This study examined a group of 10 patients with PAD before and after percutaneous lower extremity revascularization. We used a combination of MRI and MRS techniques and exercise studies to comprehensively evaluate functional changes before and after revascularization. Percutaneous lower extremity revascularization in PAD patients with progressive intermittent claudication symptoms was effective at improving calf muscle phosphocreatine recovery kinetics, suggesting an improvement in mitochondrial function. Both rest and exercise ABI improved with revascularization. Neither peak exercise tissue perfusion nor exercise parameters improved, although the study was underpowered for these endpoints.
The improvement in post-exercise calf muscle phosphocreatine recovery kinetics may result from several factors. Prior work from our group4
demonstrated that calf muscle tissue perfusion and phosphocreatine recovery kinetics are uncoupled from each other although both correlate with traditional exercise parameters. This suggests that other factors must impact calf muscle phosphocreatine recovery kinetics independent of local tissue perfusion. Perfusion index by MRI measures tissue blood flow in the calf corrected for arterial inflow, thereby measuring microvascular perfusion. With large vessel revascularization, bulk blood flow to the calf improves, which may enhance endothelial function and/or nitric oxide production that could impact the post-exercise phosphocreatine recovery time constant. Despite this, perfusion at the microvascular level may remain depressed.
The trend towards improvement in distance to onset of claudication with the 6-minute walk suggests a relationship with PCr recovery kinetics; however, it is not known if this is a causal relationship. The study was underpowered to detect an improvement in calf muscle perfusion. We may be able to detect a change in perfusion with larger patient numbers or alternative methods to evaluate calf muscle blood flow such as direct quantification with arterial spin labeling MRI.
Similar to prior studies, the improvement in ABI to near normal range with revascularization did not translate into an equal improvement in exercise capacity.7
In our study, the lack of improvement in functional capacity may be in part because only one leg was treated and PAD is typically a bilateral disease. However, there was no change in the contralateral leg ABI over the study. There was a trend towards an improvement in the distance until onset of claudication during the 6-minute walk. It may be that changes in PCr recovery kinetics are necessary for improvements in low-intensity exercise. With larger patient numbers we would anticipate greater power to detect changes in exercise parameters with percutaneous revascularization.
There is evidence of a skeletal muscle myopathy in PAD based on both histologic and biochemical abnormalities. Using light microscopy, skeletal muscle samples from PAD patients demonstrate myopathic changes which correlate with the extent of disease,13
and electron microscopy further delineated abnormal mitrochondrial structure.14
In addition, there is biochemical evidence of abnormal mitochondrial oxidation of carbohydrates15
and impaired acylcarnitine metabolism16
in patients with PAD.
Our lab and others have demonstrated the utility of 31
P magnetic resonance spectroscopy in the non-invasive evaluation of skeletal muscle metabolism in PAD.5,17
However, there are limited data regarding changes in cellular energetics for patients treated with medical therapy or revascularization in PAD. We have shown that low-density lipoprotein (LDL) lowering does not improve PCr recovery kinetics in a similar patient population.18
Zatina et al.19
found that an improvement in calf muscle phosphocreatine kinetics did not occur until several months after successful lower extremity bypass surgery. Similar to the present study, Schunk et al.20
found an improvement in PCr recovery kinetics in 31 patients with PAD who underwent percutaneous transluminal angioplasty (PTA) or vascular surgery. Further studies are needed to elucidate the mechanism of improvement in PCr recovery kinetics with revascularization.
The clinical factors which predict improvement in walking distance after percutaneous revascularization were studied by Afaq et al.21
as a reported history of walking after the procedure and prior coronary artery bypass surgery. However, almost half of the study patients were lost to follow-up and as a result the clinical predictors of exercise ability after revascularization need additional prospective evaluation.
The study by Zeller et al. shows changes in ABI similar to those seen in our study22
wherein patients treated with femoropopliteal artery stenting had an improvement in resting ABI from 0.63 ± 0.20 to 0.94 ± 0.17 as well as post-exercise testing (0.44 ± 0.23 to 0.85 ± 0.21, p
< 0.001 for both). Although the ABI is used as a clinical marker of lower extremity blood flow, we did not observe an improvement in calf muscle perfusion measured by MRI. However, a recent study by Duerschmied et al.23
used contrast ultrasound calf muscle perfusion imaging in patients at baseline and 3–5 months post-intervention, with an improvement in both ABI (0.60 to 0.85, p
= 0.001) and time-to-peak contrast enhancement (45 s to 24 s, p
= 0.015). One of the challenges in using time-to-peak measurements is the inherent influence by volume status and hemodynamic function that may vary over time. Future studies comparing ultrasound and MRI methods to determine tissue perfusion appear warranted.
Measuring calf muscle perfusion with MRI using the technique developed by our group9
identifies peak exercise microvascular calf blood flow by indexing the local tissue perfusion indexed to the nearby arterial input. It is possible that by increasing bulk flow to the calf with proximal revascularization that our technique is not sensitive enough to measure the change in microvascular blood flow. Other techniques such as arterial spin labeling MRI allow for quantification of calf muscle blood flow without the use of exogenous contrast24,25
and may offer additional insight into changes in calf muscle perfusion. Alternatively, calf muscle microvascular blood flow may not significantly improve with revascularization. The post-exercise ABI in our study improved; however, it did not return to normal levels, suggesting that post-exercise calf blood flow remains impaired despite the proximal revascularization.
The primary limitation of the study is the small sample size. This was a pilot study of 10 individuals scheduled for percutaneous lower extremity revascularization out of a larger cohort of 87 patients with PAD. This study is underpowered to examine the benefit of percutaneous revascularization on exercise measures and perfusion index. However, other larger studies have shown that there is an initial improvement in exercise capacity in patients treated with lower extremity percutaneous revascularization.21,22
It may take longer than 10 months for microvascular perfusion to improve. Another limitation is the lack of an untreated control group.
Given time constraints, we studied only the most symptomatic leg, which was scheduled for clinically indicated percutaneous revascularization, for calf muscle perfusion and energetics. However, exercise parameters are influenced by disease in both legs. Certainly some patients may have progression of their peripheral artery atherosclerosis in the non-intervened leg, which would impair their overall functional capacity. However, we did not find a significant decline in the contralateral ABI. We could not rule out instent stenosis in some cases due to stent-induced susceptibility artifact; however, rest ABI post-intervention was higher in all subjects than at baseline, making significant in-stent restenosis unlikely. When we excluded the intervened upon segments from the MRA calculations, both at baseline and post-revascularization, there was no change in the other vascular territories. We did not measure the extent of collateral blood vessels seen on MRA, which could affect the relationship between macrovascular stenosis and calf muscle measures of perfusion and metabolism.