The American College of Cardiology Foundation (ACCF) is accredited by ... Beach, California; kTulane University School of Medicine, New Orleans, Louisiana; lUniversity of Florida .... stress imaging tests such as stress echocardiography.
JACC: CARDIOVASCULAR IMAGING
VOL. 9, NO. 4, 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.2016.01.004
STATE-OF-THE-ART PAPERS
Noninvasive Imaging to Evaluate Women With Stable Ischemic Heart Disease Lauren A. Baldassarre, MD,a Subha V. Raman, MD,b James K. Min, MD,c Jennifer H. Mieres, MD,d Martha Gulati, MD,e Nanette K. Wenger, MD,f Thomas H. Marwick, MD, PHD,g Chiara Bucciarelli-Ducci, MD, PHD,h C. Noel Bairey Merz, MD,i Dipti Itchhaporia, MD,j Keith C. Ferdinand, MD,k Carl J. Pepine, MD,l Mary Norine Walsh, MD,m Jagat Narula, MD, PHD,n Leslee J. Shaw, PHD,f for the American College of Cardiology’s Cardiovascular Disease in Women Committee
JACC: CARDIOVASCULAR IMAGING CME CME Editor: Ragavendra R. Baliga, MD
CME Editor Disclosure: JACC: Cardiovascular Imaging CME Editor Ragavendra R. Baliga, MD, has reported that he has no relationships
This article has been selected as this issue’s CME activity, available online
to disclose.
at http://www.acc.org/jacc-journals-cme by selecting the CME tab on the top navigation bar.
Author Disclosure: Dr. Raman has received research support from Siemens Healthcare; and is a co-inventor and founding member of
Accreditation and Designation Statement
EXCMR. Dr. Min is a consultant for HeartFlow; is on the Scientific
The American College of Cardiology Foundation (ACCF) is accredited by
Advisory Board of Arineta; has ownership of MDDX and Autoplak; has a
the Accreditation Council for Continuing Medical Education (ACCME) to
research agreement with GE Healthcare; and is the recipient of grants
provide continuing medical education for physicians.
NIH/NIHLBI R01HL111141, NIH/NIHLBI R01HL115150, NIH/NIHLBI R01HL118019, NIH/NIHLBI U01HL105907, and NPRP09-370-3-089. Dr.
The ACCF designates this Journal-based CME activity for a maximum of
Bucciarelli-Ducci is a consultant for Circle Cardiovascular Imaging. Dr.
1 AMA PRA Category 1 Credit(s). Physicians should only claim credit
Bairey Merz has received grant support from Gilead, Practive Point, and
commensurate with the extent of their participation in the activity.
Medscape. Dr. Ferdinand is a consultant for Amgen, Sanofi, Boehringer Ingelheim, and Eli Lilly; and has received research support from Boeh-
Method of Participation and Receipt of CME Certificate To obtain credit for this CME activity, you must:
ringer Ingelheim. Dr. Pepine received grant UL1TR001427 from the National Center for Advancing Translational Sciences. Dr. Shaw has received the Dean’s Distinguished Faculty Award and the Albert E. Levy Scientific
1. Be an ACC member or JACC: Cardiovascular Imaging subscriber.
Research Award from Emory University; and has received grant support
2. Carefully read the CME-designated article available online and in this
from the Woodruff Foundation and the Antinori Foundation, and grants NIH-NHLBI R01HL118019-02, R01HL111150, and 1U01HL10556-01; and is a
issue of the journal. 3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME credit. 4. Complete a brief evaluation.
past president of the American Society of Nuclear Cardiology and President-Elect of the Society of Cardiovascular Computed Tomography. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
5. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the activity. CME Objective for This Article: After reading this article the reader should
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be able to provide an updated review on advances in noninvasive stress imaging and noninvasive coronary angiography in the evaluation of
Issue Date: April 2016
women presenting with stable, suspected ischemic heart disease.
Expiration Date: March 31, 2017
From the aYale University School of Medicine, New Haven, Connecticut; bThe Ohio State University College of Medicine, Columbus, Ohio;
c
Weill Cornell Medical College, New York, New York;
Hempstead, New York;
e
d
Hofstra Northshore–LIJ School of Medicine,
The University of Arizona College of Medicine, Tucson, Arizona; fEmory University School of
Medicine, Atlanta, Georgia; gMenzies Research Institute, Hobart, Tasmania, Australia; hUniversity of Bristol, Bristol, United Kingdom; iCedars-Sinai Medical Center, Los Angeles, California; jHoag Memorial Hospital Presbyterian Hospital, Newport Beach, California; kTulane University School of Medicine, New Orleans, Louisiana; lUniversity of Florida College of Medicine, Gainesville, Florida;
m
St. Vincent Heart Center, Indianapolis, Indiana; and the nIcahn School of Medicine at Mount Sinai,
New York, New York. Dr. Raman has received research support from Siemens Healthcare; and is a co-inventor and founding
422
Baldassarre et al.
JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 4, 2016 APRIL 2016:421–35
Noninvasive Imaging in Women With Stable IHD
Noninvasive Imaging to Evaluate Women With Stable Ischemic Heart Disease ABSTRACT Declines in cardiovascular deaths have been dramatic for men but occur significantly less in women. Among patients with symptomatic ischemic heart disease (IHD), women experience relatively worse outcomes compared with their male counterparts. Evidence to date has failed to adequately explore unique female imaging targets and their correlative signs and symptoms of IHD as major determinants of IHD risk. We highlight sex-specific anatomic and functional differences in contemporary imaging and introduce imaging approaches that leverage refined targets that may improve IHD risk prediction and identify potential therapeutic strategies for symptomatic women. (J Am Coll Cardiol Img 2016;9:421–35) © 2016 by the American College of Cardiology Foundation.
F
or more than 2 decades, population case fatal-
comparative assessments of male patients (9). The
ity
disease
ensuing selection and other biases represent sizable
have been higher for women compared with
challenges to uncover sex-specific findings that may
men (1). Recent declines in CV deaths in men have
explain the higher risk status of women with IHD
been dramatic; yet declines are significantly less
compared with men. Evidence to date fails to explore
rates
for
cardiovascular
(CV)
for women than men (2,3). The term ischemic heart
unique female imaging targets and their correlative
disease (IHD) now broadly includes higher risk
signs and symptoms of IHD as major determinants of
status associated with symptomatic patients with
IHD risk. This paper highlights sex-specific anatomic
obstructive and nonobstructive coronary artery dis-
and functional differences across imaging targets and
ease (CAD), including coronary microvascular disease
introduces contemporary imaging approaches that
(CMD) (4). Among patients with IHD, women experi-
leverage refined targets that may improve IHD risk pre-
ence relatively worse outcomes ranging from stable
diction and identify potential therapeutic strategies
angina to acute coronary syndromes (ACS) and
for symptomatic women.
heart failure compared with men (5–8). Determining sex-specific causality has been elusive because series
LIMITATIONS OF DEMAND ISCHEMIA
often include only women (9), are invasive coronary
TESTING IN WOMEN
angiographic series (6,10), or include cohorts of women with attempted case-matching to men, thus
Traditional diagnostic approaches for the assessment
limiting identification of a unique female risk profile
of risk associated with IHD are derived from the
(11). For example, the National Institutes of Health Na-
notion that identification of the consequences of
tional Heart, Lung, and Blood Institute–sponsored
flow-limiting stenosis(es) in major epicardial coro-
Women’s Ischemia Syndrome Evaluation (WISE)
nary arteries represents the major mechanism for
included only symptomatic women undergoing a vari-
ischemia. Accordingly, this concept is extended to
ety of ischemia and other physiological testing without
clinical practice guidelines and appropriate use
member of EXCMR. Dr. Min is a consultant for HeartFlow; is on the Scientific Advisory Board of Arineta; has ownership of MDDX and Autoplak; has a research agreement with GE Healthcare; and is the recipient of grants NIH/NIHLBI R01HL111141, NIH/NIHLBI R01HL115150, NIH/NIHLBI R01HL118019, NIH/NIHLBI U01HL105907, and NPRP09-370-3-089. Dr. Bucciarelli-Ducci is a consultant for Circle Cardiovascular Imaging. Dr. Bairey Merz has received grant support from Gilead, Practive Point, and Medscape. Dr. Ferdinand is a consultant for Amgen, Sanofi, Boehringer Ingelheim, and Eli Lilly; and has received research support from Boehringer Ingelheim. Dr. Pepine received grant UL1TR001427 from the National Center for Advancing Translational Sciences. Dr. Shaw has received the Dean’s Distinguished Faculty Award and the Albert E. Levy Scientific Research Award from Emory University; and has received grant support from the Woodruff Foundation and the Antinori Foundation, and grants NIH-NHLBI R01HL118019-02, R01HL111150, and 1U01HL10556-01; and is a past president of the American Society of Nuclear Cardiology and President-Elect of the Society of Cardiovascular Computed Tomography. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Jonathon Leipsic, MD, served as Guest Editor for this paper. Manuscript received December 22, 2015; revised manuscript received January 20, 2016, accepted January 21, 2016.
Baldassarre et al.
JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 4, 2016 APRIL 2016:421–35
423
Noninvasive Imaging in Women With Stable IHD
approaches
treatments (20–23). Even when accounting
ABBREVIATIONS
depend on a patient’s ability to exercise and an
for sex differences in risk factor prevalence,
AND ACRONYMS
accurate assessment pre-test probability of obstruc-
smaller body size, higher bleeding risk, and
tive CAD to guide test selection. Most integrated
other factors, women have decidedly worse
risk scores poorly categorize women as to their pre-
outcomes after coronary revascularization,
test CAD likelihood, with variable point values
particularly in the near term. The lack of
level dependent
assigned to risk factors resulting in an over- or
symptom-driven
CAC = coronary artery calcium
underestimation of CV risk (14). Moreover, women
demonstrable ischemia is a contributor to
commonly present with more atypical, less exertional
their worsening IHD outcomes. In addition, at
symptoms, which confound candidate selection and
1 year after the index evaluation, nearly 40%
angiography
accurate assessment of pre-test risk. Importantly, a
of symptomatic women have persistent or
CFR = coronary flow reserve
sizable proportion of women are unable to exercise
worsening symptoms (24). The extent to
maximally (those with prevalent obesity, diabetes,
which our diagnostic evaluation is not tailored
and orthopedic limitations), which may contribute
to women may be at the core of suboptimal
CMR = cardiac magnetic
to the lower reported sensitivity of the stress elec-
care. However, there also likely remains an
resonance
trocardiogram (29 studies, 62% sensitivity) than
unexplained residual gap in knowledge with
CV = cardiovascular
stress imaging tests such as stress echocardiography
regard to treatment effectiveness and strate-
IHD = ischemic heart disease
(14 studies, 79% sensitivity) and single-photon
gies of care optimized for women with IHD.
MBF = myocardial blood flow
emission computed tomography (SPECT) (14 studies,
Additional imaging markers not in use in our
MI = myocardial infarction
81% sensitivity) from a recent meta-analysis (15). In
contemporary diagnostic evaluation may hold
addition to a reduced diagnostic accuracy of the
promise to improve identification of high-risk
exercise electrocardiogram alone for epicardial CAD,
women.
angiography
SEX-SPECIFIC ATHEROSCLEROTIC
tomography
criteria
(12,13).
Furthermore,
these
care
for
women
ACS = acute coronary syndrome(s)
BOLD = blood oxygenation
with
CAD = coronary artery disease CTA = computed tomography
CMD = coronary microvascular disease
MR = magnetic resonance MRA = magnetic resonance
equivocal results are frequent and lead to physician uncertainty
and
contribute
to
further,
perhaps
PET = positron emission
PLAQUE VULNERABILITY
unnecessary, testing of women (16).
SPECT = single-photon emission computed
Moreover, the traditional diagnostic goal for
tomography
symptomatic women and men in whom IHD is sus-
Decades of data demonstrate that the culprit
pected has been the detection of obstructive CAD
ACS lesion often occurs in a previously documented
requiring revascularization. It is now clear that this
nonobstructive stenosis, revealing that there is
search for a functionally limiting obstructive stenosis
much to learn regarding ischemia and atheroscle-
is at a mismatch with the much greater prevalence of
rotic plaque as contributors to symptoms and future
nonobstructive CAD in women versus men (17). For
IHD risk (25). Coronary thrombosis is the most
many years, this has led to the misperception of a
common precursor of ACS (26,27), and evidence
high rate of “false-positive” (i.e., abnormal stress test
supports unique sex-specific mechanisms of ACS,
results with nonobstructive CAD) findings for women.
including differences in plaque rupture, erosion,
According to a recent systematic review, the range of
and calcified nodules (26,28,29). Plaque rupture is
abnormal test findings in the setting of non-
more common in men with culprit lesions exhibiting
obstructive CAD is 16% to 32% for stress testing using
atherosclerotic plaque features including thin-cap
electrocardiography, nuclear, echocardiography, and
fibroatheroma
(thin
cardiac magnetic resonance (CMR) (18). Conventional
thrombogenic
lipid-rich
stress imaging also has technical artifact issues
remodeling, and a high plaque burden (27,28,30–32).
related to breast tissue, obesity, and lung disease
More unique to women is the plaque erosion as a pre-
fibrous
caps
necrotic
with core),
a
large
positive
with poor exercise capacity, further contributing to
cursor of ACS (33–36), which has been variably associ-
reduced test accuracy (4). For women, the misper-
ated with more fibrous plaque (p < 0.001), less thin-cap
ception of a high “false-positive” rate may prompt
fibroatheroma (p < 0.001), a lower plaque burden (p ¼
greater uncertainty and inaction on the part of the
0.003), and a reduced remodeling index (p ¼ 0.003)
treating physician. Documented ischemia on stress
(26,33–37). These data support a sex-specific etiology
testing for women is rarely followed by intensifica-
for ACS, underscoring the importance of varying pla-
tion or alterations in anti-ischemic therapies or
que features unique to women compared with men.
referral to coronary angiography (19). Compared with
Results identifying unique atherosclerotic plaque
men, women consistently receive less intensive care,
features as precursors of worsening or unstable
including
less
symptoms have direct applicability to the pool of fe-
frequent coronary angiography or revascularization,
male candidates undergoing evaluation for suspected
and
IHD. Importantly, atherosclerotic plaque features
fewer
fewer
antianginal
lifestyle
or
risk
medications,
factor–modifying
424
Baldassarre et al.
JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 4, 2016
Noninvasive Imaging in Women With Stable IHD
APRIL 2016:421–35
F I G U R E 1 Invasive Angiogram With Nonobstructive CAD
Analysis using QCA. (Left) Coronary computed tomography angiography (CTA) evidence of high-risk plaque including positive remodeling, spotty calcification, and low-attenuation plaque; Hounsfield units (HU)