JACC: CARDIOVASCULAR IMAGING VOL. -, NO.

-, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-878X/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jcmg.2016.08.012

Plaque Composition in the Proximal

Superficial Femoral Artery and
Peripheral Artery Disease Events
Mary M. McDermott, MD,a,b Christopher M. Kramer, MD,c Lu Tian, SCD,d James Carr, MD,e
Jack M. Guralnik, MD, PHD,f Tamar Polonsky, MD,g Timothy Carroll, PHD,h Melina Kibbe, MD,i,j
Michael H. Criqui, MD, MPH,k Luigi Ferrucci, MD, PHD,l Lihui Zhao, PHD,b Daniel S. Hippe, MS,m
John Wilkins, MD,a,b Dongxiang Xu, PHD,m Yihua Liao, MS,b Walter McCarthy, MD,n Chun Yuan, PHDm

ABSTRACT

OBJECTIVES The aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the
proximal superficial femoral artery (SFA) with lower extremity peripheral artery disease (PAD) event rates and systemic
cardiovascular event rates.

BACKGROUND LRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied
previously in lower extremity arteries.

METHODS Participants with ankle-brachial index (ABI) values <1.00 were identified from Chicago medical centers
and followed annually. Magnetic resonance imaging was used to characterize SFA atherosclerotic plaque at baseline.
Medical records for hospitalizations and procedures after baseline were adjudicated for lower extremity revascularization,
amputation, and critical limb ischemia and also for new coronary events, ischemic stroke, and mortality.

RESULTS Of 254 participants with PAD, 62 (24%) had LRNC and 149 (59%) had calcium in the SFA at baseline. Cox
regression analyses were adjusted for age, sex, race, comorbidities, baseline ABI, and other confounders. SFA LRNC
was associated with an increased incidence of the combined outcome of lower extremity amputation, critical limb
ischemia, ABI decline >0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval:
1.27 to 3.75; p ¼ 0.005). The association of SFA LRNC with PAD events was maintained even when this combined
outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p ¼ 0.01).
LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke.

CONCLUSIONS Among patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and
this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA
LRNC prevent PAD events. (J Am Coll Cardiol Img 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.

From the aDepartment of Medicine Northwestern University Feinberg School of Medicine, Chicago, Illinois; bDepartment of
Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; cDepartments of Medicine,
d
Radiology, and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia; Department of Health
Research and Policy, Stanford University School of Medicine, Stanford, California; eDepartment of Radiology, Northwestern
University Feinberg School of Medicine, Chicago, Illinois; fDepartment of Epidemiology and Public Health, University of
g
Maryland School of Medicine, Baltimore, Maryland; Department of Medicine, University of Chicago, Chicago, Illinois;
h
Department of Radiology, University of Chicago, Chicago, Illinois; iJesse Brown Veterans Affairs Medical Center, Chicago,
Illinois; jDivision of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago,
Illinois; kNational Institute on Aging, Bethesda, Maryland; lDepartment of Family and Preventive Medicine, University of
m
California, San Diego, San Diego, California; Department of Radiology and Bioengineering, University of Washington, Seattle,
n
Washington; and the University Cardiovascular Surgeons, Rush University Medical Center, Chicago, Illinois. Dr. Kibbe is
currently affiliated with the Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, North
Carolina. This work was funded by the National Heart, Lung, and Blood Institute (grants R01-HL109244 and R01-HL083064).
Dr. Yuan has received grant funding from Philips Healthcare and is a member of the Philips Radiology Medical Advisory
Network. Drs. Kramer and McDermott have received research funding from Novartis. Mr. Hippe has received grant funding
from Philips Healthcare and GE Healthcare. All other authors have reported that they have no relationships relevant to the
contents of this paper to disclose. Renu Virmani, MD, served as the Guest Editor for this paper.

Manuscript received April 26, 2016; revised manuscript received July 21, 2016, accepted August 24, 2016.
2 McDermott et al. JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016
Lipid Rich Plaques in SFA and PAD Events - 2016:-–-

C
ABBREVIATIONS oronary artery atherosclerotic We also invited patients in a general medicine prac-
AND ACRONYMS plaque with a lipid-rich necrotic tice age 70 years and older who did not have histories
core (LRNC) and thin fibrous cap is of PAD to be screened with the ABI. Those with ABI
ABI = ankle-brachial index
associated with plaque rupture, thrombus values <1.00 were invited to participate. The Insti-
BMI = body mass index
formation, and an acute coronary event or tutional Review Boards at all participating sites
LRNC = lipid-rich necrotic core
progression of coronary artery atheroscle- approved the protocol. Participants gave written
MI = myocardial infarction
rosis (1–4). Similar associations have been informed consent. MRI was performed between
MRI = magnetic resonance reported for the presence of LRNC in the January 2008 and April 2010. Because MRI data
imaging
carotid arteries and subsequent cerebrovas- collection initially required more time than antici-
PAD = peripheral artery
cular events (5–8). However, the significance pated, between January 2008 and May 2008, a
disease
of LRNC in the lower extremity arteries is randomly selected 50% subset of participants under-
SFA = superficial femoral
artery
unknown. went plaque composition imaging. Once MRI data

TE = echo time
We studied whether the presence of mag- collection had become more efficient, all participants
netic resonance imaging (MRI)–measured underwent MRI for plaque composition (between
TR = repetition time
LRNC in superficial femoral artery (SFA) pla- June 2008 and April 2010) (16).
que is associated with higher rates of lower extremity INCLUSION AND EXCLUSION CRITERIA. The inclu-
peripheral artery disease (PAD) events, including sion criterion for WALCS III was an ABI <1.00 (17–19).
amputation, hospitalization for critical limb ischemia, WALCS III exclusion criteria have been described
significant ankle-brachial index (ABI) decline, and (15,16) and are summarized here. Potential partici-
lower extremity revascularization. We hypothesized pants with dementia and those with Mini-Mental
that compared with the absence of LRNC, the pres- Status Examination scores <23 were excluded
ence of LRNC in the SFA would be associated with a because it was unclear whether they could answer
higher rate of PAD events. We also studied whether questions accurately (20). Nursing home residents,
MRI-detected calcium in SFA plaque and whether wheelchair-bound patients, and patients with foot or
greater SFA plaque volume and smaller SFA luminal leg amputations were excluded because of their
area were associated with higher PAD event rates. impaired functioning. Non-English-speaking patients
Preliminary evidence suggests that local plaque were excluded. Patients with recent major surgery or
characteristics may also provide information about contraindications to MRI were excluded. Potential
risk for cardiovascular events in distant artery beds participants requiring oxygen, those who stopped a 6-
(9–14). Therefore, we studied whether LRNC and min walk test because of dyspnea, and those with
calcium in the SFA were associated with higher rates severe knee osteoarthritis were excluded (21).
of acute coronary events, ischemic stroke, and all-
ABI MEASUREMENT. The ABI was used to document
cause mortality compared with the absence of LRNC
the presence and severity of PAD. After participants
or calcium in the SFA. We also studied whether
rested supine for 5 min, a handheld Doppler probe
greater MRI-measured plaque volume in the SFA and
(Nicolet Vascular Pocket-Dop II, Natus Medical,
smaller luminal area in the SFA were associated with
Golden, Colorado) was used to measure systolic
higher rates of acute coronary events, ischemic
pressure in the right brachial, dorsalis pedis, and
stroke, and mortality.
posterior tibial arteries and left dorsalis pedis, pos-
terior tibial, and brachial arteries. Pressure measure-
METHODS
ments were repeated in reverse order. The ABI was
calculated in each leg by dividing average pressures
SUBJECTS. Participants were part of the WALCS
in that leg by the average of the 4 brachial pressures
(Walking and Leg Circulation Study) III cohort, a
(22). The ABI in the leg in which MRI was measured
longitudinal observational study designed to
was used for analyses.
examine the association of MRI-measured athero-
sclerotic plaque characteristic in the SFA with func- MRI. We imaged the SFA of the leg with the lowest
tional impairment and decline in men and women ABI. MRI data were obtained with a 1.5-T platform
with PAD (15). Enrollment occurred between October (Espree, Siemens Medical Solutions, Malvern, Penn-
26, 2007, and April 2010 (15,16). Participants were sylvania) using a 4-element phased-array surface coil
identified from among all patients diagnosed with (Nova Medical, Wilmington, Massachusetts). We
PAD in the noninvasive vascular laboratories or in imaged the proximal SFA because its superficial
vascular surgery, cardiology, and/or general medical location was more amenable to high-quality images
practices at 4 Chicago-area hospitals according to than the distal SFA. The bifurcation of the common
our Institutional Review Board approved methods. femoral artery was the reference point. Images were
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016 McDermott et al. 3
- 2016:-–- Lipid Rich Plaques in SFA and PAD Events

collected with a standard, proton density–weighted identified on the basis of signal intensities relative
turbo spin echo acquisition (repetition time [TR] to the sartorius muscle. LRNC is hypointense on
2,160 ms; echo time [TE] 8 ms; bandwidth 230 T2-weighted images, isointense or slightly hyperin-
Hz/pixel; turbo factor 15). The field of view was 120  tense on T1-weighted images, and isointense on pro-
120 mm 2, and images were acquired on a 192  192 ton density–weighted and time-of-flight images.
matrix to yield an in-plane spatial resolution of 0.625  Calcium is hypointense on T1-weighted, T2-weighted,
0.625 mm2 . Three signal averages were acquired. and time-of-flight images.
Twelve contiguous 2.5-mm cross-sectional images BASELINE COMORBIDITIES. Comorbidities assessed
in the short-axis plane were obtained, beginning at at baseline were diabetes mellitus, hypertension,
the common femoral artery bifurcation into the SFA myocardial infarction (MI), and angina. Comorbidities
and moving distally using 2-dimensional bright-blood were identified and confirmed using algorithms
time-of-flight and proton density–weighted images. developed for the Women’s Health and Aging Study
Bright-blood 2-dimensional time-of-flight images (29). The algorithms combine data from patient
(TR 31.0 ms; TE 7.2 ms) were registered to the proton report, medical record review, medications, labora-
density–weighted images and acquired using an tory values, and a primary care physician question-
identical field of view, slice thickness, and imaging naire. Hypertension was defined as patient report
matrix. This method has excellent test-retest reli- of physician-diagnosed hypertension or physician
ability (15,23). Additional turbo spin echo images designation of hypertension on the primary care
were acquired with TR and TE adjusted to provide physician questionnaire.
T1-weighted (TR 800 ms; TE 8 ms) and T2-weighted
OTHER BASELINE MEASURES. Height and weight
(TR 2,160 ms; TE 50 ms) images, respectively. These
were measured at baseline. Body mass index (BMI)
images were prescribed with identical thickness,
was calculated as weight in kilograms divided by the
location, number of slices, and signal saturation (fat
square of height in meters. Low-density lipoprotein
saturation and regional blood saturation) as the pro-
cholesterol was determined using a homogenous
ton density–weighted images. The additional contrast
direct method from Roche Diagnostics (Indianapolis,
weighting was used for plaque characterization.
Indiana). High-density lipoprotein cholesterol was
For analysis of plaque area, wall thickness, and
measured using a direct enzymatic colorimetric assay.
luminal area, 2 physician readers with cardiovascular
Cigarette smoking history was determined by self-
imaging training used CASCADE software (University
report. Participants brought medication bottles or
of Washington, Seattle, Washington). Poor-quality
medication lists to their study visit. A study investi-
images were excluded, using established criteria
gator (M.M.M.) identified which participants were
(24). Readers traced the outer boundary and the
taking statin and antiplatelet medications. The pres-
lumen of each cross-sectional image to quantify wall
ence of exertional leg symptoms and classic symptoms
thickness, wall area, and luminal area. Images for
of intermittent claudication were defined using the
each participant were assigned to 1 primary reviewer,
San Diego Claudication Questionnaire (30,31).
and tracings of arterial boundaries were reviewed by
the second reviewer to ensure accuracy. Disagree- ADJUDICATION OF LOWER EXTREMITY AND

ments were resolved via discussion and consensus. CARDIOVASCULAR EVENTS. Participants returned

Plaque area measurements were normalized for to the medical center for follow-up 1, 2, and 4 years
artery size by dividing each measure by the median of after baseline. At follow-up, participants were inter-
the total vessel area (15,25). Luminal area was viewed to identify new hospitalizations and under-
normalized per slice using total vessel area because of went repeat ABI measurement. At 3-year follow-up,
variation in vessel dimensions due to patient size. An participants were interviewed by telephone to
assessment of test-retest reliability among a 6% sub- identify new hospitalizations. Medical records for all
sample showed coefficient of variation percentage hospitalizations after baseline were retrieved and
values of 5.8 and 8.9 for mean and maximum plaque reviewed independently by 2 investigators (M.M.M.
area, respectively; the values were 7.9 for mean and and J.W.) using an abstraction form. Differences
12.9 for minimum percentage luminal area, respec- between reviewers were resolved by discussion.
tively (15). Reviewers were blinded to MRI measures.
The presence of LRNC and calcium was determined Lower extremity PAD events. Lower extremity events
at each artery cross section using validated methods indicating PAD progression were defined as medical
(26–28). Images were evaluated at the University of record–documented hospitalization for critical limb
Washington Core Reading Center in the Vascular ischemia, amputation, or lower extremity revascu-
Imaging Laboratory by 2 readers. Tissue types were larization. Decline in the ABI by >0.15 in the leg with
4 McDermott et al. JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016
Lipid Rich Plaques in SFA and PAD Events - 2016:-–-

the MRI measurement was defined as PAD progres- Associations of plaque LRNC and plaque calcium
sion (31). with PAD events, cardiovascular outcomes, and
Adjudication of acute coronary events. Acute coronary mortality were evaluated using Cox proportional
events were defined as MI, hospitalization for unsta- hazards models, adjusting for age, sex, race, diabetes,
ble angina, and cardiac death. Additional outcomes hypertension, history of MI, angina, cholesterol
were ischemic stroke and all-cause mortality. Criteria values, BMI, smoking, statin use, antiplatelet ther-
for MI were derived from the ARIC (Atherosclerosis apy, and baseline ABI. Similarly, associations of mean
Risk in Communities) and MESA (Multi-Ethnic Study plaque area tertiles and mean luminal area tertiles
of Atherosclerosis) studies (32,33). An acute MI with outcomes were evaluated using Cox propor-
required 2 of the following criteria: 1) chest pain; 2) tional hazards models, adjusting for age, sex, race,
abnormal electrocardiographic findings consistent diabetes, hypertension, history of MI, angina,
with an MI (ST-segment elevation, new left bundle cholesterol values, BMI, smoking, statins, antiplatelet
branch block, new Q waves); and 3) abnormal cardiac therapy, and baseline ABI. Analyses were performed
enzymes (troponin >2 times the upper limit of using SAS version 9.4 (SAS Institute, Cary, North
normal). Criteria for unstable angina were derived Carolina).
from the MESA and LIFE (Lifestyle Interventions and
Independence for Elders) studies (33,34). Unstable RESULTS
angina was defined as nonelective hospital admission
with a discharge diagnosis of acute coronary ischemia In total, 473 participants with PAD underwent MRI of
that was not definite or probable MI. Clinical symp- the SFA. Sixteen were excluded because of poor im-
toms were required. In addition, 1 of the following age quality. Of the remaining 457 participants, 305
was required: 1) treatment with nitrates, heparin, or underwent additional MRI data collection (T1- and
beta-blockers; 2) coronary revascularization during T2-weighted imaging) for plaque composition. Of
the hospitalization; 3) >70% obstruction of a coronary these, 13 (4.3%) did not return for any follow-up visits
artery by angiography during hospitalization; or 4) an and were considered lost to follow-up, 37 (12.0%)
electrocardiogram showing horizontal or down- were excluded because of missing data on choles-
sloping ST-segment depression or abnormal ST- terol, and 1 (0.32%) was excluded because of missing
segment elevation >1 mm, and these findings were data on smoking, leaving 254 for plaque composition
present only during chest pain. Acute coronary death analyses. Median follow-up duration was 47 months.
consisted of definite fatal MI, definite coronary heart For the analyses of plaque volume and luminal area,
disease death, and possible coronary heart disease of the 457 participants with valid MRI data, 20 (4.0%)
death (33,34). did not return for any follow-up visits, 57 (12.0%)
Ischemic stroke and mortality. The outcome of ischemic were excluded because of missing data on choles-
stroke was based on criteria from the LIFE study (34) terol, and 1 (0.22%) was excluded because of missing
and consisted of acute onset of neurological symp- data on smoking, leaving 379 for analyses of plaque
toms combined with an imaging study consistent and luminal area. Three participants with PAD were
with acute ischemic stroke. Deaths were ascertained identified from ABI screening of general medicine
from medical records and from proxies if medical patients age >70 years, and 2 of these participants
records were not available. underwent MRI of plaque composition.
STATISTICAL ANALYSES. Baseline characteristics Of 254 participants with plaque composition data,
were compared between PAD participants with versus 62 (24.4%) had LRNC and 149 (58.7%) had calcium in
without LRNC and with versus without calcium at the SFA. Seventy (27.6%) had classic symptoms of
baseline. Student t tests were used for continuous intermittent claudication, 41 (16.1%) were asymp-
variables, and chi-square tests were used for cate- tomatic, and 143 (56.3%) had exertional leg symptoms
gorical variables. Kaplan-Meier analyses compared that were not consistent with classic intermittent
cumulative rates of PAD events, acute coronary claudication. LRNC in the SFA was associated with a
events, stroke, and all-cause mortality between par- lower prevalence of former smokers and higher
ticipants with and those without LRNC and with prevalence rates of current smoking and male sex
and those without calcium, using the log-rank test compared with absence of LRNC (Table 1). LRNC was
for statistical significance. PAD events, acute coro- also associated with lower high-density lipoprotein
nary events, stroke, and all-cause mortality were cholesterol levels. Calcium was associated with older
compared across tertiles of mean luminal area and age, lower BMI, and higher high-density lipoprotein
mean plaque area using Kaplan-Meier curves and log- and was more prevalent in men, former smokers, and
rank tests. those using statins at baseline (Table 1).
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016 McDermott et al. 5
- 2016:-–- Lipid Rich Plaques in SFA and PAD Events

T A B L E 1 Associations of Superficial Femoral Artery Plaque Composition With Baseline Characteristics in Participants With Peripheral Artery Disease

Total Absence of LRNC Presence of LRNC Absence of Calcium Presence of Calcium

(n ¼ 254) (n ¼ 192) (n ¼ 62) p Value (n ¼ 105) (n ¼ 149) p Value

Age, yrs 68.53  9.96 68.72  9.33 67.94  11.76 0.591 66.15  11.69 70.20  8.17 0.001
ABI 0.67  0.17 0.68  0.18 0.66  0.16 0.308 0.70  0.18 0.66  0.17 0.054
Male 181 (71.3) 130 (67.7) 51 (82.3) 0.028 67 (63.8) 114 (76.5) 0.028
African American 83 (32.7) 60 (31.3) 23 (37.1) 0.393 37 (35.2) 46 (30.9) 0.465
Never smoker 27 (10.6) 18 (9.4) 9 (14.5) 0.253 19 (18.1) 8 (5.4) 0.001
Former smoker 163 (64.2) 133 (69.3) 30 (48.4) 0.003 58 (55.2) 105 (70.5) 0.013
Current smoker 64 (25.2) 41 (21.4) 23 (37.1) 0.013 28 (26.7) 36 (24.2) 0.651
Diabetes 108 (42.5) 78 (40.6) 30 (48.4) 0.282 44 (41.9) 64 (43.0) 0.868
BMI, kg/m2 29.89  6.54 30.14  6.72 29.10  5.92 0.277 31.09  7.29 29.04  5.82 0.013
HDL-C, mg/dl 49.01  17.40 50.37  18.36 44.80  13.27 0.028 46.43  14.08 50.83  19.24 0.047
LDL-C, mg/dl 92.08  31.97 93.43  33.16 87.90  27.83 0.237 95.56  32.54 89.63  31.45 0.146
Pulmonary disease 95 (37.4) 70 (36.5) 25 (40.3) 0.585 40 (38.1) 55 (36.9) 0.848
Cancer 40 (15.7) 32 (16.7) 8 (12.9) 0.479 16 (15.2) 24 (16.1) 0.851
Angina 54 (21.3) 41 (21.4) 13 (21.0) 0.948 17 (16.2) 37 (24.8) 0.097
MI 44 (17.3) 30 (15.6) 14 (22.6) 0.208 15 (14.3) 29 (19.5) 0.283
Stroke 42 (16.5) 31 (16.1) 11 (17.7) 0.769 18 (17.1) 24 (16.1) 0.827
Heart failure 37 (14.6) 31 (16.1) 6 (9.7) 0.209 16 (15.2) 21 (14.1) 0.799
Hypertension 237 (93.3) 182 (94.8) 55 (88.7) 0.139 98 (93.3) 139 (93.3) 0.989
On statin medication at baseline 196 (77.2) 152 (79.2) 44 (71.0) 0.181 74 (70.5) 122 (81.9) 0.033
Antiplatelet therapy 205 (80.7) 156 (81.3) 49 (79.0) 0.700 79 (75.2) 126 (84.6) 0.064
Leg symptoms
Intermittent claudication 70 (27.6) 60 (31.3) 10 (16.1) 24 (22.9) 46 (30.9)
Exertional leg symptoms other than 143 (56.3) 104 (54.2) 39 (62.9) 0.058 59 (56.2) 84 (56.4) 0.135
intermittent claudication
Asymptomatic 41 (16.1) 28 (14.6) 13 (21.0) 22 (21.0) 19 (12.8)

Values are mean  SD for continuous variables and n (%) for categorical variables. ABI values are from the leg in which MRI measures were obtained.
ABI ¼ ankle-brachial index; BMI ¼ body mass index; HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholesterol; LRNC ¼ lipid-rich necrotic core; MI ¼ myocardial infarction;
MRI ¼ magnetic resonance imaging.

Among participants with plaque composition data, diabetes, statin use, antiplatelet therapy, and base-
66 experienced 1 or more PAD events during follow- line ABI, LRNC in the SFA was associated with an
up. Of these, 38 (58%) had lower extremity revascu- increased hazard for a PAD event (p ¼ 0.005) and
larization, 8 (12%) had amputation or critical limb for any PAD event other than revascularization
ischemia, and 31 (47%) experienced ABI declines of (p ¼ 0.010) (Table 3). LRNC in the SFA was also
>0.15 compared with baseline. Seventy-five partici- associated with an increased hazard for lower
pants had acute coronary events, ischemic stroke, or extremity revascularization (p ¼ 0.013) (Table 3).
death. Of these, 38 (51%) had acute coronary events, There were no associations of SFA LRNC with
15 (20%) had ischemic stroke, and 45 (60%) died of other individual PAD events, acute coronary
any cause during follow-up. events, ischemic stroke, or all-cause mortality
Participants with LRNC in the SFA had higher rates (Table 3).
of PAD events, measured by the combined outcome of In unadjusted analyses, SFA calcium was not
lower extremity revascularization, amputation, hos- associated with PAD events (Table 2). However, cal-
pitalization for critical limb ischemia, or ABI decline cium in the SFA was associated with a lower rate of
>0.15, compared with those without LRNC in the SFA acute coronary events (Table 2). Adjusting for age,
(Figure 1, Table 2). This association remained after sex, race, cholesterol values, smoking, BMI, MI,
excluding lower extremity revascularization from the angina, hypertension, diabetes, statin use, antiplate-
composite endpoint (Figure 2, Table 2). There were no let therapy, and baseline ABI, there was no associa-
significant associations of LRNC with acute coronary tion of SFA calcium with subsequent PAD events or
events, ischemic stroke, or all-cause mortality acute coronary events, ischemic stroke, or all-cause
(Table 2). mortality (Table 4). There was no association of SFA
Adjusting for age, sex, race, cholesterol values, plaque area or luminal area with any outcome
smoking, BMI, history of MI, angina, hypertension, (Table 5).
6 McDermott et al. JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016
Lipid Rich Plaques in SFA and PAD Events - 2016:-–-

F I G U R E 1 Association of Presence Versus Absence of Lipid-Rich Necrotic Core and Subsequent Rates of Lower Extremity Events

1.0
Logrank P = 0.0020

0.8

Probability of Being Free of

Lower Extremity Events 0.6

0.4

0.2

0.0
0 10 20 30 40 50 60 70
Time (Month)
Number of Participants at Risk
Absence of LRNC 182 174 138 99 94 30 2 0
Presence of LRNC 60 52 41 28 23 6 1 0

Absence of LRNC Presence of LRNC

Lower extremity events are defined as the first occurrence of 1 of the following: lower extremity amputation, critical limb ischemia,
ankle-brachial index decline of >0.15, or lower extremity revascularization. LRNC ¼ lipid-rich necrotic core.

DISCUSSION reported that a larger LRNC, measured by MRI, was

associated with a higher rate of ipsilateral cerebro-
Our results indicate that the presence of LRNC in the vascular events over a mean follow-up of 38.2
SFA is associated with a higher rate of clinically months. However, to our knowledge, the clinical
important PAD events, measured by a composite significance of LRNC in the SFA has not been reported
outcome of lower extremity amputation, hospitali- previously.
zation for critical limb ischemia, significant ABI Guzman et al. (35) reported that computed
decline, and lower extremity revascularization. This tomography–measured calcium in the tibial artery
association was observed even after excluding lower was associated with amputation risk in 229 patients
extremity revascularizations from the composite PAD with PAD. The finding reported here, that calcium in
outcome. Associations were independent of potential the SFA is not related to subsequent lower extremity
confounders, including PAD severity, measured by events, is likely related to several factors. First,
the ABI. After adjusting for confounders, none of the computed tomography is more sensitive for detecting
plaque measures (LRNC, calcium, or plaque burden) calcium than MRI. Second, only a short proximal
was associated with events that occurred remotely segment of the SFA was imaged in the present study,
from the lower extremities such as acute coronary whereas the prior study shows that calcification is
events or ischemic stroke. more prevalent in distal segments of lower extremity
Histopathologic studies from the coronary arteries arteries. Our finding that plaque burden was not
demonstrate that coronary artery atherosclerotic associated with lower extremity events is consistent
plaque with an LRNC and a thin fibrous cap is asso- with a previous study showing that plaque burden
ciated with increased risk for plaque rupture and in the SFA is not associated with decline in 6-min
thrombus formation, resulting in an acute coronary walk (36).
event or progression of coronary artery atheroscle- Preliminary evidence supported the hypothesis
rosis (1–3). Similar associations have been reported that local plaque characteristics convey risk for
for the carotid arteries (4–8). Takaya et al. (7) atherosclerotic events in distant vascular beds. For
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016 McDermott et al. 7
- 2016:-–- Lipid Rich Plaques in SFA and PAD Events

T A B L E 2 Associations of Lipid-Rich Necrotic Core and Calcium in the Superficial Femoral Artery With Subsequent Lower Extremity
Peripheral Artery Disease Events, Acute Coronary Events, Ischemic Stroke, and All-Cause Mortality

LRNC Present in SFA LRNC Absent in SFA Calcium in SFA No Calcium in SFA
(n ¼ 62) (n ¼ 192) p Value (n ¼ 149) (n ¼ 105) p Value

Lower extremity PAD events

$1 PAD event* 25 (41.7) 41 (22.5) 0.004 33 (23.4) 33 (32.7) 0.110
$1 PAD event other than revascularization† 15 (25.0) 23 (12.6) 0.022 17 (12.1) 21 (20.8) 0.065
Any lower extremity revascularization 16 (25.8) 22 (11.5) 0.006 19 (12.8) 19 (18.1) 0.240
Amputation or critical limb ischemia 4 (6.5) 4 (2.1) 0.102 4 (2.7) 4 (3.8) 0.721
ABI decline >0.15 11 (18.6) 20 (11.1) 0.131 13 (9.4) 18 (17.8) 0.053
Acute coronary events, ischemic stroke, all-cause mortality
Coronary events, stroke, or all-cause mortality‡ 18 (29.0) 57 (29.7) 0.922 44 (29.5) 31 (29.5) 0.999
Acute coronary events 10 (16.1) 28 (14.6) 0.767 16 (10.7) 22 (21.0) 0.025
Ischemic stroke 3 (4.8) 12 (6.3) 1.000 8 (5.4) 7 (6.7) 0.666
All-cause mortality 12 (19.4) 33 (17.2) 0.698 29 (19.5) 16 (15.2) 0.385

Values are n (%). *Patients who experienced 1 or more lower extremity PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, ABI
decline of >0.15, or lower extremity revascularization. †Patients with 1 or more PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia,
or ABI decline of >0.15. ‡Participants who experienced 1 or more events. Participants may have had more than one type of event.
PAD ¼ peripheral artery disease; SFA ¼ superficial femoral artery; other abbreviations as in Table 1.

example, plaque morphology and the presence of artery characteristics between 97 participants with
arterial LRNC is typically consistent throughout >50% coronary artery stenosis and 94 participants
the vascular tree (11–13). In a case-control study, with no angiographic evidence of coronary artery
Underhill et al. (14) compared MRI-measured carotid disease. Participants with coronary artery disease had

F I G U R E 2 Association of Presence Versus Absence of Lipid-Rich Necrotic Core and Subsequent Rates of Lower Extremity Events Other
Than Lower Extremity Revascularization

1.0
Logrank P = 0.0177

0.8
Probability of Being Free of
Lower Extremity Events

0.6

0.4

0.2

0.0
0 10 20 30 40 50 60 70
Survival Time (Month)
Number of Participants at Risk
Absence of LRNC 182 180 147 105 101 33 2 0
Presence of LRNC 60 57 45 34 29 7 1 0

Absence of LRNC Presence of LRNC

Lower extremity events are defined as the first occurrence of 1 of the following: lower extremity amputation, critical limb ischemia, or
ankle-brachial index decline of >0.15. LRNC ¼ lipid-rich necrotic core.
8 McDermott et al. JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016
Lipid Rich Plaques in SFA and PAD Events - 2016:-–-

T A B L E 3 Adjusted and Unadjusted Associations of Lipid-Rich Necrotic Core in the Superficial Femoral Artery With Subsequent Lower
Extremity Peripheral Artery Disease Events, Acute Coronary Events, Ischemic Stroke, and All-Cause Mortality

Model 1, Unadjusted Model 2, Fully Adjusted

Hazard Ratio (95% CI) p Value Hazard Ratio (95% CI) p Value

Lower extremity PAD events

Any PAD event* 2.15 (1.30–3.54) 0.003 2.18 (1.27–3.75) 0.005
Any PAD event excluding revascularization† 2.16 (1.12–4.16) 0.021 2.58 (1.25–5.33) 0.010
Lower extremity revascularization 2.47 (1.30–4.70) 0.006 2.42 (1.20–4.86) 0.013
Amputation or hospitalization for critical limb ischemia. 3.12 (0.78–12.49) 0.107 2.75 (0.56–13.61) 0.215
ABI decline >0.15 1.68 (0.80–3.53) 0.169 2.20 (0.97–5.01) 0.06
Coronary and cerebrovascular events and all-cause mortality
Acute coronary event, ischemic stroke, or all-cause mortality 0.97 (0.57–1.65) 0.911 0.86 (0.49–1.51) 0.608
Acute coronary events 1.11 (0.54–2.29) 0.771 0.86 (0.38–1.94) 0.711
Ischemic stroke 0.76 (0.21–2.69) 0.671 0.80 (0.21–3.10) 0.752
All-cause mortality 1.12 (0.58–2.18) 0.728 0.93 (0.45–1.89) 0.831

Model 2 adjusted for age, sex, race, diabetes, hypertension, history of MI, angina, LDL-C, HDL-C, BMI, cigarette smoking, statin use, antiplatelet therapy, and baseline ABI.
*Patients who experienced 1 or more lower extremity PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, ABI decline of >0.15, or
lower extremity revascularization. †Patients with 1 or more PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, or ABI decline
of >0.15.
CI ¼ confidence interval; other abbreviations as in Tables 1 and 2.

a higher prevalence of carotid artery LRNC than those some arteries, intimal thickening was so severe that it
without coronary artery disease. A separate study of occluded the artery, but intimal thickening was not
community-dwelling men and women in MESA accompanied by atheromatous change (38). This
without clinically evident cardiovascular disease re- study suggests that the arterial histopathology in the
ported that MRI-measured carotid intima-media lower extremity arteries of PAD patients differs from
thickness and the presence of MRI-detected carotid arterial histopathology in the coronary or cerebro-
artery LRNC or calcium were each associated with vascular arteries.
increased rates of cardiovascular events (37). How- STUDY LIMITATIONS. First, although the sensitivity
ever, a recent histopathologic study of 176 arterial and specificity of MRI for plaque composition in the
segments from 60 amputated limbs in patients with carotid artery, including calcium and LRNC, range
PAD reported intimal thickening without atheroma- from 84% to 100% (26), MRI is not optimally sensitive
tous changes in 68% of lower extremity arteries. In for detecting arterial calcium.

T A B L E 4 Adjusted and Unadjusted Associations of Calcium in the Superficial Femoral Artery With Subsequent Lower Extremity
Peripheral Artery Disease Events, Acute Coronary Events, Ischemic Stroke, and All-Cause Mortality

Model 1, Unadjusted Model 2, Fully Adjusted

Hazard Ratio (95% CI) p Value Hazard Ratio (95% CI) p Value

Lower extremity PAD events

Any PAD event* 0.68 (0.42–1.10) 0.12 0.70 (0.40–1.21) 0.203
Any PAD event excluding revascularization† 0.60 (0.31–1.13) 0.115 0.73 (0.34–1.59) 0.432
Lower extremity revascularization 0.70 (0.37–1.32) 0.265 0.71 (0.35–1.48) 0.365
Amputation or hospitalization for critical limb ischemia 0.73 (0.18–2.93) 0.66 2.00 (0.35–11.32) 0.433
ABI decline >0.15 0.56 (0.28–1.16) 0.118 0.53 (0.22–1.32) 0.175
Coronary events, ischemic stroke, and all-cause mortality
Acute coronary event, ischemic stroke, or all-cause mortality 1.05 (0.66–1.66) 0.839 1.11 (0.66–1.87) 0.69
Acute coronary events 0.54 (0.28–1.02) 0.058 0.59 (0.28–1.25) 0.169
Ischemic stroke 0.85 (0.31–2.33) 0.747 0.72 (0.21–2.47) 0.596
All-cause mortality 1.41 (0.77–2.60) 0.267 1.66 (0.82–3.38) 0.159

Model 2 adjusted for age, sex, race, diabetes, hypertension, history of MI, angina, LDL-C, HDL-C, BMI, cigarette smoking, statin use, antiplatelet therapy, and baseline ABI.
*Patients who experienced 1 or more lower extremity PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, ABI decline of >0.15, or
lower extremity revascularization. †Patients with 1 or more PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, or ABI decline of
>0.15.
Abbreviations as in Tables 1, 2, and 3.
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2016 McDermott et al. 9
- 2016:-–- Lipid Rich Plaques in SFA and PAD Events

T A B L E 5 Unadjusted Associations of Plaque Quantity and Luminal Area With Cardiovascular Outcomes

Plaque Area Luminal Area

Tertile 1 (Lowest Tertile 3 (Highest Trend Tertile 1 (Largest Tertile 3 (Smallest

Plaque Quantity) Tertile 2 Plaque Quantity) p Value Luminal Area) Tertile 2 Luminal Area) p Value

Lower extremity PAD events

$1 PAD event* 37/119 (31.09) 38/120 (31.67) 33/120 (27.50) 0.748 39/120 (32.50) 37/120 (30.83) 32/119 (26.89) 0.624
$1 PAD event other 27/119 (22.69) 24/120 (20.00) 20/120 (16.67) 0.504 28/120 (23.33) 24/120 (20.00) 19/119 (15.97) 0.360
than revascularization†
Any lower extremity revascularization 20/126 (15.87) 18/127 (14.17) 17/126 (13.49) 0.858 20/126 (15.87) 17/127 (13.39) 18/126 (14.29) 0.851
Amputation or critical limb ischemia 5/126 (3.97) 3/127 (2.36) 4/126 (3.17) 0.718 5/126 (3.97) 3/127 (2.36) 4/126 (3.17) 0.718
ABI decline >0.15 23/118 (19.49) 21/119 (17.65) 16/118 (13.56) 0.461 24/118 (20.34) 20/119 (16.81) 16/118 (13.56) 0.381
Coronary events, ischemic stroke, and all-cause mortality
Coronary events, stroke, 29/126 (23.02) 42/127 (33.07) 39/126 (30.95) 0.179 31/126 (24.60) 39/127 (30.71) 40/126 (31.75) 0.402
or all-cause mortality‡
Acute coronary events 17/126 (13.50) 24/127 (18.90) 12/126 (9.50) 0.097 16/126 (12.70) 23/127 (18.10) 14/126 (11.10) 0.242
Ischemic stroke 9/126 (7.14) 7/127 (5.51) 7/126 (5.56) 0.826 9/126 (7.14) 7/127 (5.51) 7/126 (5.56) 0.826
All-cause mortality 17/126 (13.49) 26/127 (20.47) 25/126 (19.84) 0.279 21/126 (16.67) 22/127 (17.32) 25/126 (19.84) 0.786

Values are n/N (%). *Patients who experienced 1 or more lower extremity PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, ABI decline of >0.15, or lower
extremity revascularization. †Patients with 1 or more PAD events, consisting of lower extremity amputation, hospitalization for critical limb ischemia, or ABI decline of >0.15. ‡Participants who experienced
1 or more events. Participants may have had more than one type of event.
Abbreviations as in Tables 1 and 2.

Second, we imaged a proximal segment of the SFA whether interventions that reduce LRNC in the SFA
in the leg with the lowest ABI. Although a previous can prevent lower extremity outcomes in PAD.
study showed that the presence of LRNC in 1 lower
extremity artery is highly correlated with LRNC in the REPRINT REQUESTS AND CORRESPONDENCE: Dr.

opposite leg (13), it is conceivable that the composi- McDermott, Northwestern University Feinberg School
tion of plaque in the short proximal segment of the of Medicine, Department of Medicine, 750 North Lake
SFA that we imaged does not reflect plaque compo- Shore Drive, 10th Floor, Chicago, Illinois 60611.
sition in the rest of the lower extremity artery bed. E-mail: [email protected].
Third, the outcome of lower extremity revascular-
PERSPECTIVES
ization is determined in part by clinician deter-
minations about patient disability from PAD and
ability to safely undergo revascularization. However, COMPETENCY IN MEDICAL KNOWLEDGE: Among patients
LRNC predicted lower extremity events even after with lower extremity PAD who underwent MRI of the proximal
revascularizations were excluded. segment of the SFA, 24% had LRNC in the SFA. The presence of
Fourth, we did not collect data on whether calcium LRNC in the SFA was associated with a higher incidence of the
was eccentric or concentric within the artery. combined outcome of lower extremity amputation, critical
Fifth, we did not collect data on Rutherford limb ischemia, significant ABI decline, and lower extremity
classification. revascularization over 47-month follow-up.

TRANSLATIONAL OUTLOOK: Further study is needed to

CONCLUSIONS
confirm that LRNC in the SFA is an important predictor of adverse
lower extremity events, independent of the ABI. Further study is
Among patients with PAD, LRNC in the SFA was
also needed to determine whether interventions that reduce SFA
associated with higher rates of lower extremity PAD
LRNC prevent lower extremity events in people with PAD.
events, independent of PAD severity, measured by
the ABI. Further study is needed to determine

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