Low-dose copper infusion into the coronary circulation induces acute heart failure in diabetic rats: New mechanism of heart disease

• Published in: Biochemical pharmacology Vol. 97; no. 1; pp. 62 - 76
• Main Authors: Cheung, Carlos Chun Ho, Soon, Choong Yee, Chuang, Chia-Lin, Phillips, Anthony R.J., Zhang, Shaoping, Cooper, Garth J.S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.09.2015
• Subjects: Animals; Cardiac failure; Cardiac Output - drug effects; Chelating Agents - pharmacology; Copper - administration & dosage; Copper - blood; Coronary arteries; Coronary Circulation - drug effects; Coronary vasoconstriction; Coronary Vessels - drug effects; Coronary Vessels - physiopathology; Diabetes Mellitus, Experimental - complications; Diabetic Cardiomyopathies - blood; Diabetic Cardiomyopathies - etiology; Diabetic Cardiomyopathies - physiopathology; Diabetic Cardiomyopathies - prevention & control; Diabetic cardiomyopathy; Diastolic dysfunction; Heart - drug effects; Heart - physiopathology; Heart Failure - blood; Heart Failure - complications; Heart Failure - etiology; Heart Failure - physiopathology; In Vitro Techniques; Infusions, Intra-Arterial; Left-ventricular dysfunction; Male; Models, Biological; Perfusion; Rats, Wistar; Stroke Volume - drug effects; Up-Regulation - drug effects; Vascular Resistance - drug effects; Vasoconstriction - drug effects; Ventricular Dysfunction, Left - blood; Ventricular Dysfunction, Left - complications; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - physiopathology; Left-ventricular dysfunction; CI; Cu2+ (aq); Cardiac failure; LMEM; ECM; DCM; CuII; REML; CuI; Diabetic cardiomyopathy; Diastolic dysfunction; SEM; Coronary vasoconstriction; Coronary arteries
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2015.06.027

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=0ml/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.