Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure

Martín, Miguel; Gómez, Miguel Ángel; Guillén, F; Börnstein, Belén; Campos, Yolanda; Rubio, Juan Carlos Colomer; Calzada, Carlos Sáenz de la; Arenas, Joaquı́n

doi:10.1016/s0925-4439(00)00061-2

Cited by 54 publications

(29 citation statements)

References 29 publications

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“…A previous report examining total CPT activity showed low activity levels in patients with end-stage heart failure. 32 Gene expression analysis of mCPT-I and several enzymes involved in ␤-oxidation showed a coordinated decrease in these genes in the right ventricle from patients with pulmonary hypertension. 21 Previous studies using positron emission tomography found an accumulation of [ 11 C]palmitate in patients with congestive cardiomyopathy 33 and a reversion of this metabolic imprint when patients were treated with a ␤-blocker.…”

Section: Regulators Of Fatty Acid Metabolismmentioning

confidence: 99%

Metabolic Gene Expression in Fetal and Failing Human Heart

et al. 2001

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Background-Previous studies suggest that the failing heart reactivates fetal genes and reverts to a fetal pattern of energy substrate metabolism. We tested this hypothesis by examining metabolic gene expression profiles in the fetal, nonfailing, and failing human heart. Methods and Results-Human left ventricular tissue (apex) was obtained from 9 fetal, 10 nonfailing, and 10 failing adult hearts. Using quantitative reverse transcription-polymerase chain reaction, we measured transcript levels of atrial natriuretic factor, myosin heavy chain-␣ and -␤, and 13 key regulators of energy substrate metabolism, of which 3 are considered "adult" isoforms (GLUT4, mGS, mCPT-I) and 3 are considered "fetal" isoforms (GLUT1, lGS, and lCPT-I), primarily through previous studies in rodent models. Compared with the nonfailing adult heart, steady-state mRNA levels of atrial natriuretic factor were increased in both the fetal and the failing heart. The 2 myosin heavy chain isoforms showed the highest expression level in the nonfailing heart. Transcript levels of most of the metabolic genes were higher in the nonfailing heart than the fetal heart. Adult isogenes predominated in all groups and always showed a greater induction than the fetal isogenes in the nonfailing heart compared with the fetal heart. In the failing heart, the expression of metabolic genes decreased to the same levels as in the fetal heart. Conclusions-In the human heart, metabolic genes exist as constitutive and inducible forms. The failing adult heart reverts to a fetal metabolic gene profile by downregulating adult gene transcripts rather than by upregulating fetal genes.

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Section: Regulators Of Fatty Acid Metabolismmentioning

confidence: 99%

Metabolic Gene Expression in Fetal and Failing Human Heart

et al. 2001

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“…In mild to moderate HF, the expression and activity of metabolic enzymes are unchanged, further suggesting that metabolic abnormalities are a late phenomenon in HF [23]. In experimental models and in end-stage failing human heart, impaired myocardial FFA metabolism is accompanied by a downregulation of expression of several proteins [14,[24][25][26][27]. Ex vivo analysis also suggests that reversion to a fetal metabolic gene profile occurs mainly by repressing adult metabolic genes rather than reinducing fetal isogenes [26].…”

Section: Expression and Function Of Metabolic Proteins In Chronic Hfmentioning

confidence: 99%

Myocardial fatty acid metabolism and cardiac performance in heart failure

Tuunanen¹,

Ukkonen²,

Knuuti

2008

Curr Cardiol Rep

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It is well established that cardiac metabolism is abnormal in heart failure (HF). Experimental studies suggest that in severe HF, cardiac metabolism reverts to a more fetal-like substrate use characterized by enhanced glucose and downregulated free fatty acid (FFA) metabolism. Correspondingly, in humans, when FFA levels are similar, myocardial glucose metabolism is increased, and FFA metabolism is decreased. However, depression of left ventricular function and insulin resistance induces a shift back to greater FFA uptake and oxidation by increasing circulating FFA availability. Myocardial insulin resistance may further impair myocardial glucose uptake and lead to an energy depletion state. Experimental and preliminary clinical studies suggest that metabolic modulators enhancing myocardial glucose oxidation may improve cardiac function in patients with chronic HF. However, it has been found that acute FFA deprivation is harmful to the cardiac performance. Optimizing myocardial energy metabolism may serve as an additional approach for managing HF, but further studies are warranted.

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“…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).…”

mentioning

confidence: 99%

Chronic Activation of Peroxisome Proliferator-Activated Receptor-α with Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype without Changing the Onset of Decompensation in Pacing-Induced Heart Failure

Labinskyy¹,

Bellomo²,

Chandler³

et al. 2007

J Pharmacol Exp Ther

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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

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Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure

Cited by 54 publications

References 29 publications

Metabolic Gene Expression in Fetal and Failing Human Heart

Metabolic Gene Expression in Fetal and Failing Human Heart

Myocardial fatty acid metabolism and cardiac performance in heart failure

Chronic Activation of Peroxisome Proliferator-Activated Receptor-α with Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype without Changing the Onset of Decompensation in Pacing-Induced Heart Failure

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