title: Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease.
abstract: OBJECTIVE
  We hypothesized that low-density lipoprotein (LDL) reduction regardless of mechanism would improve calf muscle perfusion, energetics, or walking performance in peripheral arterial disease (PAD) as measured by magnetic resonance imaging and magnetic resonance spectroscopy.
  
  
  BACKGROUND
  Statins improve cardiovascular outcome in PAD, and some studies suggest improved walking performance.
  
  
  METHODS
  Sixty-eight patients with mild to moderate symptomatic PAD (age 65 ± 11 years; ankle-brachial index [ABI] 0.69 ± 0.14) were studied at baseline and annually for 2 years after beginning simvastatin 40 mg (n = 20) or simvastatin 40 mg/ezetimibe 10 mg (n = 18) if statin naïve, or ezetimibe 10 mg (n = 30) if taking a statin. Phosphocreatine recovery time was measured by (31)P magnetic resonance spectroscopy immediately after symptom-limited calf exercise on a 1.5-T scanner. Calf perfusion was measured using first-pass contrast-enhanced magnetic resonance imaging with 0.1 mM/kg gadolinium at peak exercise. Gadolinium-enhanced magnetic resonance angiography was graded. A 6-min walk and a standardized graded Skinner-Gardner exercise treadmill test with peak Vo(2) were performed. A repeated-measures model compared changes over time.
  
  
  RESULTS
  LDL reduction from baseline to year 2 was greater in the simvastatin 40 mg/ezetimibe 10 mg group (116 ± 42 mg/dl to 56 ± 21 mg/dl) than in the simvastatin 40 mg group (129 ± 40 mg/dl to 90 ± 30 mg/dl, p < 0.01). LDL also decreased in the ezetimibe 10 mg group (102 ± 28 mg/dl to 79 ± 27 mg/dl, p < 0.01). Despite this, there was no difference in perfusion, metabolism, or exercise parameters between groups or over time. Resting ABI did improve over time in the ezetimibe 10 mg group and the entire study group of patients.
  
  
  CONCLUSIONS
  Despite effective LDL reduction in PAD, neither tissue perfusion, metabolism, nor exercise parameters improved, although rest ABI did. Thus, LDL lowering does not improve calf muscle physiology or functional capacity in PAD. (Comprehensive Magnetic Resonance of Peripheral Arterial Disease; NCT00587678).
authors.affiliation: Department of Medicine, University of Virginia Health System, University of Virginia, Charlottesville, Virginia.
authors.forename: Amy M
authors.initials: AM
authors.lastname: West
authors.forename: Justin D
authors.initials: JD
authors.lastname: Anderson
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Epstein
authors.forename: Craig H
authors.initials: CH
authors.lastname: Meyer
authors.forename: Hongkun
authors.initials: H
authors.lastname: Wang
authors.forename: Klaus D
authors.initials: KD
authors.lastname: Hagspiel
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Berr
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Harthun
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Weltman
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Dimaria
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Hunter
authors.forename: John M
authors.initials: JM
authors.lastname: Christopher
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Kramer
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood; D004734:Energy Metabolism; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D007866:Leg / Q000098:blood supply*; D018810:Magnetic Resonance Angiography; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D058729:Peripheral Arterial Disease / Q000097:blood / Q000188:drug therapy*; D010725:Phosphocreatine / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D010725:Phosphocreatine; D019821:Simvastatin; D000069438:Ezetimibe