Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (alpha(1) and beta) are a key sympathetic nervous system regulator that controls cardiac function. beta-AR blockers are an established treatment for heart failure and alpha(1A)-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, alpha(1)- and beta-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.

Automated summary

The failing heart has reduced energy generation capacity, leading to diminished functions, with defects in mitochondrial functions and oxidative phosphorylation affecting glucose and fatty acid oxidation. Early clinical studies suggest inhibitors of fatty acid oxidation and mitochondrial-targeted antioxidants may improve heart function by enhancing compensatory glucose oxidation. Adrenergic receptors play a key role in regulating cardiac function and metabolic pathways, with potential therapeutic benefits through adrenergic receptor-mediated restoration of cardiac energetics.