Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone

Kennedy, Jennifer A.; Unger, Steven; Horowitz, John D.

doi:10.1016/0006-2952(96)00204-3

Cited by 196 publications

(154 citation statements)

References 30 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…18 It has been proposed that perhexiline inhibits the metabolism of free fatty acids and thereby enhances myocardial carbohydrate use (in effect improving insulin resistance 34 ) by suppressing carnitine palmitoyl transferase I and II, transporters that are crucial for the uptake of long-chain free fatty acids into mitochondria. 19,20,35 The present study supports this proposal by observing that perhexiline, in common with other metabolic modulators, 36 improved the systemic metabolic milieu by significantly decreasing serum glucose and free fatty acids. Thus, although the mechanisms of action of perhexiline are likely to be complex, its capacity to divert myocardial metabolism toward carbohydrates, especially in the context of myocardial oxygen limitation (eg, resulting from microvascular dysfunction), 12,14 is predicted to enhance the efficiency of myocardial energy generation.…”

Section: Discussionsupporting

confidence: 83%

Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

et al. 2010

View full text Add to dashboard Cite

Background-Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods and Results-Forty-six consecutive patients with symptomatic exercise limitation (peak V o 2 Ͻ75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55Ϯ0.26 years) were randomized to perhexiline 100 mg (nϭ24) or placebo (nϭ22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by 31 P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak V o 2 , symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6Ϯ1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27Ϯ0.02 to 1.73Ϯ0.02 versus 1.29Ϯ0.01 to 1.23Ϯ0.01; Pϭ0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11Ϯ0.008 to Ϫ0.01Ϯ0.005 versus 0.15Ϯ0.007 to 0.11Ϯ0.008 second; Pϭ0.03). These changes were accompanied by an improvement in primary end point (peak V O 2 ) (22.2Ϯ0.2 to 24.3Ϯ0.2 versus 23.6Ϯ0.3 to 22.3Ϯ0.2 mL ⅐ kg Ϫ1 ⅐ min Ϫ1 ; Pϭ0.003) and New York Heart Association class (PϽ0.001) (all P values ANCOVA, perhexiline versus placebo). Conclusions-In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00500552.

show abstract

Section: Discussionsupporting

confidence: 83%

Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

et al. 2010

View full text Add to dashboard Cite

show abstract

“…29 Such an approach is promising because various antiarrhythmic drugs, namely perhexiline and amiodarone, inhibit CPT-I. 30 Metabolic interventions with targeted drugs enhancing glucose use and pyruvate oxidation at the expense of fatty acid oxidation could be a reasonable approach to prevent arrhythmias in these disorders. 31 Today, the treatment of fatty acid oxidation disorders aims to provide sufficient glucose to prevent adipose tissue lipolysis.…”

Section: Fatty Acid Oxidation Disorders and Arrhythmias In 24 Patientsmentioning

confidence: 99%

Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children

et al. 1999

View full text Add to dashboard Cite

Background —The clinical manifestations of inherited disorders of fatty acid oxidation vary according to the enzymatic defect. They may present as isolated cardiomyopathy, sudden death, progressive skeletal myopathy, or hepatic failure. Arrhythmia is an unusual presenting symptom of fatty acid oxidation deficiencies. Methods and Results —Over a period of 25 years, 107 patients were diagnosed with an inherited fatty acid oxidation disorder. Arrhythmia was the predominant presenting symptom in 24 cases. These 24 cases included 15 ventricular tachycardias, 4 atrial tachycardias, 4 sinus node dysfunctions with episodes of atrial tachycardia, 6 atrioventricular blocks, and 4 left bundle-branch blocks in newborn infants. Conduction disorders and atrial tachycardias were observed in patients with defects of long-chain fatty acid transport across the inner mitochondrial membrane (carnitine palmitoyl transferase type II deficiency and carnitine acylcarnitine translocase deficiency) and in patients with trifunctional protein deficiency. Ventricular tachycardias were observed in patients with any type of fatty acid oxidation deficiency. Arrhythmias were absent in patients with primary carnitine carrier, carnitine palmitoyl transferase I, and medium chain acyl coenzyme A dehydrogenase deficiencies. Conclusions —The accumulation of arrhythmogenic intermediary metabolites of fatty acids, such as long-chain acylcarnitines, may be responsible for arrhythmias. Inborn errors of fatty acid oxidation should be considered in unexplained sudden death or near-miss in infants and in infants with conduction defects or ventricular tachycardia. Diagnosis can be easily ascertained by an acylcarnitine profile from blood spots on filter paper.

show abstract

“…It exerts multiple effects which increase efficiency of myocardial metabolism: amongst these it is known to inhibit mitochondrial carnitine palmitoyl transferase-1 [1], potentially resulting in a shift from fatty acid to glucose utilisation with more adenosine triphosphate production per unit oxygen consumption.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium

Chong

Drury

Licari

et al. 2015

Eur J Clin Pharmacol

Self Cite

View full text Add to dashboard Cite

Metabolism PharmacokineticsDrug uptake Stereoselectivity 3 ABSTRACT (150-250 words)Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilized in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to determine (1) whether the acute accumulation of perhexiline in the myocardium is stereoselective, and (2) to investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium.Method: Patients (n=129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery, were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses.Results: Myocardial uptake of both (+) and (-)-perhexiline was greater in ventricles than atria, and there was more rapid clearance of (-) .005]. Atrial uptake of (+)-enantiomer also varied directly with duration of therapy (r=0.29, p=0.004), while atrial uptake of (-)-perhexiline varied inversely with simultaneous heart rate (r=-0.22, p=0.03). 4Conclusion: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age, and displays evidence of both saturability and minor stereoselectivity.(2) Atrial uptake of (-) perhexiline may selectively modulate heart rate reduction.(Word count: 235 words) 5

show abstract

Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone

Cited by 196 publications

References 30 publications

Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children

Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium

Contact Info

Product

Resources

About