Implications of aging in the treatment of complex arrhythmias

The failing myocardium is characterized by numerous inter-related perturbations at molecular, cell and tissue level. Notably, aged myocardium and heart failure (HF) share common pathophysiologic processes and accumulating evidence suggests that impairment of sympathetic nervous system may modulate the clinical course of both entities. Within the sympathetic nervous system, adrenergic receptors (ARs) and changes in regulation of their responses are considered the connecting link for both aging and cardiovascular disease. In particular, decreased β-AR responsiveness, increased circulating catecholamines, and overall hyposensitivity to adrenergic stress are common pathophysiologic derangements in cardiovascular aging and HF [1]. We have previously shown that oral propranolol is more efficient and faster than metoprolol in the treatment of patients with implantable cardioverter-defibrillator (ICD) who experience an electrical storm (ES). This was the first study to compare the efficacy of a nonselective (propranolol) versus a selective β-blocker (metoprolol) towards the management of complex ventricular arrhythmias in HF patients [2]. It is well known that the failing human heart activates compensatory mechanisms, among which increased sympathetic activity has a key role on effector signaling and downstream targets. Adrenergic receptors are divided in two classes: α and β. In terms of β-ΑRs, β1AR is primarily located in the myocardium while β2AR is widely distributed in multiple tissues and β3-AR is found in adipose tissue [3]. As further explained in the specific study, failing myocardium exhibits a progressive decrease in β1/β2 ratio that is attributed to selective down regulation of the β1 receptors. Propranolol may effectively block signal transductions from both β1 and -unblocked from metoprololupregulated β2 cardiac receptors. Given that HF patients are also characterized by increased age, it is tempting to speculate that the combined effect of myocardium disease and aging inflates β-AR stimulation and ES represents an extreme form of sympathetic overdrive that necessitates a more potent β-blocker for prompt and successful treatment. Along this line, protein kinase A (PKA) is an important mediator of signal transduction downstream of G-protein coupled receptors in response to cAMP. Protein kinase A is comprised of two regulatory subunits, RI and RII. As PKA (and in specific, RIIβ) declines with aging, the β-adrenergic pathEditorial