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Open Access Original investigation

Treatment with a copper-selective chelator causes substantive improvement in cardiac function of diabetic rats with left-ventricular impairment

Jun Lu18, Beau Pontré34, Stephen Pickup7, Soon Y Choong1, Mingming Li1, Hong Xu9, Gregory D Gamble5, Anthony RJ Phillips126, Brett R Cowan34, Alistair A Young34 and Garth JS Cooper11011122*

Author Affiliations

1 School of Biological Sciences, University of Auckland, Auckland, New Zealand

2 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand

3 Centre for Advanced MRI, University of Auckland, Auckland, New Zealand

4 Department of Physiology, University of Auckland, Auckland, New Zealand

5 Department of Medicine, University of Auckland, Auckland, New Zealand

6 Department of Surgery, University of Auckland, Auckland, New Zealand

7 Small Animal Imaging Facility, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

8 Department of Interdisciplinary Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand

9 College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen, Guangdong Province, Peoples’ Republic of China

10 Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, University of Manchester, Manchester, M13 9PT, United Kingdom

11 School of Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom

12 Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, United Kingdom

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Cardiovascular Diabetology 2013, 12:28  doi:10.1186/1475-2840-12-28

Published: 31 January 2013

Abstract

Background

Defective copper regulation is implicated as a causative mechanism of organ damage in diabetes. Treatment with trientine, a divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it also ameliorates left-ventricular (LV) hypertrophy. However, direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking.

Methods

To determine whether trientine treatment could improve in vivo outcome, we measured cardiac function in groups of trientine-treated diabetic (TETA-DIA), non-drug-treated diabetic (DIA) and sham-treated control (SHAM) rats, by using in vivo high-field cardiac magnetic-resonance imaging (cMRI) and an ex vivo isolated-perfused working heart method. Forty age-matched animals underwent a cMRI scan after which 12 were randomized to the SHAM group and 28 underwent streptozotocin-injection; of these, 25 developed stable diabetes, and 12 were then randomized to receive no treatment for 16 weeks (DIA) and the other 13 to undergo 8-weeks’ untreated diabetes followed by 8-weeks’ drug treatment (TETA-DIA). Animals were studied again by cMRI at 8 and 16 weeks following disease induction, and finally by measurement of ex vivo cardiac function.

Results

After eight weeks diabetes, rats (DIA/TETA-DIA) had developed significant impairment of LV function, as judged by impairment of ejection fraction (LVEF), cardiac output (CO), and LV mass (LVM)/body-mass (all P < 0.001), as well as other functional indexes. LVEF, CO (both P < 0.001) and the other indexes deteriorated further at 16 weeks in DIA, whereas trientine (TETA-DIA) improved cardiac function by elevating LVEF and CO (both P < 0.001), and also partially reversed the increase in LVM/body-mass (P < 0.05). In ex vivo hearts from DIA, the CO response to increasing preload pressure was deficient compared with SHAM (P < 0.001) whereas the preload-CO relationship was significantly improved in TETA-DIA animals (P < 0.001).

Conclusions

Trientine treatment significantly improved cardiac function in diabetic rats with substantive LV impairment. These results implicate impaired copper regulation in the pathogenesis of impaired cardiac function caused by diabetic cardiomyopathy, and support ongoing studies of trientine treatment in patients with heart failure.

Keywords:
Heart failure; Cardiovascular disease; Cardiac output; Complications of diabetes; Diabetic cardiomyopathy; Diastolic function; Cardiac magnetic resonance imaging; Left-ventricular ejection fraction; Left-ventricular end systolic volume; Left-ventricular end diastolic volume; Selective copper chelation; Systolic function; Experimental therapeutics