In the failing heart, NADPH oxidase and uncoupled NO synthase utilize cytosolic NADPH to form superoxide. NADPH is supplied principally by the pentose phosphate pathway, whose rate-limiting enzyme is glucose 6-phosphate dehydrogenase (G6PD). Therefore, we hypothesized that cardiac G6PD activation drives part of the excessive superoxide production implicated in the pathogenesis of heart failure. Pacing-induced heart failure was performed in eight chronically instrumented dogs. Seven normal dogs served as control. End-stage failure occurred after 28 +/- 1 days of pacing, when left ventricular end-diastolic pressure reached 25 mm Hg. In left ventricular tissue homogenates, spontaneous superoxide generation measured by lucigenin (5 microM) chemiluminescence was markedly increased in heart failure (1338 +/- 419 vs. 419 +/- 102 AU/mg protein, P < 0.05), as were NADPH levels (15.4 +/- 1.5 vs. 7.5 +/- 1.5 micromol/gww, P < 0.05). Superoxide production was further stimulated by the addition of NADPH. The NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and the NO synthase inhibitor L-NAME (1 mM) both significantly lowered superoxide generation in failing heart homogenates by 80% and 76%, respectively. G6PD was upregulated and its activity higher in heart failure compared to control (0.61 +/- 0.10 vs. 0.24 +/- 0.03 nmol/min/mg protein, P < 0.05), while superoxide production decreased to normal levels in the presence of the G6PD inhibitor 6-aminonicotinamide. We conclude that the activation of myocardial G6PD is a novel mechanism that enhances NADPH availability and fuels superoxide-generating enzymes in heart failure.

Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-␣, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of highfrequency left ventricular pacing (HF ϩ Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. Feno (14.1 Ϯ 1.6 mm Hg) compared with HF (18.7 Ϯ 1.3 mm Hg), but it increased up to 25 Ϯ 2 mm Hg, indicating end-stage failure, in both groups after 29 Ϯ 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA ␤-oxidation pathway, was reduced in HF versus control (1.46 Ϯ 0.25 versus 2.42 Ϯ 0.24 mol/min/gram wet weight (gww); p Ͻ 0.05) but not in HF ϩ Feno (1.85 Ϯ 0.18 mol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation.The cardiac metabolic phenotype undergoes profound alterations during heart failure (HF), including defective energy production, lower mechanical efficiency, and a partial shift in energy substrate use . Oxidation of free fatty acids (FFA), which constitutes the preferential energy source for the normal heart, decreases in overt heart failure, whereas glucose oxidation markedly increases. The mechanisms underlying this phenomenon are numerous and complex. There is reduced myocardial expression and activity of key enzymes of the FFA oxidative pathway in different models of human as well as experimental heart failure (Sack et al., 1996;Martin et al., 2000;Rosenblatt et al., 2001;Osorio et al., 2002). The expression of these enzymes is under the control of the peroxisome proliferator-activated receptor (PPAR)-␣ and retinoid X receptor-␣ nuclear receptors that were also found down-regulated in the failing heart (Osorio et al., 2002;Karbowska et al., 2003). Whether such alterations in substrate metabolism play a role in the pathophysiological progression of heart failure remains an open question, with obvious implications for new therapeutic strategies based on metabolic modulators . It has

Nitric oxide (NO) inhibits myocardial glucose transport and metabolism, although the underlying mechanism(s) and functional consequences of this effect are not clearly understood. We tested the hypothesis that NO inhibits the activation of AMP-activated protein kinase (AMPK) and translocation of cardiac glucose transporters (GLUTs; GLUT-4) and reduces lactate production. Ischemia was induced in open-chest dogs by a 66% flow reduction in the left anterior descending coronary artery (LAD). During ischemia, dogs were untreated (control) or treated by direct LAD infusion of (i) nitroglycerin (NTG) (0.5 g⅐kg ؊1 ⅐min ؊1 ); (ii) 8-Br-cGMP (50 g⅐kg ؊1 ⅐min ؊1 ); or (iii) NO synthase inhibitor L-nitro-argininemethylester (40 g⅐kg ؊1 ⅐min ؊1 ; n ‫؍‬ 9 per group). Cardiac substrate oxidation was measured with isotopic tracers. There were no differences in myocardial blood flow or oxygen delivery among groups; however, at 45 min of ischemia, the activation of AMPK was significantly less in NTG (77 ؎ 12% vs. nonischemic myocardium) and 8-Br-cGMP (104 ؎ 13%), compared with control (167 ؎ 17%). Similarly, GLUT-4 translocation was significantly reduced in NTG (74 ؎ 7%) and 8-Br-cGMP (120 ؎ 11%), compared with control (165 ؎ 17%). Glucose uptake and lactate output were 30% and 60% lower in NTG compared with control. Inhibition of NO synthesis stimulated glucose oxidation (67% increase compared with control) but did not affect AMPK phosphorylation, GLUT-4 translocation and glucose uptake. Contractile function in the ischemic region was significantly improved by NTG and L-nitro-argininemethylester. In conclusion, in ischemic myocardium an NO donor inhibits glucose uptake and lactate production via a reduction in AMPK stimulation of GLUT-4 translocation, revealing a mechanism of metabolic modulation and myocardial protection activated by NO donors.heart ͉ ischemia ͉ metabolism N itric oxide (NO) affects myocardial substrate utilization, exerting an inhibitory action on myocardial glucose uptake and metabolism, although the underlying mechanisms and functional implications of this effect, in vivo, remain poorly understood. Exogenous NO, by means of its second messenger cGMP, inhibits glucose uptake and utilization in ischemic (1) as well as nonischemic isolated hearts (2) and in quiescent myocytes (3). Endogenous NO is likely to be responsible for a tonic inhibition of cardiac carbohydrate metabolism, as indicated by the marked elevation of glucose uptake, under basal conditions, in isolated hearts from endothelial NO synthase (NOS) knockout mice (4). This effect is not peculiar to in vitro preparations, because NOS blockade enhances cardiac glucose uptake and oxidation and reduces free fatty acid (FFA) utilization in conscious dogs (5, 6). Notably, NO synthesis increases in ischemic myocardium (7,8); however, the metabolic effects of endogenous NO under this pathological condition remain unclear.During ischemia, glucose uptake and glycolytic flux are markedly accelerated and assume a critical role in preserving myocyte function (9-...

Acute inhibition of nitric oxide (NO) synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1) po) for 10 days to inhibit NO synthesis, and seven were used as controls. Cardiac free fatty acid, glucose, and lactate oxidation were measured by infusion of [(3)H]oleate, [(14)C]glucose, and [(13)C]lactate, respectively. After 10 days of L-NAME administration, despite no differences in left ventricular afterload, cardiac O(2) consumption was significantly increased by 30%, consistent with a marked enhancement in baseline oxidation of glucose (6.9 +/- 2.0 vs. 1.7 +/- 0.5 micromol.min(-1).100 g(-1), P < 0.05 vs. control) and lactate (21.6 +/- 5.6 vs. 11.8 +/- 2.6 micromol.min(-1).100 g(-1), P < 0.05 vs. control). When left ventricular afterload was increased by ANG II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the L-NAME than in the control group, whereas free fatty acid oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 micromol.kg(-1).min(-1) iv) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase activity and protein expression were higher (38 and 34%, respectively) in the L-NAME than in the control group. Also, protein expression of the constitutively active glucose transporter GLUT-1 was significantly elevated (46%) vs. control. We conclude that prolonged NO deficiency causes a profound alteration in cardiac metabolic phenotype, characterized by selective potentiation of carbohydrate oxidation, that cannot be reversed by a short-term infusion of exogenous NO. This phenomenon may constitute an adaptive mechanism to counterbalance cardiac mechanical inefficiency.

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direct comparison of information derived from these databases, it is critical that these differences be taken into account in making policy decisions and guidelines based on these data repositories.

Coronary subclavian steal syndrome is a rare but important condition that occurs after a left internal mammary artery (LIMA) to coronary artery bypass in the setting of a stenotic left subclavian artery. The lack of blood flow through the subclavian artery causes the reversal of flow in the LIMA so that it essentially steals blood from the myocardium. In order to avoid this complication, many surgeons now opt to either revascularize the stenotic subclavian artery prior to coronary artery bypass grafting or to use an alternate vessel as the bypass graft. Here, we present the case of an asymptomatic patient with poor exercise tolerance who was recently diagnosed with both triple-vessel coronary disease and peripheral arterial disease, which was most notably characterized by occlusion of the left subclavian artery. This case demonstrates the surgical management of this complex clinical entity.

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