Materiały źródłowe

• #1 Peripheral Arterial Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430745/

  Peripheral arterial disease (PAD) is a circulatory problem causing a reduced blood flow through the arteries. This typically reduces blood flow to the extremities manifesting as thigh or calf pain during walking or exertion. […] In most cases of PAD, atherosclerotic plaques narrow the arterial flow lumen which restricts blood flow to the distal extremity. […] The pathophysiology of atherosclerosis involves complex interactions between cholesterol and vascular cells the details of which are beyond the scope of this article. Atherosclerotic plaque builds up slowly on the inside of arteries. In the early stages of PAD, the arteries compensate for the plaque buildup by dilating to preserve flow through the vessel. Eventually, the artery cannot dilate any further, and the atherosclerotic plaque starts to narrow the arterial flow lumen.

• #1 Peripheral artery disease (PAD) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/peripheral-artery-disease/symptoms-causes/syc-20350557

  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, called plaque, on the artery walls. […] Peripheral artery disease (PAD) is often caused by a buildup of fats, cholesterol and other substances in and on the artery walls, a condition called atherosclerosis. The buildup is called plaque. Plaque can cause arteries to narrow, blocking blood flow. In PAD, plaque collects in the arteries of the arms or legs. […] Peripheral artery disease is usually a sign of a buildup of fatty deposits in the arteries, a condition called atherosclerosis.

• #1 Peripheral artery disease – Wikipedia

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

  Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms. […] PAD is primarily caused by the buildup of fatty plaque in the arteries, which is called atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. […] The pathophysiology of atherosclerosis involves complex interactions between cholesterol and vascular cells. In the early stages of PAD, the arteries compensate for plaque buildup by dilating to preserve flow through the vessel. Eventually, the artery cannot dilate further, and the atherosclerotic plaque narrows the arterial flow lumen.

• #1 Peripheral Arterial Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430745/

  The hemodynamic consequences of atherosclerosis depend on the degree of arterial narrowing. A 50% decrease in vessel diameter corresponds to a 75% loss of cross-sectional area which is usually considered flow limiting. […] This blood flow restriction represents the hallmark of PAD and its typical symptoms. The muscles of the lower extremity require increased blood flow during ambulation to meet the increased energy demand. […] This cycle of blood flow restriction increased energy demand, and temporary muscle ischemia describes the pathophysiology of claudication due to PAD. […] Patients with PAD usually have enough collateral blood flow that they only have symptoms during activities that increase energy demand such as walking. Rarely, the PAD becomes progressively more severe, and the blood flow cannot meet the resting metabolic demands of the lower extremity. […] In the most severe cases, the toes or entire forefoot can become black and mummified as gangrene develops.

• #1 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.

• #1 Peripheral Artery Disease: Pathophysiology, Diagnosis and Treatment – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-peripheral-artery-disease-pathophysiology-diagnosis-articulo-13114115

  Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which cause inadequate blood flow to the limbs. […] From the pathophysiologic point of view, ischemia of the lower limbs can be classified as functional or critical. Functional ischemia occurs when the blood flow is normal at rest but insufficient during exercise, presenting clinically as intermittent claudication. Critical ischemia is produced when the reduction in blood flow results in a perfusion deficit at rest and is defined by the presence of pain at rest or trophic lesions in the legs. […] The pathophysiologic mechanism by which arterial insufficiency develops is based on the presence of arterial stenosis that progresses naturally to cause complete occlusion of the artery. This results in a greater or lesser degree of development of collateral supply vessels.

• #1 Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7352779/

  Peripheral arterial disease (PAD) is an atherosclerotic disease that affects a wide range of the worlds population, reaching up to 200 million individuals worldwide. PAD particularly affects elderly individuals (65 years old). […] A number of pathophysiologic pathways operate in chronic arterial ischemia of lower limbs, giving the possibility to improve therapeutic strategies and the outcome of patients. […] To clarify the positive effect originated by the PE in PAD we must to draw our attention to the presence of the oxidative stress (OxS) as a key mechanism having a role in PAD pathophysiology. It is known that PAD pathophysiology has shifted from a hemodynamic scenario towards endorsing OxS. […] The hemodynamic disturbance of peripheral circulation in PAD characterizes the chronic ischemia, which in turn damages the myofibers of the lower limb skeletal muscles.

• #1 Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7352779/

  Muscle myofibers degeneration is associated with the OxS generation, including carbonyl groups, 4-hydroxy-2-nonenal adducts and protein modifications produced by ROS. […] The chronic and long duration of the mitochondrial stress on skeletal muscle cells produces reduced performance of the HO-1 anti-oxidative defense system. […] The protective role of HO-1 in several atherosclerotic diseases was still released; however, a few data were still released concerning HO-1 in PAD. […] Since pharmacotherapy for PAD patients failed to fully achieve some objectives (walking distance improvement, pain reduction or absence, cardiac or carotid diseases morbidity, PADs outcome and prognosis, quality of life) there is an interest in new therapeutic options such as targeting the HO-1.

• #1 Pathophysiology of Peripheral Arterial Disease – ProQuest

  https://www.proquest.com/scholarly-journals/pathophysiology-peripheral-arterial-disease-pad/docview/2417164097/se-2

  The hemodynamic disturbance of peripheral circulation in PAD characterizes the chronic ischemia, which in turn damages the myofibers of the lower limb skeletal muscles. […] Mitochondrial dysfunction of skeletal muscle cells contributes to impaired muscle metabolism in PAD. […] Muscle myofibers degeneration is associated with the OxS generation, including carbonyl groups, 4-hydroxy-2-nonenal adducts and protein modifications produced by ROS. […] The chronic and long duration of the mitochondrial stress on skeletal muscle cells produces reduced performance of the HO-1 anti-oxidative defense system. […] The defensive capability of HO-1 in responding to OxS results in attenuating these ischemic situations. […] Pathophysiology of PAD is complex as it includes hemodynamic disturbances such as reduced hematic load, progressed reductions of muscle tissue perfusion, damage of muscle fibers, and reduction of cell respiratory capability.

• #1 Pathophysiology of Peripheral Arterial Disease – ProQuest

  https://www.proquest.com/scholarly-journals/pathophysiology-peripheral-arterial-disease-pad/docview/2417164097/se-2

  Peripheral arterial disease (PAD) is one of the clinical types of atherosclerotic diseases. […] It is important to highlight the close link between PAD and a high risk of acute cardiovascular events, as shown by the frequency of coronary and carotid ischemic events occurring in PAD patients. […] To clarify the positive effect originated by the PE in PAD we must to draw our attention to the presence of the oxidative stress (OxS) as a key mechanism having a role in PAD pathophysiology. It is known that PAD pathophysiology has shifted from a hemodynamic scenario towards endorsing OxS. […] Hemodynamic peripheral disturbance is paramount in provoking severe damage to skeletal muscle in patients suffering from PAD. […] Moreover, PAD patients demonstrated either low or high grades of inflammation, and active OxS, which are two pathophysiological mechanisms in PAD.

• #1 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_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.

• #1 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_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.

• #1 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_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.

• #1 Peripheral Artery Disease: Pathophysiology, Diagnosis and Treatment – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-peripheral-artery-disease-pathophysiology-diagnosis-articulo-13114115

  When the plaque ruptures, this results in thrombosis that obliterates the vascular lumen, triggering the acute syndrome. […] The clinical manifestation of PAD depends decisively on the number of territories affected. […] The degree of clinical involvement depends on 2 factors: the chronologic evolution of the process (acute or chronic) and the localization, and extension of the disease (involvement of 1 or more sectors). […] One of the most important aspects in the evaluation of patients with PAD is probably the identification of cases at greater risk of developing critical ischemia and, therefore, of losing the limb. […] The association between PAD and cerebrovascular ischemia is not as prevalent as it is with coronary disease. […] The main cause of late death in patients with PAD is ischemic heart disease (up to 50% of deaths in patients with PAD).

• #1 Peripheral Artery Disease: Pathophysiology, Diagnosis and Treatment – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-peripheral-artery-disease-pathophysiolog-articulo-13114115

  When the plaque ruptures, this results in thrombosis that obliterates the vascular lumen, triggering the acute syndrome. […] The clinical manifestation of PAD depends decisively on the number of territories affected. […] The degree of clinical involvement depends on 2 factors: the chronologic evolution of the process (acute or chronic) and the localization, and extension of the disease (involvement of 1 or more sectors). […] The clinical evolution of PAD is fairly stable, due to the development of collateral circulation, the metabolic adaptation of the muscle masses involved and the use, often unknowingly, of non-ischemic muscle groups. […] One of the most important aspects in the evaluation of patients with PAD is probably the identification of cases at greater risk of developing critical ischemia and, therefore, of losing the limb. […] The presence of several cardiovascular risk factors acts synergically, multiplying the risk of limb loss.

• #1 Peripheral Vascular Disease: Background, Pathophysiology, Prognosis

  https://emedicine.medscape.com/article/761556-overview

  Peripheral vascular disease (PVD) is a nearly pandemic condition that has the potential to cause loss of limb or even loss of life. PVD manifests as insufficient tissue perfusion initiated by existing atherosclerosis acutely compounded by either emboli or thrombi. […] PVD, also known as arteriosclerosis obliterans, is primarily the result of atherosclerosis. The atheroma consists of a core of cholesterol joined to proteins with a fibrous intravascular covering. The atherosclerotic process may gradually progress to complete occlusion of medium-sized and large arteries. The disease typically is segmental, with significant variation from patient to patient. […] Vascular disease may manifest acutely when thrombi, emboli, or acute trauma compromises perfusion. Thromboses are often of an atheromatous nature and occur in the lower extremities more frequently than in the upper extremities.

• #1 Peripheral Vascular Disease: Background, Pathophysiology, Prognosis

  https://emedicine.medscape.com/article/761556-overview

  Multiple factors predispose patients to thrombosis. These factors include sepsis, hypotension, low cardiac output, aneurysms, aortic dissection, bypass grafts, and underlying atherosclerotic narrowing of the arterial lumen. […] Emboli, the most common cause of sudden ischemia, usually are of cardiac origin (80%); they also can originate from proximal atheroma, tumor, or foreign objects. […] The site of occlusion, the presence of collateral circulation, and the nature of the occlusion (thrombus or embolus) determine the severity of the acute manifestation. Emboli tend to carry higher morbidity because the extremity has not had time to develop collateral circulation. Whether caused by embolus or thrombus, occlusion results in both proximal and distal thrombus formation as a consequence of flow stagnation.

• #1 Challenges and Opportunities in the Treatment of Vascular Calcification in Peripheral Artery Disease – Endovascular Today

  https://evtoday.com/articles/2021-sept/challenges-and-opportunities-in-the-treatment-of-vascular-calcification-in-peripheral-artery-disease

  Vascular calcification (VC) in peripheral artery disease (PAD) presents a treatment challenge. This is especially true because VC is ubiquitous, found in up to 47% to 72% of PAD patients. The pathophysiology of VC was previously attributed to elevated serum calcium levels; however, this theory has recently fallen out of favor. Calcification of the vasculature is triggered by inflammation as an active pathologic response to systemic disease. When it occurs, calcium deposition is typically seen in two of the three anatomic layers of arteries, specifically the intima and media. Intimal calcification occurs in association with a classically obstructive atherosclerotic plaque. Medial calcification (Mnckeberg sclerosis) is more prevalent in intra-abdominal and lower extremity arteries, and the complex pathophysiology of medial arteriosclerosis is thought to be associated with an upregulation of bone-associated proteins and osteoblast differentiation factors. More specifically, associated mechanisms of medial VC include an accompanying decrease in inhibition of antimineralization factors, such as pyrophosphate, which is expressed by blood vessels. Secondly, activation of vascular osteoblast-like cells induces mineralization of vascular smooth muscle cells. Increased bone turnover leads to the release of circulating nucleational complexes that act with apoptotic cells as substrate for VC.

• #1 Challenges and Opportunities in the Treatment of Vascular Calcification in Peripheral Artery Disease – Endovascular Today

  https://evtoday.com/articles/2021-sept/challenges-and-opportunities-in-the-treatment-of-vascular-calcification-in-peripheral-artery-disease

  The distribution of medial calcification extends contiguously throughout the vascular bed, resulting in arterial stiffening and decreased compliance. Medial VC is more commonly seen in the femoral artery than the popliteal artery and poses special challenges when it is present below the knee (which is common) since it affects both diagnostic accuracy (eg, noncompressible vessels lead to falsely elevated ankle-brachial index [ABI]) and interventional considerations. Its prevalence increases with age and in patients with diabetes mellitus, chronic kidney disease, obesity, and dyslipidemia. […] It is well known that the presence of PAD correlates with cardiovascular mortality, and this holds true even when correcting for coexisting cardiovascular risk factors and can help prognosticate potential outcomes. Alternatively, a meta-analysis by Renneberg et al demonstrated that arterial or valvular calcification carries a separate additional risk of broad cardiovascular events and mortality, and Yang et al showed that just the presence of VC was linked to not only mortality but also limb-specific outcomes, with increased risk of limb amputation in patients with PAD.

• #1 Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0346-8

  Atherosclerosis is a chronic inflammatory process that, in the presence of hyperlipidaemia, promotes the formation of atheromatous plaques in large vessels of the cardiovascular system. […] Atherosclerosis in peripheral arteries has a considerable impact on skeletal muscle pathophysiology. PAD patients exhibit a myopathy in the affected limbs, as a result of increased oxidative damage and mitochondrial dysfunction. […] The aim of this review is to critically discuss and assimilate current knowledge on the impact of peripheral atherosclerosis and its implications on skeletal muscle homeostasis. Accumulating data suggest that manifestations of peripheral atherosclerosis in skeletal muscle originate in a combination of increased i) oxidative stress, ii) inflammation, iii) mitochondriopathy, iv) altered myofibre morphology and fibrosis, v) chronic ischemia followed by impaired oxygen supply, vi) reduced capillary density and vii) apoptosis.

• #1 Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0346-8

  A significant source of reactive oxygen species production and oxidative stress in cardiovascular disease is the family of NADPH oxidases that contribute to several pathologies. […] The key role of APOE in atherosclerosis has been reviewed previously. […] The key role of APOE in lipoprotein metabolism is brought about by the activation of enzymes that are essential for lipoprotein breakdown. […] The majority of cholesterol in the ApoE-/- mice is distributed in VLDL and intermediate density lipoproteins (IDL)/LDL particles. […] The progression of atherosclerosis may be regulated by sex. […] High-fat and western-type diets have both been used in ApoE-/- mice and abundant evidence suggests that such dietary challenges result in aggravation of the atherosclerotic phenotype. […] Endothelial dysfunction is evident from the fifth week of western-type diet and in particular, endothelium-dependent relaxation to acetylcholine is impaired in the proximal descending aorta whereas it remains unaltered in the thoracic aorta.

• #1 Rehabilitation of, and the Effects of Exercise on Peripheral Arterial Diseases | PM&R KnowledgeNow

  https://now.aapmr.org/rehabilitation-of-and-the-effects-of-exercise-on-peripheral-arterial-diseases/

  Peripheral arterial disease (PAD), the third most common manifestation of atherosclerosis, is an atherosclerotic occlusive and thromboembolic pathophysiologic process that narrows and obstructs the arterial lumens. […] PAD has a complex pathophysiology that involves multiple cells, proteins, and pathways. The key cells to the development of athero-thrombosis are vascular endothelial cells, vascular smooth muscle cells, fibroblasts, platelets, resident stem cells, pericytes, and inflammatory cells. In patients with PAD, the vascular remodeling, inflammation, and apoptotic pathway responses that promote angiogenesis and arteriogenesis to increase blood supply to compensate for ischemia are ineffective. This leads to inadequate tissue perfusion, endothelial dysfunction, chronic inflammation, and high oxidative stress. These changes then progress to mitochondrial injury, free radical generation, muscle fiber damage, myofiber degeneration, fibrosis, and tissue damage, which could present as gangrene.

• #1 A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease

  https://www.mdpi.com/1422-0067/16/5/11294

  Peripheral artery disease (PAD) is due to the blockage of the arteries supplying blood to the lower limbs usually secondary to atherosclerosis. The pathophysiology of athero-thrombosis induced PAD is complex, and involves a large number of cells, proteins and pathways. Important cells contributing to or controlling the development of athero-thrombosis include vascular endothelial cells (ECs), vascular smooth muscle cells (SMCs), fibroblasts, platelets, resident stem cells, pericytes and inflammatory cells. Under healthy conditions the response to gradually progressive limb ischemia involves the promotion of angiogenesis and arteriogenesis in an attempt to increase the blood supply to the affected limb. In patients with CLI these compensatory responses to ischemia are ineffective. As a result, there is on-going inadequate perfusion of tissue, endothelial dysfunction, chronic inflammation and high levels of oxidative stress. All these changes lead to mitochondrial injury, free radical generation, muscle fibre damage, myofibre degeneration and fibrosis, and tissue damage, which may present as gangrene. PAD is mainly caused by atherosclerosis and associated thrombosis within the lower limb arteries leading to end organ ischemia. Potential therapies designed to accelerate arteriogenesis and angiogenesis during ischemia are under intense investigation although most of these interventions have not developed to a stage that they are ready for widespread clinical use.

• #1 Peripheral Arterial Disease (PAD)| Frankel Cardiovascular Center | Michigan Medicine

  https://www.umcvc.org/conditions-treatments/peripheral-arterial-disease-pad

  Nearly 12 million Americans have peripheral arterial disease or PAD, a vascular arterial disease that causes blockages in the arteries to the legs due to the buildup of plaque. […] Over time, smoking, poor diet and inactivity, in conjunction with diseases such as hypertension and diabetes, cause the vein walls to become rigid and narrow. […] In some PAD patients, the vascular system may compensate for the reduced blood flow by forming alternative routes, called collateral vessels, which bypass the affected vasculature. […] Because PAD most commonly results from atherosclerosis or hardening of the arteries, you can reduce your risk by following these guidelines: Don’t smoke. […] If PAD is suspected, your health care provider will perform a non-invasive test known as an ankle brachial pressure index (ABI).

• #1 Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0346-8

  Reactive oxygen species are a diverse class of reactive chemical molecules that consist of highly reactive oxygen atoms. […] In vascular diseases such as atherosclerosis, in diabetes and hypertension, there is an increase in ROS production from the vasculature and is considered an important initiator of atherogenesis by promoting proinflammatory pathways and oxidative stress that lead to endothelial dysfunction. […] Collectively, it can be speculated that systemic low grade inflammation may also affect skeletal muscle metabolic homeostasis in PAD.

• #1 Pathophysiology of Peripheral Arterial Disease – ProQuest

  https://www.proquest.com/scholarly-journals/pathophysiology-peripheral-arterial-disease-pad/docview/2417164097/se-2

  The progressed knowledge on oxidative biomarkers released in the bloodstream, and on inflammatory biomarkers in causing endothelial dysfunction suggest to us that screening the OxS both in symptomatic and in asymptomatic PAD patients will be a helpful tool to monitor the efficacy of treatments for PAD.

• #1 Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

  https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_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.

• #1 Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders

  https://www.mdpi.com/1422-0067/21/12/4393

  The chronic and long duration of the mitochondrial stress on skeletal muscle cells produces reduced performance of the HO-1 anti-oxidative defense system. […] The protective role of HO-1 in several atherosclerotic diseases was still released; however, a few data were still released concerning HO-1 in PAD. […] The last concern could be closely related to the known positive effects originating from the supervised PE both on clinical performance and on hypoxic adaptation. […] We want to encourage more studies on OxS and on oxidative biomarkers; we hypothesize that results could help us to improve and enhance knowledge of the complex pathophysiology of PAD.

• #1 Peripheral arterial disease : Role of cilostazol

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-8/Peripheral-arterial-disease-Role-of-cilostazol

  In managing PAD, it is critically important to deal with the high risk of developing severe and often fatal cardiovascular complications. The first priority is to aggressively modify RFs that enhance the progression of atherosclerosis and induce atherosclerotic complications. […] A drug with evidence of clinical utility in claudication is Cilostazol, a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. […] Cilostazol has been recommended in the international guidelines, TASC II, as first-line therapy for peripheral arterial disease because it improves the symptoms and quality of life. […] It inhibits type III phosphodiesterase (PDE) activity in platelets and in arterial and bronchiolar smooth muscle cells, thereby increasing the intracellular levels of cAMP through blocking its hydrolysis. Increased intracellular cAMP inhibits thromboxane A2 production and hence platelet aggregation by inhibiting phospholipase and cyclooxygenase in the platelets.

• #1 Peripheral arterial disease : Role of cilostazol

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-8/Peripheral-arterial-disease-Role-of-cilostazol

  Cilostazol inhibits activation-dependent alpha-granule release and P-selectin expression on the surface of platelets. The vasodilator occurs by blocking release of calcium ions from intracellular storage granules within the smooth muscle cells, thus inhibiting the contractile proteins. […] Cilostazol was generally well tolerated. Adverse events reported are diarrhea, abnormal stools, infection, rhinitis and peripheral edema in comparison with pentoxyfilline which adverse events were headache, diarrhea, abnormal stools and palpitations. […] Propionyl-L-Carnitine, one of the most potent analogues of Carnitine, restores normal Carnitine homeostasis, improves the efficiency of oxidative phosphorylation and lessens symptoms of claudication. […] Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) stimulate the development of new vessels. When bFGF protein was given intra-arterially, patients with claudication had an improvement in exercise performance.

• #1 Challenges and Opportunities in the Treatment of Vascular Calcification in Peripheral Artery Disease – Endovascular Today

  https://evtoday.com/articles/2021-sept/challenges-and-opportunities-in-the-treatment-of-vascular-calcification-in-peripheral-artery-disease

  A novel treatment strategy of calcific lesions includes catheter-guided intravascular lithotripsy (IVL) followed by balloon angioplasty. Lithotripsy is a medical procedure commonly used in urologic interventions to fragment kidney stones with shockwaves. The intra-arterial utilization of this technique aims to crack/modify calcified plaques by delivering very short bursts of very high pressure (50 atm) to the vessel wall through a low-pressure, fluid-filled balloon inflation. This action allows for facilitated balloon expansion and a decreased risk of arterial dissection and perforation. The resulting in situ fragmentation of the calcium is also hypothesized to improve the delivery of antiproliferative medications by DCB. […] VC is commonly seen in PAD. It is associated with numerous challenges in diagnosis, quantification of disease, classification ambiguity, and choice of effective treatment strategies. There is a lack of data regarding a validated treatment approach despite common intervention failures and decreased long-term vessel patency. Finding an effective treatment approach for peripheral arterial calcification poses an important challenge in an aging population with increased prevalence of the two most significant risk factors: chronic kidney disease and diabetes mellitus. Recently, IVL has been shown in the only randomized data available in this population to offer an advantage over the standard treatment strategies by delivering a better PTA result while overcoming common complications. Long-term data will determine its efficacy as an enhancement to preventing restenosis. Further studies are needed to validate current diagnostic and treatment modalities combined with further development of innovative therapies to combat VC in PAD.

• #1 Challenges and Opportunities in the Treatment of Vascular Calcification in Peripheral Artery Disease – Endovascular Today

  https://evtoday.com/articles/2021-sept/challenges-and-opportunities-in-the-treatment-of-vascular-calcification-in-peripheral-artery-disease

  Current treatment paradigms of PAD target the luminal narrowing of the affected artery. Aggressive lifestyle changes, treatment of underlying comorbidities such as chronic kidney disease, diabetes mellitus, and hypertension, along with supervised exercise are the backbone of noninvasive PAD treatment. In addition, antiplatelet and/or anticoagulant and statin therapy are indicated in all PAD patients. The available medications to reduce claudication symptoms are sparse, but the vasodilator cilostazol is effective in decreasing claudication symptoms and increasing walking distance. Notably, it has been recently shown that there is a role for low-dose rivaroxaban in PAD patients after revascularization. Rivaroxaban improved cardiovascular and limb-specific outcomes including acute limb ischemia and amputation in the recent VOYAGER PAD trial, and this has led to its approval by the FDA for this indication.

• #2 Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7352779/

  Peripheral arterial disease (PAD) is an atherosclerotic disease that affects a wide range of the worlds population, reaching up to 200 million individuals worldwide. PAD particularly affects elderly individuals (65 years old). […] A number of pathophysiologic pathways operate in chronic arterial ischemia of lower limbs, giving the possibility to improve therapeutic strategies and the outcome of patients. […] To clarify the positive effect originated by the PE in PAD we must to draw our attention to the presence of the oxidative stress (OxS) as a key mechanism having a role in PAD pathophysiology. It is known that PAD pathophysiology has shifted from a hemodynamic scenario towards endorsing OxS. […] The hemodynamic disturbance of peripheral circulation in PAD characterizes the chronic ischemia, which in turn damages the myofibers of the lower limb skeletal muscles.

• #2 Peripheral Artery Disease (PAD): Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/17357-peripheral-artery-disease-pad

  Peripheral artery disease (PAD) is plaque buildup in your leg arteries. Your leg arteries carry oxygen and nutrient-rich blood from your heart to your arms and legs. […] When you have peripheral artery disease, plaque (made of fat, cholesterol and other substances) forms gradually inside your artery walls. Slowly, this narrows your arteries. This is also known as atherosclerosis. […] Atherosclerosis that develops in the arteries of your legs or, less commonly, your arms causes peripheral arterial disease. Like atherosclerosis in your heart (coronary) arteries, a collection of fatty plaque in your blood vessel walls causes peripheral vascular disease. As plaque builds up, your blood vessels get narrower and narrower, until they’re blocked. […] The two main goals of peripheral artery disease treatments are: Reducing your risk of cardiovascular events. Improving your quality of life by easing the pain that occurs with walking.

• #2 Pathophysiology of Peripheral Artery Disease and its Diagnosis and Symptoms

  https://www.jcmedu.org/jcmedu-articles/pathophysiology-of-peripheral-artery-disease-and-its-diagnosis-and-symptoms-97903.html

  An abnormal constriction of arteries other than those that carry blood to the heart or brain is known as Peripheral Arterial Disease (PAD). […] Peripheral arterial disease is understood to be a collection of acute or chronic syndromes that are typically brought on by the presence of occlusive arterial disease and result in insufficient blood flow to the limbs. Atherosclerosis is the most typical cause of peripheral artery disease, particularly in people over the age of 40. Atherosclerosis is a constriction of the arteries brought on by a buildup of calcium and lipids in the damaged arteries’ walls. Cholesterol and vascular cells interact in a complicated way in the pathogenesis of atherosclerosis. In the early stages of PAD, the arteries widen to make up for the plaque buildup and maintain blood flow. When the artery reaches its maximum dilation, the atherosclerotic plaque begins to constrict the arterial flow lumen. Atherosclerotic plaque begins to constrict the arterial flow channel when the artery can no longer expand any further.

• #2 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.

• #2 Pathophysiology of Peripheral Artery Disease, Intermittent Claudication, and Critical Limb Ischemia | Thoracic Key

  https://thoracickey.com/pathophysiology-of-peripheral-artery-disease-intermittent-claudication-and-critical-limb-ischemia/

  Major factors that determine the pressure drop across an arterial stenosis include blood flow velocity and the resistance caused by the stenosis, which in turn is defined by the length and internal radius of the stenosis and blood viscosity. […] In patients with PAD, arterial occlusions limit increase in blood flow to exercising muscle. […] In CLI, patients typically have disease in the inflow vessels (aorta, iliac arteries) and outflow vessels (superficial femoral, popliteal and tibial arteries). […] The concept of critical artery stenosis has clinical significance. […] Thus, altered oxygen delivery to exercising skeletal muscle in PAD is related not only to the large-vessel occlusive process but also to endothelial dysfunction and impaired vasodilation. […] Peripheral artery disease is associated with altered hemorheology (flow properties of blood and its cellular components) that result in increased viscosity and altered flow as described by the Poiseuille equation.

• #2 Pathophysiology of Peripheral Artery Disease and its Diagnosis and Symptoms

  https://www.jcmedu.org/jcmedu-articles/pathophysiology-of-peripheral-artery-disease-and-its-diagnosis-and-symptoms-97903.html

  Ischemia is the condition that results from an imbalance between the blood supply and the requirements of the peripheral tissues. A lower limb blood supply restriction (ischemia) might be categorised as functional or essential from a pathophysiologic perspective. Functional ischemia manifests clinically as intermittent claudication when the blood flow is adequate during activity but abnormal at rest. Pain at rest or trophic lesions in the legs are indicators of critical ischemia, which is caused when blood flow is reduced and results in a perfusion deficit at rest. An accurate diagnosis is essential in this case since there is a real risk of losing the limb if enough blood flow is not restored, either through surgery or endovascular therapy. In order to determine the treatment indication and the prognosis in patients with PAD, it is crucial to distinguish between the two ideas.

• #2 Peripheral Artery Disease: Pathophysiology, Diagnosis and Treatment – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-peripheral-artery-disease-pathophysiolog-articulo-13114115

  Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which cause inadequate blood flow to the limbs. […] From the pathophysiologic point of view, ischemia of the lower limbs can be classified as functional or critical. Functional ischemia occurs when the blood flow is normal at rest but insufficient during exercise, presenting clinically as intermittent claudication. Critical ischemia is produced when the reduction in blood flow results in a perfusion deficit at rest and is defined by the presence of pain at rest or trophic lesions in the legs. […] The pathophysiologic mechanism by which arterial insufficiency develops is based on the presence of arterial stenosis that progresses naturally to cause complete occlusion of the artery. This results in a greater or lesser degree of development of collateral supply vessels.

• #2 Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders

  https://www.mdpi.com/1422-0067/21/12/4393

  To clarify the positive effect originated by the PE in PAD we must to draw our attention to the presence of the oxidative stress (OxS) as a key mechanism having a role in PAD pathophysiology. It is known that PAD pathophysiology has shifted from a hemodynamic scenario towards endorsing OxS. […] Hemodynamic peripheral disturbance is paramount in provoking severe damage to skeletal muscle in patients suffering from PAD. […] Moreover, PAD patients demonstrated either low or high grades of inflammation, and active OxS, which are two pathophysiological mechanisms in PAD. […] The hemodynamic disturbance of peripheral circulation in PAD characterizes the chronic ischemia, which in turn damages the myofibers of the lower limb skeletal muscles. […] Muscle myofibers degeneration is associated with the OxS generation, including carbonyl groups, 4-hydroxy-2-nonenal adducts and protein modifications produced by ROS.

• #2 Pathophysiology of Peripheral Arterial Disease – ProQuest

  https://www.proquest.com/scholarly-journals/pathophysiology-peripheral-arterial-disease-pad/docview/2417164097/se-2

  The hemodynamic disturbance of peripheral circulation in PAD characterizes the chronic ischemia, which in turn damages the myofibers of the lower limb skeletal muscles. […] Mitochondrial dysfunction of skeletal muscle cells contributes to impaired muscle metabolism in PAD. […] Muscle myofibers degeneration is associated with the OxS generation, including carbonyl groups, 4-hydroxy-2-nonenal adducts and protein modifications produced by ROS. […] The chronic and long duration of the mitochondrial stress on skeletal muscle cells produces reduced performance of the HO-1 anti-oxidative defense system. […] The defensive capability of HO-1 in responding to OxS results in attenuating these ischemic situations. […] Pathophysiology of PAD is complex as it includes hemodynamic disturbances such as reduced hematic load, progressed reductions of muscle tissue perfusion, damage of muscle fibers, and reduction of cell respiratory capability.

• #2 Peripheral Artery Disease: Pathophysiology, Diagnosis and Treatment – Revista Española de Cardiología (English Edition)

  https://www.revespcardiol.org/en-peripheral-artery-disease-pathophysiolog-articulo-13114115

  When the plaque ruptures, this results in thrombosis that obliterates the vascular lumen, triggering the acute syndrome. […] The clinical manifestation of PAD depends decisively on the number of territories affected. […] The degree of clinical involvement depends on 2 factors: the chronologic evolution of the process (acute or chronic) and the localization, and extension of the disease (involvement of 1 or more sectors). […] The clinical evolution of PAD is fairly stable, due to the development of collateral circulation, the metabolic adaptation of the muscle masses involved and the use, often unknowingly, of non-ischemic muscle groups. […] One of the most important aspects in the evaluation of patients with PAD is probably the identification of cases at greater risk of developing critical ischemia and, therefore, of losing the limb. […] The presence of several cardiovascular risk factors acts synergically, multiplying the risk of limb loss.

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