Biology Reference
In-Depth Information
1.1 Pathophysiology of IC
Typical symptoms of IC are leg-muscle fatigue, discomfort, or pain on exertion that
are relieved with rest. The underlying pathophysiology involves a limitation in
blood supply during walking/exercise leading to repeated ischemia-reperfusion
injury and dysfunctional skeletal muscle metabolism (Fig.
1
). Individuals with IC
have sufficient blood flow to the leg at rest so that limb ischemic symptoms are
absent. However, during walking, the oxygen demand in the leg skeletal muscle is
increased and in atherosclerotic arteries such demand cannot be met by increasing
blood flow. Continued muscle performance must then rely on oxygen-independent
ATP production from phosphocreatine hydrolysis and glycolysis (Greenhaff et al.
2004
). Ischemia and the accumulation of metabolic byproducts can lead to the rapid
onset of muscle pain and fatigue.
In addition to reduced blood supply, persistent pathophysiological changes occur
in the skeletal muscle of IC patients as a consequence of repeated episodes of ischemia
and reperfusion injury. Histologically, patients with PAD have a lower portion of type
I muscle fiber and fewer capillaries per muscle fiber (Askew et al.
2005
). Skeletal
muscle in these patients also demonstrates defectivemitochondrial function, including
the accumulation of acyl-coenzyme A intermediate and acylcarnitine, implying
Pathophysiology of IC
Mismatch of blood supply vs.
demand during exercise
(arterial defect due to atherosclerosis)
Structural changes in muscle
Insufficient metabolism
Reduced exercise capacity
Reduced quality of life
Improve metabolism
(Exercise, Carnitine, PDE
inhibitors?)
Increase blood supply
by attacking atherosclerosis
(PDE3 inhibitors and statins)
Future drugs
Fig. 1 Pathology of IC (
gray
box,
top
). Due to atherosclerosis, arteries are significantly narrowed,
resulting in reduced perfusion to the leg muscles during walking/exercise. Repeated ischemia and
reperfusion of the muscle causes pathological changes to the structure of the muscle and its energy
metabolism. The manifestation of these changes results in the symptoms of intermittent claudica-
tion (IC) and reduced quality of life. Future drug development may be directed toward improve-
ment of blood supply and normalization of muscle metabolism (
white
box,
bottom
)
