Assessment of Metabolic Therapy for Acute Heart Failure

[摘要] ENGLISH ABSTRACT: IntroductionAcute heart failure (AHF) is the most common primary diagnosis for hospitalized heart disease cases in Africa. Increased fatty acid oxidation (FAO) with heart failure (HF) triggers detrimental effects on the myocardium, we hypothesized that diabetic rat hearts subjected to AHF display lower cardiac function vs. controls and that Trimetazidine (TMZ) (a partial FAO inhibitor) counters this effect.Aims1)To establish an ex vivo AHF model for diabetic hearts; 2) Assess whether TMZ treatmentoffers cardioprotection to diabetic rat hearts subjected to an AHF protocol; and 3) Delineate underlying mechanisms by evaluating markers for oxidative stress, mitochondrial uncoupling, apoptosis and metabolic dysregulation.MethodsVehicle control male Wistar rats were injected with citrate buffer. To induce diabetes rats were administered streptozotocin (60 mg/kg) for one week vs. non-diabetic controls. Hearts were perfused on the Langendorff retrograde perfusion system for three phases: Stabilization - (11 mM glucose- non-diabetic, and 30 mM glucose- diabetic hearts) at 100 cm H2O (30 min); AHF – (1.5 mM palmitic acid, 2.5 mM glucose) at 20 cm H2O (35 min); and Recovery– (1.5 mM palmitic acid, 11 mM glucose or 30 mM glucose) at 100 cm H2O (30 min). 1 μM TMZ was administered at the start of recovery. In addition, we evaluated necrosis and infarct size by tetrazolium (TTC) staining at the end of the AHF phase. Western blotting was performed for markers of apoptosis (pBAD/BAD), oxidative stress (superoxide dismutase 2 [SOD2], conjugated dienes [CDs], thiobarbituric acid reactive substances (TBARS), reduced/oxidized glutathione [GSH/GSSG] analysis, oxygen radical absorbance capacity [ORAC]), mitochondrial uncoupling (uncoupling protein 2 [UCP2]) and metabolic dysregulation (advanced glycation end product [AGE] and polyol pathway analyses). We investigated direct effects of TMZ (1 μM) in H9c2 cardiomyoblasts exposed to 500 μM palmitate for 21 hours and assessed the effects of TMZ treatment on fatty acid-induced oxidative stress and apoptosis.ResultsReduced function was seen for all groups in recovery vs. controls, while AHF-diabetic showed worse outcomes vs. AHF alone. TMZ treatment resulted in a robust increase in left ventricular developed pressure (LVDP) for diabetic hearts vs. controls. Infarct size assessment showed no differences. TMZ treated diabetic hearts also displayed lower AGE and higher polyol pathway activation vs. respective controls. However, several markers of the AGE pathway did not show any significant differences for any groups. Non-diabetic and diabetic hearts displayed increased oxidative stress (TBARS) compared to their counterparts. TMZ treatment resulted in anti-apoptotic effects in hearts subjected to AHF. TMZ exhibited antioxidant effects by lowering fatty acid-induced mitochondrial oxidative stress in cells.ConclusionThis study successfully established a novel ex vivo model of AHF for the diabetic rat heart, and TMZ treatment resulted in cardioprotection for diabetic hearts. Our data suggest that TMZ may mediate some of its cardioprotective effects by acting as an anti-oxidant to lower myocardial oxidative stress triggered during AHF. The findings also indicate that TMZ treatment may lower the formation of damaging AGEs in the diabetic heart. TMZ therefore, emerges as a putative therapeutic target to be considered as sole and/or combined treatment (with more conventional drugs) for AHF patients.

[发布机构] Stellenbosch University