Improvement in Cardiac Energetics by Perhexiline in Heart Failure Due to Dilated Cardiomyopathy

Beadle, Roger; Williams, Lynne; Kuehl, Michael; Bowater, Sarah; Abozguia, Khalid; Leyva, Francisco; Yousef, Zaheer; Wagenmakers, Anton J. M.; Thiès, Frank; Horowitz, John D.; Frenneaux, Michael

doi:10.1016/j.jchf.2014.09.009

Cited by 74 publications

(48 citation statements)

References 28 publications

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“…In a recent randomized controlled trial, short-term treatment with perhexiline in patients with non-ischemic HFrEF caused a 30% increase in PCr/ATP ratio (from 1.2 to 1.5; P<0.001) and an improvement in NYHA status (Beadle, et al, 2015). However, this study found no change in cardiac substrate utilization despite these clear beneficial effects on energetic status, suggesting an alternative mechanism of action rather than CPT1 inhibition, at least with short term administration.…”

Section: Carnitine Palmitoyltransferase 1 (Cpt1) Inhibitioncontrasting

confidence: 56%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants.Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed.

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Section: Carnitine Palmitoyltransferase 1 (Cpt1) Inhibitioncontrasting

confidence: 56%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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“…Additional findings included evidence that perhexiline improved left ejection fraction, symptoms, resting and peak stress myocardial function and skeletal mass energetics [53]. Further clinical trials support a subjective improvement in symptoms of heart failure in patients treated with perhexiline [50,51,52]. The most recent available trial did produce contradictory evidence that there was no significant change in left ventricular function or BNP following perhexiline treatment, but did conclude that treatment improved cardiac energetics given the improvement in the phosphocreatine (PCr)/ATP ratio, a marker of heart failure, which correlates with the New York Heart Association (NYHA) class [50].…”

Section: Metabolic Modulating Therapeuticsmentioning

confidence: 99%

Targeting Metabolic Modulation and Mitochondrial Dysfunction in the Treatment of Heart Failure

2017

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Despite significant improvements in morbidity and mortality with current evidence-based pharmaceutical-based treatment of heart failure (HF) over the previous decades, the burden of HF remains high. An alternative approach is currently being developed, which targets myocardial energy efficiency and the dysfunction of the cardiac mitochondria. Emerging evidence suggests that the insufficient availability of ATP to the failing myocardium can be attributed to abnormalities in the myocardial utilisation of its substrates rather than an overall lack of substrate availability. Therefore, the development of potential metabolic therapeutics has commenced including trimetazidine, ranolazine and perhexiline, as well as specific mitochondrial-targeting pharmaceuticals, such as elamipretide. Large randomised controlled trials are required to confirm the role of metabolic-modulating drugs in the treatment of heart failure, but early studies have been promising in their possible efficacy for the management of heart failure in the future.

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“…Its main effect is to shift metabolism from β oxidation of fatty acids to glycolysis 144. In human studies, perhexiline improved heart failure symptom class145146 and, in one study, systolic function in heart failure with reduced ejection fraction 146. In the previously mentioned study of β agonism in a STAT3 deficient mouse, administration of perhexiline improved left ventricular function and survival in mice treated with isoproterenol 124.…”

Section: Management Of Peripartum Cardiomyopathymentioning

confidence: 97%

Peripartum cardiomyopathy

Honigberg

Givertz

2019

BMJ

119

134

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Peripartum cardiomyopathy (PPCM) is a rare, often dilated, cardiomyopathy with systolic dysfunction that presents in late pregnancy or, more commonly, the early postpartum period. Although the condition is prevalent worldwide, women with black ancestry seem to be at greatest risk, and the condition has a particularly high incidence in Nigeria and Haiti. Other risk factors include pre-eclampsia, advanced maternal age, and multiple gestation pregnancy. Although the complete pathophysiology of peripartum cardiomyopathy remains unclear, research over the past decade suggests the importance of vasculo-hormonal pathways in women with underlying susceptibility. At least some women with the condition harbor an underlying sarcomere gene mutation. More than half of affected women recover systolic function, although some are left with a chronic cardiomyopathy, and a minority requires mechanical support or cardiac transplantation (or both). Other potential complications include thromboembolism and arrhythmia. Currently, management entails standard treatments for heart failure with reduced ejection fraction, with attention to minimizing potential adverse effects on the fetus in women who are still pregnant. Bromocriptine is one potential disease specific treatment under investigation. In this review, we summarize the current literature on peripartum cardiomyopathy, as well as gaps in the understanding of this condition and future research directions.

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Improvement in Cardiac Energetics by Perhexiline in Heart Failure Due to Dilated Cardiomyopathy

Cited by 74 publications

References 28 publications

Cardiac metabolism — A promising therapeutic target for heart failure

Cardiac metabolism — A promising therapeutic target for heart failure

Targeting Metabolic Modulation and Mitochondrial Dysfunction in the Treatment of Heart Failure

Peripartum cardiomyopathy

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