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Systemic effects of intermittent claudication

An article from the e-journal of the ESC Council for Cardiology Practice

In patients with intermittent claudication by exercise provoked tissue, ischaemia causes a local pathologic response followed by reperfusion and potentially deterious systemic manifestations. By treating PAD it is not only possible to prevent the amputation of a diseased leg and to improve quality of life, it is also possible to prevent the progressive damage done to local and remote organs as well. Treatment of patients with intermittent claudication therefore may be classified into the first priority group for aggressive prevention and treatment of atherothrombosis.

Peripheral Artery Disease
Diseases of the Aorta, Peripheral Vascular Disease, Stroke


Atherosclerosis is considered a systemic disease, therefore patients with proven atherosclerotic disease are likely to have similar lesions in other vascular beds.
Patients with peripheral arterial occlusive disease (PAD) are especially prone to widespread atherosclerotic disease (1, 2).
Therefore PAD should be viewed as an indicator of potentially diffuse and significant atherosclerosis.
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.


Patients with intermittent claudication disease suffer from a temporary lack of oxygen in the legs, caused by narrowing or occlusion of the arteries.
When these patients are at rest, oxygen supply covers the oxygen needs of their basic metabolic processes in muscles and other tissues. However during exercise, oxygen consumption increases, and because of obstacles in the circulation, oxygen supply is limited and does not cover the metabolic needs of tissue distal of the narrowed arterial segment. Local ischaemia is followed by reperfusion once exercise is interrupted.
Tissue ischaemia evokes anaerobic metabolism that enhances the formation and accumulation of anaerobic metabolites and synthesis of free oxygen radicals that cause functional damage to metabolic processes in ischaemic tissues.
During reperfusion, these anaerobic metabolites are released and their entry in to the circulatory system occurs (3).
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 (4).

The basic pathophysiological process is most probably oxidative stress as a consequence of free radical generation. It occurs if the production of free radical is excessive due to internal or external factors and if the protective mechanisms are exhausted (5). 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.

Harmful effects of oxidative stress

Enhanced oxidative stress triggers an inflammatory process through activation of nuclear redox – sensitive transcription of factor [kappa] B, which upregulates genes such as cytokines, adhesion molecules, endothelium-1, and procoagulant tissue factor (6).
It was shown that in claudicants in the recovery phase, there is a temporary increase of interleukin-1b and interleukin-6 and an inverse interrelationship between walking capacity and an increase of CRP levels in the recovery phase was observed (7).
Increased oxidative stress during claudication was also confirmed by increased releases of markers of exogenous antipyrine: p-hydroxyantipyrine and o-hydroxyantipyrine (3). Reperfusion following severe ischemia incites a systemic response involving neutrophil activation, increased vascular permeability and injury. Lewis and co-workers found an increased level of the von Willebrand factor in claudicants, thus indicating increased oxidative stress and related endothelial hyperactivity or dysfunction during exercise (8).
Similarly, we demonstrated an increased release of cytokines, adhesion molecules and an accompanying decrease of flow-mediated dilation of the brachial artery during the recovery phase after claudicant pain.

Clinical relevance

The cumulative effect of repeated low-grade inflammatory responses during intermittent claudication has an unfavourable effect on the progression of atherosclerosis. This may also explain why patients with intermittent claudication are subject to a massive increase in cardiovascular morbidity and mortality rates.
These findings may also have important therapeutic implications in patients with peripheral vascular disease. By elimination of obstruction in the circulation it is possible not only to prevent amputation of a diseased leg and to improve quality of life, but through elimination of transient episodes of ischaemia it is theoretically possible to prevent progressive damage of local and remote organs. One study showed that percutaneous transluminal angioplasty reduced the free oxygen radical challenge and decreased or eliminated oxidative stress (8).
Exercise training as one of the basic treatment modalities of PAD patients could have adverse systemic effects, however some studies indicated that prolonged training is associated with the reduction of inflammatory markers and symptomatic improvement. This is probably caused by the exhausting of inflammatory potential during repeated exercise (9).
Some small scale studies indicated that vitamins and prostaglandins reduce oxidative stress in claudicants and can have therapeutic applications (10, 11).
Also, preventive measures and drugs used in secondary prevention of PAD can probably modify oxidative stress (12). For statins it was shown that besides their lipolytic effect they have anti-inflammatory properties and pleiotropic haemodynamic effects (improvement of endothelial function), through diminishing oxidative stress.
Further, the preventive effect of Aspirin is probably not only related to its antiplatelet properties but its accompanied anti-inflammatory and antioxidative effects may play an important role in prevention of atherosclerosis.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


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.
Through elimination of risk, progression of atherosclerosis is retarded and by improving local oxygen supply using revascularisation procedures, it is not only possible to enhance survival of a diseased leg but also to expect a reduction of systemic response. Therefore treatment of patients with intermittent claudication may be classifiied in the first priority group for aggressive prevention and treatment of atherothrombosis.


1. Criqui MH. Systemic atherosclerosis risk and the mandate for intervention in atherosclerotic peripheral arterial disease. Am J Cardiol 2001; 88: 43J-7J.

2. Clement DL, Boccalon H, Dormandy J, Durand-Zaleski I, Fowkes G, Brown T. A clinical approach to the management of the patients with coronary (Co) and/or carotid (Ca) artery disease who presents with leg ischaemia (Lis). Internat Angiol 2000; 19: 97-122.

3. Coolen SAJ, Wijnen MHWA, Reijenga JC, Vader HL, Roumen RMH, Huf FA. A new method for measuring oxidative stress in claudicants during strenuous exercise using free radical derivatives of antipyrine as indicators: a pilot study. Ann Clin Lab Sci 2002; 32: 181-7.

4. Tisi PV, Shearman CP. The evidence for exercise-induced inflammation in intermittent claudication: should we encourage patients to stop walking? Eur J Vasc Endovasc Surg 1998; 15: 7-17.

5. Shearman CP, Gosling P, Gwynn BR, Simms MH. Systemic effects associated with intermittent claudication. A model to study biochemical aspects of vascular disease? Eur J Vasc Surg 1988; 2: 401-4.

6. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 1998; 37: 586-600.

7. Cordova R, Martini R, D´En A, Salmistrato G, Mussap M, Plebani M, Andreozzi GM. Flogistic arterial activity or own inflammatory attitude: what acts on PAD evolution. Intern Angiol 2003; 22: 21-3.
8. Lewis DR, Day A, Baird RN, Smith FCT, Lamont PM. Angioplasty reverses the systemic effects of exercise in intermittent claudication. Brit J Surg 1999; 86: 709.

9. Tisi PV, Hulse M, Chulakadabba A, Gosling P, Shearman CP. Exercise training for intermittent claudication: does it adversely affect biochemical markers of the exercise-induced inflammatory response? Eur J Vasc Endovasc Surg 1997; 14: 344-50.

10. Wijnen MH, Coolen SA, Vader HL, Reijenga JC, Huf FA, Roumen RM. Antioxidants reduce oxidative stress in claudicants. J Surg Res 2001; 2001¸: 183-7.

11. Weiss T, Eckstein H, Weiss C, Diehm C. Neutrophil function in peripheral arterial occlusive disease: the effects of prostaglandin E1. Vasc med 1998; 3: 171-5.

12. O´Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126-31.


Vol4 N°02

Notes to editor

Prof. P. Poredos
Ljubljana, Slovenia
Chairperson of the ESC Working Group on Peripheral Circulation

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.