Stable Ischemic Heart Disease in the Female Patient

Stable Ischemic Heart Disease in the Female Patient

Leslee J. Shaw, PhD, MASNC, FACC, FAHA, FSCCT

President, Society of CV Computed TomographyPast-President, American Society of Nuclear CardiologyProfessor of MedicineCo-Director, Emory Clinical CV Research InstituteEmory University School of MedicineAtlanta, Georgia

Leslee J. Shaw, PhD, MASNC, FACC, FAHA, FSCCT

President, Society of CV Computed TomographyPast-President, American Society of Nuclear CardiologyProfessor of MedicineCo-Director, Emory Clinical CV Research InstituteEmory University School of MedicineAtlanta, Georgia

Disclosures: Dean’s Distinguished Faculty Award – Emory University; Albert E. Levy Scientific Research Award; Woodruff Foundation; Antinori Foundation: NIH-NHLBI (R01HL118019-02, R01HL111150,1U01HL10556-01).

Sex Differences In Coronary Artery Disease -Where are We in 2016?

Sex differences in presentation, diagnostic evaluation, management, & clinical outcomes for women with SIHD

Recent, 30% CVD mortality decline for women• …Increased awareness, focused clinical 

research, & application of guideline‐directed care 

• However, declines for women, across all ages, are far less than that reported for men

CVD Mortality Trends for Women & Men

Source: www.heart.org/idc/groups/heart public/@wcm/@sop/@smd/documents/downloadable/ucm_483971.pdf.

Sex Paradox in Chest Pain

Angiographic FindingsLess Obstructive CADPreserved Systolic Function / Yet more HF

Clinical ComorbidityOlder, More Diabetes, HTN…Risk Factor ClusteringMore Anginal-Equivalent /Atypical Symptoms (e.g., Dyspnea)Higher Brain Natriuretic Peptide, C Reactive Protein

Clinical OutcomesWorsening CVD Outcomes

Source: Bairey Merz JACC 2006;47:S21, Shaw Circulation 2008;117:1787, Shaw JACC 2009;54:1561-75.; Cheng Circ 2011;124: 2423-32.

Guiding Principles of Radiation Safety

Justification Optimization

Source: Wolk JACC 2014;63:380-406.

Understanding Risk-Benefit Ratio – Improve Patient Safety

Projected Risk of Radiation is Low Greater Projected Risk in Women &

in Younger Individuals Apply Risk-Benefit Decision Making

• Test Only Appropriate Indications• Engage Shared Decision Making

NIH-NHLBI Symposium: Patient-Centered Imaging - Shared Decision Making for Cardiac Imaging Procedures

Projected Incident Cancer per 10,000 Women

0123456789

CTA Tc-99mSPECT

Rb-82 PET N-13 PET

60 yr old 70 yr old

Source: Gerber JACC Imag 2010;3:528-35., Chang JACC 2010; 55:221-230., Fazel J NuclCardiol.2011;18:385-92. , Berrington de Gonzalez Circulation 2010; 122:2403-2410., Berrington Arch Intern Med 2009;169;2071-2077., Einstein JACC 2014;63:1480-1489.

0.0002%-0.0007%

Coronary Mortality in Symptomatic Women With Ischemia

0.5 1 10

Source: Hemingway JAMA 2006; 295:1404-1411.

Age Group, y

45-5455-64

65-74

WomenMen

WomenMenWomenMen

12.15.64.72.42.51.91.71.82.01.9

Coronary Mortality Compared withSex-Specific General Population Women

Men

WomenMen

WomenMen

75-84

85-89

Ambulatory pts. from Finland ages 45-89 yrs. w/ No Hx CAD, (56,441 women & 34,885 men)

2016 ASNC Information Statement: Myocardial Perfusion Imaging in Women for the Evaluation of Stable Ischemic Heart Disease –

State-of-the-Evidence & Clinical Recommendations

Viviany R. Taqueti, MD, MPH; Sharmila Dorbala, MD, MPH; David Wolinsky, MD; Brian Abbott, MD; Gary V. Heller, MD, PhD; Timothy Bateman, MD;

Jennifer H. Mieres, MD; Lawrence M. Phillips, MD; Nanette K. Wenger, MD; Leslee J. Shaw, PhD

Prognostic Accuracy ofSPECT MPI in Women

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

0% 10% 20% 30% 40% 50%

Women (n=2,904) Men (n=3,133)

% Abnormal Myocardium at Stress

CAD

Morta

lity R

ate (

% / y

r)PET Prognosis Registry: Annual CAD

Mortality for Stress Rb-82 PET

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

0% 10% 20% 30% 40% 50%

p<0.0001

Source: Kay JACC 2013 Nov 12;62(20):1866-76.

p<0.0001

*% Myocardium = Summed Stress Score / (17*4)

Coronary Flow Reserve (CFR) by Rb-82 PET

MBF: Myocardial Blood FlowSource: Bengel JACC 2009;54:1-15.

Normal

3 VD

Stress MBF

Rest MBF

Ratio

CFR= Ratio Stress / Rest MBFAbnormal <2.0

Coronary Flow Reserve by Rb-82 PET Further Defines Microvascular Dysfunction

Source: Bengel JACC 2009;54:1-15.

Normal

Diffuse /Mild CAD

Reduced Coronary Flow Reserve (CFR) on Rb-82 PET - Women Have More Nonobstructive CAD

Among Pts. with Low CFR, Women Have More Nonobstructive CADCADPI= Coronary Artery Disease Prognostic Index (Mark Circulation 1994;89:2015-2025., Min JACC 2007;50:1161–70); Source: Taqueti Circulation (ACC 2015).

Women with Low CFR – Higher CAD Event Risk

Source: Taqueti ACC 2015.

Underscores the importance of diffuse atherosclerosis & microvascular dysfunction as targets for CV risk reduction

C. Unadjusted D. Adjusted*

*Adjusted for race, pretest risk score, prior MI or PCI, diabetes, LVEF, LV ischemia, CAD severity, & early revascularization.

American College of Cardiology –CVD in Women Committee Statement

Source: Pepine JACC 2015;66:1918-33.

Angiographic CAD in Men and WomenWith Stable Chest Pain

Source: Lasse Jespersen Eur Heart J 2012;33:734-744.

11,223 ps Referred for Coronary Angiography From 1998–2009

Source: Schulman-Marcus JACC Imag 2016;9:364-372.

Women

Men

CONFIRM Registry: COronary CTA EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry

Dynamic registry of >32,000 consecutive pts1) 12 sites (US, Canada, Germany, Switzerland, Italy, & S. Korea)2) +6 sites (Miami, California, Vancouver, NY, Innsbruck, Seoul)3) +3 sites (Italy, Portugal, Poland)

Diagnosis of Obstructive CAD in Women

Source: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1132&pageaction=displayproduct#5654.

Mild-Modest Correlation Between Functional & Anatomic Tests

Myocardial Ischemia

Anatomic Stenosis≠

Mechanisms of Ischemia in Symptomatic Women

Source: Sanghavi Curr Atheroscler Rep 2015;17:34

Source: Camici J Nucl Med 2009;50:1076.

Coronary Macro- and Micro-circulation

Source: Park JACC 2012;5:1029-36., Ahmadi, Leipsic, Shaw, Narula, JAMA Cardiol 2016;1:350-357.

Stenosis-Ischemia Relationship is Variable

IWOS: Ischemia WithOut Stenosis SWOI : Stenosis WithOut Ischemia

Source: Khuddus J Interven Cardiol 2010;23:511-519.

NIH Women’s Ischemia Syndrome Evaluation: Chest Pain + No Obstructive CAD

N = 100 Women with No Stenosis

79% Prevalence ofAtherosclerotic Plaque

Understanding Relationship of Atherosclerotic Plaque with Myocardial Ischemia

Source: Ahmadi JAMA Cardiology 2016;1:350-357., Motoyama JACC 2015;66:337-346.

Measures of Positive Remodeling (PR) & Low Attenuation Plaque (LAP)

- 2-Feature + Plaque (22.2%)- 1-Feature + Plaque(3.7%)- 0-No Plaque(0.5%)

n=1,059

Events in Patients with <75% Stenosis

NIH-NHLBI PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial:

Prognosis in Women & Men by CCTA & Stress Test Findings

Source: Pagidipati JACC 2016;67:2607-2616.

HR 5.86, p<0.001HR 2.27, p=0.011

Women w/ Positive CCTA Higher Relative Hazard for Events vs. Positive Stress Test (p=0.028)

(n=2,340) (n=2,367)

(n=2,099)(n=2,160)

Unknown Factors? Metabolic AlterationsCMD Factors…

Scarred Myocardium / Unrecognized MI

Working Model of Imaging Targets Identifying IHD Risk in Women

Flow / Perfusion /WM ∆s

* Early Manifestiatons(Subendo. Ischemia)* Near- & Long-term Prognosis…

High Risk Atherosclerotic PlaquePlaque burden (volume, area)Plaque composition (mixed, non-CAC, CAC)“Lipid dense” intra-plaque coreArterial remodeling (+, -, interm.)

Nonobstructive High RiskAtherosclerotic Plaque

Stenosis 31-49%

Source: Baldassarre J Am Coll Cardiol Img 2016;9:603-617.

Interplay of Risk Across Imaging Target Types- May Necessitate Multimodality Approaches

CAD Imaging in Women - 2016

Angiographic FindingsMore Nonobstructive CADPotential for Atherosclerotic Plaque to Cause Ischemia

Nuclear MPI in Women• Considerable Evidence Supports the Utility of

SPECT & PET MPI• Impaired Coronary Flow Reserve May Detect

Underlying Vascular Abnormalities Including in the Microvasculature

• Use of CCTA Detects Stenosis + Plaque

Source: Bairey Merz JACC 2006;47:S21, Shaw Circulation 2008;117:1787, Shaw JACC 2009;54:1561-75.; Cheng Circ 2011;124: 2423-32.

Advantages:1. From typically acquired CCTA2. No additional image acquisition

– No excess radiation3. No modification to imaging protocols

– Prospective or retrospective ECG gating4. No administration of adenosine or other

medicationsDisadvantages:1. High Cost ($1,200-$1,500)2. Requires Remote Read (~6-8 hrs)3. Good Image Quality

3D FFRCT map computed

FFRCT = 0.72(can select any point on model)

FFRCT

0

5

10

15

1VD 2VD 3VD

>6-fold higher mortality for patients with 3-vessel mild CAD

HR 1.93 HR 2.74 HR 6.09

Source: Lin J Am Coll Cardiol 2011 Jul 26;58(5):510-9.

Mild Nonobstructive Stenosis & Adverse Events2,583 patients with CCTA <50% stenosis (Follow-up: 3.1 years)

Age- and Gender-Stratified Prognosis 23,854 patients w/o known CAD, 2.3 year f/u

Source: Min JACC 2011 Aug 16;58(8):849-60.

CONFIRM Registry: COronary CTA EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry

Source: Park JACC 2012;5:1029-36., Ahmadi, Leipsic, Shaw, Narula, JAMA Cardiol 2016;1:350-357.

The Stenosis-Ischemia Relationship is Far From Perfect

IWOS: Ischemia WithOut Stenosis SWOI : Stenosis WithOut Ischemia

Assess Routine ADL or DASI

High Risk

Initial ETT Strategy Initial Imaging Strategy

Selective Imaging Strategy

Abnml or Indeterminate Ex ECG

Index IHD Risk Estimate

Limited

Not Limited

CCTAStress

Imaging

Standardized Reporting of Low to High Risk Abnormalities

Low Risk

Abnormal but Non-High Risk

Initial SIHD Management Per Clinical Practice Guidelines

Resting ST Segment Abnormalities or Functional Disability

No Resting ST Segment Abnormalities

Intermediate IHD RiskIntermediate-High IHD Risk

ADL=Activities of Daily Living; DASI: Duke Activity Status IndexSource: Mieres Circulation 2014;130:350-379.

American Heart Association Statement: Noninvasive Testing in the Evaluation of Women with Suspected Ischemic Heart Disease

Comparison of FFR Between Women & Men

Source: Jing Circ Cardiovasc Interv 2013;6:662-670

Suggests that A Higher Cutoff of 0.80 May be Preferable for Women

FAME Substudy Analysis: Women vs. Men

0.75

21.1% 20.3%

0.71

39.5%

20.2%

FFR FFR ≤0.80 MACEWomen Men

Source: Kim JACC Cardiovasc Interv 2012;5:1037-42.

An FFR-guided strategy resulted in similar riskreduction for death, MI, & repeat revascularization inwomen & men.

Comparison of FFR Between Women & Men

Source: Jing Circ Cardiovasc Interv 2013;6:662-670

Suggests that A Higher Cutoff of 0.80 May be Preferable for Women

FAME Substudy Analysis: Women vs. Men

0.75

21.1% 20.3%

0.71

39.5%

20.2%

FFR FFR ≤0.80 MACEWomen Men

Source: Kim JACC Cardiovasc Interv 2012;5:1037-42.

An FFR-guided strategy resulted in similar riskreduction for death, MI, & repeat revascularization inwomen & men.

CCTA Invasive angiographyFFRCT FFR

>50% diameter stenosis >50% diameter stenosisFFRCT 0.74 Ischemia FFR 0.74 Ischemia

0.74

0.85

FFR

>50% diameter stenosis FFRCT 0.85 No ischemia FFR 0.84 No Ischemia>50% diameter stenosis

FFR

FFRCT Examples

FFR Can Now Be Derived from CCTA (FFRCT)

1. Image-Based Modeling – Segmentation of patient-specific arterial geometry

2. Heart-Vessel Interactions – Allometric scaling laws relate caliber to pressure and flow

3. Microcirculatory resistance – Mophometry laws relate coronary dimension to resistance

4. Left Ventricular Mass – Lumped-parameter model couples pulsatile coronary flow to time-varying myocardial pressure

5. Physiologic Conditions – Blood as Newtonian fluid adjusted to patient-specific viscosity

6. Induction of Hyperemia – Compute maximal coronary vasodilation

7. Fluid Dynamics – Navier-Stokes equations applied for coronary pressure

(1) (2) (3) (4) (5) (6)

140mcg/kg/mi

n

Source: Taylor JACC 2013;61:2233-2241.

Which Women May Benefit from FFRCT?

Apical lateral ischemia High grade LAD stenosis

High grade LCx stenosis No sig. RCA dx

Symptomatic patients undergoing initial testing by CCTA

Symptomatic patients undergoing CCTA with equivocal or discordant stress testing

Patients with ischemia and multiple stenoses

Patients with equivocal CCTA

FFRCT for Intermediate Stenoses

Source: Min Circulation CV Imag 2013;6:881-889.

Nonobstructive CAD in Women

In the Setting of Symptomatic IHD, Consider The Burden of Nonobstructive CAD

If Stress-Induced Ischemia, May Consider CAC to Understand Plaque Burden Moderate-Severe Ischemia, Nonobstructive CAD Observed in ~15-20%

Consider Microvascular Angina in the Differential for All Women Reduced Coronary Flow Reserve May Further Refine Diagnostic

Evaluation – Define Coronary Microvascular Dysfunction Treatment Evidence is Lacking But Reasonable Preventive &

Symptom-Guided Care Small Trials

Mostly Negative

Limited Management Recommendations

Treatment Trials

Relative Hazard for MACE in Men & Women With Stable Angina &

Nonobstructive Angiographic CAD

Source: Jespersen Eur Heart J 2012;33:734-744.

HRs (95% CI) for Patients with Nonobstructive CAD vs. Asymptomatic Women & Men

Model 1: Adjusted for AgeModel 2: Adjusted for Age, BMI, Diabetes, Smoking, & Statin / Antihypertensive Medication Use

Mild or Diffuse Epicardial

Atherosclerosis

Index Testing Strategy

Anatomy Documented Nonobstructive CAD

Stress Ischemia

Normal Coronaries

Modify Risk with Preventive Care / Symptom-Guided Care

Potential Evaluation Algorithm for Women with Nonobstructive CAD

Consider Non-Coronary Causes*

• ↓ PET Flow Reserve

• High Risk for Progressive Dz

↓ PET Flow Reserve* - Evaluate Non-Coronary Causes 1st; Adding PET in the Setting of Normal Coronaries May be Considered in Women with Persistent CP

• Rule-Out Artifact• Guideline-Directed Medical

Therapy (GDMT) – Intensity May Vary By Extent Nonobstructive CAD

Mild or Diffuse Epicardial

Atherosclerosis

Normal Coronaries

Consider Microvascular

Angina

Cascade of Mechanisms & Manifestations of Ischemia

Exposure Time of Mismatch in Myocardial Oxygen Supply / DemandNear Term Prolonged

Prog

ress

ive M

anife

stat

ions

of I

sche

mia

Micro-Infarction/ Fibrosis

Diastolic Dysfunction

Decreased Segmental Perfusion

Regional Wall Motion

↓ Subendocardial Perfusion

Systolic Dysfunction

Endothelial & Microvascular Dysfxn

Altered Metabolism

Source: Fihn JACC 2012;60(24):e44-e164.

0%2.5%

5%10%

≥15%

0.00%

0.25%

0.50%

0.75%

1.00%

<40 40 50Age (in deciles)

Younger Women (<55 years) Women (n=1,452)

Source: Kay JACC 2013 Nov 12;62(20):1866-76.

Only 2 deaths in 829 women <55 years of age (0.2%, p=0.063)

Target Selection of Appropriate Candidates

CAD Mortality (/ Year) Relationship Between Abnormal Stress PET (% Myocardium) & Age

Primary Endpoint (Clinical) – 1 YearOverall Direct

ICASelective

ICA P value

MACE (primary) 69 (4.6%) 33 (4.6%) 36 (4.6%) 1.00Non-fatal MI 4 (0.3%) 2 (0.3%) 2 (0.3%) 1.00UA 17 (1.1%) 8 (1.1%) 9 (1.1%) 1.00Urgent /

EmergentRevascularization

0 (0.0%) 0 (0.0%) 0 (0.0%) -

CVhospitalization 64 (4.3%) 31 (4.3%) 33 (4.2%) 1.00

CV Death 3 (0.2%) 1 (0.1%) 2 (0.3%) 1.00Stroke 4 (0.3%) 2 (0.3%) 2 (0.3%) 1.00

Post-Stress Testing

ICA= Invasive Coronary AngiographySelective ICA= Index Coronary CT Angiography + Selective ICAMACE= Major CAD Events

The CONSERVE TrialCOronary Computed Tomographic ANgiography for

SElective Cardiac Catheterization Relation to CardioVascular Outcomes and Economics

Hyuk-Jae Chang, Jackie Szymonifka, Dan Gebow, Ravi Bathina, Joon-Hyung Doh, Daniele Andreini, Gianluca Pontone,Andrea Baggiano, Virginia Beltrama, Jung-Hyun Choi, Jin-Won Kim, Sang-Jin Ha, So-Yeon Choi, Ae-Young Her,Sang-Wook Kim, Jang-Young Kim, Jason Cole, Eui-Young Choi, Woong Kim, Todd Villines, Rodrigo Cerci, Cezary Kepka,Uma Valeti, Fay Lin, Ibrahim Danad, Donghee Han, Ji Hyun Lee, Iksung Cho, Heo Ran, Hyung-Bok Park, Sang-Eun Lee,David Leflang, Joseph Zullo, Hae Young An, Leslee J. Shaw, Namsik Chung, James K. Min

Severance Cardiovascular Hospital, Yonsei University Health System, Seoul, South Korea; Dalio Institute of Cardiovascular Imaging,

Weil Cornell Medical College and New York-Presbyterian Hospital; MDDX; CARE Hospital and FACTS Foundation; Inje University, Ilsan Paik Hospital; Centro Cardiologico Monzino, IRCCS; Pusan National

University Hospital; Korea University Guro Hospital; Gangneung Asan Hospital; Ajou University Hospital; Kangwon National University Hospital; Chung-Ang University Hospital; Wonju Severance Hospital;

Cardiology Associates of Mobile; Gangnam Severance Hospital; Yeungnam University Hospital; Walter Reed Medical Center; Quanta Diagnostico Nuclear, Curitiba-PR; Institute of Cardiology; University of

Minnesota, Minneapolis; VU Medical Center; Asan Medical Center, University of Ulsan College of Medicine; Myongji Hospital, Seonam University College of Medicine; Emory University School of Medicine

Mechanisms of Ischemia in Symptomatic Women

Source: Sanghavi Curr Atheroscler Rep 2015 17:34

0

5

10

15

1VD 2VD 3VD

>6-fold higher mortality for patients with 3-vessel mild CAD

HR 1.93 HR 2.74 HR 6.09

Source: Lin J Am Coll Cardiol 2011 Jul 26;58(5):510-9.

Mild Nonobstructive Stenosis & Adverse Events2,583 patients with CCTA <50% stenosis (Follow-up: 3.1 years)

Reduced Coronary Flow Reserve (CFR) on Rb-82 PET - Women Have More Nonobstructive CAD

Among Pts. with Low CFR, Women Have More Nonobstructive CADCADPI= Coronary Artery Disease Prognostic Index (Mark Circulation 1994;89:2015-2025., Min JACC 2007;50:1161–70); Source: Taqueti Circulation (ACC 2015).

Proposed Pathophysiologic Link Between Abnormal Coronary Flow Reserve, Ischemia/Injury, & Outcomes

Microvascular Ischemia

Low level Myocardial 

Injury/Fibrosis

Diastolic Dysfunction

Symptom Frequency / Stability

Heart Failure/MACE

Reduced CFR

Symptomatic IHD

Defining a Unique Female‐Specific Profile

MACE= Major Adverse CAD EventsSources: Borlaug EHJ 2011;32:670-679.; Paulus JACC 2013;62:263-271; Taqueti Circulation 2015;131(6):528-35. Slide Courtesy: Viviany Taqueti, MD and Marcelo DiCarli, MD

Sex-Differences in Trial / Registry Findings

Understand the Statistical Power Limitations of Current Sex-Specific Evidence

Likely Many Female Phenotypes! Understanding Comparative Evidence for Procedures As the Male Model is So Different, Is This Our Best

Comparator?Cause precedes effect

Cause covaries with effect

Alternate explanations implausible

Causal Inference

Coronary Mortality in Symptomatic Women With Ischemia

0.5 1 10

Source: Hemingway JAMA 2006; 295:1404-1411.

Age Group, y

45-54

55-64

65-74

WomenMen

WomenMenWomenMen

12.15.64.72.4

2.5

1.9

1.71.82.01.9

Coronary Mortality Compared withSex-Specific General Population

WomenMen

WomenMen

WomenMen

75-84

85-89

Ambulatory pts. from Finland ages 45-89 yrs. w/ No HxCAD, (56,441 women & 34,885 men)

Women with Low CFR PET Have Increased CAD Events

Underscores Importance of Diffuse Atherosclerosis & Microvascular Dysfunction in Women

Unadjusted Survival Adjusted Survival*

*Adjusted for Race, Pretest Risk, Prior MI/PCI, Diabetes, LVEF, LV Ischemia, Angiographic Score Severity, & Early PCI/CABG

Source: Taqueti Circulation (in press).

The Optimal Approach to Evaluation of CADBoth Anatomy and Physiology

Source: Khuddus J Interven Cardiol 2010;23:511-519.

NIH-NHLBI WISE: Diffuse Atherosclerosis - Common Finding - Chest Pain + No Obstructive CAD

N = 100 Women79% Prevalence of Atherosclerosis& Preserved Lumen

Advancing Our Understanding of Atherosclerotic Plaque & Myocardial Ischemia

Source: Ahmadi JAMA Cardiol 2016;54:1561-75.

NIH-NHLBI WISE: Abnormal Coronary Flow Reserve Prognosis in Symptomatic Women with Nonobstructive CAD

Source: Pepine J Am Coll Cardiol 2010;55:2825–32.

Nonobstructive CAD & 1-Yr Risk of MIN=16,775 (n=1,310 Women)

Source: Maddox JAMA 2014;312:1754-1763.

Angiographic CAD in Men and WomenWith Stable Chest Pain

Source: Lasse Jespersen Eur Heart J 2012;33:734-744.

11,223 ps Referred for Coronary Angiography From 1998–2009

Source: Wilmot Circulation 2015;132:997-1002.

CHD Mortality 1979 to 2011 Age Subsets <55, 55 to 64, & ≥65 years