01 March 2017 by Wassim Fares

Prognostic value of the baseline serum sodium level in two independent cohorts of pulmonary arterial hypertension


Hyponatremia has prognostic value in heart failure and liver disease, so we studied the potential prognostic value of hyponatremia in pulmonary arterial hypertension (PAH).


We performed secondary analyses of 2 PAH cohorts: 1) United Therapeutics’ randomized clinical trials (including P0:03, P0:04, P0:05, & P0:06), and 2) A long-term PAH registry at the Cleveland Clinic.  We included adult WHO group 1 PH patients.  Our hypothesis was that baseline hyponatremia is associated with worse 1-year survival.


Baseline Na level is negatively correlated with baseline mean right atrial pressure (r= -0.09; p=0.018; r=-0.089 p=0.015 in cohorts #1 and 2 respectively).  In unadjusted analyses of cohort #1, sodium level (as a continuous variable) is associated with 1-year mortality (Hazard ratio=0.94; p=0.035).  Hyponatremia (Na <137) status loses its significance (p=0.12) in the multivariable regression Cox model when adjusted for functional class (after applying a stepwise model selection procedure to identify the confounding variable whose presence turns the effect of baseline sodium level into insignificant).  Secondary analyses using a cut-off value of < 135 mmol/liter to define hyponatremia and looking at 2-, 3-, and 4-year mortality showed overall similar results. 

These results were validated in cohort #2, which suggested the association between hyponatremia and survival is driven by poor outcomes among patients below a very low sodium cutoff of <130.  Although the sample size for patients with severe hyponatremia (Na <130) was small (31 patients), severe hyponatremia in the validation cohort was associated with poorer overall survival (53% versus 77%; p=0.01), and that the statistical significance of the association at this cutoff holds up under covariate adjustment for age, functional class, and baseline 6-minute walk distance (p<0.001).


Although baseline hyponatremia is associated with 1-year mortality, it loses its significance when adjusted for functional class in the multivariable regression Cox model.



We thank United Therapeutics Corporation for making its database available for our secondary analyses.


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Key Contributors

Anastasiia A. Rudkovskaiia MD1, Adriano R. Tonelli MD2, Youlan Rao PhD3, Raed A. Dweik MD2, Wassim H. Fares MD, MSc4 1: Bridgeport Hospital, Yale New Haven Health, Department of Internal Medicine, Bridgeport, Connecticut, USA 2: Cleveland Clinic, Respiratory Institute, Cleveland, Ohio 3: United Therapeutics Inc., Research Triangle Park, North Carolina 4: Yale University, Pulmonary Critical Care & Sleep Medicine, New Haven, CT

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