1. Evidence Based Management of Cardiovascular Disease in Women discusses the leading causes of death in Americans and how cardiovascular disease is the number one killer of women. 2. The document reviews gender differences in atherosclerosis, such as plaque erosion being more common in women than plaque rupture seen in men, making diagnosis of cardiovascular disease more difficult in women. 3. Prevention strategies discussed include reducing atherosclerosis, preventing plaque rupture and erosion, limiting thrombosis, and recognizing the presence of cardiovascular disease in women.

1. Evidence Based Management of
Cardiovascular Disease in Women
Karol E. Watson, MD, PhD, FACC
Co-director, UCLA Program in Preventive Cardiology
Associate Professor of Medicine/Cardiology
David Geffen School of Medicine at UCLA

2. Karol E. Watson
Disclosure of Financial Relationships
Consultant: Genentech, Genzyme
Clinical Trials Adjudication Committee:
Merck

3. CV disease: Leading cause of death
in Americans
493,623
500
433,825
400
Men
288,768 Women
300 268,503
Deaths
(1000s)
200
100 69,257 60,713 64,103
34,301 41,877 38,948
0 A C D E C
B A B F E
A Total CVD* C Accidents E Diabetes
B Cancer D Chronic lower respiratory diseases F Alzheimer’s Disease
*CHD, stroke, HF, hypertension, arterial diseases
Data compiled for 2002 CDC/NCHS and NHLBI.

4. Cardiovascular Disease: Leading Cause of
Death in Women
United States: 1997 Mortality
600
502,938
500
Deaths in 400 Breast cancer
41,943
Thousands 300 258,467
200
100 53,045 47,165 34,449
0
Total CVD Cancer Chronic Pneumonia Diabetes
Obstructive and Influenza Mellitus
Pulmonary
Disease
2000 Heart and Stroke Statistical Update, American Heart Association.

5. Effectiveness-Based Guidelines for the
Prevention of Cardiovascular Disease
in Women--2011 Update: A Guideline
From the American Heart Association
L. Mosca et al. Circulation. 2011 Feb 16.

7. Prevention of CHD:
• Reducing atherosclerosis
• Preventing plaque rupture
• Limiting thrombosis

8. Severe obstruction (angina, no rupture) vs
mild obstruction (no angina, likely to rupture)
Severe fibrotic plaque Vulnerable plaque
• Severe obstruction •Minor obstruction
• No lipid •Large lipid pool
• Fibrosis, Ca2+ •Thin fibrous cap
Plaque rupture
Exertional angina
• Acute MI
• (+) ETT
• Unstable angina
Revascularization • Sudden death
Anti-anginal Rx Pharmacologic stabilization
Courtesy of PH Stone, MD. Early identification of high-risk?

9. ACC – NCDR:
CAD Prevalence in Diagnostic Catheterization
Women n=19,761 Typical Angina Atypical Angina
Men n=23,868
Age Women Men Women Men
<40 13 21 4 4
40-49 20 42 7 15
50-59 32 60 12 31
60-69 42 72 18 38
70-79 53 77 31 48
>80 65 84 35 50

10. WISE: Landmark study in women
Prospective cohort study conducted at 4 US sites
Goals:
• Improve diagnostic testing for ischemic heart
disease in women
• Study pathophysiologic mechanisms for
ischemia in the absence of epicardial
coronary artery stenoses
• Evaluate the influence of menopausal status
and reproductive hormone levels on
diagnostic testing results
Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.

11. V3016
V3016 A
A B
B
AB
AB
C
C
C
C
Source: WISE – Unpublished data – S. Nissen

12. N e g a t iv e R e m o d e lin g
P o s it iv e R e m o d e lin g

13. WISE: Persistent chest pain in
women predicts future CV events
n = 673 WISE participants with chest pain at baseline
1
0.9
Event-free Without CAD
HR 1.89 (1.06–3.39)
survival (%)
0.8 P = 0.03
0.7
With CAD
HR 1.17 (0.76–1.80)
0.6 P = 0.49
0 1 2 3 4 5 6
Years from PChP diagnosis (at one year)
Neither PChP No PChP Both
No CAD CAD
PChP = persistent chest pain Johnson BD et al. Eur Heart J. 2006;27:1408-15.

14. Plaque Erosion and Outward
(Positive) Remodeling
• Plaque erosion and
Lumen thrombus formation
2x likely in women
Plaque
(men have more
erosion plaque rupture)
• Outward (positive)
remodeling-
atherosclerotic lesion
protrudes outward
Thrombus
Formation
than impinging on the
lumen
Adapted from Bellasi et al, New insights into ischemic heart disease in women.
cleveland clinic journal of medicine; 74: 585-594

15. Gender Differences
in Atherosclerosis
Women suffer more plaque
erosions (above) compared
to plaque explosions in men
(below), leading to more
acute coronary syndromes
(unstable angina) and
non-Q MI in women,
making diagnosis more
difficult and leading to
delays in treatment.
NEJM 1999

16. Perfusion CMR in Cardiac Syndrome-X
Res t S tre s s
C o ntr
• Women with chest pain
ol
suggestive of myocardial
ischemia yet no or
nonobstructive CAD (i.e.,
cardiac syndrome x) may
have subendocardial
m e -X
S yn d r o
ischemia as
demonstrated using
cardiac MR perfusion
Panting JR. New Engl J Med 2002; 346: 1948-53.

17. Prevention of CHD:
• Reducing atherosclerosis
• Preventing plaque rupture / EROSION
• Limiting thrombosis

18. Classic Cardiovascular Risk Factors
• Tobacco Smoke
• High Blood Cholesterol
• High Blood Pressure
• Physical Inactivity
• Obesity and Overweight
• Diabetes Mellitus
• Age

19. Diabetes and CV Risk in Framingham
Age 35-64 Years--30 Year Follow-up
10 P<0.001
P<0.001
8 Men
Women
Risk Ratio
6 P<0.001
P<0.001 P<0.001
4 P<0.001 P<0.001
P<0.001 P<0.05
2
0
CHD Stroke Claudication Heart Total
Failure CVD
Wilson Am J Kidney Dis 1998

20. The Metabolic Syndrome
Diagnosis is established
when ≥ 3 of risk factors are present
Risk Factor Defining Level
Abdominal obesity
( W a is t
c ir c u m f e r e n c e ) >10 2 c m
Men ( >4 0 in )
Wo me n >8 8 c m
TG ≥15 05
( >3 mn ) /d l
i g
HDL-C
Men <4 0 m g /d l
Wo me n <5 0 m g /d l
≥13 0 /≥8 5 m m
Blood pressure
Hg
Fasting glucose ≥110 m g /d l
S o u r c e : Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JA M A 2001;285:2486-2497.

21. Metabolic Syndrome and CV Mortality
• European cohort studies (6156 men and 5356
women):
• Modified WHO definition of Metabolic Syndrome
• CV mortality
–2.26 [1.61-3.17] in men
– 2.78 [1.57-4.94] in women
Hu et al. Arch Intern Med 2004; 164: 1066-76

22. Elevated Triglycerides Increase CHD Risk
Framingham Heart Study
Relative Risk for CHD
2.5
2.0
1.5
1.0
0.5 Women
0.0
50 100 150 200 250 300 350 400 Men
Meta-Analysis of 17 For every increase in serum TG level of 89
Prospective Studies
mg/dL, risk of CHD increases 30% in men and
69% in women

23. Prevention of CHD:
• Reducing atherosclerosis
• Preventing plaque rupture / EROSION
• Limiting thrombosis

24. Inflammatory Pathways in
Atherogenesis
Pro-inflammatory Risk
Factors
Primary Pro-Inflammatory Cytokines (eg, IL-1, TNF-α)
IL-6
“Messenger” Cytokine
ICAM-1 CRP
Selectins, HSPs, etc. SAA
Endothelium
and other cells
Liver
Adapted from Libby P et al.
Circulation. 1999;100:1148–1150.
Circulation

25. Hs-CRP and Risk of Future Cardiovascular
Events in Apparently Healthy Women
7
P Trend <0.002
6 Any Event
5 MI or Stroke
Relative Risk
4
3
2
1
0
1 2 3 4
<0.15 0.15–0.37 0.37–0.73 >0.73
Quartile of hs-CRP (range, mg/dL)
S o u r c e : Ridker PM et al. C irculation 1998;98:731-733.

26. Risk Factors for Future Cardiovascular
Events: Women’s Health Study
Lipoprotein(a)
Homocysteine
IL-6
TC
LDL-C
sICAM-1
SAA
Apo B
TC: HDL-C
hs-CRP
hs-CRP + TC: HDL-C
0 1.0 2.0 4.0 6.0
IL, interleukin; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; sICAM, serum intercellular adhesion
molecule; SAA, serum amyloid A; ApoB, Apolipoprotein B; HDL-C, high-density lipo-protein cholesterol; hs-CRP, high-
sensitivity C-reactive protein.
Ridker PM, et al. N Engl J Med. 2000;342:836-843.

27. High-Sensitivity C-Reactive Protein
(hsCRP)
• hsCRP should not be used for routine screening of all
women, but should be reserved for refining risk
estimates in intermediate risk patients when there is
uncertainty regarding the need to start drug therapy
• Consider statins in women over 60 years of age if,
after lifestyle modification, hsCRP remains elevated
above 2 mg/dL and no acute inflammatory process is
present (Class IIb; Level of Evidence B)
Source: Mosca 2011, Ridker 2009

28. Metabolic Syndrome and CRP
Levels
C-reactive Protein (mg/L) 8
6
4
2
0
0 1 2 3 4 5
Number of Components of the Metabolic Syndrome
Ridker PM, et al. Circulation. 2003;107:391-397. (with permission)

29. Behavioral factors associated with elevated
biomarkers of inflammation
• Increased body fat
• Smoking
• Low physical activity
• Poor aerobic fitness
• Low fruit and vegetable intake
• Low omega-3 fatty acid intake
Nicklas BJ, You T, Pahor M. Behavioral treatments for chronic systemic inflammation: effects of dietary weight loss
and exercise training. Can Med Assoc J 2005; 172:1199-1209

30. Prevention of CHD:
• Reducing atherosclerosis
• Preventing plaque rupture / EROSION
• Limiting thrombosis
• Recognizing Presence of CHD in women

31. Aspirin Evidence: Secondary Prevention
Effect of antiplatelet treatment* on vascular events**
Acute MI
Acute CVA
Prior MI
Prior CVA/TIA
Other high risk
CVD(e.g. unstable angina, heart failure)
PAD(e.g. intermittent claudication)
High risk of embolism (e.g. Afib)
Other (e.g. DM)
All trials
0.0 0.5 1.0 1.5 2.0
Antiplatelet better Control better
Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86

32. Women's Health Study:
Low-Dose Aspirin in Primary Prevention Trial
39,876 initially healthy† women, aged ≥45 yrs
Randomized, blinded, factorial
Low-Dose Aspirin Placebo
100 mg on alternate days
n=19,934 n=19,942
End points (mean, 10.1 yrs):
● Combined end point of nonfatal MI, nonfatal stroke, or total cardiovascular death
● Incidence of total malignant neoplasms of epithelial cell origin
Ridker PM. Presented at: 54th Annual Scientific Session of the American College
of Cardiology; March 7, 2005; Orlando, Fla. Ridker PM, et al. N Engl J Med. 2005;352.

33. Aspirin : Primary Prevention in Women
Womens’ Health Study (WHS)
39,876 women randomized to aspirin (100 mg every other day)
or placebo for an average of 10 years
0.02
Aspirin
Placebo
Incidence of MI
Cumulative
0.01
P=0.83
0.00
0 2 4 6 8 10
Years
Aspirin does not reduce the risk of MI in low risk women
But…
Ridker P et al. NEJM 2005;352:1293-304

34. Womens’ Health Study (WHS)
Aspirin Placebo RR 95% CI P
Primary endpoint:
Major cardiovascular event* 477 522 0.91 0.80-1.31 .13
Secondary endpoints:
Stroke 221 206 0.83 0.69-0.99 .04
Ischemic 170 221 0.76 0.63-0.93 .009
Hemorrhagic 51 41 1.24 0.82-1.87 .31
Transient ischemic attack 186 238 0.78 0.64-0.94 .01
Myocardial infarction (MI) 198 193 1.02 0.84-1.25 .83
revascularization 389 374 1.04 0.90-1.20 .61
Cardiovascular death 120 129 0.95 0.74-1.22 .68
All-cause mortality 609 642 0.95 0.85-1.06 .32
Ridker P et al. NEJM 2005;352:1293-304

35. Womens’ Health Study (WHS)
Aspirin Placebo RR 95% CI P
Smoking status
Current (n = 5235) 157 127 1.30 1.03-1.64 .03
Past/never (n = 34,605) 319 392 0.80 0.69-0.93 .003
Age (yrs)
45-54 (n = 24,025) 163 161 1.01 0.81-1.26 .92
55-64 (n = 11,754) 183 186 0.98 0.80-1.20 .84
65+ (n = 4097) 131 175 0.74 0.59-0.92 .008
Ridker P et al. NEJM 2005;352:1293-304

37. USPSTF: Risk level at which CVD events
prevented (benefit) exceeds GI harms
Men ages 45-79 Women ages 55-79 Encourage aspirin use
Encourage aspirin use when potential CVD when potential CVD benefit (strokes prevented)
benefit (MIs prevented) outweighs potential outweighs potential harm of GI hemorrhage.
harm of GI hemorrhage
10-year CHD risk 10-year stroke risk
Age 45-59 years ≥4% Age 55-59 years ≥3%
Age 60-69 years ≥9% Age 60-69 years ≥8%
Age 70-79 years ≥12% Age 70-79 years ≥11%
Men Age <45 Years and Women Age <55 Years : Do not encourage aspirin use Men &
Women Age ≥80 Years: No Recommendation (Insufficient Evidence) AHRQ Publication No. 09-05129-EF-3
Current as of March 2009

38. Women have strokes too
Age group (y) Women/Men OR 95% CI P
(%)
35 - 44 1.2/1.0 1.2142 0.4715 - 3.1268 0.6876
45 - 54 2.5/1.0 2.3903 1.3205 - 4.3267 0.0040
55 - 64 3.4/3.0 1.1256 0.6218 - 2.0376 0.6961
NHANES data from 17,061 individuals older than 18 years between
1999 and 2004

39. Stroke StatisticsU.S. Statistics
• The risk stroke doubles each decade after the age
of 55.
– ~25% of strokes occur in people < 65 years of age.
• Stroke death rates are higher for African Americans
than for whites, even at younger ages.
• Each year, about 55,000 more women than men
have a stroke.
• The risk of ischemic stroke in current smokers is
about double that of nonsmokers
• High blood pressure is the most important risk
factor for stroke.
U.S. Centers for Disease Control and Prevention and the Heart Disease and Stroke Statistics - 2010 Update

40. Effectiveness-Based Guidelines for the
Prevention of Cardiovascular Disease
in Women--2011 Update: A Guideline
From the American Heart Association
L. Mosca et al. Circulation. 2011 Feb 16.

41. Lifestyle Interventions
• Cigarette smoking DON’T! (Class I; LOE B )
• Physical activity
– 150 min/wk of moderate exercise or 75 min/wk of
vigorous exercise, performed in episodes of at least
10 min, (Class I; LOE B)
– Muscle strengthening activities on ≥2 d per week (Class I;
LOE B)
• Cardiac rehabilitation YES (Class I; LOE B)
• Dietary intake
– Diet rich in fruits, vegetables, and whole grains.
Limit saturated fat, cholesterol, alcohol, salt, and
sugar. Avoid trans-fatty acids (Class I LOE B)

42. Lifestyle Interventions (cont.)
• Weight maintenance/reduction
– Maintain or lose weight through physical activity
and appropriate caloric intake to achieve
appropriate body weight (BMI <25 kg/m2, waist
size <35 inches) (Class I; LOE B).
• Omega-3 fatty acids
– Consumption of omega-3 fatty acids in the form
of fish or in capsule form for women with
hypertriglyceridemia or for primary or
secondary prevention of CHD (Class IIb; LOE B).

43. Major Risk Factor Interventions
• Blood pressure management
– Pharmacotherapy when blood pressure is ≥140/90
mm Hg (≥130/80 mm Hg in the setting of chronic
kidney disease and diabetes. (Class I; LOE B).
• Lipid Management
– LDL-C–lowering drug therapy is recommended
(along with lifestyle) in women with CHD, other
atherosclerotic CVD, diabetes mellitus or 10-year
absolute risk >20% to achieve an LDL-C <100
mg/dL (Class I; LOE A)
– LDL-C–lowering with lifestyle therapy in all others,
even if LDL > 190 mg/dL. (Class I LOE B).

44. Major Risk Factor Interventions (cont.)
• Lipid Management (cont.)
– In women >60 years of age and with an estimated
CHD risk >10%, statins could be considered if hsCRP
>2 mg/dL after lifestyle modification and no acute
inflammatory process is present (Class IIb; LOE B)
– Niacin or fibrate therapy can be useful when HDL-C
is low (<50 mg/dL) or non–HDL-C is elevated (>130
mg/dL) in high-risk women after LDL-C goal is
reached (Class IIb; LOE B)
• Diabetes Management
– Lifestyle and/or pharmacotherapy to achieve HbA1C
<7 (Class IIa LOE B).

45. Preventive Drug Interventions
• Aspirin
• Aspirin (75–325 mg/d) in women with CHD unless
contraindicated (Class I; LOE A).
• Aspirin (75–325 mg/d) is reasonable in women
with diabetes (Class IIa; LOE B).
• Aspirin (81 mg daily or 100 mg every other day)
can be useful in women ≥65 years of age, if …
benefit for ischemic stroke and MI prevention is
likely to outweigh risk of GI bleeding and
hemorrhagic stroke (Class IIa; LOE B)
• Aspirin (81 mg daily or 100 mg every other day)
may be reasonable for women <65 years of age
for ischemic stroke prevention (Class IIb; LOE B).

46. Class III Interventions (Not Useful/Effective and
May Be Harmful)
• Menopausal therapy
– Hormone therapy … should not be used for the primary
or secondary prevention of CVD (Class III, LOA A).
• Antioxidant Supplements
– Antioxidant vitamin supplements (eg, vitamins A, C, E)
should not be used for the primary or secondary
prevention of CVD (Class III, LOA A).
• Folic Acid
– Folic Acid, with or without B6 and B12, should not be
used for the primary or secondary prevention of CVD
(Class III, LOA A).
• Aspirin for MI prevention in women <65
– Routine use of aspirin in healthy women 65 years of
age is not recommended to prevent MI (Class III, LOA B).

47. WHI E+P Trial Findings, July 2002 (avg 5.2 y)
Risks
Benefits
105% Increase Dementia
Fracture Reduction (Hip 23%)
24% Increase CHD
39% Reduction
31% Increase Colorectal Cancer
Stroke
111% Increase
Pulmonary Emboli
24% Increase
Breast Cancer
STOPPED Early, Clear
Harm
Stopped 3.3 yrs early
Also: DVTs
JAMA. 2002;288:321-333

48. WHI E Alone Trial Findings, 2004 (avg 6.8 y)
Neutral for CHD
Risks Neutral for breast cancer
49% Increase Dementia Benefits
39% Increase Stroke
34% Increase Pulmonary Fracture Reduction (Hip 39%)
Emboli
STOPPED Early,
suggestion of harm
Stopped 1.7 yrs early
Also: DVTs
JAMA 2004;291:2947-58

49. Vitamin E: Secondary Prevention
(GISSI)-Prevenzione Trial
11,324 patients with a recent MI randomized to Vitamin E (300 mg)
% Surviving (free of MI, stroke, death) for 3.5 years
or placebo
100
Primary End Point (%)*
95
90 Vitamin E
Placebo
85
80
75
RR 0.95, P=0.293
70
0 6 12 18 24 30 36 42 48
Months
Months
*Includes freedom from death, nonfatal MI, and stroke
GISSI-Prevenzione Investigators. Lancet 1999;354:447-55

50. Folic Acid and B-Vitamins: Secondary Prevention
NORVIT: 3,749 patients with a
recent myocardial infarction
randomized to 4 treatment arms
for 40 months
• Vitamin B6 (40 mg), Vitamin B12 (0.4
mg), and Folic acid (0.8 mg)†
• Vitamin B12 (0.4 mg) and Folic acid
(0.8 mg)‡
• Vitamin B6 (40 mg)^
• Placebo
†
HR=1.22, P=0.05 compared to placebo
‡
HR=1.08, P=0.31 compared to placebo
^HR=1.14, P=0.09 compared to placebo
Bonna KH et al. NEJM 2006;354:1578-1588

51. Prevention of CHD:
• Reducing atherosclerosis
• Preventing plaque rupture / EROSION
• Limiting thrombosis
• Recognizing Presence of CHD in women

52. Clinical Recognition of CAD : Gender
Differences in Heart Attack Symptoms
Typical in both sexes More common in women
• Pain, pressure, squeezing, or • Milder symptoms
stabbing pain in the chest • Sudden onset of weakness,
• Pain radiating to neck, shoulder, shortness of breath, fatigue,
back, arm, or jaw body aches, or overall feeling of
• Pounding heart illness (without chest pain)
• Difficulty breathing • Unusual feeling or mild
• Heartburn, nausea, vomiting, discomfort in the back, chest,
arm, neck, or jaw (without chest
abdominal pain
pain)
• Cold sweats or clammy skin
• Dizziness
Source: AHA &: WISE data JACC 2006

53. Women’s Early Warning Signs of Heart
Attack
• Weeks before Heart Attack (95% of women)
 Unusual fatigue (70.7%)
 Sleep disturbance (47.8%)
 Shortness of breath (42.1%)
 Indigestion (39.4%)
 Chest pain (29.7 %)
• At time of Heart Attack
 Shortness of breath (57.9%)
 Weakness (54.8%)
 Fatigue (42.9%)
 Chest pain (57%) McSweeney, JC et al. Circulation 2003; 2619-2623

54. Limited Numbers of Women in Research on
Noninvasive Testing
100
90
80
% of Patients
70
60
Women
50
40 Men
30
20
10
0
ECG ECHO MPI
Shaw LJ, et al. Coronary Artery Disease in Women.1999:327-350.

55. Diagnostic Tests in Women
 Treadmill exercise electrocardiogram is
often inaccurate
~ 33% false positive rate
~ 25% false negative rate
 Addition of nuclear imaging or exercise
echocardiogram increases predictive
accuracy to ~ 90%
SOURCE: Crouse. The Fourth Chicago Women & Heart Disease Conference, 1997.

56. AHA Consensus Statement –
Algorithm for Evaluation of
Symptomatic Women Using Cardiac
Imaging
Intermediate-high likelihood women with atypical or typical chest pain symptoms
Good Ex tolerance Diabetes, abnormal 12-L ECG, or
+ normal 12-L ECG questionable Ex capacity
Risk factor
modification +/-
Ex or pharmacologic stress imaging
anti-ischemic Rx Exercise TM
test
Low Able to Ex Unable to Ex
Int risk
Post-ETT
TM
LK Exercise Pharmacologic
stress stress
Normal or mildly Moderate-severely
abnormal with abnormal or Cardiac
normal LV function depressed EF cath
Source: Mieres Circulation 2005; 111:682–696

58. Ischemia in women may occur from mental
stress more often than physical stress
• 160 men and 24 women with known CHD underwent
exercise stress test and mental stress tests
• Women had more EKG documented ischemia during
mental stress; men more ischemia during physical
stress
Journal of Health Psychology January 2000; 5:75-85
• 170 men and 26 women with known CHD evaluated
during daily activities, exercise, and mental stress
• Women reported chest pain more often during daily
activities (P =0.04) and during laboratory mental
stressors (P =0.01); men reported chest pain more often
during exercise
Sheps et al. Am Heart J. 2001 Nov;142(5):864-71

59. CONCLUSIONS
• CHD is the leading cause of death in women
• Risk Factor Modification cornerstone of CV risk
reduction
• Pathophysiology of Angina and ACS may differ
• Preventive Strategies may differ
• Evidence-based therapies should be utilized and
therapies of no proven benefit should be avoided
• As always…evidence continues to evolve