Treatment with a copper-selective chelator causes substantive improvement in cardiac function of diabetic rats with left-ventricular impairment.
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.
School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Jun
J
Lu
Beau
B
Pontré
Stephen
S
Pickup
Soon Y
SY
Choong
Mingming
M
Li
Hong
H
Xu
Gregory D
GD
Gamble
Anthony R J
AR
Phillips
Brett R
BR
Cowan
Alistair A
AA
Young
Garth J S
GJ
Cooper
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003300:Copper; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006334:Heart Function Tests; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D014266:Trientine / Q000494:pharmacology / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology
D002614:Chelating Agents; D003300:Copper; D014266:Trientine