The WISE Study: The NHLBI-Sponsored Women

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The WISE StudyThe NHLBI-Sponsored Womens
Ischemia Syndrome EvaluationMethods 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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Outline

• Background
• WISE Overview
• Key Findings
• Implications / Impact

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Background
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Women and Heart Disease - 1
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Women and Heart Disease - 2
Cardiovascular Disease Mortality Trends for Males
and Females United States 1979-2002
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Women and Heart Disease - 3

• Prevalence of Obstructive CAD at Angiography in
  Women

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What is Myocardial Ischemia?

• 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.

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WISE Overview
The Womens Ischemia Syndrome Evaluation
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WISE Goals

• 1. Develop accurate diagnostic approaches for CAD
  detection in women.
• 2. Determine the frequency, pathophysiology, and
  significance of myocardial ischemia in the
  absence of significant CAD in women.
• 3. Evaluate the influence of hormones on
  pathophysiology and diagnostic test response.

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In Brief

• A four-center NHLBI-sponsored study
• 936 women undergoing clinically ordered coronary
  angiography
• Observational study

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Observational Study

• 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 1341-7.

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Data Collection - 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).

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Data Collection - 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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Data Collection - 3

• 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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WISE Organization
NHLBI
DSMB
Steering Committee
Coordinating Center
Core Laboratories Angiographic Hormones,
androgens, insulin, glucose Coronary
reactivity Brachial Artery ECG Lipids Phytoestroge
ns Inflammatory markers P31
PP Committee
Subcommittees Symptoms Psychosocial Hormones Mor
tality classification P31 Ischemia
Clinical Centers Univ. Alabama Medical Center
Birmingham Univ. Florida, Gainesville UPMC,
Pittsburgh Allegheny General Hosp. Pittsburgh
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WISE Timeline - 1
Sept. 1996
Oct. 2005
2000
8557 women screened 22 eligible 50 of these
enrolled (N936)
WISE Extension Annual Follow-Ups

• 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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WISE Timeline - 2
Sept. 1996
Oct. 2005
2000
8557 women screened 22 eligible 50 of these
enrolled (N936)
WISE Extension Annual Follow-Ups
ARIC
FemHRT
IVUS
WTH
EWISE
QWISE
YWISE
Sildenafil
WISE Ancillary Studies
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Population 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) 29.76.6 (14.0-57.2)
Obese (BMI gt 30) () 41
Metabolic syndrome () 47
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Population 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 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 Findings
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WISE Goals

• Develop accurate diagnostic approaches for CAD
  detection in women.
• Is classic angina diagnostic for CAD in women?
• 2. Determine the frequency, pathophysiology, and
  significance of myocardial ischemia in the
  absence of significant CAD in women.
• 3. Evaluate the influence of hormones on
  pathophysiology and diagnostic test response.

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Chest Pain / Angina

• 481 WISE women
• Symptomatic in prior year
• No prior MI or procedure
• 26 with CAD

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Angina Determination

• Ask are your symptoms
• Substernal
• Exertional / strong emotion
• Relieved w/in 10 minutes by rest/nitroglycerin
• Definitions of Angina
• Typical Angina all 3 present
• Atypical Angina 2 out of 3 present
• Nonanginal chest pain 1 present
• Asymptomatic 0 present

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Probability CAD by 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.
651210-21)
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Probability vs. WISE Prevalence of CAD by
Anginal Classification and Age
Age 45-55, n141
Age 35-45, n57
Age 65-75, n114
Age 55-65, n137
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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Angina - Conclusions

• Overall, typical angina is not a good diagnostic
  indicator of CAD in women
• After age 55, classic angina classification is
  moderately predictive of CAD.

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WISE Goals

• Develop accurate diagnostic approaches for CAD
  detection in women.
• 2. Determine the frequency, pathophysiology, and
  significance of myocardial ischemia in the
  absence of significant CAD in women.
• Is metabolic dysfunction in the heart predictive
  of cardiovascular outcomes?
• 3. Evaluate the influence of hormones on
  pathophysiology and diagnostic test response.

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P-31 Spectroscopy Metabolic Dysfunction

• Spectra from Woman Volunteer
• LV chamber
• Interventricular septum
• LV anterior wall

• Phosphorus-31 nuclear magnetic resonance
  spectroscopy (MRS)
• Normal PCr/ATP ratio 1.6
• 74 WISE women w/o CAD.
• PCr/ATP ratio measured before after handgrip
  stress
• Abnormal defined lt20 change
• Measure of metabolic function in heart muscle

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P-31 Normal vs. Abnormal
Medians (IQ Range) or Normal MRS n60 Abnormal MRS n14 (23) p
Age 56 (50-63) 57 (48-65) 0.72
lt20 Stenosis 63 64 0.91
Diabetes 18 7 0.44
BMI gt 30 30 50 0.21
Hx HTN 59 36 0.11
Fam Hx CAD 78 43 0.02
Hx Dyslipidemia 49 25 0.13
Ever Smoked 48 78 0.04
Current HT Use 52 64 0.43
No consistent relationship of CAD risk factors in
normal vs abnormal MRS
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P-31 Spectroscopy Outcomes
Risk adjusted p0.02
Source Johnson, Circulation 2004
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P-31 Spectroscopy - Conclusion

• Abnormal MRS spectroscopy results are found in
  about 20 of women with chest pain but no CAD
• This abnormality is predictive of cardiovascular
  events ischemia-related hospitalization.

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WISE Goals

• 1. Develop accurate diagnostic approaches for CAD
  detection in women.
• 2. Determine the frequency, pathophysiology, and
  significance of myocardial ischemia in the
  absence of significant CAD in women.
• 3. Evaluate the influence of hormones on
  pathophysiology and diagnostic test response.
• Is there a relationship between endogenous
  reproductive hormones and CAD?

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Hypothalamic Hypoestrogenemia

• 95 premenopausal WISE women
• No exogenous hormones (OC)
• HypoE defined as E2lt50 pg/mL FSHlt10 mlU/mL
  LHlt10 mlU/mL
• 13 (14) had CAD
• 33 (35) had hypoE
• 26 non-white (mostly AA)

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HypoE CAD
p0.01
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HypoE CADReproductive Hormones
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HypoE CADMultivariate Models
Independent Predictors of CAD
HR 95 CI p
HypoE 7.4 1.7, 33.3 0.008
Asp. Use 7.6 1.7, 33.7 0.008
ATPIII Riskgt3 8.3 1.2, 59.6 0.04
Independent Predictors of HypoE
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
c 0.86
NS variables age, race, HTN, diabetes, BMI, WHR,
smoking, family Hx, lipids, Beck depression,
stress, typical angina.
c 0.70
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Hypoestrogenemia - Conclusions

• Premenopausal women with obstructive CAD are
  highly likely to have hypothalamic
  hypoestrogenemia
• This condition is related to anxiety (as
  suggested by anti-anxiety medications) and
  diabetes.

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Summary of Key Findings

• 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.

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Publications / Publicity - 1

• 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

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Publications / Publicity - 2

• WISE workshops
• AHA Scientific Conference on Molecular,
  Integrative and Clinical Approaches to Myocardial
  Ischemia, August 2001.
• Womens Ischemic Syndrome Evaluation. Current
  Status Future Research Directions (NIH/NHLBI),
  October 2-4, 2002.

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Publications / Publicity - 3

• 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 Womens 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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Publications / Publicity - 4
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Impact
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Future Plans

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

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WISE Women and Men

• 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

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Back-Up Slides
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WISE Exclusion Criteria

• Comorbidity compromising 1-year follow-up
• Pregnancy
• Contra-indications to provocative diagnostic
  testing
• Cardiomyopathy
• NY Heart Association functional Class III-IV
  congestive heart failure
• Recent MI
• Significant valvular / congenital heart disease
• Language barrier to questionnaire testing.