Blood Flow

In normal adults, the common femoral artery blood flow measured at rest by a dye dilution technique is approximately 500 mL/min and can decrease at rest to 300 mL/min in patients with claudication. During exercise, leg blood flow in healthy persons can increase 30-fold to the working lower extremity muscles, but in patients with PAD this blood flow might not increase beyond two to three times basal flow rates. This supply-and-demand mismatch is only one cause of ischemic claudication symptoms. Other causes coexist, such as muscle deconditioning, denervation, and loss of skeletal myocytes, which also contribute to the inability to sustain functional performance.

In animal studies, limb blood flow can return to baseline within a year after femoral artery ligation owing to the development of robust collaterals. Such collaterals also occur in patients with PAD, but collateral flow does not support normal exercise perfusion. Exercise training does not cause either conduit artery blood flow or collateral circulation flow to increase to normal levels. This strongly demonstrates that other mechanism(s) of action underpin the dramatic improvement of symptoms and walking distance. In response to training, flow may be preferentially shunted from minimally active muscles (low oxygen-extraction rate) to exercising muscles (high oxygen-extraction rate). What is proved is that improvement in major conduit artery blood flow is not a prerequisite for the success of an exercise program for PAD patients.

Change in Muscle Metabolism

Skeletal muscle function depends on a continuous supply of adenosine triphosphate (ATP), which serves as an immediately available form of energy. The ATP stored in muscle is sufficient for only a short period of activity, and much larger amounts of energy are stored as creatine phosphate, which can be rapidly converted to ATP (Figure 1). During rest or light exercise, skeletal muscles use fatty acids as the main source of energy. These can only be used by the oxidative processes in the mitochondria. Increasing the exercise intensity leads to glycolysis of carbohydrate. When compared with glucose, fatty acid oxidation generates more ATP, but at a higher oxygen cost.

Trained adaptation after endurance training is manifested by the ability to use fatty acids more effectively, as demonstrated by trained athletes. In patients with PAD, aerobic generation of ATP becomes inadequate and anaerobic metabolism predominates. This results in an increase in lactic acid production and depletion of ATP and creatine phosphate, leading to pain, a slower recovery of high-energy phosphate substrate in the muscles, poor physical tolerance of exercise, and a prolonged recovery time.

There are two types of skeletal muscle fibers: type I and type II. Type I fibers have more mitochondria and higher oxidative capacity and are specialized for sustained activity such as walking or distance running. These muscle fibers require an uninterrupted blood flow to supply the large amounts of ATP that can be produced only by oxidative (aerobic) metabolism. For type II fibers, on the other hand, a limited supply of ATP can be generated from phosphocreatine and by anaerobic glycolysis and do not depend on oxidative metabolism. Thus, in these fibers the rate of energy expenditure can exceed that of energy production, with an associated oxygen debt and lactic acid production. Some studies have suggested a more preferential loss of type II fibers in patients with severe PAD that leads to a higher concentration of type I fibers than type II.

Chronic ischemia also affects other specialized cells such as those of the peripheral nervous system. In most patients with mild to moderate disease, changes caused by denervation and reinnervation are seen in both motor and sensory nerves, as reflected by the fact that 88% of patients with claudication have sensory impairment and 56% have motor weakness, with detrimental effects on walking biomechanics.

Patients with PAD have an increase in oxidative enzymes such as citrate synthase and cytochrome oxidase in the calf muscles, which is reversed following vascular bypass procedures. In animal studies, hypoxia per se does not induce an increase in the metabolic capacity of muscles; a combination of hypoxia and physical activity is required to stimulate enzyme production. Patients with claudication who exercise infrequently and athletes who stop training share the same histological findings. The requirement for ATP in patients with claudication is twice as high as in normal controls for a standard workload. This metabolic inefficiency is supported by the finding of an accumulation of acylcarnitine, a marker of muscle metabolic rate. Therefore, inefficient muscle function is produced by a multiplicity of proven mechanisms, regardless of blood flow.