Why Do We Not Assess Sympathetic Nervous System Activity in Heart Failure Management: Might GRK2 Serve as a New Biomarker?

Abstract

Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest.

The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart

“…the cardioprotective βARKct [143], Tg-RKIP mice showed an upregulation of the cardiac Grk2 transcript levels in vivo, i.e., the Grk2 transcript levels of Tg-RKIP hearts were 1.50 ± 0.06-fold higher than those of non-transgenic FVB controls (Figure 6). Upregulation of Grk2 is induced by long-term stimulation of β-adrenoceptors [142] and could reflect overstimulation of the sympathetic nervous system, which is characteristic of heart failure [14]. In this context, the upregulation of Grk2 in Tg-RKIP hearts could indicate that the Grk2-inhibition-mediated sensitisation of β-adrenoceptors by RKIP could lead to Grk2 upregulation.…”

“…During the pathogenesis of heart failure, there is an upregulation of GRK2-Grk2 , which accounts for the impaired contractile reserve of failing hearts by desensitisation and downregulation of cardiac β-adrenoceptors [ 12 , 13 , 14 , 15 , 16 , 17 , 141 ]. Inhibition of the exaggerated GRK2-Grk2 activity by a GRK2 inhibitor or (partial) Grk2 deficiency ( Adrbk1 +/−) in failing hearts restores the contractile response and contributes to the cardioprotective profile of GRK2-Grk2 inhibitors [ 13 , 14 , 15 , 16 , 17 ]. Upon improvement of the impaired cardiac function, the upregulated GRK2-Grk2 levels are normalised [ 14 , 142 ].…”

“…Inhibition of the exaggerated GRK2-Grk2 activity by a GRK2 inhibitor or (partial) Grk2 deficiency ( Adrbk1 +/−) in failing hearts restores the contractile response and contributes to the cardioprotective profile of GRK2-Grk2 inhibitors [ 13 , 14 , 15 , 16 , 17 ]. Upon improvement of the impaired cardiac function, the upregulated GRK2-Grk2 levels are normalised [ 14 , 142 ]. Likewise, therapy with a cardioprotective GRK2 inhibitor, such as the βARKct, lowered the pathologically elevated Grk2 levels of heart failure rats [ 143 ].…”

“…Upregulation of Grk2 is induced by long-term stimulation of β-adrenoceptors [ 142 ] and could reflect overstimulation of the sympathetic nervous system, which is characteristic of heart failure [ 14 ]. In this context, the upregulation of Grk2 in Tg-RKIP hearts could indicate that the Grk2-inhibition-mediated sensitisation of β-adrenoceptors by RKIP could lead to Grk2 upregulation.…”

“…GRK2 inhibition is an emerging treatment approach of heart failure. GRK2 is upregulated in failing hearts of patients with heart failure [ 12 , 13 , 14 ]. Inhibition of pathologically elevated GRK2 by different approaches, gene transfer and gene knockout showed beneficial effects in many models of cardiac dysfunction and heart failure [ 15 , 16 , 17 ].…”