Regitz-Zagrosek Vera, Hocher Berthold, Bettmann Martin, Brede Marc, Hadamek Kerstin, Gerstner Carolin, Lehmkuhl Hans Brendan, Hetzer Roland, Hein Lutz
DHZB, Augustenburger Platz 1, 13353 Berlin, Germany.
Eur Heart J. 2006 Feb;27(4):454-9. doi: 10.1093/eurheartj/ehi659. Epub 2005 Nov 18.
The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic alpha2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human alpha2C-adrenoceptor gene (alpha2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM).
We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% beta-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9 years) in event-free patients and 104 weeks (2 years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the alpha2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012).
Alpha2C-adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guidelines.
交感神经系统在心脏生长中起核心作用，但其过度刺激与慢性心力衰竭患者死亡率增加相关。突触前α2-肾上腺素能受体是控制去甲肾上腺素从交感神经释放的重要反馈调节因子。在本研究中，我们测试了人类α2C-肾上腺素能受体基因（α2CDel322 - 325）中的缺失多态性是否会影响扩张型心肌病（DCM）患者心力衰竭的进展。
从1994年开始，我们对德国心脏研究所心脏移植科的345例DCM患者进行了基因分型和表型分析。患者按照指南接受治疗（99%使用ACEI，76%使用β受体阻滞剂），并随访至2002年12月或直至首次发生事件[死亡、心脏移植或因危及生命的情况植入左心室辅助装置（LVAD）]。无事件患者的平均随访时间为249周（4.9年），发生事件患者的平均随访时间为104周（2年）。随访期间，51%的患者发生了事件：死亡（18%）、作为移植过渡植入LVAD（7%）或心脏移植（25%）。通过Kaplan - Meier分析，α2C-肾上腺素能受体中存在缺失变体Del322 - 325的DCM患者事件发生率显著降低（P = 0.0043）。Cox回归分析显示，缺失的存在与死亡率降低（相对风险：0.129，95%可信区间：0.18 - 0.9441，P = 0.044）和事件发生率降低（相对风险：0.167，95%可信区间：0.041 - 0.685，P = 0.012）相关。
α2C-肾上腺素能受体缺失可能是按照指南治疗的DCM患者事件发生率降低的一种新的、强有力的独立预测因子。
