Effect of Progenitor Cell Mobilization With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Peripheral Artery Disease
Joseph PooleKreton MavromatisJosé BinongoAli KhanQunna LiMohamed KhayataElizabeth RoccoMatthew TopelXin ZhangCharlene J. BrownMatthew A. CorriereJonathan R. MurrowSalman SherStéphanie ClémentKhuram AshrafAmr M RashedTarek KabbanyRobert B. NeumanAlanna A. MorrisArshad AliSalim S. HayekJohn N. OshinskiYoung‐sup YoonEdmund K. WallerArshed A. Quyyumi
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Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown.To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication.In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012.Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily.The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores.Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups.Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication.clinicaltrials.gov Identifier: NCT01041417.Keywords:
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Intermittent claudication
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Conservative Treatment
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Intermittent claudication
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Superficial femoral artery
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Intermittent claudication, a common symptom of peripheral arterial disease, results in insufficient blood flow and oxygen supply to lower extremity muscles. Compared to men, women with peripheral arterial disease have a higher rate of mobility loss with peripheral arterial disease due to poorer lower extremity functioning. This study evaluates the effect of supervised pain-free treadmill exercise on improving performance in women with intermittent claudication due to peripheral arterial disease in comparison to men. A total of 26 participants (women, n = 9, 34.62%; mean age = 67.58 ± 5.59 years; averaging 23.46 ± 3.91 visits and 10.46 ± 0.99 weeks in the program) diagnosed with peripheral arterial disease, with symptoms of intermittent claudication, partook in a 45 min treadmill walk, twice per week, below the participant's minimal pain threshold. Female participants' change scores showed 752%, 278% and 115% improvement in mean walking distance, duration and rate, respectively. Men improved 334%, 149% and 80%, respectively. Significant differences (p < 0.05) in pre and post measurements within each group support positive outcomes. No significant differences between groups were observed (Cohen's d effect size > 0.80). Our results suggest that women reap similar benefits from this low-intensity treadmill program in comparison to men.
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A treadmill exercise test is used in many vascular laboratories to measure the claudication time and the total walking time of patients with intermittent claudication. Three hundred and nine consecutive outpatients in the peripheral arterial disease clinic were assessed on the treadmill. Fifty-nine were unable to walk on it at all, and of the remaining 250 patients, 68 (27%) could manage five minutes of treadmill exercise, and 87 (35%) patients stopped for reasons other than intermittent claudication. Only 95 (38%) stopped walking within five minutes as a result of intermittent claudication. Fifty of these 95 patients were retested approximately 10 days later and the mean change from day 1 to day 2 in the claudication time and in the total walking time was calculated to establish the normal range. From these results, if a treadmill is to be used to infer any improvement, we calculate that the claudication time must increase by at least 63 seconds and the total walking time by 93 seconds. Treadmill testing for the assessment of symptoms, if it is used at all, should be used in conjunction with objective methods of assessment.
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In peripheral arterial disease (PAD) patients with intermittent claudication (IC), the combination of aerobic and resistance exercises could counteract muscle loss and attenuate disease progression. This study analyzed the effects of six months of a combined exercise program on walking ability, lower limb body composition, cardiovascular risk factors, and Ankle-Brachial Index (ABI).Twenty-three patients (age 63.2±1.5 years and ABI 0.58±0.07) with PAD and IC were allocated to a control group (CG) or a supervised exercise group (SUP). Ten patients underwent six months of treadmill walking combined with resistance exercises, three times a week. The CG (N.=13) received a recommendation for walking. All patients were measured at baseline (M0), after three months (M3), and six months (M6).During constant treadmill protocol, the claudication onset time/distance (COT/COD), absolute claudication time/distance (ACT/ACD), and number of pauses of overall patients significantly improved at M3 and M6. Between groups were found significant differences in COT and COD at M6 (P=0.005 and P=0.007, respectively); and in ACT and ACD at M3 (P=0.003 for both) and at M6 (P=0.005 and P=0.005, respectively), with major improvements in the SUP. Over the six months, a significant group effect was found in fat-free mass (P=0.041) and predicted muscle mass (P=0.039) of the lower ABI leg, with greater improvements in the SUP.A supervised exercise program that combines aerobic and resistance training improves PAD symptoms and has additional benefits for patients. Patients in the program showed improvements in walking ability, lower-limb body composition, perceived exertion, and heart rate during treadmill walking.
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Prevalence of intermittent claudication is often used to calculate the prevalence of critical leg ischemia (CLI), a more severe form of peripheral arterial disease (PAD). Although this logical course of the disease is intellectually appealing, not all patients with CLI have experienced any symptoms of previous claudication. A total of 100 consecutive patients with objective evidence of critical ischemia, as evaluated by non-invasive testing in the authors’ vascular laboratory, were subjected to a structured interview to evaluate how often peripheral arterial disease is presented with symptoms of CLI as the initial complaint. In all, 37 patients had never experienced claudication prior to the development of CLI. Furthermore, 12 of 63 patients who suffered from previous claudication did not have any claudication symptoms at the time of the development of CLI. Of the 37 patients with CLI as the first sign of PAD, 20 had diabetes - four of whom with manifest diagnosed neuropathy. The patients without previous claudication more frequently had ulcers as the initial symptom of CLI (89%) than those with claudication (59%), whose disease first progressed to rest pain. Altogether, 25 patients did not walk enough to develop symptoms of claudication. In conclusion, every patient presenting with symptoms potentially related to CLI should undergo vascular laboratory measurements regardless of whether he/she has a history of claudication or not. This is especially true in limbs with unhealed skin lesions.
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Changes in the segmental blood pressures (BP) in the legs after five years of follow-up and factors related to the changes were studied in 93 non-operated non-diabetic patients with intermittent claudication. Independent variables affecting the ankle/arm BP index (ABI) in the more affected leg were the initial ABI, smoking, duration of claudication and location of the stenoses (whether single or multiple). ABI was stable in non-smokers but decreased in smokers. It also decreased in patients with multiple stenoses at the initial examination but not in those with single stenoses. The correlation between subjective changes in claudication and changes in the ankle BP was poor. In the less affected leg, ABI decreased both in smokers and non-smokers but stenoses in legs without signs of stenoses initially developed to a greater extent in smokers than in non-smokers. Smoking is an important risk factor for progression of the occlusive atherosclerotic disease in intermittent claudication. Patients with multiple stenoses seem to have a more progressive occlusive disease.
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