Salt-sensitive Subjects Research Articles

SALT SENSITIVITY AND CHRONIC KIDNEY DISEASE IN PATIENTS WITH ARTERIAL HYPERTENSION: CLINICAL SYMPTOMS

The purpose of the research to assess the frequency of salt sensitivity and chronic kidney disease (CKD) in population of essential arterial hypertension (EAH) patients and some clinical symptoms based on salt sensitivity/salt resistance and CKD appearance.Material and methods. 100 patients with EAH II stage participated in the study. All participant underwent a complex of clinical and laboratory examinations. Salt sensitivity / salt resistance was determined by Weinberger M.H. based method. CKD was defined by glomerular filtration rate (GFR) according to the CKD-EPI equation taking into account creatinine and Cystatin-C blood level (KDIGO, 2024).Results. EAH patients with CKD (GFR ≤60 ml/min/1.73m2, for ≥3 months), as well as salt-sensitive patients, more often complain of breath’ shortness, cardiac pain - by 17.5-18.8% (р≤0.05-0.022), peripheral edema - by 41.7-52.1% (р<0.001), headache and sleep impairment – by 24.2-32.0% (р≤0.016-0.001), rhythm and conduction disturbances – by 28.8- 34.1% (р≤0.004-0.001), show signs of depression – by 17.4-33.7% (р≤0.039-0.001). The risk of cardialgia, arrhythmias/blockades, signs of depression, suffocation, impaired sleep, headaches in EAH patients increases 2.4-4.2 times in salt-sensitive subjects (OR95%CI:1.0-10.33; p≤0.044), for CKD – 2.3-3.8 times (OR95%CI:1.04-8.86; p≤0.031). The probability of peripheral edema increases twice as much in salt-sensitive patients – almost 14 times (OR95%CI:4.73-41.06; p<0.001), than in CKD patients – 6.3 times (OR95%CI:2.60-15.37; p<0.001). The risk of gastrointestinal disorders increases almost three times (p=0.03) in salt-sensitive individuals and the CKD presence elevates the chances of fatigue and general weakness almost 4 times (p=0.001).Conclusion. Salt sensitivity and CKD appearance worsen the EAH clinical course.

Salt-sensitive trait of normotensive individuals is associated with altered autonomous cardiac regulation: a randomized controlled intervention study.

Blood pressure (BP) responses to sodium intake show great variation, discriminating salt-sensitive (SS) from salt-resistant (SR) individuals. The pathophysiology behind salt sensitivity is still not fully elucidated. We aimed to investigate salt-induced effects on body fluid, vascular tone, and autonomic cardiac response with regard to BP change in healthy normotensive individuals. We performed a randomized crossover study in 51 normotensive individuals with normal body mass index and estimated glomerular filtration rate. Subjects followed both a low-Na+ diet (LSD, <50 mmol/day) and a high-Na+ diet (HSD, >200 mmol/day). Cardiac output, systemic vascular resistance (SVR), and cardiac autonomous activity, through heart rate variability and cross-correlation baroreflex sensitivity (xBRS), were assessed with noninvasive continuous finger BP measurements. In a subset, extracellular volume (ECV) was assessed by iohexol measurements. Subjects were characterized as SS if mean arterial pressure (MAP) increased ≥3 mmHg after HSD. After HSD, SS subjects (25%) showed a 6.1-mmHg (SD 1.9) increase in MAP. No differences between SS and SR in body weight, cardiac output, or ECV were found. SVR was positively correlated with Delta BP (r = 0.31, P = 0.03). xBRS and heart rate variability were significantly higher in SS participants compared to SR participants after both HSD and LSD. Sodium loading did not alter heart rate variability within groups. Salt sensitivity in normotensive individuals is associated with an inability to decrease SVR upon high salt intake that is accompanied by alterations in autonomous cardiac regulation, as reflected by decreased xBRS and heart rate variability. No discriminatory changes upon high salt were observed among salt-sensitive individuals in body weight and ECV.NEW & NOTEWORTHY Extracellular fluid expansion in normotensive individuals after salt loading is present in both salt-sensitive and salt-resistant individuals and is not discriminatory to the blood pressure response to sodium loading in a steady-state measurement. In normotensive subjects, the ability to sufficiently vasodilate seems to play a pivotal role in salt sensitivity. In a normotensive cohort, differences in sympathovagal balance are also present in low-salt conditions rather than being affected by salt loading. Whereas treatment and prevention of salt-sensitive blood pressure increase are mostly focused on renal sodium handling and extracellular volume regulation, our study suggests that an inability to adequately vasodilate and altered autonomous cardiac functioning are additional key players in the pathophysiology of salt-sensitive blood pressure increase.

S-50-5: SALT SENSITIVITY AS MARKER FOR HYPERTENSION MANAGEMENT

Arterial hypertension is one of the most critical risk factors for cardiovascular (CV) disease, stroke, and chronic kidney disease (CKD). According to the current guidelines on hypertension management, the identification of one or more CV risk factors requires an earlier and more intensive treatment paradigm. Salt sensitivity (SSy), defined as susceptibility to changes in blood pressure related to dietary salt intake, is a well-known independent risk factor for CV disease in both the general and hypertensive population, even though it is not included in current guidelines. Is has been reported that SSy affects 30_50% of hypertensive and 25% of normotensive subjects. Salt sensitivity is more common in the elderly, women, African Americans, and patients with CKD and insulin resistance. The diagnosis of SSy is complex and not entirely standardized. The two main methods for SSy assessment are the dietary protocol versus the acute salt load. The dietary protocols typically evaluate the blood pressure variation between short periods of low and high sodium diet and often differ in both the duration and the amount of salt intake. Acute test (which consists of an i.v. infusion of 2 L of physiological solution over 2 hours) evaluates mean blood pressure (MBP) variation between the end and the start of the infusion. Three different blood pressure responses are possible: no substantial variation [salt resistant (SR) subjects], an increase in blood pressure [salt sensitive (SS) subjects], or a paradoxical decrease in blood pressure [reverse salt sensitive (RSS) subjects]. Although RSS subjects have been recognized as a third distinct group since the early 1990 s, many studies included them in the group of SR subjects. Recently, the concept of reverse salt sensitivity has been re-evaluated in relation to CV risk. Previous studies have shown an increased risk of developing cardiovascular events, hypertensive heart disease and microalbuminuria among SS patients. In our recent paper, the SS and RSS condition appear to be equivalent risk factors for CV events in hypertensives. Finally, a J curve relationship between dietary salt and cardiovascular damage has been proposed. Different pathophysiological mechanisms can be involved in SSy: renal autoregulation (Pressure natriuresis curve), Renin angiotensin aldosterone system, sympathetic nervous system activity, Insulin resistance, peripheral vascular resistances, sodium storage skin, genetic predisposition. Classification according to salt sensitivity can help in personalization of salt intake indication, intensity of therapy and timing of follow up.

423.6: Salt Sensitivity in Living Kidney Donors: A New Cardiovascular Risk Factor?

Introduction: Kidney transplantation with living donor (LKD) is associated with longer graft and patient survival compared with deceased donor organs. Until recently, it was believed that the long-term risk of end-stage renal disease (ESRD), cardiovascular events (CVE) or death in LKD is similar to or even smaller than the general population. Normotensive salt-sensitive (Ss) subjects over 25 years old have a mortality similar to that of hypertensive subjects, while salt-resistant (Sr) normotensive subjects have a longer survival. Objective: To compare, in healthy subjects that we have studied to be a LKD, the levels of 24 hour mean ambulatory blood pressure monitoring (24 hs mABPM), kidney function and left ventricular mass index (LVMI) between Ss and Sr, before and a year after donation. Methods: Data from 42 LKD were included. There were 34 (82%) women, with a mean age of 49 (11) years (range 26 to 66 years). None had a history of kidney disease, diabetes, CVE or hypertension. The subjects were placed on a high-salt diet containing 250 mmol Na for 7 days and on a low-salt diet containing 30 mmol Na during the following 7 days. Compliance with the diet was assessed twice a week by measurement of 24-hour urinary Na excretion (NaUE). On the last day of both the high and low-salt periods, 24-hour ABPM was performed with an automated, noninvasive device. Salt-sensitivity (SS) was defined by a significant decrease (P<0.05) of 24 hs mABPM from high to low salt intake. Trans-thoracic m-mode echocardiograms were performed on the last day of the first period. LV mass was calculated according to the Penn convention and corrected for body surface area to produce the LVMI. Data with normal and nonparametric distribution were expressed as mean and standard deviation (SD) or median and interquartile range (ICR), Student t test and Wilcoxon test were used respectively, P values < 0.05 were considered to be statistically significant. Results: SS was found in 13 of the 42 living kidney donors (31%). The Ss group were older than Sr 53 (10) vs 47 (10) years, but it was not statistically significant (p=0.08). Pre-donation, with high-salt diet the 24 hs mABPM was significantly greater in Ss than in Sr, without any differences in creatinine clearence (CrCl), 24 hs NaUE and 24 hs potassium urinary (KUE) excretion. On the other hand with low-salt diet we did not find any significant differences in 24 hs mABPM, CrCl, NaUE and KUE between groups. LVMI was significantly greater in Ss than in Sr donors. One year after donation we found the same statistically differences in 24 hs mABPM with high-salt diet and no differences with the low-salt diet. Again LVMI was significantly greater in Ss than in Sr donors. The increase of LVMI after donation was significant only in Ss donors (23,2 vs 4,5 g/m2). Conclusion: Ss healthy LKD showed a greater LVMI than Sr ones and a greater increment one year after donation. The study of SS could be included to make kidney transplantation with living donor organs safer.

Abstract P246: Relationship Between Urinary Sodium/potassium Ratio And Systolic Blood Pressure In Salt Sensitive Subjects In The Dash-sodium Trial

Excessive salt intake is associated with hypertension and cardiovascular morbidity. However, identifying those at risk of salt sensitive hypertension (SSH) remains a challenge due to its unequal distribution among populations and inaccurate assessment of dietary sodium (Na) and potassium (K) intake. The objective of this study was to compare indices of dietary Na intake in relation to systolic blood pressure (SBP) in salt sensitive (SS) and salt resistant (SR) subjects from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial. We hypothesized that when compared to urinary Na or K independently, Na/K ratio is a better predictor of SSH when defined as a 5-10 mmHg change in SBP from low to high dietary Na. Among 404 Black and White subjects, baseline classifications included 177 SS and 227 SR. After diet randomization, on the control 107 were SS and 92 SR and on the DASH 70 were SS and 135 SR. Descriptive statistics, bivariate analysis, followed by linear regression models for baseline and multilevel mixed-effects models after intervention were used to assess the relationship between SBP and dietary Na (as measured by urinary Na/K ratio or Na and K independently) using SS as a categorical factor. SBP was consistently associated with SS, Na/K ratio, and age in all models . At baseline, SBP was significantly higher in SS and SR subjects of the same race and sex, after controlling for age and urinary Na/K ratio and was highest for White females, SS:142.3 (138.8, 145.7) vs. SR:133.2 (130.7, 135.7), and for Black males, SS:137.0 (133.8, 140.1) vs. SR: 129.6 (127.0, 132.3). On average, SBP increased 1.02 (0.065, 1.98) mmHg with each unit increase in Na/K ratio and 3.30 (2.41, 4.19) mmHg with each 10-year increase in age. After randomization and exposure to increasing levels of sodium, SBP increased in SS subjects on the control diet:125.3 (123.2, 127.3) to 136.8 (134.8, 138.9), an effect that was greater in White vs Black females and in Black vs White males. SBP increased in SS subjects on the DASH diet: 121.4 (118.8, 124.0) to 131.2 (128.7, 133.7), but there were no differences by race and sex. These results suggest that a 5-10 mmHg change in SBP in subjects on a typical American diet and Na/K ratio are good predictors of SSH and that the DASH diet may help to reduce race and sex disparities.

Abstract 11: Single Cell Eccite-seq Analysis Reveal An Important Role Of Monocyte-specific Nlrp3 Inflammasome For Salt-sensitivity Of Hypertension In Humans

Salt sensitivity of blood pressure is an independent predictor of death due to cardiovascular events. Diagnosis of salt-sensitivity is not feasible in the clinic, making it difficult to investigate therapeutic strategies. We hypothesized that NLRP3-inflammasome and IL-1β production in monocytes plays a role in salt-sensitive hypertension. We phenotyped salt-sensitivity of blood pressure using an acute inpatient Weinberger protocol of an isocaloric high salt diet and rapid intravenous salt-loading, followed by low salt diet and furosemide-induced salt-depletion. Ambulatory blood pressure was continuously monitored and averaged for the days of salt-loading and salt-depletion. Blood samples were obtained at baseline, salt-loading, and after salt-depletion. Median age was 54 years (44-55), 3 of the 5 subjects were female, screening systolic blood pressure was 140 mmHg (134-148), diastolic blood pressure was 88 mmHg (84-99), and BMI was 35 kg/m 2 (30-39). Using cell hashing and ECCITE-seq analysis, we profiled transcriptomes in multiple immune cell types using antibody-derived tags (ADTs). UMAP clustering of different cell types were identified by ADTs including monocyte markers CD14 and CD16. Interestingly, UMAP visualization of CD14+ and CD16+ clusters indicated a greater decrease in CD14+ clusters after salt-depletion in the salt-resistant subjects than the salt-sensitive; however the salt-sensitive subjects had a greater decrease in CD16+ clusters than the salt-resistant group after both salt-loading and salt-depletion. These data were confirmed using flow cytometry. Unlike in salt-resistant participants, we found that within monocyte clusters, salt-sensitivity was associated with down regulation of the inflammasome components NLRP3 (0.386 ± 1.18 vs. 0.197 ± 0.778) and IL-1β (0.858 ± 2.32 vs. 0.159 ± 0.925) following salt-depletion. Using flow cytometry, we found Δ% isoLG+ CD14+/CD16+ monocytes correlated with salt-sensitivity of blood pressure (r=0.88, 95% CI, p=0.05). These results suggest that the inflammasome and monocyte activation are dynamically regulated by dietary salt in vivo and can serve as a potential diagnostic biomarker for salt-sensitivity of blood pressure.

The Effects of Short-Term Changes in Sodium Intake on Plasma Marinobufagenin Levels in Patients with Primary Salt-Sensitive and Salt-Insensitive Hypertension.

Increased marinobufagenin (MBG) synthesis has been suggested in response to high dietary salt intake. The aim of this study was to determine the effects of short-term changes in sodium intake on plasma MBG levels in patients with primary salt-sensitive and salt-insensitive hypertension. In total, 51 patients with primary hypertension were evaluated during acute sodium restriction and sodium loading. Plasma or serum concentrations of MBG, natriuretic pro-peptides, aldosterone, sodium, potassium, as well as hematocrit (Hct) value, plasma renin activity (PRA) and urinary sodium and potassium excretion were measured. Ambulatory blood pressure monitoring (ABPM) and echocardiography were performed at baseline. In salt-sensitive patients with primary hypertension plasma MBG correlated positively with diastolic blood pressure (ABPM) and serum NT-proANP concentration at baseline and with serum NT-proANP concentration after dietary sodium restriction. In this subgroup plasma MBG concentration decreased during sodium restriction, and a parallel increase of PRA was observed. Acute salt loading further decreased plasma MBG concentration in salt-sensitive subjects in contrast to salt insensitive patients. No correlation was found between plasma MBG concentration and left ventricular mass index. In conclusion, in salt-sensitive hypertensive patients plasma MBG concentration correlates with 24-h diastolic blood pressure and dietary sodium restriction reduces plasma MBG levels. Decreased MBG secretion in response to acute salt loading may play an important role in the pathogenesis of salt sensitivity.

Role of Rho in Salt-Sensitive Hypertension.

A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies.

Salt sensitivity and hypertension.

Salt sensitivity refers to the physiological trait present in mammals, including humans, by which the blood pressure (BP) of some members of the population exhibits changes parallel to changes in salt intake. It is commoner in elderly, females, Afro-Americans, patients with chronic kidney disease (CKD) and insulin resistance. Increased salt intake promotes an expansion of extracellular fluid volume and increases cardiac output. Salt-sensitive individuals present an abnormal kidney reaction to salt intake; the kidneys retain most of the salt due to an abnormal over-reactivity of sympathetic nervous system and a blunted suppression of renin-angiotensin axis. Moreover, instead of peripheral vascular resistance falling, salt-sensitive subjects present increased vascular resistance due mainly to impaired nitric oxide synthesis in endothelium. Recent studies have shown that part of the dietary salt loading accumulates in skin. Hypertensive and patients with CKD seem to have more sodium in skin comparing to healthy ones. However, we still have not fully explained the link between skin sodium, BP and salt sensitivity. Finally, although salt sensitivity plays a meaningful role in BP pathophysiology, it cannot be used by the physician in everyday patient's care, mainly due to lack of a simple and practical diagnostic test.

Differential effects of low-dose sacubitril and/or valsartan on renal disease in salt-sensitive hypertension.

Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 μg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.

Abstract 060: Increased Urinary Potassium Excretion Does Not Associate With Reduced Systolic Blood Pressure in the Dietary Approaches to Stop Hypertension Sodium Trial

Aim: The 2019 National Academy of Science, Engineering and Medicine Dietary Reference Intakes (DRI) for Sodium (Na) and Potassium (K) Report concluded there remains insufficient evidence to establish potassium DRIs. This study investigated the association between Na and K excretion and blood pressure in salt sensitive (SS) vs. salt resistant (SR) subjects in the Dietary Approaches to Stop Hypertension Sodium (DASH-Na) Trial. Methods: Via the NHLBI BioLINCC we accessed the DASH-Na dataset containing data on systolic blood pressure (SBP), 24-h urinary Na and K excretion at screening (regular diet [no dietary intervention]; 186 SS and 222 SR adults) and post 1-month DASH diet (increased K intake; 72 SS and 123 SR adults). The relationships between SBP, urinary Na and K excretion and Na:K ratio were assessed via linear regression with SS vs. SR as a categorical factor. Results: At screening, on a regular diet, urinary Na excretion (adjusted for gender) positively correlated with increased SBP in SS but not SR individuals (SS - 1g increase in Na excretion increases SBP 1.1±0.3mmHg - up to 5g Na excretion/day). In contrast, despite urinary K excretion of &lt;1g/day correlating with increased SBP in both SS and SS subjects, increased urinary K excretion (range 1-4g/day) did not correlate with changes in SBP in either SS or SR individuals. The urinary Na to K ratio (Na:K) was not significantly associated with SBP in SS or SR subjects. At the urinary Na excretion range 3-5g/day, equivalent to US Na intake, increased urinary K excretion had no effect on SBP in either SS or SR individuals. On the DASH diet; SBP was reduced in SS (-4.5±1.3mmHg) and SR (-8.3±0.8mmHg, P&lt;0.05) subjects. However, no correlation was observed between the reduction in SBP and urinary K excretion or urinary Na:K ratio in either in SS or SR individuals on the DASH diet. Conclusion: These data show in the DASH-Na trial population increased urinary K excretion does not correlate with reductions in SBP irrespective of the salt sensitivity of blood pressure. Our data support the recent DRI recommendation not to propose K intake guidelines and suggest that further evidence is required to support the establishment of a Na:K intake ratio to reduce SBP.

Abstract P2049: Mitochondrial Respiration And Biogenesis In The Glomeruli Of Dahl Ss Rats

The mechanisms of salt-sensitive (SS) hypertension are complex and far from clear. Available medications are insufficient to control blood pressure (BP) in the SS subjects, and there is a need for the development of novel effective therapies. SS hypertension is accompanied with an early onset of proteinuria, which results from the loss of podocytes. Many reports highlight that in this disease ultrastructural abnormalities and deficient metabolism in the renal mitochondria may precede histological injury. We hypothesized that podocyte damage occurs in part due to mitochondria dysfunction. Dahl SS rats were used here as an established animal model of SS hypertension. All rats were fed a 0.4% NaCl (normal salt, NS) diet until 8 weeks of age when they were challenged with a high salt (HS) 4% NaCl diet for 21 days. At the end of the protocol BP was measured, kidneys were cleared from blood, tissues were collected, and cortical glomeruli were isolated and subjected to imaging, WB and other applications. Systolic BP was elevated in the HS diet fed rats (171±9 vs 148±6 mmHg in HS vs NS diet fed rats). HS diet fed rats exhibited renal lesions, kidney hypertrophy, decreased GFR and exacerbated glomeruli damage compared to the NS group. We did not observe changes in the renal cortical expression of PGC1α; cortical mtDNA content (ND1 and ND6 gene expression vs genomic DNA) was not affected by a HS diet. Seahorse assay performed on freshly isolated glomeruli revealed that basal mitochondria respiration, maximal respiration, and spare respiratory capacity were lower in the HS group (28 ± 14%, 47 ± 15% and 37 ± 9% lower, respectively, vs NS group). No difference was observed in ATP production, or mitochondrial Complex V (ATPase) activity (expressed as oxidation rate of NADH and measured in glomerular pellets). Using confocal imaging and mitoPY1 staining we detected higher baseline H 2 O 2 level, lower antioxidant capacity, and fragmented mitochondria in the podocytes of the glomeruli isolated from HS diet fed group. EM analysis showed that HS mitochondria have structural abnormalities (swelling, enlargement, less defined cristae, and reduced number). We conclude that glomerular mitochondria in SS hypertension are functionally and structurally impaired.

PRECISION MEDICINE

Objective:For decades, it has been widely accepted that initiation of salt-induced hypertension involves a type of kidney dysfunction (natriuretic handicap) which causes salt-sensitive subjects to excrete less of a sodium load than normal subjects and to undergo abnormal increases in cardiac output,

Effect of Salt Intake on the Serum Cardiotrophin-1 Levels in Chinese Adults

Background: Dietary sodium affects fluctuations in blood pressure (BP) and vascular function. Cardiotrophin-1 (CT-1), a stress-induced cytokine that belongs to the interleukin 6 family, is released by cells in response to potentially harmful stresses and plays a pivotal role in congestive heart failure, hypertension and arterial stiffness. In this study, we performed a randomized trial to confirm the effects of altered salt intake on the serum CT-1 levels in humans. Methods: Forty-four subjects (18–65 years of age) were selected from a rural community in northern China. All subjects initially maintained a baseline period for 3 days, transitioned to a low-salt (LS) diet for 7 days (3.0 g/day of NaCl) and then a high-salt (HS) diet for an additional 7 days (18.0 g/day of NaCl). Results: For the whole group, the serum CT-1 concentrations were significantly increased in the HS period compared to those of the LS period (293.50 ± 137.70 vs. 360.40 ± 162.83 pg/mL, p = 0.040). The serum CT-1 concentrations significantly decreased from the baseline period to the LS diet (419.91 ± 123.50 to 256.49 ± 109.75 pg/mL, p < 0.01) and significantly increased from the LS to HS diet (256.49 ± 109.75 to 414.39 ± 191.21 pg/mL, p < 0.01). These changes were observed in salt-sensitive (SS) individuals but not in salt-resistant (SR) individuals. In addition, a significant positive relationship was observed between the changes in the CT-1 concentrations and systolic BP as well as the changes in the mean arterial pressure from the LS period to the HS period (r = 0.376, p = 0.012; r = 0.311, p = 0.040). The serum CT-1 concentrations were positively correlated with the 24-h urinary sodium-to-potassium (Na/K) excretion ratios during both of the LS and HS diet intervention periods in SS subjects (r = 0.621, p < 0.01), but this correlation was not evident in SR subjects (r = 0.208, p = 0.107). Conclusions: Our study indicates that variations in dietary salt intake affect the serum CT-1 levels in Chinese adults.

Changing views on the common physiologic abnormality that mediates salt sensitivity and initiation of salt-induced hypertension: Japanese research underpinning the vasodysfunction theory of salt sensitivity.

High-salt intake is one of the major dietary determinants of increased blood pressure and cardiovascular disease. Thus, there is scientific and medical interest in understanding the mechanistic abnormalities mediating the pressor effects of salt (salt sensitivity). According to historical theory, salt sensitivity stems from an impairment in renal function (referred to as "abnormal pressure natriuresis" or a "natriuretic handicap"), which causes salt-sensitive subjects to excrete a sodium load more slowly, and retain more of it than salt-resistant normotensive controls. However, this historical view has come under intense scrutiny because of growing awareness that in salt-sensitive subjects, acute salt loading does not usually induce greater increases in sodium balance and cardiac output than those induced by salt loading in salt-resistant normotensive controls. Here we highlight pioneering studies from Japan that challenge the historical thinking and provide insights into a contemporary theory of salt sensitivity termed the "vasodysfunction theory." According to this theory, initiation of salt-induced hypertension usually involves abnormal vascular resistance responses to increased salt intake, not greater renal retention of a salt load in salt-sensitive subjects than in normal subjects. By shifting the focus from the historical theory to a contemporary final common pathway for the pathogenesis of salt sensitivity, research from Japan is building the scientific foundation for more effective approaches to the prevention and treatment of salt-induced hypertension. Among the most promising approaches are dietary strategies for reducing the risk for salt-induced hypertension that do not depend on reducing salt consumption in the population.

A1319 The responses of the inflammatory marker, pentraxin 3, to dietary sodium and potassium interventions

Objectives: Pentraxin-3 is a sensitive marker of inflammation that plays dual roles, pathogenic and cardioprotective, in the progression of cardiovascular diseases. Inflammation is intimately involved in salt-induced hypertension. We investigated the responses of pentraxin-3 to sodium and potassium supplementation to elucidate the potential role of pentraxin-3 in salt-induced hypertension. Methods: 48 participants were enrolled from northwest China. All subjects were maintained on a 3-day normal diet, which was sequentially followed by a 7-day low sodium diet, a 7-day high sodium diet and a 7-day high sodium plus potassium diet. Plasma concentrations of pentraxin-3 were assessed using ELISA. Results: Plasma pentraxin-3 decreased significantly during the low salt period compared to baseline (0.57 ± 0.19 ng/ml vs. 0.72 ± 0.33 ng/ml, p = 0.012) and increased during the high salt period (0.68 ± 0.26 ng/ml vs. 0.57 ± 0.19 ng/ml, p = 0.037). Potassium supplementation inhibited the salt-induced increase in pentraxin-3 (0.56 ± 0.21 ng/ml vs. 0.68 ± 0.26 ng/ml, p = 0.015). Ln-transformed pentraxin-3 at baseline was inversely correlated with BMI (r = −0.349, p = 0.02), DBP (r = −0.414, p = 0.005), MAP (r = −0.360, p = 0.017). We found a positive correlation between the ln-transformed concentrations of pentraxin-3 and 24-h urinary sodium during low and high Na+ periods (r = 0.269, p = 0.012) and a negative relationship with 24 h urinary potassium excretion during the high salt and high salt plus potassium period (r = − 0.246, p = 0.02). These correlations remained significant after adjusting for confounders. Pentraxin-3 responses were more prominent in salt sensitive subjects than salt- resistant subjects. Conclusion: Dietary salt and potassium interventions significantly altered circulating pentraxin-3.

A1458 Effect of Salt Intake on Plasma and Urinary Uric Acid Levels in Chinese Adults

Objectives: Uric acid (UA) has been proposed as an important risk factor for cardiovascular and renal morbidity. We conducted an interventional trial to assess the effects of altered salt intake on plasma and urine UA levels and the relationship between UA levels and salt sensitivity in humans. Methods: Ninety subjects (18–65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for 7 days (3.0 g/day, NaCl), and a high-salt diet for an additional 7 days (18.0 g/day of NaCl). Results: The plasma UA levels were significantly increased from baseline to the low-salt diet and decreased from the low-salt to high-salt diet. In contrast, the daily urinary levels of UA were significantly decreased from baseline to the low-salt diet and increased from the low-salt to high-salt diet. Also, 24-h urinary sodium excretions were inversely correlated with the plasma UA, and positively correlated with the urinary UA excretions. Additionally, salt-sensitive subjects were associated with a significantly higher plasma UA changes in comparison to salt-resistant subjects, and a negative correlation between the degree of salt sensitivity and plasma UA difference was observed. Conclusion: The present study indicates that variations in dietary salt intake affect the plasma and urine, and plasma UA may be involved in the pathophysiological process of salt sensitivity.

P597Endothelial dysfunction, arterial stiffness and cardiovascular risk in normotensive salt sensitive subjects

P597Endothelial dysfunction, arterial stiffness and cardiovascular risk in normotensive salt sensitive subjects

The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension.

For decades, it has been widely accepted that initiation of salt-induced hypertension involves a type of kidney dysfunction (natriuretic handicap), which causes salt-sensitive subjects to initially excrete less of a sodium load than normal subjects and undergo abnormal increases in cardiac output, and therefore blood pressure. Here we discuss emerging views that renal vasodysfunction, not natriuretic dysfunction (subnormal sodium excretion), is usually a critical factor initiating salt-induced hypertension. Serious logical issues have been raised with arguments supporting historical views that natriuretic dysfunction initiates hypertension in response to increased salt intake. Most salt-sensitive humans do not have a 'natriuretic handicap' causing them to excrete a sodium load more slowly and retain more of it than salt-resistant normal subjects. Mounting evidence indicates that in most salt-sensitive subjects, renal vasodysfunction, defined as impaired renal vasodilation and abnormally increased renal vascular resistance in response to increased salt intake, in the absence of greater sodium retention than in salt-loaded normal subjects, is involved in initiation of salt-induced hypertension. To advance discovery, prevention, and treatment of primary abnormalities causing salt-induced hypertension, greater research emphasis should be placed on identifying mechanisms mediating subnormal renal vasodilation and abnormally increased renal vascular resistance in response to high-salt diets.

Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects.

We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na+/24 hours, HiNa) and depletion (10 mEq Na+/24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrienoic acids) were considered the total converted 14,15-urine pool. We report ultra-performance liquid chromatography/tandem mass spectrometry plasma EETs, DHETs, and their sum (plasma total pool) for the 3 regioisomers (8,9-, 11,12-, 14,15-) and their sum (08,15-). In salt-resistant subjects, urine total pool was unchanged by HiNa, decreased by LoNa, and correlated with urine sodium excretion, fractional excretion of Na+, and Na+/K+ ratio for the 3 days of the experiment combined (P<0.03). In contrast, plasma total pool increased in LoNa and did not correlate with natriuresis or Na+/K+ ratio but showed correlations between EETs, blood pressures, and catecholamines and between DHETs and aldosterone (P<0.03). Urine total pool of salt-sensitive was lower than that of salt-resistant subjects in certain phases of the experiment, lacked responses to changes in salt balance, and exhibited limited correlations with natriuresis and Na+/K+ ratio during LoNa only. Plasma total pool of salt-sensitive was lower than in salt-resistant subjects and did not correlate with blood pressures or aldosterone but did with catecholamines. We conclude that the urine total pool reflects a renal pool involved in regulation of natriuresis, whereas the plasma total pools are of systemic origin, uninvolved in Na+ excretion, perhaps contributing to regulation of vascular tone. Data suggest that abnormalities in EETs in salt-sensitive subjects participate in their renal or vascular dysfunction, which has potential therapeutic implications.