Post on 24-Dec-2015
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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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Women and Heart Disease - 2Women and Heart Disease - 2
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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Women and Heart Disease - 3Women and Heart Disease - 3
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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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.
Data Collection - 2Data Collection - 2
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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
Data Collection - 3Data Collection - 3
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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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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.
WISE GoalsWISE Goals
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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.
WISE GoalsWISE Goals
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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?
WISE GoalsWISE Goals
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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)
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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.
Publications / Publicity - 2Publications / Publicity - 2
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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
Publications / Publicity - 3Publications / Publicity - 3
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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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• 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