Abstract
BackgroundDefective 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.MethodsTo 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.ResultsAfter 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).ConclusionsTrientine 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.
Highlights
Cardiovascular disease is the leading cause of morbidity and mortality in diabetes, but effective treatments for established heart failure in diabetes are limited [1,2,3]
We have previously identified a pathogenetic disorder of copper regulation that occurs in both type-1 diabetes (T1DM) and T2DM [5,6], and have shown that it is a probable cause of the cardiovascular and renal complications of diabetes [5,7,8,9] and a new target for pharmacological intervention [5,6,10]
Effects of diabetes and trientine treatment on blood glucose and body-weight Work-flows were as shown in Figure 1 and data and statistical analysis as summarized in Tables 1, 2, 3, 4
Summary
Cardiovascular disease is the leading cause of morbidity and mortality in diabetes, but effective treatments for established heart failure in diabetes are limited [1,2,3]. The prognosis of heart failure is poor in patients with type-2 diabetes (T2DM)a, the most common form of this disease [4] This poor prognosis persists in spite of best available treatment with existing classes of medications including glucose-lowering, antihypertensive, and lipid-lowering drugs, as well as betablockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) amongst others. We have shown that trientine (triethylenetetramine dihydrochloride) [10], acts in vivo as a Cu(II)-selective chelator that can prevent or ameliorate cardiovascular and renal disease in diabetic rats [5,8,11]. A divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it ameliorates left-ventricular (LV) hypertrophy. Direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking
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