Thr164Ile polymorphism of β2-adrenergic receptor negatively modulates cardiac contractility:: implications for prognosis in patients with idiopathic dilated cardiomyopathy

Background: beta 2-adrenergic receptor Thr164lle (threonine (Thr) is replaced by an isoleucine (Ile) at codon 164) polymorphism was postulated to contribute to lower exercise tolerance and poor prognosis in patients with congestive heart failure. However, heart failure is associated with several abnormalities of beta receptor signalling, and underlying mechanisms are not clear. Objectives: To investigate whether Thr164lle polymorphism negatively modulates myocardial contractile performance and is associated with adverse long-term prognosis of patients with congestive heart failure. Methods: Among 55 subjects, cardiac contractile response to the b2-adrenergic receptor agonist terbutaline was assessed from the peak myocardial velocity of systolic shortening (Sm) in 18 subjects with the lle-164 variant and 37 matched controls. In total, 24 subjects had normal left ventricular (LV) function and 31 presented with congestive heart failure due to idiopathic dilated cardiomyopathy. Results: In patients with normal LV function, peak terbutaline-induced increase (Delta) in Sm was lower in subjects with the lle-164 variant than in controls (Delta 33% (4%) vs Delta 56% (4%), p<0.01). In patients with heart failure, subjects with Ile-164 showed further severe reduction of beta 2-adrenergic-mediated increase in Sm as compared with controls with heart failure (Delta 20% (5%) vs Delta 39% (4%), p<0.05). Patients with heart failure with Ile-164 showed a severely blunted force-frequency relationship in response to agonist stimulation. At 2-years of follow-up, patients with heart failure with the Ile-164 variant showed higher incidence of adverse events than controls with heart failure (75% (6/8)] vs 30% (7/23), p<0.05). Conclusions: The b2-adrenergic Thr164lle polymorphism directly modulates adrenergic-mediated cardiac responses in patients with normal and failing myocardium. Furthermore, blunted beta 2 adrenergic-mediated myocardial contractile response in patients with Ile-164 variant seems to adversely modulate the course of congestive heart failure.