cardiovascular-agents and etomoxir

The failing heart has an increased metabolic demand and at the same time suffers from impaired energy efficiency, which is a detrimental combination. Therefore, therapies targeting the energy-deprived failing heart and rewiring cardiac metabolism are of great potential, but are lacking in daily clinical practice. Metabolic impairment in heart failure patients has been well characterized for patients with reduced ejection fraction, and is coming of age in patients with 'preserved' ejection fraction. Targeting cardiomyocyte metabolism in heart failure could complement current heart failure treatments that do improve cardiovascular haemodynamics, but not the energetic status of the heart. In this review, we discuss the hallmarks of normal cardiac metabolism, typical metabolic disturbances in heart failure, and past and present therapeutic targets that impact on cardiac metabolism.

Topics: Acetyl-CoA C-Acyltransferase; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Dichloroacetic Acid; Energy Metabolism; Enzyme Inhibitors; Epoxy Compounds; Fatty Acids; Glucose; Heart Failure; Humans; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Perhexiline; Ranolazine; Stroke Volume; Trimetazidine

The ever-increasing burden of ischaemic heart disease and its common manifestation chronic angina pectoris calls for the exploration of other treatment options for those patients who despite the maximum conventional pharmacological and surgical interventions continue to suffer. Such exploration has led to the increasing use of new metabolically acting antianginal agents and the re-emergence of an old and somewhat forgotten pharmacological agent, perhexiline maleate. This review aims to update the cardiac nurse with knowledge to manage the care a patient receiving perhexiline maleate treatment and provide a brief review of three new metabolic agents: trimetazidine, ranolazine and etomoxir.

Topics: Acetanilides; Angina Pectoris; Calcium Channel Blockers; Cardiovascular Agents; Carnitine O-Palmitoyltransferase; Drug Monitoring; Epoxy Compounds; Fatty Acids; Half-Life; Humans; Metabolic Clearance Rate; Nurse's Role; Nursing Assessment; Patient Education as Topic; Patient Selection; Perhexiline; Piperazines; Randomized Controlled Trials as Topic; Ranolazine; Treatment Outcome; Trimetazidine; Vasodilator Agents

Despite advances in treatment, chronic heart failure is still associated with significant morbidity and a poor prognosis. The scope for further advances based on additional neurohumoral blockade is small. Effective adjunctive therapies acting via a different cellular mechanism would, therefore, be attractive. Energetic impairment seems to contribute to the pathogenesis of heart failure. The findings from several studies have shown that the so-called metabolic agents could have potential as adjunctive therapies in heart failure. These agents cause a shift in the substrate used by the heart away from free fatty acids, the oxidation of which normally provides around 70% of the energy needed, towards glucose. The oxygen cost of energy generation is lessened when glucose is used as the substrate. In this review we aim to draw attention to the metabolic alteration in heart failure and we present evidence supporting the use of metabolic therapy in heart failure.

Topics: Acetanilides; Adrenergic beta-Antagonists; Animals; Cardiac Output, Low; Cardiovascular Agents; Energy Metabolism; Epoxy Compounds; Fatty Acids, Nonesterified; Glycine; Heart; Humans; Myocardium; Oxygen; Perhexiline; Piperazines; Ranolazine; Trimetazidine

Antianginal drugs that exert their anti-ischaemic effects primarily by altering myocardial metabolism have recently attracted attention. They have the potential to relieve symptoms in patients with refractory angina who are already on "optimal" medical therapy and have disease that is not amenable to revascularisation, making these drugs an attractive addition to therapy, particularly for the elderly population. In some cases, they may even be used as first-line treatment. These drugs increase glucose metabolism at the expense of free-fatty-acid metabolism, enhancing oxygen efficiency during myocardial ischaemia. Whilst they have been demonstrated to reduce ischaemia in several clinical trials, their use remains limited. This review aims to draw attention to these "metabolic" antianginal drugs while surveying the evidence supporting their use and mode of action. Four metabolic antianginal drugs are reviewed: perhexiline, trimetazidine, ranolazine, and etomoxir. We also discuss the metabolic actions of glucose-insulin-potassium and beta-blockers and describe myocardial metabolism during normal and ischaemic conditions. The potential of these metabolic agents may extend beyond the treatment of ischaemia secondary to coronary artery disease. They offer significant promise for the treatment of symptoms occurring due to inoperable aortic stenosis, hypertrophic cardiomyopathy, and chronic heart failure.

Topics: Acetanilides; Adrenergic beta-Antagonists; Angina Pectoris; Cardiovascular Agents; Drug Therapy, Combination; Enzyme Inhibitors; Epoxy Compounds; Glucose; Humans; Hypoglycemic Agents; Insulin; Myocardial Ischemia; Myocardium; Perhexiline; Piperazines; Potassium; Ranolazine; Trimetazidine

Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.

Topics: Acetanilides; Angina Pectoris; Animals; Calcium; Cardiovascular Agents; Clinical Trials as Topic; Enzyme Inhibitors; Epoxy Compounds; Fatty Acids; Gene Expression; Glucose; Heart Failure; Humans; Hypoglycemic Agents; Methylhydrazines; Myocytes, Cardiac; Oxidation-Reduction; Piperazines; Ranolazine; Rats; Rats, Wistar; Sarcoplasmic Reticulum; Trimetazidine; Up-Regulation; Vasodilator Agents

A number of anti-anginal agents (perhexiline, amiodarone, trimetazidine) have been shown to inhibit myocardial carnitine palmitoyltransferase-1, which controls access of long-chain fatty acids to mitochondrial sites of beta-oxidation. In view of clinical data suggesting that perhexiline improves symptomatic status in unstable angina pectoris, and the known role of mitochondrial beta-oxidation in platelet metabolism, we compared the platelet carnitine palmitoyltransferase-1 inhibitory and putative anti-aggregatory effects of perhexiline, amiodarone and trimetazidine with those of specific carnitine palmitoyltransferase-1 inhibitors: etomoxir and hydroxyphenylglyoxylate in both normal subjects and patients with stable angina. All of the compounds examined inhibited platelet carnitine palmitoyltransferase-1 activity; rank order of potency etomoxir > malonyl-CoA > hydroxyphenylglyoxylate > amiodarone > or = perhexiline > trimetazidine. However, only perhexiline, amiodarone and trimetazidine inhibited platelet aggregation. We conclude that (a) the carnitine palmitoyltransferase-1 inhibitors perhexiline, amiodarone and trimetazidine exert significant anti-aggregatory effects which may be therapeutically relevant and, (b) these effects are independent of carnitine palmitoyltransferase-1 inhibition.

Topics: Adult; Aged; Amiodarone; Blood Platelets; Cardiovascular Agents; Carnitine O-Palmitoyltransferase; Case-Control Studies; Enzyme Inhibitors; Epoxy Compounds; Fatty Acids; Female; Humans; Male; Middle Aged; Perhexiline; Platelet Aggregation; Trimetazidine; Vasodilator Agents