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

177 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 Vo(2) <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 (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), 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 Vo(2)) (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.
Original languageEnglish
Pages (from-to)1562-1569
Number of pages8
JournalCirculation
Volume122
Issue number16
Early online date4 Oct 2010
DOIs
Publication statusPublished - 19 Oct 2010

Keywords

  • cardiomyopathy
  • exercise
  • hypertrophy
  • metabolism
  • spectroscopy

Cite this

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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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 Vo(2) <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 (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), 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 Vo(2)) (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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author = "Khalid Abozguia and Perry Elliott and William McKenna and Phan, {Thanh Trung} and Ganesh Nallur-Shivu and Ibrar Ahmed and Maher, {Abdul R.} and Kulvinder Kaur and Jenny Taylor and Anke Henning and Houman Ashrafian and Hugh Watkins and Michael Frenneaux",
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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

PY - 2010/10/19

Y1 - 2010/10/19

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 Vo(2) <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 (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), 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 Vo(2)) (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.

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 Vo(2) <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 (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), 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 Vo(2)) (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.

KW - cardiomyopathy

KW - exercise

KW - hypertrophy

KW - metabolism

KW - spectroscopy

U2 - 10.1161/CIRCULATIONAHA.109.934059

DO - 10.1161/CIRCULATIONAHA.109.934059

M3 - Article

VL - 122

SP - 1562

EP - 1569

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 16

ER -