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

The WISE Study: The NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation Methods and Findings. B. Delia Johnson, Ph.D. Research Associate, EDC Epidemiology Seminar Series, October 6, 2005 Graduate School of Public Health, University of Pittsburgh. Outline. Background WISE Overview

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

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  1. The WISE Study:The NHLBI-Sponsored Women’s 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

  2. Outline • Background • WISE Overview • Key Findings • Implications / Impact

  3. Background

  4. Women and Heart Disease - 1

  5. Women and Heart Disease - 2 Cardiovascular Disease Mortality Trends for Males and Females United States: 1979-2002

  6. Women and Heart Disease - 3 Prevalence of Obstructive CAD at Angiography in Women

  7. 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.

  8. WISE Overview The Women’s Ischemia Syndrome Evaluation

  9. 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.

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

  11. 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 1:341-7.

  12. 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).

  13. 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.

  14. 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

  15. WISE Organization Steering Committee NHLBI DSMB Coordinating Center Core Laboratories Angiographic Hormones, androgens, insulin, glucose Coronary reactivity Brachial Artery ECG Lipids Phytoestrogens Inflammatory markers P31 P&P Committee Subcommittees Symptoms & Psychosocial Hormones Mortality classification P31 Ischemia Clinical Centers Univ. Alabama Medical Center Birmingham Univ. Florida, Gainesville UPMC, Pittsburgh Allegheny General Hosp. Pittsburgh

  16. WISE Timeline - 1 Sept. 1996 Oct. 2005 2000 8557 women screened 22% eligible; 50% of these enrolled (N=936) 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

  17. WISE Timeline - 2 Sept. 1996 Oct. 2005 2000 8557 women screened 22% eligible; 50% of these enrolled (N=936) WISE Extension: Annual Follow-Ups ARIC FemHRT IVUS WTH EWISE QWISE Sildenafil YWISE WISE Ancillary Studies

  18. Population Characteristics - 1

  19. Population Characteristics - 2

  20. Reasons for Catheterization

  21. Key Findings

  22. 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.

  23. Chest Pain / Angina • 481 WISE women • Symptomatic in prior year • No prior MI or procedure • 26% with CAD

  24. 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

  25. 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. 65:1210-21)

  26. Probability vs. WISE Prevalence* of CAD by Anginal Classification and Age Age 35-45, n=57 Age 45-55, n=141 Age 65-75, n=114 Age 55-65, n=137 * 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.

  27. 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.

  28. 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.

  29. 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 <20% change • Measure of metabolic function in heart muscle

  30. P-31 Normal vs. Abnormal No consistent relationship of CAD risk factors in normal vs abnormal MRS

  31. P-31 Spectroscopy & Outcomes Risk adjusted p=0.02 Source: Johnson, Circulation 2004

  32. 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.

  33. 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?

  34. Hypothalamic 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. HypoE & CAD p=0.01

  36. HypoE & CADReproductive Hormones

  37. HypoE & CADMultivariate Models Independent Predictors of CAD Independent Predictors of HypoE c = 0.86 NS variables: age, race, HTN, diabetes, BMI, WHR, smoking, family Hx, lipids, Beck depression, stress, typical angina. c = 0.70

  38. 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.

  39. 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.

  40. 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

  41. Publications / Publicity - 2 • 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.

  42. 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 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

  43. Publications / Publicity - 4

  44. Impact

  45. Future Plans • WISE 3 – • A new cohort • Apply new knowledge • Learn from past mistakes • Validate our findings • generate new hypotheses • Clinical Trials

  46. 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

  47. Back-Up Slides

  48. 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.

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