Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy

Khalid Abozguia, Perry Elliott, William McKenna, Thanh Trung Phan, Ganesh Nallur-Shivu, Ibrar Ahmed, Abdul R. Maher, Kulvinder Kaur, Jenny Taylor, Anke Henning, Houman Ashrafian, Hugh Watkins, Michael Frenneaux

Research output: Contribution to journalArticle

181 Citations (Scopus)

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 &OV0312;o2 <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 P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak &OV0312;o2, 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 VO2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL • kg-1 • min; 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.

Original languageEnglish (US)
Pages (from-to)1562-1569
Number of pages8
JournalCirculation
Volume122
Issue number16
DOIs
StatePublished - Oct 19 2010
Externally publishedYes

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Perhexiline
Hypertrophic Cardiomyopathy
Exercise
Phosphocreatine
Adenosine Triphosphate
Heart Rate
Placebos
Radionuclide Ventriculography
Magnetic Resonance Spectroscopy
Quality of Life
Serum

Keywords

  • cardiomyopathy
  • exercise
  • hypertrophy
  • metabolism
  • spectroscopy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Abozguia, K., Elliott, P., McKenna, W., Phan, T. T., Nallur-Shivu, G., Ahmed, I., ... Frenneaux, M. (2010). Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation, 122(16), 1562-1569. https://doi.org/10.1161/CIRCULATIONAHA.109.934059

Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. / Abozguia, Khalid; Elliott, Perry; McKenna, William; Phan, Thanh Trung; Nallur-Shivu, Ganesh; Ahmed, Ibrar; Maher, Abdul R.; Kaur, Kulvinder; Taylor, Jenny; Henning, Anke; Ashrafian, Houman; Watkins, Hugh; Frenneaux, Michael.

In: Circulation, Vol. 122, No. 16, 19.10.2010, p. 1562-1569.

Research output: Contribution to journalArticle

Abozguia, K, Elliott, P, McKenna, W, Phan, TT, Nallur-Shivu, G, Ahmed, I, Maher, AR, Kaur, K, Taylor, J, Henning, A, Ashrafian, H, Watkins, H & Frenneaux, M 2010, 'Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy', Circulation, vol. 122, no. 16, pp. 1562-1569. https://doi.org/10.1161/CIRCULATIONAHA.109.934059
Abozguia, Khalid ; Elliott, Perry ; McKenna, William ; Phan, Thanh Trung ; Nallur-Shivu, Ganesh ; Ahmed, Ibrar ; Maher, Abdul R. ; Kaur, Kulvinder ; Taylor, Jenny ; Henning, Anke ; Ashrafian, Houman ; Watkins, Hugh ; Frenneaux, Michael. / Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. In: Circulation. 2010 ; Vol. 122, No. 16. pp. 1562-1569.
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T1 - Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy

AU - Abozguia, Khalid

AU - Elliott, Perry

AU - McKenna, William

AU - Phan, Thanh Trung

AU - Nallur-Shivu, Ganesh

AU - Ahmed, Ibrar

AU - Maher, Abdul R.

AU - Kaur, Kulvinder

AU - Taylor, Jenny

AU - Henning, Anke

AU - Ashrafian, Houman

AU - Watkins, Hugh

AU - Frenneaux, Michael

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N2 - 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 &OV0312;o2 <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 P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak &OV0312;o2, 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 VO2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL • kg-1 • min; 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.

AB - 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 &OV0312;o2 <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 P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak &OV0312;o2, 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 VO2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL • kg-1 • min; 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.

KW - cardiomyopathy

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KW - hypertrophy

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