Metabolic Manipulation in Chronic Heart Failure

Conventional measures used for the treatment of chronic heart failure act predominantly by reducing the work performed by the heart. In a recent study, the investigators showed that one drug (perhexiline) substantially improved symptoms and cardiac function in heart failure. The investigators wish to confirm these findings and test whether or not this drug acts by altering the heart's energy source thus augmenting the energetic status and work efficiency of the heart.

Perhexiline maleate is an antianginal agent which increases the efficiency of energy production by shifting substrate utilisation from free fatty acids towards glucose. We showed that perhexiline therapy was highly effective in improving exercise capacity, symptoms and cardiac function in patients with systolic heart failure of both ischaemic and non ischaemic aetiology. Perhexiline acts by inhibiting both carnitine palmitoyl transferase-1 (CPT-1) and CPT-2, which are key enzymes in mitochondrial free fatty acid uptake. This leads to increased myocardial glucose substrate utilization. Further we wish to ascertain whether or not this drug improves cardiac energetics and efficiency by altering substrate utilization. In this proposal we will assess the cardiac function (by cardiac Magnetic Resonance Imaging MRI), cardiac energetic status (by cardiac Magnetic Resonance Spectroscopy MRS), cardiac efficiency (via pressure-volume loops) and substrate utilization (via left and right heart catheterization), following one month of perhexiline therapy or placebo in patients with symptomatic idiopathic dilated cardiomyopathy on optimal conventional heart failure medications. An interim analysis is planned after 20 patients.

Inclusion Criteria: Optimally-medicated idiopathic dilated cardiomyopathy Symptomatic ( NYHA IIb-III) Impaired left ventricular systolic function (EF < 40%) Exclusion Criteria: Abnormal liver function tests (defined as above twice the upper limit of normal (ULN)) Concomitant use of Amiodarone , Quinidine , Haloperidol or Selective serotonin (5HT) uptake inhibitors such as Fluoxetine and Paroxetine which may inhibit the CYP2D6 enzyme. Pre-existing evidence of peripheral neuropathy. Women of childbearing potential. Patients with implantable cardiac devices (or any other contraindication to MRI). Obesity ( BMI > 32) Obstructive sleep apnea syndrome Patients with known hypersensitivity to perhexiline Patients with impaired renal function (Creatinine > 250 µmol/L) Valvular heart disease defined as more than moderate valvular stenosis or regurgitation. Atrial Fibrillation

Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, Yousef Z, Wagenmakers AJ, Thies F, Horowitz J, Frenneaux MP. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 2015 Mar;3(3):202-11. doi: 10.1016/j.jchf.2014.09.009. Epub 2015 Jan 28.

Beadle RM, Williams LK, Abozguia K, Patel K, Leon FL, Yousef Z, Wagenmakers A, Frenneaux MP. Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial. Trials. 2011 Jun 6;12:140. doi: 10.1186/1745-6215-12-140.