Vascular effects of sodium and potassium intake

Cardiovascular diseases (CVD) are the main cause of death worldwide. Annually, about 17.5 million people die from CVD, accounting for ~30% of deaths worldwide. Elevated blood pressure (BP) is a major risk factor for CVD and the largest single contributor to global mortality. BP is a modifiable risk factor that is largely determined by lifestyle factors, including diet. Dietary minerals, in particular sodium and potassium, play an important role in BP regulation. While adverse effects of sodium and beneficial effects of potassium on BP have repeatedly been shown in human intervention studies, evidence on other vascular effects of these dietary minerals is still scarce. Therefore, we investigated the BP effects of sodium and potassium intake in healthy humans in a broader (patho)physiological context, focusing also on endothelial function, arterial stiffness, fluid regulation and heart rate. In Chapter 2, the effects of sodium and potassium supplementation on BP and arterial stiffness were examined by means of a randomized placebo-controlled crossover trial. Thirty-six untreated Dutch individuals with mildly elevated BP on a fully controlled diet that was relatively low in sodium (2-3 g/d) and potassium (2-3 g/d) received capsules with sodium (3 g/d), potassium (3 g/d) or placebo, for 4 weeks each, in random order. After each intervention, fasting office BP, 24-h ambulatory BP and measures of arterial stiffness were assessed. The results of this study showed that increased sodium intake strongly raised office and ambulatory systolic BP (7-8 mmHg) whereas increased potassium intake lowered systolic BP (3-4 mmHg). Potassium supplementation increased ambulatory HR, but office HR was not affected. Measures of arterial stiffness were not materially affected by increased sodium or potassium intake, possibly due to the relatively short intervention period. In the same study we investigated the effects of increased sodium and potassium intake on the functional measure of endothelial function (flow-mediated dilation), and on a comprehensive set of biomarkers of endothelial dysfunction and low-grade inflammation (Chapter 3). Four weeks of supplemental sodium had no effect on brachial flow-mediated dilation, or on the blood biomarkers of endothelial dysfunction and low-grade inflammation, except for an increase in serum endothelin-1 (a biomarker of endothelial dysfunction). Potassium supplementation improved flow-mediated dilation by 1.2% and tended to lower the low-grade inflammation marker interleukin-8. This suggests that potassium may beneficially influence vascular health by improving endothelial function. In a post-hoc analysis of the same study in 35 untreated individuals, the humoral effects of supplemental sodium and potassium were assessed using a panel of markers that are involved in osmoregulation and volume regulation (Chapter 4). Results showed that supplemental sodium increased plasma natriuretic peptides and plasma copeptin, and suppressed the renin-angiotensin system. Supplemental potassium decreased plasma MR-pro-ANP, increased plasma copeptin, and stimulated the renin-angiotensin system. These findings suggest that the mineral-induced changes in BP elicit several counter regulatory mechanisms to maintain volume homeostasis. In Chapter 5, the effect of potassium supplementation on heart rate was assessed in a meta-analysis of 22 randomized, placebo-controlled trials in healthy adults. Overall, increasing potassium intake by 2-3 g/d for at least two weeks did not affect resting heart rate. 24-h Ambulatory heart rate was not significantly affected in subgroup analysis of 4 RCTs, including ours. Other subgroup analyses for characteristics of the study and study population also showed no significant effects, and there was no evidence for a dose-response relationship. These results suggest that increasing potassium intake is not expected to adversely affect heart rate in apparently healthy adults. In Chapter 6, BP associations for sodium and potassium intake using different dietary assessment methods were examined. Data of 993 healthy Dutch adults not on antihypertensive medication were analyzed using a cross-sectional approach. Sodium and potassium intake were estimated from two non-consecutive 24-h urinary samples (considered as the gold standard), two non-consecutive web-based 24-h recalls, and a validated 180-item food frequency questionnaire (FFQ). This study showed no significant associations of sodium intake with BP, regardless of the dietary assessment method used. Potassium intake estimated from 24-h urine and FFQ was inversely associated with BP (~1.5 mmHg reduction per 1 g/d increment). This suggests that dietary assessment methods in cross-sectional studies may be inadequate for estimating the association of sodium intake with BP, but may yield reliable results for potassium intake. As discussed in Chapter 7, the studies presented in this thesis indicate that increasing sodium intake from a recommended level to a level that is common in Western societies for four weeks strongly raises BP in individuals with an untreated mildly elevated BP. The results for endothelial function and arterial stiffness are inconclusive, and hence more (longer-term) studies are warranted. Increasing the intake of potassium lowers BP and improves endothelial function, even in individuals on a relatively low-sodium diet. Both sodium and potassium intake affected fluid parameters, likely indicating that compensatory responses are stimulated to maintain body fluid balance. Although in our RCT ambulatory heart rate was increased after supplemental potassium, the meta-analysis showed that increasing potassium intake is unlikely to affect heart rate in apparently healthy adults. When evaluating the effectiveness of sodium and potassium intake on cardiovascular health, results obtained from observational studies should be interpreted with caution, particularly for sodium intake. Around the world people consume on average 9-12 g of salt and 2-4 g of potassium on a daily basis. A more optimal intake of sodium and potassium can be achieved through adherence to dietary guidelines and product reformulation by food industry. This could reduce BP by more than 10 mmHg and lower the number of cardiovascular deaths by at least one-quarter in Western populations.</p

Effects of Potassium or Sodium Supplementation on Mineral Homeostasis: A Controlled Dietary Intervention Study

CONTEXT: Although dietary potassium and sodium intake may influence calcium-phosphate metabolism and bone health, the effects on bone mineral parameters, including fibroblast growth factor 23 (FGF23), are unclear. OBJECTIVE: Here, we investigated the effects of potassium or sodium supplementation on bone mineral parameters. DESIGN, SETTING, PARTICIPANTS: We performed a post hoc analysis of a dietary controlled randomized, blinded, placebo-controlled crossover trial. Prehypertensive individuals not using antihypertensive medication (n = 36) received capsules containing potassium chloride (3 g/d), sodium chloride (3 g/d), or placebo. Linear mixed-effect models were used to estimate treatment effects. RESULTS: Potassium supplementation increased plasma phosphate (from 1.10 ± 0.19 to 1.15 ± 0.19 mmol/L, P = 0.004), in line with an increase in tubular maximum of phosphate reabsorption (from 0.93 ± 0.21 to 1.01 ± 0.20 mmol/L, P < 0.001). FGF23 decreased (114.3 [96.8-135.0] to 108.5 [93.5-125.9] RU/mL, P = 0.01), without change in parathyroid hormone and 25-hydroxy vitamin D3. Fractional calcium excretion decreased (from 1.25 ± 0.50 to 1.11 ± 0.46 %, P = 0.03) without change in plasma calcium. Sodium supplementation decreased both plasma phosphate (from 1.10 ± 0.19 to 1.06 ± 0.21 mmol/L, P = 0.03) and FGF23 (from 114.3 [96.8-135.0] to 108.7 [92.3-128.1] RU/mL, P = 0.02). Urinary and fractional calcium excretion increased (from 4.28 ± 1.91 to 5.45 ± 2.51 mmol/24 hours, P < 0.001, and from 1.25 ± 0.50 to 1.44 ± 0.54 %, P = 0.004, respectively). CONCLUSIONS: Potassium supplementation led to a decrease in FGF23, which was accompanied by increase in plasma phosphate and decreased calcium excretion. Sodium supplementation reduced FGF23, but this was accompanied by dec

Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose-response meta-analysis of prospective cohort studies

With a growing number of prospective cohort studies, an updated dose-response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to September 2016. Random-effect meta-analyses with summarised dose-response data were performed for total (high-fat/low-fat) dairy, milk, fermented dairy, cheese and yogurt. Non-linear associations were investigated using the spine models and heterogeneity by subgroup analyses. A total of 29 cohort studies were available for meta-analysis, with 938,465 participants and 93,158 mortality, 28,419 CHD and 25,416 CVD cases. No associations were found for total (high-fat/low-fat) dairy, and milk with the health outcomes of mortality, CHD or CVD. Inverse associations were found between total fermented dairy (included sour milk products, cheese or yogurt; per 20 g/day) with mortality (RR 0.98, 95% CI 0.97-0.99; I2 = 94.4%) and CVD risk (RR 0.98, 95% CI 0.97-0.99; I2 = 87.5%). Further analyses of individual fermented dairy of cheese and yogurt showed cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI 0.95-1.00; I2 = 82.6%) per 10 g/day, but not yogurt. All of these marginally inverse associations of totally fermented dairy and cheese were attenuated in sensitivity analyses by removing one large Swedish study. This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality. For future studies it is important to investigate in more detail how dairy products can be replaced by other foods

Encapsulated sodium supplementation of 4weeks does not alter salt taste preferences in a controlled low sodium and low potassium diet

Preference for saltiness is learned by oral exposure to salt taste; however, some data suggest a role for bodily sodium and potassium levels on salt taste preferences as well. The objective was to investigate whether encapsulated sodium and potassium supplementation lead to altered salt taste responses among adults with high blood pressure on a low sodium and low potassium diet. Twenty-six participants with untreated upper-range prehypertension or stage 1 hypertension were on a fully controlled low sodium and low potassium diet (both targeted at 2 g/day) for 13 weeks. Participants received capsules with sodium (3 g/d), potassium (3 g/d), or placebo, for 4 weeks each, in randomized order in a double blind crossover design. Sensory evaluation was done before and after each supplementation period and involved ratings of pleasantness and intensity in different salt (NaCl) concentrations in food and water, desire-to-eat salty food, and detection threshold for NaCl. Neither sodium supplementation nor potassium supplementation led to alterations in salt taste responses in food and water, and did not affect detection threshold (P= 0.59). There was no clear role for sodium or potassium supplementation on desire-to-eat salty food. In addition, we did not find effects of reduced oral exposure to salt over weeks, through the sodium-reduced diet, on salt taste preferences, in contrast to earlier studies. In conclusion, the results of this study suggest preference for saltiness is independent of changes in bodily sodium or potassium levels.</p

Encapsulated sodium supplementation of 4weeks does not alter salt taste preferences in a controlled low sodium and low potassium diet

Preference for saltiness is learned by oral exposure to salt taste; however, some data suggest a role for bodily sodium and potassium levels on salt taste preferences as well. The objective was to investigate whether encapsulated sodium and potassium supplementation lead to altered salt taste responses among adults with high blood pressure on a low sodium and low potassium diet. Twenty-six participants with untreated upper-range prehypertension or stage 1 hypertension were on a fully controlled low sodium and low potassium diet (both targeted at 2 g/day) for 13 weeks. Participants received capsules with sodium (3 g/d), potassium (3 g/d), or placebo, for 4 weeks each, in randomized order in a double blind crossover design. Sensory evaluation was done before and after each supplementation period and involved ratings of pleasantness and intensity in different salt (NaCl) concentrations in food and water, desire-to-eat salty food, and detection threshold for NaCl. Neither sodium supplementation nor potassium supplementation led to alterations in salt taste responses in food and water, and did not affect detection threshold (P= 0.59). There was no clear role for sodium or potassium supplementation on desire-to-eat salty food. In addition, we did not find effects of reduced oral exposure to salt over weeks, through the sodium-reduced diet, on salt taste preferences, in contrast to earlier studies. In conclusion, the results of this study suggest preference for saltiness is independent of changes in bodily sodium or potassium levels.</p

Effects of sodium and potassium supplementation on endothelial function: a fully controlled dietary intervention study

High Na and low K intakes have adverse effects on blood pressure, which increases the risk for CVD. The role of endothelial dysfunction and inflammation in this pathophysiological process is not yet clear. In a randomised placebo-controlled cross-over study in untreated (pre)hypertensives, we examined the effects of Na and K supplementation on endothelial function and inflammation. During the study period, subjects were provided with a diet that contained 2·4 g/d of Na and 2·3 g/d of K for a 10 460 kJ (2500 kcal) intake. After 1-week run-in, subjects received capsules with supplemental Na (3·0 g/d), supplemental K (2·8 g/d) or placebo, for 4 weeks each, in random order. After each intervention, circulating biomarkers of endothelial function and inflammation were measured. Brachial artery flow-mediated dilation (FMD) and skin microvascular vasomotion were assessed in sub-groups of twenty-two to twenty-four subjects. Of thirty-seven randomised subjects, thirty-six completed the study. Following Na supplementation, serum endothelin-1 was increased by 0·24 pg/ml (95 % CI 0·03, 0·45), but no change was seen in other endothelial or inflammatory biomarkers. FMD and microvascular vasomotion were unaffected by Na supplementation. K supplementation reduced IL-8 levels by 0·28 pg/ml (95 % CI 0·03, 0·53), without affecting other circulating biomarkers. FMD was 1·16 % (95 % CI 0·37, 1·96) higher after K supplementation than after placebo. Microvascular vasomotion was unaffected. In conclusion, a 4-week increase in Na intake increased endothelin-1, but had no effect on other endothelial or inflammatory markers. Increased K intake had a beneficial effect on FMD and possibly IL-8, without affecting other circulating endothelial or inflammatory biomarkers

Effects of potassium supplementation on markers of osmoregulation and volume regulation:results of a fully controlled dietary intervention study

Objective:Lifestyle measures including dietary sodium restriction and increased potassium intake are recognized to lower blood pressure (BP). Potassium was found to be effective in reducing BP at higher levels of sodium intake, but to have little effect when sodium intake is restricted. The humoral mechanisms underlying these sodium intake dependent effects of potassium are unknown. We investigated the effects of potassium supplementation on top of a fully controlled sodium-restricted diet on markers of osmoregulation and volume regulation.Methods:In this post-hoc analysis, we included 35 (pre)hypertensive individuals participating in a randomized, double-blind, placebo-controlled crossover trial. Individuals received capsules containing sodium [3.0g (130mmol)/day], potassium [2.8g (72mmol)/day], or placebo for three four-week periods. Linear mixed-effect models were used to estimate the effects of potassium supplementation compared with placebo. Skewed data were ln-transformed before analysis.Results:Increased potassium intake was associated with a significant decrease in 24-h BP (-3.6/-1.6mmHg). Furthermore, we found a significant decrease in ln MR-proANP [-0.08 (95% confidence interval -0.15, -0.01) pmol/l, P=0.03] and significant increases in 24-h heart rate [2.5 (0.9, 4.0) bpm, P=0.002], ln plasma copeptin [0.11 (0.01, 0.20) pmol/l, P=0.02], ln renin [0.34 (0.08, 0.60) IU/ml, P=0.01], and ln aldosterone [0.14 (0.07, 0.22) nmol/l,

Effects of Potassium or Sodium Supplementation on Mineral Homeostasis: A Controlled Dietary Intervention Study

Context: Although dietary potassium and sodium intake may influence calcium-phosphate metabolism and bone health, the effects on bone mineral parameters, including fibroblast growth factor 23 (FGF23), are unclear. Objective: Here, we investigated the effects of potassium or sodium supplementation on bone mineral parameters. Design, setting, participants: We performed a post hoc analysis of a dietary controlled randomized, blinded, placebo-controlled crossover trial. Prehypertensive individuals not using antihypertensive medication (n = 36) received capsules containing potassium chloride (3 g/d), sodium chloride (3 g/d), or placebo. Linear mixed-effect models were used to estimate treatment effects. Results: Potassium supplementation increased plasma phosphate (from 1.10 +/- 0.19 to 1.15 +/- 0.19 mmol/L, P = 0.004), in line with an increase in tubular maximum of phosphate reabsorption (from 0.93 +/- 0.21 to 1.01 +/- 0.20 mmol/L, P <0.001). FGF23 decreased (114.3 [96.8-135.0] to 108.5 [93.5-125.9] RU/mL, P = 0.01), without change in parathyroid hormone and 25-hydroxy vitamin D 3. Fractional calcium excretion decreased (from 1.25 +/- 0.50 to 1.11 +/- 0.46 %, P = 0.03) without change in plasma calcium. Sodium supplementation decreased both plasma phosphate (from 1.10 +/- 0.19 to 1.06 +/- 0.21 mmol/L, P = 0.03) and FGF23 (from 114.3 [96.8-135.0] to 108.7 [92.3-128.1] RU/mL, P = 0.02). Urinary and fractional calcium excretion increased (from 4.28 +/- 1.91 to 5.45 +/- 2.51 mmol/24 hours, P <0.001, and from 1.25 +/- 0.50 to 1.44 +/- 0.54 %, P = 0.004, respectively). Conclusions: Potassium supplementation led to a decrease in FGF23, which was accompanied by increase in plasma phosphate and decreased calcium excretion. Sodium supplementation reduced FGF23, but this was accompanied by decrease in phosphate and increase in fractional calcium excretion. Our results indicate distinct effects of potassium and sodium intake on bone mineral parameters, including FGF23

Supplementation of the Pure Flavonoids Epicatechin and Quercetin Affects Some Biomarkers of Endothelial Dysfunction and Inflammation in (Pre)Hypertensive Adults: A Randomized Double-Blind, Placebo-Controlled, Crossover Trial

Background: Consumption of flavonoid-rich foods such as cocoa and tea may reduce cardiovascular disease risk. The flavonoids epicatechin (in cocoa and tea) and quercetin (in tea) probably play a role by reducing endothelial dysfunction and inflammation, 2 main determinants of atherosclerosis. Objective: We studied the effects of supplementation of pure epicatechin and quercetin on biomarkers of endothelial dysfunction and inflammation. Methods: Thirty-seven apparently healthy (pre)hypertensive men and women (40–80 y) participated in a randomized, double-blind, placebo-controlled crossover trial. Participants ingested (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for a period of 4 wk, in random order. Plasma biomarkers of endothelial dysfunction and inflammation were measured at the start and end of each 4-wk intervention period. The differences in changes over time between the intervention and placebo periods (¿intervention - ¿placebo) were calculated and tested with a linear mixed model for repeated measures. Results: Epicatechin changed ¿epicatechin - ¿placebo for soluble endothelial selectin (sE-selectin) by -7.7 ng/mL (95% CI: -14.5, -0.83; P = 0.03) but did not significantly change this difference (-0.30; 95% CI: -0.61, 0.01; P = 0.06) for the z score for endothelial dysfunction. Quercetin changed ¿quercetin - ¿placebo for sE-selectin by -7.4 ng/mL (95% CI: -14.3, -0.56; P = 0.03), that for IL-1ß by -0.23 pg/mL (95% CI: -0.40, -0.06; P = 0.009), and that for the z score for inflammation by -0.33 (95% CI: -0.60, -0.05; P = 0.02). Conclusions: In (pre)hypertensive men and women, epicatechin may contribute to the cardioprotective effects of cocoa and tea through improvements in endothelial function. Quercetin may contribute to the cardioprotective effects of tea possibly by improving endothelial function and reducing inflammation. This trial was registered at clinicaltrials.gov as NCT01691404