Lower extremity manifestations of peripheral artery disease: the pathophysiologic and functional implications of leg ischemia.

Lower extremity peripheral artery disease (PAD) is frequently underdiagnosed, in part because of the wide variety of leg symptoms manifested by patients with PAD and in part because of the high prevalence of asymptomatic PAD. In primary care medical practices, 30% to 60% of patients with PAD report no exertional leg symptoms and ≈45% to 50% report exertional leg symptoms that are not consistent with classic intermittent claudication. The prevalence and extent of functional impairment and functional decline in PAD may also be underappreciated. Functional impairment and functional decline are common in PAD, even among those who are asymptomatic. Lower extremity ischemia is also associated with pathophysiologic changes in calf skeletal muscle, including smaller calf muscle area, increased calf muscle fat content, impaired leg strength, and impaired metabolic function. People with severe PAD have poorer peroneal nerve conduction velocity compared with people with mild PAD or no PAD. The degree of ischemia-related pathophysiologic changes in lower extremity muscles and peripheral nerves of people with PAD are associated with the degree of functional impairment. New interventions are needed to improve functional performance and prevent mobility loss in the large number of patients with PAD, including in those who are asymptomatic or who have exertional leg symptoms other than claudication.

Pulmonary hospitalizations and ischemic heart disease events in patients with peripheral artery disease.

The prognostic significance of acute pulmonary events in people with lower extremity peripheral artery disease (PAD) is unknown. We hypothesized that an acute pulmonary event (hospitalization for pneumonia and/or chronic lower respiratory disease (CLRD) exacerbation) would be associated with a higher rate of subsequent ischemic heart disease (IHD) events in PAD. A total of 569 PAD participants were systematically identified from among patients in Chicago medical practices and followed longitudinally. Hospitalizations after enrollment were evaluated and adjudicated for pulmonary events. The primary outcome was adjudicated myocardial infarctions, unstable angina, and IHD death. Of 569 PAD participants, 34 (6.0%) were hospitalized for a pulmonary event (11 CLRD exacerbation and 23 pneumonia) during a mean follow-up of 1.52 years±0.80. Participants hospitalized for a pulmonary event had a higher rate of subsequent IHD events than those not hospitalized for a pulmonary event (10/34 (29%) vs 38/535 (7.1%), p<0.001). After adjusting for age, sex, race, comorbidities, and other confounders, a pulmonary hospitalization was associated with an increased risk of a subsequent IHD event (hazard ratio (HR) = 12.42, 95% confidence interval (CI) = 5.35 to 28.86, p<0.001). Non-pulmonary hospitalizations were also associated with IHD events (HR = 3.39, 95% CI = 1.78 to 6.44, p<0.001), but this association was less strong compared to pulmonary hospitalizations and IHD events ( p = 0.011 for difference in the strength of association). In conclusion, hospitalization for an acute pulmonary event was associated with higher risk for subsequent IHD events in PAD. Future study should examine whether hospitalization for pulmonary events warrants increased surveillance or potential intervention to prevent IHD events in PAD.

Changes in D-dimer and inflammatory biomarkers before ischemic events in patients with peripheral artery disease: The BRAVO Study.

Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event.

Functional impairment in peripheral artery disease and how to improve it in 2013.

Lower extremity peripheral artery disease (PAD) affects 8 million men and women in the United States and will be increasingly common as the U.S. population lives longer with chronic disease. People with PAD have poorer walking endurance, slower walking velocity, and poorer balance, compared with individuals without PAD. People with PAD may reduce their walking activity to avoid leg symptoms. Thus, clinicians should not equate stabilization or improvement in exertional leg symptoms with stabilization or improvement in walking performance in PAD. In addition, even asymptomatic PAD patients have greater functional impairment and faster functional decline than individuals without PAD. Of the 2 FDA-approved medications for treating claudication symptoms, pentoxifylline may not be more efficacious than placebo, whereas cilostazol confers a modest improvement in treadmill walking performance. Supervised treadmill walking exercise is associated with substantial improvement in walking endurance, but many PAD patients do not have access to supervised exercise programs. Unsupervised walking exercise programs may be beneficial in PAD, but data are mixed.

Pathophysiological changes in calf muscle predict mobility loss at 2-year follow-up in men and women with peripheral arterial disease.

BACKGROUND: Associations of pathophysiological calf muscle characteristics with functional decline in people with lower extremity peripheral arterial disease are unknown. METHODS AND RESULTS: Three hundred seventy participants with peripheral arterial disease underwent baseline measurement of calf muscle area, density, and percent fat with the use of computed tomography. Participants were followed up annually for 2 years. The outcome of mobility loss was defined as becoming unable to walk 1/4 mile or walk up and down 1 flight of stairs without assistance among those without baseline mobility limitations. Additional outcomes were > or =20% decline in 6-minute walk distance and becoming unable to walk for 6 minutes continuously among participants who walked continuously for 6 minutes at baseline. With adjustment for age, sex, race, body mass index, the ankle-brachial index, smoking, physical activity, relevant medications, and comorbidities, lower calf muscle density (P for trend <0.001) and lower calf muscle area (P for trend=0.039) were each associated with increased mobility loss rates. Compared with participants in the highest baseline tertiles, participants in the lowest tertile of calf muscle percent fat had a hazard ratio of 0.18 for incident mobility loss (95% confidence interval, 0.06 to 0.55; P=0.003), and participants in the lowest tertile of muscle density had a 3.50 hazard ratio for incident mobility loss (95% confidence interval, 1.28 to 9.57; P=0.015). No significant associations of calf muscle characteristics with 6-minute walk outcomes were observed. CONCLUSIONS: Our findings suggest that interventions to prevent mobility loss in peripheral arterial disease should focus on reversing pathophysiological findings in calf muscle.

The association of lesion eccentricity with plaque morphology and components in the superficial femoral artery: a high-spatial-resolution, multi-contrast weighted CMR study.

BACKGROUND: Atherosclerotic plaque morphology and components are predictors of subsequent cardiovascular events. However, associations of plaque eccentricity with plaque morphology and plaque composition are unclear. This study investigated associations of plaque eccentricity with plaque components and morphology in the proximal superficial femoral artery using cardiovascular magnetic resonance (CMR). METHODS: Twenty-eight subjects with an ankle-brachial index less than 1.00 were examined with 1.5 T high-spatial-resolution, multi-contrast weighted CMR. One hundred and eighty diseased locations of the proximal superficial femoral artery (about 40 mm) were analyzed. The eccentric lesion was defined as [(Maximum wall thickness- Minimum wall thickness)/Maximum wall thickness] >or= 0.5. The arterial morphology and plaque components were measured using semi-automatic image analysis software. RESULTS: One hundred and fifteen locations were identified as eccentric lesions and sixty-five as concentric lesions. The eccentric lesions had larger wall but similar lumen areas, larger mean and maximum wall thicknesses, and more calcification and lipid rich necrotic core, compared to concentric lesions. For lesions with the same lumen area, the degree of eccentricity was associated with an increased wall area. Eccentricity (dichotomous as eccentric or concentric) was independently correlated with the prevalence of calcification (odds ratio 3.78, 95% CI 1.47-9.70) after adjustment for atherosclerotic risk factors and wall area. CONCLUSIONS: Plaque eccentricity is associated with preserved lumen size and advanced plaque features such as larger plaque burden, more lipid content, and increased calcification in the superficial femoral artery.

Physical performance in peripheral arterial disease: a slower rate of decline in patients who walk more.

BACKGROUND: Exercise rehabilitation programs increase treadmill walking performance in patients with peripheral arterial disease (PAD) and intermittent claudication. However, it is unknown whether patients with PAD who walk for exercise regularly have less functional decline than those with less walking activity. OBJECTIVE: To determine whether patients with PAD who report that they walk for exercise 3 or more times per week have less annual functional decline than those who walk for exercise less frequently. DESIGN: Prospective cohort study with a median follow-up of 36 months (interquartile range, 24 to 36 months). SETTING: Academic medical center. PARTICIPANTS: 417 men and women with PAD. MEASUREMENTS: Participants were classified at baseline and annually according to the number of times they reportedly walked for exercise each week. Functional assessments (6-minute walk distance, 4-meter walking speed, summary performance score) were measured at baseline and annually. Results were adjusted for age, sex, ethnicity, comorbid conditions, body mass index, ankle-brachial index, education, leg symptoms, cigarette use, geriatric depression score, previous year's level of functioning, and patterns of missing data. RESULTS: Compared with those who exercised less frequently, patients who walked for exercise 3 or more times per week had a significantly smaller average annual decline in 6-minute walking distance (-48.0 feet per year compared with -56.6 feet per year for those who walked 1 to 2 times per week and -79.4 feet per year for nonexercisers; P for trend = 0.037). Patients who walked for exercise at least 3 times per week experienced a smaller average annual decline in the usual-paced 4-meter walking velocity (-0.014 m/s per year compared with -0.022 m/s per year for those who walked 1 to 2 times per week and -0.045 m/s per year for nonexercisers; P = 0.005). Similar findings were observed for the fast-paced 4-meter walk. The subset of asymptomatic patients who walked for exercise 3 or more times per week had annual declines in 6-minute walking performance (P = 0.107), normal-paced walking velocity (P = 0.065), and the summary performance score (P = 0.115); however, these declines were smaller than those observed in asymptomatic participants who walked fewer than 3 times per week. LIMITATIONS: Because this was an observational study, associations reported here cannot be construed as causal relationships. Sample sizes for subgroup analyses were small, which limited statistical power. CONCLUSION: Among patients with PAD, self-directed walking exercise performed at least 3 times weekly is associated with significantly less functional decline during the subsequent year. Similar trends were observed in the subset of asymptomatic patients with PAD. These findings may be particularly important for the numerous patients with PAD who do not have access to supervised walking exercise programs.

Does lower-extremity arterial disease predict future falling among older men and women?

The purpose of this study was to determine whether lower-extremity peripheral arterial disease (PAD) is an independent risk factor for falls among older persons. Men and women 55 years old and older participated. Subjects with PAD (n = 86) were identified from a noninvasive vascular laboratory and a general medicine practice. Randomly selected controls without PAD (n = 82) were identified from the same medicine practice. Subjects were categorized into PAD (ankle brachial index, <0.90) or controls (ankle brachial index, 0.90 to 1.50). Subjects underwent a comprehensive baseline evaluation for fall risk. Prospective fall data were obtained using monthly mail-in postcards and structured telephone interviews over a mean follow-up of 9.6 +/- 2.9 months. Two independent investigators blinded to PAD status reviewed each fall incident for its eligibility. A total of 37 subjects (22%) had at least 1 eligible fall. In an unadjusted Cox regression model, the relative risk of falling was lower among PAD subjects than among controls (relative risk, 0.54; 95% confidence interval, 0.28 to 1.06). After adjustment for age, gender, history of frequent falls in the last year, number of comorbidities, and balance and gait abnormalities, PAD was significantly associated with a lower risk of falling (relative risk, 0.43; 95% confidence interval, 0.21 to 0.87) as compared with controls. PAD is associated with a lower risk of falling as compared with persons without PAD among older men and women. Future study is needed to determine whether reduced levels of physical activity among patients with PAD account for the lower rate of falling observed here.

Conjugated equine estrogens and peripheral arterial disease risk: the Women's Health Initiative.

BACKGROUND: Estradiol reduced progression of ultrasonographic carotid disease in a randomized trial. No trials of unopposed estrogen for prevention of lower extremity arterial disease or aortic aneurysm have been conducted. METHODS: The Estrogen Alone trial randomized 10739 postmenopausal women with prior hysterectomy, mean age 63.6 +/- 7.3 years, to conjugated equine estrogens (CEE 0.625 mg/d) or placebo and documented health outcomes over an average of 7.1 +/- 1.6 years. RESULTS: A trend toward increased risk of peripheral arterial events with CEE was observed (hazard ratio [HR] 1.32, 95% CI 0.99-1.77). Carotid arterial events (HR 1.19, 95% CI 0.82-1.74), lower extremity arterial events (HR 1.41, 95% CI 0.86-2.32), and abdominal aortic aneurysm (HR 2.40, 95% CI 0.92-6.23) were more frequent, but not individually significant, in the CEE group. However, the composite of lower extremity arterial disease/abdominal aortic aneurysm was significantly more frequent among women assigned to CEE (HR 1.63, 95 % CI 1.05-2.51). In subgroup analyses, no clear pattern of risk with CEE was apparent by age or by time since menopause. CONCLUSIONS: Unopposed CEE conferred no protection against peripheral arterial disease among generally healthy postmenopausal women; in fact, there was a suggestion of increased risk.

The magnitude of the problem of peripheral arterial disease: epidemiology and clinical significance.

The prevalence of lower extremity peripheral arterial disease (PAD) varies across populations, based on the groups studied and the detection methods used. The ankle-brachial index (ABI) is a more sensitive tool for PAD detection than is screening for intermittent claudication (IC); only about 10% to 30% of patients diagnosed with PAD based on the ABI have classic symptoms of IC. The prevalence of PAD increases markedly with older age and in persons with diabetes or a history of smoking; prevalence also is elevated in persons with hyperlipidemia, hypertension, or chronic kidney disease. PAD is more prevalent in primary care medical practices than in community-dwelling populations. PAD (defined as an ABI < 0.90) is associated with a twofold to three-fold increased risk of cardiovascular mortality. Borderline and low-normal ABI values, as well as elevated ABI values (> 1.30 or > 1.40), are increasingly recognized as being associated with elevated cardiovascular mortality. Persons with PAD have significantly increased functional impairment and elevated rates of functional decline relative to those without PAD.

Effect of a Long-Term Physical Activity Intervention on Resting Pulse Rate in Older Persons: Results from the Lifestyle Interventions and Independence for Elders Study.

OBJECTIVES: To assess the utility of a long-term physical activity (PA) intervention for reducing resting pulse rate (RPR) in older persons. DESIGN: Community. SETTING: Lifestyle Interventions and Independence for Elders Study. PARTICIPANTS: Individuals aged 70 to 89 (N = 1,635, 67.2% women) were randomized to a moderate-intensity PA intervention (n = 818) or a health education-based successful aging (SA) intervention (n = 817). MEASUREMENTS: RPR was recorded at baseline and 6, 18, and 30 months. Longitudinal changes in RPR of intervention groups were compared using a mixed-effects analysis of covariance model for repeated-measure outcomes, generating least squares means with standard errors (SEs) or 95% confidence intervals (CIs). RESULTS: Mean duration of the study was 2.6 years (median 2.7 years, interquartile range 2.3-3.1 years). The average effect of the PA intervention on RPR over the course of the study period was statistically significant but clinically small (average intervention difference = 0.84 beats/min; 95% CI = 0.17-1.51; Paverage = .01), with the most pronounced effect observed at 18 months (PA, 66.5 beats/min (SE 0.32 beats/min); SA, 67.8 beats/min (SE 0.32 beats/min); difference = 1.37 beats/min, 95% CI = 0.48-2.26 beats/min). The relationship became somewhat weaker and was not statistically significant at 30 months. There were no significant differences between several prespecified subgroups. CONCLUSION: A long-term moderate-intensity PA program was associated with a small and clinically insignificant slowing of RPR in older persons. Whether PA can deliver a beneficial reduction in RPR requires further examination in older adults.

Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study.

BACKGROUND: The associations of low (<0.90) and high (>1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting. METHODS AND RESULTS: We examined all-cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3+/-2.2 years (36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI (0.90 < or =ABI < or =1.40). Death from all causes occurred in 1022 participants (23.3%; 27.9 deaths per 1000 person-years), and of these, 272 (26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI (44.4%, 26.9%, and 36.5%), respectively (P<0.0001). Adjusted risk estimates for all-cause mortality were 1.69 (1.34 to 2.14) for low and 1.77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI. CONCLUSIONS: The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40.

Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease.

BACKGROUND: We determined whether statin use (versus nonuse) is associated with superior lower-extremity functioning independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease. METHODS AND RESULTS: Participants included 392 men and women with an ankle brachial index (ABI) <0.90 and 249 with ABI 0.90 to 1.50. Functional outcomes included 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ABI, comorbidities, education level, medical insurance status, cholesterol, and other confounders, participants taking statins had better 6-minute walk performance (1276 versus 1218 feet, P=0.045), faster walking velocity (0.93 versus 0.89 m/s, P=0.006), and a higher summary performance score (10.2 versus 9.4, P<0.001) than participants not taking statins. Positive associations were attenuated slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity and the summary performance score. We did not find significant associations between lower-extremity functioning and aspirin, ACE inhibitors, vasodilators, or beta-blockers. CONCLUSIONS: Statin use is associated with superior leg functioning compared with no statin use, independent of cholesterol levels and other potential confounders. These data suggest that non-cholesterol-lowering properties of statins may favorably influence functioning in persons with and without peripheral arterial disease.

D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease.

BACKGROUND: We determined whether higher levels of D-dimer, C-reactive protein (CRP), fibrinogen, and serum amyloid A are associated independently with functional impairment in patients with and without peripheral arterial disease (PAD). METHODS AND RESULTS: Participants were 370 men and women with PAD (ankle brachial index <0.90) and 231 without PAD. Functional outcomes were 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ankle brachial index, comorbidities, and other potential mediators and confounders, D-dimer levels were associated independently and inversely with performance on all 3 functional measures in the entire cohort and among patients with and without PAD, respectively. Adjusting for known and potential confounders, CRP levels were associated independently with 6-minute walk distance and the summary performance score among participants with PAD. No significant associations were observed between CRP and the functional measures among participants without PAD. Fibrinogen and SAA levels were not associated independently with the functional measures. CONCLUSIONS: Higher D-dimer levels are associated with poorer functioning among individuals with and without PAD. Higher CRP levels were associated with poorer 6-minute walk performance and a lower summary performance score among participants with PAD but not among those without PAD. Additional study is needed to determine whether D-dimer and CRP are involved in the pathophysiology of functional impairment or whether they are simply sensitive markers of the extent of systemic atherosclerosis.