Peripheral arterial disease (PAD) is widely present in general population and increases with ageing determining progressive inability and relevant social costs, with progression to more severe ischemia . This pathology presetns also high incidence of cardiovascular morbidity and mortality. Rehabilitation with exercise prescription and comprehensive secondary prevention has great benefits in patients with PAD in order to increase walking capacity and reducing cardiovascular morbidity. In patients with PAD, the reduction in tissue perfusion generates some potential adaptation mechanisms and other mechanisms are elicited by exercise. Functional impairment in PAD is determined by several mechanisms: arterial obstruction , inflammation with platelets/leukocyte activation, endothelial activation/dysfunction, blood rehology changes, modifications in skeletal muscle phenotype (mitochondrial dysfunction). Exercise can ameliorate these mechanisms and potentially prevent clinical deterioration. Training, with specific standardized protocols, especially using supervised sessions, has documented a great efficacy in increasing walking distance also in comparison with drugs and revascularization in claudicants. Exercise programs adopted in PAD treatment has some important goals: 1) to reduce symptoms at the legs; 2) to increase walking distance and improve; and (3) to prevents cardiovascular events. Physical training with standardized protocols has added into main international guidelines for the treatment of PAD. Reduction in blood flow is the main haemodynamic parameter determining PAD symptoms. The mechanism induced in claudication is certainly an imbalance between oxygen demand and supply. However inconsistency between occlusion extension and functional impairment suggests that some other mechanisms are involved. Endothelium dysfunction plays certainly a pivotal role in determining also functional impairment: in fact, nitric oxide reduced bioavailability produces a depressed hyperemic capacity, rise in inflammation and platelets/leukocyte adhesion. PAD symptoms are also linked to mitochondrial dysfunction. In the muscles of these patients, mitochondrial function is abnormal and energy production is reduced with high reactive oxygen species generation and consequent endothelial damage. Furthermore muscle cells have increased apoptosis, reduction in capillarization and in type I fibers content. Chronic inflammation, as demonstrated by elevation of C-reactive protein, interleukin-6 and ICAM-1, enhances the risk of developing PAD. Inflammation is also associated with higher rate of progression of PAD and with major cardiovascular event rate. Exercise training has demonstrated to improve these aspects; in particular it can increase arteriogenesis and angiogenesis with vessels enlargement and remodelling, this phenomenon can be activated by a more efficient nitric oxide production and growth factors release. Exercise improves also mithocondrial function with more efficient energetic production and ameliorated peroxisome proliferator–activated receptor-gamma coactivator-1 function that can improve endothelial function and capillary growth. Training can also improve carnitine metabolism. Inflammation has positive reduction by exercise with decrease of C-reactive protein, fibrinogen, ICAM-1 and interleukin-6. Exercise prescription is crucial and different types of protocols can elicit more or less these mechanisms. Some data suggest that reaching ischemia during training can be useful in stimulating some compensatory mechanisms, but a more profound ischemia may have some negative consequences. Although this point is object of research, we should consider muscle pain during exercise (marker if ischemia) as the referring point for grading rehabilitation program in order to stimulate compensatory systems without eliciting damage. References 1) Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386. 2) McDermott MM, Greenland P, Liu K, Guralnik JM, Criqui MH, Dolan NC, Chan C, Celic L, Pearce WH, Schneider JR, Sharma L, Clark E, Gibson D, Martin GJ. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA. 2001;286:1599 –1606 3) Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608 –1621. 4) Diehm C, Allenberg JR, Pittrow D, Mahn M, Tepohl G, Haberl RL, Darius H, Burghaus I, Trampisch HJ. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation. 2009;120:2053–2061. 5) McDermott MM, Guralnik JM, Ferrucci L, Tian L, Liu K, Liao Y, Green D, Sufit R, Hoff F, Nishida T, Sharma L, Pearce WH, Schneider JR, Criqui MH. Asymptomatic peripheral arterial disease is associated with more adverse lower extremity characteristics than intermittent claudication. Circulation. 2008;117:2484 –2491. 6) Garg PK, Tian L, Criqui MH, Liu K, Ferrucci L, Guralnik JM, Tan J, McDermott MM. Physical activity during daily life and mortality in patients with peripheral arterial disease. Circulation. 2006;114:242–248. 7) Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5–S67. 8) Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain: a meta-analysis. JAMA. 1995;274: 975–980. 9) Arosio E. , De Marchi S., Zannoni M., Prior M., Lechi A. Effect of Glutathione Infusion on Leg Arterial Circulation, Cutaneous Microcirculation, and Pain-Free Walking Distance in Patients With Peripheral Obstructive Arterial Disease: A Randomized, Double-Blind, Placebo-Controlled Trial. Mayo Clin Proc. 2002;77:754-759. 10) Prior BM, Lloyd PG, Ren J, Li H, Yang HT, Laughlin MH, Terjung RL. Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats. Am J Physiol. 2004;287:H2434–H2447. 12) Patel TH, Kimura H, Weiss CR, Semenza GL, Hofmann LV. Constitutively active HIF-1alpha improves perfusion and arterial remodeling in an endovascular model of limb ischemia. Cardiovasc Res. 2005;68: 144–154. 13) Yu J, deMuinck ED, Zhuang Z, Drinane M, Kauser K, Rubanyi GM, Qian HS, Murata T, Escalante B, Sessa WC. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci U S A. 2005;102:10999 –11004. 14) Brass EP, Hiatt WR. Acquired skeletal muscle metabolic myopathy in atherosclerotic peripheral arterial disease. Vasc Med. 2000;5:55–59. 15) McDermott MM, Ferrucci L, Liu K, Criqui MH, Greenland P, Green D, Guralnik JM, Ridker PM, Taylor LM, Rifai N, Tian L, Zheng J, Pearce WH, Schneider JR, Vonesh E. D-dimer and inflammatory markers as predictors of functional decline in men and women with and without peripheral arterial disease. J Am Geriatr

S .De Marchi: Ischemia and adaptation in peripheral arterial disease: the recovery through the pain.

DE MARCHI, Sergio
2013-01-01

Abstract

Peripheral arterial disease (PAD) is widely present in general population and increases with ageing determining progressive inability and relevant social costs, with progression to more severe ischemia . This pathology presetns also high incidence of cardiovascular morbidity and mortality. Rehabilitation with exercise prescription and comprehensive secondary prevention has great benefits in patients with PAD in order to increase walking capacity and reducing cardiovascular morbidity. In patients with PAD, the reduction in tissue perfusion generates some potential adaptation mechanisms and other mechanisms are elicited by exercise. Functional impairment in PAD is determined by several mechanisms: arterial obstruction , inflammation with platelets/leukocyte activation, endothelial activation/dysfunction, blood rehology changes, modifications in skeletal muscle phenotype (mitochondrial dysfunction). Exercise can ameliorate these mechanisms and potentially prevent clinical deterioration. Training, with specific standardized protocols, especially using supervised sessions, has documented a great efficacy in increasing walking distance also in comparison with drugs and revascularization in claudicants. Exercise programs adopted in PAD treatment has some important goals: 1) to reduce symptoms at the legs; 2) to increase walking distance and improve; and (3) to prevents cardiovascular events. Physical training with standardized protocols has added into main international guidelines for the treatment of PAD. Reduction in blood flow is the main haemodynamic parameter determining PAD symptoms. The mechanism induced in claudication is certainly an imbalance between oxygen demand and supply. However inconsistency between occlusion extension and functional impairment suggests that some other mechanisms are involved. Endothelium dysfunction plays certainly a pivotal role in determining also functional impairment: in fact, nitric oxide reduced bioavailability produces a depressed hyperemic capacity, rise in inflammation and platelets/leukocyte adhesion. PAD symptoms are also linked to mitochondrial dysfunction. In the muscles of these patients, mitochondrial function is abnormal and energy production is reduced with high reactive oxygen species generation and consequent endothelial damage. Furthermore muscle cells have increased apoptosis, reduction in capillarization and in type I fibers content. Chronic inflammation, as demonstrated by elevation of C-reactive protein, interleukin-6 and ICAM-1, enhances the risk of developing PAD. Inflammation is also associated with higher rate of progression of PAD and with major cardiovascular event rate. Exercise training has demonstrated to improve these aspects; in particular it can increase arteriogenesis and angiogenesis with vessels enlargement and remodelling, this phenomenon can be activated by a more efficient nitric oxide production and growth factors release. Exercise improves also mithocondrial function with more efficient energetic production and ameliorated peroxisome proliferator–activated receptor-gamma coactivator-1 function that can improve endothelial function and capillary growth. Training can also improve carnitine metabolism. Inflammation has positive reduction by exercise with decrease of C-reactive protein, fibrinogen, ICAM-1 and interleukin-6. Exercise prescription is crucial and different types of protocols can elicit more or less these mechanisms. Some data suggest that reaching ischemia during training can be useful in stimulating some compensatory mechanisms, but a more profound ischemia may have some negative consequences. Although this point is object of research, we should consider muscle pain during exercise (marker if ischemia) as the referring point for grading rehabilitation program in order to stimulate compensatory systems without eliciting damage. References 1) Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386. 2) McDermott MM, Greenland P, Liu K, Guralnik JM, Criqui MH, Dolan NC, Chan C, Celic L, Pearce WH, Schneider JR, Sharma L, Clark E, Gibson D, Martin GJ. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA. 2001;286:1599 –1606 3) Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608 –1621. 4) Diehm C, Allenberg JR, Pittrow D, Mahn M, Tepohl G, Haberl RL, Darius H, Burghaus I, Trampisch HJ. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation. 2009;120:2053–2061. 5) McDermott MM, Guralnik JM, Ferrucci L, Tian L, Liu K, Liao Y, Green D, Sufit R, Hoff F, Nishida T, Sharma L, Pearce WH, Schneider JR, Criqui MH. Asymptomatic peripheral arterial disease is associated with more adverse lower extremity characteristics than intermittent claudication. Circulation. 2008;117:2484 –2491. 6) Garg PK, Tian L, Criqui MH, Liu K, Ferrucci L, Guralnik JM, Tan J, McDermott MM. Physical activity during daily life and mortality in patients with peripheral arterial disease. Circulation. 2006;114:242–248. 7) Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5–S67. 8) Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain: a meta-analysis. JAMA. 1995;274: 975–980. 9) Arosio E. , De Marchi S., Zannoni M., Prior M., Lechi A. Effect of Glutathione Infusion on Leg Arterial Circulation, Cutaneous Microcirculation, and Pain-Free Walking Distance in Patients With Peripheral Obstructive Arterial Disease: A Randomized, Double-Blind, Placebo-Controlled Trial. Mayo Clin Proc. 2002;77:754-759. 10) Prior BM, Lloyd PG, Ren J, Li H, Yang HT, Laughlin MH, Terjung RL. Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats. Am J Physiol. 2004;287:H2434–H2447. 12) Patel TH, Kimura H, Weiss CR, Semenza GL, Hofmann LV. Constitutively active HIF-1alpha improves perfusion and arterial remodeling in an endovascular model of limb ischemia. Cardiovasc Res. 2005;68: 144–154. 13) Yu J, deMuinck ED, Zhuang Z, Drinane M, Kauser K, Rubanyi GM, Qian HS, Murata T, Escalante B, Sessa WC. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci U S A. 2005;102:10999 –11004. 14) Brass EP, Hiatt WR. Acquired skeletal muscle metabolic myopathy in atherosclerotic peripheral arterial disease. Vasc Med. 2000;5:55–59. 15) McDermott MM, Ferrucci L, Liu K, Criqui MH, Greenland P, Green D, Guralnik JM, Ridker PM, Taylor LM, Rifai N, Tian L, Zheng J, Pearce WH, Schneider JR, Vonesh E. D-dimer and inflammatory markers as predictors of functional decline in men and women with and without peripheral arterial disease. J Am Geriatr
2013
ischemia, training
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/954958
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