β2-肾上腺素能受体的Thr164Ile多态性对心脏收缩力具有负向调节作用：对特发性扩张型心肌病患者预后的影响。
Thr164Ile polymorphism of beta2-adrenergic receptor negatively modulates cardiac contractility: implications for prognosis in patients with idiopathic dilated cardiomyopathy.
作者信息
Barbato Emanuele, Penicka Martin, Delrue Leen, Van Durme Frederic, De Bruyne Bernard, Goethals Marc, Wijns William, Vanderheyden Marc, Bartunek Jozef
机构信息
Molecular Biology and Cardiology Unit, Cardiovascular Center and Cardiovascular Research Center, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium.
出版信息
Heart. 2007 Jul;93(7):856-61. doi: 10.1136/hrt.2006.091959.
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.
OBJECTIVES
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.
背景
β2肾上腺素能受体苏氨酸164异亮氨酸多态性（第164位密码子处的苏氨酸（Thr）被异亮氨酸（Ile）取代）被推测与充血性心力衰竭患者运动耐量降低及预后不良有关。然而，心力衰竭与β受体信号传导的多种异常有关，其潜在机制尚不清楚。
目的
研究苏氨酸164异亮氨酸多态性是否对心肌收缩性能产生负性调节作用，并与充血性心力衰竭患者的不良长期预后相关。
方法
在55名受试者中，通过测量18名携带异亮氨酸164变体的受试者和37名匹配对照者的心肌收缩期缩短峰值速度（Sm），评估对β2肾上腺素能受体激动剂特布他林的心脏收缩反应。共有24名受试者左心室（LV）功能正常，31名因特发性扩张型心肌病出现充血性心力衰竭。
结果
在左心室功能正常的患者中，携带异亮氨酸164变体的受试者特布他林诱导的Sm峰值增加（Δ）低于对照组（Δ33%（4%）对Δ56%（4%），p<0.01）。在心力衰竭患者中，与心力衰竭对照组相比，携带异亮氨酸164的受试者β2肾上腺素能介导的Sm增加进一步严重降低（Δ20%（5%）对Δ39%（4%），p<0.05）。携带异亮氨酸164的心力衰竭患者对激动剂刺激的力-频率关系严重钝化。在2年的随访中，携带异亮氨酸164变体的心力衰竭患者不良事件发生率高于心力衰竭对照组（75%（6/8）对30%（7/23），p<0.05）。
结论
β2肾上腺素能苏氨酸164异亮氨酸多态性直接调节正常和衰竭心肌患者的肾上腺素能介导的心脏反应。此外，携带异亮氨酸164变体的患者β2肾上腺素能介导的心肌收缩反应钝化似乎对充血性心力衰竭的病程产生不利影响。
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