The WISE Study: The NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation Methods and Findings

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The WISE Study:The WISE Study:The NHLBI-Sponsored Women’s The NHLBI-Sponsored Women’s Ischemia Syndrome EvaluationIschemia Syndrome Evaluation

Methods and FindingsMethods and Findings

B. Delia Johnson, Ph.D.Research Associate, EDC

Epidemiology Seminar Series, October 6, 2005

Graduate School of Public Health, University of Pittsburgh

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• Background

• WISE Overview

• Key Findings

• Implications / Impact

OutlineOutline

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BackgroundBackground

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Women and Heart Disease - 1Women and Heart Disease - 1

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Cardiovascular Disease Mortality Trends for Males and Females

United States: 1979-2002

380

400

420

440

460

480

500

520

79 81 83 85 87 89 91 93 95 97 99 01

Years

Dea

ths

in T

ho

usa

nd

s

Males Females

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Prevalence of Obstructive CAD at Angiography in Women

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• Insufficient amount of oxygen reaching the heart muscle;

• Often exercise or anxiety induced;

• Reversible dysfunction or prolonged & severe;

• Chest pain or “silent;”

• Transient ECG abnormalities;

• Over time, the affected heart tissue may die;

• Many possible causes:– Obstructed coronary arteries (CAD)

– Endothelial dysfunction

– coronary vasoconstriction

– Microvascular insufficiency.

What is Myocardial Ischemia?What is Myocardial Ischemia?

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WISE OverviewWISE Overview

The Women’s Ischemia Syndrome Evaluation

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1. Develop accurate diagnostic approaches for CAD 1. Develop accurate diagnostic approaches for CAD detection in women.detection in women.

2. Determine the frequency, pathophysiology, and 2. Determine the frequency, pathophysiology, and significance of myocardial ischemia in the absence significance of myocardial ischemia in the absence of significant CAD in women.of significant CAD in women.

3. Evaluate the influence of hormones on 3. Evaluate the influence of hormones on pathophysiology and diagnostic test response. pathophysiology and diagnostic test response.

WISE GoalsWISE Goals

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• A four-center NHLBI-sponsored studyA four-center NHLBI-sponsored study

• 936 women undergoing clinically 936 women undergoing clinically ordered coronary angiographyordered coronary angiography

• Observational studyObservational study

In BriefIn Brief

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• A type of study in which individuals are observed or certain outcomes measured;

• No attempt to affect the outcome (e.g. no treatment);

• Advantage: natural setting;

• Drawbacks: - Hawthorne effect;

- Association vs. causality;

• Low in “Hierarchy of Evidence” - ???*

*Concato 2004, NeuroRx 1:341-7.

Observational StudyObservational Study

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1. All Sites: WISE Core Data• Core lab quantitative angiographic analysis

• Demographics (age, race)

• CAD risk factors (smoking, diabetes)

• Medical hx (comorbidities, meds)

• Reproductive hx (hysterectomy, HRT use)

• Physical exam (weight, BP)

• DASI (functional capacity)

• Symptom history

• Psychological inventories (Beck, Spielberger)

• Block dietary data

• Baseline ECG

• Annual follow-up (adverse events, resource use)

• Study termination (lost to FU, withdrew consent).

Data Collection - 1Data Collection - 1

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2. All Sites – Core Lab Blood Assays

• Lipids (HDL, triglycerides)

• Reproductive hormones (estradiol, FSH)

• Androgens (testosterone, androsteindione)

• Inflammatory markers (hs-CRP, SAA)

• Phytoestrogens (genistein, daidzein)

• Insulin, fasting glucose.


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3. Site-Specific Diagnostic Tests (# done)• Provocative coronary reactivity (coronary diameter

change, flow reserve) (166)• Brachial artery ultrasound (381)• Exercise ECG (289)• Pharmacological ECG (289)• Dobutamine stress echo (171)• SPECT (radionuclide perfusion) (452)• MRI perfusion (177)• LV mass (107)• Holter monitoring (163)• P-31 (MRI spectroscopy) (292)• PROCEDURAL SYMPTOM QUESTIONNAIRE


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NHLBI DSMBSteering Committee

P&P Committee

Coordinating Center

Clinical Centers

Univ. Alabama Medical Center Birmingham

Univ. Florida, Gainesville

UPMC, Pittsburgh

Allegheny General Hosp. Pittsburgh

Subcommittees

Symptoms & Psychosocial

Hormones

Mortality classification

P31

Ischemia

Core Laboratories

Angiographic

Hormones, androgens, insulin, glucose

Coronary reactivity

Brachial Artery

ECG

Lipids

Phytoestrogens

Inflammatory markers

P31

WISE OrganizationWISE Organization

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Sept.

1996

Oct.

2005

20008557 women screened22% eligible; 50% of

these enrolled (N=936)

WISE Extension:

Annual Follow-Ups

WISE Timeline - 1WISE Timeline - 1

WISE Extension Goals:

• Determine incremental prognostic value of novel WISE tests

• Determine prognostic value of female reproductive variables

• Determine cost effectiveness of WISE tests

• Genetics

• Inflammatory markers

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Sept.

1996

Oct.

2005

20008557 women screened22% eligible; 50% of

these enrolled (N=936)

WISE Extension:

Annual Follow-Ups

FemHRT

QWISE

IVUS WTH EWISE

WISE Ancillary Studies

YWISE

ARIC

WISE Timeline - 2WISE Timeline - 2

Sildenafil

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Population Characteristics - 1Population Characteristics - 1

Age – years [mean + SD (range)] 58 + 12 (21-86)

Postmenopausal (%) 76

Ethnic minority (%) 19

Chest pain or other symptoms (%) 94

CAD (50%+ stenosis) (%) 39

Prior MI or revascularization (%) 29

BMI [mean + SD (range)] 29.7+6.6 (14.0-57.2)

Obese (BMI > 30) (%) 41

Metabolic syndrome (%) 47

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Population Characteristics - 2Population Characteristics - 2

Rx: Lipid Lowering (%) 29

Rx: Anti-Hypertensive (%) 48

Rx: Psychoactive (%) 30

Hx smoking (%) 53

Current smoking (%) 20

Diabetes (%) 25

Hx hypertension (%) 59

Hx dyslipidemia (%) 55

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Reasons for CatheterizationReasons for Catheterization

Chest pain 92%

Shortness of breath 58%

Abnormal stress test 45%

Syncope 10%

Preoperative clearance 4%

Unknown 1%

Other (e.g. fatigue, dizziness, nausea, EKG changes) 12%

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Key FindingsKey Findings

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1.1. Develop accurate diagnostic approaches Develop accurate diagnostic approaches for CAD detection in women.for CAD detection in women.

• Is classic angina diagnostic for CAD in women?Is classic angina diagnostic for CAD in women?

2. Determine the frequency, pathophysiology, 2. Determine the frequency, pathophysiology, and significance of myocardial ischemia in and significance of myocardial ischemia in the absence of significant CAD in women.the absence of significant CAD in women.

3. Evaluate the influence of hormones on 3. Evaluate the influence of hormones on pathophysiology and diagnostic test pathophysiology and diagnostic test response.response.


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• 481 WISE women481 WISE women

• Symptomatic in prior yearSymptomatic in prior year

• No prior MI or procedureNo prior MI or procedure

• 26% with CAD26% with CAD

Chest Pain / AnginaChest Pain / Angina

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Ask: are your symptomsAsk: are your symptoms

• SubsternalSubsternal

• Exertional / strong emotionExertional / strong emotion

• Relieved w/in 10 minutes by rest/nitroglycerinRelieved w/in 10 minutes by rest/nitroglycerin

Definitions of Angina:Definitions of Angina:

• Typical Angina: all 3 presentTypical Angina: all 3 present

• Atypical Angina: 2 out of 3 presentAtypical Angina: 2 out of 3 present

• Nonanginal chest pain: 1 presentNonanginal chest pain: 1 present

• ““Asymptomatic:” 0 presentAsymptomatic:” 0 present

Angina DeterminationAngina Determination

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Probability* CAD Probability* CAD by Anginal Classification and Age in Womenby Anginal Classification and Age in Women

Age 35-45 Age 45-55

Age 55-65 Age 65-75

*Data from Diamond (1980 J Clin Invest. 65:1210-21)

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Probability vs. WISE Prevalence* of CAD by Anginal Probability vs. WISE Prevalence* of CAD by Anginal Classification and AgeClassification and Age

Age 45-55, n=141Age 35-45, n=57

Age 55-65, n=137 Age 65-75, n=114

* Adjusted for diabetes, dyslipidemia, smoking, SBP

Source: Johnson et al. Chapter 10 in Shaw & Redberg (Eds.) Contemporary Cardiology: Coronary Disease in Women. Humana Press 2004.

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• Overall, typical angina is not a good diagnostic Overall, typical angina is not a good diagnostic indicator of CAD in women;indicator of CAD in women;

• After age 55, classic angina classification is After age 55, classic angina classification is moderately predictive of CAD.moderately predictive of CAD.

Angina - ConclusionsAngina - Conclusions

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1.1. Develop accurate diagnostic approaches Develop accurate diagnostic approaches for CAD detection in women.for CAD detection in women.

2. 2. Determine the frequency, pathophysiology, Determine the frequency, pathophysiology, and significance of myocardial ischemia in and significance of myocardial ischemia in the absence of significant CAD in womenthe absence of significant CAD in women..

– Is metabolic dysfunction in the heart predictive Is metabolic dysfunction in the heart predictive of cardiovascular outcomes?of cardiovascular outcomes?

3. Evaluate the influence of hormones on 3. Evaluate the influence of hormones on pathophysiology and diagnostic test pathophysiology and diagnostic test response.response.


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P-31 Spectroscopy: Metabolic P-31 Spectroscopy: Metabolic DysfunctionDysfunction

• Phosphorus-31 nuclear magnetic resonance spectroscopy (MRS); Phosphorus-31 nuclear magnetic resonance spectroscopy (MRS);

• Normal PCr/ATP ratio ≈ 1.6Normal PCr/ATP ratio ≈ 1.6

• 74 WISE women w/o CAD. 74 WISE women w/o CAD.

• PCr/ATP ratio measured before & after handgrip stress PCr/ATP ratio measured before & after handgrip stress

• Abnormal defined Abnormal defined <<20% change20% change

• Measure of metabolic function in heart muscleMeasure of metabolic function in heart muscle

Spectra from Woman Volunteer:

A) LV chamber

B) Interventricular septum

C) LV anterior wall

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Medians (IQ Range) or %Normal MRS

n=60

Abnormal MRS

n=14 (23%)p

AgeAge 56 (50-63) 57 (48-65) 0.72

<20% Stenosis<20% Stenosis 63 64 0.91

DiabetesDiabetes 18 7 0.44

BMI BMI >> 30 30 30 50 0.21

Hx HTNHx HTN 59 36 0.11

Fam Hx CADFam Hx CAD 78 43 0.02

Hx DyslipidemiaHx Dyslipidemia 49 25 0.13

Ever SmokedEver Smoked 48 78 0.04

Current HT UseCurrent HT Use 52 64 0.43

P-31 Normal vs. AbnormalP-31 Normal vs. Abnormal

No consistent relationship of CAD risk factors in normal vs abnormal MRS

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P-31 Spectroscopy & OutcomesP-31 Spectroscopy & Outcomes

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 6 12 18 24 30 36

Months to First Event

Fre

ed

om

fro

m E

ven

ts

No CAD/Normal MRS(n=60)

No CAD/AbnormalMRS (n=14)

CAD (n=352)

Source: Johnson, Circulation 2004

Risk adjusted p=0.02

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• Abnormal MRS spectroscopy results Abnormal MRS spectroscopy results are found in about 20% of women are found in about 20% of women with chest pain but no CAD;with chest pain but no CAD;

• This abnormality is predictive of This abnormality is predictive of cardiovascular events – ischemia-cardiovascular events – ischemia-related hospitalization.related hospitalization.

P-31 Spectroscopy - ConclusionP-31 Spectroscopy - Conclusion

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1. Develop accurate diagnostic approaches for 1. Develop accurate diagnostic approaches for CAD detection in women.CAD detection in women.

2. Determine the frequency, pathophysiology, 2. Determine the frequency, pathophysiology, and significance of myocardial ischemia in and significance of myocardial ischemia in the absence of significant CAD in women.the absence of significant CAD in women.

3. 3. Evaluate the influence of hormones on Evaluate the influence of hormones on pathophysiology and diagnostic test pathophysiology and diagnostic test response.response.

– Is there a relationship between endogenous Is there a relationship between endogenous reproductive hormones and CAD?reproductive hormones and CAD?


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Hypothalamic HypoestrogenemiaHypothalamic Hypoestrogenemia

• 95 premenopausal WISE women

• No exogenous hormones (OC)

• HypoE defined as: E2<50 pg/mL + FSH<10 mlU/mL + LH<10 mlU/mL

• 13 (14%) had CAD

• 33 (35%) had hypoE

• 26% non-white (mostly AA)

35

29

69

0

20

40

60

80

100

% W

ith

Hyp

oE

No CAD N=82 CAD N=13

HypoE & CADHypoE & CAD

p=0.01

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HypoE & CADHypoE & CADReproductive HormonesReproductive Hormones

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HR 95% CI p

HypoE 7.4 1.7, 33.3 0.008

Asp. Use 7.6 1.7, 33.7 0.008

ATPIII Risk>3%

8.3 1.2, 59.6 0.04

Independent Predictors of CAD

HR 95% CI p

Anti-Anx. Meds

4.6 1.3, 15.7 0.02

Anti-Dep. Meds

0.1 .01, .92 0.04

Diabetes 3.4 1.1, 10.2 0.03

Independent Predictors of HypoE

NS variables: age, race, HTN, diabetes, BMI, WHR, smoking, family Hx, lipids, Beck depression, stress, typical angina.

HypoE & CADHypoE & CADMultivariate ModelsMultivariate Models

c = 0.86

c = 0.70

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• Premenopausal women with obstructive Premenopausal women with obstructive CAD are highly likely to have hypothalamic CAD are highly likely to have hypothalamic hypoestrogenemia;hypoestrogenemia;

• This condition is related to anxiety (as This condition is related to anxiety (as suggested by anti-anxiety medications) suggested by anti-anxiety medications) and diabetes. and diabetes.

Hypoestrogenemia - ConclusionsHypoestrogenemia - Conclusions

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• Diagnostic approaches for CAD Detection:– Chest pain is not a good indicator of CAD in women;

• Myocardial Ischemia:– Coronary metabolic dysfunction occurs in about 20% of

women with chest pain and no CAD;– It is highly predictive of CV events in these women;

• Influence of Hormones:– Angiographic PRE women with CAD are highly likely to

have hypothalamic hypoestrogenemia.

Summary of Key FindingsSummary of Key Findings

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57 peer-reviewed publications. Additional topics:

– Markers of ischemia– Psychosocial / socioeconomic / ethnicity– Obesity / metabolic syndrome– Functional capacity– Inflammatory markers / biomarkers– Genetics– Quality of care– Cost assessment– Renal insufficiency / anemia / diabetes– WISE menopausal algorithm– Novel risk factors

Publications / Publicity - 1Publications / Publicity - 1

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• WISE workshops:

– AHA Scientific Conference on Molecular, Integrative and Clinical Approaches to Myocardial Ischemia, August 2001.

– Women’s Ischemic Syndrome Evaluation. Current Status & Future Research Directions (NIH/NHLBI), October 2-4, 2002.


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• 118 abstracts at scientific meetings:– American Heart Association– American College of Cardiology– Society for Cardiovascular Magnetic Resonance– International Congress on Coronary Artery Disease– North American Menopause Society– Inter-American Society of Hypertension– American Psychosomatic Society– AHA Forum on Quality of Care and Outcomes Research in

Cardiovascular Disease and Stroke– European Society of Cardiology– International Society for Magnetic Resonance in Medicine– Society for Cardiac Angiography and Interventions– AHA Council on Cardiovascular Disease Epidemiology– International Symposium on Women’s Health and Menopause– American Society for Clinical Pharmacology and Therapeutics– Heart Failure Society of America– First International Conference on Women, Heart Disease and Stroke– World Congress of Cardiology


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ImpactImpact

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• WISE 3 –– A new cohort– Apply new knowledge– Learn from past mistakes– Validate our findings – generate new hypotheses

• Clinical Trials

Future PlansFuture Plans

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• Sherry Kelsey, PhD• Kevin Kip, PhD• Richard Holubkov, PhD• Marian Olson, MS• Genevieve Barrow, MS• Candace McClure, BS• Gretchen Gierach, MPH• Angela Pattison, BS• Joe Bondi, BA

WISE Women and MenWISE Women and Men

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Back-Up SlidesBack-Up Slides

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• Comorbidity compromising 1-year follow-up;Comorbidity compromising 1-year follow-up;• Pregnancy;Pregnancy;• Contra-indications to provocative diagnostic Contra-indications to provocative diagnostic

testing;testing;• Cardiomyopathy;Cardiomyopathy;• NY Heart Association functional Class III-IV NY Heart Association functional Class III-IV

congestive heart failure;congestive heart failure;• Recent MI;Recent MI;• Significant valvular / congenital heart disease;Significant valvular / congenital heart disease;• Language barrier to questionnaire testing.Language barrier to questionnaire testing.

WISE Exclusion CriteriaWISE Exclusion Criteria

The WISE Study: The NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation Methods and Findings

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