Cardiomyocyte Life-Death Decisions in Response to Chronic β-Adrenergic Signaling
β-adrenergic signaling in the heart is a double-edged sword. In the short-term, it enhances cardiac function, whereas chronic high-level activation results in heart failure. In this issue of Circulation Research, Zhang et al1 investigate mechanisms that mediate β-adrenergic–induced cell death and, in doing so, uncover a survival pathway of potential clinical relevance.
Article, see p 498
A basic principle of cardiac pharmacology is that acute activation of β-adrenergic receptors (referred to herein as β-receptors) increases heart rate (chronotropy), contractility (inotropy), and relaxation of heart muscle (lusitropy) to augment cardiac systolic and diastolic performance. These responses couple cardiac function with physiological demands, such as exercise, and provide compensatory mechanisms when the circulation is threatened by insults, such as hemorrhage or sudden deterioration in cardiac function. The major ligand in this context is norepinephrine, a catecholamine derived primarily from the postganglionic sympathetic neurons that innervate the heart and, to a lesser extent, from the adrenal medulla.
Given the beneficial hemodynamic effects of acute β-adrenergic signaling, cardiologists in the 1980s hypothesized that activation of this pathway may benefit patients with advanced heart failure, a condition with an astounding 5-year mortality of ≈50%. Indeed this approach improved cardiac hemodynamics in the short term, but it soon became apparent that chronic treatment results in marked increases in patient mortality.2 Conversely, β-receptor blockade reduced mortality,3 a finding presaged by small studies decades earlier.4 These paradoxical findings were at odds with the accepted notion that improvement of hemodynamics alone should be sufficient to stem the progression of heart failure. The resolution of these data ultimately necessitated a new paradigm. In this model, catecholamines initially help the failing heart to compensate for decreased pump function. However, when present chronically at high levels, they function as toxins that promote adverse cardiac remodeling and progressive …