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.

Distinct osmoregulatory responses to sodium loading in patients with altered glycosaminoglycan structure: a randomized cross-over trial.

BACKGROUND: By binding to negatively charged polysaccharides called glycosaminoglycans, sodium can be stored in the body-particularly in the skin-without concurrent water retention. Concordantly, individuals with changed glycosaminoglycan structure (e.g. type 1 diabetes (DM1) and hereditary multiple exostosis (HME) patients) may have altered sodium and water homeostasis. METHODS: We investigated responses to acute (30-min infusion) and chronic (1-week diet) sodium loading in 8 DM1 patients and 7 HME patients in comparison to 12 healthy controls. Blood samples, urine samples, and skin biopsies were taken to investigate glycosaminoglycan sulfation patterns and both systemic and cellular osmoregulatory responses. RESULTS: Hypertonic sodium infusion increased plasma sodium in all groups, but more in DM1 patients than in controls. High sodium diet increased expression of nuclear factor of activated t-cells 5 (NFAT5)-a transcription factor responsive to changes in osmolarity-and moderately sulfated heparan sulfate in skin of healthy controls. In HME patients, skin dermatan sulfate, rather than heparan sulfate, increased in response to high sodium diet, while in DM1 patients, no changes were observed. CONCLUSION: DM1 and HME patients show distinct osmoregulatory responses to sodium loading when comparing to controls with indications for reduced sodium storage capacity in DM1 patients, suggesting that intact glycosaminoglycan biosynthesis is important in sodium and water homeostasis. Trial registration These trials were registered with the Netherlands trial register with registration numbers: NTR4095 ( https://www.trialregister.nl/trial/3933 at 2013-07-29) and NTR4788 ( https://www.trialregister.nl/trial/4645 at 2014-09-12).

Microvascular Permeability after an Acute and Chronic Salt Load in Healthy Subjects: A Randomized Open-label Crossover Intervention Study.

BACKGROUND: Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects. METHODS: Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min. RESULTS: Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P < 0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g · h; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of I-labeled albumin (-0.03 [-3.3 to 3.2] % cpm · g · h; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading. CONCLUSIONS: Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.

Quantification of nonosmotic sodium storage capacity following acute hypertonic saline infusion in healthy individuals.

The assumption that sodium accumulation in the human body is always accompanied by water retention has been challenged by data showing that sodium can be stored nonosmotically. Here we investigated the contribution of nonosmotic sodium storage to short-term sodium homeostasis after hypertonic saline infusion in healthy individuals on a low-sodium diet. During four hours after infusion, we compared the observed changes in plasma sodium concentration and urinary cation excretion with changes that were calculated with the Adrogue-Madias and Nguyen-Kurtz formula, formulations widely implemented to guide the treatment of dysnatremias. We included 12 healthy non-smoking male individuals with normal blood pressure, body mass index, and kidney function. Right after infusion, the average observed plasma sodium change from baseline (3.5 mmol/L) was similar to the predicted changes by the Adrogue-Madias (3.3 mmol/L) and Nguyen-Kurtz formula (3.1 mmol/L). However, the observed plasma sodium concentration change after four hours (-1.8 mmol/L) was very different from the changes as predicted by the Adrogue-Madias (0.4 mmol/L) and the Nguyen-Kurtz formula (-0.9 mmol/L). Moreover, only 47% and 55%, respectively, of the expected sodium and potassium excretion were retrieved in the urine. Thus, healthy individuals are able to osmotically inactivate significant amounts of sodium after hypertonic saline infusion. Further research is needed to uncover factors that determine nonosmotic sodium storage.

Role of the vascular wall in sodium homeostasis and salt sensitivity.

Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume.

The blood pressure lowering potential of sulodexide--a systematic review and meta-analysis.

AIMS: Sulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti-albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta-analysis, we therefore investigated the antihypertensive effects of sulodexide treatment. METHODS: We selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data. RESULTS: Eight studies, totalling 3019 subjects (mean follow-up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P < 0.001). Higher baseline systolic and diastolic BP were significantly associated with larger systolic (r(2)=0.83, P < 0.001) and diastolic BP (r(2)=0.41, P = 0.02) reductions after sulodexide treatment. In addition, systolic (r(2)=0.41, P = 0.03) and diastolic BP reductions (r(2)=0.60, P = 0.005) were significantly associated with albuminuria reduction. CONCLUSION: Our data suggest that sulodexide treatment results in a significant BP reduction, especially in hypertensive subjects. This indicates that endothelial glycosaminoglycans might be an independent therapy target in cardiovascular disease. Future studies should further address the BP lowering potential of sulodexide.

BK virus disease after allogeneic stem cell transplantation: a cohort analysis.

The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.

Transcapillary escape rate of 125I-albumin in relation to timing of blood sampling: the need for standardization.

BACKGROUND: Increased vascular permeability is an early sign of vascular damage and can be measured with the transcapillary escape rate of albumin (TERalb). Although TERalb has a multi-exponential kinetic model, most published TERalb data are based on mono-exponential kinetic models with variation in blood sampling schemes. Aim of this posthoc study was to evaluate the influence of variation in blood sampling schemes and the impact of mono- or bi-exponential analyses on the calculation of TERalb. Study participants were part of a cross-over intervention study protocol, investigating effects of sodium loading on blood pressure, endothelial surface layer and microcirculation. Multiple blood samples were drawn between 3 and 60 min after injection of radioactive iodide labeled human serum albumin (rHSA). RESULTS: In total 27 male participants with 54 measurements were included. For all participants the maximum serum radioactivity was reached within 20 min, while 85% of the participants had their maximum serum activity within 10 min. The TERalb calculated with the subsequently chosen T20-60 min reference scheme (6.19 ± 0.49%/h) was significantly lower compared to the TERalb of the T3-60 min, T5-60 min, and Tmax - 60 min schemes. There was no significant difference between the T20-60 min reference scheme and the T10-60 min and T15-60 min schemes. Bi-exponential kinetic modeling did not result in significant different observations compared to the mono-exponential kinetic analysis. CONCLUSIONS: As there is variation in the timing of the maximum serum radioactivity of rHSA, blood sampling schemes starting before 10 min after administration of rHSA will result in a significant overestimation of TERalb. In addition, variation in kinetic modeling did not result in significant changes in TERalb. Therefore, we emphasize the need to standardize TERalb and for practical and logistical reasons advocate the use of a mono-exponential model with blood sampling starting 20 min after rHSA administration.

Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses.

BACKGROUND: Hereditary Multiple Exostoses (HME) is a rare autosomal disorder characterized by the presence of multiple exostoses (osteochondromas) caused by a heterozygous loss of function mutation in EXT1 or EXT2; genes involved in heparan sulfate (HS) chain elongation. Considering that HS and other glycosaminoglycans play an important role in sodium and water homeostasis, we hypothesized that HME patients have perturbed whole body volume regulation and osmolality in response to high sodium conditions. METHODS: We performed a randomized cross-over study in 7 male HME patients and 12 healthy controls, matched for age, BMI, blood pressure and renal function. All subjects followed both an 8-day low sodium diet (LSD, <50 mmol/d) and high sodium diet (HSD, >200 mmol/d) in randomized order. After each diet, blood and urine samples were collected. Body fluid compartment measurements were performed by using the distribution curve of iohexol and 125I-albumin. RESULTS: In HME patients, HSD resulted in significant increase of intracellular fluid volume (ICFV) (1.2 L, p = 0.01). In this group, solute-mediated water clearance was significantly lower after HSD, and no changes in interstitial fluid volume (IFV), plasma sodium, and effective osmolality were observed. In healthy controls, HSD did not influence ICFV, but expanded IFV (1.8 L, p = 0.058) and increased plasma sodium and effective osmolality. CONCLUSION: HME patients show altered body fluid distribution and osmoregulation after HSD compared to controls. Our results might indicate reduced interstitial sodium accumulation capacity in HME, leading to ICFV increase. Therefore, this study provides additional support that HS is crucial for maintaining constancy of the internal environment.

High-salt intake affects retinal vascular tortuosity in healthy males: an exploratory randomized cross-over trial.

The retinal microcirculation is increasingly receiving credit as a relatively easily accessible microcirculatory bed that correlates closely with clinical cardiovascular outcomes. The effect of high salt (NaCl) intake on the retinal microcirculation is currently unknown. Therefore, we performed an exploratory randomized cross-over dietary intervention study in 18 healthy males. All subjects adhered to a two-week high-salt diet and low-salt diet, in randomized order, after which fundus photographs were taken and assessed using a semi-automated computer-assisted program (SIVA, version 4.0). Outcome parameters involved retinal venular and arteriolar tortuosity, vessel diameter, branching angle and fractal dimension. At baseline, participants had a mean (SD) age of 29.8 (4.4) years and blood pressure of 117 (9)/73 (5) mmHg. Overall, high-salt diet significantly increased venular tortuosity (12.2%, p = 0.001). Other retinal parameters were not significantly different between diets. Changes in arteriolar tortuosity correlated with changes in ambulatory systolic blood pressure (r = - 0.513; p = 0.04). In conclusion, high-salt diet increases retinal venular tortuosity, and salt-induced increases in ambulatory systolic blood pressure associate with decreases in retinal arteriolar tortuosity. Besides potential eye-specific consequences, both phenomena have previously been associated with hypertension and other cardiovascular risk factors, underlining the deleterious microcirculatory effects of high salt intake.

Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial.

INTRODUCTION: Patients with type 1 diabetes are susceptible to hypertension, possibly resulting from increased salt sensitivity and accompanied changes in body fluid composition. We examined the effect of a high-salt diet (HSD) in type 1 diabetes on hemodynamics, including blood pressure (BP) and body fluid composition. RESEARCH DESIGN AND METHODS: We studied eight male patients with type 1 diabetes and 12 matched healthy controls with normal BP, body mass index, and renal function. All subjects adhered to a low-salt diet and HSD for eight days in randomized order. On day 8 of each diet, extracellular fluid volume (ECFV) and plasma volume were calculated with the use of iohexol and 125I-albumin distribution. Hemodynamic measurements included BP, cardiac output (CO), and systemic vascular resistance. RESULTS: After HSD, patients with type 1 diabetes showed a BP increase (mean arterial pressure: 85 (5) mm Hg vs 80 (3) mm Hg; p<0.05), while BP in controls did not rise (78 (5) mm Hg vs 78 (5) mm Hg). Plasma volume increased after HSD in patients with type 1 diabetes (p<0.05) and not in controls (p=0.23). There was no significant difference in ECFV between diets, while HSD significantly increased CO, heart rate (HR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in type 1 diabetes but not in controls. There were no significant differences in systemic vascular resistance, although there was a trend towards an HSD-induced decrease in controls (p=0.09). CONCLUSIONS: In the present study, patients with type 1 diabetes show a salt-sensitive BP rise to HSD, which is accompanied by significant increases in plasma volume, CO, HR, and NT-proBNP. Underlying mechanisms for these responses need further research in order to unravel the increased susceptibility to hypertension and cardiovascular disease in diabetes. TRIAL REGISTRATION NUMBERS: NTR4095 and NTR4788.

Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation-a proof-of-concept study.

Type 1 diabetes patients are more prone to have hypertension than healthy individuals, possibly mediated by increased blood pressure (BP) sensitivity to high salt intake. The classical concept proposes that the kidney is central in salt-mediated BP rises, by insufficient renal sodium excretion leading to extracellular fluid volume expansion. Recent animal-derived findings, however, propose a causal role for disturbance of macrophage-mediated lymphangiogenesis. Its relevance for humans, specifically type 1 diabetes patients, is unknown. The present study aimed to assess responses of type 1 diabetes patients to a dietary salt load with regard to BP, extracellular fluid volume (using precise iohexol measurements), and CD163+ macrophage and lymphatic capillary density in skin biopsies. Also, macrophage expression of HLA-DR (a proinflammatory marker) and CD206 (an anti-inflammatory marker) was assessed. Type 1 diabetes patients (n = 8) showed a salt-sensitive BP increase without extracellular fluid volume expansion. Whereas healthy controls (n = 12), who had no BP increase, showed increased skin CD163+ and HLA-DR+ macrophages and dilation of lymphatic skin vasculature after the dietary salt load, these changes were absent (and in case of HLA-DR more heterogenic) in type 1 diabetes patients. In conclusion, we show that salt sensitivity in type 1 diabetes patients cannot be explained by the classical concept of extracellular fluid volume expansion. Rather, we open up a potential role for macrophages and the lymphatic system. Future studies on hypertension and diabetes need to scrutinize these phenomena.

High-salt intake affects sublingual microcirculation and is linked to body weight change in healthy volunteers: a randomized cross-over trial.

BACKGROUND: The pathophysiology of salt-sensitive hypertension remains uncertain, but may involve microvascular alterations. High-salt intake decreases microvascular density in hypertensive patients, but due to lack of studies in normotensive patients the causal pathway remains unclear. We studied whether high-salt intake decreases sublingual microvascular density in normotensive individuals and assessed the influence of body weight on changes in microvascular density. METHODS: In an open label randomized cross-over trial 18 healthy men were included to study the effect of a 2-week high-salt (>12 g/day) and low-salt (<3 g/day) diet on microvascular (diameter <20 µm) density with sublingual sidestream darkfield imaging. We used sublingual nitroglycerin (NTG) to recruit microvessels. RESULTS: There was no significant difference in microvascular density between diets (0.96 ±â€Š3.88 mm/mm; P = 0.31, following NTG; and -0.03 ±â€Š1.64 mm/mm; P = 0.95, without NTG). Increased salt intake was correlated with a decrease in microvascular density following NTG (r = -0.47; P = 0.047), but not without NTG (r = 0.06; P = 0.800). The decrease in microvascular density following high-salt intake was significantly larger for those with a large change in body weight as compared with those with a small changer in body weight (-0.79 ±â€Š1.35 and 0.84 ±â€Š1.56 mm/mm respectively, P = 0.031). CONCLUSION: We demonstrate in healthy volunteers that higher salt intake is correlated with decreased sublingual microvascular density following administration of NTG and; larger changes in body weight following high-salt intake coincide with a larger decrease in microvascular density. Changes in microvascular density occurred without blood pressure effects, indicating that high-salt load as such contributes to microvascular changes, and may precede hypertension development.