Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failure

Abstract

SUMMARYAcute decompensated heart failure (ADHF) is responsible for more than 1 million hospital admissions each year in the US. Clinicians and scientists have developed therapeutic strategies that reduce mortality in patients with chronic heart failure (HF). Despite the widely appreciated magnitude of the ADHF problem, there is still a critical gap in our understanding of the cellular mechanisms involved and effective treatment strategies for hospitalized patients. Irrespective of the etiology, patients with ADHF present with similar symptoms (e.g. edema, altered hemodynamics and congestion) as multiple signaling pathways converge in a common phenotypic presentation. Investigations have shown that patients with ADHF have increased catecholamine levels, which cause chronic stimulation of β-adrenergic receptors. This overstimulation leads to chronic G-protein activation and perturbations in myocyte signaling, as the patient's heart attempts to adapt to progressive HF. Over time, these compensatory signaling mechanisms ultimately fail, and maladaptive signaling prevails with progressive worsening of symptoms. This Review summarizes some of the changes that occur during chronic adrenergic stimulation, and examines how downstream contractile dysfunction and myocyte death can alter the prognosis of patients with HF hospitalized for acute events.

Facilitatory Interplay in α1aand β2Adrenoceptor Function Reveals a Non-GqSignaling Mode: Implications for Diversification of Intracellular Signal Transduction

“…The expression of the ␣ 1A -and ␤ 2 -ARs in myocardial tissue and their functional balance has been linked to the pathogenesis and progression of heart failure, implicating maladaption of adrenoceptor signaling (Huang et al, 2007;Feldman et al, 2008;Woodcock et al, 2008). The development of heart failure in humans is accompanied by an increase in catecholamine levels and a decrease in density and signaling of the predominant adrenoceptor in the healthy heart, ␤ 1 -AR (Lohse et al, 2003), with no changes in the levels of expression of ␤ 2 -AR (Feldman et al, 2008;Woodcock et al, 2008).…”

“…The development of heart failure in humans is accompanied by an increase in catecholamine levels and a decrease in density and signaling of the predominant adrenoceptor in the healthy heart, ␤ 1 -AR (Lohse et al, 2003), with no changes in the levels of expression of ␤ 2 -AR (Feldman et al, 2008;Woodcock et al, 2008). Because ␣ 1A -AR expression is maintained in heart failure, and the natural ligand norepinephrine is shared by both ␣-and ␤-adrenoceptors, ␣ 1A -and ␤ 2 -ARs are suggested to play greater roles in maintaining cardiac performance in failing hearts (Brodde, 1991;Skomedal et al, 1997;Woodcock et al, 2008).…”

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

“…In heart failure, dysregulation of βAR signaling is associated with myocyte apoptosis, cardiac remodeling and dysfunction as well as death (63). GRK2 expression is also elevated in heart failure; while this may serve as a compensatory mechanism at the initial stage of the disease, upregulation of GRK2 in heart failure worsens cardiac function (64,65).…”

Cardiac gene therapy: Recent advances and future directions

“…As a result, the adrenergic activation increases the Protein Kinase A (PKA), Ca 2+ Calmodulin-Dependent Protein Kinase II, and diastolic Ca 2+ levels. This also disrupts Phosphoinositol 3 kinase (PI3K/AKT) signaling and thus, leads to several negative consequences including mitochondrial swelling and cytochrome-C release [8]. β-blockers are able to slow down mortality and control symptoms but they do not alter the course of disease.…”