Peripheral Arterial Disease Pathogenesis

The underlying disease process in PAD is the result of atherosclerosis in the arterial circulation of the lower extremity, caused by similar pathogenic mechanisms as for coronary and cerebral atherosclerosis. Arterial occlusive disease results in reduced blood flow, particularly to the calf muscles during exercise in patients with claudication, but with critical leg ischemia, blood flow is inadequate to meet the resting metabolic demands of the limb.

Importantly, altered hemodynamics do not completely explain the pathophysiology of claudication.

Work from several laboratories has demonstrated secondary changes in the skeletal muscle of patients with PAD that are consistent with motor nerve injury and loss of type II muscle fibers leading to muscle weakness.

In addition, these patients acquire a metabolic myopathy characterized by the presence of somatic mutations in the mitochondrial genome, alteration in the expression of mitochondrial enzymes, and the accumulation of metabolic intermediates that have functional significance. These abnormalities are associated with specific defects in the activity of complex I and complex III of the electron transport chain that provide further evidence of a chronic, ischemia-induced myopathy in PAD.

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