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Background-Failing human myocardium is characterized by an attenuated contractile response to ␤-adrenergic receptor (␤AR) stimulation due to changes in this signaling cascade, including increased expression and activity of the ␤-adrenergic receptor kinase (␤ARK1). This leads to desensitization and downregulation of ␤ARs. Previously, expression of a peptide inhibitor of ␤ARK1 (␤ARKct) has proven beneficial in several animal models of heart failure (HF). Methods and Results-To test the hypothesis that inhibition of ␤ARK1 could improve ␤-adrenergic signaling and contractile function in failing human myocytes, the ␤ARKct was expressed via adenovirus-mediated (Ad␤ARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. Ad␤ARKct also contained the marker gene, green fluorescent protein, and successful gene transfer was confirmed via fluorescence and immunoblotting. Compared with uninfected failing myocytes (control), the velocities of both contraction and relaxation in the Ad␤ARKct-treated cells were increased in response to the ␤-agonist isoproterenol Key Words: myocytes Ⅲ heart failure Ⅲ gene therapy F ailing human myocardium is characterized by a decreased responsiveness to ␤-adrenergic stimulation. 1 This is attributed to a reduction in the myocardial density of ␤-adrenergic receptors (␤ARs) and functional uncoupling of the ␤AR pathway. 2 ␤ARs, like other G-protein-coupled receptors (GPCRs), undergo desensitization and downregulation in response to ongoing stimulation. GPCR kinases (GRKs) phosphorylate activated receptors, which leads to an incapacity for further G-protein stimulation. 3 For ␤ARs, the most important GRK appears to be GRK2, or ␤ARK1, which desensitizes ␤ARs and other GPCRs via membrane translocation dependent on direct binding to dissociated ␤␥-subunits of G proteins (G ␤␥ ). 4 In human heart failure (HF), the expression and activity of ␤ARK1 are elevated, which contributes to the lack of ␤-adrenergic reserve. 5 This is probably the result of enhanced sympathetic nervous system activity and excessive catecholamine stimulation of ␤ARs associated with the failing heart. 6It has been demonstrated in numerous animal models that inhibition of ␤ARK1 translocation with a peptide containing the G ␤␥ -binding site (␤ARKct) can lead to in vivo ␤ARK1 inhibition and rescue of HF. 3,4 Cardiac expression of the ␤ARKct, whether in transgenic mice or after intracoronary gene delivery to larger animal models of HF, can improve myocardial function and lead to enhanced responsiveness to catecholamines through preservation of ␤AR density and G-protein coupling. [7][8][9][10][11][12] Currently, it is unknown whether expression of the ␤ARKct peptide will lead to improvement of function in the failing human heart. Because myocytes from failing human hearts are characterized by an attenuated response to ␤AR stimulation and contractile dysfunction, 13,14 we sought to determine, as an ultimate "proof of concept" for ␤ARK1 inhibition fo...

No difference in player performance after concussion was found whether the player did or did not miss games before return. Return without missing games may be associated with experience and timing of injury within a season and less likely after newer guidelines.