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  The metabolic modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

Abozguia, K., Elliott, P., McKenna, W., Phan, T., Nallur-Shivu, G., Ahmed, I., et al. (2010). The metabolic modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy. Circulation, 122(16), 1562-1569. doi:10.1161/​CIRCULATIONAHA.109.934059.

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Abozguia, K, Author
Elliott, P, Author
McKenna, W, Author
Phan, TT, Author
Nallur-Shivu, G, Author
Ahmed, I, Author
Maher, AR, Author
Kaur, K, Author
Taylor, J, Author
Henning, Anke1, Author              
Ashrafian, H, Author
Watkins, H, Author
Frenneaux, M, Author
Affiliations:
1Institute for Biomedical Engineering, University and ETH Zurich, ou_persistent22              

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 Abstract: Background—Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. 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.

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 Dates: 2010-10
 Publication Status: Published in print
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 Identifiers: DOI: 10.1161/​CIRCULATIONAHA.109.934059
BibTex Citekey: AbozguiaEMPNAMKTHAWF2010
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Title: Circulation
Source Genre: Journal
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Pages: - Volume / Issue: 122 (16) Sequence Number: - Start / End Page: 1562 - 1569 Identifier: -