title: Low-dose copper infusion into the coronary circulation induces acute heart failure in diabetic rats: New mechanism of heart disease.
abstract: Diabetes impairs copper (Cu) regulation, causing elevated serum Cu and urinary Cu excretion in patients with established cardiovascular disease; it also causes cardiomyopathy and chronic cardiac impairment linked to defective Cu homeostasis in rats. However, the mechanisms that link impaired Cu regulation to cardiac dysfunction in diabetes are incompletely understood. Chronic treatment with triethylenetetramine (TETA), a Cu²⁺-selective chelator, improves cardiac function in diabetic patients, and in rats with heart disease; the latter displayed ∼3-fold elevations in free Cu²⁺ in the coronary effluent when TETA was infused into their coronary arteries. To further study the nature of defective cardiac Cu regulation in diabetes, we employed an isolated-perfused, working-heart model in which we infused micromolar doses of Cu²⁺ into the coronary arteries and measured acute effects on cardiac function in diabetic and non-diabetic-control rats. Infusion of CuCl₂ solutions caused acute dose-dependent cardiac dysfunction in normal hearts. Several measures of baseline cardiac function were impaired in diabetic hearts, and these defects were exacerbated by low-micromolar Cu²⁺ infusion. The response to infused Cu²⁺ was augmented in diabetic hearts, which became defective at lower infusion levels and underwent complete pump failure (cardiac output = 0 ml/min) more often (P < 0.0001) at concentrations that only moderately impaired function of control hearts. To our knowledge, this is the first report describing the acute effects on cardiac function of pathophysiological elevations in coronary Cu²⁺. The effects of Cu²⁺ infusion occur within minutes in both control and diabetic hearts, which suggests that they are not due to remodelling. Heightened sensitivity to the acute effects of small elevations in Cu²⁺ could contribute substantively to impaired cardiac function in patients with diabetes and is thus identified as a new mechanism of heart disease.
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Carlos Chun Ho
authors.initials: CC
authors.lastname: Cheung
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Choong Yee
authors.initials: CY
authors.lastname: Soon
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Chuang
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Anthony R J
authors.initials: AR
authors.lastname: Phillips
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, The University of Auckland, Auckland, New Zealand.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre for Molecular BioDiscovery, Faculty of Science, The University of Auckland, Auckland, New Zealand; Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK; The Centre for Advanced Discovery and Experimental Therapeutics, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK; The Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK. Electronic address: g.cooper@auckland.ac.nz.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000008:administration & dosage / Q000097:blood*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000097:blood / Q000150:complications / Q000209:etiology* / Q000503:physiopathology; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D017208:Rats, Wistar; D013318:Stroke Volume / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000150:complications / Q000209:etiology / Q000503:physiopathology
chemical_list: D002614:Chelating Agents; D003300:Copper; C029892:cupric chloride
keywords: Cardiac failure; Coronary arteries; Coronary vasoconstriction; Diabetic cardiomyopathy; Diastolic dysfunction; Left-ventricular dysfunction