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Regeneration of the Heart in Diabetes by Selective Copper Chelation

¹ School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
² Department of Medicine, University of Auckland, Auckland, New Zealand
³ South Auckland Diabetes Service, Middlemore Hospital, Otahuhu, New Zealand
⁴ Department of Anatomy with Radiology, University of Auckland, Auckland, New Zealand
⁵ Department of Cardiology, Greenlane Hospital, Auckland, New Zealand
⁶ Department of Chemistry, Faculty of Science, University of Auckland, Auckland, New Zealand
⁷ Department of Physiology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
⁸ Department of Developmental Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu^II-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and ß₁ integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

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