Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure

Abstract

Aims: Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium-conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure.

Methods and results: Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18-1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89-1.06, P = 0.52).

Conclusion: Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area.

Keywords: Heart failure; Hypochloraemia; Hyponatraemia; Mortality; Serum chloride; Serum sodium.

Figure 1

Scatterplot of baseline serum chloride and serum sodium. The size of the dot indicates the number of patients at each integer value of sodium and chloride with that value as per the ‘Scale’ legend.

Figure 2

Box plot of baseline loop diuretic dose based on groups defined by the presence or absence of hyponatraemia or hypochloraemia. Boxes represent the 25th to 75th percentile, the line represents the median, and whiskers the 10th and 90th percentile. P < 0.001 for all comparisons apart from the comparison between patients with isolated hypochloraemia and those with hypochloraemia and hyponatraemia (rightward two boxes) where P = 0.72.

Figure 3

Survival plots of the groups defined by hypochloraemia and hyponatraemia at baseline (A), 3 months (B), and 12 months (C). Low Na: hyponatraemia defined as a serum sodium ≤135 mmol/L. Low Cl: hypochloraemia defined as serum chloride ≤96 mmol/L. P < 0.001 for overall differences between groups. P ≤0.017 for the difference between isolated hypochloraemia and isolated hyponatraemia at all time points.

Figure 4

Relationship between serum chloride (A) and serum sodium (B) and mortality risk. Risk was calculated relative to the cohort mean value (101.3 mmol/L for serum chloride and 138.9 mmol/L for serum sodium.) The blue reference line indicates a relative risk of 1. CI, confidence interval.