Low-Normal Serum Sodium Identified as a Risk Factor for CVD/Death

Pam Harrison

August 14, 2015

More evidence has emerged that mild hyponatremia, even within the normal sodium range, as well as hypernatremia are both associated with increased risk of cardiovascular disease and mortality in older men with no history of coronary heart disease, heart failure, or stroke, the British Regional Heart Study indicates[1].

The study was published online August 5, 2015 in Nutrition, Metabolism and Cardiovascular Diseases.

"Electrolyte disorders are common in the elderly," lead author Dr Goya Wannamethee (University College London, UK) told heartwire from Medscape in written correspondence.

"And clinicians should monitor low serum sodium levels even within the normal sodium range in older people, as the presence of mild hyponatremia in the absence of renal dysfunction or the use of diuretics may require further investigation to assess patients for the presence of other CVD risk factors or possible underlying ill-health such as chronic inflammation."

The British Regional Heart Study is a prospective study of CVD involving 7735 men between 40 and 59 years of age drawn from one general practice in each of 24 representative British towns.

Men were screened between 1978 and 1980. From 1998 to 2000, all surviving men, now between 60 and 79 years of age, were invited for a 20-year follow-up examination on which the current analysis was based.

Sodium was measured by an ion-selective electrode. Ion-selective electrodes are a technology that allows researchers to directly measures cations and anions such as sodium and fluoride. The electrical potential created as sodium ions transverse the membrane can be compared with a reference electrode to determine the sodium ion concentration, and between-batch imprecision is <2%.

A total of 3099 men were included in the current analysis. Total mortality and morbidity events were based on follow-up from rescreening in 1998–2000 to June 2010, with a mean follow-up of 11 years.

During the 11-year follow-up, there were 528 major CVD events, including fatal coronary heart disease, nonfatal MI, stroke and CVD death, and 873 total deaths.

The mean serum sodium level in the overall cohort was 139.8 mEq/L. Hyponatremia, defined as a serum sodium <136 mEq/L, was present in 6.7% of the cohort, while hypernatremia, defined as a serum sodium ≥145 mEq/L, was present in only 1.8% of the cohort overall.

"A significant U-shaped relationship was seen, with overall CVD events and total mortality with risk increasing below levels of 139 mEq/L and above 143 mEq/L," the authors report (both P<0.0001).

On the basis of these findings, men were grouped into five categories: <136 (hyponatremia), 136–138 (low normal), 139–143, 144, and >145 (hypernatremia) mEq/L.

"Men with sodium levels below 139 mEq/L and men with hypernatremia showed significantly higher risk of major CVD events than men with sodium levels between 139 and 143 mEq/L, even after adjustment for potential confounders, diabetes, blood pressure, blood lipids, lung function, and estimated glomerular filtration rate (eGFR)," investigators report.

Hyponatremia and low sodium levels were also associated with a significantly increased risk of mortality, they add.

The increased risk of mortality in those with low normal serum sodium was attenuated but remained significant even after men with eGFR <60 mL/min/1.73m2, diuretics users, and current smokers were excluded.

Mortality Rates/1000 Person-years for Total Mortality in Men Without CHD, Stroke, or Heart Failure

Serum sodium (mEq/L) Mortality rate/1000 person-years (n) Model 1, HR (95% CI)*
<136 43.9 (83) 1.30 (1.02–1.66)
136-138 1.39 (230) 1.30 (1.11–1.53)
139-143 24.6 (508) 1.00
144 30.7 (33) 1.25 (0.87–1.78)
≥145 35.4 (14) 1.54 (0.97–2.44
Model 1 was adjusted for age, smoking, alcohol intake, physical activity, social class, BMI, use of antihypertensive drugs, diabetes, lung function, systolic blood pressure, and eGFR

No Association With Potassium

In contrast to serum sodium, no consistent association was seen between potassium and overall CVD events.

As researchers point out, hyponatremia is usually defined as serum sodium <136 mEq/L, but a more conservative definition of hyponatremia has been proposed at higher serum sodium levels (<138 mEq/L).

"The significantly increased risk of CVD and mortality seen at circulating sodium levels between 136 and 138 mEq/L in the present study supports this more conservative definition," the authors observe.

"And it suggests that in older adults, even levels between 136 and 138 mEq/L—levels usually considered to be within the normal range [and that were] present in nearly a quarter of the men—may be a marker of mortality and CVD risk."

As previously reported by heartwire , the authors of the Prospective Urban Rural Epidemiology (PURE) study also reported a "J-shaped" curve and the risk of death or major CVD events and estimated dietary sodium intake over a 3.7-year follow-up.

The risk of adverse outcomes in PURE was also lowest for subjects with moderate sodium urinary excretion levels. In the study, sodium urinary excretion levels served as a surrogate for estimated dietary sodium intake.

The PURE study was, however, criticized by relying on a fasting morning-urine sodium test to estimate dietary sodium intake rather than using multiple 24-hour urine collections, which are considered to be a more accurate measure of estimated dietary sodium intake.

The British Regional Heart Study is a British Heart Foundation (BHF) research group and receives support from the BHF program. The authors have no relevant financial relationships.

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