Pleiotropic mechanisms of action of perhexiline in heart failure

ABSTRACT

Introduction: The re-purposing of the anti-anginal drug perhexiline (PHX) has resulted in symptomatic improvements in heart failure (HF) patients. The inhibition of carnitine palmitoyltransferase-1 (CPT-1) has been proposed as the primary mechanism underlying the therapeutic benefit of PHX. This hypothesis is contentious.

Areas covered: We reviewed the primary literature and patent landscape of PHX from its initial development in the 1960s through to its emergence as a drug beneficial for HF. We focused on its physico-chemistry, molecular targets, tissue accumulation and clinical dosing.

Expert opinion: Dogma that the beneficial effects of PHX are due primarily to potent myocardial CPT-1 inhibition is not supported by the literature and all available evidence point to it being extremely unlikely that the major effects of PHX occur via this mechanism. In vivo PHX is much more likely to be an inhibitor of surface membrane ion channels and also to have effects on other components of cellular metabolism and reactive oxygen species (ROS) generation across the cardiovascular system. However, the possibility that minor effects of PHX on CPT-1 underpin disproportionately large effects on myocardial function cannot be entirely excluded, especially given the massive accumulation of the drug in heart tissue.

KEYWORDS:

• Perhexiline
• carnitine palmitoyltransferase
• heart failure
• metabolism
• modulation
• therapy

Article highlights

• In contrast to recent dogma, we propose that it is unlikely that the therapeutic benefit of perhexiline in patients with HF is due, in large part, to the inhibition of CPT-1.

• All available data suggests that PHX is a drug of low potency, low specificity and low selectivity that interacts with multiple surface membrane ion channels and other intracellular components that impinge on cellular metabolism and the generation of reactive oxygen species (ROS).

• The possibility that minor effects of PHX on CPT-1 underpin disproportionately large effects on myocardial function cannot be excluded, especially given the massive accumulation of PHX in myocardial tissue.

• A scheme is described that considers the pleiotropic effects of PHX via the inhibition of surface membrane ion channels and its accumulation in mitochondrial membranes.

• The combined action of PHX on multiple targets throughout the cardiovascular system probably underpins the symptomatic improvements in HF patients.

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Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This research has been supported by charitable grants from the British Heart Foundation [FS/09/028/27602], the Wellcome Trust [094219/Z/10/Z], and Cardiff University (Cardiff Partnership Fund).