Beta-adrenergic adaptation in idiopathic dilated cardiomyopathy: differences between children and adults.

The study of Miyamoto et al. found differences in beta-adrenergic adaptation to heart failure (HF) in explanted heart tissue between children and adults with symptomatic dilated cardiomyopathy (DCM). Differences included: (i) down-regulation of beta-1and beta2-adrenergic receptors in children but maintained beta-2-adrenergic receptor expression in adults; and (ii), in children, uncoupling of the beta-1-adrenergic receptors and stimulatory G-proteins, among others. An important family of cell surface protein receptors, the G-protein-coupled receptors (GPCRs), enable cells to sense and respond to outside signals. For children with cardiomyopathy and heart failure, we need a better understanding of the structure– function relationships and the detailed regulation of GCPRs, as well as the drugs that stimulate or inhibit these relationships. Understanding beta-adrenergic adaptation in children with HF should indicate how cardiomyocytes interact with their extracellular environment and adapt to new situations, such as when epinephrine acts on cells to increase blood pressure and heart rate. Miyamoto and colleagues observed that the GCPR signalling system has become the target of prescription drugs, including betablockers, to relieve HF. In fact, about half of all medications act on these receptors, so learning about them is key to developing better drugs. The GPCR initiates a cascade of signals into the cell, prompting it to respond appropriately, as well as a secondary cascade in which a feedback signal leads to desensitization. A molecule called beta-arrestin binds to the GPCR and reduces or temporarily stops GPCR’s sensitivity. Beta-arrestin, in addition to receptor desensitization, is involved in receptor endocytosis and activating extracellular signal-regulated kinase (ERK) and other mitogen-activated protein (MAP) kinases. GPCRs use two major signalling mechanisms—one mediated through the classical activation of G-proteins and the other through activation of beta-arrestins. The observation that GPCRs signal through G-protein and beta-arrestin pathways has profound implications for understanding cell biology and drug development. Here, we review differences between children and adults with DCM and emphasize the need to better understand the genetic causes, clinical course, and biomarkers of cardiovascular disease, including beta-adrenergic adaptation (Figure 1). The course of paediatric cardiomyopathy, regardless of aetiology, is usually progressive; its prevention should occur in children at risk of or with ventricular dysfunction (Figure 1). The identification of cardiomyopathy risk factors helps to identify high-risk populations that through screening may lead to: (i) early diagnosis, institution of disease-specific therapies, and alteration of disease course; and (ii) primary prevention of disease by targeted strategies (Figure 1). Further understanding of adrenergic adaptation in this population will determine its role in defining risk and aetiology. The developmentally regulated assembly of the ternary complex model of receptor interactions with a GTP-binding G-protein to form a high-affinity receptor–G-protein complex that activates adenylate cyclase is a dynamic process during early cardiac development. This development is characterized by high densities of beta-adrenergic receptors on cardiomyocytes, high levels of adenylate cyclase activity, and high intracellular cyclic AMP concentrations. In the developing heart, the rate-limiting step for functional beta-adrenergic sensitivity and agonist responsivity is functional coupling of the G-protein to the GPCR. Before functional coupling, the embryonic heart is insensitive to beta-adrenergic agonist chronotropic and inotropic stimulation. Therefore, when considering the responses of children and adults with adult HF, normal developmental changes in beta-adrenergic adaptation in children must be considered, in addition to HF changes.