of the studies into hypertension published in the period 1997-2016, including assessment of the contributions from major countries, particularly those in the European Union. This study also allowed us to validate our methodology, which could be used to evaluate research policies and to promote international cooperation.

Abstract Background Endothelin Receptor Antagonists (ERAs) have been investigated for the treatment of a variety of cardiovascular conditions because of their potent vasodilating properties. However, until now, ERAs have only been registered for the treatment of pulmonary arterial hypertension and scleroderma-induced digital ulcers. This class of drugs may also be useful in the treatment of difficult to control hypertension with a medical need. Purpose To investigate the efficacy and safety of various doses of the new dual ERA, aprocitentan, in the treatment of hypertension in order to determine the most appropriate dose(s) for further clinical development using an unattended, automated office BP (AOBP) device (BpTRU). This Phase 2 trial was registered at ClinicalTrials.gov [NCT02603809]. Methods Eligible patients with hypertension (mean sitting systolic/diastolic BP 149.7/97.6 mmHg) received aprocitentan 5, 10, 25 or 50 mg, matching placebo or lisinopril 20 mg as a positive control, once daily for 8 weeks using a randomised, double-blind, parallel-group study design. AOBP was assessed at baseline and weeks 2, 4, 8, and 10 (withdrawal) by recording multiple BP readings with the patient resting quietly. Additionally, 24 h ambulatory BP monitoring was performed at baseline and week 8. Results A total of 490 eligible patients were randomised to the double-blind phase with 430 subjects successfully completing 8 weeks of treatment. Decreases in sitting systolic/diastolic AOBP, from baseline to week 8 were 10.3/6.3, 15.0/9.9, 18.5/12.0 and 15.1/10.0 mmHg for aprocitentan 5, 10, 25, and 50 mg, respectively vs. 7.7/4.9 mmHg for placebo and 12.8/8.4 mmHg for lisinopril. No changes in heart rate or body weight were observed for any dose of aprocitentan. Modelling the dose-response suggested that the maximal effect of aprocitentan is achieved at a dose of approximately 25 mg and that 70% of this effect is already observed at a dose of 10 mg. Aprocitentan treatment was associated with decreases in haemoglobin, haematocrit, and albumin which exhibited a monotonic dose-response relationship, in line with its known vasodilating effects. Estimated increases in plasma volume were 3.0%, 5.1%, 6.9%, and 9.5% for aprocitentan 5, 10, 25, and 50 mg, respectively, vs. 1.6% for lisinopril and a decrease of 0.3% for placebo. All these values are below the accepted pathophysiological threshold of 10%. The overall incidence of adverse events observed in the aprocitentan groups (ranging from 22.0% to 40.2%) was similar to that seen in the placebo group (36.6%). Overall, the most common events were hypertension, headache, and nasopharyngitis. Conclusions These findings support the use of aprocitentan at doses between 10 and 25 mg for further investigation as a potential treatment for hypertension. Acknowledgement/Funding Actelion conducted study. Drug discovery & early clinical pipeline demerged during Johnson & Johnson acquisition. Idorsia supported abstract.

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (low-renin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.

HomeCirculation: Genomic and Precision MedicineVol. 11, No. 4Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension? Francois Alhenc-Gelas, MD and Joel Menard, MD Francois Alhenc-GelasFrancois Alhenc-Gelas INSERM U1138, Paris-Descartes University, Sorbonne University, France. Search for more papers by this author and Joel MenardJoel Menard INSERM U1138, Paris-Descartes University, Sorbonne University, France. Search for more papers by this author Originally published12 Apr 2018https://doi.org/10.1161/CIRCGEN.118.002139Circulation: Genomic and Precision Medicine. 2018;11:e002139See Article by McDonough et alAbundance of a protein in tissues or fluids is probably a quantitative genetic trait in most or even all cases. This can, however, be difficult recognizing and quantifying, depending on whether cellular or secreted proteins are considered and whether synthesis is mainly constitutive or also under the influence of potent physiological, lifestyle-related factors.The issue can be exemplified by protein components of vasomotor peptide systems, renin–angiotensin, and kallikrein–kinin. Genetic determinism of angiotensin-converting enzyme (kininase II) level in plasma or kallikrein activity in urine has been recognized long ago, through familial transmission studies.1,2 Molecular basis for the genetic variability was documented later when gene structure became known.3,4 Genetic polymorphism of plasma angiotensinogen level has also been documented, in that case through genotype–phenotype association study and further gene studies addressing causality and mechanism.5,6These cellular and secreted proteins, angiotensin-converting enzyme, kallikrein, and angiotensinogen are mainly synthesized constitutively, only submitted to mild hormonal influences. There is little or no interference of hemodynamic status and dietary factors with the effect of genetic background, explaining the observation of a strong heritable component of the population variance of plasma or urinary level in transmission and genomic association studies.7 What about renin?Renin Level As a Genetic Trait?Renin synthesis and secretion are largely modulated, acutely and chronically, by renal hemodynamic status, sympathetic nervous system activity, and sodium balance. Renin is synthesized as prorenin in various tissues, but prorenin is only activated in the kidney, in juxtaglomerular cells. Both prorenin and active renin are secreted in plasma. Measurement of active renin has both physiological and clinical relevance and is used, routinely for diagnosis of secondary forms of hypertension. Excess renin secretion is the primary cause of hypertension in renal artery stenosis, and deregulation of the renin-extracellular fluid volume balance is considered to play a prominent role in essential hypertension, a well-established genetic disorder.8 Accordingly, documenting genetic variability in renin level may not only have cognitive interest but also diagnosis application.However, although renin secretion displays large intersubject variability but good within-subject reproducibility,9 there is no strong evidence for a genetic determinism of plasma renin level. Renin is influenced by ethnicity, but this may be linked to renal physiological status. No familial transmission of prorenin or active renin level has been documented to date, albeit mild evidence for heritability was obtained in a twin study.10,11 Instead, intersubject variability in plasma renin activity (PRA) has been linked, in hypertensive subjects, to urinary sodium excretion, a typical lifestyle-related parameter reflecting dietary sodium intake and, at steady state, extracellular fluid volume.8The issue of genetic influence on PRA can nevertheless be addressed through genomic association studies. The approach can now benefit from whole genome scanning.12Renin As a Pharmacogenomic Biomarker?A genome-wide association study (GWAS) of renin is reported by Mc Donough et al13 in the present issue of Circulation: Genomic and Precision Medicine. The study was performed in hypertensive subjects from the PEAR I and PEAR II cohorts (Pharmacogenomic Evaluation of Antihypertensive Responses) and comprises an interesting attempt at the pharmacogenomic extension.Strength of the Mc Donough et al13 study relies on the quality of the cohorts and use of a centralized, reference method for measuring PRA. The PEAR studies address pharmacogenomic evaluation of antihypertensive responses. In PEAR I, the discovery cohort for the renin study, hydrochlorothiazide, a diuretic, or atenolol, a β-blocking agent, were administered as first-line treatment.Several single-nucleotide polymorphisms (SNPs) in several different genomic regions were found to be associated, at a reasonable level of statistical confidence, with baseline PRA, especially in white subjects. Introduction in the analysis of urinary sodium excretion did not alter the main associations. Some of the PRA-associated variants were further tested, through an original prioritization procedure, for functionality by expression quantitative trait locus analysis in RNA from blood cells and for replication of association with PRA in PEAR II.The pharmacogenomic-based prioritization system used for testing SNPs is worth commenting on because of its clinical basis. Prioritization was based on the association of SNP with blood pressure response to hydrochlorothiazide and atenolol. Studies have indeed documented that, at the population level, hypertensive subjects having high PRA respond better to β-blocking agents, whereas those having low PRA respond better to diuretics.14 The former are considered to have renin rather than volume dependent hypertension and the latter the opposite, although this may be sort of an oversimplification. β-blocking agents lower blood pressure in large part through inhibition of renin secretion.15 Therefore, combining the 2 phenotypes, PRA and PRA-dependent therapeutic response may seem logical, providing dual biochemical, and functional (pharmacological) appraisal of renin status in hypertensive subjects. In addition, the approach can identify pharmacogenomic biomarkers.The result of this prioritization attempt is interesting but probably less impressive than may have been expected by the authors: association of candidate SNPs with the expected therapeutic response was observed for 8 SNPs in Whites and 4 in Blacks but in all cases effect was dissociated among the 2 drugs, in partial disagreement with the renin hypothesis. No perfect SNP associated with PRA and with both atenolol and hydrochlorothiazide responses, in the expected directions, was identified in the study. It can be also noted that the variants previously found to be associated with blood pressure response to these drugs in PEAR did not come out in the renin GWAS.13PRA and therapeutic response to antihypertensive agents are 2 different, only partly overlapping phenotypes and this may explain dissociation among drugs, among ethnic groups and among studies. Also, issues of power and multiple testing arise, and chance finding may not be excluded in all cases. Replication of the pharmacogenomic associations has not been tested, but this may be eventually done in PEAR II.Accordingly, SNPs that passed pharmacogenomic prioritization are good candidates for physiological and pharmacological studies, especially if they displayed functionality and replication in PEAR II. The corresponding genomic regions can be further studied for identifying candidate genes and approaching causality. But those that did not pass prioritization should nevertheless be considered for replication of association with PRA in PEAR II and in other studies.Renin and GWASThere have been to date 2 GWAS of renin, performed either in normotensive or in hypertensive populations. Both were published in the Journal.12,13 Results do not overlap between studies. This may tentatively be explained by differences in ethnic composition and health status between the populations studied. In the first study,12 the plasma (pre)kallikrein gene (not to be confounded with tissue kallikrein discussed above) and the kininogen gene were found to be associated with active renin level. The corresponding locus did not come out in the present study.It is interesting to note that prekallikrein is activated during blood sampling in the contact system of coagulation and can convert prorenin to active renin, in vitro.16 It is not known whether this may have influenced the data in both studies.Overall, renin GWAS illustrate the difficulty of documenting genotype–phenotype relationship for proteins that may not have a strong genetic determinism. The authors have addressed the issue in well-phenotyped populations and by using powerful genome analysis procedures. As usual, let’s wait for replication and further gene identification.Considering plasma prorenin as a phenotype in studies might also clarify the issue. Clinical investigation of the renin–angiotensin system has been characterized by the extreme precautions taken to correct results of active renin measurement, either by enzymatic or immunoradiometric assays, according to age, position, time of the day, sodium intake, or urinary sodium excretion. These conditions, necessary for providing accurate diagnosis information, are not fulfilled in most epidemiological studies and many therapeutic trials. Nevertheless, in less stringent conditions than for clinical care, measurement of active renin has been able to predict the incidence of hypertension and major cardiovascular events.17,18But the measurement of active renin might not be the most suitable phenotype for investigating the association of renin level with polymorphisms or mutations in molecular genetic studies. The protein gene product is prorenin, which is subsequently activated and released by the kidney. Prorenin is also produced outside the kidney and is less sensitive to physiological variations governing active renin release. Large samples of subjects will still be necessary for detecting relevant association, but prorenin measurement is easy to perform by trypsin activation or immunometric assay.19 Measuring prorenin should allow investigating a different genetic association than that of active renin release by the kidney.20 Both prorenin and active renin are key regulators of the sodium-pressure loop, with a very likely genetic component.The study by McDonough et al13 is the second attempt to look at GWA of renin, but for several reasons, statistical power and choice of phenotype, it should open an avenue rather than close a research.Sources of FundingThis study supported by INSERM, Paris-Descartes University, Sorbonne University.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circgenetics.ahajournals.orgFrancois Alhenc-Gelas, MD, INSERM U1138, Paris-Descartes University, Sorbonne University, Cordeliers Research Center, 15 Rue de l’Ecole de Medecine, 75006 Paris, France. E-mail [email protected]References1. Cambien F, Alhenc-Gelas F, Herbeth B, Andre JL, Rakotovao R, Gonzales MF, et al. Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study.Am J Hum Genet. 1988; 43:774–780.MedlineGoogle Scholar2. Berry TD, Hasstedt SJ, Hunt SC, Wu LL, Smith JB, Ash KO, et al. A gene for high urinary kallikrein may protect against hypertension in Utah kindreds.Hypertension. 1989; 13:3–8.LinkGoogle Scholar3. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.J Clin Invest. 1990; 86:1343–1346. doi: 10.1172/JCI114844.CrossrefMedlineGoogle Scholar4. Slim R, Torremocha F, Moreau T, Pizard A, Hunt SC, Vuagnat A, et al. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity.J Am Soc Nephrol. 2002; 13:968–976.CrossrefMedlineGoogle Scholar5. 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Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects.Am J Hypertens. 1999; 12:451–459.CrossrefMedlineGoogle Scholar16. Derkx FH, Bouma BN, Schalekamp MP, Schalekamp MA. An intrinsic factor XII- prekallikrein-dependent pathway activates the human plasma renin-angiotensin system.Nature. 1979; 280:315–316.CrossrefMedlineGoogle Scholar17. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.N Engl J Med. 1991; 324:1098–1104. doi: 10.1056/NEJM199104183241605.CrossrefMedlineGoogle Scholar18. Tomaschitz A, Pilz S, Ritz E, Morganti A, Grammer T, Amrein K, et al. Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure.Eur Heart J. 2011; 32:2642–2649. doi: 10.1093/eurheartj/ehr150.CrossrefMedlineGoogle Scholar19. Simon D, Badouaille G, Pau B, Guyene TT, Corvol P, Ménard J. Measurement of active renin by the 4G1 anti-human renin monoclonal antibody.Clin Exp Hypertens A. 1987; 9:1333–1340.MedlineGoogle Scholar20. Martini AG, Xa LK, Lacombe MJ, Blanchet-Cohen A, Mercure C, Haibe-Kains B, et al. Transcriptome analysis of human reninomas as an approach to understanding juxtaglomerular cell biology.Hypertension. 2017; 69:1145–1155. doi: 10.1161/HYPERTENSIONAHA.117.09179.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jung J and Kim H (2022) Shared genetic etiology and antagonistic relationship of plasma renin activity and systolic blood pressure in a Korean cohorts, Genomics, 10.1016/j.ygeno.2022.110334, 114:3, (110334), Online publication date: 1-May-2022. April 2018Vol 11, Issue 4 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002139PMID: 29650769 Originally publishedApril 12, 2018 Keywordsessential hypertensionKallikrein-Kinin Systemrenin-angiotensin systemEditorialsGenome-Wide Association Studyreningenetic determinismpharmacogeneticsPDF download Advertisement SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemClinical StudiesGenetic, Association StudiesHypertensionPharmacology

Whether working conditions contribute to social inequalities in cardiovascular disease is still a matter of debate. The present study investigates the extent to which the social gradient in the incidence of common behavioral and clinical risk factors is explained by work environment. In a well-characterized cohort of 20,625 middle-aged French civil servants followed for 25 years, social status and work environment were globally measured at baseline by combining respectively four socioeconomic indicators (education, wealth, income, occupational grade) and 25 physical, biomechanical, organizational and psychosocial occupational exposures. These 2 global measures are strongly correlated with each other (p < 0.0001), lower is social status, worse is work environment. In proportional hazard regression models adjusted for sex, age and parental cardiovascular disease, low social status increases the incidence of 9 risk factors with hazard ratios ranging from 1.12 to 1.72 while bad work environment increases the incidence of 7 risk factors with hazard ratios ranging from 1.15 to 2.02. Structural equation models to discrete-time survival analysis with moderated mediation show that bad work environment explains nearly 50% of the global effect of low social status on the incidence of the 9 risk factors (p < 0.01). This mediating effect varies substantially from one risk factor to another, explaining 32-39% of social gradients in the risk of physical inactivity, obesity, diabetes, dyslipidemia and 64-90% of gradients in the risk of hypertension, sleep complaints and depression (all p < 0.01). No significant mediating effect of work environment is found for social gradients in the incidence of non-moderate alcohol consumption and smoking. These results suggest that work environment mediates a large part of the social gradient in the incidence of several common cardiovascular risk factors, emphasizing the necessity to include working conditions in policies aimed to reduce social inequalities in health.