TY - JOUR
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 &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
KW - exercise
KW - hypertrophy
KW - metabolism
KW - spectroscopy
UR - http://www.scopus.com/inward/record.url?scp=78049509377&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78049509377&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.109.934059
DO - 10.1161/CIRCULATIONAHA.109.934059
M3 - Article
C2 - 20921440
AN - SCOPUS:78049509377
SN - 0009-7322
VL - 122
SP - 1562
EP - 1569
JO - Circulation
JF - Circulation
IS - 16
ER -