Pleiotropic mechanisms of action of perhexiline in heart failure

Abstract

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.

Mitochondrial dysfunction in pathophysiology of heart failure

“…Short-term treatment with perhexiline has improved symptoms and bioenergetics in heart failure patients (51,152,153). However, the clinical benefits of perhexiline have recently been attributed to pleiotropic mechanisms, as perhexiline did not alter cardiac substrate utilization in heart failure patients (153,154).…”

Metabolic Alterations in Inherited Cardiomyopathies

“…Perhexiline, a metabolic drug that shifts substrate utilization from FA towards glucose, induced modest improvements of the exercise capacity in symptomatic HCM patients [78] and reduced cardiac mass in a mouse model of HCM [79]. However, one must question whether the positive effects of perhexiline in symptomatic HCM are indeed caused by a shift from FA to glucose utilization or are mediated by the pleiotropic effects of the drug [80]. In fact, perhexiline also rebalances carbon and nucleotide fluxes via increases of lactate and amino acid uptake to maintain cardiac output [81], but may additionally reduce oxidative stress [79,82,83].…”

Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

“… 69 The therapeutic benefit of perhexiline may be the resultant of its multiple pleiotropic actions. 70 Far from inducing a simple shift from fatty acid to glucose oxidation, perhexiline may cause complex rebalancing of carbon and nucleotide phosphate fluxes to increase metabolic flexibility and to maintain cardiac output. 71 The benefit of metabolic drug therapy may depend on the ability of the heart to shift from mitochondrial lipid to glucose oxidation.…”