title: Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure.
abstract: BACKGROUND
  Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional β-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients.
  
  
  OBJECTIVE
  The independent prognostic value of blood GRK2 measurements in HF patients has never been investigated; thus, the purpose of this study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients.
  
  
  RESULTS
  We prospectively studied 257 HF patients with mean left ventricular ejection fraction of 31.4±8.5%. At the time of enrollment, plasma norepinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variables were measured. The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause mortality was assessed using the Cox proportional hazard model including demographic, clinical, instrumental, and laboratory data. Over a mean follow-up period of 37.5±20.2 months (range, 3-60 months), there were 102 CV deaths. Age, left ventricular ejection fraction, New York Heart Association class, chronic obstructive pulmonary disease, chronic kidney disease, N-terminal-pro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mortality in HF patients. GRK2 levels showed an additional prognostic and clinical value over demographic and clinical variables. The independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality.
  
  
  CONCLUSIONS
  Lymphocyte GRK2 protein levels can independently predict prognosis in patients with HF.
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pagano
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Pasquale Perrone
authors.initials: PP
authors.lastname: Filardi
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Grazia Daniela
authors.initials: GD
authors.lastname: Femminella
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Valentina
authors.initials: V
authors.lastname: Parisi
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Daniela
authors.initials: D
authors.lastname: Liccardo
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Klara
authors.initials: K
authors.lastname: Komici
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Gambino
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Maria Loreta
authors.initials: ML
authors.lastname: D'Amico
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Claudio
authors.initials: C
authors.lastname: de Lucia
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolillo
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Dino Franco
authors.initials: DF
authors.lastname: Vitale
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.).
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferrara
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.). walter.koch@temple.edu dleosco@unina.it.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: From the Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., G.G., D.F.V., N.F.); Division of Geriatrics, Department of Translational Medical Sciences (G.R., G.P., G.D.F., V.P., A.C., D. Liccardo, K.K., G.G., M.L.D.'A., C.d.L., N.F., D. Leosco), Division of Cardiology, Department of Advanced Biomedical Sciences (P.P.F., B.T.), Federico II University of Naples, Naples, Italy; SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy (S.P.); and Department of Pharmacology, Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., D. Liccardo, W.J.K.). walter.koch@temple.edu dleosco@unina.it.
authors.forename: Dario
authors.initials: D
authors.lastname: Leosco
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002318:Cardiovascular Diseases / Q000401:mortality; D002423:Cause of Death; D005260:Female; D005500:Follow-Up Studies; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000097:blood*; D006333:Heart Failure / Q000097:blood* / Q000201:enzymology / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D009026:Mortality; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013318:Stroke Volume; D013564:Sympathetic Nervous System / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: G-protein-coupled receptor kinase 2; beta-adrenergic receptors; heart failure; natriuretic peptide, brain; prognosis