Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure

Abstract

Recchia FA. Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure. Am J Physiol Heart Circ Physiol 295: H2098 -H2105, 2008. First published September 26, 2008 doi:10.1152/ajpheart.00471.2008.-When recovering from heart failure (HF), the myocardium displays a marked plasticity and can regain normal gene expression and function; however, recovery of substrate oxidation capacity has not been explored. We tested whether cardiac functional recovery is matched by normalization of energy substrate utilization during post-HF recovery. HF was induced in dogs by pacing the left ventricle (LV) at 210 -240 beats/min for 4 wk. Tachycardia was discontinued, and the heart was allowed to recover. An additional group was studied in HF, and healthy dogs served as controls (n ϭ 8/group). Cardiac free fatty acids (FFAs) and glucose oxidation were measured with [ 3 H]oleate and [ 14 C]glucose. At 10 days of recovery, hemodynamic parameters returned to control values; however, the contractile response to dobutamine remained depressed, LV end-diastolic volume was 28% higher than control, and the heart mass-to-body mass ratio was increased (9.8 Ϯ 0.4 vs. 7.5 Ϯ 0.2 g/kg, P Ͻ 0.05). HF increased glucose oxidation (76.8 Ϯ 19.7 nmol ⅐ min Ϫ1 ⅐ g Ϫ1 ) and decreased FFA oxidation (20.7 Ϯ 6.4 nmol ⅐ min Ϫ1 ⅐ g Ϫ1 ), compared with normal dogs (24.5 Ϯ 6.3 and 51.7 Ϯ 9.6 nmol ⅐ min Ϫ1 ⅐ g Ϫ1 , respectively), and reversed to normal values at 10 days of recovery (25.4 Ϯ 6.0 and 46.6 Ϯ 6.7 nmol ⅐ min Ϫ1 ⅐ g Ϫ1 , respectively). However, similar to HF, the recovered dogs failed to increase glucose and fatty acid uptake in response to pacing stress. The activity of myocardial citrate synthase and aconitase was significantly decreased during recovery compared with that in control dogs (58 and 27% lower, respectively, P Ͻ 0.05), indicating a persistent reduction in mitochondrial oxidative capacity. In conclusion, cardiac energy substrate utilization is normalized in the early stage of post-HF recovery at baseline, but not under stress conditions. dilated cardiomyopathy; fatty acids; glucose; tachypacing THE CAPACITY OF THE FAILING heart to recover and restore, at least in part, a normal structure and function has been well demonstrated, both in animal models (12,13,26,28) and in patients (3,25). In pacing-induced heart failure (HF), an established model of dilated cardiomyopathy, hemodynamic and neurohormonal alterations, as well as myocyte function, return to control level within the first 2 wk of recovery after discontinuation of cardiac stimulation (28). Moreover, a number of studies have been performed in end-stage HF patients sustained with mechanical left ventricular (LV) assist devices while awaiting cardiac transplantation. The availability of ventricular tissue samples collected during the procedures of assist device implantation and removal has stimulated a strong interest in the molecular and cellular alterations occurring before and after mechanical unloading. Mechanical assistance favors reverse remodeling at...

Chronic heart failure selectively induces regional heterogeneity of insulin-responsive glucose transporters

“…Therefore, we used a model that maintains LV dysfunction at stimulation rates that are closer to normal ranges for conscious dogs and that induced a progressive development of HF. In addition, we previously demonstrated that 16 wk of RV tachypacing induced irreversible systolic dysfunction (up to 7 wk after termination of pacing), which is in contrast with previous reports of canine tachypacing models (23,30). Further experiments are required to determine the effect of the duration of HF on the regulation of myocardial glucose transport.…”

“…emic dilated cardiomyopathy, a switch of substrate selection toward glucose oxidation remains controversial, as several studies reported increased, unchanged, or decreased glucose uptake in the failing heart (12,13,16,17,20,23,26,31). In particular, there is recent evidence suggesting that chronic HF may promote metabolic changes, such as insulin resistance resulting in decreased glucose uptake and utilization (1,17,37).…”

Metabolic adaptation to chronic hypoxia in cardiac mitochondria

“…The decrease in aconitase was independent of a decrease in protein content, indicating that regulation of aconitase in hypoxia was likely via post-translational regulation. Downregulation of aconitase activity has also been identified in heart failure, suggesting a common signalling pathway (potentially via HIF) or conserved enzyme target [41]. In certain cell lines and genetic models, changes in aconitase have been linked to upstream changes in the iron-sulphur cluster assembly protein ISCU and frataxin [6,14,36].…”

Myocyte repolarization modulates myocardial function in aging dogs

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