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.

Serum Chloride and Sodium Interplay in Patients With Acute Myocardial Infarction and Heart Failure With Reduced Ejection Fraction

“…44 In the chronic HF setting, low serum chloride has also been associated with dismal outcome. 10,11 An additional explanation for the differences found between these different populations is that HF and post-MI are distinct settings with different presentations, treatments, and prognosis, despite the fact that ≈60% of our population had left ventricular ejection fraction <35% and ≈20% had HF history, without significant interaction in these subgroups (Table VII in the Data Supplement). In particular, fluid management plays a central role in HF therapy.…”

Hypochloremia and Diuretic Resistance in Heart Failure

“…Some support for the biological importance of the above in humans is provided by the growing epidemiologic literature which suggests that hypochloremia is prognostically important in heart failure, independent of hyponatremia, a finding also observed in the current cohort (Figure 3). 17–19 …”

“…14–16 To that end, several recent epidemiologic studies have identified low chloride, rather than sodium, as the primary ion driving the poor survival in HF previously attributed to hyponatremia. 17–19 Despite mounting data on the importance of chloride in HF from the basic sciences and large epidemiological studies, we lack an understanding of the mechanisms by which chloride plays a role in disease pathophysiology.…”

Dynamic changes in serum chloride concentrations during worsening of heart failure and its recovery following conventional diuretic therapy: A single‐center study

“…Blood tests included measurements of hemoglobin, hematocrit, total protein, albumin, electrolytes, blood urea nitrogen, creatinine, and serum b‐type natriuretic peptide levels. In the present study, hyponatremia and hypochloremia were defined as a serum sodium concentration of ≤135 mEq/L and a serum chloride concentration of ≤96 mEq/L …”