Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism

Abstract

Objectives: We aimed to investigate the pathophysiology of peripheral arterial disease (PAD) by examining magnetic resonance imaging (MRI) and spectroscopic (MRS) correlates of functional capacity.

Background: Despite the high prevalence, morbidity, and cost of PAD, its pathophysiology is incompletely understood.

Methods: Eighty-five patients (age 68 +/- 10 years) with mild-to-moderate PAD (ankle-brachial index 0.69 +/- 0.14) had their most symptomatic leg studied by MRI/MRS. Percent wall volume in the superficial femoral artery was measured with black blood MRI. First-pass contrast-enhanced MRI calf muscle perfusion and (31)P MRS phosphocreatine recovery time constant (PCr) were measured at peak exercise in calf muscle. All patients underwent magnetic resonance angiography (MRA), treadmill testing with maximal oxygen consumption measurement, and a 6-min walk test.

Results: Mean MRA index of number and severity of stenoses was 0.84 +/- 0.68 (normal 0), % wall volume 74 +/- 11% (normal 46 +/- 7%), tissue perfusion 0.039 +/- 0.015 s(-1) (normal 0.065 +/- 0.013 s(-1)), and PCr 87 +/- 54 s (normal 34 +/- 16 s). MRA index, % wall volume, and ankle-brachial index correlated with most functional measures. PCr was the best correlate of treadmill exercise time, whereas calf muscle perfusion was the best correlate of 6-min walk distance. No correlation was noted between PCr and tissue perfusion.

Conclusions: Functional limitations in PAD are multifactorial. As measured by MRI and spectroscopy, atherosclerotic plaque burden, stenosis severity, tissue perfusion, and energetics all play a role. However, cellular metabolism is uncoupled from tissue perfusion. These findings suggest a potential role for therapies that regress plaque, increase tissue perfusion, and/or improve cellular metabolism. (Comprehensive Magnetic Resonance of Peripheral Arterial Disease; NCT00587678).

Figure 1. MR plaque and calf muscle perfusion images, MR angiogram, and MRS phosphocreatine recovery curve all from the same patient with peripheral arterial disease

(A) High resolution black blood MRI of the superficial femoral artery (SFA) in cross section. The vessel lumen is denoted by gray arrow and vessel wall by black arrow. Note the large amount of atherosclerotic plaque in the vessel wall. (B) MR angiogram of the SFA. The arrow denotes a severe stenosis in the proximal left SFA which corresponds to the vessel wall image in (A). (C) Post-exercise contrast enhanced peak perfusion of the calf muscle in cross section. Note the heterogeneous signal intensity. Arrows depict the muscle groups (anterior tibialis and soleus muscles) with the greatest contrast enhancement i.e. perfusion. (D) The graph is a plot of phosphocreatine recovery with relative phosphocreatine concentration on the Y axis and time in seconds on the X axis. The phosphocreatine recovery time constant (PCr) is calculated using a mono-exponential fit of this data.

Figure 2

Correlation between PCr and tissue perfusion demonstrating the lack of significant relationship between the two parameters (y = 7.52×10⁻⁶× + 0.038, r= 0.03, p=0.82).

Figure 3

Correlation demonstrating positive relationship between tissue perfusion and 6-minute walk distance (y = 8857× + 672, r=0.32, p<0.01).

Figure 4

Correlation demonstrating the inverse relationship between PCr and treadmill exercise time (y=−2.1× + 680, r= −0.22, p<0.05).