Increased cardiac G-protein coupled receptor kinase-2 (GRK2) expression/activity are pivotal events in the pathogenesis of heart failure (HF)-related β-adrenergic receptor (βAR) dysfunction. Importantly, in human HF, abnormalities of βAR signaling in the heart can be mirrored in circulating lymphocytes and are correlated with HF severity. In the present study we evaluated whether lymphocyte GRK2 can predict long-term survival in elderly HF patients and its potential additive prognostic value over currently used biomarkers.Methods
At this aim, we prospectively studied 221 elderly (mean age 72.5 ± 10.2) patients with advanced post-ischemic HF. Lymphocyte GRK2 protein, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and norepinephrine were measured at baseline, together with functional parameters (left ventricular ejection fraction, NYHA class). Cardiac-related mortality was evaluated during a mean follow up period of 37 ± 12 months.Results
Patients were stratified according to GRK2 quartiles. Mean age, comorbidity , and NYHA functional class progressively increased along with lymphocyte GRK2 levels. Kaplan-Meyer survival curves obtained according to quartiles of GRK2 and NT-proBNP showed a significant progressive increase of cardiovascular mortality rates from quartile 1 to 4 for both biomarkers. The additional prognostic information of lymphocyte GRK2 protein levels to serum NT-proBNP concentrations, was also examined in subanalyses. In a multivariate model using simultaneously the fourth quartiles of the two markers versus quartile 1 through 3 together with the clinical variables, the markers displayed prognostic information even when analyzed in the same model (cardiovascular mortality: hazard ratio for fourth quartile of GRK2 3.42 [95% CI, 1.15-6.02] and hazard ratio for fourth quartile of NT-proBNP 5.01 [95% CI, 1.43-17.6]). The Kaplan-Meyer analysis of cardiovascular mortality supported a crucial additive prognostic value of lymphocyte GRK2 over NT-proBNP. In fact, patients with low-medium concentrations of both markers (Quartliles 1-3) showed a cardiovascular mortality rate of 20.6%, whereas, patients with low-medium NT-proBNP levels (Quartiles 1-3) but high lymphocyte GRK2 (Quartile 4) presented a mortality of 79.4%.Conclusions
Our data offer the first demonstration that GRK2 has a potent, independent, prognostic value in patients with severe post-ischemic HF. Moreover, lymphocyte GRK2 protein levels offer important additive prognostic information over NT-proBNP that actually represents the most utilized HF biomarker in the clinical practice.