The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Rupp, Heinz; Zarain‐Herzberg, Ángel; Maisch, Bernhard

doi:10.1007/s00059-002-2428-x

Cited by 88 publications

(78 citation statements)

References 145 publications

(183 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here, WY-14,643 feeding, alone or with etomoxir, increased both cardiac UCP2 and UCP3 protein levels in wild-type but not PPAR␣ Ϫ/Ϫ mice. Etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase-1 originally developed for treating type 2 diabetes (34), has no acute cardiovascular effects in rats, as shown by unaltered heart rate and blood pressure (35). Etomoxir feeding increases cardiac lipid droplet number (36) and, due to systemic inhibition of ␤-oxidation, increases plasma FFA levels (22,37).…”

Section: Discussionmentioning

confidence: 99%

Plasma Free Fatty Acids and Peroxisome Proliferator–Activated Receptor α in the Control of Myocardial Uncoupling Protein Levels

et al. 2005

View full text Add to dashboard Cite

Diabetic patients have abnormal cardiac energy metabolism associated with high plasma free fatty acid (FFA) concentrations. We investigated whether high plasma FFAs increase mitochondrial uncoupling protein (UCP) levels in the mouse heart by activating the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR)␣. We used Western blotting to measure UCP protein levels in isolated cardiac mitochondria from PPAR␣ T he phosphocreatine (PCr)-to-ATP ratio, an index of myocardial energetic status, has been shown to correlate negatively with plasma free fatty acid (FFA) concentrations in patients with type 2 diabetes (1), but the cellular link between energy metabolism and circulating FFA concentrations has yet to be defined. Conditions that increase plasma FFA levels, such as high-fat feeding, fasting, and streptozotocin (STZ)-induced diabetes, increase cardiac and skeletal muscle mitochondrial uncoupling protein (UCP)3 levels in the rat (2-5). A positive correlation between circulating FFA concentrations and both UCP2 and UCP3 protein levels occurs in human heart (6), suggesting that plasma FFAs may control UCP levels in the heart. The UCPs are believed to dissipate the proton electrochemical gradient by allowing protons to reenter the mitochondrial matrix without the concomitant synthesis of ATP (7).Long-chain FFAs are natural ligands for the peroxisome proliferator-activated receptors (PPARs) (8 -10), and the UCP genes have PPAR response elements in their promoter regions (11,12). Thus, plasma FFAs control cardiac UCP levels via PPAR activation. The PPAR␣ link has been shown by decreased UCP3 mRNA levels in the PPAR␣ Ϫ/Ϫ mouse heart and increased UCP3 mRNA levels in rat heart after treatment with the specific PPAR␣ agonist, WY-14,643 (5). Most studies of changes in cardiac UCPs, associated with alterations in circulating metabolite concentrations, have reported UCP mRNA levels (5,10,13,14), yet UCP mRNA and protein do not necessarily change in parallel (15,16).Studies in brown adipose tissue (15,16) and gastrocnemius muscle (16) have demonstrated that dramatic changes in levels of UCP2 or UCP3 transcripts were translated to much smaller changes, or no significant changes, at the protein level. Dietary conjugated linoleic acid was found to increase skeletal muscle UCP3 protein in mice, despite unchanged UCP3 mRNA levels (17). These findings indicate complex posttranslational control of UCP levels and expose a limitation in the conclusions drawn from studies that have demonstrated changes only in UCP mRNA. Furthermore, changes in mRNA are not necessarily concordant between studies; for example, treatment with WY-14,643 increased UCP2 mRNA in rat cardiomyocytes (9) but not in rat heart (5). To draw conclusions about UCP function, it is important to use protein level measurements.In this study, we have investigated the links between plasma FFA concentrations, PPAR␣, and UCPs by measuring cardiac UCP2 and UCP3 protein levels in mutant PPAR␣ Ϫ/Ϫ mice and two mouse models of diabetes known to have hi...

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma Free Fatty Acids and Peroxisome Proliferator–Activated Receptor α in the Control of Myocardial Uncoupling Protein Levels

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Experimental studies have also demonstrated that pharmacological interventions that stimulate glucose oxidation directly by activation of pyruvate dehydrogenase (PDH) or indirectly by inhibition of fatty acid oxidation result in improved recovery after ischemia and reperfusion (47). Furthermore, inhibitors of fatty acid oxidation (e.g., trimetazadine and ranolazine), which shift the balance from fatty acid to carbohydrate use, have recently been evaluated clinically as anti-ischemic agents (19,38,42).…”

mentioning

confidence: 99%

Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

Lloyd

Wang

Zeng

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used 1 H and 13 C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and 13 C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a ϳ50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and ϳ30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia. nuclear magnetic resonance spectroscopy; energy metabolism; lactate; pyruvate; ATP

show abstract

“…Several drugs that affect cellular metabolism have been investigated over the last decades. [39][40][41] Their mechanism of action is believed to involve inhibition of oxidation of free fatty acids in ischaemic myocytes. Since glucose metabolism requires less oxygen per mole of adenosine triphosphate generated, it is preferable to fatty acid oxidation when oxygen availability is limited in underperfused myocardium.…”

Section: Trimetazidine In Heart Failurementioning

confidence: 99%

The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelins

Milinković

Rosano

Lopatin

et al. 2016

Cardiac Failure Review

View full text Add to dashboard Cite

TherapeuticsAccess at: www.CFRjournal.com Chronic heart failure (HF), a complex and heterogeneous clinical syndrome, is a major cause of morbidity and mortality worldwide, and represents a major challenge to health care systems. The prevalence of HF and the number of hospitalisations is rising, even more in the ageing population.1 The direct costs of HF management reached 1-2 % of total health care expenditure and approximately two-thirds are attributable to hospitalisations. In 2012, in 197 countries, covering 99 % of the world's population, the overall cost of HF management was estimated at US$108 billion per annum, and is predicted to rise. 4 Around 60 % of total HF patients has HFrEF, which is associated with high reninangiotensin-aldosterone and sympathetic nervous systems activation.Most recent therapeutic improvements in these patients are due to the use of pharmacological agents that modulate these neuro-hormonal axes, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers and mineralocorticoid receptor antagonists (MRAs). The beneficial effects of these treatments include the reduction of HF mortality by approximately one-third in a period of two decades. Despite this success, HF mortality rates remain high:the 5-year survival is worse than in many cancers. 5,6The 2016 European Society of Cardiology (ESC) HF guidelines recommend ACEI and beta-blockers as first-line therapy in symptomatic patients with HFrEF. 4 However, both registries and clinical reports underline that the treatment of HF patients is suboptimal much more than expected, and that the heart rate is increased despite beta-blocker therapy.7-12 The registry of 12,440 patients demonstrated heterogeneity in treatment strategies, due to the drug side effects and contraindications.7 A European registry 13 reported that only 17 % of patients were receiving the optimal combination and recommended dose of diuretic, ACEI and beta-blockers. Results from a French registry on 50,000 HF patients 14 also confirmed suboptimal treatment of HF, demonstrating that after the first month following hospitalisation for worsening HF, only 47 % received an ACEI, 54 % a beta-blocker, and 17 % MRAs. The I Brazilian Registry of Heart Failure (BREATHE) 15 , conducted in 57 hospitals in Brazil, revealed that 69 % of HF patients were receiving an ACEI or ARB, 60 % a beta-blocker, and 49 % MRAs. However, only 17 % were receiving all three drugs together. Therefore, a need to identify a novel pathways and strategies for HF treatment is obvious and clinically justified. This article reviews the clinical evidence and guidelines recommendations for the use of two novel therapies in HF: ivabradine and trimetazidine. AbstractThe prevalence of heart failure (HF) is increasing, representing a major cause of death and disability, and a growing financial burden on healthcare systems. Despite the use of effective treatments with both drugs and devices, mortality remains high. There is therefore a need for new and effective therapeutic a...

show abstract

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Cited by 88 publications

References 145 publications

Plasma Free Fatty Acids and Peroxisome Proliferator–Activated Receptor α in the Control of Myocardial Uncoupling Protein Levels

Plasma Free Fatty Acids and Peroxisome Proliferator–Activated Receptor α in the Control of Myocardial Uncoupling Protein Levels

Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelins

Contact Info

Product

Resources

About