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Shao Q, Wang H, Li S, Zeng M, Zhang S, Yan X. IRF5 Mediates Artery Inflammation in Salt-Sensitive Hypertension by Regulating STAT1 and STAT2 Phosphorylation to Increase ESM1 Transcription: Insights from Bioinformatics and Mechanistic Analysis. Int J Mol Sci 2025; 26:3722. [PMID: 40332339 PMCID: PMC12027925 DOI: 10.3390/ijms26083722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/04/2025] [Accepted: 04/06/2025] [Indexed: 05/08/2025] Open
Abstract
Salt-sensitive hypertension (SSH) is closely associated with arterial inflammation, yet its molecular mechanisms remain unclear. In this study, we utilized deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice, which exhibited elevated blood pressure and significant arterial inflammation. Single-cell RNA sequencing (scRNA-seq) identified interferon regulatory factor 5 (IRF5) and its downstream targets, signal transducer and activator of transcription (STAT), as key regulators of these inflammatory changes. In vivo, IRF5 levels were significantly elevated in the DOCA group, while STAT1 and STAT2 protein levels were comparable to those in the normal salt group. However, nuclear levels of phosphorylated STAT1 (pSTAT1) and phosphorylated STAT2 (pSTAT2) were markedly higher in the DOCA group. Furthermore, scRNA-seq analysis showed increased IRF5 expression in endothelial cells (ECs) in both human and mouse aorta samples. In vitro, IRF5 knockdown in artery ECs led to a reduction in nuclear pSTAT1 and pSTAT2 expression. These results suggest that IRF5 promotes STAT1 and STAT2 phosphorylation, enabling their nuclear translocation. Additionally, RNA sequencing indicated a positive correlation between endothelial cell-specific molecule 1 (ESM1) and STAT1/STAT2. Using the UCSC and JASPAR databases, we identified multiple binding sites for the STAT1::STAT2 dimer on the ESM1 promoter. Luciferase reporter assays revealed enhanced ESM1 transcription following pSTAT1::pSTAT2 binding, and pinpoint potential binding sites. Chromatin Immunoprecipitation Quantitative PCR (ChIP-qPCR) further confirmed the specific binding sites between the pSTAT1::pSTAT2 dimer and the ESM1 promoter. These findings highlight the critical role of the IRF5-pSTAT1::pSTAT2-ESM1 pathway in the pathogenesis of SSH and suggest potential therapeutic targets.
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Affiliation(s)
- Qiaoyu Shao
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; (Q.S.); (H.W.); (S.L.); (M.Z.)
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Hao Wang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; (Q.S.); (H.W.); (S.L.); (M.Z.)
| | - Shicheng Li
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; (Q.S.); (H.W.); (S.L.); (M.Z.)
| | - Mengying Zeng
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; (Q.S.); (H.W.); (S.L.); (M.Z.)
| | - Shuyang Zhang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; (Q.S.); (H.W.); (S.L.); (M.Z.)
- Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Xiaowei Yan
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China; (Q.S.); (H.W.); (S.L.); (M.Z.)
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Hu JH, Wang SX, Wang Y, Cao L, Ru K, Xu W, Wang L, Zhang J. Association between salt sensitivity of blood pressure and dietary habits in survey population: A case-control study. Clin Nutr ESPEN 2024; 64:229-235. [PMID: 39299607 DOI: 10.1016/j.clnesp.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 09/02/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular diseases (CVDs) and links dietary salt with blood pressure. However, the study on the relationship between SSBP and dietary habits is rare. This study investigated the relationship between diet and SSBP in different blood pressure statues. METHODS 1459 subjects were assigned into four groups based on a case (hypertension)-control (normotension) study of SSBP and hypertension: 561 Salt-sensitive hypertension (SSH) and 235 non-salt-sensitive hypertension (NSSH) and 424 salt-sensitive normotension (SSN) and 239 non-salt-sensitive normotension (NSSN). Foods information of weekly or daily intakes were recalled. SSBP was tested with the modified salt stress test and was diagnosed with the Sullivan criteria. RESULTS Compared with the NSSH and SSN groups, SSH group have lower intake of fresh fruits (both P < 0.05). Furthermore, NSSN group have the lowest intake of red meat, and bacon (P < 0.05). SSH group have the lowest intake of fresh vegetables (P < 0.05). SSN group have the highest intake of eggs, dairy products, white meat (all P < 0.05). In hypertensive patients, staple food (OR = 0.37, 95%CI: 0.10-0.64) was associated with decreased risk of salt sensitivity. In normotensive subjects, white meat (OR = 0.28, 95%CI: 0.14-0.43) was associated with reduced risk of salt sensitivity, bacon (OR = 5.39, 95%CI: 2.11-8.67) and dairy products (OR = 4.22, 95%CI: 1.82-6.56) and red meat (OR = 2.95, 95%CI: 1.15-4.84) were associated with elevated risk of salt sensitivity. CONCLUSIONS Dietary habits play an important role in SSBP and the role varies with blood pressure especially among population.
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Affiliation(s)
- Ji-Hong Hu
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China.
| | - Shu-Xia Wang
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Yun Wang
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Liangjia Cao
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Keye Ru
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Wenjuan Xu
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Li Wang
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Jiaxuan Zhang
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
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van Rooyen D, Bandulik S, Coon G, Laukemper M, Kumar-Sinha C, Udager AM, Lee C, Wachtel H, Cohen DL, Luther JM, Giordano T, Turcu A, Warth R, Rainey WE, Rege J. Somatic Mutations in MCOLN3 in Aldosterone-Producing Adenomas cause Primary Aldosteronism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.20.619295. [PMID: 39484451 PMCID: PMC11526969 DOI: 10.1101/2024.10.20.619295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase ( CYP11B2 ) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of CYP11B2 transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increased CYP11B2 expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in MCOLN3 which encodes for mucolipin-3 (TRPML3) - a highly conserved inwardly-rectifying, cation-permeable channel. These MCOLN3 mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing MCOLN3 mutations in humans. Functional studies suggest MCOLN3 Y391D might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased CYP11B2 transcription and aldosterone production. This study implicates mutated MCOLN3 as a driver of aldosterone excess in primary aldosteronism. Significance Statement Primary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in human MCOLN3 in aldosterone-producing adenomas (APAs) devoid of known mutations. In vitro investigations showed the MCOLN3 variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.
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Navaneethabalakrishnan S, Goodlett B, Smith H, Montalvo R, Cardenas A, Mitchell B. Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages. Clin Sci (Lond) 2024; 138:921-940. [PMID: 38949840 PMCID: PMC11250104 DOI: 10.1042/cs20240699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/18/2024] [Accepted: 07/01/2024] [Indexed: 07/02/2024]
Abstract
Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads. However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN). Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN). AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet. Control mice were provided standard diet and tap water. AVE treatment significantly attenuated BP and inflammation in mice with SSHTN. Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN. Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice. These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses. Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN. Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.
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Affiliation(s)
| | - Bethany L. Goodlett
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Hannah L. Smith
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Robert A. Montalvo
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Alyssa Cardenas
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Brett M. Mitchell
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
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Abstract
This interdisciplinary review explores the intricate nexus between HIV infection, nutrition, adrenal gland function, and cardiovascular health, highlighting a critical aspect of HIV management often overlooked in current literature. With the advent of antiretroviral therapy, the life expectancy of people living with HIV has dramatically improved, transforming HIV into a manageable chronic condition. However, this success brings forth new challenges, notably an increased risk of cardiovascular diseases among people living with HIV. We examine the normal physiology of the adrenal gland, including its role in mineral metabolism, a crucial facet of nutrition. We discuss the evolution of knowledge tying adrenal pathology to cardiovascular disease. We explore the impact of HIV on adrenal gland findings from a gross pathology perspective, as well as the clinical impact of adrenal insufficiency in HIV. The review further elucidates the role of nutrition in this context, considering the double burden of undernutrition and obesity prevalent in regions heavily affected by HIV. By aggregating findings from longitudinal studies and recent clinical trials, the review presents compelling evidence of increased cardiovascular disease among people living with HIV compared with people without HIV. It highlights the critical role of the adrenal glands in regulating nutrient metabolism and its implications for cardiovascular health, drawing attention to the potential for dietary interventions and targeted therapies to mitigate these risks. This review urges a paradigm shift in the management of HIV, advocating for a holistic approach that incorporates nutritional assessment and interventions into routine HIV care to address the complex interplay between HIV, adrenal function, and cardiovascular health. Through this lens, we offer insights into novel therapeutic strategies aimed at reducing cardiovascular risk in people living with HIV, contributing to the ongoing efforts to enhance the quality of life and longevity in this population.
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Affiliation(s)
- Anxious J Niwaha
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene & Tropical Medicine, Uganda Research Unit, Entebbe (A.J.N.)
| | - James Brian Byrd
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor (J.B.B.)
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Simon Y, Jacques D, Bkaily G. High salt-induced morphological and glycocalyx remodeling of human vascular smooth muscle cells is reversible but induces a high sodium salt-like sensitive memory. Can J Physiol Pharmacol 2023; 101:437-446. [PMID: 37290125 DOI: 10.1139/cjpp-2023-0087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Our recent work showed that short-term treatment (1-2 days) with high sodium salt had no effect on the morphology of human vascular smooth muscle cells (hVSMCs). However, chronic (long-term treatment, 6-16 days) high sodium salt (CHSS) induced hypertrophy and decreased the relative density of the glycocalyx in hVSMCs. Whether this CHSS effect is reversible at both the morphological and the intracellular calcium and sodium levels is unknown. In the present study, we tested the hypothesis that the effect of CHSS on the morphological and functional levels of hVSMCs is reversible. However, it induced an irreversible increase in the sensitivity of the cells following short-term treatment with high extracellular Na+. We tested the effects of the removal of CHSS treatment on the morphology and intracellular sodium and calcium of hVSMCs. Our results showed that restoring average sodium concentration (145 mM) modeled back the relative density of the glycocalyx, the intracellular resting calcium and sodium levels, and the whole cell and nuclear volumes of hVSMCs. In addition, it induced a permanent remodeling of hVSMCs' response to a short-term increase in the extracellular level of sodium salt by developing spontaneous cytosolic and nuclear calcium waves. Our results showed that CHSS is reversible at both the morphological and basal intracellular ionic levels. However, it maintained a high sensitivity to short-term elevation of extracellular sodium. These results suggest that even if chronic high salt is corrected, it induces a high sodium salt-like sensitive memory.
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Affiliation(s)
- Yanick Simon
- Department of immunology and Cell Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Danielle Jacques
- Department of immunology and Cell Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Ghassan Bkaily
- Department of immunology and Cell Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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King JB, Pinheiro LC, Ringel JB, Bress AP, Shimbo D, Muntner P, Reynolds K, Cushman M, Howard G, Manly JJ, Safford MM. Multiple Social Vulnerabilities to Health Disparities and Hypertension and Death in the REGARDS Study. Hypertension 2022; 79:196-206. [PMID: 34784734 PMCID: PMC8665033 DOI: 10.1161/hypertensionaha.120.15196] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Social vulnerabilities increase the risk of developing hypertension and lower life expectancy, but the effect of an individual's overall vulnerability burden is unknown. Our objective was to determine the association of social vulnerability count and the risk of developing hypertension or dying over 10 years and whether these associations vary by race. We used the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) and included participants without baseline hypertension. The primary exposure was the count of social vulnerabilities defined across economic, education, health and health care, neighborhood and built environment, and social and community context domains. Among 5425 participants of mean age 64±10 SD years of which 24% were Black participants, 1468 (31%) had 1 vulnerability and 717 (15%) had ≥2 vulnerabilities. Compared with participants without vulnerabilities, the adjusted relative risk ratio for developing hypertension was 1.16 (95% CI, 0.99-1.36) and 1.49 (95% CI, 1.20-1.85) for individuals with 1 and ≥2 vulnerabilities, respectively. The adjusted relative risk ratio for death was 1.55 (95% CI, 1.24-1.93) and 2.30 (95% CI, 1.75-3.04) for individuals with 1 and ≥2 vulnerabilities, respectively. A greater proportion of Black participants developed hypertension and died than did White participants (hypertension, 38% versus 31%; death, 25% versus 20%). The vulnerability count association was strongest in White participants (P value for vulnerability count×race interaction: hypertension=0.046, death=0.015). Overall, a greater number of socially determined vulnerabilities was associated with progressively higher risk of developing hypertension, and an even higher risk of dying over 10 years.
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Affiliation(s)
- Jordan B. King
- Department of Population Health Sciences, School of Medicine, University of Utah,Institute for Health Research, Kaiser Permanente Colorado
| | | | | | - Adam P. Bress
- Department of Population Health Sciences, School of Medicine, University of Utah
| | - Daichi Shimbo
- Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons
| | - Paul Muntner
- Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham
| | - Kristi Reynolds
- Department of Research and Evaluation, Kaiser Permanente Southern California,Department of Health Systems Science, Kaiser Permanente School of Medicine
| | - Mary Cushman
- Department of Medicine, Larner College of Medicine, University of Vermont
| | - George Howard
- Department of Biostatistics, Ryals School of Public Health, University of Alabama at Birmingham
| | - Jennifer J. Manly
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons
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Alwis US, Verbakel I, Pauwaert K, Delanghe J, Dossche L, Van Camp J, Roggeman S, Everaert K. The Influence of Salt Sensitivity Phenotype on Sodium Excretion and Diuresis: A Chrononutrition Pilot Study. Int J Clin Pract 2022; 2022:9608962. [PMID: 35685516 PMCID: PMC9159230 DOI: 10.1155/2022/9608962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/06/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Chrononutrition studies on interaction of diet/nutrients on endogenous circadian clocks and meal timing on metabolic homeostasis may be of importance in the management of nocturnal polyuria (NP), owing to loss of circadian rhythm in nighttime urination. Dietary salt restriction is an increasingly popular lifestyle recommendation for NP patients. AIM This study aims to evaluate the effect of an acute salt load on diuresis and to study the phenomenon of salt sensitivity. Methodology. Young, healthy men (n = 21, fasted and sober) ingested 500 ml of water on the control day and 8 g and 12 g of salt with water (500 ml) on two other days. Blood and urine samples were collected at 0 hrs, 2 hrs, and 4 hrs and voided volumes were recorded. Diuresis, serum and urine osmolality, sodium, potassium, urea, and creatinine were measured. Salt sensitivity was determined based on the rate of sodium excretion. RESULTS Compared to 8 g, ingestion of 12 g of salt significantly increased diuresis after 4 hrs. Pure water load induced fast diuresis, whereas salt and water load initially reduced diuresis and promoted late increase in diuresis. The total voided volume was significantly lower in the salt sensitive individuals. CONCLUSION Taken together, salt sensitivity profile and type and time of fluid intake are important considerations to build effective personalized lifestyle recommendations for NP patients, which needs further investigation.
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Affiliation(s)
| | - Irina Verbakel
- Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium
| | - Kim Pauwaert
- Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium
| | - Joris Delanghe
- Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
| | - Lien Dossche
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
- Department of Pediatric Nephrology, Ghent University, 9000 Ghent, Belgium
| | - John Van Camp
- Department of Food Technology, Safety and Health, Ghent University, 9000 Ghent, Belgium
| | - Saskia Roggeman
- Research and Policy Department, Psychiatric Center Sint-Jan-Baptist, 9060 Zelzate, Belgium
| | - Karel Everaert
- Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium
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Peng W, Xie Y, Cao H, Qi H, Liu K, Xia J, Liu Z, Liu X, Li B, Wen F, Zhang F, Zhang L. Association study of fasting blood glucose and salt sensitivity of blood pressure in community population: The EpiSS study. Nutr Metab Cardiovasc Dis 2021; 31:2366-2375. [PMID: 34090770 DOI: 10.1016/j.numecd.2021.04.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS To evaluate the association between fasting blood glucose (FBG) and salt sensitivity of blood pressure (SSBP). METHODS AND RESULTS This study is based on the baseline survey of systemic epidemiology of salt sensitivity study. Subjects were classified into salt sensitive (SS) and salt resistant groups according to blood pressure (BP) changes during the modified Sullivan's acute oral saline load and diuresis shrinkage test. Multivariate logistic and linear regression were used to evaluate associations between FBG with SS or BP changes. A total of 2051 participants were included in the analyses with 581 (28.33%) for SS. Multiple analysis showed that for every interquartile range increase in FBG, the OR (95%CI) for SS was 1.140 (1.069, 1.215), β (95%CI) for mean arterial pressure change (ΔMAP1), systolic and diastolic BP changes during saline load were 0.421 (0.221, 0.622), 0.589 (0.263, 0.914) and 0.340 (0.149, 0.531), respectively. Compared to the lowest FBG quartile (Q1), the OR (95%CI) for SS in Q3 and Q4 were 1.342 (1.014, 1.776) and 1.577 (1.194, 2.084), respectively. Compared to subjects with normal FBG, the β (95%CI) for ΔMAP1 was 0.973 (0.055, 1.891) in subjects with impaired FBG, and was 1.449 (0.602, 2.296) in patients with diabetes mellitus. Stratified analyses showed significant and stronger associations between FBG with SSBP in youngers, females, hypertensives, non-diabetics, non-current smokers and non-current drinkers. CONCLUSION Our findings suggest FBG is an independent, dose-dependent associated factor for SSBP, and prevention of SS focusing on controlling FBG elevation in the early stage is important.
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Affiliation(s)
- Wenjuan Peng
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Yunyi Xie
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Han Cao
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Han Qi
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & the Advanced Innovation Center for Human Brain Protection, Beijing Anding Hospital, School of Mental Health, Capital Medical University, Beijing 100088, China
| | - Kuo Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Juan Xia
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Zheng Liu
- Science Department, Peking University People's Hospital, Beijing 100044, China
| | - Xiaohui Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Bingxiao Li
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Fuyuan Wen
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Fengxu Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China
| | - Ling Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, and Beijing Municipal Key Laboratory of Clinical Epidemiology Beijing, 100069, China.
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Kim SS, Park S, Jin HS. Interaction between ALDH2 rs671 and life habits affects the risk of hypertension in Koreans: A STROBE observational study. Medicine (Baltimore) 2021; 100:e26664. [PMID: 34260573 PMCID: PMC8284761 DOI: 10.1097/md.0000000000026664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 06/28/2021] [Indexed: 01/04/2023] Open
Abstract
Aldehyde dehydrogenase-2 (ALDH2) is associated with the risk of hypertension, and the effects of lifestyle factors on blood pressure vary according to genotype. Among the Han Chinese, the risk of hypertension is lower in the group with the rs671 A allele than in the group with the G allele, and there is a significant association between the frequency of fried food consumption and hypertension. However, the A allele significantly increases the risk of hypertension with increased fried food intake. This study aimed to investigate the effect of the relationship between ALDH2 polymorphism and complex lifestyle habits (fried food consumption and exercise) on hypertension.rs671 polymorphisms of ALDH2 were examined using Korean genome and epidemiology data from 8157 hypertensive cases and 9550 controls. Further, we investigated whether the A allele is protective against hypertension in Koreans and explored the effect of the combination of fried food intake and exercise habits on hypertension by genotype.The genotype frequencies of rs671, which is specific to East Asia, were 2.51% AA, 26.66% GA, and 70.83% GG in the Korean population. The group with inactive aldehyde dehydrogenase-2 had a low odds ratio [OR = 0.75 (95% CI:0.69-0.80), P = 4.35 × 10-14] of hypertension, and low metabolism of acetaldehyde. Subjects carrying the A allele exhibited an increased risk of hypertension with increased fried food intake without exercise [OR = 2.256 (95% CI:1.094-4.654), P = .028].ALDH2 polymorphism and complex lifestyle habits (fried food consumption and exercise) are associated with the risk of hypertension. Further, the A allele is associated with a low risk of hypertension, but it increases the risk of hypertension as fried food intake without exercise increases.
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11
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Schmidt IM, Waikar SS. Separate and Unequal: Race-Based Algorithms and Implications for Nephrology. J Am Soc Nephrol 2021; 32:529-533. [PMID: 33510038 PMCID: PMC7920170 DOI: 10.1681/asn.2020081175] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Insa M Schmidt
- Section of Nephrology, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
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12
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Contribution of systemic blood flow to untreated or inadequately controlled systolic--diastolic or isolated systolic hypertension in a community sample of African ancestry. J Hypertens 2020; 39:526-537. [PMID: 32868640 DOI: 10.1097/hjh.0000000000002635] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIMS Age-related increases in systemic blood flow [stroke volume (SV), cardiac output (CO), and aortic flow (Q)] contribute substantially to untreated or inadequately controlled (uncontrolled) blood pressure (BP) in Africa. We aimed to identify the haemodynamic determinants of uncontrolled systolic--diastolic (Syst--diast HT) versus uncontrolled isolated systolic (ISH) or diastolic (IDH) hypertension. METHODS Using central arterial pressure and aortic outflow tract velocity and diameter measurements (echocardiography), the haemodynamic correlates of BP were determined in 725 community participants of African ancestry (19.6% uncontrolled Syst--diast HT, 9.2% uncontrolled ISH, 11.3% uncontrolled IDH). RESULTS Independent of confounders, compared with those with a normotensive BP, those with uncontrolled Syst--diast HT had increases in SV, CO, Q, systemic vascular resistance (SVR) and aortic characteristic impedance (Zc) and decreases in total arterial compliance (TAC) (P < 0.05--P < 0.0001). In multivariate regression models, uncontrolled Syst--diast HT was as strongly associated with Q, SV or CO as with SVR (P = 0.04--P = 0.20), Zc (P = 0.74--P < 0.0005) and TAC (P = 0.43--P < 0.005). Independent of confounders, compared with normotensive individuals those with uncontrolled ISH had increases in SV, CO, Q and Zc but not SVR, and decreases in TAC (P < 0.05-P < 0.0001), and those with IDH only had increases in SVR (P < 0.0001). Uncontrolled ISH was more strongly associated with Q, SV and CO than with SVR (P < 0.0005), but less than with TAC (P < 0.05--P < 0.0005). CONCLUSION In groups of African ancestry living in Africa, hypertension because of increases in either SBP or DBP is as strongly associated with increases in systemic flow (SV, Q) as with arterial and arteriolar effects (Zc, TAC, SVR).
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13
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Woodiwiss AJ, Mmopi KN, Peterson V, Libhaber C, Bello H, Masiu M, Fernandes DDS, Tade G, Mthembu N, Peters F, Sareli P, Norton GR. Distinct Contribution of Systemic Blood Flow to Hypertension in an African Population Across the Adult Lifespan. Hypertension 2020; 76:410-419. [DOI: 10.1161/hypertensionaha.120.14925] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Although hypertension in groups of African ancestry is volume-dependent, the relative impact of systemic flow (stroke volume, peak aortic flow [Q]) versus vascular mechanisms (systemic vascular resistance, aortic characteristic impedance [Zc], total arterial compliance) components of arterial load has not been evaluated across the adult age range. In participants of African ancestry (n=824, age=16–99 years, 68.3% female), using central arterial pressure and aortic velocity and diameter measurements in the outflow tract, we determined the hemodynamic correlates of age-related increases in blood pressure. Strong independent positive relations between age and stroke volume or peak aortic Q were noted (
P
<0.0001), effects associated with ventricular end diastolic volume and aldosterone-to-renin ratios. Age-related increases in mean arterial pressure were associated with stroke volume and not systemic vascular resistance. Although age-Q relations began from early adulthood, initially an inverse association between age and aortic Zc (
P
<0.0001) driven by increments in aortic root diameter (
P
<0.0001) prevented an enhanced systolic blood pressure and pulse pressure. When Zc began to positively relate to age (
P
<0.0001), age-Q relations translated into increases in forward wave pressures and hence systolic blood pressure and pulse pressure. Age relations with pulse pressure were as strongly determined by Q as by Zc or total arterial compliance (0.027±0.001 versus 0.028±0.001 and 0.032±0.003 mm Hg per yearly increase in pulse pressure produced by Q, Zc, and total arterial compliance;
P
<0.0001). Uncontrolled hypertension (confirmed with 24-hour blood pressure) was determined more by Q, Zc, and total arterial compliance than by increases in systemic vascular resistance (
P
<0.0005 for comparison). In conclusion, relationships between age and systemic blood flow contribute markedly to hypertension in groups of African origins.
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Affiliation(s)
- Angela J. Woodiwiss
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Keneilwe N. Mmopi
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Vernice Peterson
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Carlos Libhaber
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Hamza Bello
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Mohlabani Masiu
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Daniel Da Silva Fernandes
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Grace Tade
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Nonhlanhla Mthembu
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Ferande Peters
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Pinhas Sareli
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Gavin R. Norton
- From the Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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14
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Citterio L, Delli Carpini S, Lupoli S, Brioni E, Simonini M, Fontana S, Zagato L, Messaggio E, Barlassina C, Cusi D, Manunta P, Lanzani C. Klotho Gene in Human Salt-Sensitive Hypertension. Clin J Am Soc Nephrol 2020; 15:375-383. [PMID: 31992575 PMCID: PMC7057312 DOI: 10.2215/cjn.08620719] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/23/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Hypertension is a common aging-related disorder. Salt intake is one of the main environmental factors contributing to the development of hypertension. Transgenic mice with one-half Klotho deficiency displayed a spontaneous BP increase and salt-sensitive hypertension in response to high sodium intake. Usually circulating levels of α-Klotho decrease with age, and this reduction may be stronger in patients with several aging-related diseases. This study aimed at exploring the association of Klotho with salt sensitivity in humans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The role of Klotho polymorphisms and α-Klotho serum levels was evaluated in patients with hypertension who were treatment naive and underwent an acute salt-sensitivity test (discovery n=673, intravenous 2 L of 0.9% saline in 2 hours). Salt sensitivity was defined as a mean BP increase of >4 mm Hg at the end of the infusion. A total of 32 single nucleotide polymorphisms in the Klotho gene (KL), previously identified with a genome-wide association study, were used in the genetic analysis and studied for a pressure-natriuresis relationship. RESULTS Of the patients with hypertension, 35% were classified as salt sensitive. The most relevant polymorphism associated with pressure natriuresis was the common missense single nucleotide polymorphism rs9536314, and the GG and GT genotypes were more represented among patients who were salt sensitive (P=0.001). Those carrying the G allele showed a less steep pressure-natriuresis relationship, meaning that a significant increase in mean BP was needed to excrete the same quantity of salt compared with patients who were salt resistant. KL rs9536314 also replicated the pressure-natriuresis association in an independent replication cohort (n=193) and in the combined analysis (n=866). There was an inverse relationship between circulating Klotho and mean BP changes after the saline infusion (r=-0.14, P=0.03). Moreover, circulating α-Klotho was directly related to kidney function at baseline eGFR (r=0.22, P<0.001). CONCLUSIONS KL rs9536314 is associated with salt-sensitive hypertension in patients with hypertension who are treatment naive. Moreover, circulating α-Klotho levels were mainly related to diastolic BP changes at the end of a salt load and to eGFR as an expression of kidney aging.
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Affiliation(s)
- Lorena Citterio
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Simona Delli Carpini
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Sara Lupoli
- Department of Health Sciences, University of Milan, Filarete Foundation, Milan, Italy
| | - Elena Brioni
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Marco Simonini
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Simone Fontana
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Laura Zagato
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Elisabetta Messaggio
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Cristina Barlassina
- Department of Health Sciences, University of Milan, Filarete Foundation, Milan, Italy
| | - Daniele Cusi
- Institute of Biomedical Technologies, National Research Council of Italy (Consiglio Nazionale delle Ricerche, CNR), Milan, Italy; and
- Bio4Dreams Scientific Unit, Bio4Dreams—Business Nursery for Life Sciences, Milan, Italy
| | - Paolo Manunta
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Chiara Lanzani
- Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
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15
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Frame AA, Puleo F, Kim K, Walsh KR, Faudoa E, Hoover RS, Wainford RD. Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. Am J Physiol Renal Physiol 2019; 317:F1623-F1636. [PMID: 31608673 DOI: 10.1152/ajprenal.00264.2019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl- cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.
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Affiliation(s)
- Alissa A Frame
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Franco Puleo
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Kiyoung Kim
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Kathryn R Walsh
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
| | - Elizabeth Faudoa
- College of Arts and Sciences, Boston University, Boston, Massachusetts
| | - Robert S Hoover
- Research Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia.,Division of Nephrology, Department of Medicine, Emory University, Atlanta, Georgia
| | - Richard D Wainford
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
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16
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Central antihypertensive effects of chronic treatment with RB150: an orally active aminopeptidase A inhibitor in deoxycorticosterone acetate-salt rats. J Hypertens 2019; 36:641-650. [PMID: 28968260 DOI: 10.1097/hjh.0000000000001563] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE Hyperactivity of the brain renin-angiotensin (Ang) system has been implicated in the development and maintenance of hypertension. AngIII, one of the main effector peptides of the brain renin-Ang system, exerts a tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of hypertension. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. When given orally in acute treatment in hypertensive rats, RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain, inhibits brain APA activity and decreases BP. We investigate, here, the antihypertensive effects of chronic oral RB150 (50 mg/kg per day) treatment over 24 days in alert hypertensive deoxycorticosterone acetate-salt rats. METHODS We measured variations in Brain APA enzymatic activity, SBP, plasma arginine vasopressin levels and metabolic parameters after RB150 chronic administration. RESULTS This resulted in a significant decrease in SBP over the 24-day treatment period showing that no tolerance to the antihypertensive RB150 effect was observed throughout the treatment period. Chronic RB150 treatment also significantly decreased plasma arginine vasopressin levels and increased diuresis, which participate to BP decrease by reducing the size of fluid compartment. Interestingly, we observed an increased natriuresis without modifying both plasma sodium and potassium levels. CONCLUSION Our results strengthen the interest of developing RB150 as a novel central-acting antihypertensive agent and evaluating its efficacy in salt-sensitive hypertension.
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17
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Kokubo Y, Padmanabhan S, Iwashima Y, Yamagishi K, Goto A. Gene and environmental interactions according to the components of lifestyle modifications in hypertension guidelines. Environ Health Prev Med 2019; 24:19. [PMID: 30857519 PMCID: PMC6410507 DOI: 10.1186/s12199-019-0771-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 02/24/2019] [Indexed: 12/24/2022] Open
Abstract
Risk factors for hypertension consist of lifestyle and genetic factors. Family history and twin studies have yielded heritability estimates of BP in the range of 34–67%. The most recent paper of BP GWAS has explained about 20% of the population variation of BP. An overestimation of heritability may have occurred in twin studies due to violations of shared environment assumptions, poor phenotyping practices in control cohorts, failure to account for epistasis, gene-gene and gene-environment interactions, and other non-genetic sources of phenotype modulation that are suspected to lead to underestimations of heritability in GWAS. The recommendations of hypertension guidelines in major countries consist of the following elements: weight reduction, a healthy diet, dietary sodium reduction, increasing physical activity, quitting smoking, and moderate alcohol consumption. The hypertension guidelines are mostly the same for each country or region, beyond race and culture. In this review, we summarize gene-environmental interactions associated with hypertension by describing lifestyle modifications according to the hypertension guidelines. In the era of precision medicine, clinicians who are responsible for hypertension management should consider the gene-environment interactions along with the appropriate lifestyle components toward the prevention and treatment of hypertension. We briefly reviewed the interaction of genetic and environmental factors along the constituent elements of hypertension guidelines, but a sufficient amount of evidence has not yet accumulated, and the results of genetic factors often differed in each study.
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Affiliation(s)
- Yoshihiro Kokubo
- Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka, 565-8565, Japan. .,Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
| | - Sandosh Padmanabhan
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Yoshio Iwashima
- Division of Hypertension and Nephrology, Department of Medicine, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kazumasa Yamagishi
- Department of Public Health Medicine, Faculty of Medicine, and Health Services Research and Development Center, University of Tsukuba, Tsukuba, Japan
| | - Atsushi Goto
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
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18
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Gonzalez-Vicente A, Saez F, Monzon CM, Asirwatham J, Garvin JL. Thick Ascending Limb Sodium Transport in the Pathogenesis of Hypertension. Physiol Rev 2019; 99:235-309. [PMID: 30354966 DOI: 10.1152/physrev.00055.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The thick ascending limb plays a key role in maintaining water and electrolyte balance. The importance of this segment in regulating blood pressure is evidenced by the effect of loop diuretics or local genetic defects on this parameter. Hormones and factors produced by thick ascending limbs have both autocrine and paracrine effects, which can extend prohypertensive signaling to other structures of the nephron. In this review, we discuss the role of the thick ascending limb in the development of hypertension, not as a sole participant, but one that works within the rich biological context of the renal medulla. We first provide an overview of the basic physiology of the segment and the anatomical considerations necessary to understand its relationship with other renal structures. We explore the physiopathological changes in thick ascending limbs occurring in both genetic and induced animal models of hypertension. We then discuss the racial differences and genetic defects that affect blood pressure in humans through changes in thick ascending limb transport rates. Throughout the text, we scrutinize methodologies and discuss the limitations of research techniques that, when overlooked, can lead investigators to make erroneous conclusions. Thus, in addition to advancing an understanding of the basic mechanisms of physiology, the ultimate goal of this work is to understand our research tools, to make better use of them, and to contextualize research data. Future advances in renal hypertension research will require not only collection of new experimental data, but also integration of our current knowledge.
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Affiliation(s)
| | - Fara Saez
- Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio
| | - Casandra M Monzon
- Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio
| | - Jessica Asirwatham
- Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio
| | - Jeffrey L Garvin
- Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio
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19
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Thi Minh Nguyen T, Miura K, Tanaka-Mizuno S, Tanaka T, Nakamura Y, Fujiyoshi A, Kadota A, Tamaki J, Takebayashi T, Okamura T, Ueshima H. Association of blood pressure with estimates of 24-h urinary sodium and potassium excretion from repeated single-spot urine samples. Hypertens Res 2018; 42:411-418. [PMID: 30523292 DOI: 10.1038/s41440-018-0152-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/26/2018] [Accepted: 06/10/2018] [Indexed: 02/07/2023]
Abstract
While the association between 24-h urinary sodium and potassium excretion with blood pressure is well established, the relationships of these ions to spot urine measurements are unclear. Our purpose is to assess the association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. Spot urine and blood pressure were collected annually during a 5-year period from 4360 Japanese workers with ages ranging from 19 to 55 years. Estimates of 24-h sodium and potassium excretion were based on Tanaka's formula. Overall, a single standard deviation increase in the estimated sodium excretion (36.5 mmol/day) was associated with a 1.3 mmHg higher systolic blood pressure and a 0.8 mmHg higher diastolic blood pressure (P < 0.001). A single standard deviation increase in estimated potassium excretion (8.9 mmol/day) was associated with a 1.1 mmHg lower systolic blood pressure and a 0.7 mmHg lower diastolic blood pressure (P < 0.001). As a combined measure of the excretion of both electrolytes, the estimated 24-h sodium-to-potassium ratio was positively associated with both blood pressures (P < 0.001). Associations of blood pressure with sodium and the sodium-to-potassium ratio increased with age and were stronger in men compared to women. Associations with potassium and the sodium-to-potassium ratio were stronger in individuals who were overweight. The findings provide evidence for an association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. As convenient measures of dietary intake for each electrolyte, repeated spot urine samples may be useful for assessing hypertension risk, especially in men, older individuals, and overweight individuals.
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Affiliation(s)
- Trang Thi Minh Nguyen
- Department of Public Health, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.,Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Katsuyuki Miura
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan. .,Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
| | | | | | - Yasuyuki Nakamura
- Department of Food Science and Human Nutrition, Ryukoku University, Otsu, Japan
| | - Akira Fujiyoshi
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Aya Kadota
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan.,Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan
| | - Junko Tamaki
- Department of Hygiene and Public Health, Osaka Medical University, Takatsuki, Japan
| | - Toru Takebayashi
- Department of Preventive Medicine and Public Health, Keio University, Tokyo, Japan
| | - Tomonori Okamura
- Department of Preventive Medicine and Public Health, Keio University, Tokyo, Japan
| | - Hirotsugu Ueshima
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan.,Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan
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20
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Wenner MM, Paul EP, Robinson AT, Rose WC, Farquhar WB. Acute NaCl Loading Reveals a Higher Blood Pressure for a Given Serum Sodium Level in African American Compared to Caucasian Adults. Front Physiol 2018; 9:1354. [PMID: 30327611 PMCID: PMC6174209 DOI: 10.3389/fphys.2018.01354] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 09/07/2018] [Indexed: 01/13/2023] Open
Abstract
Purpose: African American individuals are more prone to salt-sensitive hypertension than Caucasian individuals. Small changes in serum sodium (Na+) result in increased blood pressure (BP). However, it remains unclear if there are racial differences in BP responsiveness to increases in serum Na+. Therefore, the purpose of this investigation was to determine if African American adults have altered BP responsiveness to acute changes in serum Na+ compared to Caucasian adults. Methods: We measured beat-by-beat BP, serum Na+, plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone (Aldo) during a 60-min 3% NaCl infusion (hypertonic saline infusion, HSI) in 39 participants (19 African Americans, age: 23 ± 1, 20 Caucasians, age: 25 ± 1). Data reported as African American vs. Caucasian cohort, mean ± SEM. Results: Baseline BP and serum Na+ were similar between groups and increased during HSI in both African American and Caucasian participants (p < 0.01). However, the peak change in serum Na+ was greater in African American participants (Δ5.8 ± 0.34 vs. Δ4.85 ± 0.38 mmol/L, p = 0.03). There was a significant group effect (p = 0.02) and an interaction between race and serum Na+ on systolic BP (p = 0.02). Larger categorical changes in serum Na+ corresponded to changes in systolic BP (p < 0.01) and African American participants demonstrated greater systolic BP responses for a given categorical serum Na+ increase (p < 0.01). Baseline Aldo was lower in African American adults (7.2 ± 0.6 vs. 12.0 ± 1.9 ng/dL, p = 0.03), there was a trend for lower baseline PRA (0.59 ± 0.9 vs. 1.28 ± 0.34 ng/mL/h, p = 0.07), and baseline Ang II was not different (14.2 ± 1.8 vs. 18.5 ± 1.4 pg/mL, p = 0.17). PRA and Aldo decreased during the HSI (p ≤ 0.01), with a greater decline in PRA (Δ–0.31 ± 0.07 vs. Δ–0.85 ± 0.25 ng/mL/h, p < 0.01) and Aldo (Δ–2.5 ± 0.5 vs. Δ–5.0 ± 1.1 ng/dL, p < 0.01) in Caucasian participants. However, the racial difference in PRA (p = 0.57) and Aldo (p = 0.59) reduction were no longer significant following baseline covariate analysis. Conclusion: African American individuals demonstrate augmented serum Na+ to an acute hypertonic saline load and greater systolic BP responsiveness to a given serum Na+. The altered BP response may be attributable to lower basal PRA and Aldo and a subsequently blunted RAAS response during the HSI.
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Affiliation(s)
- Megan M Wenner
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, United States
| | - Erin P Paul
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, United States
| | - Austin T Robinson
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, United States
| | - William C Rose
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, United States
| | - William B Farquhar
- Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, United States
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21
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Poledne R, Zicha J. Human genome evolution and development of cardiovascular risk factors through natural selection. Physiol Res 2018; 67:155-163. [PMID: 29726690 DOI: 10.33549/physiolres.933885] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Impressive advances in molecular genetic techniques allow to analyze the effects of natural selection on the development of human genome. For example, the trend towards blonde hair and blue eyes was documented. The approach to analyze possible effects of natural selection on the evolution of recent phenotypes with high risk of cardiovascular disease has not been described yet. A possible effect on the evolution of two main risk factors - hypercholesterolemia and hypertension - is presented. The close relationship of non-HDL cholesterol blood concentration to the proportion of pro-inflammatory macrophages in human visceral adipose tissue might be a result of long-lasting natural selection. Individuals with higher proportion of this phenotype might also display a higher ability to fight infection, which was very common in human setting from prehistory until Middle Ages. Successful battle against infections increased the probability to survive till reproductive age. Similar hypothesis was proposed to explain frequent hypertension in African Americans. A long-lasting selection for higher ability to conserve sodium during long-term adaptation to low sodium intake and hot weather was followed by a short-term (but very hard) natural selection of individuals during transatlantic slave transport. Only those with very high capability to retain sodium were able to survive. Natural selection of phenotypes with high plasma cholesterol concentration and/or high blood pressure is recently potentiated by high-fat high-sodium diet and overnutrition. This hypothesis is also supported by the advantage of familial hypercholesterolemia in the 19th century (at the time of high infection disease mortality) in contrast to the disadvantage of familial hypercholesterolemia during the actual period of high cardiovascular disease mortality.
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Affiliation(s)
- R Poledne
- Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.
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22
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Titze J, Luft FC. Speculations on salt and the genesis of arterial hypertension. Kidney Int 2018; 91:1324-1335. [PMID: 28501304 DOI: 10.1016/j.kint.2017.02.034] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 02/17/2017] [Accepted: 02/21/2017] [Indexed: 12/25/2022]
Abstract
Blood pressure salt sensitivity and salt resistance are mechanistically imperfectly explained. A prescient systems medicine approach by Guyton and colleagues-more than 50 years ago-suggested how salt intake might influence blood pressure. They proposed that a high-salt diet engenders sodium accumulation, volume expansion, cardiac output adjustments, and then autoregulation for flow maintenance. The autoregulation in all vascular beds increases systemic vascular resistance, causing the kidneys to excrete more salt and water, thus reducing systems to normal and minimizing any changes in blood pressure. This schema, which is remarkably all encompassing, included all regulatory mechanisms Guyton could identify at the time. Guyton introduced the idea that the kidney is central, particularly concerning the regulation of renal pressure natriuresis. Numerous criticisms have been subsequently raised, particularly recently. Kurtz and colleagues argue that the ability of individuals to respond with an appropriate vasodilatory response to increased salt intake is pivotal. Data exist to address that issue. Salt-resistant hypertensive models provide additional information. We identified a mendelian form of hypertension not related to sodium reabsorption in the distal nephron. The hypertension develops because of increased systemic vascular resistance. In addition, we rediscovered a third salt-storage glycose-aminoglycan-related compartment, largely in the skin. This compartment operates independently of renal function, and when perturbed, is associated with salt sensitivity. More recently, we found novel molecular mechanisms demonstrating how large salt quantities are excreted by the kidneys with minimal water losses. We introduce novel interpretations as to how the kidneys excrete salt when the intake is high. The findings could have relevance as to how blood pressure may be regulated at varying salt intakes. Our purposes are to provide the readership with a banquet of thoughts to digest, to pursue Guyton's ideas, and to adjust them accordingly.
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Affiliation(s)
- Jens Titze
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Friedrich C Luft
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine, Charité Medical Faculty, Berlin, Germany.
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Frame AA, Wainford RD. Mechanisms of altered renal sodium handling in age-related hypertension. Am J Physiol Renal Physiol 2018; 315:F1-F6. [PMID: 29442548 DOI: 10.1152/ajprenal.00594.2017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The prevalence of hypertension rises with age to approximately two out of three adults over the age of 60 in the United States. Although the mechanisms underlying age-related hypertension are incompletely understood, sodium homeostasis is critical to the long-term regulation of blood pressure and there is strong evidence that aging is associated with alterations in renal sodium handling. This minireview focuses on recent advancements in our understanding of the vascular, neurohumoral, and renal mechanisms that influence sodium homeostasis and promote age-related hypertension.
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Affiliation(s)
- Alissa A Frame
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine and The Whitaker Cardiovascular Institute , Boston, Massachusetts
| | - Richard D Wainford
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine and The Whitaker Cardiovascular Institute , Boston, Massachusetts
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Mirmiran P, Bahadoran Z, Nazeri P, Azizi F. Dietary sodium to potassium ratio and the incidence of hypertension and cardiovascular disease: A population-based longitudinal study. Clin Exp Hypertens 2018; 40:772-779. [PMID: 29381403 DOI: 10.1080/10641963.2018.1431261] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE There is an interaction between dietary sodium/potassium intake in the pathogenesis of hypertension (HTN) and cardiovascular disease (CVD). The aim of this study was to investigate the association of dietary sodium to potassium (Na/K) ratio and the risk of HTN and CVD in a general population of Iranian adults. METHODS In this prospective cohort study, adults men and women with complete baseline data were selected from among participants of the Tehran Lipid and Glucose Study and were followed up for 6.3 years for incidence of HTN and CVD outcomes. Dietary sodium and potassium were assessed using a valid and reliable 168-item food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between dietary sodium, potassium and their ratio and risk of outcomes. RESULTS During the study follow-up, 291 (15.1%) and 79 (5.0%) new cases of HTN and CVD were identified, respectively. No significant association was observed between usual intakes of sodium, potassium and dietary Na/K ratio with the incidence of HTN. There was no significant association between dietary intakes of sodium and potassium per se and the risk of CVD, whereas when dietary sodium to potassium ratio was considered as exposure in the fully-adjusted Cox regression model, and participants in the highest compared to lowest tertile had a significantly increased risk of CVD (HR = 2.19, 95% CI = 1.16-4.14). CONCLUSIONS Our findings suggest that high dietary Na/K ratio could contribute to increased risk of CVD events.
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Affiliation(s)
- Parvin Mirmiran
- a Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology , National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Zahra Bahadoran
- b Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Pantea Nazeri
- b Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Fereidoun Azizi
- c Endocrine Research Center , Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
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Mellendick K, Shanahan L, Wideman L, Calkins S, Keane S, Lovelady C. Diets Rich in Fruits and Vegetables Are Associated with Lower Cardiovascular Disease Risk in Adolescents. Nutrients 2018; 10:E136. [PMID: 29382069 PMCID: PMC5852712 DOI: 10.3390/nu10020136] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/18/2018] [Accepted: 01/23/2018] [Indexed: 12/17/2022] Open
Abstract
Obesity and cardiovascular disease (CVD) risk are public health concerns in adolescents, yet few studies have examined the association of their diet to CVD risk factors. This study investigated associations between diet, body mass index (BMI), waist circumference (WC), blood pressure (BP), and blood lipids in 163 16-17 year olds. Diet recall data were converted into Healthy Eating Index-2010 (HEI) to assess diet quality. Differences in diet between groups with normal or obese BMI, normal or hypertensive BP, and normal or altered lipids were determined. Associations between diet and BMI, WC, BP, and lipids, controlling for race, gender, and socioeconomic status, were examined. Mean HEI was 49.2 (±12.0), with no differences observed between groups. HEI was not associated with any CVD risk. Sweetened beverage consumption was higher in obese adolescents, and positively related to total cholesterol (TC). Fruit intake was negatively related to BMI and diastolic BP. Total vegetable intake was negatively related to systolic BP. Greens and beans were negatively related to TC and LDL. Whole grains were negatively related to HDL. This research suggests a cardioprotective effect of diets rich in fruits and vegetables, as well as low in sweetened beverages in adolescents.
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Affiliation(s)
- Kevan Mellendick
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC, 27412, USA.
| | - Lilly Shanahan
- Jacobs Center for Productive Youth Development, University of Zurich, CH-8050 Zurich, Switzerland.
| | - Laurie Wideman
- Department of Kinesiology, University of North Carolina at Greensboro, Greensboro, NC, 27412, USA.
| | - Susan Calkins
- Department of Human Development & Family Studies, Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, 27412, USA.
| | - Susan Keane
- Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, 27412, USA.
| | - Cheryl Lovelady
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC, 27412, USA.
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Brewster LM, Oudman I, Nannan Panday RV, Khoyska I, Haan YC, Karamat FA, Clark JF, van Montfrans GA. Creatine kinase and renal sodium excretion in African and European men on a high sodium diet. J Clin Hypertens (Greenwich) 2018; 20:334-341. [PMID: 29357199 DOI: 10.1111/jch.13182] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/26/2017] [Accepted: 09/30/2017] [Indexed: 01/11/2023]
Abstract
Creatine kinase (CK) rapidly regenerates ATP for Na+ /K+ -ATPase driven sodium retention throughout the kidney. Therefore, we assessed whether resting plasma CK is associated with sodium retention after a high sodium diet. Sixty healthy men (29 European and 31 African ancestry) with a mean age of 37.2 years (SE 1.2) were assigned to low sodium intake (< 50 mmol/d) during 7 days, followed by 3 days of high sodium intake (> 200 mmol/d). Sodium excretion (mmol/24-h) after high sodium was 260.4 (28.3) in the high CK tertile versus 415.2 (26.3) mmol/24-h in the low CK tertile (P < .001), with a decrease in urinary sodium excretion of 98.4 mmol/24-h for each increase in log CK, adjusted for age and African ancestry. These preliminary results are in line with the energy buffering function of the CK system, but more direct assessments of kidney CK will be needed to further establish whether this enzyme enhances sodium sensitivity.
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Affiliation(s)
- Lizzy M Brewster
- Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Inge Oudman
- Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Rani V Nannan Panday
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Inna Khoyska
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Yentl C Haan
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Fares A Karamat
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Joseph F Clark
- The Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH, USA
| | - Gert A van Montfrans
- Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Kirabo A. A new paradigm of sodium regulation in inflammation and hypertension. Am J Physiol Regul Integr Comp Physiol 2017; 313:R706-R710. [PMID: 28931546 DOI: 10.1152/ajpregu.00250.2017] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/28/2017] [Accepted: 09/12/2017] [Indexed: 01/13/2023]
Abstract
Dysregulation of sodium (Na+) balance is a major cause of hypertensive cardiovascular disease. The current dogma is that interstitial Na+ readily equilibrates with plasma and that renal excretion and reabsorption is sufficient to regulate extracellular fluid volume and control blood pressure. These ideas have been recently challenged by the discovery that Na+ accumulates in tissues without commensurate volume retention and activates immune cells, leading to hypertension and autoimmune disease. However, objections have been raised to this new paradigm, with some investigators concerned about where and how salt is stored in tissues. Further concerns also include how Na+ is mobilized from tissue stores and how it interacts with various organ systems to cause hypertension and end-organ damage. This review assesses these two paradigms of Na+ regulation in the context of inflammation-mediated hypertension and cardiovascular disease pathogenesis. Also highlighted are future perspectives and important gaps in our understanding of how Na+ is linked to inflammation and hypertension. Understanding mechanisms of salt and body fluid regulation is the sine qua non of research efforts to identify therapeutic targets for hypertension and cardiovascular disease.
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Affiliation(s)
- Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and .,Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville Tennessee
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Associations between aldehyde dehydrogenase 2 (ALDH2) rs671 genetic polymorphisms, lifestyles and hypertension risk in Chinese Han people. Sci Rep 2017; 7:11136. [PMID: 28894224 PMCID: PMC5593832 DOI: 10.1038/s41598-017-11071-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 08/16/2017] [Indexed: 02/07/2023] Open
Abstract
Hypertension is a multiple factor disease which was influenced by gene, environment, and lifestyle. Several studies confirmed that the ALDH2 rs671 polymorphism is associated with hypertension. However, the evidence remains inconclusive. Whether lifestyle affects blood pressure in different genotype groups have not been clarified, either. The subjects were adult Chinese Han people who received health examination in the period from December 2014 to December 2015. Detection of the ALDH2 r671 polymorphism was determined by polymerase chain reaction. Lifestyle data were collected using self-administered questionnaires. Basic characteristics and fasting venous blood sample were collected at baseline. 4018 subjects were eligible for participation.The frequencies of the ALDH2 rs671 genotype were 68.67% (GG), 28.67%(GL), 2.66%(LL), respectively. Pepole who harbored the L allele were less likely to develop incident hypertension. There was a significant association between food frequency and hypertension in the L genotype group. Fried food intake was significantly increased the risk of hypertension in the L genotype group. Our study suggested that ALDH2 rs671 L-genotypes are protective factors for hypertension in Han Chinese. Consumption of fried food accelerated the development of hypertension in individuals with poor metabolism of acetaldehyde.
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Naser AM, Unicomb L, Doza S, Ahmed KM, Rahman M, Uddin MN, Quraishi SB, Selim S, Shamsudduha M, Burgess W, Chang HH, Gribble MO, Clasen TF, Luby SP. Stepped-wedge cluster-randomised controlled trial to assess the cardiovascular health effects of a managed aquifer recharge initiative to reduce drinking water salinity in southwest coastal Bangladesh: study design and rationale. BMJ Open 2017; 7:e015205. [PMID: 28864689 PMCID: PMC5588995 DOI: 10.1136/bmjopen-2016-015205] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 06/16/2017] [Accepted: 07/13/2017] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Saltwater intrusion and salinisation have contributed to drinking water scarcity in many coastal regions globally, leading to dependence on alternative sources for water supply. In southwest coastal Bangladesh, communities have few options but to drink brackish groundwater which has been associated with high blood pressure among the adult population, and pre-eclampsia and gestational hypertension among pregnant women. Managed aquifer recharge (MAR), the purposeful recharge of surface water or rainwater to aquifers to bring hydrological equilibrium, is a potential solution for salinity problem in southwest coastal Bangladesh by creating a freshwater lens within the brackish aquifer. Our study aims to evaluate whether consumption of MAR water improves human health, particularly by reducing blood pressure among communities in coastal Bangladesh. METHODS AND ANALYSIS The study employs a stepped-wedge cluster-randomised controlled community trial design in 16 communities over five monthly visits. During each visit, we will collect data on participants' source of drinking and cooking water and measure the salinity level and electrical conductivity of household stored water. At each visit, we will also measure the blood pressure of participants ≥20 years of age and pregnant women and collect urine samples for urinary sodium and protein measurements. We will use generalised linear mixed models to determine the association of access to MAR water on blood pressure of the participants. ETHICS AND DISSEMINATION The study protocol has been reviewed and approved by the Institutional Review Boards of the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b). Informed written consent will be taken from all the participants. This study is funded by Wellcome Trust, UK. The study findings will be disseminated to the government partners, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT02746003; Pre-results.
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Affiliation(s)
- Abu Mohd Naser
- Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Leanne Unicomb
- Environmental Health & Interventions Unit, Enteric and Respiratory Infections Program, Infectious Disease Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
| | - Solaiman Doza
- Environmental Health & Interventions Unit, Enteric and Respiratory Infections Program, Infectious Disease Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
| | | | - Mahbubur Rahman
- Environmental Health & Interventions Unit, Enteric and Respiratory Infections Program, Infectious Disease Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
| | - Mohammad Nasir Uddin
- Environmental Health & Interventions Unit, Enteric and Respiratory Infections Program, Infectious Disease Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
| | - Shamshad B Quraishi
- Analytical Chemistry Laboratory, Atomic Energy Centre, Bangladesh Atomic EnergyCommission, Dhaka, Bangladesh
| | - Shahjada Selim
- Department of Endocrinology & Metabolism, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mohammad Shamsudduha
- Institute for Risk and Disaster Reduction, Departmentof Geography, University College London, London, UK
| | - William Burgess
- Department of Earth Sciences, University College London, London, UK
| | - Howard H Chang
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Matthew O Gribble
- Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Thomas F Clasen
- Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Stephen P Luby
- Stanford Woods Institute for the Environment & Freeman Spogli Institute for International Studies, Stanford University, Stanford, California, USA
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Hallow KM, Gebremichael Y. A Quantitative Systems Physiology Model of Renal Function and Blood Pressure Regulation: Application in Salt-Sensitive Hypertension. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2017; 6:393-400. [PMID: 28556624 PMCID: PMC5488119 DOI: 10.1002/psp4.12177] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 01/05/2017] [Accepted: 01/23/2017] [Indexed: 01/13/2023]
Abstract
Salt‐sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt‐resistant (SR) individuals. In this study we used a systems pharmacology model of renal function (presented in a companion article) to evaluate the ability of proposed mechanisms to produce salt‐sensitivity. The model reproduced previously published data on renal functional changes in response to salt‐intake, and also predicted that glomerular pressure, a variable that is not easily evaluated clinically but is a key factor in renal injury, increases with salt intake in SS hypertension. We then used the model to generate mechanistic insight into the differential blood pressure and glomerular pressure responses to angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, and calcium channel blockers observed in SS and SR hypertension.
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Affiliation(s)
- K M Hallow
- University of Georgia, Athens, Georgia, USA
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31
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Tu W, Eckert GJ, Decker BS, Howard Pratt J. Varying Influences of Aldosterone on the Plasma Potassium Concentration in Blacks and Whites. Am J Hypertens 2017; 30:490-494. [PMID: 28338830 PMCID: PMC5861550 DOI: 10.1093/ajh/hpx006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 01/04/2017] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Aldosterone acts to restrain the extracellular potassium (K+) concentration. Blacks have on average lower plasma aldosterone concentrations (PACs) than Whites. Whether this ethnic difference is associated with similar changes in the concentration of K+ is unclear. METHODS Subjects were Blacks and Whites from an observational study of blood pressure regulation. PAC was known to be significantly lower in Blacks than Whites. We sought to test the hypothesis that the concentration of K+ remains constant despite variability in PAC. Initial enrollment took place in childhood in 1986. Some of the original enrollees were studied again in adulthood: 160 healthy Blacks and 271 healthy Whites (ages 5 to 39 years; all were studied as children and as adults). RESULTS Plasma renin activity [a biomarker of angiotensin II and, more proximally, extracellular fluid volume (ECFV)] and PAC were lower in Blacks (P < 0.0354 and P < 0.001, respectively, for all ages). At the same time no ethnic difference in levels of K+ was observed regardless of age. Plasma K+ concentration and PAC associated differently based on ethnicity: PAC increased in Blacks by 1.5-2.0 and in Whites by 2.3-3.0 ng/dl per mmol/l increase in K+ (P < 0.001). CONCLUSIONS Lower aldosterone levels in Blacks did not translate into higher K+ concentrations. We speculate that reaching the right concentration of K+ was an endpoint of aldosterone production in the presence of varying levels of ECFV and angiotensin II.
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Affiliation(s)
- Wanzhu Tu
- Department of Biostatistics, Indiana University Center for Aging Research, Regenstrief Institute, Indianapolis, Indiana, USA
- Indiana University Center for Aging Research, Regenstrief Institute, Indianapolis, Indiana, USA
| | - George J Eckert
- Department of Biostatistics, Indiana University Center for Aging Research, Regenstrief Institute, Indianapolis, Indiana, USA
| | - Brian S Decker
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - John Howard Pratt
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush V.A. Medical Center, Indianapolis, Indiana, USA
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Abstract
Twin studies show that about half the risk of hypertension development is inherited. Mendelian hypertension has elucidated astounding basic pathways contributing to hypertension over (presumably) dietary salt intake or directly through increased peripheral vascular resistance. The Mendelian mutations exercise large effects on blood pressure. Inversely, studying the entire human genome for sources signaling blood pressure has yielded many signals with small effects. Thus far, few loci have been validated or translated into targets. Both genetic strategies are necessary, and much remains to be done.
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Affiliation(s)
- Friedrich C Luft
- Charité Medical Faculty, Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine, Lindenbergerweg 80, Berlin 13125, Germany.
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33
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Pilic L, Pedlar CR, Mavrommatis Y. Salt-sensitive hypertension: mechanisms and effects of dietary and other lifestyle factors. Nutr Rev 2016; 74:645-58. [PMID: 27566757 DOI: 10.1093/nutrit/nuw028] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Salt sensitivity, which is an increase in blood pressure in response to high dietary salt intake, is an independent risk factor for cardiovascular disease and mortality. It is associated with physiological, environmental, demographic, and genetic factors. This review focuses on the physiological mechanisms of salt sensitivity in populations at particular risk, along with the associated dietary factors. The interplay of mechanisms such as the renin-angiotensin aldosterone system, endothelial dysfunction, ion transport, and estrogen decrease in women contributes to development of salt sensitivity. Because of their effects on these mechanisms, higher dietary intakes of potassium, calcium, vitamin D, antioxidant vitamins, and proteins rich in L-arginine, as well as adherence to dietary patterns similar to the DASH (Dietary Approaches to Stop Hypertension) diet, can be beneficial to salt-sensitive populations. In contrast, diets similar to the typical Western diet, which is rich in saturated fats, sucrose, and fructose, together with excessive alcohol consumption, may exacerbate salt-sensitive changes in blood pressure. Identifying potential mechanisms of salt sensitivity in susceptible populations and linking them to protective or harmful dietary and lifestyle factors can lead to more specific guidelines for the prevention of hypertension and cardiovascular disease.
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Affiliation(s)
- Leta Pilic
- L. Pilic, C.R. Pedlar, and Y. Mavrommatis are with the School of Sport, Health and Applied Science, St Mary's University, Twickenham, London, United Kingdom. CR Pedlar is with the Cardiovascular Performance Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Charles R Pedlar
- L. Pilic, C.R. Pedlar, and Y. Mavrommatis are with the School of Sport, Health and Applied Science, St Mary's University, Twickenham, London, United Kingdom. CR Pedlar is with the Cardiovascular Performance Program, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Yiannis Mavrommatis
- L. Pilic, C.R. Pedlar, and Y. Mavrommatis are with the School of Sport, Health and Applied Science, St Mary's University, Twickenham, London, United Kingdom. CR Pedlar is with the Cardiovascular Performance Program, Massachusetts General Hospital, Boston, Massachusetts, USA
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Farquhar WB, Edwards DG, Jurkovitz CT, Weintraub WS. Dietary sodium and health: more than just blood pressure. J Am Coll Cardiol 2016; 65:1042-50. [PMID: 25766952 DOI: 10.1016/j.jacc.2014.12.039] [Citation(s) in RCA: 211] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 12/09/2014] [Accepted: 12/16/2014] [Indexed: 12/24/2022]
Abstract
Sodium is essential for cellular homeostasis and physiological function. Excess dietary sodium has been linked to elevations in blood pressure (BP). Salt sensitivity of BP varies widely, but certain subgroups tend to be more salt sensitive. The mechanisms underlying sodium-induced increases in BP are not completely understood but may involve alterations in renal function, fluid volume, fluid-regulatory hormones, the vasculature, cardiac function, and the autonomic nervous system. Recent pre-clinical and clinical data support that even in the absence of an increase in BP, excess dietary sodium can adversely affect target organs, including the blood vessels, heart, kidneys, and brain. In this review, the investigators review these issues and the epidemiological research relating dietary sodium to BP and cardiovascular health outcomes, addressing recent controversies. They also provide information and strategies for reducing dietary sodium.
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Affiliation(s)
- William B Farquhar
- Department of Kinesiology & Applied Physiology, College of Health Sciences, University of Delaware, Newark, Delaware
| | - David G Edwards
- Department of Kinesiology & Applied Physiology, College of Health Sciences, University of Delaware, Newark, Delaware
| | - Claudine T Jurkovitz
- Department of Medicine, Section of Cardiology, Christiana Care Outcomes Research Center, Christiana Care Health System, Newark, Delaware
| | - William S Weintraub
- Department of Medicine, Section of Cardiology, Christiana Care Outcomes Research Center, Christiana Care Health System, Newark, Delaware.
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Impact of Salt Intake on the Pathogenesis and Treatment of Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 956:61-84. [DOI: 10.1007/5584_2016_147] [Citation(s) in RCA: 174] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Mellendijk L, Wiesmann M, Kiliaan AJ. Impact of Nutrition on Cerebral Circulation and Cognition in the Metabolic Syndrome. Nutrients 2015; 7:9416-39. [PMID: 26580647 PMCID: PMC4663605 DOI: 10.3390/nu7115477] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 10/12/2015] [Accepted: 11/03/2015] [Indexed: 12/12/2022] Open
Abstract
The increasing prevalence of Metabolic Syndrome (MetS), defined as the clustering of abdominal obesity, dyslipidemia, hypertension, and hyperglycemia, appears to be driving the global epidemics cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Nutrition has a major impact on MetS and plays an important role in the prevention, development, and treatment of its features. Structural and functional alterations in the vasculature, associated with MetS, might form the link between MetS and the increased risk of developing CVD and T2DM. Not only does the peripheral vasculature seem to be affected, but the syndrome has a profound impact on the cerebral circulation and thence brain structure as well. Furthermore, strong associations are shown with stroke, cognitive impairment, and dementia. In this review the impact of nutrition on the individual components of MetS, the effects of MetS on peripheral and cerebral vasculature, and its consequences for brain structure and function will be discussed.
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Affiliation(s)
- Laura Mellendijk
- Department of Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6500 HB, The Netherlands.
| | - Maximilian Wiesmann
- Department of Anatomy & Geriatric Medicine, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6500 HB, The Netherlands.
| | - Amanda J Kiliaan
- Department of Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6500 HB, The Netherlands.
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Campbell NR, Bovet P, Schutte AE, Lemogoum D, Nkwescheu AS. High Blood Pressure in Sub-Saharan Africa: Why Prevention, Detection, and Control are Urgent and Important. J Clin Hypertens (Greenwich) 2015; 17:663-7. [PMID: 26073791 PMCID: PMC8032170 DOI: 10.1111/jch.12599] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
| | - Pascal Bovet
- IUMSPLausanne University HospitalLausanneSwitzerland
| | - Aletta Elisabeth Schutte
- Hypertension in Africa Research TeamNorth West UniversityPotchefstroomSouth Africa
- MRC Research Unit on Hypertension and Cardiovascular DiseaseNorth‐West UniversitySouth Africa
| | | | - Armand Seraphin Nkwescheu
- Cameroon Society of Epidemiology and Health Operations ResearchMinistry of Public Health of CameroonYaoundeCameroon
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Burnier M, Wuerzner G, Bochud M. Salt, blood pressure and cardiovascular risk: what is the most adequate preventive strategy? A Swiss perspective. Front Physiol 2015; 6:227. [PMID: 26321959 PMCID: PMC4535281 DOI: 10.3389/fphys.2015.00227] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/27/2015] [Indexed: 12/17/2022] Open
Abstract
Among the various strategies to reduce the incidence of non-communicable diseases reduction of sodium intake in the general population has been recognized as one of the most cost-effective means because of its potential impact on the development of hypertension and cardiovascular diseases. Yet, this strategic health recommendation of the WHO and many other international organizations is far from being universally accepted. Indeed, there are still several unresolved scientific and epidemiological questions that maintain an ongoing debate. Thus what is the adequate low level of sodium intake to recommend to the general population and whether national strategies should be oriented to the overall population or only to higher risk fractions of the population such as salt-sensitive patients are still discussed. In this paper, we shall review the recent results of the literature regarding salt, blood pressure and cardiovascular risk and we present the recommendations recently proposed by a group of experts of Switzerland. The propositions of the participating medical societies are to encourage national health authorities to continue their discussion with the food industry in order to reduce the sodium intake of food products with a target of mean salt intake of 5–6 grams per day in the population. Moreover, all initiatives to increase the information on the effect of salt on health and on the salt content of food are supported.
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Affiliation(s)
- Michel Burnier
- Service of Nephrology and Hypertension, Department of Medicine, University Hospital Lausanne, Switzerland
| | - Gregoire Wuerzner
- Service of Nephrology and Hypertension, Department of Medicine, University Hospital Lausanne, Switzerland
| | - Murielle Bochud
- Institut Universitaire de Médecine Sociale et Préventive, University Hospital Lausanne, Switzerland
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Abstract
PURPOSE OF REVIEW High dietary salt intake is detrimental in hypertensive and salt-sensitive individuals; however, there are a large number of normotensive salt-resistant individuals for whom dietary salt may also be harmful as a result of the blood pressure-independent effects of salt. This review will focus on the growing evidence that salt has adverse effects on the vasculature, independent of blood pressure. RECENT FINDINGS Data from both animal and human studies provide evidence that salt impairs endothelial function and increases arterial stiffness, independent of blood pressure. High dietary salt results in oxidative stress and increased endothelial cell stiffness, which impair endothelial function, whereas transforming growth factor beta promotes increased arterial stiffness in the presence of endothelial dysfunction. SUMMARY Health policies and most clinical research are focused on the adverse effects of dietary salt on blood pressure; however, there is an increasing body of evidence to support a deleterious effect of dietary salt on endothelial function and arterial stiffness independent of blood pressure. Endothelial dysfunction and increased arterial stiffness are predictors of cardiovascular disease; therefore, reducing excess dietary salt should be considered important for overall vascular health in addition to blood pressure.
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Echouffo-Tcheugui JB, Kengne AP, Erqou S, Cooper RS. High Blood Pressure in Sub-Saharan Africa: The Urgent Imperative for Prevention and Control. J Clin Hypertens (Greenwich) 2015. [PMID: 26224428 DOI: 10.1111/jch.12620] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
| | - Andre P Kengne
- South African Medical Research Council and University of Cape Town, Cape Town, South Africa.,The George Institute for Global Health, Sydney, NSW, Australia
| | - Sebhat Erqou
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Richard S Cooper
- Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Chicago, IL
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Franceschini N, Chasman DI, Cooper-DeHoff RM, Arnett DK. Genetics, ancestry, and hypertension: implications for targeted antihypertensive therapies. Curr Hypertens Rep 2015; 16:461. [PMID: 24903233 DOI: 10.1007/s11906-014-0461-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hypertension is the most common chronic condition seen by physicians in ambulatory care and a condition for which life-long medications are commonly prescribed. There is evidence for genetic factors influencing blood pressure variation in populations and response to medications. This review summarizes recent genetic discoveries that surround blood pressure, hypertension, and antihypertensive drug response from genome-wide association studies, while highlighting ancestry-specific findings and any potential implication for drug therapy targets. Genome-wide association studies have identified several novel loci for inter-individual variation of blood pressure and hypertension risk in the general population. Evidence from pharmacogenetic studies suggests that genes influence the blood pressure response to antihypertensive drugs, although results are somewhat inconsistent across studies. There is still much work that remains to be done to identify genes both for efficacy and adverse events of antihypertensive medications.
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Affiliation(s)
- Nora Franceschini
- Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, 137 E. Franklin St., Suite 306, Chapel Hill, NC, USA,
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Saab KR, Kendrick J, Yracheta JM, Lanaspa MA, Pollard M, Johnson RJ. New insights on the risk for cardiovascular disease in African Americans: the role of added sugars. J Am Soc Nephrol 2015; 26:247-57. [PMID: 25090991 PMCID: PMC4310665 DOI: 10.1681/asn.2014040393] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 06/30/2014] [Indexed: 12/26/2022] Open
Abstract
African Americans are at increased risk for cardiovascular and metabolic diseases, including obesity, high BP, diabetes, CKD, myocardial infarction, and stroke. Here we summarize the current risks and provide an overview of the underlying risk factors that may account for these associations. By reviewing the relationship between cardiovascular and renal diseases and the African-American population during the early 20th century, the historic and recent associations of African heritage with cardiovascular disease, and modern population genetics, it is possible to assemble strong hypotheses for the primary underlying mechanisms driving the increased frequency of disease in African Americans. Our studies suggest that underlying genetic mechanisms may be responsible for the increased frequency of high BP and kidney disease in African Americans, with particular emphasis on the role of APOL1 polymorphisms in causing kidney disease. In contrast, the Western diet, particularly the relatively high intake of fructose-containing sugars and sweetened beverages, appears to be the dominant force driving the increased risk of diabetes, obesity, and downstream complications. Given that intake of added sugars is a remediable risk factor, we recommend clinical trials to examine the reduction of sweetened beverages as a primary means for reducing cardiovascular risk in African Americans.
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Affiliation(s)
- Karim R Saab
- Renal Division, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado
| | - Jessica Kendrick
- Renal Division, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado
| | - Joseph M Yracheta
- Department of Pharmaceutics, University of Washington, School of Pharmacy, Seattle, Washington
| | - Miguel A Lanaspa
- Renal Division, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado; Colorado Research Partners LLC, Aurora, Colorado; and
| | | | - Richard J Johnson
- Renal Division, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado; Colorado Research Partners LLC, Aurora, Colorado; and
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Williams SF, Nicholas SB, Vaziri ND, Norris KC. African Americans, hypertension and the renin angiotensin system. World J Cardiol 2014; 6:878-889. [PMID: 25276290 PMCID: PMC4176798 DOI: 10.4330/wjc.v6.i9.878] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 06/28/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system (RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovascular and chronic kidney disease makes treatment with RAS inhibitors more compelling. Despite lower circulating renin levels and a less significant fall in blood pressure in response to RAS inhibitors in African Americans, numerous clinical trials support the efficacy of RAS inhibitors to improve clinical outcomes in this population, especially in those with hypertension and risk factors for cardiovascular and related diseases. Here, we discuss the rationale of RAS blockade as part of a comprehensive approach to attenuate the high rates of premature morbidity and mortality associated with hypertension among African Americans.
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Tu W, Eckert GJ, Hannon TS, Liu H, Pratt LM, Wagner MA, Dimeglio LA, Jung J, Pratt JH. Racial differences in sensitivity of blood pressure to aldosterone. Hypertension 2014; 63:1212-8. [PMID: 24711519 DOI: 10.1161/hypertensionaha.113.02989] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Blacks in comparison with whites are at risk for a more serious form of hypertension with high rates of complications. Greater sodium retention is thought to underlie the blood pressure (BP)-determining physiology of blacks, but specific mechanisms have not been identified. In a prospective observational study of BP, 226 black children and 314 white children (mean age, 10.6 years) were enrolled initially. Assessments were repeated in 85 blacks and 136 whites after reaching adulthood (mean age, 31 years). The relationship of BP to plasma aldosterone concentration in the context of the prevailing level of plasma renin activity was studied in blacks and whites. In a secondary interventional study, 9-α fludrocortisone was administered for 2 weeks to healthy adult blacks and whites to simulate hyperaldosteronism. BP responses in the 2 race groups were then compared. Although black children had lower levels of plasma renin activity and plasma aldosterone, their BP was positively associated with the plasma aldosterone concentration, an effect that increased as plasma renin activity decreased (P=0.004). Data from black adults yielded similar results. No similar relationship was observed in whites. In the interventional study, 9-α fludrocortisone increased BP in blacks but not in whites. In conclusion, aldosterone sensitivity is a significant determinant of BP in young blacks. Although its role in establishing the risk of hypertension is not known, it could be as relevant as the actual level of aldosterone.
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Affiliation(s)
- Wanzhu Tu
- 541 Clinical Dr, CL 365a, Indianapolis, IN 46202-5111.
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Allen AR, Gullixson LR, Wolhart SC, Kost SL, Schroeder DR, Eisenach JH. Dietary sodium influences the effect of mental stress on heart rate variability: a randomized trial in healthy adults. J Hypertens 2014; 32:374-82. [PMID: 24284498 DOI: 10.1097/hjh.0000000000000045] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Dietary sodium influences intermediate physiological traits in healthy adults independent of changes in blood pressure. The purpose of this study was to test the hypothesis that dietary sodium affects cardiac autonomic modulation during mental stress. METHOD In a prospective, randomized cross-over design separated by 1 month between diets, 70 normotensive healthy young adults (F/M: 44/26, aged 18-38 years) consumed a 5-day low (10 mmol/day), normal (150 mmol), and high (400 mmol) sodium diet followed by heart rate variability (HRV) recordings at rest and during 5-min computerized mental arithmetic. Women were studied in the low hormone phase of the menstrual cycle following each diet. RESULTS Diet did not affect resting blood pressure, but heart rate (HR) (mean ± SE) was 66 ± 1, 64 ± 1, and 63 ± 1 bpm in low, normal, and high sodium conditions, respectively (analysis of variance P = 0.02). For HRV, there was a main effect of sodium on resting SD of normalized RR intervals (SDNN), square root of the mean squared difference of successive normalized RR intervals (RMSSD), high frequency, low-frequency normalized units (LFnu), and high-frequency normalized units (HFnu) (P < 0.01 for all). The response to low sodium was most marked and consistent with sympathetic activation and reduced vagal activity, with increased LFnu and decreased SDNN, RMSSD, and HFnu compared to both normal and high sodium conditions (P ≤0.05 for all). Dietary sodium-by-mental stress interactions were significant for mean NN, RMSSD, high-frequency power, LFnu, and low frequency/high frequency ratio (P < 0.05 for all). The interactions signify that sodium restriction evoked an increase in resting sympathetic activity and reduced vagal activity to the extent that mental stress caused modest additional disruptions in autonomic balance. Conversely, normal and high sodium evoked a reduction in resting sympathetic activity and incremental increase in resting vagal activity, which were disrupted to a greater extent during mental stress compared to low sodium. CONCLUSION We conclude that autonomic control of HRV at rest and during mental stress is altered by dietary sodium in healthy normotensive young adult men and women.
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Affiliation(s)
- Alexander R Allen
- aDepartment of Anesthesiology and Biomedical Engineering bBiomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
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Martillotti G, Ditisheim A, Burnier M, Wagner G, Boulvain M, Irion O, Pechère-Bertschi A. Increased salt sensitivity of ambulatory blood pressure in women with a history of severe preeclampsia. Hypertension 2013; 62:802-8. [PMID: 23980074 DOI: 10.1161/hypertensionaha.113.01916] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cardiovascular diseases are the principal cause of death in women in developed countries and are importantly promoted by hypertension. The salt sensitivity of blood pressure (BP) is considered as an important cardiovascular risk factor at any BP level. Preeclampsia is a hypertensive disorder of pregnancy that arises as a risk factor for cardiovascular diseases. This study measured the salt sensitivity of BP in women with a severe preeclampsia compared with women with no pregnancy hypertensive complications. Forty premenopausal women were recruited 10 years after delivery in a case-control study. Salt sensitivity was defined as an increase of >4 mm Hg in 24-hour ambulatory BP on a high-sodium diet. The ambulatory BP response to salt was significantly increased in women with a history of preeclampsia compared with that of controls. The mean (95% confidence interval) daytime systolic/diastolic BP increased significantly from 115 (109-118)/79 (76-82) mm Hg on low-salt diet to 123 (116-130)/80 (76-84) on a high-salt diet in women with preeclampsia, but not in the control group (from 111 [104-119]/77 [72-82] to 111 [106-116]/75 [72-79], respectively, P<0.05). The sodium sensitivity index (SSI=Δmean arterial pressure/Δurinary Na excretion×1000) was 51.2 (19.1-66.2) in women with preeclampsia and 6.6 (5.8-18.1) mm Hg/mol per day in controls (P=0.015). The nocturnal dip was blunted on a high-salt diet in women with preeclampsia. Our study shows that women who have developed preeclampsia are salt sensitive before their menopause, a finding that may contribute to their increased cardiovascular risk. Women with a history of severe preeclampsia should be targeted at an early stage for preventive measures of cardiovascular diseases.
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Affiliation(s)
- Gabriella Martillotti
- Hypertension Unit, University Hospitals of Geneva, 4, Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland.
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Izzo JL. Hemodynamics. Hypertension 2013. [DOI: 10.2217/ebo.12.535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Joseph L Izzo
- Joseph L Izzo Jr is Professor of Medicine, Pharmacology and Toxicology, and Chief of Clinical Pharmacology at the University at Buffalo, State University of New York (SUNY-Buffalo; NY, USA). He is also Clinical Director of Medicine at the Erie County Medical Center, Buffalo (NY, USA). Training includes a MD from Johns Hopkins (MD, USA), an internal medicine residency at Washington University (MO, USA) and a research fellowship in the Hypertension–Endocrine branch of the National Heart, Lung and Blood
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High sodium:potassium intake ratio increases the risk for all-cause mortality: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. J Nutr Sci 2013; 2:e13. [PMID: 25191561 PMCID: PMC4153038 DOI: 10.1017/jns.2013.4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 11/01/2012] [Accepted: 11/30/2012] [Indexed: 01/13/2023] Open
Abstract
Increased dietary Na intake and decreased dietary K intake are associated with higher blood pressure. It is not known whether the dietary Na:K ratio is associated with all-cause mortality or stroke incidence and whether this relationship varies according to race. Between 2003 and 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans aged 45 years or older. Diet was assessed using the Block 98 FFQ and was available on 21 374 participants. The Na:K ratio was modelled in race- and sex-specific quintiles for all analyses, with the lowest quintile (Q1) as the reference group. Data on other covariates were collected using both an in-home assessment and telephone interviews. We identified 1779 deaths and 363 strokes over a mean of 4·9 years. We used Cox proportional hazards models to obtain multivariable-adjusted hazard ratios (HR). In the highest quintile (Q5), a high Na:K ratio was associated with all-cause mortality (Q5 v. Q1 for whites: HR 1·22; 95 % CI 1·00, 1·47, P for trend = 0·084; for blacks: HR 1·36; 95 % CI 1·04, 1·77, P for trend = 0·028). A high Na:K ratio was not significantly associated with stroke in whites (HR 1·29; 95 % CI 0·88, 1·90) or blacks (HR 1·39; 95 % CI 0·78, 2·48), partly because of the low number of stroke events. In the REGARDS study, a high Na:K ratio was associated with all-cause mortality and there was a suggestive association between the Na:K ratio and stroke. These data support the policies targeted at reduction of Na from the food supply and recommendations to increase K intake.
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Nguyen H, Odelola OA, Rangaswami J, Amanullah A. A review of nutritional factors in hypertension management. Int J Hypertens 2013; 2013:698940. [PMID: 23691281 PMCID: PMC3649175 DOI: 10.1155/2013/698940] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 03/15/2013] [Indexed: 12/18/2022] Open
Abstract
Hypertension is a major health problem worldwide. Its attendant morbidity and mortality complications have a great impact on patient's quality of life and survival. Optimizing blood pressure control has been shown to improve overall health outcomes. In addition to pharmacological therapies, nonpharmacological approach such as dietary modification plays an important role in controlling blood pressure. Many dietary components such as sodium, potassium, calcium, and magnesium have been studied substantially in the past decades. While some of these nutrients have clear evidence for their recommendation, some remain controversial and are still of ongoing study. Dietary modification is often discussed with patients and can provide a great benefit in blood pressure regulation. As such, reviewing the current evidence will be very useful in guiding patients and their physician and/or dietician in decision making. In this review article of nutritional factors in hypertension management, we aim to examine the role of nutritional factors individually and as components of whole dietary patterns.
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Affiliation(s)
- Ha Nguyen
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA
| | - Olaide A. Odelola
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA
| | - Janani Rangaswami
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA
| | - Aman Amanullah
- Noninvasive Cardiology, Albert Einstein Medical Center, Clinical Professor of Medicine, Jefferson Medical College of Thomas Jefferson University, 5501 Old York Road, HB-3, Philadelphia, PA 19141, USA
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Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Müller DN, Schmieder RE, Cavallaro A, Eckardt KU, Uder M, Luft FC, Titze J. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension 2013; 61:635-40. [PMID: 23339169 DOI: 10.1161/hypertensionaha.111.00566] [Citation(s) in RCA: 302] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
High dietary salt intake is associated with hypertension; the prevalence of salt-sensitive hypertension increases with age. We hypothesized that tissue Na(+) might accumulate in hypertensive patients and that aging might be accompanied by Na(+) deposition in tissue. We implemented (23)Na magnetic resonance imaging to measure Na(+) content of soft tissues in vivo earlier, but had not studied essential hypertension. We report on a cohort of 56 healthy control men and women, and 57 men and women with essential hypertension. The ages ranged from 22 to 90 years. (23)Na magnetic resonance imaging measurements were made at the level of the calf. We observed age-dependent increases in Na(+) content in muscle in men, whereas muscle Na(+) content did not change with age in women. We estimated water content with conventional MRI and found no age-related increases in muscle water in men, despite remarkable Na(+) accumulation, indicating water-free Na(+) storage in muscle. With increasing age, there was Na(+) deposition in the skin in both women and men; however, skin Na(+) content remained lower in women. Similarly, this sex difference was found in skin water content, which was lower in women than in men. In contrast to muscle, increasing Na(+) content was paralleled with increasing skin water content. When controlled for age, we found that patients with refractory hypertension had increased tissue Na(+) content, compared with normotensive controls. These observations suggest that (23)Na magnetic resonance imaging could have utility in assessing the role of tissue Na(+) storage for cardiovascular morbidity and mortality in longitudinal studies.
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Affiliation(s)
- Christoph Kopp
- Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN 37232, USA
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