Effect of propionylcarnitine on changes in endothelial function and plasma levels of adhesion molecules induced by acute exercise in patients with intermittent claudication

In patients with intermittent claudication, treadmill exercise may cause acute deterioration of endothelial function and increase in plasma concentrations of adhesion molecules. The authors evaluated the efficacy of intravenously administered propionylcarnitine (PLC)in preventing these phenomena. Thirty-six claudicants with postexercise decrease in brachial artery flow-mediated dilation (FMD)were randomized to either placebo or PLC (600 mg as a single bolus followed by 1 mg/kg/min for 60 minutes).In the 18 patients randomized to placebo, FMD markedly decreased with exercise before (from 6.8 +/-0.4% to 4.0 +/-0.4%; p < 0.001) and after treatment (from 6.5 +/-0.4% to 4.4 +/-0.5%; p < 0.001). By contrast, in the PLC group, FMD significantly decreased with exercise before treatment (from 8.0 +/-0.7% to 4.4 +/-0.4%; p < 0.001), but not after active drug administration (from 7.1 +/-0.7% to 6.0 +/-0.6%; p = 0.067). The difference between treatments was not significant (p = 0.099; ANOVA). However, in the PLC group, the authors found that the greater the exercise-induced deterioration in endothelial function before treatment, the greater the capacity of PLC to prevent a postexercise decrease in FMD (r = -0.50, p = 0.034). Accordingly, they analyzed data in the 19 patients with a baseline exercise-induced decrease in FMD >or=45% (ie, the median FMD reduction in the entire group of 36 patients), and found that the exercise-induced FMD decrease was less after PLC than after placebo (p = 0.046, ANOVA). In the same subgroup, the exercise-induced increase in plasma concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) was significantly higher before than after treatment in patients randomized to PLC (23.4 +/-5% vs 15.3 +/-7%, p = 0.007). In conclusion, in patients with intermittent claudication suffering from a greater endothelial derangement after treadmill, PLC administration provided a protective effect against deterioration of FMD and increase of sVCAM-1 induced by exercise.     

Improved functional outcomes following exercise rehabilitation in patients with intermittent claudication

BACKGROUND: The purposes of this study were to identify predictors of increased claudication distances following exercise rehabilitation in peripheral arterial occlusive disease (PAOD) patients with intermittent claudication and determine whether improved claudication distances translated into increased free-living daily physical activity in the community setting. METHODS: Sixty-three patients were recruited (age, 68+/-1 years, mean +/- standard error). Patients were characterized on treadmill claudication distances, walking economy, peripheral circulation, cardiopulmonary function, self-perceived ambulatory function, body composition, baseline comorbidities, and free-living daily physical activity before and after a 6-month treadmill exercise program. RESULTS: Exercise rehabilitation increased distance to onset of claudication pain by 115% (178+/-22 m to 383+/-34 m; p < .001) and distance to maximal claudication pain by 65% (389+/-29 m to 641+/-34 m; p < .001). The increased distance to onset of pain was independently related to a 27% increase in calf blood flow (r = .42, p < .001) and to baseline age (r = -.26, p < .05), and the increased distance to maximal pain was predicted by a 10% increase in peak oxygen uptake (r = .41, p < .001) and by a 10% improvement in walking economy (r = -.34, p < .05). Free-living daily physical activity increased 31% (337+/-29 kcal/day to 443+/-37 kcal/day; p < .001) and was related to the increases in treadmill distances to onset (r = .24, p < .05) and to maximal pain (r = .45, p < .001). CONCLUSIONS: Increased claudication distances following exercise rehabilitation are mediated through improvements in peripheral circulation, walking economy, and cardiopulmonary function, with younger patients having the greatest absolute ambulatory gains. Furthermore, improved symptomatology translated into enhanced community-based ambulation.     

Comorbidities and exercise capacity in older patients with intermittent claudication.

Patients with peripheral arterial disease (PAD) and intermittent claudication often have coronary artery disease (CAD) and other comorbid medical problems. There is a paucity of information on the impact of coexistent medical conditions on exercise capacity and functional status in patients with PAD. This study examined the impact of CAD, diabetes, cigarette smoking, prior peripheral surgical revascularization and other medical conditions on claudication pain times and peak oxygen capacity (VO2) during maximal effort treadmill testing in 119 male outpatient volunteers (ankle-brachial index (ABI) of 0.65 +/- 0.2, mean +/- SEM) with a history of Fontaine Stage II PAD. Smoking status was significantly related to ambulatory function. Current smokers had a lower peak VO2 expressed in l/min than either former or never smokers (ANCOVA adjusted for age, p = 0.003). However, after adjustment for body weight, there was only a trend for a difference in peak VO2 between current (13.2 +/- 0.5 ml/kg per min), former (14.2 +/- 0.4 ml/kg per min) and never (15.4 +/- 1.0 ml/kg per min) smokers (ANCOVA, p = 0.10). Current smokers had a shorter time to onset of claudication pain (p = 0.023) and shorter maximal claudication pain times (p = 0.029) than former or never smokers (p = 0.023). The ABI 1 min after cessation of exercise was also lower in smokers compared to former and never smokers (p = 0.018). There were no significant differences in functional performance measures or time to recovery from maximal claudication pain when patients were categorized on the presence or absence of CAD, diabetes, peripheral revascularization, arthritis, hypertension or dyslipidemia. Therefore, smoking adversely affected exercise capacity in these PAD patients, whereas the presence of CAD, diabetes and other medical problems had a relatively minor impact on exercise capacity. In conclusion, the relatively minor impact of comorbid medical conditions on walking ability in patients with PAD reflects the overwhelming limitation in ambulatory function due to the claudication pain.     

Supervised and home-based exercise training for patients with intermittent claudication

Home-based exercise training, applied as the primary treatment in patients with intermittent claudication, has produced inconsistent effects on walking capacity in previous published studies. The aim of the present study was to evaluate whether a home-based exercise training program could maintain improved walking capacity and other functional variables achieved through a supervised exercise training program. The present design was a 48-week self-controlled study. The first 12-week period was a control stage in which no prescribed exercise program was provided, the second 12-week period was a supervised treadmill-walking training program and the following 24-week period was a home-based exercise program. Twenty-two subjects with intermittent claudication were recruited initially; 15 of them (14 men and one woman) completed the whole program. Walking capacity, peak oxygen uptake, walking economy and ankle-brachial index were measured at baseline and at 12, 24 and 48 weeks. There was no significant change in the measured variables after the control stage. The 12-week supervised treadmill-walking training program significantly increased pain-free walking time, maximal walking time and peak oxygen uptake. Walking economy was also significantly improved. These improvements were successfully maintained after 24 weeks of home-based training. The results indicated that 12 weeks of supervised treadmill-walking training followed by a home-based training program is an effective model of exercise rehabilitation for patients with intermittent claudication.     

The acute effects of cigarette smoking on treadmill exercise distances in patients with stable intermittent claudication

The hypothesis that smoking has an acute effect on treadmill exercise performance in patients with peripheral vascular disease was investigated in a crossover trial. Twelve patients with stable intermittent claudication who were regular smokers attended on two occasions within one week and treadmill tests were performed after 1/2, 1, 1 1/2, and 2 hours. Immediately before the second exercise test, two standard cigarettes were smoked or an unlit cigarette was "sham-smoked." Because participants could not be blinded, an attempt to control for patient bias was made. Half were told that we expected smoking to make no difference or possibly cause some improvement, and half were told that we expected it to make no difference or possibly cause some deterioration. These explanations and the order of study days were determined by balanced randomization. Suggestion had a significant influence on claudication distance immediately after smoking (p less than 0.01) but no significant effect on walking distance. Combining data from both groups assumes that no overall bias was introduced by the explanations given. Immediately after smoking, small, nonsignificant increases in claudication distance (+10%, 95% CI-7%, +27%) and walking distance (+9%, 95% CI-2%, +19%) were observed. Smoking caused a mean increase in heart rate of 9 beats per minute, which persisted for one hour, but no consistent change in blood pressure. The results show that suggestion may have a significant influence on treadmill exercise distances. Smoking is unlikely to have an important acute effect on exercise performance in claudicants.     

Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria

Objectives: We sought to investigate the effects of short- and long-term vitamin C therapy on endothelial dysfunction in patients with homocystinuria. Background: Untreated homocystinuria due to cystathionine -synthase deficiency is associated with premature atherothrombotic disease; 25% of untreated patients suffer a vascular event by the age of 16 years and 50% by 29 years. Treatment directed at reducing homocysteine accumulation significantly reduces this risk. However, despite optimal treatment and compliance, hyperhomocysteinaemia usually persists and individuals exhibit endothelial dysfunction indicative of an adverse cardiovascular prognosis. Additional intervention is therefore required to further reduce cardiovascular risk. Methods: We investigated the endothelial effects of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent responses to nitroglycerin (NTG) were measured using high-resolution ultrasonic vessel wall-tracking. Results: Baseline: Plasma total homocysteine was 100.8 ± 61.6 and 9.2 ± 1.9 mol/L in the patient and control groups, respectively (p < 0.001). FMD responses were impaired in the patient group (20 ± 40 m) compared with the controls (116 ± 30 m) (p < 0.001). Vitamin C administration: FMD responses in the patient group improved both acutely, 160 ± 65 m at 4 h (p < 0.001), and chronically, 170 ± 70 m at 2 weeks (p < 0.001) and 170 ± 40 m at 6 months (p < 0.001). FMD responses in the control group were unaltered (p = 0.526). Within both groups, neither the vascular response to NTG nor plasma homocysteine was altered (p > 0.4). Conclusions: Vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease.     

Lactate and pyruvate kinetics after treadmill exercise in patients with intermittent claudication

Lactate and pyruvate movements in arterial and venous blood during recovery following treadmill exercise in 8 patients with arterial occlusive disease were studied by means of a two-compartment model. Blood lactate and pyruvate concentration curves over the recovery period were found to fit a two-exponential time function including a rapidly increasing and a slowly decreasing component. The velocity constants gamma 2 were dependent on the exercise load. The time of lactate disappearance during recovery decreased with the work load in patients with intermittent claudication. The velocity constant of the arterial blood pyruvate decrease was similar to that of the simultaneously measured lactate indicating that the rate of lactate removal is closely related to that of pyruvate. In conclusion, the use of the model allows to study factors likely to modify the coefficients, such as physical training, therapeutic effects and active recovery.     

Indications for and limitations of exercise training in patients with intermittent claudication

BACKGROUND: The selection of candidates for exercise training among patients with intermittent claudication is still a matter of debate. PATIENTS AND METHODS: Forty-nine patients with intermittent claudication due to arteriosclerosis obliterans were tested. Forty-six patients were men and 3 were women, with an average age of 65 years (range, 46 to 76 years). The patients walked on a treadmill at 2.4 km/h on a 12% upgrade followed by an appropriate period of rest for 30 minutes twice a day during a 3-week hospitalization. Programs were individualized for each patient. Four parameters were assessed after exercise training: (1) Ankle-brachial index (ABI) at rest, (2) Fall in ABI after 40 m of treadmill walking (ABI Fall 40), (3) the recovery time (RT 40) required for the ABI to return to resting levels after 40 m of walking, and (4) the maximal walking distance (MWD) on the treadmill. RESULTS: The average ABI at rest before the 3-week training period was 0.60 +/- 0.02 (mean +/- SE), and after training it was 0.62 +/- 0.02. There was a small although not statistically significant increase in the ABI after training. This increase in the ABI did not exceed 0.21. The average ABI Fall 40 before training was 0.36 +/- 0.01, and after training it was 0.30 +/- 0.02. The average RT 40 before training was 9.9 +/- 0.8 min, and after training it was 6.2 +/- 0.6 min. There were significant decreases in the ABI Fall 40 and RT 40 after training (p < 0.01 and p < 0.001, respectively). The MWD increased after training in 48 of the 49 patients. The average MWD increased from 134 +/- 13 m to 226 +/- 32 m after training (p < 0.001). The occlusion levels did not influence the results as training effects and hemodynamic parameters. Fourteen of 49 patients desired arterial reconstruction after exercise training. CONCLUSIONS: Patients with shorter RT 40's before training achieved greater increases in the MWD after training. In patients with an RT 40 under 12 min, exercise training is indicated. However, there is some discrepancy between the increase in MWD and the degree of satisfaction in individual patients.     

Effects of home versus supervised exercise for patients with intermittent claudication.

PURPOSE: This study was performed to test the efficacy of a supervised, hospital-based exercise program compared with a home-based exercise program involving minimal supervision, for both walking ability and quality of life measures in patients with exercise-limiting intermittent leg claudication. METHODS: Twenty-one patients were assigned randomly to 12 weeks of supervised exercise or to a home-based exercise group. After 12 weeks the participants in the supervised group transitioned to a home-based program. Both groups were then reevaluated at the end of 24 weeks. The initial claudication distance (ICD) and absolute claudication distance (ACD) on progressive treadmill exercise was measured at baseline, 12 weeks, and 24 weeks. Additionally, self-reported quality of life status was evaluated using the MOS SF-36 questionnaire. RESULTS: Each group improved (P < 0.01) ACD from baseline to 12 weeks, which was sustained at the 24-week follow-up. Both groups experienced similar long-term improvements (P < 0.05) in ACD (521.5 +/- 253.4 meters to 741.9 +/- 365.6 meters for the supervised group, 532.2 +/- 263.5 meters to 715.0 +/- 394.4 meters in the home group, P not significant, between groups). The supervised group experienced a greater improvement (P < 0.01) in the ICD after 12 weeks than the home group but not at 24 weeks. The on-site group also experienced significant improvements in ICD after 24 weeks (P < 0.05). Neither group manifested an improvement in self-reported physical function or mental health as assessed by the MOS SF-36. CONCLUSION: A structured exercise program was more effective in improving the ICD over a 24-week period than a less formal, home-based program. However, if patients are screened properly and receive adequate instruction, a home-based program can be a safe, low-cost alternative providing similar long-term (24 weeks) exercise benefits in ACD.     

Acute impairment of the endothelial function by maximal treadmill exercise in patients with intermittent claudication, and its improvement after supervised physical training.

AIM: The aim of this study was to determine the effects of maximal exercise and of physical training on endothelial function (EF) of patients with intermittent claudication (IC). METHODS: EF, assessed by ultrasonography of the brachial artery, has been measured in 22 male patients with IC before (pre-exercise EF) and after (postexercise EF) maximal treadmill test. Absolute claudication distance (ACD) and ankle brachial index (ABI) have been measured too. The measurements have been repeated after 18 days (3 times weekly, for 6 weeks) of supervised physical training. RESULTS: Before training, the pre-exercise EF was 7.6+/-2.94 and postexercise EF 5.28+/-3.3 (-33.2%) (P<0.01). After training, the pre-exercise EF was 10.3+/-4.04, whilst postexercise EF was 7.79+/-2.56 (-18.97%) (P<0.01). The differences between the pre-exercise value before and after training and between the postexercise value before and after training were significant (P<0.01). ACD and ABI after training increased respectively from 93.95 to 166.55 m and from 0.67 to 0.71 (P<0.001). CONCLUSIONS: Endothelial dysfunction takes a relevant part in the pathophysiology of IC, with 2/3 of the patients showing an EF lower than the pathological cut-off. Maximal exercise worsens the EF, according to the trend associated with the acute inflammatory response. All these features suggest that physical activity in IC should not utilize the maximal working load, in order to avoid the high inflammatory activation and the acute complications of atherosclerotic plaque. The supervised physical training, besides confirming itself as the most effective means to increase the walking ability, also proved to be able to improve the EF of these patients, as described about other diseases. It is probable that moderate hemodynamic stress reduces the levels of the inflammatory markers and increases the flow-mediated vasodilation through an ischemic preconditioning. The increased walking ability, associated with the improvement of EF could improve the heavy systemic outcome of claudicant patients, as it has been demonstrated in patients with coronary heart disease. Further prospective survival studies on cardiovascular outcomes of trained claudicant patients are needed.     

Leg showering therapy in patients with intermittent claudication

Ten patients with intermittent claudication were treated using a recently constructed "chair" in which the seated patient has alternately warm and cool water flushed over the legs and feet. A trial treatment was given for 25 minutes, three times a week for 5 weeks. Ankle/arm index, skin perfusion pressure and calf blood flow all remained unchanged immediately after such a series of treatment. Even at follow-up 6 months later, values were unchanged but for a minute increase in ankle/arm index in the poorer leg. Walking capacity was additionally measured and an improvement was seen, also after 6 months. The role of the contrast temperature treatment in this improvement is, however, unclear.     

Effect of treadmill exercise on blood gases and acid-base balance in patients with intermittent claudication

Blood gases and lactate and pyruvate concentration were measured in arterial and popliteal venous blood in 6 control subjects and 34 patients with intermittent claudication before, during, and after treadmill exercise of 10 min duration. Oxygen saturation, oxygen extraction, base excess, and standard bicarbonate were calculated. The transition from resting supine position to upright position on the treadmill caused the popliteal venous oxygen saturation to fall from 49.4% to 26.3%. In patients, during exercise a further decrease (to 11%) was observed. During treadmill exercise the popliteal venous PO2 did not fall below 16.5 +/- 1.1 mm Hg in the controls. Individual values during exercise varied between 6.4 mm Hg and 17.9 mm Hg in patients. A critical oxygen pressure was reached in 10 patients. Lactate concentration was found to increase to values as high as 14 mmol/l in popliteal venous blood. The lactate-pyruvate ratio varied between 12.9 and 106.3 during exercise, and the corresponding values for venous blood pH were 7.38 and 6.92. Changes in the PCO2, lactate, and pH in arterial and popliteal venous blood showed a significant correlation. The decrease in the base excess was greater than the corresponding increase in the blood lactate concentration. It is concluded that analysis of the acid-base balance in patients with intermittent claudication is best carried out by the regional catheterization technique.     

Alteration in angiogenic and anti-angiogenic forms of vascular endothelial growth factor-A in skeletal muscle of patients with intermittent claudication following exercise training

The aims of this study were twofold: (1) to identify whether peripheral artery disease (PAD) patients had increased muscle concentration of angiogenic VEGF-A, anti-angiogenic VEGF???b or VEGF receptor 1 (VEGF-R1) when compared with control subjects, and (2) to evaluate whether exercise training in PAD patients was associated with changes in muscle concentration of VEGF-A, VEGF???b or VEGF-R1. At baseline, 22 PAD and 30 control subjects underwent gastrocnemius muscle biopsy. Twelve PAD patients were treated with supervised exercise training (SET) and underwent muscle biopsy after 3 weeks and 12 weeks of training and had sufficient tissue to measure VEGF-A, VEGF???b and VEGF-R1 concentrations in skeletal muscle lysates by ELISA. Muscle concentrations of VEGF-A and VEGF???b were similar in PAD patients versus controls at baseline. At both time points after the start of SET, VEGF-A levels decreased and there was a trend towards increased VEGF???b concentrations. At baseline, VEGF-R1 concentrations were lower in PAD patients when compared with controls but did not change after SET. Skeletal muscle concentrations of VEGF-A are not different in PAD patients when compared with controls at baseline. SET is associated with a significant reduction in VEGF-A levels and a trend towards increased VEGF???b levels. These somewhat unexpected findings suggest that further investigation into the mechanism of vascular responses to exercise training in PAD patients is warranted.     

Exaggerated endothelin release in response to acute mental stress in patients with intermittent claudication

Endothelin-1 (ET-1) is an endothelial-derived 21-amino-acid peptide with potent vasoconstrictor and mitogenic properties implicated in several cardiovascular disorders. To evaluate the plasma ET-1 response to mental stress in patients with intermittent claudication, plasma endothelin concentrations were measured by radioimmunoassay in 15 claudicant outpatients (13 men and 2 women; mean age 62 +/- 4 years) and in 15 sex- and age-matched healthy control subjects (12 men and 3 women; mean age 60 +/- 8 years) before and after mental arithmetic performed for 10 minutes. Venous blood samples were drawn from an antecubital vein at baseline, at the end of the mental arithmetic, and at 10 minutes of recovery. Baseline ET-1 values were higher in patients with intermittent claudication as compared with control subjects (4.5 +/- 0.5 pmol/L and 2.2 +/- 0.3 pmol/L, respectively, p < 0.0001). At the end of mental stress, ET-1 levels rose significantly in both groups from baseline (p < 0.001) reaching a higher value in patients with intermittent claudication than in control subjects (5.6 +/- 0.7 pmol/L and 2.4 +/- 0.4 pmol/L, respectively, p < 0.0001). The percent increases (delta%) in ET-1 plasma concentrations from baseline in response to mental stress were significantly greater in claudicant patients than in control subjects (+23 +/- 9% and +9 +/- 7%, respectively, p < 0.0001). ET-1 plasma concentrations returned to baseline values similarly in both groups at minute 10 of the recovery period. These findings show that acute mental stress causes an exaggerated release of ET-1 in patients with intermittent claudication and suggest that this could be a potential pathophysiological mechanism through which mental stress may trigger adverse acute cardiac events and accelerate progression of atherosclerosis in these patients.     

Diagnostic work-up of patients with intermittent claudication.

In this paper a number of techniques are described that provide information concerning the functional disturbances caused by anatomic lesions within the vascular system in patients with intermittent claudication. These techniques are part of a currently growing entity that is called the "Vascular Laboratory". Main characteristics of these techniques are that they are painless, atraumatic and without any danger to the patient. Therefore, they can both be used for diagnosis as well as for follow-up of the patients. Moreover, many of them are useful for detecting stenotic lesions at an early stage of evolution. In any patient with intermittent claudication, the walking distance, oscillography at rest and after exercise and systolic blood pressure determination should be performed. Segmental plethysmography is extremely sensitive mainly when performed together with systolic blood pressure determination. Venous occlusion plethysmography has been significantly improved in recent years and is capable of providing direct information concerning the circulation through the diseased limb. There seems to be tremendous improvement in the techniques using ultrasound allowing presently construction of an anatomic picture of the vessels (Ultrasonic arteriography).