Mechanisms of the training response in patients with peripheral arterial disease – a review

Exercise training has proved to be a beneficial treatment for patients with peripheral arterial disease (PAD) suffering from the symptom of intermittent claudication. The mechanism by which symptomatic improvement occurs is unclear. The review summarises the mechanism of the training response in patients with PAD, focusing on improvements in bloodflow as well as biochemical, muscle recruitment and psychological adaptations. Possible areas of future research are suggested.


Introduction
Peripheral arterial disease (PAD) is characterised by the presence of atherosclerotic plaque in the peripheral arteries causing reduced blood flow to the peripheral limbs.Reduced blood flow results in ischaemia.The pain of intermittent claudication is felt, particularly during exercise. 1The word 'claudicare' means to limp.Typically the patient with PAD will experience pain (either in the buttock, thigh or calf muscle) distal to the atherosclerotic obstruction.Studies have shown that exercise training is an important and effective therapy for patients with PAD.The effects of exercise training on PAD and intermittent claudication have been reviewed. 2pically exercise programmes continue for 6 weeks to 6 months and vary in the mode of exercise training used.In a meta-analysis by Gardner et al. 18 of 21 studies on exercise training in patients with PAD, PFWD increased 179% and the MWD increased 122% following exercise training. 18Despite the clear evidence of patients clinically benefiting from exercise training, the mechanism(s) of the training response remains unclear.Several mechanisms have been proposed and researched and these will be discussed in this paper.

Improvements in blood flow -increased collateral circulation and increased endothelium-dependent dilation
Skinner and Strandness 3 claimed that exercise training increased collateral circulation to the ischaemic muscle.They found a reduction in the post-exercise hyperaemic response with exercise training. 3Postexercise hyperaemia is when blood flow increases to the ischaemic muscle after exercise, and as a result blood flow decreases to the foot, causing a reduction in ankle pressure.The greater the reduction in ankle pressure, the greater the extent of the underlying peripheral arterial disease as blood is shunted to the ischaemic muscle. 19Therefore the authors argued that because this post-exercise hyperaemic response was dampened by exercise training, exercise training must improve blood flow to the ischaemic limb and stated that this was through collateral growth (although they did not prove this).
In that same period, Alpert et al. 4 documented that exercise training increased absolute blood flow to the lower limbs (measured by the 133 Xe clearance method) and also attributed this to the development of a collateral circulation. 4enty years later a study by Carter et al. 5 also found that systolic ankle pressure recovery to normal levels following the post-exercise hyperaemic response was more rapid after a period of exercise training.Furthermore, an increase in walking tolerance was related to a decrease in the time of the ankle pressure to return to pre-exercise levels but not to any other haemodynamic variables (absolute ankle pressure and ABI), 5 and therefore the development of an increased collateral circulation and improved blood flow was unlikely.In support of this study, Jonason and Ringqvist 6 found that post-exercise ankle pressure (from minute 2 -16) was higher after a period of exercise training.However, there was no change in calf blood flow at rest or post-ischaemic maximum blood flow measured by strain gauge plethysmography.They attributed this reduction in post-exercise hyperaemia to 'a more optimal distribution and utilization of available blood flow with exercise training'. 6erefore neither Carter et al. 5 or Jonason and Ringqvist 6 could attribute increased walking tolerance following exercise training to increased blood flow to the lower limb through an increased collateral circulation.Subsequently two more studies have shown that blood flow to the lower limb as measured by strain gauge plethysmography increases with exercise training. 7,8However, neither of the above studies proved that improvement in blood flow is due to an increased collateral circulation.
More recently a study in subjects with mild hypertension found that after 12 weeks of exercise training, forearm blood flow increased significantly in response to acetylcholine (an endothelium-dependent vasodilator) but not to isosorbide dinitrate (an endotheliumindependent vasodilator) in the exercise group but not in the control group. 20Studies using the elderly 21,22 or patients with coronary artery disease 23 and on animals with chronic coronary occlusion 24 have revealed that exercise training improves endotheliumdependent vasorelaxation through an increase in the release of nitric oxide.
Endothelial cells release nitric oxide, a lipid-soluble gas, in response to the stimulus of increased blood flow through the vessel lumen (as would happen during exercise). 25Indeed, it is apparent that a depressed endothelial function is more likely to improve with exercise training than in patients with normal endothelial function (i.e. in the young and healthy).It has been shown in patients with PAD that endotheliumdependent dilation is impaired or depressed.This was shown by measuring maximum brachial artery diameter and flow after brachial artery occlusion (with a blood pressure cuff) in patients with PAD and controls. 27Only one study has shown that exercise rehabilitation improves endothelial-dependent dilation in older patients with PAD. 9 This study found a 60% improvement in the flow-mediated brachial arterial diameter as well as in the resting arterial diameter.However, this study was not randomised or controlled.
It is perhaps the improved endothelial-dependent vasodilation that is responsible for improvements in walking tolerance and blood flow.It is possible that improved endothelial-dependent vasodilation in patients with PAD as a result of exercise training allows for a less pronounced and shorter duration post-exercise hyperaemic response and decrease in ankle pressure after a bout of exercise, which would explain the findings of the studies completed in the 1960s and 1980s.
Finally, it may not only be the endothelium that is responsible for vasodilation in patients with PAD.Further examination is also required of the ability of the smooth-muscle cells of the arteries to cause vasodilation in response to adenosine in patients with PAD.A study by Hambrecht et al. 23 found that coronary blood flow reserve (the ratio of the mean peak flow velocity to the resting velocity after adenosine infusion) increased significantly after 4 weeks of training in patients with coronary artery disease. 23Future research should examine this response to exercise training in patients with PAD.

Biochemical adaptations in skeletal muscle in patients with PAD following exercise training
Because patients with PAD have reduced blood flow to the exercising limb(s), it has been suggested that anaerobic glycolysis resulting from ischaemia increases the lactate concentration in the skeletal muscles and blood, which leads to claudication pain. 27,10is was summarised in a review article by Tan et al., 28 who stated, 'In patients with peripheral vascular disease, increasing the workload causes an inequality in the supply of and demand for oxygen.Aerobic generation of ATP becomes inadequate and anaerobic metabolism predominates.The result is an increase in lactic acid production, and a depletion of ATP and creatine phosphate, leading to pain.' Support for this theory is found in studies that have shown that improvements in walking tolerance following exercise training in patients with PAD occur alongside increases in the number of oxidative enzymes found in the skeletal muscle, 11,10 improvements in oxygen extraction by the skeletal muscles 12,29 and a decrease in the concentration of acylcarnatines 16 (produced during skeletal muscle ischaemia).The theory is that these adaptations delay the onset of anaerobic glycolyis, lactate accumulation and pain.This theory of walking intolerance in patients with PAD stems from the popular cardiovascular/anaerobic theory of fatigue which suggests that fatigue develops when the exercising skeletal muscles fail to get enough oxygen to them and as a result have to rely on anaerobic glycolysis to produce enough ATP to continue exercising. 30 by-product of anaerobic glycolysis is lactate accumulation in the skeletal muscles and blood.
A recent study in this laboratory found that although venous lactate concentrations increased following a graded treadmill exercise test, the values were very low (2.08±1.6 to 3.28±1.39mmol.l - ) and furthermore did not correlate to PFWD or MWD in patients with PAD. 15 Others have found that venous and arterial lactate concentrations were higher in patients with PAD at maximal exercise capacity than in age-matched controls at maximal exercise capacity 29 and lower after surgical reconstruction or physical training in these patients. 29,16However, concentrations of blood lactate never reached higher than 4 mmol.l - in these studies.Values in a normal population at maximal exercise capacity reach far greater values than this (7.59mmol.l - ) and the subjects never experience claudication. 31,32In skeletal muscle, there was no significant difference in lactate concentration values between patients with PAD and controls at maximal exercise capacity. 16erefore, the suggestion that accumulation of lactate in the skeletal muscles and blood leads to claudication pain, is unlikely.There has to be some other mechanism for the pain that patients with PAD experience.

Muscle recruitment response to claudication and exercise training
Recently it has been suggested that fatigue in the normal population develops when muscle recruitment is reduced by the motor cortex, causing exercise to terminate.This happens because inhibitory reflexes arise from the exercising muscles and feedback to the spinal cord and motor cortex, reducing skeletal muscle recruitment.This theory has been previously reviewed. 33,34e influence of the central nervous system on muscle recruitment is commonly measured using surface electromyography (EMG).EMG comprises of the sum of electrical contributions made by the active motor units which are detected by electrodes placed on the skin surface overlying the muscle. 35Few studies have investigated muscle activity in patients with PAD after interventions including exercise training response and percutaneous transluminal angioplasty (PTA).The only published studies investigating EMG in these patients have studied changes in median frequency (MDF, the frequency value which divides the power density spectrum of EMG signal into two equal halves), nerve conduction velocity of peroneal and tibial nerves 36,37,33,17 and a recent case study investigating changes in EMG after angioplasty. 38A study conducted by Pedrinelli et al. 17 examined muscle fibre conduction velocity (MFCV) and MDF of the tibialis anterior muscle during tetanic electrical stimulations in patients with PAD and controls.MFCV ranges did not differ significantly between patients and healthy controls.However, MDF of both the ischaemic and non-ischaemic legs were found to be significantly lower than the controls, as the healthy limb also showed a decrease in MDF.This finding suggests that chronic ischaemia was not the cause of lower MDF in patients with PAD.It is of interest to note that this study used a 3-week walking programme intervention, which resulted in improved exercise tolerance, raised initial MDF but not to normal values after the walking programme; and unchanged MFCV in patients with PAD.These findings suggest that central drive increases following a supervised walking programme and factors other than ischaemia and physical inactivity underlie the abnormal EMG signal in patients with PAD.A case study conducted by Albertus-Kajee et al. 38 on a patient with PAD came to similar conclusions, where muscle activity in the diseased leg was found to increase after angioplasty.They explain this increase in EMG as a possible increase in central drive to the lower limbs after angioplasty, which resulted in an increase in functional capacity.Interestingly, the blood lactate concentrations were low ranging between 2.00 and 1.75 mmol.l - before angioplasty and 1.75 -1.50 mmol.l - after angioplasty.
The influence of muscle recruitment on the training response in these patients is therefore of special interest and needs to be further investigated.Although the use of EMG in the evaluation of this disease is still in early development, it provides a non-invasive assessment and understanding of the physiopathology of skeletal muscle involvement in patients with PAD.

Psychological adaptations to exercise training
Some of the improvement in exercise tolerance noted with exercise training in patients with intermittent claudication may be attributed to psychological factors.This was made apparent in a review where a number of important predictors of the outcome of an exercise programme were identified. 39The best correlation with good outcome of the exercise programme was belief that the exercise would lead to an improvement in walking status.Moreover, patients can be influenced by the level of motivation they feel on the particular day of testing.This was made apparent in a study which noted: 'The psychology involved when walking with pain was highlighted by the two-thirds of patients who said they could walk no further but then immediately walked 15 -45 m to the rest room'. 40stly it seems that as patients subject themselves to pain, their pain tolerance improves.Gardner et al. 18 found in a meta-analysis that claudication pain end-point used during an exercise training programme was the most important independently related predictor of the positive change in PFWD distance and MWD in patients with intermittent claudication. 18The longer patients 'walked into' their pain during training, the more PFWD and MWD improved after training.Therefore, factors including the belief that the exercise training will work, motivation to walk and improvements in pain tolerance can affect walking tolerance.If it is true that the motor cortex reduces muscle recruitment in response to pain then these psychological factors could perhaps act against central regulation, allowing for the patient to train longer and eliciting better functional results.This is an area of future research.

Conclusion
Early research attributed improvements in walking distances with exercise training to improvements in collateral circulation or peripheral adaptations in the exercising skeletal muscles.This review indicates that endothelium-dependent dilation improves with exercise training and should be researched further in controlled, randomised trials.Moreover, the possibility that the central governor causes exercise to terminate in patients with PAD should be investigated, especially in the light that factors including the belief that the exercise training will work, motivation to walk and improvements in pain tolerance affect walking distances in patients with PAD.

18
Improved pain tolerance through exposure to pain Claudication pain end point used during training was the most important predictor of change in PFWD Meta-analysis of controlled trials AP = ankle pressure; ABI = ankle brachial index; Cyt-ox = Cytochrome-c oxidase; MDF = median frequency; MWD= mean walking distance; PFWD= pain-free walking distance.