title: Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure.
abstract: Chloride plays a role in renal salt sensing, neurohormonal activation, and regulation of diuretic targets, and hypochloremia predicts mortality in acute heart failure (AHF). AHF therapies, such as diuretics, alter chloride homeostasis. We studied the association between (changes in) chloride levels and diuretic responsiveness, decongestion, and mortality in patients with AHF.
  
  
  
  Patients hospitalized for AHF in the PROTECT trial (n=2033) with serum chloride levels within 24 hours of admission and 14 days later were studied (n=1960). Hypochloremia was defined as serum chloride <96 mEq/L. Mean baseline chloride was 100.8±5.0 mEq/L. Low baseline chloride was associated with high bicarbonate, poor diuretic response, less hemoconcentration, and worsening heart failure (all P<0.01). Newly developed hypochloremia at day 14 was common and associated with a decline in renal function and an increase in blood urea nitrogen (P<0.01). In multivariable analyses, chloride measured at day 14, but not baseline chloride, was strongly and independently associated with mortality through 180 days (hazard ratio per unit decrease: 1.07 [1.03-1.10]; P<0.001). In comparison, sodium was not significantly associated with mortality after multivariable adjustment at any time point. Hypochloremia at baseline that resolved was not associated with mortality (P=0.55), but new or persistent hypochloremia at day 14 was associated with increased mortality (hazard ratio: 3.11 [2.17-4.46]; P<0.001).
  
  
  
  Low serum chloride at AHF hospital admission was strongly associated with impaired decongestion. New or persistent hypochloremia 14 days later was independently associated with reduced survival, whereas hypochloremia that resolved by day 14 was not.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354458.
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Jozine M
authors: JM
authors: Ter Maaten
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Kevin
authors: K
authors: Damman
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Jennifer S
authors: JS
authors: Hanberg
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Michael M
authors: MM
authors: Givertz
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Marco
authors: M
authors: Metra
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Christopher M
authors: CM
authors: O'Connor
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: John R
authors: JR
authors: Teerlink
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Piotr
authors: P
authors: Ponikowski
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Gad
authors: G
authors: Cotter
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Beth
authors: B
authors: Davison
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: John G
authors: JG
authors: Cleland
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Daniel M
authors: DM
authors: Bloomfield
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Hans L
authors: HL
authors: Hillege
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Dirk J
authors: DJ
authors: van Veldhuisen
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.). a.a.voors@umcg.nl.
authors: Adriaan A
authors: AA
authors: Voors
authors: From the University Medical Center, University of Groningen, The Netherlands (J.M.t.M., K.D., H.L.H., D.J.v.V., A.A.V.); Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT (J.M.t.M., J.S.H., J.M.T.); Brigham and Women's Hospital, Boston, MA (M.M.G.); University of Brescia, Italy (M.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.M.O.); University of California at San Francisco and San Francisco Veterans Affairs Medical Center (J.R.T.); Medical University, Clinical Military Hospital, Wroclaw, Poland (P.P.); Momentum Research, Durham, NC (G.C., B.D.); University of Hull, Kingston upon Hull, United Kingdom (J.G.C.); Merck Research Laboratories, Rahway, NJ (D.M.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.M.T.).
authors: Jeffrey M
authors: JM
authors: Testani
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002712:Chlorides / Q000097:blood*; D018450:Disease Progression; D004232:Diuretics / Q000009:adverse effects / Q000627:therapeutic use*; D015536:Down-Regulation; D004351:Drug Resistance; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006760:Hospitalization; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014970:Xanthines / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D002712:Chlorides; D004232:Diuretics; D014970:Xanthines; C073525:rolofylline
keywords: blood urea nitrogen; chlorides; creatinine; diuretics; electrolytes