title: Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights.
abstract: Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature.
  
  
  
  Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio.
  
  
  
  Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Jennifer S
authors: JS
authors: Hanberg
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Veena
authors: V
authors: Rao
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Jozine M
authors: JM
authors: Ter Maaten
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Olga
authors: O
authors: Laur
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Meredith A
authors: MA
authors: Brisco
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: F
authors: F
authors: Perry Wilson
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Justin L
authors: JL
authors: Grodin
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Mahlet
authors: M
authors: Assefa
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: J
authors: J
authors: Samuel Broughton
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Noah J
authors: NJ
authors: Planavsky
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Tariq
authors: T
authors: Ahmad
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Lavanya
authors: L
authors: Bellumkonda
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: W H Wilson
authors: WH
authors: Tang
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.).
authors: Chirag R
authors: CR
authors: Parikh
authors: From the Program of Applied Translational Research (J.S.H., V.R., J.M.t.M., O.L., F.P.W., M.A., J.S.B., C.R.P., J.M.T.) and Department of Internal Medicine (F.P.W., T.A., L.B., C.R.P., J.M.T.), Yale University School of Medicine, New Haven, CT; Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.M.t.M.); Cardiovascular Division, Department of Medicine, Medical University of South Carolina, Charleston (M.A.B.); Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, CT (F.P.W.); Section of Heart Failure and Cardiac Transplantation, the Cleveland Clinic, OH (J.L.G., W.H.W.T.); and Department of Geology and Geophysics, Yale University, New Haven, CT (N.J.P.). jeffrey.testani@yale.edu.
authors: Jeffrey M
authors: JM
authors: Testani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002712:Chlorides / Q000097:blood* / Q000627:therapeutic use; D003237:Connecticut; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D004351:Drug Resistance; D005260:Female; D005665:Furosemide / Q000009:adverse effects / Q000627:therapeutic use*; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010865:Pilot Projects; D011446:Prospective Studies; D012083:Renin / Q000097:blood; D012307:Risk Factors; D012964:Sodium / Q000097:blood; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D002712:Chlorides; D049994:Sodium Potassium Chloride Symporter Inhibitors; D005665:Furosemide; D012964:Sodium; D012083:Renin
keywords: cardiorenal syndrome; chloride; diuretics