Serum Chloride Levels Track With Survival in Patients With Pulmonary Arterial Hypertension

Naal, Tawfeq; Abuhalimeh, Batool; Khirfan, Ghaleb; Dweik, Raed A.; Tang, W.H. Wilson; Tonelli, Adriano R.

doi:10.1016/j.chest.2018.04.022

Cited by 28 publications

(25 citation statements)

References 29 publications

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“…Our data may provide a molecular explanation of the increased mortality associated with hypochloremia in PAH (14,15) and in left heart failure patients (33)(34)(35). Based on our findings, we propose hypochloremia activates WNK1, which subsequently heightens glucose uptake resulting in excess protein O-GlcNAcylation and glycation.…”

Section: Discussionsupporting

confidence: 56%

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

Prisco

Eklund

Thenappan

et al. 2021

Preprint

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Objectives: Investigate how WNK1 inhibition modulates glucotoxicity, mitochondrial/peroxisomal protein regulation and metabolism, and right ventricular (RV) function in pulmonary arterial hypertension (PAH). Determine how hypochloremia impacts RV function in PAH patients. Background: In PAH-induced RV failure, GLUT1/GLUT4 expression is elevated, which increases glucose uptake and glycolytic flux to compensate for mitochondrial dysfunction. However, the resultant consequences of the glucose-mediated post-translational modifications (PTM), protein O-GlcNAcylation/glycation in RV failure are understudied. WNK1, a chloride-sensitive kinase, increases GLUT1/GLUT4 expression in skeletal muscle, but its regulation in RV dysfunction is unexplored. Methods: Rats were treated with WNK463 (small molecule WNK inhibitor) or vehicle starting two weeks after monocrotaline injection. Immunoblots quantified protein abundance/PTMs. Mitochondrial/peroxisomal proteomics and global metabolomics evaluated glucose metabolism and mitochondrial/peroxisomal function. Pulmonary vascular and cardiac histology, echocardiography, and pressure-volume loop analysis quantified RV function and PAH severity. Finally, the relationship between hypochloremia, a WNK1-activating state, and RV function was evaluated in 217 PAH patients. Results: WNK463 decreased WNK1/GLUT1/GLUT4 expression, normalized glucose metabolite levels, which dampened excess protein O-GlcNAcylation/glycation. Integration of RV mitochondrial/peroxisomal proteomics and metabolomics identified fatty acid oxidation (FAO) as the most dysregulated metabolic pathway. WNK463 enhanced FAO as demonstrated by increased expression of mitochondrial FAO proteins and normalization of RV acylcarnitines. WNK463 reduced glutaminolysis induction and lipotoxicity, two secondary consequences of diminished FAO. WNK463 augmented RV systolic and diastolic function independent of pulmonary vascular disease severity. In PAH patients, hypochloremia resulted in more severe RV dysfunction. Conclusions: WNK463 combated RV glucotoxicity and impaired FAO, which directly improved RV function.

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Section: Discussionsupporting

confidence: 56%

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

Prisco

Eklund

Thenappan

et al. 2021

Preprint

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“…The progressive course of cirrhosis with portal hypertension and splanchnic vasodilatation leads to the development of effective arterial hypovolemia and activation of endogenous vasoconstrictor systems causing various complications, including cirrhotic cardiomyopathy, hepatorenal syndrome, and hepatopulmonary syndrome [ 22 , 23 ]. Since serum chloride has been recognized to play a critical role in modulation of renin secretion, renal salt sensing, tubuloglomerular feedback, and regulation of sodium transporter [ 21 , 24 , 25 ], it is mechanistically conceivable that hypochloremia could promote greater cirrhosis-related complications and risk for death. Future prospective studies should examine the influence of hypochloremia on the development of cirrhosis-related complications.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, some researchers have changed their focus from sodium to its often overlooked counter ion in salt, the chloride [20]. Growing evidence have shown that hypochloremia is associated with a higher risk of mortality in patients with acute or chronic heart failure, chronic kidney disease, and pulmonary hypertension [7][8][9][10][11][12]21]. It is noteworthy that multiple studies have shown that serum chloride had better prognostic predictability than serum sodium [9,10,12].…”

Section: Discussionmentioning

confidence: 99%

Lower serum chloride concentrations are associated with increased risk of mortality in critically ill cirrhotic patients: an analysis of the MIMIC-III database

2021

BMC Gastroenterol

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Background Cirrhosis can be complicated by electrolyte abnormalities, but the major focus has been concentrated on the clinical significance of serum sodium levels. Emerging studies have identified hypochloremia as an independent prognostic marker in patients with chronic heart failure and chronic kidney disease. The aim of this study was to investigate whether serum chloride levels were associated with mortality of critically ill cirrhotic patients. Methods Critically ill cirrhotic patients were identified from the Multi-parameter Intelligent Monitoring in Intensive Care III Database. The primary outcome was ICU mortality. Logistic regression was used to explore the association between serum chloride levels and ICU mortality. The area under the receiver operating characteristic curves (AUC) was used to assess the performance of serum chloride levels for predicting ICU mortality. Results A total of 1216 critically ill cirrhotic patients were enrolled in this study. The overall ICU mortality rate was 18.8%. Patients with hypochloremia had a higher ICU mortality than those with non-hypochloremia (34.2% vs. 15.8%; p < 0.001). After multivariable risk adjustment for age, gender, ethnicity, chloride, sodium, Model for End-stage Liver Disease score, Sequential Organ Failure Assessment score, Elixhauser comorbidity index, mechanical ventilation, vasopressors, renal replacement therapy, acute kidney injury, hemoglobin, platelet, and white blood cell, serum chloride levels remained independently associated with ICU mortality (OR 0.94; 95% CI 0.91–0.98; p = 0.002) in contrast to serum sodium levels, which were no longer significant (OR 1.03; 95% CI 0.99–1.08; p = 0.119). The AUC of serum chloride levels (AUC, 0.600; 95% CI 0.556–0.643) for ICU mortality was statistically higher than that of serum sodium levels (AUC, 0.544; 95% CI 0.499–0.590) (p < 0.001). Conclusions In critically ill cirrhotic patients, serum chloride levels are independently and inversely associated with ICU mortality, thus highlighting the prognostic role of serum chloride levels which are largely overlooked.

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“…7,9 There is a growing body of evidence suggesting important role of chloride in patients with chronic HF, subsets of HF with Hypochloraemia and readmission in heart failure preserved and reduced ejection fraction, acute myocardial infarction, and systemic and pulmonary hypertension. [10][11][12] At the same time, the prognostic role of chloride as a biomarker in HF remains in question. 13 Meanwhile, trials to determine if interventions in serum chloride levels will have a positive effect on HF treatment are currently underway (NCT03446651).…”

Section: Discussionmentioning

confidence: 99%

Hypochloraemia and 30 day readmission rate in patients with acute decompensated heart failure

et al. 2020

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Aims Despite recent advances in guideline-directed therapy, rehospitalization rates for acute decompensated heart failure (ADHF) remain high. Recently published studies demonstrated the emerging role of hypochloraemia as a predictor of poor outcomes in patients with ADHF. This study sought to determine the correlation between low serum chloride and 30 day hospital readmission in patients with ADHF. Methods and resultsWe retrospectively reviewed electronic medical records of 1504 patients who were admitted to one 700 bed US tertiary care centre with the diagnosis of ADHF between June 2013 and December 2014. Of the 1504 reviewed records, 1241 were selected for further analysis. Hypochloraemia (either on admission or at discharge) was identified in 289 patients (23.3%) and was associated with significantly higher 30 day hospital readmission rate or death (42.2% vs. 33.7%, P = 0.008). This association persisted in multivariate analysis when controlling for serum sodium, weight loss, diuretic dose, adjunct thiazide use, serum blood urea nitrogen, and BNP levels (OR: 1.35, 95% CI: 1.02-1.77, P = 0.033); however, the predictive value of the overall model was low (Naglkerke R 2 = 0.040). Hypochloraemia was also found to be associated with increased 12 month mortality in our cohort (31.4% vs. 20.2%, P = 0.015) that correlates with the results of previously published studies.Conclusions Low serum chloride measured in patients admitted for ADHF is independently but weakly associated with increased 30 day readmission rate and demonstrated low predictive value as a potential biomarker in this cohort.

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Serum Chloride Levels Track With Survival in Patients With Pulmonary Arterial Hypertension

Abstract: Serum chloride at 6 months from the PAH diagnosis is a strong and independent predictor of mortality in patients with idiopathic or heritable PAH, even after adjusting serum sodium, renal function, diuretic, and prostacyclin analog usage.

Cited by 28 publications

References 29 publications

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

Lower serum chloride concentrations are associated with increased risk of mortality in critically ill cirrhotic patients: an analysis of the MIMIC-III database

Hypochloraemia and 30 day readmission rate in patients with acute decompensated heart failure

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