Dietary Fructose and Sodium Consumed during Early Mid-Life Are Associated with Hypertensive End-Organ Damage by Late Mid-Life in the CARDIA Cohort.

We aimed to investigate how dietary fructose and sodium impact blood pressure and risk of hypertensive target organ damage 10 years later. Data from n = 3116 individuals were obtained from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Four groups were identified based on the four possible combinations of the lower and upper 50th percentile for sodium (in mg) and fructose (expressed as percent of total daily calories). Differences among groups were ascertained and logistic regression analyses were used to assess the risk of hypertensive target organ damage (diastolic dysfunction, coronary calcification and albuminuria). Individuals in the low-fructose + low-sodium group were found to have lower SBP compared to those in the low-fructose + high-sodium and high-fructose + high-sodium groups (p < 0.05). The highest risk for hypertensive target organ damage was found for albuminuria only in the high-fructose + high-sodium group (OR = 3.328, p = 0.006) while female sex was protective across all groups against coronary calcification. Our findings highlight that sodium alone may not be the culprit for hypertension and hypertensive target organ damage, but rather when combined with an increased intake of dietary fructose, especially in middle-aged individuals.

Utilizing Quality of Life Adjusted Days Alive and Out of Hospital in Heart Failure Clinical Trials.

BACKGROUND: In heart failure (HF) trials, there has been an emphasis on utilizing more patient-centered outcomes, including quality of life (QoL) and days alive and out of hospital. We aimed to explore the impact of QoL adjusted days alive and out of hospital as an outcome in 2 HF clinical trials. METHODS: Using data from 2 trials in HF (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT] and Study of Dietary Intervention under 100 mmol in Heart Failure [SODIUM-HF]), we determined treatment differences using percentage days alive and out of hospital (%DAOH) adjusted for QoL at 18 months as the primary outcome. For each participant, %DAOH was calculated as a ratio between days alive and out of hospital/total follow-up. Using a regression model, %DAOH was subsequently adjusted for QoL measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score. RESULTS: In the GUIDE-IT trial, 847 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 59.0 (interquartile range, 40.8-74.3), which did not change over 18 months. %DAOH was 90.76%±22.09% in the biomarker-guided arm and 88.56%±25.27% in the usual care arm. No significant difference in QoL adjusted %DAOH was observed (1.09% [95% CI, -1.57% to 3.97%]). In the SODIUM-HF trial, 796 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 69.8 (interquartile range, 49.3-84.3), which did not change over 18 months. %DAOH was 95.69%±16.31% in the low-sodium arm and 95.95%±14.76% in the usual care arm. No significant difference was observed (1.91% [95% CI, -0.85% to 4.77%]). CONCLUSIONS: In 2 large HF clinical trials, adjusting %DAOH for QoL was feasible and may provide complementary information on treatment effects in clinical trials.

Long-Term Effect of Salt Substitution for Cardiovascular Outcomes : A Systematic Review and Meta-analysis.

BACKGROUND: Salt substitution is a simple yet increasingly promising strategy to improve cardiovascular outcomes. PURPOSE: To evaluate the long-term effects of salt substitution on cardiovascular outcomes. DATA SOURCES: PubMed, EMBASE, Cochrane CENTRAL, and CINAHL searched from inception to 23 August 2023. Trial registries, citation analysis, and hand-search were also done. STUDY SELECTION: Randomized controlled trials (RCTs) comparing provision of or advice to use a salt substitute with no intervention or use of regular salt among adults for 6 months or longer in total study duration. DATA EXTRACTION: Two authors independently screened articles, extracted data, and assessed risk of bias. Primary outcomes include mortality, major cardiovascular events (MACE), and adverse events at 6 months or greater. Secondary and post hoc outcomes include blood pressure, cause-specific mortality, and urinary excretion at 6 months or greater. Random-effects meta-analyses were done and certainty of effect estimates were assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). DATA SYNTHESIS: Of the 16 included RCTs, 8 reported on primary outcomes. Most (n = 7 of 8) were done in China or Taiwan, 3 were done in residential facilities, and 7 included populations of older age (average 62 years) and/or with higher-than-average cardiovascular risk. In this population, salt substitute may reduce risk for all-cause mortality (6 RCTs; 27 710 participants; rate ratio [RR], 0.88 [95% CI, 0.82 to 0.93]; low certainty) and cardiovascular mortality (4 RCTs; 25 050 participants; RR, 0.83 [CI, 0.73 to 0.95]; low certainty). Salt substitute may result in a slight reduction in MACE (3 RCTs; 23 215 participants; RR, 0.85 [CI, 0.71 to 1.00]; very low certainty), with very low-certainty evidence of serious adverse events (6 RCTs; 27 995 participants; risk ratio, 1.04 [CI, 0.87 to 1.25]). LIMITATIONS: The evidence base is dominated by a single, large RCT. Most RCTs were from China or Taiwan and involved participants with higher-than-average cardiovascular risk; therefore, generalizability to other populations is very limited. CONCLUSION: Salt substitution may reduce all-cause or cardiovascular mortality, but the evidence for reducing cardiovascular events and for not increasing serious adverse events is uncertain, particularly for a Western population. The certainty of evidence is higher among populations at higher cardiovascular risk and/or following a Chinese diet. PRIMARY FUNDING SOURCE: National Health and Medical Research Council. (PROSPERO: CRD42022327566).

Dissociation of Hypertension and Renal Damage After Cessation of High-Salt Diet in Dahl Rats.

BACKGROUND: Every year, thousands of patients with hypertension reduce salt consumption in an effort to control their blood pressure. However, hypertension has a self-sustaining character in a significant part of the population. We hypothesized that chronic hypertension leads to irreversible renal damage that remains after removing the trigger, causing an elevation of the initial blood pressure. METHODS: Dahl salt-sensitive rat model was used for chronic, continuous observation of blood pressure. Rats were fed a high salt diet to induce hypertension, and then the diet was switched back to normal sodium content. RESULTS: We found that developed hypertension was irreversible by salt cessation: after a short period of reduction, blood pressure grew even higher than in the high-salt phase. Notably, the self-sustaining phase of hypertension was sensitive to benzamil treatment due to sustaining epithelial sodium channel hyperactivity, as shown with patch-clamp analysis. Glomerular damage and proteinuria were also irreversible. In contrast, some mechanisms, contributing to the development of salt-sensitive hypertension, normalized after salt restriction. Thus, flow cytometry demonstrated that dietary salt reduction in hypertensive animals decreased the number of total CD45+, CD3+CD4+, and CD3+CD8+ cells in renal tissues. Also, we found tubular recovery and improvement of glomerular filtration rate in the postsalt period versus a high-salt diet. CONCLUSIONS: Based on earlier publications and current data, poor response to salt restriction is due to the differential contribution of the factors recognized in the developmental phase of hypertension. We suggest that proteinuria or electrolyte transport can be prioritized over therapeutic targets of inflammatory response.

Low-sodium diet with adequate water intake improved the clinical efficacy in Ménière's disease.

BACKGROUND: Ménière's disease (MD) is a common idiopathic inner ear disorder in otorhinolaryngology characterized by recurrent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus and ear fullness. OBJECTIVE: To study the effects of low-sodium diet with adequate water intake on the clinical efficacy in MD. METHODS: Fifty patients diagnosed with stage-3 unilateral MD were randomly divided into control group(n = 25) and experimental group(n = 25). The control group was given routine medication therapy, and the experimental group was restricted to an sodium intake of 1500 mg/d and a water intake of 35 ml/kg/d based in addition to the routine medication therapy. The two groups were assessed using pure tone audiometry, electrocochleography, Tinnitus Handicap Inventory (THI), and Dizziness Handicap Inventory (DHI). RESULTS: The pure tone audiometry and electrocochleography showed better improvements after treatment in the experimental group than the control group (p < 0.05). The THI improved values in the experimental group were significantly higher than the control group (p < 0.001). The DHI improved values in the experimental group were significantly higher than the control group (p = 0.004). CONCLUSIONS AND SIGNIFICANCE: Low-sodium diet with adequate water intake improved the hearing and alleviated vertigo and tinnitus in MD patients.

The effect of salt substitution on frequency and severity of headache: results from the SSaSS cluster-randomised controlled trial of 20,995 participants.

BACKGROUND: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. METHODS: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). RESULTS: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). CONCLUSION: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

Sodium and water dynamics in the progression of chronic kidney disease: mechanisms and clinical significance.

AIM: Lifestyle modifications can postpone the progression of chronic kidney disease toward its terminal stage. This mini-review aims to explore the impact of salt and water intake on the progression of chronic kidney disease (CKD) and provide insights into the optimal consumption levels to preserve the glomerular filtration rate. METHODS: We reviewed relevant literature to examine the association between salt and water consumption and CKD progression. Our analysis includes discussions on the pathophysiology, findings from clinical trials, and recommended intake guidelines. RESULTS: Sodium intake, often linked to cardiovascular risk and CKD progression, has shown a complex J-shaped association in some studies, leading to uncertainty about the ideal salt intake level. Sodium and fluid retention are key factors contributing to hypertension, a well-established risk factor for CKD progression. Low-sodium diets have demonstrated promise in reducing blood pressure and enhancing the effects of renin-angiotensin-aldosterone system inhibitors in non-dialysis CKD patients. However, a debate persists regarding the independent effect of salt restriction on CKD progression. Despite medical recommendations, salt consumption remains high among CKD patients. Additionally, the role of water consumption in CKD remains controversial despite its established benefits for CKD prevention in the general population. CONCLUSION: Lifestyle modifications involving salt and water intake can influence the progression of CKD. While low-sodium diets have shown potential for mitigating hypertension and proteinuria in non-dialysis CKD patients, their independent impact on CKD progression warrants further investigation. The role of water consumption in CKD remains uncertain, and there is a need for additional research in this area. Clinicians should consider individualized dietary recommendations for CKD patients to help preserve the glomerular filtration rate and improve overall outcomes.

Sex influences blood pressure but not blood pressure variability in response to dietary sodium and potassium in salt-resistant adults.

Dietary sodium and potassium have been shown to affect blood pressure (BP) but their influence on BP variability (BPV) is less studied as is the influence of sex. The aim of this study was to compare 24 h BP and short-term BPV in response to varying dietary levels of sodium and potassium in healthy non-obese normotensive salt-resistant adults. We hypothesized that high sodium would increase short-term BP and BPV while the addition of high potassium would counteract this increase. Furthermore, we hypothesized that women would experience greater increases in BPV under high sodium conditions compared to men while potassium would attenuate this response. Thirty-seven participants (17 M/20 W; 27 ± 5 years old; BMI 24.3 ± 3 kg/m2) completed seven days each of the following randomized diets: moderate potassium/low sodium (MK/LS), moderate potassium/high sodium (MK/HS) and high potassium/high sodium (HK/HS). BP and short-term BPV were assessed using 24 h ambulatory BP monitoring starting on day 6. BPV was calculated using the average real variability (ARV) index. Twenty-four hour, daytime, and nighttime systolic BP (SBP) were lower in women compared to men regardless of diet. However, 24 h and daytime SBP were lowered in women on the HK/HS diet compared to the MK/HS diet. There were no significant effects of diet or sex for 24 h, daytime or nighttime SBP ARV. However, men exhibited a higher 24 hDBP ARV than women regardless of diet. In conclusion, a high potassium diet lowered BP under high sodium conditions in women alone while men exhibited higher short-term BPV that was not influenced by diet.

Estradiol modulation of behavioral and physiological body fluid control during repeated dietary sodium deprivation.

The low salt diet is a first line treatment for hypertension, but it is a difficult diet to maintain. As a result, patients may alternate between periods of high and low salt intake, the effects of which are unclear. Importantly, blood pressure increases in women after menopause, suggesting that estrogen plays a role in preventing hypertension. At present, however, it is unknown if the behavioral and physiological impact of alternating episodes on the low salt diet may be altered by the presence of estrogen. Our goals were to assess salt intake and body fluid hormones with repeated dietary sodium deprivations. Using ovariectomized rats with (EB) and without (OIL) estrogen treatment, we subjected rats to one or two dietary sodium deprivations using low salt laboratory chow. 0.5 M NaCl and water intakes were recorded after each period of regular chow or deprivation. After deprivation, rats were sacrificed, and trunk blood was collected for analysis of vasopressin, norepinephrine, epinephrine, and aldosterone levels. Plasma sodium concentration, plasma protein concentration, body weight, and uterine weight were also measured. There was no difference in the salt intakes of OIL- or EB-treated rats after one or two dietary sodium deprivations. However, EB-treated rats drank a less concentrated solution overall, suggesting less overcompensation after dietary sodium deprivation. Additionally, after a single episode of dietary sodium deprivation, EB-treated rats' consumption remained elevated above baseline even after returning to regular laboratory chow. These behavioral differences were not explained by alterations in vasopressin, norepinephrine, epinephrine, or aldosterone. Plasma sodium and plasma protein concentrations also did not show alterations related to the change in behavior. Further research is necessary to determine the mechanism behind these changes in intake in EB-treated rats, which may ultimately be clinically relevant for both pre- and postmenopausal women on the low salt diet.

Age differences in the impact of dietary salt on metabolism, blood pressure and cognitive function in male rats.

The influence of salt consumption on physiological processes, especially blood pressure (BP), metabolism, and cognition, remains a topical concern. While guidelines endorse reduced salt diets, there are gaps in understanding the age-specific implications and challenges in adherence. The present study delved into the differential effects of salt intake on young adult and aged male rats over a 12-week period, using control, low-, and high-salt diets. Key metrics, such as BP, cognition, and general parameters, were monitored. Our findings revealed significant age-dependent effects of salt intake on survival rates, body weight, blood sodium, blood glucose, blood lipids, BP, heart rates, and cognition. Notably, young adult rats did not show significant sodium level changes on a high-salt diet, whereas aged rats experienced increased sodium levels even on a normal salt diet. Blood glucose levels decreased significantly in aged rats on a high-salt diet but remained stable in young adults. Aged rats had the highest survival rates on low-salt diets. Low-salt diets led to reduced BP in both age groups, more significantly in young adults. Young adult rats displayed increased BP variability on both high- and low-salt diets, while a decrease in BP variability was exclusive to aged rats on a low-salt diet. There were significant differences across age groups in short-term memory, but not in long-term memory. The study provides a nuanced understanding of the age-dependent physiological effects of salt intake, suggesting the necessity of age-specific guidelines for public health.

Effects of Behavioral Interventions for Salt Reduction on Blood Pressure and Urinary Sodium Excretion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Hypertension is a prevalent cardiovascular condition, with excessive sodium intake being a significant risk factor. Various studies have investigated measures to reduce salt intake, including integrated lifestyle interventions and health education. However, the effectiveness of behavioral interventions focused solely on salt reduction remains unclear. This systematic review and meta-analysis aimed to investigate the effects of a behavioral intervention based on salt reduction on blood pressure and urinary sodium excretion. A comprehensive search of the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of Science was conducted to identify relevant literature. Study and intervention characteristics were extracted for descriptive synthesis, and the quality of the included studies was assessed. A total of 10 studies, comprising 4,667 participants (3,796 adults and 871 children), were included. The interventions involved the provision of salt-restriction spoons or devices, salt-reduction education, self-monitoring devices for urinary sodium, and salt-reduction cooking classes. Meta-analysis results showed that behavioral interventions focused on salt reduction significantly reduced systolic blood pressure (SBP) (-1.17 mmHg; 95% CI, -1.86 to -0.49), diastolic blood pressure (DBP) (-0.58 mmHg; 95% CI, -1.07 to -0.08) and urinary sodium excretion (-21.88 mmol/24 hours; 95% CI, -32.12 to -11.64). These findings suggest that behavioral change interventions centered on salt reduction can effectively lower salt intake levels and decrease blood pressure levels. However, to enhance effectiveness, behavioral interventions for salt reduction should be combined with other salt-reduction strategies.

Twenty-four-hour Urinary Salt Excretion on Admission Predicts Significant Weight Loss with Seven-day Dietary Salt Restriction in Hospitalized Patients with Chronic Kidney Disease: A Single-center Study.

In patients with chronic kidney disease (CKD), restricting dietary salt is recommended to prevent fluid retention. Rapid weight loss is often observed when CKD patients with a high salt intake are hospitalized and started on a low-salt diet. We investigated the effects of 7-day dietary salt restriction on weight loss in hospitalized patients with CKD. During the 7-day hospitalization, a low-salt (6 g/day) and low-protein (0.6-0.8 g/kg/day ideal body weight) diet was served to all patients. Urine samples were collected for the first 24 h after admission, and patients were divided into quartiles (Q1-Q4) by urinary salt excretion. Body weight was measured on days 1 and 7. Weight loss after admission was compared among the groups. Factors associated with weight loss were evaluated by multivariate logistic regression. The mean age of the patients was 70.3 ± 11.7 years, and 73% were male. Mean weight loss was 1.6 ± 1.7 kg on day 7. Weight loss was significantly greater in Q3 and Q4 than in Q1 (P = 0.009 and P <0.001, respectively). In the univariate analysis, weight loss correlated positively with 24-h urinary salt excretion on admission (γ2 = 0.146) and body mass index (γ2 = 0.223). The 24-h urinary salt excretion on admission and BMI were independently associated with weight loss of >2 kg. The adjusted odds ratios (95% confidence interval) were 1.24 (1.13-1.36) and 1.15 (1.07-1.22), respectively. Twenty-four-hour urinary salt excretion on admission is useful for predicting significant weight loss with short-term dietary salt restriction.

Effect of Dietary Sodium on Blood Pressure: A Crossover Trial.

Importance: Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied. Objectives: To examine the distribution of within-individual BP response to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use. Design, Setting, and Participants: Prospectively allocated diet order with crossover in community-based participants enrolled between April 2021 and February 2023 in 2 US cities. A total of 213 individuals aged 50 to 75 years, including those with normotension (25%), controlled hypertension (20%), uncontrolled hypertension (31%), and untreated hypertension (25%), attended a baseline visit while consuming their usual diet, then completed 1-week high- and low-sodium diets. Intervention: High-sodium (approximately 2200 mg sodium added daily to usual diet) and low-sodium (approximately 500 mg daily total) diets. Main Outcomes and Measures: Average 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure. Results: Among the 213 participants who completed both high- and low-sodium diet visits, the median age was 61 years, 65% were female and 64% were Black. While consuming usual, high-sodium, and low-sodium diets, participants' median systolic BP measures were 125, 126, and 119 mm Hg, respectively. The median within-individual change in mean arterial pressure between high- and low-sodium diets was 4 mm Hg (IQR, 0-8 mm Hg; P < .001), which did not significantly differ by hypertension status. Compared with the high-sodium diet, the low-sodium diet induced a decline in mean arterial pressure in 73.4% of individuals. The commonly used threshold of a 5 mm Hg or greater decline in mean arterial pressure between a high-sodium and a low-sodium diet classified 46% of individuals as "salt sensitive." At the end of the first dietary intervention week, the mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet was 8 mm Hg (95% CI, 4-11 mm Hg; P < .001), which was mostly similar across subgroups of age, sex, race, hypertension, baseline BP, diabetes, and body mass index. Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively. Conclusions and Relevance: Dietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT04258332.