醛脱氢酶2（ALDH2）Glu504Lys多态性对慢性心力衰竭中硝酸甘油反应的影响及降钙素基因相关肽（CGRP）的参与

Influence of ALDH2 Glu504Lys polymorphism on nitroglycerin response in chronic heart failure and involvement of Calcitonin Gene Related Peptide (CGRP).

作者信息

Peng Li-Ming, Chen Xiao-Ping, Sun Ji, Guo Yi-Jie, Li Ling, Mo Long, Xie Wei, Li Yuan-Jian, Yang Tian-Lun, Li Chuan-Chang

机构信息

Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha, Hunan, China.

出版信息

Int J Clin Pharmacol Ther. 2012 Oct;50(10):701-11. doi: 10.5414/CP201635.

DOI:10.5414/CP201635

PMID:22909898

Abstract

OBJECTIVE

The aim of this study was to investigate whether the neuropeptide calcitonin gene related peptide (CGRP) contributes to nitroglycerin (GTN) response in patients with chronic heart failure (CHF) and the association with the mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys (ALDH2*2) polymorphism.

METHODS

This is a 2-period, placebo-controlled clinical study. An intravenous infusion of saline followed by GTN (20 μg/min), each for 2 hours, respectively, was given to 49 stable CHF patients. Blood pressure (BP), heart rate (HR) and respiratory rate (RR) were measured at baseline, at 10 min, 30 min, 1.0 h, 1.5 h, and 2.0 h after initiation of saline infusion and initiation of GTN therapy. Blood samples were drawn for the determination of plasma CGRP for 49 patients at baseline, and at 2.0 h after initiation of saline and GTN infusion, respectively. Global clinical status of the patients was evaluated. Left ventricular ejection (LVEF), left ventricular end-diastolic volume (LVEDV), stroke volume (SV) and cardiac output (CO) were measured with 2D echocardiography with Simpson's biplane method (Pillip HP sonos 5500) by the same investigator at baseline and at 2.0 h after initiation of saline and GTN infusion.

RESULTS

Systolic blood pressure (SBP), diastolic blood pressure (DBP), and left ventricular end-diastolic volume (LVEDV) were decreased, while left ventricular ejection fraction (LVEF) was increased at the end of GTN infusion (p < 0.001, respectively). Saline infusion showed no hemodynamic effects. At the end of GTN infusion, ALDH2*1/1 homozygous patients showed higher degrees of both the absolute decrease in SBP (DSBP) (p < 0.001) and increase in LVEF (p < 0.001) than carriers of the ALDH22 allele. Mean plasma concentration of CGRP was increased after GTN infusion (p < 0.001), but not changed after saline infusion (p > 0.05). Changes in plasma concentration of CGRP correlated positively with the improvement in LVEF (r = 0.400, p = 0.004), while correlated negatively with changes in SBP (r = -0.300, p = 0.036) and LVEDV (r = -0.290, p = 0.043).

CONCLUSIONS

ALDH2*2 polymorphism is associated with contributions of CGRP to GTN response in CHF patients.

摘要

目的

本研究旨在探讨神经肽降钙素基因相关肽（CGRP）是否对慢性心力衰竭（CHF）患者的硝酸甘油（GTN）反应有影响，以及与线粒体乙醛脱氢酶-2（ALDH2）Glu504Lys（ALDH2*2）多态性的关联。

方法

这是一项为期2个阶段的安慰剂对照临床研究。对49例病情稳定的CHF患者分别静脉输注生理盐水2小时，随后静脉输注GTN（20μg/分钟）2小时。在输注生理盐水和GTN治疗开始后的基线、10分钟、30分钟、1.0小时、1.5小时和2.0小时测量血压（BP）、心率（HR）和呼吸频率（RR）。分别在基线以及输注生理盐水和GTN开始后2.0小时采集49例患者的血样，用于测定血浆CGRP。评估患者的整体临床状况。由同一位研究者在基线以及输注生理盐水和GTN开始后2.0小时，采用二维超声心动图的Simpson双平面法（Pillip HP sonos 5500）测量左心室射血分数（LVEF）、左心室舒张末期容积（LVEDV）、每搏输出量（SV）和心输出量（CO）。

结果

GTN输注结束时，收缩压（SBP）、舒张压（DBP）和左心室舒张末期容积（LVEDV）降低，而左心室射血分数（LVEF）升高（p均<0.001）。输注生理盐水未显示血流动力学效应。GTN输注结束时，ALDH2*1/1纯合子患者的SBP绝对下降幅度（DSBP）（p<0.001）和LVEF升高幅度均高于ALDH22等位基因携带者（p<0.001）。GTN输注后血浆CGRP的平均浓度升高（p<0.001），但输注生理盐水后未改变（p>0.05）。血浆CGRP浓度的变化与LVEF的改善呈正相关（r = 0.400，p = 0.004），而与SBP的变化（r = -0.300，p = 0.036）和LVEDV的变化（r = -0.290，p = 0.043）呈负相关。