Evaluate Women With Stable Ischemic Heart Disease

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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)