Jennifer S Hanberg1, Veena Rao1, Jozine M Ter Maaten1, Olga Laur1, Meredith A Brisco1, F Perry Wilson1, Justin L Grodin1, Mahlet Assefa1, J Samuel Broughton1, Noah J Planavsky1, Tariq Ahmad1, Lavanya Bellumkonda1, W H Wilson Tang1, Chirag R Parikh1, Jeffrey M Testani2. 1. 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.). 2. 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.
Abstract
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.
BACKGROUND: 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. METHODS AND RESULTS: 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 nonhypochloremicpatients 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 ureanitrogen to creatinine ratio. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.
Authors: Justin L Grodin; Frederik H Verbrugge; Stephen G Ellis; Wilfried Mullens; Jeffrey M Testani; W H Wilson Tang Journal: Circ Heart Fail Date: 2016-01 Impact factor: 8.790
Authors: Jeffrey M Testani; Meredith A Brisco; Jennifer Chen; Brian D McCauley; Chirag R Parikh; W H Wilson Tang Journal: J Am Coll Cardiol Date: 2013-06-07 Impact factor: 24.094
Authors: Alexander T Piala; Thomas M Moon; Radha Akella; Haixia He; Melanie H Cobb; Elizabeth J Goldsmith Journal: Sci Signal Date: 2014-05-06 Impact factor: 8.192
Authors: Veena S Rao; Noah Planavsky; Jennifer S Hanberg; Tariq Ahmad; Meredith A Brisco-Bacik; Francis P Wilson; Daniel Jacoby; Michael Chen; W H Wilson Tang; David Z I Cherney; David H Ellison; Jeffrey M Testani Journal: J Am Soc Nephrol Date: 2017-07-24 Impact factor: 10.121
Authors: Veena S Rao; Jeffrey M Turner; Matthew Griffin; Devin Mahoney; Jennifer Asher; Sangchoon Jeon; Peter S Yoo; Nabil Boutagy; Attila Feher; Albert Sinusas; F Perry Wilson; Fredric Finkelstein; Jeffrey M Testani Journal: Circulation Date: 2020-01-08 Impact factor: 29.690
Authors: Antonios Charokopos; Matthew Griffin; Veena S Rao; Lesley Inker; Krishna Sury; Jennifer Asher; Jeffrey Turner; Devin Mahoney; Zachary L Cox; F Perry Wilson; Jeffrey M Testani Journal: Clin J Am Soc Nephrol Date: 2019-04-22 Impact factor: 8.237
Authors: Juan B Ivey-Miranda; Brendan Stewart; Zachary L Cox; Wendy McCallum; Christopher Maulion; Olyvia Gleason; Grace Meegan; Jonathan G Amatruda; Julieta Moreno-Villagomez; Devin Mahoney; Jeffrey M Turner; F Perry Wilson; Michelle M Estrella; Michael G Shlipak; Veena S Rao; Jeffrey M Testani Journal: Circ Heart Fail Date: 2021-10-25 Impact factor: 8.790
Authors: Tawfeq Naal; Batool Abuhalimeh; Ghaleb Khirfan; Raed A Dweik; W H Wilson Tang; Adriano R Tonelli Journal: Chest Date: 2018-04-24 Impact factor: 9.410