Author + information
- Received October 29, 2010
- Revision received March 29, 2011
- Accepted April 7, 2011
- Published online July 1, 2011.
- Mary M. McDermott, MD⁎,†,⁎ (, )
- Kiang Liu, PhD†,
- Timothy J. Carroll, PhD‡‡,
- Lu Tian, ScD§§,
- Luigi Ferrucci, MD, PhD¶¶,
- Debiao Li, PhD‡,
- James Carr, MD‡,
- Jack M. Guralnik, MD, PhD##,
- Melina Kibbe, MD§,¶,
- William H. Pearce, MD∥,¶,
- Chun Yuan, PhD⁎⁎⁎,
- Walter McCarthy, MD#,
- Christopher M. Kramer, MD‡‡‡,
- Huimin Tao, MS†,
- Yihua Liao, MS†,
- Elizabeth Talley Clark, MD††,
- Dongxiang Xu, PhD†††,
- Jarett Berry, MD§§§,
- Jennifer Orozco, MMS, PA⁎⁎,
- Leena Sharma, MD⁎ and
- Michael H. Criqui, MD, MPH∥∥
- ↵⁎Reprint requests and correspondence:
Dr. Mary M. McDermott, Departments of Medicine and Preventive Medicine, Northwestern University Feinberg School of Medicine, 750 North Lake Shore Drive, 10th Floor, Chicago, Illinois 60611
Objectives We studied associations of magnetic resonance imaging measurements of plaque area and relative percent lumen reduction in the proximal superficial femoral artery with functional performance among participants with peripheral arterial disease.
Background The clinical significance of directly imaged plaque characteristics in lower extremity arteries is not well established.
Methods A total of 454 participants with an ankle brachial index <1.00 underwent magnetic resonance cross-sectional imaging of the proximal superficial femoral artery and completed a 6-min walk test, measurement of 4-m walking velocity at usual and fastest pace, and measurement of physical activity with a vertical accelerometer.
Results Adjusting for age, sex, race, body mass index, smoking, statin use, comorbidities, and other covariates, higher mean plaque area (1st quintile [least plaque]: 394 m, 2nd quintile: 360 m, 3rd quintile: 359 m, 4th quintile: 329 m, 5th quintile [greatest plaque]: 311 m; p trend <0.001) and smaller mean percent lumen area (1st quintile [greatest plaque]: 319 m, 2nd quintile: 330 m, 3rd quintile: 364 m, 4th quintile: 350 m, 5th quintile: 390 m; p trend <0.001) were associated with shorter distance achieved in the 6-min walk test. Greater mean plaque area was also associated with slower usual-paced walking velocity (p trend = 0.006) and slower fastest-paced 4-m walking velocity (p trend = 0.003). Associations of mean plaque area and mean lumen area with 6-min walk distance remained statistically significant even after additional adjustment for the ankle brachial index and leg symptoms.
Conclusions Among participants with peripheral arterial disease, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated independently with poorer functional performance, even after adjusting for the ankle brachial index and leg symptoms.
High-resolution magnetic resonance imaging (MRI) has emerged as a promising modality for direct atherosclerotic plaque imaging (1,2). However, little is known about associations of MRI-measured plaque area or lumen area with functional impairment in peripheral arterial disease (PAD). We used MRI to directly image cross sections of the superficial femoral artery (SFA) (Fig. 1). We studied associations of plaque area and percent lumen area in the SFA with functional impairment in PAD. We hypothesized that greater plaque area and smaller percent lumen area in the SFA would be associated with greater functional impairment, independently of age, comorbidities, and other potential confounders. We also hypothesized that significant associations of more adverse plaque characteristics with greater functional impairment would be eliminated after additional adjustment for the ankle brachial index (ABI).
Participants were identified from among consecutive PAD patients in the noninvasive vascular laboratories at Northwestern Memorial Hospital and 3 other Chicago-area medical centers. Participants were also identified from among lists of consecutive patients with a diagnosis of PAD in the vascular surgery, cardiology, endocrinology, general medicine, and geriatric practices at Northwestern Medical Faculty Foundation and in the vascular surgery practice at the Jesse Brown VA Medical Center. A small number of participants were identified from among men and women age 70 years and older in Northwestern's largest general internal medicine practice who were screened with the ABI and found to have an ABI <1.00 (Fig. 2). To maximize comparability with participants with previously established PAD, a minimum age of 70 years was required for participants identified in general medicine. The protocol was approved by the Institutional Review Boards of Northwestern University Feinberg School of Medicine and all participating sites. Participants gave written informed consent.
The inclusion criterion was an ABI <1.00. This inclusion criterion was selected because truly normal ABI values are 1.10 to 1.40 (3–5) and because including participants with ABI <1.00 ensured a broad range of severity of lower extremity atherosclerosis. Presence of intermittent claudication was not an inclusion criterion.
Potential participants with dementia and those with a Mini-Mental Status Examination score <23 (6) were excluded. Nursing home residents, wheelchair-bound patients, and patients with foot or leg amputations were excluded because of their severely impaired functioning. Non–English-speaking patients were excluded because investigators were not fluent in non-English languages. We excluded potential participants who required oxygen therapy, had contraindications to MRI testing, stopped the 6-min walk test due to shortness of breath, had recent major surgery, or had severe knee osteoarthritis. Severe arthritis was defined based on the presence of radiograph-measured osteoarthritis Kellgren-Lawrence score of 4 among participants who reported pain in or around their knee(s) on most days (7). All participants who reported pain in or around their knees on most days underwent a knee radiograph. Potential participants with bilateral superficial femoral artery stents were excluded, because the stents interfered with plaque imaging. Individuals with aortoiliac disease and those taking cilostazol were not excluded.
Ankle brachial index measurement
After participants rested supine for 5 min, a handheld Doppler probe (Nicolet Vascular Pocket Dop II, Golden, Colorado) was used to measure systolic pressures in this order: right brachial, dorsalis pedis, and posterior tibial arteries and left dorsalis pedis, posterior tibial, and brachial arteries. Pressures were repeated in reverse order. The ABI was calculated in each leg by dividing average pressures in each leg by the average of the 4 brachial pressures (8). Average brachial pressures in the arm with highest pressure were used when 1 brachial pressure was higher than the opposite brachial pressure in both measurement sets, and when the 2 brachial pressures differed by 10 mm Hg or more in at least 1 measurement set, because in such cases, subclavian stenosis was possible (9). Data from undetectable or incompressible dorsalis pedis and posterior tibial arteries were excluded from the ABI calculation. However, none of the participants had both undetectable dorsalis pedis and posterior tibial pressures in 1 leg, and no potential participants were excluded because of undetectable dorsalis pedis or posterior tibial pressures. Limbs with noncompressible vessels in both the dorsalis pedis and posterior tibial vessels were excluded from analyses.
Magnetic resonance imaging
We imaged the SFA because it is the most common site of lower extremity atherosclerosis (10,11) and because it supplies the calf muscle, which is typically symptomatic in patients with PAD. The leg with lowest ABI was imaged. However, if the leg with the lowest ABI had an SFA stent, the opposite leg was imaged. MRI data were obtained with a 1.5-T (Siemens, Malvern, Pennsylvania) platform using 4-element phased-array surface coils. We imaged the proximal region of the SFA because its superficial location was more amenable to high quality images than the distal SFA was. The bifurcation of the common femoral artery served as the reference point. Twelve consecutive 2.5-mm cross-sectional images were obtained, moving distally from the most proximal point of the SFA, using 2-dimensional bright blood time-of-flight and proton-density weighted images. Fat suppression was applied in black-blood sequences to improve image quality. This method has excellent test–retest reliability (12).
CASCADE software (Cascade Software Corporation, Seattle, Washington) was used by 2 physician-reviewers to trace the outer boundary and the lumen of each cross-sectional image of the SFA. CASCADE software quantified the plaque area based on the tracings. Plaque measurements were normalized for artery size (13). Specifically, for each participant, the measured mean and maximum plaque area were divided by the median of the outer wall area. To normalize lumen area measures, the mean and minimum lumen area were dividing by the outer wall area at each site. This normalization allowed us to take into account the fact that a given plaque size may have a different impact on study outcomes, depending on the size of the artery. Each reported plaque measure is normalized using these methods.
Images for each participant were assigned to a primary reviewer, and arterial tracings were reviewed by the second reviewer to ensure accuracy. In addition, independent readings by the 2 reviewers of the same artery were compared. The coefficient of variation percent values for these test inter-rater reliability assessments were 2.11 for mean plaque area, 4.24 for maximum plaque area, 1.77 for mean percent lumen reduction, and 1.77 for maximum percent lumen reduction.
A 6% subsample of participants returned on a second day for test–retest reliability assessment of MRI measurements. The coefficient of variation percent values for these test–retest reliability assessments were 5.8 for mean plaque area, 8.9 for maximum plaque area, 7.9 for mean percent lumen area, and 12.9 for minimum percent lumen area.
Participants walk up and down a 100-foot hallway for 6 min with instructions to cover as much distance as possible (14,15). The distance walked at the end of 6 min was recorded. The intraclass correlation coefficient for test–retest reliability of the 6-min walk was 0.90 (p < 0.001) among 155 PAD participants in our laboratory who completed 2 tests 1 to 2 weeks apart (15).
Four-meter walking velocity
Walking velocity was measured with a 4-m walk performed at “usual” and “fastest” paces, based on previous study (14). For the usual-paced walk, participants were advised to walk at a normal pace, as if they were “walking down the street to go to the store.” For the fast-paced walk, participants were advised to walk at their fastest speed. Each walk was performed twice. The faster walk in each pair was used in analyses (14).
Physical activity measurement
We used a vertical accelerometer (Caltrac, Muscle Dynamics Fitness Network Inc., Torrance, California) to measure physical activity continuously over 7 days using previously described methods (16,17). The accelerometer was programmed identically for all participants, allowing us to compare physical activity levels between participants, irrespective of individual variation in age, weight, height, and sex (16,17). Programmed in this way, the accelerometers measured “activity units.”
Algorithms developed for the Women's Health and Aging Study and the Cardiovascular Health Study were used to document comorbidities (18). These algorithms combine data from patient report, physical examination, medical record review, medications, laboratory values, and a primary care physician questionnaire (18). Comorbidities assessed were angina pectoris, diabetes mellitus, myocardial infarction, stroke, heart failure, pulmonary disease, cancer, spinal stenosis, and disk disease. Criteria from the American College of Rheumatology were used to diagnose knee and hip osteoarthritis (9,19).
Leg symptoms were classified using the San Diego claudication questionnaire (20). Intermittent claudication was defined as exertional calf pain that does not begin at rest, causes the participant to stop walking, and resolves within 10 min of rest. Participants without claudication were either asymptomatic (i.e., no exertional leg symptoms) or had exertional leg symptoms not consistent with claudication.
Height and weight were measured at the study visit. Body mass index (BMI) was calculated as weight/height (kg/m2). Cigarette smoking history was measured with self-report. Participants brought their medication bottles or a list of medications to their study visit. Medication names were recorded. The study principal investigator (M.M.M.) identified which participants were taking statin medications, but was blinded to participant characteristics.
Quintiles of mean and maximum plaque area and mean and minimum percent lumen area in the SFA, respectively, were defined. Differences in continuous and dichotomous variables were compared across these quintiles using analyses of variance and chi-square tests, respectively. Six-min walk performance, usual-paced and fastest-paced 4-m walking velocity, and physical activity levels were compared across quintiles of each plaque measure using analyses of covariance, adjusting for age, race, sex, smoking, BMI, statins, and comorbidities (model 1). These analyses were repeated with additional adjustment for the ABI (model 2). Model 2 was repeated adding adjustment for leg symptoms (model 3). For each plaque characteristic, pairwise comparisons were made between the lowest quintile and each of the remaining 4 quintiles.
With 454 PAD participants, this study had 80% power to detect a minimum partial correlation coefficient of 0.14 between 2 continuous measures, based on a 2-sided test at the significance level of 0.05. Analyses were performed using SAS statistical software (version 9.0, SAS Inc., Cary, North Carolina).
Figure 3 shows participation and exclusion rates among potential participants contacted for study. Of 3,391 men and women with PAD who received a recruitment letter, 1,161 did not respond. Of the remainder, 504 met 1 or more exclusion criteria, 954 refused participation, and 304 could not be scheduled or did not show for their study visit, leaving 468 PAD participants. An additional 4 PAD participants were identified from among patients in the general internal medicine practice who were screened with the ABI (Fig. 3). Of these 473 PAD participants, 16 had poor quality MR images and 3 were missing data for covariates, leaving 454 PAD participants.
Greater mean plaque area and smaller mean percent lumen area were each associated with older age, lower ABI values, higher prevalences of intermittent claudication, and lower prevalences of asymptomatic PAD (Table 1).
Adjusting for age, sex, race, smoking, BMI, statin use, and comorbidities, higher mean plaque area was associated with shorter distance achieved in the 6-min walk (p trend <0.001), slower usual-paced walking velocity (p trend = 0.006), and slower fastest-paced walking velocity (p trend = 0.002) (Table 2, model 1). After additional adjustment for ABI, these associations were attenuated but remained statistically significant (Table 2, model 2). After additional adjustment for leg symptoms, only associations of greater plaque area with shorter 6-min walk distance and slower rapid-paced 4-m walking velocity remained statistically significant (Table 2, model 3).
Adjusting for age, sex, race, smoking, BMI, statin use, and comorbidities, higher maximum plaque area was associated with shorter distance achieved in the 6-min walk (p trend <0.001), slower usual-paced walking velocity (p trend = 0.001), and slower fastest-paced walking velocity (p trend = 0.023) (Table 2, model 1). Associations of greater maximal plaque area with shorter 6-min walk distance and slower usual-paced 4-m walking velocity remained statistically significant after additional adjustment for the ABI (Table 2, model 2) and after additional adjustment for leg symptoms (Table 2, model 3).
Adjusting for age, sex, race, smoking, BMI, statin use, and comorbidities, lower mean percent lumen area was associated with shorter distance achieved in the 6-min walk (p trend <0.001), slower usual-paced walking velocity (p trend = 0.047), and slower fastest-paced walking velocity (p trend = 0.006) (Table 2, model 1). However, these associations were no longer significant after additional adjustment for the ABI.
Adjusting for age, sex, race, smoking, BMI, statin use, and comorbidities, smaller minimum percent lumen area was associated with shorter distance achieved in the 6-min walk (p trend <0.001), slower usual-paced walking velocity (p trend = 0.005), slower fastest-paced walking velocity (p trend = 0.002), and lower physical activity (p trend = 0.041) (Table 2, model 1). After additional adjustment for ABI, these associations remained statistically significant for the 6-min walk, usual-paced 4-m walking velocity, and fast-paced 4-m walking velocity (Table 2, model 2). After additional adjustment for leg symptoms, only associations of minimum percent lumen area with 6-min walk and rapid-paced 4-m walking velocity remained statistically significant (Table 2, model 3).
Among 454 PAD participants, our findings demonstrate, for the first time, that greater mean and maximum plaque area and smaller percent minimum lumen area in the proximal SFA are associated significantly and independently with poorer functional performance, even after adjusting for the ABI. Prior work by Anderson et al. (13) demonstrated that greater plaque area was associated with poorer 6-min walk performance (r = –0.30) and poorer maximum treadmill walking distance (r = –0.32) in 85 participants with PAD. However, these associations were not adjusted for confounders such as age, comorbidities, or the ABI (13). Identifying characteristics associated with the degree of functional impairment in PAD is important because these associations may provide clues to interventions that may improve functional performance in PAD.
Although participants with aorto-iliac (inflow) disease were included in the study, our results still demonstrated that plaque area and lumen area in the proximal superficial femoral artery were associated significantly with the degree of functional impairment in PAD. Our results suggest that plaque burden in the proximal superficial femoral artery may be a sensitive measure of lower extremity atherosclerotic disease burden, which in turn may be related to functional performance.
Associations of mean and maximum plaque area and minimum percent lumen area in the proximal SFA with some measures of functional performance remained statistically significant, even after adjustment for the ABI. This finding indicates that some associations of greater plaque area and smaller percent lumen area with greater functional performance were independent of the ABI. The ABI is influenced by medial arterial calcinosis and does not change substantially over time, even as lower extremity perfusion deteriorates (21). Our findings suggest that mean and maximum plaque area and minimum percent lumen reduction may be better measures of the imbalance between oxygen supply and demand during walking than the resting ABI. It is also important to point out that some associations of plaque measures with functional impairment were further attenuated after additional adjustment for leg symptoms.
Glagov et al. (22) described the phenomenon of expansive remodeling, in which atherosclerotic plaque expands outwardly from the vessel wall, possibly in an attempt to maintain arterial lumen size as atherosclerosis develops. In our analyses, mean and maximum plaque area were more consistently associated significantly with impaired functional performance than mean percent lumen area. Our results suggest that for patients with PAD, outward plaque growth may not be protective against detrimental associations of lower extremity atherosclerotic plaque with impaired functional performance. However, expansive remodeling is most protective in arteries with lesser percent lumen reduction and may be less applicable to people with established or more severe PAD (22).
First, our findings may not be generalizable to PAD patients who did not meet our inclusion criteria, including potential participants with contraindications to MRI testing. Only 8 participants had an ABI <0.30. Thus, are findings are not generalizable to participants with critical limb ischemia. Second, we imaged the proximal superficial femoral artery because it is most amenable to MR imaging. The degree to which plaque area and percent lumen area in the proximal superficial femoral artery represent the degree of plaque area or percent lumen reduction in other sections of the SFA is unknown. Third, our methods did not allow us to separate calcification from other aspects of measured atherosclerotic plaque. Associations of plaque area with functional performance may have differed if our plaque area measurements excluded calcification. Fourth, we did not collect data in all participants on maximal stenosis of lower extremity atherosclerosis in each limb. Thus, our data could not be adjusted for this information.
This study demonstrates that greater plaque area and smaller plaque lumen are associated with greater functional impairment in participants with PAD. Our results should not be interpreted as a recommendation for additional or alternative diagnostic testing as compared with current clinical practice in patients with PAD. Further study is needed to determine whether plaque area and percent lumen reduction in the proximal SFA are associated with the degree of decline in functional performance among participants with PAD. Further study is also needed to determine whether interventions that reverse plaque burden can improve functional performance in PAD.
Dr. Li is currently affiliated with the Department of Radiology and Bioengineering, Cedars Sinai Medical Center, Los Angeles, California. Supported by funding from the National Heart, Lung, and Blood Institute (R01-HL083064), by the Intramural Research Program of the National Institute on Aging, and by the Jesse Brown VA Medical Center. Dr. Yuan receives research support from VP Diagnostics and from Philips Healthcare. Dr. Kramer receives research support from Siemens Healthcare. Dr. Xu is a technical consultant for VP Diagnostics and owner of Imaging Biomarker Solutions. All other authors have reported that they have no relationships to disclose. Eike Nagel, MD, PhD, served as Guest Editor for this article.
- Abbreviations and Acronyms
- ankle brachial index
- body mass index
- magnetic resonance imaging
- peripheral arterial disease
- superficial femoral artery
- Received October 29, 2010.
- Revision received March 29, 2011.
- Accepted April 7, 2011.
- American College of Cardiology Foundation
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