Methods and Results—Forty-six consecutive patients with symptomatic exercise limitation (peak V̇o2 <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by 31P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak V̇o2, symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to −0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak V̇o2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg−1 · min−1; P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo).
Conclusions—In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00500552.