Cooper G J S, Young A A, Gamble G D, Occleshaw C J, Dissanayake A M, Cowan B R, Brunton D H, Baker J R, Phillips A R J, Frampton C M, Poppitt S D, Doughty R N
Level 4, School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Diabetologia. 2009 Apr;52(4):715-22. doi: 10.1007/s00125-009-1265-3. Epub 2009 Jan 27.
AIMS/HYPOTHESIS: Cu(II)-selective chelation with trientine ameliorates cardiovascular and renal disease in a model of diabetes in rats. Here, we tested the hypothesis that Cu(II)-selective chelation might improve left ventricular hypertrophy (LVH) in type 2 diabetic patients.
We performed a 12 month randomised placebo-controlled study of the effects of treatment with the Cu(II)-selective chelator trientine (triethylenetetramine dihydrochloride, 600 mg given orally twice daily) on LVH in diabetic patients (n = 15/group at baseline) in an outpatient setting wherein participants, caregivers and those assessing outcomes were blinded to group assignment. Using MRI, we measured left ventricular variables at baseline, and at months 6 and 12. The change from baseline in left ventricular mass indexed to body surface area (LVM(bsa)) was the primary endpoint variable.
Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVM(bsa) by 5.0 +/- 7.2 g/m(2) (mean +/- SD) at month 6 (when 14 trientine-treated and 14 placebo-treated participants were analysed; p = 0.0056 compared with placebo) and by 10.6 +/- 7.6 g/m(2) at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p = 0.0088), whereas LVM(bsa) was unchanged by placebo treatment. In a multiple-regression model that explained ~75% of variation (R (2) = 0.748, p = 0.001), cumulative urinary Cu excretion over 12 months was positively associated with trientine-evoked decreases in LVM(bsa).
CONCLUSIONS/INTERPRETATION: Cu(II)-selective chelation merits further exploration as a potential pharmacotherapy for diabetic heart disease.
Australian New Zealand Clinical Trials Registry ACTRN 12609000053224 FUNDING: The Endocore Research Trust; Lottery Health New Zealand; the Maurice and Phyllis Paykel Trust; the Foundation of Research, Science and Technology (New Zealand); the Health Research Council of New Zealand; the Ministry of Education (New Zealand) through the Maurice Wilkins Centre for Molecular Biodiscovery; and the Protemix Corporation.
目的/假设：在大鼠糖尿病模型中，曲恩汀对铜（II）的选择性螯合作用可改善心血管和肾脏疾病。在此，我们检验了铜（II）选择性螯合可能改善2型糖尿病患者左心室肥厚（LVH）这一假设。
我们进行了一项为期12个月的随机安慰剂对照研究，在门诊环境中，研究铜（II）选择性螯合剂曲恩汀（二盐酸三乙烯四胺，每日口服两次，每次600毫克）对糖尿病患者左心室肥厚的治疗效果（基线时每组15例）。参与者、护理人员和评估结果的人员均对分组情况不知情。使用磁共振成像（MRI），我们在基线时以及第6个月和第12个月测量左心室变量。以体表面积校正的左心室质量（LVM(bsa)）相对于基线的变化是主要终点变量。
糖尿病患者在基线时存在左心室肥厚且射血分数保留。曲恩汀治疗在第6个月时使LVM(bsa)降低了5.0±7.2 g/m²（平均值±标准差）（分析了14例接受曲恩汀治疗和14例接受安慰剂治疗的参与者；与安慰剂相比，p = 0.0056），在第12个月时降低了10.6±7.6 g/m²（分析了9例接受曲恩汀治疗和13例接受安慰剂治疗的参与者；p = 0.0088），而安慰剂治疗时LVM(bsa)无变化。在一个解释了约75%变异的多元回归模型中（R² = 0.748，p = 0.001），12个月内累积尿铜排泄量与曲恩汀引起的LVM(bsa)降低呈正相关。
结论/解读：铜（II）选择性螯合作为糖尿病性心脏病的一种潜在药物治疗方法值得进一步探索。
澳大利亚新西兰临床试验注册中心ACTRN 12609000053224 资助：Endocore研究信托基金；新西兰彩票健康基金；莫里斯和菲利斯·佩克尔信托基金；（新西兰）研究、科学与技术基金会；新西兰健康研究委员会；（新西兰）教育部通过莫里斯·威尔金斯分子生物发现中心；以及Protemix公司。
