Materiały źródłowe

• #1 Claudication – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/claudication/symptoms-causes/syc-20370952

  Claudication is pain caused by too little blood flow to muscles during exercise. Most often this pain occurs in the legs after walking at a certain pace and for a certain amount of time depending on the severity of the condition. […] Claudication is technically a symptom of disease, most often peripheral artery disease, a narrowing of arteries in the limbs that restricts blood flow. […] Claudication is usually a symptom of peripheral artery disease, in which the arteries that supply blood to the arms or legs, usually the legs, are narrowed. The narrowing is usually due to a buildup of fatty deposits (plaques) on the artery walls. […] Claudication is most often a symptom of peripheral artery disease. The peripheral arteries are the large vessels that deliver blood to the legs and arms.

• #2 Intermittent Claudication: Symptoms & Treatment

  https://my.clevelandclinic.org/health/symptoms/22046-intermittent-claudication

  Intermittent claudication is muscle pain that happens when you’re active and then stops when you rest. This happens when your body can’t meet your muscles’ need for oxygen. It’s usually a symptom of blood flow problems. Claudication-related pain happens because your blood isn’t moving through your body well. This can be a sign of serious health issues. The main cause of intermittent claudication is a condition called peripheral artery disease (PAD). This condition happens with atherosclerosis, a buildup of a wax-like substance called plaque (atheroma) on the inside of your arteries. As that buildup gets worse, there’s less room for blood to flow through those arteries. PAD happens when plaque buildup narrows the arteries that feed your limbs (especially your legs). Much like a closed lane on a road causes traffic to slow down and back up, narrowing of your blood vessels slows down blood flow to your limbs. Intermittent claudication treatment can take various forms. All of them aim to improve blood flow where you feel pain. While treatments can’t cure or reverse this symptom, they can improve it. Claudication increases your risk for serious heart and circulatory problems. This is why treatment usually involves preventive measures to avoid those complications. Many of the at-home treatments for intermittent claudication can also help prevent it. While it’s not always possible to prevent it completely, it may be possible to delay when it develops.

• #3 Claudication – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/claudication/symptoms-causes/syc-20370952

  Peripheral artery disease is damage to an artery that restricts the flow of blood in an arm or leg (a limb). When you’re at rest, the limited blood flow is generally enough. When you’re active, however, the muscles aren’t getting enough oxygen and nutrients to work well and remain healthy. […] Damage to peripheral arteries is usually caused by atherosclerosis. Atherosclerosis is the buildup of fats, cholesterol and other substances in and on the artery walls. This buildup is called plaque. The plaque can cause the arteries to narrow, blocking blood flow. The plaque can also burst, leading to a blood clot.

• #4 Claudication: Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/21972-claudication

  Claudication is muscle pain from blood flow issues in your legs. This happens because of narrowing in your arteries. […] Claudication is a classic symptom of peripheral artery disease (a narrowing of the blood vessels in your legs) and atherosclerosis (hardening of the arteries). Peripheral artery disease and atherosclerosis increase your risk of heart attack and stroke. […] Claudication causes include circulation issues that keep your body from getting the amount of oxygen it needs. All the cells in your body need oxygen to function. When youre more active, even just for a short walk, the cells in your muscles need more oxygen. […] When people with poor circulation are more active, they feel pain. This is because their muscles need more oxygen than their body can provide. This type of pain is most common in your legs, but can also happen in your arms.

• #5 Intermittent Claudication – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430778/

  Intermittent claudication occurs due to atherosclerosis-mediated narrowing of lower extremity vessels. […] The key feature of intermittent claudication is that the muscle discomfort is reproducible. […] The most common location of plaque formation in peripheral arterial disease is in the superficial femoral artery, which may lead to IC symptoms in the calf. […] The resting blood flow in these individuals is similar to healthy adults, but during exercise or physical activity, the blood cannot flow through the areas of obstruction. […] Intermittent claudication is a common manifestation of peripheral arterial disease (PAD), which includes atherosclerotic stenosis of arteries in the extremities. […] The pain usually comes on during physical activity and subsides after a period of rest. […] The typical presentation of intermittent claudication is lower extremity pain during ambulation that is relieved with rest. […] Intermittent claudication is a very common problem seen in patients with diabetes mellitus and people who smoke.

• #6 Intermittent Claudication – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430778/

  Intermittent claudication occurs due to atherosclerosis-mediated narrowing of lower extremity vessels. […] The key feature of intermittent claudication is that the muscle discomfort is reproducible. […] The most common location of plaque formation in peripheral arterial disease is in the superficial femoral artery, which may lead to IC symptoms in the calf. […] The resting blood flow in these individuals is similar to healthy adults, but during exercise or physical activity, the blood cannot flow through the areas of obstruction. […] Intermittent claudication is a common manifestation of peripheral arterial disease (PAD), which includes atherosclerotic stenosis of arteries in the extremities. […] The pain usually comes on during physical activity and subsides after a period of rest. […] The typical presentation of intermittent claudication is lower extremity pain during ambulation that is relieved with rest. […] Intermittent claudication is a very common problem seen in patients with diabetes mellitus and people who smoke.

• #7 Intermittent Claudication | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/23609

  Intermittent claudication occurs due to atherosclerosis-mediated narrowing of lower extremity vessels. […] The subsequent dysfunction of endothelial cells promotes localized deposition of oxidized-LDL and synthesis of pro-inflammatory factors. […] This creates a fibro-inflammatory plaque that propagates as macrophages are recruited and become resident foam cells as they phagocytize the oxidized-LDL. […] The most common location of plaque formation in peripheral arterial disease is in the superficial femoral artery, which may lead to IC symptoms in the calf. […] The resting blood flow in these individuals is similar to healthy adults, but during exercise or physical activity, the blood cannot flow through the areas of obstruction.

• #8 Intermittent Claudication | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/23609

  Intermittent claudication occurs due to atherosclerosis-mediated narrowing of lower extremity vessels. […] The subsequent dysfunction of endothelial cells promotes localized deposition of oxidized-LDL and synthesis of pro-inflammatory factors. […] This creates a fibro-inflammatory plaque that propagates as macrophages are recruited and become resident foam cells as they phagocytize the oxidized-LDL. […] The most common location of plaque formation in peripheral arterial disease is in the superficial femoral artery, which may lead to IC symptoms in the calf. […] The resting blood flow in these individuals is similar to healthy adults, but during exercise or physical activity, the blood cannot flow through the areas of obstruction.

• #9 Peripheral Arterial Occlusive Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/460178-overview

  Claudication, which is defined as reproducible ischemic muscle pain, is one of the most common manifestations of peripheral arterial occlusive disease (PAOD) caused by atherosclerosis. Claudication occurs during physical activity and is relieved after a short rest. Pain develops because of inadequate blood flow. […] Single or multiple arterial stenoses produce impaired hemodynamics at the tissue level in patients with PAOD. Arterial stenoses lead to alterations in the distal perfusion pressures available to affected muscle groups. […] In PAOD, however, blood flow cannot maximally increase in muscle tissue during exercise, because proximal arterial stenoses prevent compensatory vasodilation. When the metabolic demands of the muscle exceed blood flow, claudication symptoms ensue. At the same time, a longer recovery period is required for blood flow to return to baseline once exercise is terminated.

• #10 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Pathogenesis of Limb Complications and Walking Impairment in PAD […] Arterial obstruction by flow-limiting lesions underlies the lower extremity manifestations of PAD. In a demand-ischemia model, intermittent claudication reflects inadequate augmentation of skeletal muscle perfusion during exercise. Several lines of evidence, however, indicate that the drivers of the limb symptoms in PAD are more complex. Atherosclerotic disease occurs in the context of multiple disease processes that interfere with exercise ability. Potential mechanisms are detailed in the Figure and the current evidence supporting the role of reduced blood flow, vascular dysfunction, altered muscle metabolism, impaired angiogenesis, and inflammatory activation in producing limb discomfort and functional limitation is discussed in this section.

• #11 Peripheral Arterial Occlusive Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/460178-overview

  Claudication, which is defined as reproducible ischemic muscle pain, is one of the most common manifestations of peripheral arterial occlusive disease (PAOD) caused by atherosclerosis. Claudication occurs during physical activity and is relieved after a short rest. Pain develops because of inadequate blood flow. […] Single or multiple arterial stenoses produce impaired hemodynamics at the tissue level in patients with PAOD. Arterial stenoses lead to alterations in the distal perfusion pressures available to affected muscle groups. […] In PAOD, however, blood flow cannot maximally increase in muscle tissue during exercise, because proximal arterial stenoses prevent compensatory vasodilation. When the metabolic demands of the muscle exceed blood flow, claudication symptoms ensue. At the same time, a longer recovery period is required for blood flow to return to baseline once exercise is terminated.

• #12 Peripheral Arterial Occlusive Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/460178-overview

  Claudication, which is defined as reproducible ischemic muscle pain, is one of the most common manifestations of peripheral arterial occlusive disease (PAOD) caused by atherosclerosis. Claudication occurs during physical activity and is relieved after a short rest. Pain develops because of inadequate blood flow. […] Single or multiple arterial stenoses produce impaired hemodynamics at the tissue level in patients with PAOD. Arterial stenoses lead to alterations in the distal perfusion pressures available to affected muscle groups. […] In PAOD, however, blood flow cannot maximally increase in muscle tissue during exercise, because proximal arterial stenoses prevent compensatory vasodilation. When the metabolic demands of the muscle exceed blood flow, claudication symptoms ensue. At the same time, a longer recovery period is required for blood flow to return to baseline once exercise is terminated.

• #13 Peripheral Arterial Occlusive Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/460178-overview

  Claudication, which is defined as reproducible ischemic muscle pain, is one of the most common manifestations of peripheral arterial occlusive disease (PAOD) caused by atherosclerosis. Claudication occurs during physical activity and is relieved after a short rest. Pain develops because of inadequate blood flow. […] Single or multiple arterial stenoses produce impaired hemodynamics at the tissue level in patients with PAOD. Arterial stenoses lead to alterations in the distal perfusion pressures available to affected muscle groups. […] In PAOD, however, blood flow cannot maximally increase in muscle tissue during exercise, because proximal arterial stenoses prevent compensatory vasodilation. When the metabolic demands of the muscle exceed blood flow, claudication symptoms ensue. At the same time, a longer recovery period is required for blood flow to return to baseline once exercise is terminated.

• #14 Peripheral Arterial Occlusive Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/460178-overview

  In the atherosclerotic limb, each stenotic segment acts to reduce the pressure head experienced by distal muscle groups. Correspondingly, at rest, the measured blood pressure at the ankle is less than that measured in a healthy person. Once physical activity starts, the reduction in pressure produced by the atherosclerotic lesion becomes more significant, and the distal pressure is greatly diminished. […] The phenomenon of increased blood flow causing decreased pressure distally to an area of stenosis is a matter of physics. Poiseuille calculated energy losses across areas of resistance with varying flow rates by using the following equation: Pressure difference = 8QvL/r4 where Q is flow, v is viscosity, L is the length of the stenotic area, and r is the radius of the open area within the stenosis. In this equation, the pressure gradient is directly proportional to the flow and the length of the stenosis and inversely proportional to the fourth power of the radius. Thus, although increasing the flow rate directly increases the pressure gradient at any given radius, these effects are much less marked than those due to changes in the radius of the stenosis. […] Because the radius is raised to the fourth power, it is the factor that has the most dramatic impact on a pressure gradient across a lesion. This impact is additive when two or more occlusive lesions are located sequentially within the same artery.

• #15 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Vascular Dysfunction in PAD […] Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. A healthy vascular endothelium produces several vasodilator substances, including nitric oxide, which has pluripotent vascular benefits such as inhibiting platelets, reducing smooth muscle proliferation, preventing leukocyte adhesion, and promoting angiogenesis. Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. Vascular dysfunction may also exacerbate the vasoconstrictive effects of catecholamines and limit flow-mediated dilation. Together, the effects of abnormal endothelial function may worsen clinical symptoms in PAD. […] Several studies have described the clinical relevance of endothelial dysfunction in PAD. Measures of endothelium-dependent vasodilator function, including brachial artery flow-mediated dilation and acetylcholine-induced vasodilation, are lower in patients with PAD. Both conduit and microvascular endothelial function were evaluated in 1,320 subjects, including 377 with PAD, and compared with patients with CAD; the patients with PAD had more severe impairment of multiple metrics of vasodilator function. The presence of endothelial dysfunction in patients with PAD is consistent with a systemic disruption of vascular function. Impairment of the hyperemic blood flow response is associated with functional impairment in PAD. There is evidence connecting greater brachial flow-mediated dilation to greater physical activity in daily life in patients with PAD. Recent studies related impaired brachial flow-mediated dilation with reduced self-reported walking ability and 6-minute walk test. Interestingly, patients with PAD have decreased superficial femoral artery flow-mediated dilation associated with lesion severity. Arterial stiffness measures, including higher pulse pressure and augmentation index, also are associated with reduced walking time in patients with PAD. Endothelial dysfunction measured by brachial flow-mediated dilation and reactive hyperemia predicts a higher risk of events after vascular surgery. Whether endothelial dysfunction predicts progressive functional impairment has not been evaluated.

• #16 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Vascular Dysfunction in PAD […] Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. A healthy vascular endothelium produces several vasodilator substances, including nitric oxide, which has pluripotent vascular benefits such as inhibiting platelets, reducing smooth muscle proliferation, preventing leukocyte adhesion, and promoting angiogenesis. Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. Vascular dysfunction may also exacerbate the vasoconstrictive effects of catecholamines and limit flow-mediated dilation. Together, the effects of abnormal endothelial function may worsen clinical symptoms in PAD. […] Several studies have described the clinical relevance of endothelial dysfunction in PAD. Measures of endothelium-dependent vasodilator function, including brachial artery flow-mediated dilation and acetylcholine-induced vasodilation, are lower in patients with PAD. Both conduit and microvascular endothelial function were evaluated in 1,320 subjects, including 377 with PAD, and compared with patients with CAD; the patients with PAD had more severe impairment of multiple metrics of vasodilator function. The presence of endothelial dysfunction in patients with PAD is consistent with a systemic disruption of vascular function. Impairment of the hyperemic blood flow response is associated with functional impairment in PAD. There is evidence connecting greater brachial flow-mediated dilation to greater physical activity in daily life in patients with PAD. Recent studies related impaired brachial flow-mediated dilation with reduced self-reported walking ability and 6-minute walk test. Interestingly, patients with PAD have decreased superficial femoral artery flow-mediated dilation associated with lesion severity. Arterial stiffness measures, including higher pulse pressure and augmentation index, also are associated with reduced walking time in patients with PAD. Endothelial dysfunction measured by brachial flow-mediated dilation and reactive hyperemia predicts a higher risk of events after vascular surgery. Whether endothelial dysfunction predicts progressive functional impairment has not been evaluated.

• #17 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/ja

  Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. […] Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. […] In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. […] Chronic limb ischemia initiates several vascular structural adaptations. […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. […] Inflammatory activation participates in the development of atherosclerosis and may play a part in the generation of limb symptoms.

• #18 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Vascular Dysfunction in PAD […] Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. A healthy vascular endothelium produces several vasodilator substances, including nitric oxide, which has pluripotent vascular benefits such as inhibiting platelets, reducing smooth muscle proliferation, preventing leukocyte adhesion, and promoting angiogenesis. Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. Vascular dysfunction may also exacerbate the vasoconstrictive effects of catecholamines and limit flow-mediated dilation. Together, the effects of abnormal endothelial function may worsen clinical symptoms in PAD. […] Several studies have described the clinical relevance of endothelial dysfunction in PAD. Measures of endothelium-dependent vasodilator function, including brachial artery flow-mediated dilation and acetylcholine-induced vasodilation, are lower in patients with PAD. Both conduit and microvascular endothelial function were evaluated in 1,320 subjects, including 377 with PAD, and compared with patients with CAD; the patients with PAD had more severe impairment of multiple metrics of vasodilator function. The presence of endothelial dysfunction in patients with PAD is consistent with a systemic disruption of vascular function. Impairment of the hyperemic blood flow response is associated with functional impairment in PAD. There is evidence connecting greater brachial flow-mediated dilation to greater physical activity in daily life in patients with PAD. Recent studies related impaired brachial flow-mediated dilation with reduced self-reported walking ability and 6-minute walk test. Interestingly, patients with PAD have decreased superficial femoral artery flow-mediated dilation associated with lesion severity. Arterial stiffness measures, including higher pulse pressure and augmentation index, also are associated with reduced walking time in patients with PAD. Endothelial dysfunction measured by brachial flow-mediated dilation and reactive hyperemia predicts a higher risk of events after vascular surgery. Whether endothelial dysfunction predicts progressive functional impairment has not been evaluated.

• #19 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Vascular Dysfunction in PAD […] Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. A healthy vascular endothelium produces several vasodilator substances, including nitric oxide, which has pluripotent vascular benefits such as inhibiting platelets, reducing smooth muscle proliferation, preventing leukocyte adhesion, and promoting angiogenesis. Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. Vascular dysfunction may also exacerbate the vasoconstrictive effects of catecholamines and limit flow-mediated dilation. Together, the effects of abnormal endothelial function may worsen clinical symptoms in PAD. […] Several studies have described the clinical relevance of endothelial dysfunction in PAD. Measures of endothelium-dependent vasodilator function, including brachial artery flow-mediated dilation and acetylcholine-induced vasodilation, are lower in patients with PAD. Both conduit and microvascular endothelial function were evaluated in 1,320 subjects, including 377 with PAD, and compared with patients with CAD; the patients with PAD had more severe impairment of multiple metrics of vasodilator function. The presence of endothelial dysfunction in patients with PAD is consistent with a systemic disruption of vascular function. Impairment of the hyperemic blood flow response is associated with functional impairment in PAD. There is evidence connecting greater brachial flow-mediated dilation to greater physical activity in daily life in patients with PAD. Recent studies related impaired brachial flow-mediated dilation with reduced self-reported walking ability and 6-minute walk test. Interestingly, patients with PAD have decreased superficial femoral artery flow-mediated dilation associated with lesion severity. Arterial stiffness measures, including higher pulse pressure and augmentation index, also are associated with reduced walking time in patients with PAD. Endothelial dysfunction measured by brachial flow-mediated dilation and reactive hyperemia predicts a higher risk of events after vascular surgery. Whether endothelial dysfunction predicts progressive functional impairment has not been evaluated.

• #20 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Vascular Dysfunction in PAD […] Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. A healthy vascular endothelium produces several vasodilator substances, including nitric oxide, which has pluripotent vascular benefits such as inhibiting platelets, reducing smooth muscle proliferation, preventing leukocyte adhesion, and promoting angiogenesis. Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. Vascular dysfunction may also exacerbate the vasoconstrictive effects of catecholamines and limit flow-mediated dilation. Together, the effects of abnormal endothelial function may worsen clinical symptoms in PAD. […] Several studies have described the clinical relevance of endothelial dysfunction in PAD. Measures of endothelium-dependent vasodilator function, including brachial artery flow-mediated dilation and acetylcholine-induced vasodilation, are lower in patients with PAD. Both conduit and microvascular endothelial function were evaluated in 1,320 subjects, including 377 with PAD, and compared with patients with CAD; the patients with PAD had more severe impairment of multiple metrics of vasodilator function. The presence of endothelial dysfunction in patients with PAD is consistent with a systemic disruption of vascular function. Impairment of the hyperemic blood flow response is associated with functional impairment in PAD. There is evidence connecting greater brachial flow-mediated dilation to greater physical activity in daily life in patients with PAD. Recent studies related impaired brachial flow-mediated dilation with reduced self-reported walking ability and 6-minute walk test. Interestingly, patients with PAD have decreased superficial femoral artery flow-mediated dilation associated with lesion severity. Arterial stiffness measures, including higher pulse pressure and augmentation index, also are associated with reduced walking time in patients with PAD. Endothelial dysfunction measured by brachial flow-mediated dilation and reactive hyperemia predicts a higher risk of events after vascular surgery. Whether endothelial dysfunction predicts progressive functional impairment has not been evaluated.

• #21 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/ja

  Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. […] Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. […] In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. […] Chronic limb ischemia initiates several vascular structural adaptations. […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. […] Inflammatory activation participates in the development of atherosclerosis and may play a part in the generation of limb symptoms.

• #22 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Impaired Angiogenesis and Reduced Microcirculatory Flow […] Chronic limb ischemia initiates several vascular structural adaptations. Insufficient blood supply produced by arterial ischemia induces a complex program of vascular growth. Multiple factors have been identified that regulate angiogenesis in animal models, including vascular endothelial growth factor (VEGF), fibroblast growth factor, hepatocyte growth factor, and hypoxia-inducible factor 1-. In addition, specific bone marrow-derived cells may target regions of ischemia and promote vessel regeneration. Genetic regulators, including microRNA, are also important for angiogenesis. MicroRNA93 shows lower expression in animals genetically predisposed to severe clinical phenotypes such as hindlimb ischemia. In animal models, there is abundant evidence that therapies stimulating angiogenesis increase skeletal muscle perfusion and restore functional status.

• #23 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Impaired Angiogenesis and Reduced Microcirculatory Flow […] Chronic limb ischemia initiates several vascular structural adaptations. Insufficient blood supply produced by arterial ischemia induces a complex program of vascular growth. Multiple factors have been identified that regulate angiogenesis in animal models, including vascular endothelial growth factor (VEGF), fibroblast growth factor, hepatocyte growth factor, and hypoxia-inducible factor 1-. In addition, specific bone marrow-derived cells may target regions of ischemia and promote vessel regeneration. Genetic regulators, including microRNA, are also important for angiogenesis. MicroRNA93 shows lower expression in animals genetically predisposed to severe clinical phenotypes such as hindlimb ischemia. In animal models, there is abundant evidence that therapies stimulating angiogenesis increase skeletal muscle perfusion and restore functional status.

• #24 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/ja

  Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. […] Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. […] In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. […] Chronic limb ischemia initiates several vascular structural adaptations. […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. […] Inflammatory activation participates in the development of atherosclerosis and may play a part in the generation of limb symptoms.

• #25 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. One study found that lower capillary density in PAD patients, as assessed by skeletal muscle biopsy, was associated with reduced functional measures including peak walking time. Similarly, imaging studies using MRI or contrast-enhanced ultrasound have demonstrated lower microvascular flow in the calf musculature in PAD patients. Exercise blood flow measured by contrast ultrasound was related to claudication time in a treadmill test. Also, reduced skeletal muscle blood flow as measured by MR during exercise was associated with impaired 6-minute walking time. Taken together, evidence from clinical investigations supports the concept that microcirculatory dysfunction affects limb function in patients with PAD, and that enhanced calf blood flow may be a therapeutic avenue. Thus, pro-angiogenic therapy approaches to treating PAD have been used in many studies of growth factor and cell-based therapies. As reviewed recently, these clinical trials have failed to convincingly demonstrate a reduction in limb symptoms, including pain and wound healing.

• #26 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  There are a number of potential explanations for the disappointment with pro-angiogenic interventions in patients with PAD. Translational studies emphasize the relevance of systemic disease and risk factors to impaired angiogenesis in clinical PAD. Paradoxically, patients with PAD have higher levels of VEGF-A, a key promoter of angiogenesis. A recent study found evidence that an anti-angiogenic isoform of VEGF, VEGF-165b, is upregulated in both preclinical models and patients with PAD. The enhanced expression of anti-angiogenic VEGF is driven by the pro-inflammatory Wnt5a/JNK pathway, which is activated by obesity. Thus, metabolic dysfunction may mediate inadequate angiogenesis in PAD by generating anti-angiogenic factors and complicate the responses to therapies aimed to stimulate angiogenesis. Resolvin D2, an anti-inflammatory regulator of tissue reparative responses, is important in both hindlimb ischemia models and patients with PAD. Resolvin D2 treatment enhances arteriogenesis and reduces inflammation, including in diabetic animals. Thus, the next generation of pro-angiogenic therapies may require evaluation in animal models with metabolic dysfunction and target both inflammation and vascular growth.

• #27 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  There are a number of potential explanations for the disappointment with pro-angiogenic interventions in patients with PAD. Translational studies emphasize the relevance of systemic disease and risk factors to impaired angiogenesis in clinical PAD. Paradoxically, patients with PAD have higher levels of VEGF-A, a key promoter of angiogenesis. A recent study found evidence that an anti-angiogenic isoform of VEGF, VEGF-165b, is upregulated in both preclinical models and patients with PAD. The enhanced expression of anti-angiogenic VEGF is driven by the pro-inflammatory Wnt5a/JNK pathway, which is activated by obesity. Thus, metabolic dysfunction may mediate inadequate angiogenesis in PAD by generating anti-angiogenic factors and complicate the responses to therapies aimed to stimulate angiogenesis. Resolvin D2, an anti-inflammatory regulator of tissue reparative responses, is important in both hindlimb ischemia models and patients with PAD. Resolvin D2 treatment enhances arteriogenesis and reduces inflammation, including in diabetic animals. Thus, the next generation of pro-angiogenic therapies may require evaluation in animal models with metabolic dysfunction and target both inflammation and vascular growth.

• #28 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  There are a number of potential explanations for the disappointment with pro-angiogenic interventions in patients with PAD. Translational studies emphasize the relevance of systemic disease and risk factors to impaired angiogenesis in clinical PAD. Paradoxically, patients with PAD have higher levels of VEGF-A, a key promoter of angiogenesis. A recent study found evidence that an anti-angiogenic isoform of VEGF, VEGF-165b, is upregulated in both preclinical models and patients with PAD. The enhanced expression of anti-angiogenic VEGF is driven by the pro-inflammatory Wnt5a/JNK pathway, which is activated by obesity. Thus, metabolic dysfunction may mediate inadequate angiogenesis in PAD by generating anti-angiogenic factors and complicate the responses to therapies aimed to stimulate angiogenesis. Resolvin D2, an anti-inflammatory regulator of tissue reparative responses, is important in both hindlimb ischemia models and patients with PAD. Resolvin D2 treatment enhances arteriogenesis and reduces inflammation, including in diabetic animals. Thus, the next generation of pro-angiogenic therapies may require evaluation in animal models with metabolic dysfunction and target both inflammation and vascular growth.

• #29 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/ja

  Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. […] Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. […] In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. […] Chronic limb ischemia initiates several vascular structural adaptations. […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. […] Inflammatory activation participates in the development of atherosclerosis and may play a part in the generation of limb symptoms.

• #30 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Skeletal Muscle Alterations and Mitochondrial Dysfunction […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. Altered skeletal muscle structural and metabolic properties magnify ischemia-induced functional impairment. Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity. Further, the skeletal muscle displays lower density and higher fat content, which may limit muscle function. On muscle biopsy, there is greater muscle cell apoptosis and reduced type I fiber content, which may interfere with performance. Ischemia also damages peripheral nerve function, with evidence of poor nerve conduction in patients with severe PAD. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. Both the circulating and muscle levels of intermediates of oxidative phosphorylation, including acylcarnitines, are higher in PAD, suggesting reduced mitochondrial metabolism. In the muscle tissue, mitochondrial mass is higher; however, there is lower activity of several mitochondrial complexes impeding ATP generation and enhancing reactive oxygen species production. Altered mitochondrial function restricts oxygen utilization and may also promote endothelial dysfunction as mitochondrial-derived oxidants reduce nitric oxide bioactivity. Muscle fiber degeneration is associated with evidence of oxidative stress, including carbonyl groups and 4-hydroxy-2-nonenal adducts, protein modifications produced by reactive oxygen species. Mitochondrial function is also important in angiogenesis, consistent with the notion of coupling of vascular and muscular parameters. In hindlimb ischemia models, peroxisome-proliferator-activated receptor- coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, promotes vascular regeneration.

• #31 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Skeletal Muscle Alterations and Mitochondrial Dysfunction […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. Altered skeletal muscle structural and metabolic properties magnify ischemia-induced functional impairment. Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity. Further, the skeletal muscle displays lower density and higher fat content, which may limit muscle function. On muscle biopsy, there is greater muscle cell apoptosis and reduced type I fiber content, which may interfere with performance. Ischemia also damages peripheral nerve function, with evidence of poor nerve conduction in patients with severe PAD. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. Both the circulating and muscle levels of intermediates of oxidative phosphorylation, including acylcarnitines, are higher in PAD, suggesting reduced mitochondrial metabolism. In the muscle tissue, mitochondrial mass is higher; however, there is lower activity of several mitochondrial complexes impeding ATP generation and enhancing reactive oxygen species production. Altered mitochondrial function restricts oxygen utilization and may also promote endothelial dysfunction as mitochondrial-derived oxidants reduce nitric oxide bioactivity. Muscle fiber degeneration is associated with evidence of oxidative stress, including carbonyl groups and 4-hydroxy-2-nonenal adducts, protein modifications produced by reactive oxygen species. Mitochondrial function is also important in angiogenesis, consistent with the notion of coupling of vascular and muscular parameters. In hindlimb ischemia models, peroxisome-proliferator-activated receptor- coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, promotes vascular regeneration.

• #32 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/ja

  Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. […] Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. […] In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. […] Chronic limb ischemia initiates several vascular structural adaptations. […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. […] Inflammatory activation participates in the development of atherosclerosis and may play a part in the generation of limb symptoms.

• #33 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Skeletal Muscle Alterations and Mitochondrial Dysfunction […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. Altered skeletal muscle structural and metabolic properties magnify ischemia-induced functional impairment. Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity. Further, the skeletal muscle displays lower density and higher fat content, which may limit muscle function. On muscle biopsy, there is greater muscle cell apoptosis and reduced type I fiber content, which may interfere with performance. Ischemia also damages peripheral nerve function, with evidence of poor nerve conduction in patients with severe PAD. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. Both the circulating and muscle levels of intermediates of oxidative phosphorylation, including acylcarnitines, are higher in PAD, suggesting reduced mitochondrial metabolism. In the muscle tissue, mitochondrial mass is higher; however, there is lower activity of several mitochondrial complexes impeding ATP generation and enhancing reactive oxygen species production. Altered mitochondrial function restricts oxygen utilization and may also promote endothelial dysfunction as mitochondrial-derived oxidants reduce nitric oxide bioactivity. Muscle fiber degeneration is associated with evidence of oxidative stress, including carbonyl groups and 4-hydroxy-2-nonenal adducts, protein modifications produced by reactive oxygen species. Mitochondrial function is also important in angiogenesis, consistent with the notion of coupling of vascular and muscular parameters. In hindlimb ischemia models, peroxisome-proliferator-activated receptor- coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, promotes vascular regeneration.

• #34 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Skeletal Muscle Alterations and Mitochondrial Dysfunction […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. Altered skeletal muscle structural and metabolic properties magnify ischemia-induced functional impairment. Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity. Further, the skeletal muscle displays lower density and higher fat content, which may limit muscle function. On muscle biopsy, there is greater muscle cell apoptosis and reduced type I fiber content, which may interfere with performance. Ischemia also damages peripheral nerve function, with evidence of poor nerve conduction in patients with severe PAD. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. Both the circulating and muscle levels of intermediates of oxidative phosphorylation, including acylcarnitines, are higher in PAD, suggesting reduced mitochondrial metabolism. In the muscle tissue, mitochondrial mass is higher; however, there is lower activity of several mitochondrial complexes impeding ATP generation and enhancing reactive oxygen species production. Altered mitochondrial function restricts oxygen utilization and may also promote endothelial dysfunction as mitochondrial-derived oxidants reduce nitric oxide bioactivity. Muscle fiber degeneration is associated with evidence of oxidative stress, including carbonyl groups and 4-hydroxy-2-nonenal adducts, protein modifications produced by reactive oxygen species. Mitochondrial function is also important in angiogenesis, consistent with the notion of coupling of vascular and muscular parameters. In hindlimb ischemia models, peroxisome-proliferator-activated receptor- coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, promotes vascular regeneration.

• #35 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Skeletal Muscle Alterations and Mitochondrial Dysfunction […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. Altered skeletal muscle structural and metabolic properties magnify ischemia-induced functional impairment. Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity. Further, the skeletal muscle displays lower density and higher fat content, which may limit muscle function. On muscle biopsy, there is greater muscle cell apoptosis and reduced type I fiber content, which may interfere with performance. Ischemia also damages peripheral nerve function, with evidence of poor nerve conduction in patients with severe PAD. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. Both the circulating and muscle levels of intermediates of oxidative phosphorylation, including acylcarnitines, are higher in PAD, suggesting reduced mitochondrial metabolism. In the muscle tissue, mitochondrial mass is higher; however, there is lower activity of several mitochondrial complexes impeding ATP generation and enhancing reactive oxygen species production. Altered mitochondrial function restricts oxygen utilization and may also promote endothelial dysfunction as mitochondrial-derived oxidants reduce nitric oxide bioactivity. Muscle fiber degeneration is associated with evidence of oxidative stress, including carbonyl groups and 4-hydroxy-2-nonenal adducts, protein modifications produced by reactive oxygen species. Mitochondrial function is also important in angiogenesis, consistent with the notion of coupling of vascular and muscular parameters. In hindlimb ischemia models, peroxisome-proliferator-activated receptor- coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, promotes vascular regeneration.

• #36 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Skeletal Muscle Alterations and Mitochondrial Dysfunction […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. Altered skeletal muscle structural and metabolic properties magnify ischemia-induced functional impairment. Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity. Further, the skeletal muscle displays lower density and higher fat content, which may limit muscle function. On muscle biopsy, there is greater muscle cell apoptosis and reduced type I fiber content, which may interfere with performance. Ischemia also damages peripheral nerve function, with evidence of poor nerve conduction in patients with severe PAD. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. Both the circulating and muscle levels of intermediates of oxidative phosphorylation, including acylcarnitines, are higher in PAD, suggesting reduced mitochondrial metabolism. In the muscle tissue, mitochondrial mass is higher; however, there is lower activity of several mitochondrial complexes impeding ATP generation and enhancing reactive oxygen species production. Altered mitochondrial function restricts oxygen utilization and may also promote endothelial dysfunction as mitochondrial-derived oxidants reduce nitric oxide bioactivity. Muscle fiber degeneration is associated with evidence of oxidative stress, including carbonyl groups and 4-hydroxy-2-nonenal adducts, protein modifications produced by reactive oxygen species. Mitochondrial function is also important in angiogenesis, consistent with the notion of coupling of vascular and muscular parameters. In hindlimb ischemia models, peroxisome-proliferator-activated receptor- coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, promotes vascular regeneration.

• #37 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/ja

  Arterial insufficiency in PAD reflects both fixed and dynamic reductions in blood flow. […] Diminished nitric oxide bioactivity in the leg impedes the augmentation of blood flow with exercise. […] In patients with PAD, inadequate angiogenesis and collateral formation may potentiate limb ischemia and serve as a mechanism driving functional impairment. […] Chronic limb ischemia initiates several vascular structural adaptations. […] Repeated episodes of ischemia have deleterious effects on the limb skeletal musculature. […] Mitochondrial dysfunction contributes to impaired skeletal muscle metabolism in PAD. […] Inflammatory activation participates in the development of atherosclerosis and may play a part in the generation of limb symptoms.

• #38 Systemic effects of intermittent claudication

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-4/vol4n2-Title-Systemic-Effects-of-Intermittent-Claudication

  In patients with intermittent claudication in every ischaemia reperfusion cycle, there is an inflammatory response with an increase in the baseline of markers of chronic inflammation. […] The cumulative effect of repeated low-grade inflammatory responses during intermittent claudication has an unfavourable effect on the progression of atherosclerosis. […] These findings support the evidence that PAD is only one facet of atherosclerosis and that local transient episodes of ischaemia in claudication may cause systemic deterioratious manifestation.

• #39 Systemic effects of intermittent claudication

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-4/vol4n2-Title-Systemic-Effects-of-Intermittent-Claudication

  In patients with intermittent claudication in every ischaemia reperfusion cycle, there is an inflammatory response with an increase in the baseline of markers of chronic inflammation. […] The cumulative effect of repeated low-grade inflammatory responses during intermittent claudication has an unfavourable effect on the progression of atherosclerosis. […] These findings support the evidence that PAD is only one facet of atherosclerosis and that local transient episodes of ischaemia in claudication may cause systemic deterioratious manifestation.

• #40 Systemic effects of intermittent claudication

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-4/vol4n2-Title-Systemic-Effects-of-Intermittent-Claudication

  In patients with intermittent claudication by exercise provoked tissue, ischaemia causes a local pathologic response followed by reperfusion and potentially deterious systemic manifestations. […] However, besides its relation to other atherosclerotic diseases that are caused by similar or identical pathogenic mechanisms, ischaemia of the peripheral muscles induced by physical exercise (intermittent claudication) in PAD patients has immediate systemic effects. […] Thus in patients with intermittent claudication, locally provoked tissue ischaemia causes a local pathological response followed by reperfusion and potentially deterious systemic manifestation. This can result in functional or even in structural disorders of any organ system local and remote. […] The basic pathophysiological process is most probably oxidative stress as a consequence of free radical generation.

• #41 Systemic effects of intermittent claudication

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-4/vol4n2-Title-Systemic-Effects-of-Intermittent-Claudication

  In patients with intermittent claudication in every ischaemia reperfusion cycle, there is an inflammatory response with an increase in the baseline of markers of chronic inflammation. […] The cumulative effect of repeated low-grade inflammatory responses during intermittent claudication has an unfavourable effect on the progression of atherosclerosis. […] These findings support the evidence that PAD is only one facet of atherosclerosis and that local transient episodes of ischaemia in claudication may cause systemic deterioratious manifestation.

• #42 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Altered muscle metabolism also reflects reduced nutrient uptake related to systemic metabolic disturbances in PAD patients. Patients with PAD display insulin resistance and insulin resistance predicts a higher risk of developing clinical PAD. By evaluating skeletal muscle glucose uptake with PET, it has been shown that PAD patients with intermittent claudication have calf muscle insulin resistance. Additional studies are required to link muscle insulin resistance to functional parameters in PAD and to determine whether interventions to promote insulin sensitivity will reduce limb symptoms. […] Skeletal muscle dysfunction, including mitochondrial abnormalities, affects walking ability in PAD. Both decreased calf muscle content and altered fiber type relate to reduced functional parameters. Importantly, mitochondrial dysfunction assessed by MR spectroscopy to evaluate phosphocreatine recovery is associated with lower treadmill walking time. PAD patients with greater amounts of muscle acylcarnitine accumulation have greater degrees of exercise limitation. Evidence of myofiber damage is associated with both reduced walking distance and muscle strength in patients with claudication. Further, altered regulation of a cytoskeletal protein, desmin, is associated with reduced mitochondrial respiratory function and functional capacity in PAD. There is evidence of inadequate mitochondrial clearance through autophagy in the skeletal muscle in PAD that associates with walking parameters, consistent with increased mitochondrial damage. Greater levels of daily activity is associated with healthy calf muscle parameters. Several aspects of skeletal muscle phenotype, including increased calf muscle fat and decreased muscle density, predicted 2-year functional decline in a longitudinal study. Evidence of reduced mitochondrial biogenesis is associated with higher overall mortality, which is potentially mediated through reduced physical activity.

• #43 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Altered muscle metabolism also reflects reduced nutrient uptake related to systemic metabolic disturbances in PAD patients. Patients with PAD display insulin resistance and insulin resistance predicts a higher risk of developing clinical PAD. By evaluating skeletal muscle glucose uptake with PET, it has been shown that PAD patients with intermittent claudication have calf muscle insulin resistance. Additional studies are required to link muscle insulin resistance to functional parameters in PAD and to determine whether interventions to promote insulin sensitivity will reduce limb symptoms. […] Skeletal muscle dysfunction, including mitochondrial abnormalities, affects walking ability in PAD. Both decreased calf muscle content and altered fiber type relate to reduced functional parameters. Importantly, mitochondrial dysfunction assessed by MR spectroscopy to evaluate phosphocreatine recovery is associated with lower treadmill walking time. PAD patients with greater amounts of muscle acylcarnitine accumulation have greater degrees of exercise limitation. Evidence of myofiber damage is associated with both reduced walking distance and muscle strength in patients with claudication. Further, altered regulation of a cytoskeletal protein, desmin, is associated with reduced mitochondrial respiratory function and functional capacity in PAD. There is evidence of inadequate mitochondrial clearance through autophagy in the skeletal muscle in PAD that associates with walking parameters, consistent with increased mitochondrial damage. Greater levels of daily activity is associated with healthy calf muscle parameters. Several aspects of skeletal muscle phenotype, including increased calf muscle fat and decreased muscle density, predicted 2-year functional decline in a longitudinal study. Evidence of reduced mitochondrial biogenesis is associated with higher overall mortality, which is potentially mediated through reduced physical activity.

• #44 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Altered muscle metabolism also reflects reduced nutrient uptake related to systemic metabolic disturbances in PAD patients. Patients with PAD display insulin resistance and insulin resistance predicts a higher risk of developing clinical PAD. By evaluating skeletal muscle glucose uptake with PET, it has been shown that PAD patients with intermittent claudication have calf muscle insulin resistance. Additional studies are required to link muscle insulin resistance to functional parameters in PAD and to determine whether interventions to promote insulin sensitivity will reduce limb symptoms. […] Skeletal muscle dysfunction, including mitochondrial abnormalities, affects walking ability in PAD. Both decreased calf muscle content and altered fiber type relate to reduced functional parameters. Importantly, mitochondrial dysfunction assessed by MR spectroscopy to evaluate phosphocreatine recovery is associated with lower treadmill walking time. PAD patients with greater amounts of muscle acylcarnitine accumulation have greater degrees of exercise limitation. Evidence of myofiber damage is associated with both reduced walking distance and muscle strength in patients with claudication. Further, altered regulation of a cytoskeletal protein, desmin, is associated with reduced mitochondrial respiratory function and functional capacity in PAD. There is evidence of inadequate mitochondrial clearance through autophagy in the skeletal muscle in PAD that associates with walking parameters, consistent with increased mitochondrial damage. Greater levels of daily activity is associated with healthy calf muscle parameters. Several aspects of skeletal muscle phenotype, including increased calf muscle fat and decreased muscle density, predicted 2-year functional decline in a longitudinal study. Evidence of reduced mitochondrial biogenesis is associated with higher overall mortality, which is potentially mediated through reduced physical activity.

• #45 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  Altered muscle metabolism also reflects reduced nutrient uptake related to systemic metabolic disturbances in PAD patients. Patients with PAD display insulin resistance and insulin resistance predicts a higher risk of developing clinical PAD. By evaluating skeletal muscle glucose uptake with PET, it has been shown that PAD patients with intermittent claudication have calf muscle insulin resistance. Additional studies are required to link muscle insulin resistance to functional parameters in PAD and to determine whether interventions to promote insulin sensitivity will reduce limb symptoms. […] Skeletal muscle dysfunction, including mitochondrial abnormalities, affects walking ability in PAD. Both decreased calf muscle content and altered fiber type relate to reduced functional parameters. Importantly, mitochondrial dysfunction assessed by MR spectroscopy to evaluate phosphocreatine recovery is associated with lower treadmill walking time. PAD patients with greater amounts of muscle acylcarnitine accumulation have greater degrees of exercise limitation. Evidence of myofiber damage is associated with both reduced walking distance and muscle strength in patients with claudication. Further, altered regulation of a cytoskeletal protein, desmin, is associated with reduced mitochondrial respiratory function and functional capacity in PAD. There is evidence of inadequate mitochondrial clearance through autophagy in the skeletal muscle in PAD that associates with walking parameters, consistent with increased mitochondrial damage. Greater levels of daily activity is associated with healthy calf muscle parameters. Several aspects of skeletal muscle phenotype, including increased calf muscle fat and decreased muscle density, predicted 2-year functional decline in a longitudinal study. Evidence of reduced mitochondrial biogenesis is associated with higher overall mortality, which is potentially mediated through reduced physical activity.

• #46 Neurogenic claudication – Wikipedia

  https://en.wikipedia.org/wiki/Neurogenic_claudication

  Neurogenic claudication (NC), also known as pseudoclaudication, is the most common symptom of lumbar spinal stenosis (LSS) and describes intermittent leg pain from impingement of the nerves emanating from the spinal cord. […] NC is a medical condition most commonly caused by damage and compression to the lower spinal nerve roots. […] The International Association for the Study of Pain defines neurogenic claudication as „pain from intermittent compression and/or ischemia of a single or multiple nerve roots within an intervertebral foramen or the central spinal canal”. […] This definition reflects the current hypotheses for the pathophysiology of NC, which is thought to be related to the compression of lumbosacral nerve roots by surrounding structures, such as hypertrophied facet joints or ligamentum flavum, bone spurs, scar tissue, and bulging or herniated discs.

• #47 Neurogenic Claudication And Vascular Claudication – OrthoPaedia

  https://www.orthopaedia.com/neurogenic-claudication-and-vascular-claudication/

  Neurogenic claudication and vascular claudication are distinct clinical entities that share a similar clinical symptom: pain and impaired walking. […] Additionally, they share a common basic pathological mechanism, ischemia, although the targets of ischemia are different. […] Neurogenic claudication is caused by nerve ischemia in the spine. The most common etiology is spinal stenosis, namely degenerative spondylosis and its associated potentially-compressive phenomena (bone overgrowth, disc protrusion, facet arthritis). […] Decreased space in the spinal canal compresses the thoracic spinal cord or lumbar nerve roots and impedes perfusion accordingly. The resultant ischemia can lead to pain and weakness in the buttock and posterior thigh; the calf can be involved, but the symptoms are usually proximal.

• #48 Neurogenic claudication – Wikipedia

  https://en.wikipedia.org/wiki/Neurogenic_claudication

  Neurogenic claudication (NC), also known as pseudoclaudication, is the most common symptom of lumbar spinal stenosis (LSS) and describes intermittent leg pain from impingement of the nerves emanating from the spinal cord. […] NC is a medical condition most commonly caused by damage and compression to the lower spinal nerve roots. […] The International Association for the Study of Pain defines neurogenic claudication as „pain from intermittent compression and/or ischemia of a single or multiple nerve roots within an intervertebral foramen or the central spinal canal”. […] This definition reflects the current hypotheses for the pathophysiology of NC, which is thought to be related to the compression of lumbosacral nerve roots by surrounding structures, such as hypertrophied facet joints or ligamentum flavum, bone spurs, scar tissue, and bulging or herniated discs.

• #49 Neurogenic claudication – Wikipedia

  https://en.wikipedia.org/wiki/Neurogenic_claudication

  Neurogenic claudication (NC), also known as pseudoclaudication, is the most common symptom of lumbar spinal stenosis (LSS) and describes intermittent leg pain from impingement of the nerves emanating from the spinal cord. […] NC is a medical condition most commonly caused by damage and compression to the lower spinal nerve roots. […] The International Association for the Study of Pain defines neurogenic claudication as „pain from intermittent compression and/or ischemia of a single or multiple nerve roots within an intervertebral foramen or the central spinal canal”. […] This definition reflects the current hypotheses for the pathophysiology of NC, which is thought to be related to the compression of lumbosacral nerve roots by surrounding structures, such as hypertrophied facet joints or ligamentum flavum, bone spurs, scar tissue, and bulging or herniated discs.

• #50 Neurogenic claudication – Wikipedia

  https://en.wikipedia.org/wiki/Neurogenic_claudication

  Degenerative disc disease (DDD) may trigger the pathogenesis of neurogenic claudication. […] The compression of these spinal nerve roots that control sensation and movement in the lower body results in the tingling, pain and weakness NC patients often experience. […] However, because the severity of symptoms does not correlate well with the degree of stenosis and nerve root compression, a clear understanding of the specific pathogenesis remains challenging. […] The ischemic theory proposes that poor blood supply to the spinal nerve roots results in NC. […] In contrast, the venous stasis theory proposes that a combination of low oxygen levels and metabolite buildup are responsible due to venous backup at the cauda equina. […] These changes in blood flow may occur during back extension when shifts in vertebral structures and ligaments narrow the spinal canal and compress the neurovasculature. […] Compared to a neutral position, extended spines exhibit 15% less cross-sectional area of the intervertebral foramina, and nerve root compression is present one-third of the time. […] These dynamic changes in the shape of the spinal canal are more pronounced in individuals with spinal stenosis.

• #51 Neurogenic claudication – Wikipedia

  https://en.wikipedia.org/wiki/Neurogenic_claudication

  Degenerative disc disease (DDD) may trigger the pathogenesis of neurogenic claudication. […] The compression of these spinal nerve roots that control sensation and movement in the lower body results in the tingling, pain and weakness NC patients often experience. […] However, because the severity of symptoms does not correlate well with the degree of stenosis and nerve root compression, a clear understanding of the specific pathogenesis remains challenging. […] The ischemic theory proposes that poor blood supply to the spinal nerve roots results in NC. […] In contrast, the venous stasis theory proposes that a combination of low oxygen levels and metabolite buildup are responsible due to venous backup at the cauda equina. […] These changes in blood flow may occur during back extension when shifts in vertebral structures and ligaments narrow the spinal canal and compress the neurovasculature. […] Compared to a neutral position, extended spines exhibit 15% less cross-sectional area of the intervertebral foramina, and nerve root compression is present one-third of the time. […] These dynamic changes in the shape of the spinal canal are more pronounced in individuals with spinal stenosis.

• #52 Claudication: Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/21972-claudication

  The pain goes away when you rest because your circulation can keep up with the lower oxygen demand. Claudication is also a concern because the pain it causes when walking often keeps people from being active. Stopping physical activity only makes the claudication worse. […] Claudication treatment can start with things you can do yourself. If your case becomes more severe, you may need medicine or a procedure. Treating claudication is important because it usually means you have peripheral artery disease or another circulatory disease that can be life-changing and even deadly. […] Walking is the best type of physical activity for claudication. This improves your blood flow by opening your blood vessels wider. […] If medicines dont work, your provider may want to do a minimally invasive treatment. They may use angioplasty to treat a narrow or blocked artery by using a catheter. A provider may also put a stent into an artery they open to help it stay that way. Another option is bypass surgery to reroute blood flow. Providers only use surgery in severe cases.

• #53 Exercise therapy for intermittent claudication in peripheral artery disease

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-13/exercise-therapy-for-intermittent-claudication-in-peripheral-artery-disease

  The potential biomechanical or biochemical mechanisms underlying the benefits of exercise therapy are exercise-induced angiogenesis, enhanced nitric oxide-dependent vasodilatation of the microcirculation, improved hemorheology, reduced vascular inflammation, improved glucose and fatty acid metabolism in skeletal muscle, improved muscle bioenergetics and oxidative stress, improved peripheral nerve function, and so on. […] In summary, the mechanisms underlying the response to exercise training include improvements in blood perfusion, muscle metabolism and mitochondrial function, peripheral nerve function, and walking efficiency. […] Exercise therapy has multiple benefits via multiple mechanisms in PAD patients with intermittent claudication, including reduced limb symptoms, improved functional capacity, and reduced systemic cardiovascular risk.

• #54 Claudication: Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/21972-claudication

  The pain goes away when you rest because your circulation can keep up with the lower oxygen demand. Claudication is also a concern because the pain it causes when walking often keeps people from being active. Stopping physical activity only makes the claudication worse. […] Claudication treatment can start with things you can do yourself. If your case becomes more severe, you may need medicine or a procedure. Treating claudication is important because it usually means you have peripheral artery disease or another circulatory disease that can be life-changing and even deadly. […] Walking is the best type of physical activity for claudication. This improves your blood flow by opening your blood vessels wider. […] If medicines dont work, your provider may want to do a minimally invasive treatment. They may use angioplasty to treat a narrow or blocked artery by using a catheter. A provider may also put a stent into an artery they open to help it stay that way. Another option is bypass surgery to reroute blood flow. Providers only use surgery in severe cases.

• #55 Intermittent Claudication | The Role of Physiotherapy in Managing Peripheral Artery Disease | Blog by CB Physiotherapy, Active Healing for Pain Free Life. – CB Physiotherapy

  https://cbphysiotherapy.in/blog/intermittent-claudication-the-role-of-physiotherapy-in-managing-peripheral-artery-disease

  Intermittent claudication is a common manifestation of peripheral arterial disease (PAD), characterized by pain or muscle cramps in the legs during physical activity. This condition arises due to reduced blood flow to the lower extremities, limiting the supply of oxygen and nutrients to the muscles. […] The primary cause of intermittent claudication is atherosclerosis, a condition where fatty deposits (plaque) accumulate within the arteries, leading to narrowing and reduced blood flow. As a consequence, the muscles in the affected region receive inadequate oxygen, causing pain and discomfort. […] The mechanism behind the efficacy of exercise lies in its ability to stimulate the development of collateral blood vessels. These collateral vessels act as natural bypass routes, facilitating improved blood flow to the affected muscles. […] By focusing on peripheral muscle conditioning, physiotherapists aim to enhance the efficiency of oxygen utilization and reduce the perceived effort during physical activities.

• #56 A Primary Care Approach to the Patient with Claudication | AAFP

  https://www.aafp.org/pubs/afp/issues/2000/0215/p1027.html

  Walking improves the symptoms of claudication in several ways. […] Cilostazol is a phosphodiesterase inhibitor that suppresses platelet aggregation and acts as a direct arterial vasodilator. […] Identifying the patient with intermittent claudication is highly important. Successful management of the disease involves aggressive risk factor modification, antiplatelet therapy and an exercise program. Overall, the prognosis for the diseased extremity is favorable. However, the excessive five- and 10-year mortality rate is heavily influenced by underlying cardiovascular disease.

• #57 Topic of Vascular Claudication | PPT

  https://www.slideshare.net/slideshow/topic-of-vascular-claudication/69991910

  Symptoms of claudication associated with PAD usually manifest in the muscle groups below the hemodynamically significant lesion. […] The natural history of IC is marked by slow progression to shorter walking distances, but it rarely reaches the level of CLI. The risk of major amputation is less than 5% over a 5-year period. […] Cilostazol is an effective pharmacological therapy that can improve symptoms and walking distance in patients with claudication. […] Cilostazol improves maximal walking distance by 40% to 60% after 12 to 24 weeks of therapy. […] Cilostazol (100 mg orally 2 times per day) is effective to improve symptoms and increase walking distance in patients with lower extremity PAD and intermittent claudication (in the absence of heart failure). […] Revascularization is recommended only in cases of severe claudication, and only after medical therapy has failed.

• #58 Exercise therapy for intermittent claudication in peripheral artery disease

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-13/exercise-therapy-for-intermittent-claudication-in-peripheral-artery-disease

  The potential biomechanical or biochemical mechanisms underlying the benefits of exercise therapy are exercise-induced angiogenesis, enhanced nitric oxide-dependent vasodilatation of the microcirculation, improved hemorheology, reduced vascular inflammation, improved glucose and fatty acid metabolism in skeletal muscle, improved muscle bioenergetics and oxidative stress, improved peripheral nerve function, and so on. […] In summary, the mechanisms underlying the response to exercise training include improvements in blood perfusion, muscle metabolism and mitochondrial function, peripheral nerve function, and walking efficiency. […] Exercise therapy has multiple benefits via multiple mechanisms in PAD patients with intermittent claudication, including reduced limb symptoms, improved functional capacity, and reduced systemic cardiovascular risk.

• #59 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/28123169/

  Peripheral artery disease (PAD) affects more than 200 million adults worldwide. […] Potential mechanistic drivers of claudication in addition to arterial obstruction include inflammation, vascular dysfunction, reduced microvascular flow, impaired angiogenesis, and altered skeletal muscle function. […] An improved understanding of the pathophysiology of limb symptoms has the potential to accelerate development of novel therapeutic strategies to increase functional capacity in patients with PAD.

• #60 Peripheral Arterial Disease – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/peripheral-arterial-disorders/peripheral-arterial-disease

  For relief of claudication, pentoxifylline 400 mg orally 3 times a day with meals or cilostazol 100 mg orally twice a day may be used to relieve intermittent claudication by improving blood flow and enhancing tissue oxygenation in affected areas; however, neither pentoxifylline nor cilostazol is a substitute for risk factor modification and exercise. […] ACE inhibitors and angiotensin II receptor blockers (ARBs) have several beneficial effects. They are antiatherogenic and are potent vasodilators. […] Other drugs that may relieve claudication are being studied; they include L-arginine (the precursor of endothelium-dependent vasodilator), nitric oxide, vasodilator prostaglandins, and angiogenic growth factors (eg, vascular endothelial growth factor [VEGF], basic fibroblast growth factor [bFGF]).

• #61 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  There are a number of potential explanations for the disappointment with pro-angiogenic interventions in patients with PAD. Translational studies emphasize the relevance of systemic disease and risk factors to impaired angiogenesis in clinical PAD. Paradoxically, patients with PAD have higher levels of VEGF-A, a key promoter of angiogenesis. A recent study found evidence that an anti-angiogenic isoform of VEGF, VEGF-165b, is upregulated in both preclinical models and patients with PAD. The enhanced expression of anti-angiogenic VEGF is driven by the pro-inflammatory Wnt5a/JNK pathway, which is activated by obesity. Thus, metabolic dysfunction may mediate inadequate angiogenesis in PAD by generating anti-angiogenic factors and complicate the responses to therapies aimed to stimulate angiogenesis. Resolvin D2, an anti-inflammatory regulator of tissue reparative responses, is important in both hindlimb ischemia models and patients with PAD. Resolvin D2 treatment enhances arteriogenesis and reduces inflammation, including in diabetic animals. Thus, the next generation of pro-angiogenic therapies may require evaluation in animal models with metabolic dysfunction and target both inflammation and vascular growth.

• #62 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/81/3/81_CJ-16-1286/_html/-char/en

  There are a number of potential explanations for the disappointment with pro-angiogenic interventions in patients with PAD. Translational studies emphasize the relevance of systemic disease and risk factors to impaired angiogenesis in clinical PAD. Paradoxically, patients with PAD have higher levels of VEGF-A, a key promoter of angiogenesis. A recent study found evidence that an anti-angiogenic isoform of VEGF, VEGF-165b, is upregulated in both preclinical models and patients with PAD. The enhanced expression of anti-angiogenic VEGF is driven by the pro-inflammatory Wnt5a/JNK pathway, which is activated by obesity. Thus, metabolic dysfunction may mediate inadequate angiogenesis in PAD by generating anti-angiogenic factors and complicate the responses to therapies aimed to stimulate angiogenesis. Resolvin D2, an anti-inflammatory regulator of tissue reparative responses, is important in both hindlimb ischemia models and patients with PAD. Resolvin D2 treatment enhances arteriogenesis and reduces inflammation, including in diabetic animals. Thus, the next generation of pro-angiogenic therapies may require evaluation in animal models with metabolic dysfunction and target both inflammation and vascular growth.

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