Dynamic Changes in Lymphocyte GRK2 Levels in Cardiac Transplant Patients: A Biomarker for Left Ventricular Function

Abstract

BackgroundEnhancing our prognostic capabilities in terms of response to evidence-based therapies in heart failure (HF) may lead to improved patient outcomes and a more cost-eff ective approach to this complex syndrome. Biomarkers appropriately satisfy this role by providing the potential to enhance our diagnostic, therapeutic, and prognostic approach to the complex treatment of HF patients. Th ere have been many research endeavors examining various natriuretic peptides, extracellular and intracellular molecules, neurohormones, and infl ammatory mediators with the hope of providing insight into the pathophysiologic mechanism(s) of left ventricular (LV) systolic dysfunction, the volume-overload state, decompensation, and prognosis.1 Despite these discoveries, we still lack a complete understanding of the complex pathophysiology of HF and response to various therapies.Evidence-based medical therapies, including β-adrenergic receptor (βAR) antagonists (β-blockers), angiotensin-converting enzyme (ACE) inhibitors, and aldosterone receptor antagonists, are the cornerstones of pharmacologic therapy for LV systolic dysfunction and congestive HF. It is unclear as to why LV systolic function improves and sometimes even normalizes in some patients, while others show no improvement in ejection fraction or LV remodeling refl ected in ventricular dimensions.We, and others, have previously studied how these G protein-coupled receptors (GPCRs) are dysregulated in the heart.2,3 Much of this work has focused on GPCR kinases (GRKs), which are responsible for the desensitization of βARs and other receptors in the heart dampening signal transduction throughout the myocyte. G protein-coupled receptor kinase 2 (GRK2) is the most abundant GRK expressed in cardiac myocytes, and it has been known for over a decade that this kinase is elevated in failing myocardium. 4 Importantly, we have shown that human myocardial levels of GRK2 are mirrored by levels found in white blood cells.5 Moreover, levels of blood GRK2 expression were inversely correlated with LV systolic function, and higher levels of expression were seen with more advanced New York Heart Association (NYHA) functional classes of HF. 5Of note, we have previously found that modalities that improve cardiac function and reverse LV remodeling can decrease GRK2 levels in both cardiac tissue and white blood cells.6 This was shown in severe HF patients undergoing implantation of mechanical LV assist devices (LVADs), which are an important therapeutic option for many patients needing additional hemodynamic support either as a bridge to ventricular recovery or cardiac transplantation or as destination therapy. 7 LVAD patients were followed with cardiac and blood samples taken at the time of LVAD implantation and also 2-3 months later during cardiac transplantation, and LV unloading caused a signifi cant downregulation of cardiac GRK2 and improved βAR signaling, which was mirrored in decreased lymphocyte levels of GRK2.6 Th is fi nding supports our hypothesis that blood GRK2 levels may be ...

Targeting the β-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure

“…Similar results were reported by Bonita et al 42 in HF patients undergoing heart transplantation. In this study, both cardiac and lymphocyte GRK2 levels significantly declined after surgery, consistent with improved cardiac function in the transplanted heart.…”

Linking Cardiac Insulin Resistance and Heart Failure: Grk2 as an Integrative Node

“…Overall, our data put forward GRK2 as a new molecular link among aging, insulin resistance/obesity and cardiovascular co-morbidities. Since circulating GRK2 levels have been shown to mirror cardiac expression [18] and increased levels of this protein are found in peripheral blood cells from metabolic syndrome patients [11] and from heart failure patients [19][20] , in particular in those with diabetes mellitus [21] , it will be interesting to explore the potential use of GRK2 as a prognostic cardiovascular risk marker when co-morbidities such as diabetes, insulin resistance and obesity are present.…”

GRK2 Inhibition in Heart Failure: Something Old, Something New

“…Increasing interest into the role GRK2 plays in cardiovascular pathophysiology is due to the fact that this kinase is upregulated in several different pathologic conditions, such as cardiac ischemia, hypertrophy, and hypertension [32][33][34][35][36][37][38]. In HF, cardiac GRK2 protein levels are elevated in the early stages of the disease and several lines of evidence suggest this kinase can serve as a potential novel biomarker of cardiac dysfunction in human HF [38][39][40]. Currently, the general consensus is that the excessive amount of catecholamine "hitting" the receptor from its extracellular side is an early trigger for increased GRK2 levels/activity in HF, thus leading to a reduction in AR density and responsiveness and resulting in further deterioration of cardiac function [11].…”