Cross-Sectional Positive Association of Serum Lipids and Blood Pressure With Serum Sodium Within the Normal Reference Range of 135-145 mmol/L

Abstract

Objective: Serum sodium concentration is maintained by osmoregulation within normal range of 135 to 145 mmol/L. Previous analysis of data from the ARIC study (Atherosclerosis Risk in Communities) showed association of serum sodium with the 10-year risk scores of coronary heart disease and stroke. Current study evaluated the association of within-normal-range serum sodium with cardiovascular risk factors.

Approach and results: Only participants who did not take cholesterol or blood pressure medications and had sodium within normal 135 to 145 mmol/L range were included (n=8615), and the cohort was stratified based on race, sex, and smoking status. Multiple linear regression analysis of data from ARIC study was performed, with adjustment for age, blood glucose, insulin, glomerular filtration rate, body mass index, waist to hip ratio, and calorie intake. The analysis showed positive associations with sodium of total cholesterol, low-density lipoprotein cholesterol, and total cholesterol to high-density lipoprotein cholesterol ratio; apolipoprotein B; and systolic and diastolic blood pressure. Increases in lipids and blood pressure associated with 10 mmol/L increase in sodium are similar to the increases associated with 7 to 10 years of aging. Analysis of sodium measurements made 3 years apart demonstrated that it is stable within 2 to 3 mmol/L, explaining its association with long-term health outcomes. Furthermore, elevated sodium promoted lipid accumulation in cultured adipocytes, suggesting direct causative effects on lipid metabolism.

Conclusions: Serum sodium concentration is a cardiovascular risk factor even within the normal reference range. Thus, decreasing sodium to the lower end of the normal range by modification of water and salt intake is a personalizable strategy for decreasing cardiovascular risks.

Keywords: blood pressure; cardiovascular diseases; cholesterol; risk factors; stroke.

Figure 1. 3D Mesh Plots, visualising level of plasma cholesterol, apolipoproteins and Blood pressure as functions of serum sodium concentration and age observed in ARIC study participants

Plasma sodium is positively associated with blood level of A) Total Cholesterol, B) LDL-cholesterol, C) Total Cholesterol to HDL-cholesterol ratio, D) Apolipoprotein B, E) Systolic BP and F) Diastolic BP. See also Table 1 and Table IIS presenting results of the multivariable regression analysis.

Figure 2. Serum sodium is stable in individuals over a long time

Analysis of serum sodium of ARIC study participants measured in two visits 3 years apart. A) Assessment of long-term intraindividual variability of serum sodium concentration. Scatterplot depicting the correlation between serum sodium measured in each person during visit 1 versus that measured in the same person in visit 2. B, C) Degree of stability of serum sodium. B) Frequency distribution histogram of differences of serum Na⁺ concentration between the two visits. For 45% of ARIC participants the difference does not exceed 1 mmol/l, for 65% - 2 mmol/l and for 94% - 3 mmol/l. C) The difference of serum Na⁺ concentration between 2 visits versus the mean serum sodium of each person (mean±SD). The variability of serum Na is higher at the ends of normal range (SD increases from 2.5 mmol/l in the middle part of normal range to 3-4 mmol/l at 135 and 145 mmol/l).

Figure 3. Elevated extracellular sodium increases lipids accumulation in cultured adipocytes

A ) Overview of adipocytes differentiation protocol. 3T3-L1 pre-adipocytes were grown on 96 well plates. Differentiation to adipocytes was performed by changing the medium for 3 days to the medium supplemented with differentiation factors and containing different concentrations of sodium: 135, 145, 155 and 165 mmol/l. After 3 days, differentiation factors were removed and adipocytes were maintained in medium with different sodium concentrations. B) Representative images of adipocytes at day 6 and day 12 after differentiation start showing accumulation of lipid droplets. Cells maintained in medium with 145 mmol/l sodium accumulated more lipids than cells in 135 mmol/l sodium. C) Representative image of adipocytes stained with AdipoRed for quantification of lipids content. D) Time course of lipid accumulation in adipocytes maintained in media containing different concentrations of sodium. Lipids content is quantified as Integral Green Fluorescence from corresponding wells of 96 well plate. Data are presented as mean ± SEM, N=5; *P<0.05; **P<0.01, unpaired, two-tailed t test relative to 135 mmol/l (significance level is similar for 145,155 and 165 mmol/l). See related Figure IIS.