Serum Chloride Levels Predict Survival in Pulmonary Arterial Hypertension

By Adriano Tonelli, MD

New evidence from our recent study published in Chest suggests that serum chloride concentration is not only an important biomarker in left heart failure, but also a strong and independent predictor of mortality in patients with pulmonary arterial hypertension (PAH).

It has been recognized that hypochloremia is associated with increased mortality in patients with left heart failure, and that serum chloride may be a better predictor of outcomes than serum sodium, possibly by reflecting a broader homeostatic imbalance. However, to this point, the impact of serum chloride in right heart failure resulting from PAH had not been investigated.

The only blood biomarker currently recommended and routinely used in clinical practice for predicting PAH outcomes is brain natriuretic peptide (BNP). Recent evidence suggests high creatinine and low serum sodium are associated with increased mortality in PAH. Additionally, PAH patients with hyponatremia have worse functional capacity, more pronounced hemodynamic severity and higher hospitalization rates.

Our research team hypothesized that serum chloride levels could predict the long-term survival of patients with PAH, even when adjusted for serum sodium levels, renal function and use of prostacyclin analogs.

Study design

To prove our hypothesis, we conducted a retrospective data analysis of 277 patients with idiopathic or heritable PAH who had a metabolic panel performed at the time of their diagnostic right heart catheterization. Our cohort was reduced to 254 when we eliminated patients who did not have a six-month follow-up electrolyte determination. Patients in the study were predominantly female (73 percent), age 33-69, with idiopathic (88 percent) and heritable (12 percent) PAH.

The median survival after the initial and six-month laboratory testing was 105 months and 99 months, respectively. After adjusting for age, sex, use of diuretics at baseline and pulmonary vascular resistance (PVR), we noted that only blood urea nitrogen (BUN) and creatinine predicted survival at PAH diagnosis. With the same adjustments, serum chloride, BUN and creatinine measured at six months predicted long-term survival. Serum chloride at six months remained a significant predictor of survival when adjusted for age, sex, PVR, use of diuretics at six months, and treatment with parenteral prostacyclin analogs, serum sodium or creatinine.

Of the 254 patients who had a laboratory determination at six months, 235 were followed for at least two years. During this time, 59 (23.2 percent) patients died. Serum chloride at six months showed an AUC of 0.69 (95% CI; 0.63-0.75) for discriminating patients who died during the two-year interval. A serum chloride at six months carried a sensitivity of 45.8 percent, specificity of 87.5 percent, and positive likelihood ratio of 3.7 for predicting two-year mortality. The difference in serum chloride between baseline and six months showed an AUC of 0.69 (0.61-0.78). By comparison, serum sodium as well as BUN and creatinine at six months revealed an AUC of 0.60 (95% CI; 0.50-0.75) and 0.61 (95% CI; 0.53-0.70), respectively, for predicting two-year mortality.

Results at diagnosis and six months postdiagnosis

In our relatively large cohort of patients with well-characterized idiopathic or heritable PAH, we noted that the prevalence of hypochloremia at PAH diagnosis was low. Further, we noted that serum chloride levels at PAH diagnosis did not significantly affect long-term survival.

However, six months after diagnosis, a lower serum chloride was a significant predictor of long-term mortality, even when adjusted for the use of diuretics or parenteral prostacyclin analogs, serum creatinine and sodium. A lower serum chloride at six months was associated with older age, worse functional capacity and renal function, and a larger left atrium and higher pulmonary wedge pressure.

Limitations of our study included those associated with any retrospective data analysis. Additionally, 38 patients (13 percent) did not have six-month follow-up; additional NT-pro-BNP was not used as a covariate in our models given that this determination was available in a third of patients; and results may not be pertinent to other pulmonary hypertension groups or causes of PAH besides the idiopathic or heritable form.

In summary, a lower serum chloride level six months after diagnosis is an important biomarker for patients with idiopathic or heritable PAH, even when adjusted by serum sodium levels, renal function and diuretic or parenteral prostacyclin analog use. This finding is consistent with studies in left heart failure and, as such, has significant prognostic implications.

Dr. Tonelli is staff in the departments of Pulmonary Medicine, Critical Care Medicine and Pathobiology.