Modification of myocardial substrate use as a therapy for heart failure

Abozguia, Khalid; Clarke, Kieran; Lee, Leong; Frenneaux, Michael

doi:10.1038/ncpcardio0583

Cited by 77 publications

(59 citation statements)

References 66 publications

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“…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

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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.

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Section: Discussionsupporting

confidence: 83%

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

et al. 2010

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“…However, these effects were not related to an improvement of EC coupling, but rather to a delay of mitochondrial matrix acidification by a mechanism unrelated to the sarcolemmal NHE [162]. Furthermore, beneficial effects of ranolazine on mitochondrial energetics have so far been related to its ability to decrease fatty-acid oxidation, promote glucose oxidation, and by increasing pyruvate dehydrogenase complex activity [1,125,192] rather than by improving EC coupling. Thus, at this point, it is unknown whether reducing [Na + ] i per se improves mitochondrial energetics, especially in heart failure.…”

Section: Discussionmentioning

confidence: 97%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…Severe HF is associated with a reversion of cardiac metabolism from a use principally of free fatty acid metabolism in the healthy heart to enhanced glucose oxidation in the failing heart (Tuunanen et al 2008). Glucose oxidation is favored during hypoxia or ischemia, as a more oxygen-efficient substrate (Abozguia et al 2006). The administration of metabolic regulators increasing carbohydrate oxidation, e.g., propionyl L-carnitine, has been shown to improve ATP production in the human heart (Bartels et al 1992).…”

Section: Mitochondrial Function In the Prevention And Treatment Cardimentioning

confidence: 99%

Mitochondria in the human heart

Lemieux

Hoppel

2009

J Bioenerg Biomembr

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The heart relies mainly on mitochondrial metabolism to provide the energy needed for pumping blood to oxygenate the organs of the body. The study of mitochondrial function in the human heart faces many obstacles and elucidation of the role of mitochondria in cardiac diseases has relied mainly on studies with animal models. Cardiac diseases are the leading cause of mortality worldwide. With the emergence of new therapies to treat and prevent heart disease, some aiming at metabolic modulation, a need for acquiring a better understanding of mitochondrial function in the human heart becomes apparent. Our review is aimed at specific evaluation of the human heart in terms of (1) methods to understand mitochondrial function, with particular emphasis on integrated function, (2) data on the role of mitochondrial dysfunction in cardiovascular disease, and (3) possible applications of this knowledge in the treatment of patients with cardiac disease.

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Modification of myocardial substrate use as a therapy for heart failure

Cited by 77 publications

References 66 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

Excitation-contraction coupling and mitochondrial energetics

Mitochondria in the human heart

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