Middle age serum sodium levels in the upper part of normal range and risk of heart failure

Abstract

Aims: With increasing prevalence of heart failure (HF) owing to the ageing population, identification of modifiable risk factors is important. In a mouse model, chronic hypohydration induced by lifelong water restriction promotes cardiac fibrosis. Hypohydration elevates serum sodium. Here, we evaluate the association of serum sodium at middle age as a measure of hydration habits with risk to develop HF.

Methods and results: We analysed data from Atherosclerosis Risk in Communities study with middle age enrolment (45-66 years) and 25 years of follow-up. Participants without water balance dysregulation were selected: serum sodium within normal range (135-146 mmol/L), not diabetic, not obese and free of HF at baseline (N = 11 814). In time-to-event analysis, HF risk was increased by 39% if middle age serum sodium exceeded 143 mmol/L corresponding to 1% body weight water deficit [hazard ratio 1.39, 95% confidence interval (CI) 1.14-1.70]. In a retrospective case-control analysis performed on 70- to 90-year-old attendees of Visit 5 (N = 4961), serum sodium of 142.5-143 mmol/L was associated with 62% increase in odds of left ventricular hypertrophy (LVH) diagnosis [odds ratio (OR) 1.62, 95% CI 1.03-2.55]. Serum sodium above 143 mmol/L was associated with 107% increase in odds of LVH (OR 2.07, 95% CI 1.30-3.28) and 54% increase in odds of HF (OR 1.54, 95% CI 1.06-2.23). As a result, prevalence of HF and LVH was increased among 70- to 90-year-old participants with higher middle age serum sodium.

Conclusion: Middle age serum sodium above 142 mmol is a risk factor for LVH and HF. Maintaining good hydration throughout life may slow down decline in cardiac function and decrease prevalence of HF.

Keywords: Heart failure; Hydration; Left ventricular hypertrophy; Prevention; Risk factors; Sodium.

Structured Graphical Abstract

Analysis of 25 years follow-up data from Atherosclerosis Risk in Communities studies reveals increased risk to develop heart failure (HF) and left ventricular hypertrophy (LVH) among study participants with middle age serum sodium above 142 mmol/l. Left panels (beginning of the study): participants are divided into 4 groups based on serum sodium levels. Middle panels (follow-up: time-to-event analysis): increased incidence of HF in higher sodium groups with adjusted hazard ratio reaching 1.39 when serum sodium exceeds 143 mmol/l. Right panels (end of the 25 years follow-up: 70–90 year old participants): Increased prevalence of HF and LVH and accelerated hypertrophic left ventricular remodelling in higher sodium groups.

Figure 1

Study analyses overview. After selecting 11 814 ARIC study participants based on exclusion criteria, time-to-event analysis for heart failure was performed with exposure variables related to hydration status measured at the beginning of the study. The associations were first assessed with continuous exposure variables followed by splitting the continuous ranges into groups and identifying thresholds for significant increase of heart failure risk. Applicability of the findings for older population was tested by repeating time-to-event analysis in 5185 participants who lived until 70–90 years old and attended Visit 5 evaluation. Association of middle age serum sodium with left ventricular hypertrophy and heart failure was assessed in the Visit 5 attendees by logistic regression analysis.

Figure 2

Metrics of reduced hydration assessed at middle age are associated with increased risk to develop heart failure. (A) The cumulative incidence functions for heart failure and for mortality not related to heart failure over 25 years of follow-up in ARIC study participants. (B) Higher serum sodium within normal range of 135–146 mmol/L is associated with increased risk to develop heart failure. The model is adjusted for age as continuous variable and for heart failure risk factors: sex—male vs. female as reference; race—black vs. white as reference; current smoking vs. no smoking as reference used as categorical covariates, as well as body mass index, total cholesterol and estimated glomerular filtration rate used as continuous covariates. Categorical variable adjusting for blood pressure status contains four categories taking into account blood pressure measured values and use of blood pressure medications. High blood pressure is defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg. Lower panels show distribution histograms for continuous variables used in the model. (C) Hazard ratios for exposure variables related to hydration and salt intake resulting from Fine–Gray subdistribution PH models for risk of heart failure. The models were run with the same covariates as used in serum sodium model shown in (B). See Supplementary material online, Tables S2–S5 for full models results. Water deficit was calculated as (60 × (1 − (140 ÷ [Na⁺])); Tonicity 1: (2[Na⁺] + [Glucose]/18); Tonicity 2: (2[Na⁺] + [Glucose]/18 + 2[K⁺]). Lower panels show distribution histograms for the exposure variables used in the models. See Supplementary material online, Figure S1 for distribution histograms related to haematocrit and Supplementary material online, Tables S2–S5 for full models results.

Figure 3

Study participants can be divided into groups with significantly different cumulative incidence functions for heart failure if divisions are based on sodium, water deficit or tonicity. CART algorithm was used to split study participants into groups based on hydration-related variables that showed significant association with HF in Fine–Gray models shown in Figure 2. Cumulative heart failure incidence at the end of follow-up was used as outcome variable for the splitting algorithms. (A) Examples of CART algorithm outcome for group splitting based on sodium and tonicity 1 (2[Na] + [Glucose]/18). (B) Histograms showing distributions of the study participants according to tested variables. Groups identified by CART algorithm are shown in different colours. % of heart failure cases in each group are shown above each histogram. (C) Cumulative incidence functions for heart failure accounting for competing mortality plotted separately for each group. P-values from Gray’s test for equality of cumulative incidence functions are shown on the plots.

Figure 4

High normal sodium (>143 mmol/L), water deficit (>1% body weight) and tonicity-1 (>290 mosmol/kg) are associated with significant increase in risk of heart failure in adjusted Fine–Gray subdistribution proportional hazard model accounting for competing mortality. The models are adjusted for the same heart failure risk factors described in legend for Figure 2B. Left panel: Full results for the model with sodium as exposure variable. Right panels: Overview of results from Fine–Gray subdistribution PH model shown for sodium on left panel but run with other exposure variables related to hydration. See Supplementary material online, Figures S6 and S7 for full models results.

Figure 5

Higher serum sodium at Visits 1 and 2 is associated with increased risk of left ventricular hypertrophy and heart failure at Visit 5 at ages 70–90 years. Only participants from original analysis cohort who attended Visit 5 and did not have left ventricular hypertrophy at Visit 2 were included in the analysis (n = 4961). (A) Retrospective case-control analysis of factors associated with increased odds to develop left ventricular hypertrophy and heart failure: multivariable logistic regression. The model is adjusted for same covariates described in Figure 2B legend. (B) 3D Mesh Plot, visualizing Cornell voltage criteria values obtained at Visit 5 for left ventricular hypertrophy diagnosis as functions of serum sodium concentration at Visits 1 and 2 and age at Visit 5. Participants with serum sodium in upper half of normal range have higher Cornel voltage that increases with age at higher rate. (C) 3D Mesh Plot, visualizing change in Cornell voltage values between Visits 1 and 5 for each study participant as functions of serum sodium at Visits 1 and 2 and age at Visit 5. Size of left ventricle increases more and at younger age in participants whose middle age serum sodium was higher.

Figure 6

Prevalence of left ventricular hypertrophy and heart failure in ARIC study participants at Visit 5 depending on average serum sodium concentration measured at Visits 1 and 2. Shown is percent of people (70–90 years) who had left ventricular hypertrophy and heart failure diagnosis at the time of Visit 5 examination depending on their serum sodium measured at Visits 1 and 2 (45–66 years). Higher sodium is associated with higher prevalence of left ventricular hypertrophy and heart failure in all Visit 5 participants (left panels) and in groups created based on gender and race (right panels): W/F, white females; W/M, white males; B/F, black (African American) females; B/M, black (African American) males.