Perhexiline Therapy in Heart Failure With Preserved Ejection Fraction Syndrome

Up to 50% of patients with symptoms of heart failure have a preserved left ventricular ejection fraction (HFpEF syndrome). Current therapy for systolic heart failure is targeted at inducing vasodilation and counteracting neuro-endocrine activation. There is a lack of a corresponding evidence base for the treatment of HEpEF. We have previously shown that perhexiline, an agent that increases the efficiency of energy production by shifting substrate utilization from free fatty acids towards glucose, was highly effective in improving exercise capacity, symptoms and cardiac function in patients with systolic heart failure. We have also recently shown that energy deficiency plays a major role in the pathophysiology of HFpEF. In this proposal we therefore aim to investigate the effectiveness of perhexiline in 70 HFpEF patients, in a 3 month randomised, double-blind, controlled trial. An interim analysis is planned after 20 patients.

Inclusion criteria

• HFpEF will be defined as:

• Clinical features consistent with heart failure
• LVEF ≥ 50%, with no evidence of significant valvular disease
• No hypertrophic cardiomyopathy, and no evidence of pericardial constriction
• Peak VO2 < 80% predicted, with RER>1 and with a pattern of gas exchange on metabolic exercise testing indicating a cardiac cause for limitation)
• Patients recruited will be in sinus rhythm

Exclusion criteria

• BMI >35
• Objective evidence of lung disease on formal lung function testing
• Reversible myocardial ischaemia on contrast-enhanced myocardial stress Echocardiography, and no evidence of exercise-induced mitral regurgitation (>2+)
• Impaired hepatic function; known hypersensitivity to perhexiline