Unilateral Peripheral Arterial Disease Research Articles

Micro-Lightguide Spectrophotometry (O2C) for Lower Limb Perfusion: Effects of Exercise Walking in Claudicants.

Background Exercise walking has improved walking capacity in patients with intermittent claudication without affecting the macrocirculation reflected in ankle pressures. We wanted to investigate microcirculation in the skin related to exercise walking by using Micro-Lightguide Spectrophotometry (O2C). Materials and Methods Twenty-eight patients with intermittent claudication-bilateral in 17-were included in a 12 weeks of structured home-based exercise program. The pain-free and maximal walking distances were determined on a treadmill. Saturation and flow, monitored by O2C, were examined immediately before and after the treadmill test. O2C examination took place before as well as after completion of the exercise program. Ankle-brachial index was obtained before treadmill testing. Results As expected, walking performance improved significantly without affecting ankle pressures. Neither oxygen saturation nor flow, assessed at 2 mm depth, was affected following a 12 weeks of exercise program. We observed a significant decrease in oxygen saturation and flow upon treadmill testing in the both limbs in patients with bilateral peripheral arterial disease (PAD). In contrast, the treadmill test elicited no changes in the opposite and asymptomatic limb in patients with only unilateral PAD. Conclusion The findings suggest that O2C may be used to study microcirculatory changes. However, it is best suited for the study of phenomena resulting in major changes as it eliminates some inherent variability.

The efficacy of transcutaneous electrical nerve stimulation on the improvement of walking distance in patients with peripheral arterial disease with intermittent claudication: study protocol for a randomised controlled trial: the TENS-PAD study

BackgroundIn patients with peripheral arterial disease (PAD), walking improvements are often limited by early pain onset due to vascular claudication. It would thus appear interesting to develop noninvasive therapeutic strategies, such as transcutaneous electrical nerve stimulation (TENS), to improve the participation of PAD patients in rehabilitation programmes, and thus improve their quality of life. Our team recently tested the efficacy of a single 45-min session of 10-Hz TENS prior to walking. TENS significantly delayed pain onset and increased the pain-free walking distance in patients with class-II PAD. We now seek to assess the efficacy of a chronic intervention that includes the daily use of TENS for 3 weeks (5 days a week) on walking distance in Leriche-Fontaine stage-II PAD patients.Methods/designThis is a prospective, double-blind, multicentre, randomised, placebo-controlled trial. One hundred subjects with unilateral PAD (Leriche-Fontaine stage II) will be randomised into two groups (1:1). For the experimental group (TENS group): the treatment will consist of stimulation of the affected leg (at a biphasic frequency of 10 Hz, with a pulse width of 200 μs, maximal intensity below the motor threshold) for 45 min per day, in the morning before the exercise rehabilitation programme, for 3 weeks, 5 days per week. For the control group (SHAM group): the placebo stimulation will be delivered according to the same modalities as for the TENS group but with a voltage level automatically falling to zero after 10 s of stimulation. First outcome: walking distance without pain. Secondary outcomes: transcutaneous oxygen pressure (TcPO2) measured during a Strandness exercise test, peak oxygen uptake (VO2 peak), endothelial function (EndoPAT®), Ankle-brachial Pressure Index, Body Mass Index, lipid profile (LDL-C, HDL-C, triglycerides), fasting glycaemia, HbA1c level, and the WELCH questionnaire.DiscussionTENS-PAD is the first randomised controlled trial that uses transcutaneous electrical therapy as an adjuvant technique to improve vascular function in the treatment of PAD. If the results are confirmed, this technique could be incorporated into the routine care in cardiovascular rehabilitation centers and used in the long term by patients to improve their walking capacity.Trial registrationClinicalTrials.gov, ID: NCT02678403. Registered on 9 February 2016. Sponsor: Toulouse University Hospital.

Investigating a Model for Acute Ischemic Pain in Humans

Background: The pathophysiology of acute ischemic pain is not well established. The aim of the present study was to investigate acute ischemic pain in humans with a view to establish a scientific model to perform future studies. We examined whether peripheral nerve damage and acute inflammation occur during short episodes of acute ischemia. Methods: Eleven patients with unilateral peripheral arterial disease (PAD) performed treadmill exercise until intolerable ischemic pain urged them to stop. Blood samples were taken before, immediately after treadmill exercise and after a period of recovery. S100B-serum was detected via Elecsys® S100B Immunoassay and IL-6 levels determined via COBAS® IL6 Elecsys 2010. Results: Treadmill exercise led to intolerable exercise-induced ischemic pain (Numeric Rating Scale) 9 ± 0.3 (0- 10, mean ± SEM)) in the PAD affected leg. Reduced ankle/brachial-index (ABI) (0.13 ± 0.05 mean ± SEM) with a mean ankle pressure of 26 ± 9 mmHg, pO2, pH and increased serum lactate indicated that severe ischemia occurred in the PAD affected leg. The inflammation marker IL-6 increased locally and systemically post exercise (n.s.). Conclusion: We present an effective method to examine acute ischemic pain in humans. By focusing on changes in metabolic parameters in the affected limb, this model could potentially help to evaluate and detect changes during acute ischemic pain and thus contribute to the understanding of the underlying pathophysiology.

Evidence that cutaneous microvascular dysfunction in peripheral arterial disease is due to reduced nitric oxide (678.9)

We investigated the role of nitric oxide (NO) in cutaneous microvascular dysfunction in patients with symptomatic unilateral peripheral arterial disease (PAD) and in limbs of disease‐free, age‐matched controls in response to local skin warming. In 5 patients with unilateral PAD and 10 age‐matched controls, skin blood flow (SkBF) was measured using laser‐Doppler flowmetry. Local skin temperature was controlled with heater probe holders. Microdialysis was used to administer L‐NAME to inhibition NO synthase activity. Ringer’s was perfused at control sites. Data are presented as cutaneous vascular conductance (SkBF / blood pressure). Vasodilation (plateau phase) at the untreated skin sites was significantly lower in the diseased limb of the PAD patients (70.20 ± 12.41 %max) compared to the healthy contralateral limb (85.14 ± 9.26 %max, P = 0.021) and the response achieved in the control participants (86.58 ± 6.99 %max, P = 0.003). There were no differences between the NO‐inhibited skin sites of the PAD patients and healthy participants (38.32 %max vs. 38.72 %max, P = 0.395) or between the diseased and healthy leg of the PAD patients (37.19 %max, P = 0.393). The primary findings of this study are that cutaneous vasodilation is markedly reduced in response to local skin warming and this decreased response appears to be due to NO.

Função muscular em indivíduos com doença arterial obstrutiva periférica: Uma revisão sistemática

The purpose of this study was to summarize the evidence regarding muscle strength and endurance in peripheral arterial disease (PAD) subjects. Systematic review of original articles in MEDLINE, LILACS and SciELO databases, by the year 2009 was performed. Most of studies which compared strength of the leg or hip/thigh of PAD subjects and control subjects reported lower muscle strength in PAD subjects. Most of the studies which compared muscular strength between limbs in individuals with unilateral PAD (diseased and non-diseased limb) reported lower leg strength in the diseased limb. The studies which compared muscular endurance between individuals with PAD and control subjects reported lower muscular endurance in subjects with PAD. Moreover, the studies which compared muscular endurance between limbs in individuals with unilateral PAD reported lower muscular endurance in the affected limb. The summary of the evidences indicates that subjects with PAD had lower levels of strength and endurance than control subjects. Furthermore, even in patients who had unilateral PAD, muscle strength and endurance were reduced in the leg affected by the disease.

External work is deficient in both limbs of patients with unilateral PAD

External work was utilized to measure differences between the unaffected and the affected limb in patients with unilateral peripheral arterial disease compared to healthy controls. Patients with unilateral peripheral arterial disease have shown deficits in peak joint powers during walking in the unaffected and affected legs. However, no research has detailed the amount of work that is being performed by each leg compared to healthy controls even though such an analysis would provide valuable information on the energy output from the affected and the unaffected legs. Two hypotheses were tested: (a) the unaffected and affected leg would perform less work than healthy controls in a pain-free state, and (b) the onset of symptomatic claudication pain would result in further changes in the external work. Results showed that during a pain-free state, both the unaffected and affected legs perform less work than the healthy controls. After onset of claudication pain, the work output by the affected limb becomes further decreased while the unaffected limb experiences changes in negative external work. These findings combined with recent evidence of decreased peak powers in both legs in unilateral peripheral arterial disease patients reflects altered pathomechanics in both limbs compared to healthy controls.

Joint torques and powers are reduced during ambulation for both limbs in patients with unilateral claudication

Symptomatic peripheral arterial disease (PAD) results in significant gait impairment. In an attempt to fully delineate and quantify these gait alterations, we analyzed joint kinematics, torques (rotational forces), and powers (rotational forces times angular velocity) in patients with PAD with unilateral claudication for both the affected and nonaffected legs. Twelve patients with unilateral PAD (age, 61.69 +/- 10.53 years, ankle-brachial index [ABI]: affected limb 0.59 +/- 0.25; nonaffected limb 0.93 +/- 0.12) and 10 healthy controls (age, 67.23 +/- 12.67 years, ABI >1.0 all subjects) walked over a force platform to acquire gait kinetics, while joint kinematics were recorded simultaneously. Data were collected for the affected and nonaffected limbs during pain free (PAD-PF) and pain induced (PAD-P) trials. Kinetics and kinematics were combined to quantify torque and powers during the stance period from the hip, knee, and ankle joints. The affected limb demonstrated significantly (P <.05) reduced ankle plantar flexion torque compared to controls during late stance in both PAD-PF and PAD-P trials. There were significant reductions in ankle plantar flexion power generation during late stance for both the affected (P <.05) and nonaffected limbs (P <.05) compared to control during PAD-PF and PAD-P trials. No significant differences were noted in torque comparing the nonaffected limbs in PAD-PF and PAD-P conditions to control for knee and hip joints throughout the stance phase. Significant reductions were found in knee power absorption in early stance and knee power generation during mid stance for both limbs of the patients with PAD as compared to control (P <.05). Patients with PAD with unilateral claudication demonstrate significant gait impairments in both limbs that are present even before they experience any claudication symptoms. Overall, our data demonstrate significantly reduced ankle plantar flexion torque and power during late stance with reduced knee power during early and mid stance for the affected limb. Further studies are needed to determine if these findings are dependent on the location and the severity of lower extremity ischemia and whether the changes in the nonaffected limb are the result of underlying PAD or compensatory changes from the affected limb dysfunction.

The effect of claudication pain on temporal and spatial gait measures during self-paced ambulation

We determined the effect of claudication pain on temporal and spatial gait characteristics, and on ambulatory symmetry at preferred and rapid self-selected walking paces in patients with unilateral peripheral arterial disease (PAD). Twenty-eight patients with PAD limited by intermittent claudication were studied. Patients ambulated at their preferred and rapid paces over a 7.3-meter portable gait mat system while they were pain-free and after experiencing claudication pain. The order of the pain-free and painful walking trials was randomized, and the following gait parameters were obtained: velocity, cadence, stride length, swing time, stance time, single-support time, and double-support time. During the self-selected rapid pace, patients walked 3% slower (p = 0.020) while in pain due to a 3% shorter stride length (p < 0.001), and they were in double-stance longer (p = 0.024). Claudication pain in the symptomatic leg resulted in an increase in single-stance (p = 0.007). Furthermore, gait became asymmetrical with pain, as the symptomatic leg spent a higher percentage of the gait cycle in the swing phase (p < 0.01) and lower percentages in stance (p < 0.01) and single-stance (p < 0.01) than the asymptomatic leg. Ambulation was symmetrical for all measures during the pain-free trial. In conclusion, claudication pain slows ambulatory velocity at preferred and rapid paces, and increases asymmetry when ambulatory function is challenged with rapid walking. The reduced ambulatory speed with the development of claudication pain may be an adaptation to elicit a safer and less destabilizing gait pattern.

Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: A phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication

Conclusion: A single set of intramuscular injections of adenoviral vascular endothelial growth factor 121 (adVEGF121) did not result in exercise improvement, increased ankle-brachial index, or improved quality of life in patients with intermittent claudication. Summary: Growth of new blood vessels to improve symptomatic ischemia is termed therapeutic angiogenesis. This trial, the Regional Angiogenesis with Vascular Endothelial Growth Factor (RAVE) trial was the first major randomized study to evaluate the safety and efficacy of adVEGF121 gene transfer in treatment of peripheral vascular disease. A replication-deficient adenovirus encoding the 121 amino acid isoform of VEGF was injected into the lower extremities of subjects with unilateral peripheral arterial disease. The 105 patients were stratified on the basis of diabetic status. All had unilateral exercise-limiting intermittent claudication, and were randomized to either high-dose or low-dose adVEGF121 therapy or placebo. Drug was given as 20 intramuscular injections in the ipsilateral leg in a single session. At 12 weeks there were no differences in change in peak walking time among the placebo, low-dose, and high-dose groups. In addition, secondary end points of ankle-brachial index, claudication onset time, and quality-of-life assessment (short-form health survey [36 items] and Walking Impairment Questionnaire) did not differ among the groups at 12 and 26 weeks. No major safety issues were identified through 1 year of follow-up. Comment: Several possible impairments to adenoviral transfection of adult skeletal muscle may have contributed to the negative results of this study. Possible impairments to transfection include muscle fascia, connective tissue, and lower concentrations in skeletal muscle of the Coxsackie adenoviral receptor. Angiogenesis for treatment of peripheral arterial disease is still more an interesting idea than practical reality.

Increased muscle mass and mitochondrial content in chronically ischemic skeletal muscle

Studies in patients with peripheral arterial disease (PAD) have demonstrated alterations in leg skeletal muscle and its mitochondria. In patients with unilateral PAD, some of these changes are not limited to the ischemic limb (IL), but also affect the contra-lateral nonischemic one (NIL). We developed an animal model of unilateral hindlimb ischemia to further examine these alterations. Six month old, C57BL/6 mice (N = 12) underwent unilateral common femoral artery ligation/division (12 IL) and sham contra-lateral operation (12 NIL). An additional 6 mice (12 limbs) had no operation and served as controls (CON). At 12 weeks after initial operation the deep red gastrocnemius was harvested with wet weight and total protein measured. Mitochondrial content was evaluated by measuring the activity of citrate synthase (enzyme specific for mitochondrial content). The protein content per unit of wet weight and mitochondrial content per unit of protein were also calculated as indices of the relative protein and mitochondrial density in the muscle. IL had significantly higher wet weight, protein content and citrate synthase activity compared to both NIL and CON hindlimbs. There was no difference between NIL and CON limbs. Protein and mitochondrial density were no different in IL, NIL and CON limbs. In our model chronic ischemia is associated with a significant increase of muscle mass and total mitochondrial content. Ischemic muscle appears to hypertrophy while maintaining its overall protein and mitochondrial density. Unilateral hindlimb ischemia resulted in no significant changes in the contra-lateral nonischemic limb. TABLE—ABSTRACT P83Wet weight (mg)Protein content (mg)Citrate synthase (umol/min)Protein/ weight %Citrate synthase/ proteinIL11.7 ± .4§€1.2 ± .1§€1.7 ± .5§€12.7 ± .61.5 ± .8NIL9.9 ± .31.0 ± .11.4 ± .814.4 ± 1.21.4 ± .9CON9.3 ± .5.8 ± .11.3 ± .113.2 ± 1.01.5 ± .1§= significant when compared to NIL,€= significant compared to CON.

Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease

Peripheral arterial disease (PAD) is associated with metabolic derangements and accumulation of the common 4977 bp mitochondrial DNA (mtDNA) deletion mutation. The current study was undertaken to test the hypothesis that PAD is associated with multiple mtDNA deletions. Gastrocnemius biopsies were obtained from nine patients with unilateral PAD. DNA extracted from the biopsies was analyzed for mtDNA deletions using a primer-shift PCR strategy. Multiple primers and strict, prospective criteria were used to identify deletions. PAD was associated with multiple mtDNA deletions (average of 8.2 distinct deletions in muscle from the hemodynamically affected limb). mtDNA injury was present in both the worse- and less-affected limbs of the unilateral PAD patients, and the estimated degree of mtDNA injury was strongly correlated in the two limbs on an intra-subject basis. The 4977 bp deletion was frequently identified, but was not always the deletion of highest frequency in individual samples. The estimated relative frequency of the 4977 bp deletion was correlated with the overall mtDNA injury in the biopsies. In summary, PAD is associated with mtDNA injury as reflected by multiple deletion mutations. As the mutations are not limited to the ischemic limb in unilateral patients, they are unlikely to contribute to the pathophysiology of claudication.

Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease

Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease

Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: alterations with disease.

Muscle mitochondrial content is tightly regulated, and requires the expression of both nuclear and mitochondrial genes. In addition, muscle mitochondrial content is a major determinant of aerobic exercise capacity in healthy subjects. The current study was designed to test the hypothesis that in healthy humans, muscle mitochondrial DNA (mtDNA) content is correlated with citrate synthase activity (a representative nuclear-encoded mitochondrial enzyme) and aerobic exercise capacity as defined by whole-body peak oxygen consumption (VO2). Furthermore, it was postulated that these relationships might be altered with disease. Twelve healthy and five paraplegic subjects underwent exercise testing and vastus lateralis muscle biopsy sampling. An additional ten healthy subjects and eight patients with unilateral peripheral arterial disease (PAD) underwent exercise testing and gastrocnemius muscle biopsy sampling. Citrate synthase activity and mtDNA content were positively correlated in the vastus lateralis muscles from the healthy subjects. This relationship was similar in muscle from paraplegic subjects. mtDNA content was positively correlated with peak VO2 in the healthy subjects and in the paraplegic subjects in whom peak VO2 had been elicited by functional electrical stimulation of the muscle. In contrast, the PAD subjects demonstrated higher mtDNA contents than would have been predicted based on their claudication-limited peak VO2. Thus, in healthy humans there are strong relationships between muscle mtDNA content and both muscle citrate synthase activity and peak VO2. These relationships are consistent with coordinant nuclear DNA and mtDNA expression, and with mitochondrial content being a determinant of aerobic exercise capacity. The relationships seen in healthy humans are quantitatively similar in paraplegic patients, but not in patients with PAD, a disease which is associated with a metabolic myopathy. The relationships between mtDNA content, mitochondrial enzyme activities and exercise capacity provide insight into the physiologic and pathophysiologic regulation of muscle mitochondrial expression.

Skeletal muscle mitochondrial DNA injury in patients with unilateral peripheral arterial disease.

Patients with peripheral arterial disease (PAD) have exercise limitation due to claudication-limited pain and metabolic alterations in skeletal muscle. PAD is also associated with oxidative stress, which is a known cause of mitochondrial DNA (mtDNA) injury. The present study was designed to test the hypothesis that PAD is associated with mtDNA injury, as reflected by an increased frequency of a specific 4977-base pair (bp) mtDNA deletion mutation. The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subjects with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increased deletion frequency and the hemodynamically affected (worse affected) PAD limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse-affected limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA content, citrate synthase activity, and cytochrome c oxidase activity were not different in the muscle from the 3 limb populations. However, the ratio of citrate synthase to cytochrome c oxidase was higher in the worse- versus less-affected limbs of PAD patients. The present study demonstrates a large increase in the frequency of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.

Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease.

Patients with peripheral arterial disease (PAD) have abnormalities of carnitine metabolism that may contribute to their functional impairment. To test the hypothesis that muscle acylcarnitine generation (intermediates in oxidative metabolism) in patients with PAD provides a marker of the muscle dysfunction, 10 patients with unilateral PAD and 6 age-matched control subjects were studied at rest, and the patients were studied during exercise. At rest, biopsies of the gastrocnemius muscle in the patients' nonsymptomatic leg revealed a normal carnitine pool and lactate content compared with control subjects. In contrast, the patients' diseased leg had higher contents of lactate and long-chain acylcarnitines than controls. The muscle short-chain acylcarnitine content in the patients' diseased leg at rest was inversely correlated with peak exercise performance (r = -0.75, P less than 0.05). With graded treadmill exercise, only patients who exceeded their individual lactate threshold had an increase in muscle short-chain acylcarnitine content in the nonsymptomatic leg, which was identical to the muscle carnitine response in normal subjects. In the patients' diseased leg, muscle short-chain acylcarnitine content increased with exercise from 440 +/- 130 to 900 +/- 200 (SE) nmol/g (P less than 0.05). In contrast to the nonsymptomatic leg, there was no increase in muscle lactate content in the diseased leg with exercise, and the change in muscle carnitine metabolism was correlated with exercise duration (r = 0.82, P less than 0.01) and not with the lactate threshold. We conclude that energy metabolism in ischemic muscle of patients with PAD is characterized by the accumulation of acylcarnitines.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle denervation in peripheral arterial disease.

Muscle function is often severely impaired in peripheral arterial disease (PAD), but the effects of repeated ischemic events upon nerve and muscle are incompletely characterized. We performed comprehensive electrophysiologic studies and skeletal muscle histologic analysis in six patients with unilateral PAD and five control subjects matched for age and activity level. In the PAD patients, all ischemic legs showed both electrophysiologic and histologic evidence of chronic partial denervation-reinnervation restricted to distal muscles. Two of the PAD patients had evidence of milder distal denervation in the nonischemic legs. Two of the controls had denervation in at least one leg, but in each case electrophysiologic findings were pathognomonic of L-5 and S-1 radiculopathies. All other control legs and nonischemic legs were normal. These results suggest that recurrent ischemia associated with PAD may cause muscle denervation, which may be one of the mechanisms responsible for decreased exercise performance in these patients.