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[Figure: see text].

Dietary salt restriction is a well-established approach to lower blood pressure and reduce cardiovascular disease risk in hypertensive individuals. However, little is currently known regarding the effects of salt restriction on central and peripheral hemodynamic responses to exercise in those with hypertension. Therefore, this study sought to determine the impact of salt restriction on the central and peripheral hemodynamic responses to static-intermittent handgrip (HG) and dynamic single-leg knee extension (KE) exercise in individuals with hypertension. Twenty-two subjects (14 men and 8 women, 51 ± 10 yr, 173 ± 11 cm, 99 ± 23 kg) forewent their antihypertensive medication use for at least 2 wk before embarking on a 5-day liberal salt (LS: 200 mmol/day) diet followed by a 5-day restricted salt (RS: 10 mmol/day) diet. Subjects were studied at rest and during static intermittent HG exercise at 15, 30, and 45% of maximal voluntary contraction and KE exercise at 40, 60, and 80% of maximum KE work rate. Salt restriction lowered resting systolic blood pressure (supine: -12 ± 12 mmHg, seated: -17 ± 12 mmHg) and diastolic blood pressure (supine: -3 ± 9 mmHg, seated: -5 ± 7 mmHg, P < 0.05). Despite an ~8 mmHg lower mean arterial blood pressure during both HG and KE exercise following salt restriction, neither central nor peripheral hemodynamics were altered. Therefore, salt restriction can lower blood pressure during exercise in subjects with hypertension, reducing the risk of cardiovascular events, without impacting central and peripheral hemodynamics during either arm or leg exercise. NEW & NOTEWORTHY This is the first study to examine the potential blood pressure-lowering benefit of a salt-restrictive diet in individuals with hypertension without any deleterious effects of exercising blood flow. While mean arterial pressure decreased by ~8 mmHg following salt restriction, these findings provide evidence for salt restriction to provide protective effects of reducing blood pressure without inhibiting central or peripheral hemodynamics required to sustain arm or leg exercise in subjects with hypertension.

Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor's rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure., (© 2014 American Heart Association, Inc.)

How interactions of an individual's genetic background and environmental factors, such as dietary salt intake, result in age-associated blood pressure elevation is largely unknown. Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation and modification of gene transcription. We have shown previously that hypertensive African-American minor allele carriers of the LSD1 single nucleotide polymorphism (rs587168) display blood pressure salt sensitivity. Our goal was to further examine the effects of LSD1 genotype variants on interactions between dietary salt intake, age, and blood pressure. We found that LSD1 single nucleotide polymorphism (rs7548692) predisposes to increasing salt sensitivity during aging in normotensive Caucasian subjects. Using a LSD1 heterozygous knockout mouse model, we compared blood pressure values on low (0.02 % Na(+)) vs. high (1.6 % Na(+)) salt intake. Our results demonstrate significantly increased blood pressure salt sensitivity in LSD1-deficient compared to wild-type animals with age, confirming our findings of salt sensitivity in humans. Elevated blood pressure in LSD1(+/-) mice is associated with total plasma volume expansion and altered renal Na(+) excretion. In summary, our human and animal studies demonstrate that LSD1 is a genetic factor that interacts with dietary salt intake modifying age-associated blood pressure increases and salt sensitivity through alteration of renal Na(+) handling.

Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) of the sodium-bicarbonate co-transporter gene (SLC4A5) are associated with hypertension. We tested the hypothesis that SNPs in SLC4A5 are associated with salt sensitivity of blood pressure in 185 whites consuming an isocaloric constant diet with a randomized order of 7 days of low Na(+) (10 mmol/d) and 7 days of high Na(+) (300 mmol/d) intake. Salt sensitivity was defined as a ≥ 7-mm Hg increase in mean arterial pressure during a randomized transition between high and low Na(+) diet. A total of 35 polymorphisms in 17 candidate genes were assayed, 25 of which were tested for association. Association analyses with salt sensitivity revealed 3 variants that associated with salt sensitivity, 2 in SLC4A5 (P<0.001) and 1 in GRK4 (P=0.020). Of these, 2 SNPs in SLC4A5 (rs7571842 and rs10177833) demonstrated highly significant results and large effects sizes, using logistic regression. These 2 SNPs had P values of 1.0 × 10(-4) and 3.1 × 10(-4) with odds ratios of 0.221 and 0.221 in unadjusted regression models, respectively, with the G allele at both sites conferring protection. These SNPs remained significant after adjusting for body mass index and age (P=8.9 × 10(-5) and 2.6 × 10(-4) and odds ratios 0.210 and 0.286, respectively). Furthermore, the association of these SNPs with salt sensitivity was replicated in a second hypertensive population. Meta-analysis demonstrated significant associations of both SNPs with salt sensitivity (rs7571842 [P=1.2 × 10(-5)]; rs1017783 [P=1.1 × 10(-4)]). In conclusion, SLC4A5 variants are strongly associated with salt sensitivity of blood pressure in 2 separate white populations.

Context: It is assumed that in individuals with type 2 diabetes mellitus (T2DM), blood pressure sensitivity to salt intake and the frequency of a low renin state are both increased compared with the nondiabetic population. However, studies supporting these assumptions may have been confounded by participant inclusion criteria, and study results may reflect target organ damage., Objective: The objective of this study was to examine in a cohort of T2DM 1) the frequency of salt sensitivity of blood pressure and 2) whether alterations of the renin-angiotensin-aldosterone system (RAAS) contribute to salt sensitivity in this population., Design, Patients, and Methods: Within participants of the HyperPATH cohort, four groups were analyzed: 1) T2DM with hypertension (HTN), n=51; 2) T2DM without HTN, n=30; 3) HTN only, n=451; and 4) normotensive, n=209. Phenotype studies were conducted after participants completed two dietary phases: liberal sodium (200 mmol/d) and low sodium (10 mmol/d) for 7 d each. Participants were admitted overnight to a clinical research center after each diet, and supine measurements of the RAAS before and after a 60-min angiotensin II infusion (3 ng/kg·min) were obtained., Results: Multivariate regression analysis demonstrated that T2DM status (all individuals with T2DM vs. individuals without T2DM) was not associated with the change in mean arterial pressure between the low and liberal sodium diets after accounting for age, gender, body mass index, race, and baseline blood pressure (T2DM status, P=0.5). Furthermore, two intermediate phenotypes of altered RAAS, low renin, and nonmodulation (NMOD), were associated with salt-sensitive blood pressure but occurred at different frequencies in the T2DM-HTN and HTN groups (low renin, 12% T2DM-HTN vs. 29% HTN; NMOD, 41% T2DM-HTN vs. 27% HTN; P=0.01)., Conclusion: The frequency of NMOD in participants with T2DM was significantly higher compared with HTN, suggesting that the salt sensitivity often seen in T2DM is driven by NMOD.

Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

Genome scans for identifying susceptibility loci for pulse pressure have produced inconclusive results. A heterogeneity-based genome search meta-analysis was applied to available genome-scan data on pulse pressure. A genome search meta-analysis divides the whole genome into 120 bins and identifies bins that rank high on average in terms of linkage statistics across genome scans unweighted or weighted by study size. The significance of each bin's average rank (right-sided test) and heterogeneity among studies (left-sided test) was calculated using a Monte Carlo test. The meta-analysis involved 7 genome scans, 3 consisting of subjects of European descent. Of the 120 bins, 5 bins had significant average rank (P(rank)0.05), indicating variation in the strength of association. Further investigation of these regions may help to direct the identification of candidate genes for pulse pressure variation.

Background: Arterial stiffness is reported in numerous family studies to be heritable. Linkage analysis has identified genomic regions that likely harbor genes contributing to its phenotypic expression. We sought to identify loci contributing to arterial stiffness in a large group of African-American hypertensive families., Methods: We performed a genome scan on 1251 African Americans in families participating in the HyperGEN (Hypertension Genetic Epidemiology Network) study. Children of the hypertensive proband generation were also included in the analysis. Arterial stiffness was estimated as pulse pressure (PP; systolic - diastolic blood pressure [BP]) divided by echocardiographically determined stroke volume (SV). The PP/SV ratio was adjusted for several nongenetic sources of variation, including demographic and lifestyle factors. The residual phenotype was analyzed using multipoint variance components linkage implemented in SOLAR 2.0.3., Results: Arterial stiffness was 20% heritable in African Americans. Two regions were highly suggestive of linkage, one between markers D1S1665 and D1S1728 in the 215-cM region of chromosome 1 (LOD = 3.08), and another between D14S588 and D14S606 in the 85-cM region of chromosome 14 (LOD = 2.42). Two candidate genes (GPR-25, SMOC-1) are located in the linked regions. SMOC-1 is of physiological interest because it codes a secreted glycoprotein with five domains, each containing regions homologous to those on other proteins that mediate cell-matrix interactions. GPR-25 is homologous to receptors involved in BP regulation., Conclusions: At least two chromosomal regions in humans are likely to harbor genes contributing to interindividual variation in PP/SV ratio, an index of arterial stiffness, in African Americans.

Familial combined hyperlipidemia (FCHL), with a marked elevation of apolipoprotein B (apoB), is estimated to cause 10-20% of premature coronary artery disease. However, little data are available to demonstrate the associations of apoB with pulse pressure and glucose levels in FCHL families in China. This study was to investigate the potential influence factors for blood pressure and glucose phenotypes in FCHL families by multiple linear regression analysis. We recruited 147 FCHL relatives and 90 spouses, aged 30 to 60 years, from 42 Chinese families with FCHL. Our results showed that triglyceride and low density lipoprotein cholesterol were associated with fasting glucose levels (all P<0.05). Body mass index and glucose significantly correlated to systolic blood pressure, diastolic blood pressure, and mean arterial pressure, respectively (all P<0.05). Furthermore, apoB was significantly related to pulse pressure and glucose in FCHL families (all P<0.05). Thus, this study demonstrates that apoB is significantly associated with pulse pressure and glucose levels in FCHL families. Accordingly, our data suggest that apoB may be a candidate risk marker for pulse pressure and glucose in FCHL populations.

The NaHCO3 cotransporter gene (SLC4A5) on chromosome 2 encodes a protein that transports sodium and bicarbonate across the cell membrane and regulates cellular pH. The National Heart, Lung, and Blood Institute Family Blood Pressure Program found linkage of blood pressure-related traits to the chromosomal region containing SLC4A5 and phenotype associations with single nucleotide polymorphisms (SNPs) in this gene. However, the results were inconsistent over various phenotypes and SNPs. Nevertheless, the evidence was strong enough to propose this gene as a blood pressure-related gene. To extend these findings, SLC4A5 SNPs were genotyped in an independent set of 96 Utah pedigrees of 1040 adult subjects at baseline, 760 of whom were followed longitudinally for 10 years. After adjusting for age, gender, body mass index, and polygenic correlations within pedigrees, SNP hcv1137534 was significantly associated with both systolic blood pressure and diastolic blood pressure (DBP) at baseline (unadjusted P=0.009 and P=0.043; respectively) and at 10-year follow-up (P=0.008 and P=0.007; respectively). In secondary tests of association of baseline-stressed blood pressure, hcv1137534 was borderline or significantly associated with DBP change during an isometric handgrip test (P=0.054), DBP change from supine to standing (P=0.020), and DBP change after a 50 degrees tilt (P=0.034). There was no evidence for compensation of abnormal SLC4A5 sodium transport by genotype-specific differences in sodium-lithium countertransport, lithium-potassium cotransport, altered plasma sodium, chloride, or CO2 levels. Therefore, in these Utah pedigrees, the SLC4A5 gene was significantly associated with blood pressure and persisted after 10 years of follow-up. These results additionally confirm the involvement of SLC4A5 with blood pressure control, although the mechanism is still unclear.

Overt and subclinical hypothyroidism are associated with increased systemic vascular resistance and hypertension. We examined the relationship between thyroid function and blood pressure homeostasis in euthyroid individuals. A total of 284 subjects (68% hypertensive) consumed high- (200 mmol) and low- (10 mmol) sodium diets, and their blood pressure responses were assessed as percentage change in the mean arterial pressure (MAP). p-Aminohippuric acid clearance was used to estimate effective renal plasma flow. Renal vascular resistance (RVR) was calculated as MAP divided by effective renal plasma flow. Serum free T(4) index (FTI) was lower (P < 0.0001) and TSH was higher (P = 0.046) in hypertensive compared with normotensive subjects independent of other baseline characteristics. FTI (beta = -1.51, P < 0.0001), baseline MAP, and race independently predicted MAP salt sensitivity. The FTI relationship with salt sensitivity adjusted for baseline MAP and race was similar among normotensive (beta = -1.42, P = 0.008) and hypertensive subjects (beta = -1.66, P = 0.0001). FTI correlated negatively with high- (P = 0.0001) and low- (P = 0.008) salt RVR, whereas TSH correlated positively with high- (P = 0.016) and low- (P = 0.012) salt RVR independent of age, gender, race, and body mass index. We have found that FTI is lower and TSH is higher in hypertensive compared with normotensive euthyroid subjects and that FTI independently predicts blood pressure salt sensitivity. These data show that the influence of thyroid function on blood pressure homeostasis extends into euthyroid range and likely reflects the action of thyroid hormone on peripheral vasculature.

High pulse pressure, a measure of arterial aging, is an important predictor of cardiovascular and general mortality. It has been suggested that the genetic etiology of pulse pressure is the same as systolic blood pressure. We performed a genome-wide, multipoint, parametric linkage analysis in 26 large, extended Utah pedigrees to locate genes affecting pulse pressure. Four parametric models were considered, including dominant and recessive modes of inheritance involving genes for high and low pulse pressure. Linkage analysis revealed 11 regions with a logarithm of the odds (LOD) >1.5, including 2 regions attaining genome-wide suggestive evidence for linkage after accounting for multiple tests. Inspecting pedigree-specific multipoint linkage evidence suggested that these 2 regions localized to 15.7 cM on chromosome 8p (LOD=2.89), between markers D8S136 and D8S1477, and 20.0 cM on chromosome 12q (LOD=2.59), between D12S1300 and D12S2070. Both regions were identified better by pulse pressure compared with equivalent analyses with systolic or diastolic blood pressure. Results for pulse pressure overlapped favorably with those of others for related blood pressure phenotypes and support the hypothesis that genes with pleiotropic effects on blood pressure phenotypes do exist, but that the genetic etiologies are not identical. In conclusion, our results suggest that pulse pressure might be of use for identifying genes involved in blood pressure phenotypes and arterial aging.

Objective: The contribution of salt intake to the pathogenesis of hypertension holds longstanding interest. Recent studies employed the sensitivity of blood pressure (BP) to salt intake as an intermediate phenotype. The validity of this approach relative to the homogeneity of sodium-sensitive hypertension was investigated while simultaneously controlling multiple putative factors., Methods: Blood pressure responses to shifts in salt intake were measured in 274 individuals with essential hypertension in steady-state sodium balance on high (200 mEq) and low (10 mEq) sodium intakes. Univariate and multivariate analyses predicted systolic and diastolic sodium sensitivity based on interactions among demographic factors (age, gender, race, body mass index) and hypertensive type [low-renin (LR), modulator (M), non-modulator (NM)]., Results: The influence of hypertension type on systolic salt sensitivity (SSS) depended on gender (P = 0.03). In females, highest SSS was in LR (21, 14, 13 mmHg for LR, M, NM, P = 0.02), while in males highest SSS was in NM (11, 10, 16 mmHg for LR, M, NM, P = 0.07). Age predicted SSS without interacting with other factors, producing a 2.4 mmHg increase per decade (P = 0.02). Hypertension type affected diastolic salt sensitivity (DSS) (P = 0.002) without interacting with other factors. M had less DSS (6 mmHg) than LR (9 mmHg) and NM (11 mmHg) (P < 0.01)., Conclusions: For subjects in sodium balance, the distributions of SSS and DSS were unimodal and the mechanisms mediating SSS and DSS were different. Controlling for multiple demographic factors, at least two hypertensive types have largest BP responses to sodium intake, reducing the usefulness of blood pressure sensitivity to salt intake as an intermediate phenotype.

Background: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.Objective: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure.Design: Cross-sectional study.Setting: 4 U.S. academic medical centers.Participants: Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408).Measurements: Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h.Results: Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism.Limitation: Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics.Conclusion: The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension.Primary Funding Source: National Institutes of Health. [ABSTRACT FROM AUTHOR]

BACKGROUND Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms. METHODS We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/-). RESULTS The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN-SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/- mice. No significant associations were observed with other volume regulated systems. CONCLUSIONS These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention. [ABSTRACT FROM AUTHOR]

The renin gene has been previously reported to be associated with essential hypertension in a variety of ethnic groups. However, no studies have systematically evaluated the relationship between single nucleotide polymorphisms (SNPs) representing coverage of the entire renin gene and hypertension risk. To evaluate the association between renin gene variation and hypertension we investigated data on HyperPATH cohort with 570 hypertensive and 222 normotensive Caucasian subjects. Six tagging SNPs and resultant haplotypes were tested for associations with hypertension risk, followed by mean arterial pressure (MAP), plasma renin activity (PRA) and the change in MAP in response to angiotensin II (AngII) infusion (AngII ΔMAP). The A allele of SNP rs6693954 and the haplotype containing rs6696954A were significantly associated with higher risk for hypertension (OR = 1.98, p = 0.0001; OR = 1.63 p = 0.0005, respectively). The same haplotype block was also associated with altered PRA levels and blunted AngII ΔMAP (global p-value = 0.02, 0.047, respectively). Our results confirm that polymorphisms in the renin gene are associated with increased risk for hypertension in an independent cohort, and that the underlying mechanism may reside in the interaction of renin activity and vascular responsiveness to angiotensin II. [ABSTRACT FROM PUBLISHER]

BackgroundPrior evidence suggests a link between inflammation and hypertension. Interleukin-6 (IL-6) has been implicated in animal studies to play an important role in angiotensin II (ANGII)-mediated hypertension. The aim of this study was to examine the relationship of IL-6 and renin-angiotensin system (RAS) activity in human hypertension.MethodsData from 385 hypertensives and 196 normotensives are included in this report. Blood pressure and laboratory evaluation were performed on liberal and low sodium diets. IL-6 response to an ANGII infusion was evaluated to assess the effect of acute RAS activation.ResultsHypertensives had higher baseline IL-6 and C-reactive protein (CRP) compared with normotensives on both diets. IL-6 increased in response to ANGII in hypertensives and normotensives (28% in hypertensives, 31% in normotensives, P ≤ 0.001 for change from baseline). In the setting of RAS activation by a low salt diet, multivariate regression analysis adjusted for age, body mass index (BMI), gender, race, and hypertension status demonstrated an independent positive association of plasma renin activity (PRA) with CRP (β = 0.199, P < 0.001). There was no significant difference in IL-6 or CRP levels between liberal and low sodium diets.ConclusionThese findings confirm an association between hypertension and inflammation and provide human data supporting previous evidence from animal studies that IL-6 plays a role in ANGII-mediated hypertension. Notably, compared to levels on a liberal sodium diet, neither IL-6 nor CRP were higher with activation of the RAS by a low salt diet indicating that a low sodium diet is not inflammatory despite increased RAS activity.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.113 [ABSTRACT FROM AUTHOR]

Introduction: Concentrations of 1,25-hydroxyvitamin D have been positively associated with dietary sodium and salt sensitivity (SS) of blood pressure (BP), and inversely with plasma renin activity (PRA). We investigated the association between PRA and 25-hydroxyvitamin D (25OHD), the most clinically relevant vitamin D metabolite, and whether 25OHD associates with SS of BP in renin phenotypes of hypertension.Methods: We performed cross-sectional analyses on 223 Caucasian subjects with hypertension maintained in high and low dietary sodium balance. Subjects were distinguished as having low-renin (LR) or normal-renin (NR) hypertension. Multivariable linear regression was used to evaluate adjusted relationships.Results: Increasing 25OHD concentrations were inversely associated with PRA (p < 0.05) on both salt diets. Furthermore, 25OHD was associated with SS of BP in LR hypertension (b = 0.62, p = 0.04), but not in NR hypertension (b = 0.06, p = 0.59). In an adjusted multivariable interaction model, renin status (LR vs. NR) was a significant effect modifier of the relationship between 25OHD and SS of BP (p = 0.04).Conclusions: Our findings suggest that 25OHD is inversely associated with PRA and positively associated with SS of BP in LR hypertension subjects. These results extend and support prior evidence indicating an interaction between dietary sodium, the RAS, and vitamin D that influences BP in hypertension. [ABSTRACT FROM PUBLISHER]

Abstract: Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium <20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium >150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 ± 12.5 years (range, 18-65) and with body mass index of 25.3 ± 4.0 kg/m2, were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 ± 1.6 vs 2.4 ± 1.7, P < .01). Serum aldosterone (21.0 ± 14.3 vs 3.4 ± 1.5 ng/dL, P < .001), 24-hour urine aldosterone (63.0 ± 34.0 vs 9.5 ± 6.5 μg/d, P < .001), and 24-hour urine norepinephrine excretion (78.0 ± 36.7 vs 67.9 ± 39.8 μg/d, P < .05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation. [Copyright &y& Elsevier]

Background: Left ventricular (LV) mass and wall thickness are closely associated with measures of body size and blood pressure and also correlated with systolic and diastolic function, suggesting a contribution of common physiologic mechanisms, including pleiotropic genes, to their covariation. Methods: Doppler echocardiography was performed in 434 African-American (1344 individuals) and 284 white families (1119 individuals). We conducted a genome-wide linkage scan for LV mass, LV structure and function, and composite factors derived from a factor analysis of LV structure and function in the HyperGEN Study population. Results: Factor analysis identified (i) a LV wall thickness factor correlated strongly with interventricular septal thickness (IVSTd) and posterior wall thickness (PWTd) and (ii) a LV diastolic filling factor strongly correlated with early and atrial phase peak transmitral filling velocities. The LV phenotypes and composite factor scores were analyzed in multipoint variance components linkage model implemented in SOLAR with 387 microsatellite markers. In whites, the two highest LODs were 3.42 for LV atrial phase peak filling velocity at 144 cM on chromosome 1 and 3.12 for the LV wall thickness factor at 160 cM on chromosome 7. The peak LODs of the component traits (IVSTd and PWTd) clustered at the same region as the composite factor. Adjusting the factor score for body mass index (BMI) substantially reduced the peak LOD at this region (LOD = 1.92). Bivariate linkage analysis of the composite factor with BMI improved LOD to 3.42 at 158 cM. Also in whites, suggestive linkage was observed on chromosomes 2 and 4 for LV mass, chromosomes 3, 5, 10, and 17 for LV atrial phase peak filling velocity, and chromosome 10 for LV diastolic filling factor. In African Americans, suggestive linkage was observed on chromosome 12 for LV mass, chromosome 21 for IVSTd, and chromosome 3 for LV internal diameter at end-diastole. Conclusion: Our study suggests that a region on chromosome 7 contains pleiotropic genes contributing to the variations of both LV wall thickness and BMI in whites. [ABSTRACT FROM AUTHOR]

Background: We have shown that increased cardiac output is related to both fat-free mass and fat mass in obesity. Objective: We studied the association of body fat distribution and body composition with flow-resistance relations in overweight. Design: We studied 521 overweight, nonobese participants in the Hypertension Genetic Epidemiology Network (HyperGEN) Study-a component of the National Heart, Lung, and Blood Institute Family Blood Pressure Program, designed to assess the genetic basis of hypertension. Participants had normal ventricular function and no cardiovascular disease: 261 with central fat distribution (CFD) (waist girth >88 cm in women and > 102 cm in men) and 260 with peripheral fat distribution (PFD). Fat-free mass (FFM) and fat mass (FM) were measured by bioelectric impedance. Body composition was estimated as FM/FFM. Echocardiographic stroke volume (SV) and cardiac output (CO) were measured. Results: Hypertension was present in 73% of the subjects with PFD and in 78% with CFD. Overweight with CFD was associated with greater FM/FFM in both normotensive and hypertensive participants. After FFM, age, sex, and race were controlled for, SV and CO were higher in subjects overweight with CFD than in those with PFD, whereas peripheral resistance was not significantly different. Differences in CO between CFD and PFD were reduced after further adjustment for FM. After the covariates were controlled for, hypertensive subjects had higher peripheral resistance and lower arterial compliance than did normotensive participants, but cardiac output was not significantly different. Conclusion: CFD is associated with more severe abnormalities in body composition and with higher CO independently of FFM in overweight, nonobese subjects. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) response to infused angiotensin II (Ang II) has been widely used to characterize hypertensive subjects. High cholesterol levels hav recently been found to enhance this response in young men, suggesting an important new link between atherosclerosis and hypertension. The present study assessed the familial resemblance of the BP response following an Ang II infusion and measured the factors affecting the trait in a large set of hypertensive men and women. After a low-salt diet for 7 days a 30-min infusion of Ang II was administered to 218 white hypertensive patients (28 singletons, 80 sibling pairs, 10 trios). Age and gender were significantly correlated to the Ang II systolic but not to the diastolic BP response. Conversely, cholesterol level and especially low-density lipoprotein (LDL) were correlated to both systolic and diastolic changes. Multivariate analysis showed that age, gender, and LDL were the three parameters that explained the systolic BP change whereas plasma LDL remained the only variable significantly correlated to the diastolic BP change. Significant familial resemblances in the Ang II induced systolic and diastolic BP response were observed, especially in female pairs. On this limited number of subjects, suggestive evidence for association and linkage was found between the trait, A1166C, and (CA)n repeat polymorphisms of the Ang II type 1 receptor (AT1R) gene. In conclusion, the Ang II induced BP change is strongly related to plasma LDL in hypertensive men and women, stressing the importance of the lipid profile as a contributor to BP regulation. Familial resemblance of this intermediate phenotype is sex dependent and may be partly explained by polymorphisms of the AT1R gene. [ABSTRACT FROM AUTHOR]

Uric acid and the state of the intrarenal renin-angiotensin system in humans.Background.Experimental hyperuricemia is marked by an activated intrarenal renin-angiotensin system (RAS). The renal vascular response to exogenous angiotensin II (Ang II) provides an indirect measure of intrarenal RAS activity. We tested the hypothesis that the serum uric acid concentration predicts the renal vascular response to Ang II.Methods.A total of 249 subjects in high sodium balance had the renal plasma flow (RPF) response to Ang II measured. Para-aminohippuric acid (PAH) clearance was used to estimate RPF. Multivariable regression analysis determined if the serum uric acid concentration independently predicts the RPF response to Ang II. Variables considered included age, gender, race, body mass index (BMI), hypertension status, blood pressure, basal RPF, creatinine clearance, serum insulin, serum glucose, serum high-density lipoprotein (HDL), serum triglycerides, and plasma renin activity (PRA).Results.Uric acid concentration negatively correlated with the RPF response to Ang II (r=−0.37,P<0.001). In univariate analysis, age, BMI, hypertension, triglycerides, and blood pressure were negatively associated, and basal RPF, HDL, and female gender were positively associated with the RPF response to Ang II. In multivariable analysis, serum uric acid concentration independently predicted the RPF response to Ang II (β=−5.3,P<0.001).Conclusion.Serum uric acid independently predicted blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated intrarenal RAS. This could be due to a direct effect of uric acid or reflect a more fundamental renal process. These data may have relevance to the association of uric acid with risk for hypertension and nephropathy. [ABSTRACT FROM AUTHOR]

Effects of gender and genotype on the phenotypic expression of nonmodulating essential hypertension. Nonmodulation describes a subset of the normal/high renin essential hypertensive population. It is an inherited trait. This report reviews the genetic and gender data recently available that discuss the modification of the expression of the nonmodulating phenotype. Both the adrenal and the renal blood flow markers for nonmodulation are associated with a single nucleotide polymorphism (SNP) in the coding region of the angiotensinogen gene at codon 235. Even though the nonmodulating phenotype is associated with a somatic gene, gender modifies its expression. In women, the expression of the nonmodulating phenotype is approximately half of that in men. Additional analysis suggests that this gender difference is almost entirely explained by a difference in the frequency of nonmodulation in younger premenopausal women. In older, likely postmenopausal women, there is no gender difference. This suggests that the expression of the nonmodulating phenotype, presumably secondary to changes in the expression of the angiotensinogen gene, is modulated by female sex hormones. [ABSTRACT FROM AUTHOR]