Sudden cardiac death due to β2-agonist therapy: is a genetic basis overlooked?

rysms associated with human immunodeficiency virus (HIV) infection. β 2-adrenoceptor agonists have long been widely used for the management of certain conditions, including chronic obstructive pulmonary disease (COPD). However, in recent years, sudden cardiac death (SCD) associated with the use of β 2-adrenoceptor agonists has raised significant concerns about the safety profile of these agents. These drugs may have the potential to induce SCD in a proportion of susceptible subjects with structural heart diseases (SHD) including cardiomyopathies, and should not be routinely prescribed before ruling out these pathologies. 1 A case of SCD with an undiagnosed cardiomyopathy, possibly associated with the administration of a β 2-adrenoceptor agonist (for a bronchial asthma attack) has recently been reported, suggesting the presence of SHD as the most important determinant of SCD due to β 2-agonist therapy. 1 However, as described below, SCD due to β 2-agonist therapy may also be closely associated with individual genetic susceptibility, particularly in subjects with apparently normal hearts, suggesting the need for thorough investigation of all candidates of β 2-agonist therapy, with regard to clinical clues to an electrophysiological genetic basis for β 2-agonist-induced SCD, before prescribing these drugs. Genetically determined arrhythmogenic entities including ion channelopathies and catecholaminergic ventricular tachycar-dia (VT) have been regarded as important aetiologies of SCD, particularly in young victims 2 with apparently normal hearts. Ion channelopathies may be overt or obscure in terms of resting ECG signs (with or without QT-interval prolongation) and generally present with a spectrum of clinical symptoms (syncopal attacks, SCD) that may be triggered by a variety of internal or external factors, including QT-interval-prolonging drugs. 2 Previously, we reported a case of torsades de pointes (TdP) with a severely prolonged corrected QT (QTc) interval induced by an initial low-dose sotalol intake in the presence of a normal basal QTc interval, suggesting an individual genetic susceptibility to drug-induced pro-arrhythmia. 3 Besides eliciting proclivity for malign arrhythmias in the presence of structural heart diseases and triggering acute coronary syndromes (ACS) in susceptible subjects, β-receptor stimulation is also well known to prolong QT interval. Therefore, it may be suggested that TdP due to a severely prolonged QT interval may be propounded as one of the fundamental mechanisms of β 2-agonist-related SCD in subjects with a genetic basis for drug-induced pro-arrhythmia. Consistent with this notion, in a retrospective study comprising a large population of patients with long-QT syndrome (LQTS),