Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease

Abstract

Objectives: 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).

Figure 1. Post-Exercise Calf Muscle Perfusion

First-pass contrast-enhanced calf muscle perfusion at baseline (A) and year 1 (B) in the same patient in the study group treated with simvastatin + ezetimibe. Increased signal intensity is seen in the anterior tibialis and soleus muscles at both time points (perfusion index: A = 0.37, B = 0.52).

Figure 2. PCr Plots

Phosphocreatine (PCr) recovery time plots at baseline (A) and year 1 (B) in a patient in the study group treated with simvastatin + ezetimibe with respective PCr recovery time constants of 98 and 121 s.

Figure 3. Representative MRA Images

Contrast-enhanced magnetic resonance angiography (MRA) images at baseline (A) and year 1 (B) from a patient in the study group treated with simvastatin + ezetimibe showing improvement in the appearance of superficial femoral artery stenosis (arrows) over time (MRA index: A = 0.44, B = 0.38).