title: Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure.
abstract: BACKGROUND
  Increased cardiac G protein-coupled receptor kinase-2 (GRK2) expression has a pivotal role at inducing heart failure (HF)-related β-adrenergic receptor (βAR) dysfunction. Importantly, abnormalities of βAR signalling in the failing heart, including GRK2 overexpression, are mirrored in circulating lymphocytes and correlate with HF severity. Exercise training has been shown to exert several beneficial effects on the failing heart, including normalization of cardiac βAR function and GRK2 protein levels. In the present study, we evaluated whether lymphocyte GRK2 levels and short-term changes of this kinase after an exercise training programme can predict long-term survival in HF patients.
  
  
  METHODS
  For this purpose, we prospectively studied 193 HF patients who underwent a 3-month exercise training programme. Lymphocyte GRK2 protein levels, plasma N-terminal pro-brain natriuretic peptide, and norepinephrine were measured at baseline and after training along with clinical and functional parameters (left ventricular ejection fraction, NYHA class, and peak-VO2). Cardiac-related mortality was evaluated during a mean follow-up period of 37 ± 20 months.
  
  
  RESULTS
  Exercise was associated with a significant reduction of lymphocyte GRK2 protein levels (from 1.29 ± 0.52 to 1.16 ± 0.65 densitometric units, p < 0.0001). Importantly, exercise related changes of GRK2 (delta values) robustly predicted survival in our study population. Interestingly, HF patients who did not show reduced lymphocyte GRK2 protein levels after training presented the poorest outcome.
  
  
  CONCLUSIONS
  Our data offer the first demonstration that changes of lymphocyte GRK2 after exercise training can strongly predict outcome in advanced HF.
authors.affiliation: Fondazione S. Maugeri, Istituto di Telese, Benevento, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.forename: Gennaro
authors.initials: G
authors.lastname: Galasso
authors.forename: Grazia D
authors.initials: GD
authors.lastname: Femminella
authors.forename: Valentina
authors.initials: V
authors.lastname: Parisi
authors.forename: Carmela
authors.initials: C
authors.lastname: Zincarelli
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pagano
authors.forename: Claudio
authors.initials: C
authors.lastname: De Lucia
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.forename: Daniela
authors.initials: D
authors.lastname: Liccardo
authors.forename: Caterina
authors.initials: C
authors.lastname: Marciano
authors.forename: Carlo
authors.initials: C
authors.lastname: Vigorito
authors.forename: Francesco
authors.initials: F
authors.lastname: Giallauria
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferrara
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Furgi
authors.forename: Pasquale Perrone
authors.initials: PP
authors.lastname: Filardi
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Dario
authors.initials: D
authors.lastname: Leosco
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D015536:Down-Regulation; D005081:Exercise Therapy; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000201:enzymology / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000097:blood; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013318:Stroke Volume; D013997:Time Factors; D016896:Treatment Outcome; D016277:Ventricular Function, Left
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; D009638:Norepinephrine
keywords: G protein-coupled receptor kinase-2; biomarker; exercise training; heart failure; β-Adrenergic receptor