β-Adrenergic Receptor Desensitization/Down-Regulation in Heart Failure: A Friend or Foe?

Cardiac sympathetic activation, mediated by β-adrenergic receptors (β-ARs), normally increases cardiac contraction and relaxation. Accomplishing this task requires a physiological, concerted Ca signaling, being able to increase Ca release from sarcoplasmic reticulum (SR) in systole and speed up Ca re-uptake in diastole. In heart failure (HF) myocardial β-ARs undergo desensitization/down-regulation due to sustained sympathetic adrenergic activation. β-AR desensitization/down-regulation diminishes adrenergic signaling and cardiac contractile reserve, and is conventionally considered to be detrimental in HF progression. Abnormal Ca handling, manifested as cardiac ryanodine receptor (RyR2) dysfunction and diastolic Ca leak (due to sustained adrenergic activation) also occur in HF. RyR2 dysfunction and Ca leak deplete SR Ca store, diminish Ca release in systole and elevate Ca levels in diastole, impairing both systolic and diastolic ventricular function. Moreover, elevated Ca levels in diastole promote triggered activity and arrhythmogenesis. In the presence of RyR2 dysfunction and Ca leak, further activation of the β-AR signaling in HF would worsen the existing abnormal Ca handling, exacerbating not only cardiac dysfunction, but also ventricular arrhythmogenesis and sudden cardiac death. Thus, we conclude that β-AR desensitization/down-regulation may be a self-preserving, adaptive process (acting like an intrinsic β-AR blocker) protecting the failing heart from developing lethal ventricular arrhythmias under conditions of elevated sympathetic drive and catecholamine levels in HF, rather than a conventionally considered detrimental process. This also implies that medications simply enhancing β-AR signaling (like β-AR agonists) may not be so beneficial unless they can also correct dysfunctional Ca handling in HF.