Mechanisms of Disease: β-adrenergic receptors—alterations in signal transduction and pharmacogenomics in heart failure

Abstract

Beta-adrenergic signaling is an important regulator of myocardial function. During the progression of heart failure (HF), a reproducible series of biochemical events occurs that affects beta-adrenergic receptor (beta-AR) signaling and cardiac function. Furthermore, there are pathophysiologic alterations in the expression and regulation of proteins that are regulated by beta-ARs during HF. Analyses of these complex signaling pathways have led to a better understanding of HF mechanisms and the use of beta-adrenergic antagonists, which have notably altered HF-related morbidity and mortality. Despite therapeutic advances that have affected beta-AR signaling, HF remains a leading cause of hospitalization and a principal cause of death in industrialized nations. In this review, we summarize current insights into beta-adrenergic signal-transduction pathways, the best-described beta-AR polymorphisms, and therapies that target the beta-AR pathway in HF.

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

“…β-Adrenergic-receptor (βAR) signaling has a key role in myocyte performance, and alterations in these signaling pathways are well-established disease pathways in HF. 2,3 Despite extensive guidelines for managing patients with chronic HF, few prospective randomized trials have studied patients with acute decompensated HF (ADHF); hence, there is no consensus on how these patients should be managed. The lack of effective treatment options is partly a consequence of the poor understanding we have of mechanisms in acute HF and the lack of prospective clinical trials demonstrating a change in mortality in ADHF with treatment.…”

“…Additional events that further exacerbate HF, such as fibrosis, pathological remodeling, dyssynchrony and hypertrophy, occur following the decrease in number of myocytes and worsening ECC associated with ADHF, leading to the progressive irreversibility of the disease. 3 For demonstrative purposes only, we have selected the βAR to illustrate how its interactions with other signaling cascades can increase cell death through necrosis, apoptosis and perhaps autophagy (all three processes referred to as 'cell death', hereafter) and decrease contractile function (i.e. ECC; Figure 1).…”

Ancillary risk information and pharmacogenetic tests: social and policy implications

“…The validity of several well-cited examples of pharmacogenetic associations -CETP variants and response to statins, alpha-adducin and response to diuretics, and ACE variants and response to ACE inhibitors -have recently been called into question. [27][28][29][30][31][32] In addition, well-known and wellstudied polymorphisms such as these may be more likely to be studied for their associated pharmacogenetic effects, which may introduce bias when conducting inquiries such as ours.…”

What will be the role of I-123 MIBG in improving the outcome of medically treated heart failure patients?

“…Treatment with b-blockers has been shown to reduce cardiac work, up-regulate post-synaptic adrenergic receptors, 4 and with carvedilol, for example, reduce proliferation, possibly through antioxidant properties. 5 b-blockers reduce the risk of death in patients with chronic HF (CHF).…”