Thr164Ile polymorphism of beta2-adrenergic receptor negatively modulates cardiac contractility: implications for prognosis in patients with idiopathic dilated cardiomyopathy.
BACKGROUND
Beta2-adrenergic receptor Thr164Ile (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.


OBJECTIVE
To investigate whether Thr164Ile 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 beta2-adrenergic receptor agonist terbutaline was assessed from the peak myocardial velocity of systolic shortening (Sm) in 18 subjects with the Ile-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 Ile-164 variant than in controls (Delta33% (4%) vs Delta56% (4%), p<0.01). In patients with heart failure, subjects with Ile-164 showed further severe reduction of beta2-adrenergic-mediated increase in Sm as compared with controls with heart failure (Delta20% (5%) vs Delta39% (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 beta2-adrenergic Thr164Ile polymorphism directly modulates adrenergic-mediated cardiac responses in patients with normal and failing myocardium. Furthermore, blunted beta2 adrenergic-mediated myocardial contractile response in patients with Ile-164 variant seems to adversely modulate the course of congestive heart failure.
Barbato
Emanuele
E
Molecular Biology and Cardiology Unit, Cardiovascular Center and Cardiovascular Research Center, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium.
Penicka
Martin
M
Delrue
Leen
L
Van Durme
Frederic
F
De Bruyne
Bernard
B
Goethals
Marc
M
Wijns
William
W
Vanderheyden
Marc
M
Bartunek
Jozef
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D013726:Terbutaline / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D013726:Terbutaline