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The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 23, 2016, and the American Heart Association Executive Committee on February 23, 2016. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The American Heart Association requests that this document be cited as follows: Elijovich F, Weinberger MH, Anderson CAM, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL; on behalf of the American Heart Association Professional and Public Education Committee of the Council on Hypertension; Council on Functional Genomics and Translational Biology; and Stroke Council. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68:e7-e46. doi: 10.1161/HYP.0000000000000047.Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the "Copyright Permissions Request Form" appears on the right side of the page. Figure 2 shows the major effect of aging in increasing the prevalence of SSBP in both normotensive and hypertensive subjects. An important and encouraging observation is that the multiple phenotypic characteristics described in pure SS strains of rodents reproduce those observed in humans, indicating that the phenotypic cluster of SSBP can be brought out in humans by the current techniques used in carefully controlled research. Additionally, despite the unquestionable influence of environmental factors in the determination of SSBP in humans, estimates of its heritability have been as high as 74% in blacks 9 and 50% in Chinese subjects, 10 both higher than those for hypertension. Salt Sensitivity of Blood PressureAn important issue is the clinical significance of the SSBP phenotype. There was increasing understanding that it represents an abnormality. The reasons w...

Background-Twenty-hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that produces vasoconstriction and inhibition of renal tubular sodium transport. In Dahl rats, a 20-HETE deficiency plays a role in salt-sensitive (SS) hypertension. In humans, there are no data on regulation of 20-HETE by salt intake or on a role for this compound in SS hypertension. Methods and Results-Thirteen salt-resistant (SR) and 13 SS hypertensive subjects had urine 20-HETE excretion measured during salt-loading and depletion. In all patients, 20-HETE was 66.6% higher in the salt-replete (1.75Ϯ0.25 g/h) than in the salt-depleted state (1.05Ϯ0.16, PϽ0.003). There was no difference in 20-HETE excretion between SR and SS patients in either state of salt balance. In SR patients, sodium excretion during salt-loading correlated with 20-HETE (rϭ0.61, PϽ0.03) but not with blood pressure. In contrast, in SS patients, sodium excretion did not correlate with 20-HETE but did correlate with blood pressure (rϭ0.66, PϽ0.02). Finally, in the SS group only, there was a negative correlation between body mass index and 20-HETE excretion (rϭ-0.79, PϽ0.002) that was present during both salt-loading and depletion. Conclusions-We demonstrate for the first time that 20-HETE excretion is regulated by salt intake in hypertension. We find a disrupted relationship between sodium excretion and 20-HETE in SS patients, which results in dependence of their salt excretion on blood pressure and may be related to the magnitude of their obesity. We conclude that salt-sensitivity of blood pressure in essential hypertension may result from impairment of a natriuretic mechanism dependent on 20-HETE. (Circulation. 2003;107:574-578.)

AimsMonocytes play an important role in hypertension. Circulating monocytes in humans exist as classical, intermediate, and non-classical forms. Monocyte differentiation can be influenced by the endothelium, which in turn is activated in hypertension by mechanical stretch. We sought to examine the role of increased endothelial stretch and hypertension on monocyte phenotype and function.Methods and resultsHuman monocytes were cultured with confluent human aortic endothelial cells undergoing either 5% or 10% cyclical stretch. We also characterized circulating monocytes in normotensive and hypertensive humans. In addition, we quantified accumulation of activated monocytes and monocyte-derived cells in aortas and kidneys of mice with Angiotensin II-induced hypertension. Increased endothelial stretch enhanced monocyte conversion to CD14++CD16+ intermediate monocytes and monocytes bearing the CD209 marker and markedly stimulated monocyte mRNA expression of interleukin (IL)-6, IL-1β, IL-23, chemokine (C-C motif) ligand 4, and tumour necrosis factor α. STAT3 in monocytes was activated by increased endothelial stretch. Inhibition of STAT3, neutralization of IL-6 and scavenging of hydrogen peroxide prevented formation of intermediate monocytes in response to increased endothelial stretch. We also found evidence that nitric oxide (NO) inhibits formation of intermediate monocytes and STAT3 activation. In vivo studies demonstrated that humans with hypertension have increased intermediate and non-classical monocytes and that intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells, and macrophages with activated STAT3.ConclusionsThese findings provide insight into how monocytes are activated by the vascular endothelium during hypertension. This is likely in part due to a loss of NO signalling and increased release of IL-6 and hydrogen peroxide by the dysfunctional endothelium and a parallel increase in STAT activation in adjacent monocytes. Interventions to enhance bioavailable NO, reduce IL-6 or hydrogen peroxide production or to inhibit STAT3 may have anti-inflammatory roles in hypertension and related conditions.

We investigated 24-hour hemodynamic changes produced by salt loading and depletion in eight salt-sensitive (SS) and 13 salt-resistant (SR) normotensive volunteers. After salt loading, mean arterial pressure (MAP) was higher in SS (96.5±2.8) than SR (84.2±2.7 mmHg), p<0.01, owing to higher total peripheral resistance (TPR) in SS (1791±148) than SR (1549±66 dyn.cm−5.sec−1), p=0.05, whereas cardiac output (CO) was not different between groups (SS 4.5±0.3 vs SR 4.4±0.2 l/min, ns). Following salt depletion, CO was equally reduced in both groups. TPR increased 24±6% (p<0.001) in SR, whose MAP remained unchanged. In contrast, TPR did not change in SS (1±6%, ns). Thus, their MAP was reduced, abolishing the MAP difference between groups. SS had higher E/e’ ratios than SR in both phases of the protocol. In these 21 subjects and in 32 hypertensive patients, Na+ balance was similar in SR and SS during salt loading or depletion. However, SR did not gain weight during salt retention (−158±250 g), whereas SS did (819±204), commensurate to isoosmolar water retention. During salt depletion, SR lost the expected amount of weight for isoosmolar Na+ excretion, whereas SS lost a greater amount that failed to fully correct the fluid retention from the previous day. We conclude that SS are unable to modulate TPR in response to salt depletion, mirroring their inability to vasodilate in response to salt loading. We suggest that differences in water balance between SS and SR indicate differences in salt-and-water storage in the interstitial compartment that may relate to vascular dysfunction in SS.

Abstract-Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (Pϭ0.0005) and refines the location of the blood pressure QTL. (Hypertension. 1999;34:4-7.)Key Words: hypertension, essential Ⅲ linkage Ⅲ chromosome 17 Ⅲ blood pressure Ⅲ obesity E ssential hypertension is one of the most common cardiovascular diseases, affecting 15% to 20% of the population. It is an important risk factor for heart and kidney failure, myocardial ischemia, and stroke. 1 Essential hypertension is considered a complex disease with significant genetic and environmental components that interact to play a role in blood pressure variation. 2 Many candidate genes have been reported to contribute to the susceptibility to hypertension in clinical studies. [3][4][5] The stroke-prone spontaneously hypertensive rat and the Dahl salt-sensitive hypertensive rat have proved to be useful tools in identifying quantitative trait loci (QTL) that contribute to blood pressure variations. 6 -11 Evidence of a blood pressure QTL was found on rat chromosomes 2, 10 10, 6 -11 and X. 7 The rat chromosome 10 QTL is located near the angiotensin-converting enzyme (ACE) locus. The ACE locus is an attractive candidate gene because of its role in the renin-angiotensin system and the association between several polymorphisms in the ACE locus with blood pressure levels in some studies, 12-14 although other studies failed to confirm this finding. [15][16][17] Human chromosome 17 is syntenic with rat chromosome 10, and evidence for linkage between this blood pressure QTL has been reported in French/UK hypertensive sib pairs. 18 These markers are 18 cM proximal to the ACE locus. In addition, linkage of pseudohypoaldosteronism type IIB (hypertension, hyperkalemia, and normal renal glomerular filtration) to this region has been reported in several families. 19 In this study, we tested a series of microsatellite markers near this chromosome 17 blood pressure QTL in a collection of white and black sib pairs from the United States. Evidence of linkage was found in our collection of white sib pairs. MethodsProbands were identified from hypertension clinics in Massachusetts and Texas. Extensive family histories, including medical history, risk factor information, ethnic background, and demographics, were taken. Boston Medical Center Institutional Review Board for Human Subjects approved this study, and all subjects gave informed consent. Blood samples were collected from 74 white patients and 97 of their affected sibs (125 sib pairs) and from 45 black patients...

Abstract-A role for a deficit in transport actions of 20-hydroxyeicosatetraenoic acid (20-HETE) in hypertension is supported by the following: (1) diminished renal 20-HETE in Dahl-S rats; (2) altered salt-and furosemide-induced 20-HETE responses in salt-sensitive hypertensive subjects; and (3) increased population risk for hypertension in C allele carriers of the T8590C polymorphism of CYP4A11, which encodes an enzyme with reduced catalytic activity. We determined T8590C genotypes in 32 hypertensive subjects, 25 of whom were phenotyped for salt sensitivity of blood pressure and insulin sensitivity. Urine 20-HETE was lowest in insulin-resistant, salt-sensitive subjects (Fϭ5.56; PϽ0.02). Genotypes were 13 TT, 2 CC, and 17 CT. C allele frequency was 32.8% (blacks: 38.9%; whites: 25.0%). C carriers (CCϩCT) and TT subjects were similarly distributed among salt-and insulin-sensitivity phenotypes. C carriers had higher diastolic blood pressures and aldosterone:renin and waist:hip ratios but lower furosemide-induced fractional excretions of Na and K than TT. The T8590C genotype did not relate to sodium balance or pressure natriuresis. However, C carriers, compared with TT, had diminished 20-HETE responses to salt loading after adjustment for serum insulin concentration and resetting of the negative relationship between serum insulin and urine 20-HETE to a 1-g/h lower level of 20-HETE. The effect of C was insulin independent and equipotent to 18 U/mL of insulin (⌬20-HETEϭ 2.84Ϫ0.054ϫinsulinϪ0.98ϫC; r 2 ϭ0.53; Fϭ11.1; PϽ0.001). Hence, genetic (T8590C) and environmental (insulin) factors impair 20-HETE responses to salt in human hypertension. We propose that genotype analyses with sufficient homozygous CC will establish definitive relationships among 20-HETE, salt sensitivity of blood pressure, and insulin resistance. Key Words: hypertension Ⅲ obesity Ⅲ arachidonic acid Ⅲ cytochrome P450 Ⅲ insulin Ⅲ insulin resistance T he monooxygenase derivative of arachidonic acid synthesized by CYP450 enzymes, 20-hydroxyeicosatetraenoic acid (20-HETE), is a candidate for participation in blood pressure regulation and hypertension. This could be via excess of its potent vasoconstrictor actions 1-4 or deficiency of its inhibition of tubular transport, normally exerted at the NKCC cotransporter of the thick ascending limb and at the ubiquitous renal tubular Na-K-ATPase. [5][6][7][8] Studies in Dahl-S rats 9 -11 and in angiotensin II-induced hypertension in mice 12 support the view that a diminished effect of 20-HETE on renal transport is an important mechanism in experimental hypertension. Human population studies on polymorphisms of CYP4A11 that diminish its catalytic activity to synthesize 20-HETE 13,14 are consistent with this interpretation.Our studies in essential hypertension documented abnormal 20-HETE responses to physiological 15 and pharmacological 16 natriuresis and negative relationships with serum insulin 17 but not diminished urinary excretion of 20-HETE, as expected from observations in rodents. Because Dahl-S rats are not ...

-Our data suggest that salt-depleted salt-sensitive hypertensives with blunted renin responses exhibit enhanced catecholamine-stimulated endothelin levels and may therefore respond better than unselected patients with essential hypertension to endothelin receptor blockers.