1. Exercise Therapy For Intermittent Claudication
Wang Yan 王焱 Ph D.
Xiamen Heart Center
Zhongshan Hospital Xiamen University

2. Peripheral arterial disease
Peripheral arterial disease(PAD)
Peripheral arterial disease
Superior mesenteric artery & celiac artery (Intestines)
Common iliac artery
(Legs)
Ischemia:
decreased oxygen-rich blood to an area, which can cause pain and dysfunction
Narrowed artery
Carotid artery (Brain)
Aorta (to body)
Intermittent Claudication:
A typical symptom of PAD, defined as walking induced pain in one or both legs that dose not go away with continued walking and is relieved only by rest.
外周动脉性疾病（Peripheral arterial disease， PAD）是由于外周动脉粥样硬化导致动脉狭窄、闭塞引起的缺血性疾病，间歇性跛行（Intermittent Claudication）是其典型临床表现，

3. Decreased quality of life Limit activities of daily living
Limit recreational activities
Possible amputation(s) with progression of underlying PAD
Decreased
life expectancy
PAD shortens life expectancy by 10 years
Increased mortality rate
3 fold increased risk of death from all causes and 6 fold increase in risk of cardiovascular related death in patients with large vessel PAD compared with age and gender-matched patients with same risk factors but without PAD
大量流行病学资料表明，间歇性跛行与心脑血管事件发病率、死亡率密切相关。随着社会整体生活水平的提高和人口的老龄化，下肢动脉硬化闭塞症的发病率逐年增高 .60岁以上人口中的发生率约为10-15%，40-60%患者合并有其他心血管系统疾病，严重全身性其5年死亡率分别达30%，5-10%非致死性心血管事件的发生率，均高于同期年龄人口的3倍
Am J Cardiol. 2001;87 (suppl):3D-13D

4. Treatments For Claudication
Be considered first
PAD及Claudication治疗困难，一般原则上采用药物治疗，有的可获症状改善，但有的疗效不佳，或反有副作用，如抗血小板药物的耐药性及严重的出血并发症等
等。近期在手术方法中增加了腔内血管成形术，在90年代早期美国曾风行一时，手术数增加了24倍，较旁路转流术明显为多(后者仅增加1倍)，但截肢率未见明显下降.尤其对于弥漫多节段病变以及广泛的小动脉闭塞者，药物及外科手术治疗显得相当棘手。由此再度强调了保守治疗的重要性。运动疗法（Exercise therapy）很早就被提出但一直未受重视，近些年来，相当多的研究表明运动对改善侧枝循环和肌肉组织血流量、增加肌肉摄氧能力和代谢、改变血液流变学以及本身的经济性等特点，为该类疾病的治疗提供了新的思路。
N Engl J Med, Vol. 347, No. 24,1941

5. Introduction of TASC VASCULAR SURGERY Number 1, Part 2:S93
SUPPLEMENT TO
In order to ensure an appropriate management algorithms and to achieve the optimal outcome for PAD patients, a group of experts in managing these patients had formulated the TransAtlantic Inter-Society Consensus (TASC). The TASC Working Group consisted of 14 MD societies across United States & Europe who had formulated the TASC Guidelines in the management of PAD based in current evidence-based medicine.
J O U R N A L O F
VASCULAR
SURGERY
VOLUME 31 NUMBER 1 PART 2 JANUARY 2000
TASC
Management of Peripheral Arterial Disease (PAD)
TransAtlantic Inter-Society Consensus (TASC)
Number 1, Part 2:S93
Section A: Introduction
Section B: Intermittent Claudication
Section C: Acute Limb Ischemia
A. Introduction
A1. Objectives and Methodology of the Consensus Process
A2. Epidemiology, Natural History, Risk Factors
A3. Outcome Assessment Methodology in Peripheral Arterial Disease
A4. Economic Aspects of Peripheral Arterial Disease
B. Intermittent Claudication
B1. Introduction and Characterization of Patients
B2. Evaluation
B3. Outcome Assessment of Intermittent Claudication in Clinical Practice.
B4. Treatment of Intermittent Claudication
B5. Economic Aspects of Intermittent Claudication
B5. Clinical Trial Issues in Intermittent Claudication
C. Acute Limb Ischemia
C1. Definition and Nomenclature for Acute Limb Ischemia
C2. Evaluation
C3. Outcome Assessment Methodology in Acute Limb Ischemia
C4. Treatment for Acute Limb Ischemia
C5. Economic Aspects of Acute Limb Ischemia
C6. Clinical Trial Issues in Acute Limb Ischemia
D. Chronic Critical Limb Ischemia
C1. Definition and Nomenclature for Chronic Critical Limb Ischemia
C3. Outcome Assessment Methodology in Chronic Critical Limb Ischemia
C4. Treatment for Chronic Critical Limb Ischemia
C5. Economic Aspects of Critical Leg Ischemia
C6. Clinical Trial Issues in Critical Leg Ischemia
Section D: Critical Limb Ischemia
Developed by the
107 Recommendations
47 Critical Issues
TASC Working Group
Mosby
J Vasc Surg. 2000;31(1 Part 2):S1-S296

7. Functional Benefits of Exercise Therapy
Potential Mechanisms of Improvement
Exercise Prescription

8. Functional Benefits of Exercise Therapy
Meta-analysis*:
Improved pain-free walking distance by an average of 179%, maximal walking distance of 122%
Cochrane Collaboration#:
Improved maximal walking time by 150% (74~230%)
运动疗法的作用:许多大型前瞻性的临床研究证实，运动疗法对于间歇性跛行患者有明显获益。Gardner等荟萃研究表明，运动疗法能够使得每周至少运动3次、每次至少30分钟、持续6个月或以上的间歇性跛行患者的无痛行走距离增加180%，最长行走距离增加120%。 Cochrane Collaboration荟萃了包含1200例患者的22个随机临床研究亦表明，运动疗法能延长最大行走时间150%，明显优于服用西洛他唑等药物治疗。截至目前，运动疗法的标准时程仍未确立，但疗效在初始训练4周后就能显现出来，且训练时间越长、效果越好，当然必须严密的监督下进行。所以，运动疗法作为一疗效确切、损伤性小、并发症小的治疗方案对于间歇性跛行的患者可以被优先考虑。
* JAMA 1995;274:975-80
# Cochrane Database Syst Rev CD00990

9. Effects of Exercise Training on Claudication
Meta-analysis of 21 Studies
200 *
Exercise Training
180
Control
160
140 *
120
Change in Treadmill Walking Distance (%)
100 80 60 40 20
* P < 0.05
Onset of Claudication Pain
Maximal Claudication Pain
Gardner AW, Poehlman ET. JAMA. 1995;274:
Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA. 1995;274: 9

10. Functional Benefits of Exercise Therapy
Meta-analysis*:
Improved pain-free walking distance by an average of 179%, maximal walking distance of 122%
Cochrane Collaboration#:
Improved maximal walking time by 150% (74~230%)
运动疗法的作用:许多大型前瞻性的临床研究证实，运动疗法对于间歇性跛行患者有明显获益。Gardner等荟萃研究表明，运动疗法能够使得每周至少运动3次、每次至少30分钟、持续6个月或以上的间歇性跛行患者的无痛行走距离增加180%，最长行走距离增加120%。 Cochrane Collaboration荟萃了包含1200例患者的22个随机临床研究亦表明，运动疗法能延长最大行走时间150%，明显优于服用西洛他唑等药物治疗。截至目前，运动疗法的标准时程仍未确立，但疗效在初始训练4周后就能显现出来，且训练时间越长、效果越好，当然必须严密的监督下进行。所以，运动疗法作为一疗效确切、损伤性小、并发症小的治疗方案对于间歇性跛行的患者可以被优先考虑。
* JAMA 1995;274:975-80
# Cochrane Database Syst Rev CD00990

11. Potential Mechanisms of Improvement
Formation of Collateral Vessels and angiogenesis
Changes in Endothelial Function
The Hemorheologic Hypothesis
Increases in Muscle Metabolism and Oxygen Extration
Inflammation and Muscle Injury
Effects to Risk Factors of Atherosclerosis

12. Formation of Collateral Vessels and angiogenesis
In healthy subjects, exercise therapy up-regulated the expression of vascular endothelial growth factor (VEGF) messenger RNA (mRNA) in calf muscle, with the size of the increase related in a dose-dependent fashion to the degree of metabolic stress.
In healthy subjects, exercise therapy up-regulated the expression of vascular endothelial growth factor (VEGF) messenger RNA (mRNA) in calf muscle, with the size of the increase related in a dose-dependent fashion to the degree of metabolic stress Am J Pisol 1999,276 H679

13. Formation of Collateral Vessels and angiogenesis (2)
运动疗法可通过血流对于血管壁的切应力的提高以及机体血管内皮细生长因子（Vascular endothelium growth factor，VEGF）mRNA信号表达，诱导内皮细胞增殖和分化，促进侧枝动脉形成和毛细血管的新生。运动还能诱导血管适应性改变，导致骨骼肌局部血流量的提高，增加毛细血管密度。有学者提出运动性血管新生（angiogenesis）的概念且相关理论研究正在进行中，有望在将来进一步阐述运动疗法的作用机制。
cardianet.org/images/resimg/za_1.jpg

14. Changes in Endothelial Function
Endothelial vasodilator function was impaired in patients with claudication
Short term exercise stimulates endothelium-dependent vasolidatation by enhancing the release of nitric oxide and prostacyclin
过去多数研究表明，在PAD及合并有其他动脉粥样硬化因素如2型糖尿病、高血压、高血脂及代谢综合征的患者中，内皮源性NO合成减少，内皮舒张功能受损。
McAllister研究显示反复运动训练导致血管切应力增加，促进NO及前列腺素合成增加，改善内皮依赖性血管舒张功能。

15. Changes in Endothelial Function
Exercise improved endothelial-dependent dilation, and calf blood flow in older PAD patients with intermittent claudication.
Am J Crdio

16. The Hemorheologic Hypothesis
Enhance collateral-dependent blood flow to the hind-muscles
but in humans are moderately* or limited#
Redistribution of blood flow: from inactive to active muscles
improved blood and plasma-viscosity,
filtered the ability of autologous red cells and red-cell aggregation
。Yong 和Mathien发现运动疗法能使PAD大鼠模型的下肢血流明显增加。但过去在大量的人体研究均显示运动训练后患者下肢血流量并未明显增加，而认为运动导致下肢血液从不活跃的肌肉（inactive muscles）流向运动中的肌肉——血流重新分布（redistribution of blood flow）是主要原因。Gardner在其荟萃研究亦认为运动后下肢血流量增加有限，而认为间歇性跛行患者的运动耐受量增加是疗效关键所在。
* Circulation 1990;81:602-9.
#J Am Geriatr Soc 2001;49:755-62

17. 2 months of exercise therapy improved Plasma viscosity, blood cell filterability, and maximal walking distance significantly
(Exercise vs.contrl, P<0.05)
血浆粘度下降，血细胞滤过能力增加
Circulation 1987:76:

18. Increases in Muscle Metabolism and Oxygen Extration
Patients with claudication
have an imbalance between
oxygen supply and demand
lactate ↑
intermediates of oxidative metabolism ↑
(short-chain acylcarnitines)
Exercise
Mitochondria ↑
肌肉的运动功能依赖于持续供应以合成ATP。在休息和轻度运动时骨骼肌主要利用脂肪酸作为主要的能量来源，但在运动强度增加时发生碳水化合物酵解。脂肪酸生成更多的ATP，但消耗更多的氧，运动训练的目的在于使玻行者更有效利用脂肪酸。在周围血管疾病患者，运动负荷使氧供和氧需不相等，ATP的有氧代谢不充分，而无氧代谢占主导地位，最终乳酸生成增加，ATP和肌酸磷酸盐缺乏。运动训练能使PAD患者肌肉发生结构和功能的改变，l.J A pplP hysiol, 1996;8 1:780-78如肌纤维线粒体数目增加，最大限度地增加脂肪酸有氧氧化利用度，减少无氧酵解和乳酸的形成，使得ATP生成增加。
the oxidative capacity of calf skeletal muscle ↑
Up-regulation of muscle enzyme activity
ATP ↑
l.J A pplP hysiol, 1996;8 1:780-78

19. Inflammation and Muscle Injury
Ischemia increases free-radical formation, neutrophil action, and systemic vascular endothelial damage
Exercise can lessen ischemia at any achieved workload and decrease markers of systemic inflammation:
serum amyloid A protein
C-reactive protein
the urinary ratio of albumin to creatinine…
Tisi等的研究表明间歇性跛行的患者可由于反复活动后疼痛导致下肢肌肉缺血，进而产生炎症反应：氧自由基生成增加、中性粒细胞激活进而影响全身性血管内皮损伤；同时急性反应蛋白如CRP、血清淀粉样A蛋白（serum amyloid A protein）亦受到激活，进一步加重内皮损害，导致白细胞相互粘附，阻塞微循环。经过积极的运动疗法，上述反应炎症激活的指标均明显减少，明显减轻炎症，从而改善局部血液动力学，这与心肌缺血预适应的原理相似。

20. Effects to Risk Factors of Atherosclerosis
Additional benefits that go beyond improvements in functional capacity and claudication
Exercise may also improve systemic cardiovascular health:
reduce blood pressure
improve lipid profile (↑HDL , ↓TG )
better glycemic control (in diabetic patients)
reduce central obesity
improve weight lose ……
运动疗法对于动脉粥样硬化危险因素具有独立的优势，如运动能够降低甘油三酯水平，升高高密度脂蛋白，降低血压，维持2型糖尿病患者胰岛素用量以及减少向心性肥胖等。

21. Conclusion of Mechanisms
↑Nitric oxide synthase
Improved endothelial function
↑Prostacyclin
↓Free radicals
Reduced inflammation
Possible vascular angiogenesis
↑ VEGF
Exercise therapy
↑ Muscle oxidative capacity
Improved muscle metabolism
Although exercise training has multiple beneficial effects, current knowledge does not permit accurate estimation of the relative contribution of each mechanism.
Exercise-induced increases in functional capacity and lessening of claudication symptoms may be explained by several mechanisms, including measurable improvements in endothelial vasodilator function, skeletal-muscle metabolism, blood viscosity, and inflammatory responses (Fig). Theevidence of exercise-training–induced increases in leg blood flow and oxygen delivery is less robust, and these mechanisms are unlikely to account for the large improvements in pain-free walking that can be achieved. Improvements in the biomechanics of walking also contribute to increased walking ability.
↑ Muscle enzyme activity
↑ Blood viscosity and filterability
Improved hemorheology
↓ Red-cell aggregation

22. Key Elements of an Effective PAD Therapeutic Claudication Exercise Program
Primary clinician role:
Establish the PAD diagnosis using the ABI measurement or other objective vascular laboratory evaluations
Determine that claudication is the major symptom limiting exercise
Discuss risk/benefit of claudication therapeutic alternatives, including pharmacological, percutaneous, and surgical interventions
Initiate systemic atherosclerosis risk modification
Perform treadmill stress testing
Provide formal referral to a claudication exercise rehabilitation program
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

23. Supervised Exercise Rehabilitation
Exercise Prescription
Supervised Exercise Rehabilitation
A program of supervised exercise training is recommended as an initial treatment modality for patients with intermittent claudication.
Supervised exercise training should be performed for a minimum of 30 to 45 minutes, in sessions performed at least three times per week for a minimum of 12 weeks.
I级:有充分的证据和/或一致的意见认为所采用 的方法或治疗是有用的和有效的. II级:对所采用的方法或治疗存在一定的争论或 分歧. IIa级:总的意见是倾向于有用的/有效的. IIb级:总的意见是倾向于作用较小. III级:一般认为所采用的方法或治疗是无效的或 在一定情况下是有害的.
- ACC/AHA 2005 Guidelines for the management of Patients with Peripheral Arterial Disease 23

24. The PAD Exercise Training Prescription
Rest
Cool
Down
Warm-up
Warm-up: Approximately 5 minutes
Repeated exercise periods: End at moderate claudication level
Rest Periods: Until claudication abates
This exercise interventional program has not been shown to be efficacious in a “home” setting. It requires a specific procedure and environment, much like invasive interventional procedures.

25. Key Elements of an Effective PAD Therapeutic Claudication Exercise Program
Exercise Guidelines for Claudication:
Warm-up and cool-down period: 5 to 10 minutes each
Types of exercise:
Treadmill and track walking are the most effective exercise for claudication
Resistance training has conferred benefit to individuals with other forms of cardiovascular disease, and its use, as tolerated, for general fitness is complementary to but not a substitute for walking
Intensity:
The initial workload of the treadmill is set to a speed and grade that elicit claudication symptoms within 3 to 5 minutes
Patients walk at this workload until they achieve claudication of moderate severity, which is then followed by a brief period of standing or sitting rest to permit symptoms to resolve
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

26. Key Elements of an Effective PAD Therapeutic Claudication Exercise Program
Exercise Guidelines for Claudication:
Duration:
The exercise-rest-exercise pattern should be repeated throughout the exercise session
The initial duration will usually include 35 minutes of intermittent walking and should be increased by 5 minutes each session until 50 minutes of intermittent walking can be accomplished
Frequency
Treadmill or track walking 3 to 5 times per week
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

27. Key Elements of an Effective PAD Therapeutic Claudication Exercise Program
Role of Direct Supervision:
As patients improve their walking ability, the exercise workload should be increased by modifying the treadmill grade or speed (or both) to ensure that there is always the stimulus of claudication pain during the workout
As patients increase their walking ability, there is the possibility that cardiac signs and symptoms may appear (e.g., dysrhythmia, angina, or ST-segment depression). These events should prompt physician re-evaluation
These general guidelines should be individualized and based on the results of treadmill stress testing and the clinical status of the patient. A full discussion of the exercise precautions for persons with concomitant diseases can be found elsewhere for diabetes *
*(Ruderman N, Devlin JT, Schneider S, Kriska A. Handbook of Exercise in Diabetes. Alexandria, Va: American Diabetes Association; 2002), (ACSM's Guidelines for Exercise Testing and Prescription. In: Franklin BA, ed. Baltimore, Md: Lippincott Williams & Wilkins; 2000), (Guidelines for Cardiac Rehabilitation and Secondary Prevention/American Association of Cardiovascular and Pulmonary Rehabilitation. Champaign, Ill: Human Kinetics; 1999).
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

28. PAD Guideline-Based Care: Claudication Treatment via Home Exercise
IIa
IIb
III B
The usefulness of unsupervised exercise
programs is not well established as an
effective initial treatment modality for
patients with intermittent claudication.
The lack of proven efficacy for home-based, unsupervised exercise may be due to:
A lack of compliance with the minimum “exercise dose”;
A lack of progression of the workload in the absence of professional supervision;
A lack of confidence by the patient that it is safe to advance into moderate claudication discomfort severity.
Hirsch AT, et al. J Am Col Cardiol. 2006;47: 28

29. Exercise combined with other treatments
Exercise therapy may augment the effects of other treatments for claudication.
The combination of revascularization procedures (bypass surgery and angioplasty)and exercise was more effective than either intervention alone.
Patients may also benefit from the use of pharmacologic therapies

30. Conclusions
Exercise therapy is an effective treatment for claudication.
Increses in functional capacity and lessening of claudication symptoms may be explained by several mechanisms.
A supervised hospital- or clinic-based prescription, which ensures that patients are receiving a standardized exercise stimulus in a safe enviroment, is effective.

31. Thanks for your attention!