Abstract
In his 1892 “The Principles and Practice of Medicine,” William Osler described so-called ‘intermittent lameness’ as a symptom of peripheral artery disease (PAD) and recognized that ‘the loss of function and the pain in the muscles were due to the relative ischemia.’ 1 A century of subsequent study has confirmed that relative lack of perfusion to the lower extremities due to arterial insufficiency is indeed a critical prerequisite for a diagnosis of PAD and for development of symptoms of claudication. 2 However, it has also been increasingly recognized that hemodynamic stenosis does not, in and of itself, adequately explain the degree of symptoms in patients with PAD. Although restoration of blood flow (via surgical or endovascular revascularization) produces substantial symptomatic improvement, relief is not always complete. Moreover, non-invasive therapies for claudication symptoms, such as cilostazol and exercise training, improve walking time without a measurable change in blood flow.3,4 Recognizing the lack of correlation between measures of arterial stenosis (such as the ankle-brachial index, or ABI) and functional capacity has led many investigators to explore non-hemodynamic factors that might contribute to the pathophysiology of intermittent claudication. Putative non-hemodynamic contributors include impaired endothelial function, inflammation, insulin resistance, and skeletal muscle metabolic dysfunction, all of which have been noted in patients with PAD.
Several lines of evidence suggest that impaired metabolism in the skeletal muscles in patients with PAD and intermittent claudication may play an important role. Earlier shifts to anaerobic metabolism during exercise and elevated lactate levels even at rest have been reported. 5 In addition, in gastrocnemius muscle biopsies from patients with PAD, there are decreased levels of mitochondrial enzymes and inappropriate accumulation of intermediates of oxidative metabolism, such as acylcarnitines, suggesting ineffective cellular metabolism.6,7 PAD is also associated with insulin resistance and impaired skeletal muscle uptake of nutrients, such as glucose, that are critical for energy generation.8,9 Whether these and other abnormalities can be reversed by any of our existing therapies, be it exercise training or revascularization, remains unknown.
In this issue of Vascular Medicine, West and colleagues seek to understand whether restoration of blood flow by percutaneous intervention of the lower extremities can improve measures of calf muscle metabolism and tissue perfusion. 10 Their group has previously demonstrated in elegant work using 31P magnetic resonance spectroscopy that phosphocreatine (PCr) recovery after exercise is delayed in patients with claudication, providing additional evidence of ineffective oxidative phosphorylation in the skeletal muscle of PAD patients. Using novel magnetic resonance techniques, they have also demonstrated that reduced calf muscle metabolism correlates with impaired exercise capacity but not with local tissue perfusion. In the current study, they demonstrate an improvement in calf muscle energetics, measured as an improvement in PCr recovery time, in 10 patients undergoing percutaneous intervention for lifestyle-limiting claudication. There was a corresponding increase in ABI, but no increase in walking time, which likely reflects a lack of statistical power given the small sample size. The authors conclude that these data suggest that restoration of blood flow leads to improved skeletal muscle metabolic function.
Though the data are provocative, to claim causality and ascribe the improvement in PCr recovery to restoration of blood flow alone is premature. The confounding effect of improved physical activity 10 months after revascularization cannot be discounted. Given that symptoms improve soon after revascularization, patients will naturally walk more. Increased physical activity, as occurs with formal exercise training, is a proven effective treatment for claudication and one of the best non-invasive treatment options available for patients with claudication. After engaging in an exercise program, individuals with PAD can improve walking ability by as much as 120-150%. 4 In fact, the recently published CLEVER (The Claudication: Exercise Versus Endoluminal Revascularization) trial found that supervised exercise training for six months in patients with aorto-iliac disease and claudication resulted in a greater improvement in walking time than optimal medical therapy alone or revascularization. 11 Although the exact mechanism by which exercise improves walking distance in PAD is not understood, Hiatt and colleagues have shown that exercise promotes advantageous metabolic adaptations in skeletal muscle in patients with claudication, including 30% increase in peak oxygen consumption (V02) and improved intermediary metabolism, indicated by decreased calf muscle short-chain acylcarnitine levels. 12 Although with such a small sample size, West and colleagues did not see statistically significant changes in exercise time, six minute walk test, or peak V02, it remains possible that the metabolic changes noted in the current study are not a result of restoration of blood flow, but instead the result of improved physical activity.
Despite these limitations, the authors are to be applauded for their efforts to think ‘outside the hemodynamics box.’ What is eminently clear is that the pathophysiology of intermittent claudication is complex and multifactorial. Atherosclerotic stenosis is a necessary component, but future studies are required to better understand the relative contributions of non-hemodynamic factors that likely contribute to claudication symptoms. Work of this nature will hopefully guide the development and application of novel non-invasive therapies to improve functional impairment in these patients.
The potential for clinical impact is tremendous. PAD is highly prevalent, estimated to affect more than 7 million adults in the US alone. 13 Upwards of 10-35% have typical claudication symptoms, many more likely have atypical symptoms, and treatment options are sorely limited at present. 2 A lack of understanding of the underlying pathophysiology has been a critical barrier to the development of novel therapies for this disease. But exploring the mechanisms by which our existing therapies actually produce a clinical benefit is a pretty good place to start.