Women and Coronary Artery Disease (CAD)

Module 2 Risk Factors and Gender Differences 1

Supported by an unrestricted educational grant from Fujisawa Healthcare, Inc.

2

Gender Differences in Atherosclerosis

• Women undergoing coronary angiography have more diffuse atherosclerosis measured by IVUS, more total compromised lumen adjusted for BSA throughout the arterial tree compared to men (WISE study) • Women and men have similar magnitude of atherosclerosis, but it looks and functions differently, possibly for estrogen-related reasons. • A consequence of more diffuse atherosclerosis might be more microvascular disease (limited flow reserve) that is not due to obvious obstructive disease* *C. Noel Bairey-Merz. WISE study data ACC 3/2002 3

Gender Differences in Atherosclerosis

• • • 1996 Farb et al: two distinct plaque morphologies in sudden coronary death (SCD) Plaque rupture: thin fibrous cap over a large necrotic core heavily infiltrated by foamy macrophages: 60% of thrombi in SCD Plaque Erosion: thrombus over a base rich in smooth muscle with a proteoglycan-rich matrix (necrotic core is often absent): 40% of thrombi in SCD Farb A, et al.

Circulation.

1996 4

Gender Differences in Atherosclerosis

• • 1999 Arbustini et al: Plaque erosion: major substrate for coronary thrombosis in acute myocardial infarction (MI); 291/298 patients (98% with MI) had coronary thrombi at autopsy Of the 25% of this autopsy cohort with plaque erosion: women = 37% and men = 18% 5 Arbustini E, et al.

Heart.

1999

6

Gender Differences in Atherosclerosis

• 1998 Burke et al: effect of risk factors on the mechanism of acute thrombosis and SCD in women (N = 51 women died from SCD) • Plaque erosion was highly correlated with cigarette smoking and was the most frequent type of coronary thrombosis seen in women <50 years • Plaque rupture: most frequent mode of coronary thrombosis in women >50 years and correlated with elevated serum total cholesterol Burke AP, et al.

Circulation.

1998

Gender Differences in Atherosclerosis

• • Older women who die suddenly of coronary thrombosis or hypercholesterolemia have plaque rupture in contrast to plaque erosion and have severe coronary arterial stenosis and a large burden of calcium plaque Younger women who die suddenly of coronary thrombosis: cigarette smokers, plaque erosion, relatively little coronary arterial narrowing, and less calcium plaque at autopsy 7 Burke AP, et al.

Circulation.

1998

Gender Differences in Atherosclerosis

• Potential explanations – Estrogen reduces cellular hypertrophy and enhances vessel wall elasticity, possibly contributing to less lumen intrusion for the same amount of atherosclerosis – Estrogen reduces smooth muscle cell migration and lower collagen deposition in response to injury, which may lead to thinner fibrous plaque in women – Estrogen and progesterone upregulate degradative collagenases and inflammatory markers (hsCRP) 8

Warning Signs and Symptoms of CAD

9

Gender Differences in Heart Attack Symptoms Typical in both sexes

• Pain, pressure, squeezing, or stabbing pain in the chest • Pain radiating to neck, shoulder, back, arm, or jaw • Pounding heart, change in rhythm • Difficulty breathing • Heartburn, nausea, vomiting, abdominal pain • Cold sweats or clammy skin • Dizziness

Typical in women

• Milder symptoms (without chest pain) • Sudden onset of weakness, shortness of breath, fatigue, body aches, or overall feeling of illness (without chest pain) • Unusual feeling or mild discomfort in the back, chest, arm, neck, or jaw (without chest pain) 10

11

Gender Differences in Emergency Department Presentation for CAD Without Chest Pain 50 40 30 20 10 0

48 35 41 D ysp ne a N au se a/ vo m iti ng 14 33 In di ge st io n 22 26 19 Fa tig ue

Women (n = 90) Men (n =127)

22 11 19 S w ea tin g A rm /sh ou ld er p ai n 8 Milner KA, et al.

Am J Cardiol.

1999

Less Common Heart Attack Symptoms in Women

• Milder symptoms without accompanying chest pain • Sudden onset of weakness, shortness of breath, fatigue, body aches, overall feeling of illness • Burning sensation in the chest, may be mistaken as heartburn • An “unusual” feeling or mild discomfort in the back, chest, arm, neck, or jaw 12

Women and CAD

Which Risk Factors Predispose Women to CAD?

13

Major Risk Factors for Heart Disease Modifiable

High blood pressure Abnormal cholesterol levels Diabetes Cigarette smoking Obesity Physical inactivity

Nonmodifiable Emerging Risk Factors

Family history Age Gender Homocysteine Elevated lipoprotein (a) levels Clotting factors Markers of inflammation (CRP) 14 Grundy SM, et al.

Circulation.

1998; Grundy SM.

Circulation.

Braunwald E.

N Engl J Med.

1997; Grundy SM, et al.

J Am Coll Cardiol.

1999 1999

Emerging Risk Factors

• Lipoprotein (a) • Homocysteine • Prothrombotic factors • Proinflammatory factors • Impaired fasting glucose • Subclinical atherosclerosis – Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) – Abnormal internal or common carotid, ankle-arm index <0.9, coronary Ca 2+ 15

(EBT) Calcium and Low Density Lipoprotein (LDL) Cholesterol r = 0.06, P = 0.49

100 90 80 70 60 50 40 30 20 10 0 0 50 100 150 LDL cholesterol (mg/dL) 200 250 Hecht.

J Am Coll Cardiol.

2001

17

US Adults With High Blood Pressure (1988-1994) 80 70 60 50 40 30 20 10 0

8.1

10.6

1.6

6.2

25-34 White males Black males White females Black females

14.3

29.5

8.5

35-44 22.9

29.1

58.0

63.0

54.9

65.2

61.7

44.3

48.8

43.0

41.4

22.0

45-54 Ages 55-64 65-74 75.6

59.0

71.3

76.1

77.9

75+

American Heart Association.

2002 Heart and Stroke Statistical Update.

2001

18

Predicted Cardiac Survival by Peak Systolic Blood Pressure

0.98

1 0.96

0.94

0.92

0.9

0.88

0.86

50

P

< .001

Men Women 100 150 200 250 Peak systolic blood pressure (mm Hg) 300 Shaw LJ. AHA abstract. 2000

19

US Adults With LDL Cholesterol of 130 mg/dL or Higher (1988-1994) 50 40 30 20 10 0

48.6

43.3

49.6

43.7

Men Women

46.3

41.6

43.6

41.6

Total population Non-Hispanic whites Non-Hispanic blacks Mexican Americans

American Heart Association.

2002 Heart and Stroke Statistical Update.

2001

Diabetes and CAD in Women

20

21

Diabetes Creates Higher Risks for Women With CAD

• 65% of diabetics die from heart disease or stroke • 4.2 million American women have diabetes – Diabetes increases CAD risk 3-fold to 7-fold in women vs 2 fold to 3-fold in men – Diabetes doubles the risk of second heart attack in women but not in men • Every year, heart disease kills 50,000 more American women than men • Statistics are particularly high among African American women American Heart Association Centers for Disease Control and Prevention Manson JE, et al.

Prevention of Myocardial Infarction.

1996

Lowest Survival Rates for Diabetic Women

• CAD mortality rates in diabetics, especially women, have not decreased to the same extent as those in the general population • In a large cohort referred for coronary disease, diabetic women had the highest mortality rates – Estimate of ischemic burden with stress myocardial perfusion imaging significantly improved risk stratification in diabetic women compared with clinical risk alone – Stratification by the number of ischemic vessels demonstrated a significant linear increase in cardiac events with escalating ischemic burden (sex-diabetes interaction,

P

= .016) Gu K, et al.

JAMA.

1999 Giri S, et al.

Circulation.

2002 22

Lowest Survival Rates for Diabetic Women

Diabetic men Nondiabetic men Diabetic women Nondiabetic women 0-vessel ischemia 93.8

99.0

99.0

98.8

Death 1-vessel ischemia 93.0

96.5

80.0* 97.5

 2-vessel ischemia 91.3

95.0

81.3* 97.0

0-vessel ischemia 86.3

93.8

96.5

95.5

Death/MI 1-vessel ischemia 77.0

88.0

72.5* 85.0

 2-vessel ischemia 79.0

85.0

60.0* 77.5

*

P

< .05. Extent of ischemia was determined by the number of vascular territories (0, 1, or 2 vessels) involved in the reversible perfusion defect.

23 Giri S, et al.

Circulation.

2002

24

Diabetes: Powerful Risk Factor for CAD in Women

• Framingham Heart Study – Women with diabetes mellitus had relative risk of 5.4% for CAD vs women without diabetes – Men with diabetes had relative risk of 2.4% • Nurses’ Health Study – Relative risk of 6.3% for total cardiovascular (CV) mortality – Even if women had diabetes for <4 years, their risk of CAD was significantly elevated Kannel W.

Am Heart J.

1987 Manson J, et al.

Arch Intern Med.

1991

25

Diabetes Mellitus in US: Higher Mortality Risk in Women

Age group

45-64 65-74 Men

3.4

2.0

Relative Risk

Women

4.6

3.1

75+

1.6

2.0

In Adult Treatment Panel III, diabetes is regarded as a CAD risk equivalent; lowers LDL goal <100 mg/dL) Geiss LS, et al.

Diabetes in America

(2nd ed). 1995

Diabetes: High Blood Sugar

• Diabetes is a abnormally high level of blood sugar (or glucose) indicating the body’s inability to process glucose • ~ 6 million women in the US have physician diagnosed diabetes – ~ 3 million are undiagnosed • Risk of death from heart disease is 3 times higher in women with diabetes • Diabetes doubles the risk of a second heart attack in women but not in men 26

Gender Differences in Risk Factors: Diabetes Mellitus

• Far more powerful coronary risk factor for women than men, negating much of the protective effects of the female sex • Nurses Health Study: maturity onset diabetes  7-fold increase in risk of a CV event 3- to • The coronary prognosis is substantially worse for diabetic women than diabetic men: diabetic women with MI have doubled the risk of reinfarction and 4-fold likelihood of developing heart failure • Coronary revascularization: women diabetics > male diabetics (may be a factor in the less favorable outcome of women) 27

Diabetes: A Major Risk Factor for Heart Disease

28 • Majority of people with type 2 (adult-onset) diabetes have additional risk factors for heart disease • 2 out of 3 people with diabetes die of some type of cardiovascular disease (CVD) • Aggressive therapy for diabetes and high blood pressure is usually needed and can reduce your risk of heart disease and its associated complications Robertson C,

RN.

2001; Grundy SM et al.

Circulation.

1998; American Heart Association.

2001 Heart and Stroke Statistical Update.

2000; Bakris GL, et al,

Am J Kid Dis

. 2000

Gender Differences in Risk Factors: Elevated Cholesterol

• Secondary prevention – 4S trial (Scandinavian Simvastatin Survival Study) – 4444 men and women with angina or prior MI randomized to placebo or simvastatin – 827 women – Overall mortality benefit with a 35% reduction in major cardiac events • Primary prevention – Observational data: decrease in LDL and increase in high density lipoprotein (HDL) reduced CAD risk – Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS): women experienced a 46% reduction in first major coronary event with an average 25% reduction in LDL cholesterol 29

Clinical Identification of the Metabolic Syndrome

• Abdominal obesity – Men – Women • Triglycerides (TG) • HDL cholesterol – Women – Men • Blood pressure • Fasting glucose >102 cm (>40 in) >88 cm (>35 in) >150 mg/dL <50 mg/dL <40 mg/dL >130/>85 mm Hg >110 mg/dL 30 National Heart, Lung, and Blood Institute

Impact of Triglyceride Levels on Relative Risk of CAD

Framingham Heart Study 2.5

2 1.5

1 0.5

0 Women Men 0.55

0.65

1 0.8

50 100 1.4

0.75

150 1.45

1 200 1.8

1.2

250 1.85

1.3

300 2.2

1.25

350 2.15

1.25

400 31 Castelli WP.

Can J Cardiol.

1988

32

Women and CAD Risk Factors

• Higher prevalence of avoidable risk factors 1 – ↑ blood cholesterol – ↑ physical inactivity – ↑ overweight (body mass index, 25.0-29.9) • Diabetes is a more powerful risk factor for CAD 2 – 3- to 7-fold in women vs 2- to 3-fold in men • ↓ HDL cholesterol levels more predictive of CAD 2 • Women counseled less about nutrition, exercise, and weight control 2 1. American Heart Association.

1999 Heart and Stroke Statistical Update.

1998 2. Mosca L, et al.

Circulation.

1999

Comparison of NCEP ATP-III Scores by EBT Calcium Scores

33 Low risk High risk 53.5% 46.5% 62.3% 37.7% EBT+ NCEP risk score EBT Hecht HS.

J Am Coll Cardiol.

2001

MI or Death Often First Sign of CAD

Percentage of patients whose first CAD diagnosis is MI or death 62% 46% 34 Men Women Levy D, et al.

Textbook of Cardiovascular Medicine.

1998

35

Impact of Cholesterol Levels on Risk of Death

Multiple Risk Factor Intervention Trial 35 30 25 20 15 10 5 0 <182 182-202 203-220 221-244 Total cholesterol (mg/dL) 245+ Neaton JD, et al.

Arch Intern Med.

1992

36

Simvastatin Survival Study Significant Event* Reduction in Men and Women 0 -10 -20 -30

P

= .01

P

< .00001

Women -40 -35%

Women n = 827

-34%

Men n = 3,617

Men -50

*Includes coronary heart disease (CHD) death; definite or probable nonfatal MI; or resuscitated cardiac arrest. Simvastatin reduced the risk of heart attacks* as effectively for women as for men. Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. The Scandinavian Simvastatin Survival Study.

Lancet

. 1994

Lovastatin Reduced the Risk of First Acute Major Coronary Events in the AFCAPS Trial

0 -10 -20 -30 -40 -50 -60 Men n = 5608

-37%

Women n = 997 Older n = 3180 Smokers n = 818 Hypertension n = 1448 Diabetes n = 155

-46% -31% -38% -58% -42%

37

Smoking

• Single most preventable cause of death in US • Smoking by women causes 150% more deaths from heart disease than lung cancer • Women who smoke are 2-6 times more likely to suffer a heart attack • Use of birth control pills in smokers compounds cardiac risk 38

39

Overweight

70 60 50 40 30 20 10 0 Prevalence of Overweight in Americans Aged 20-74 Years 49 55 53 61 40 41 42 51 Men 1960-1962 1971-1974 1976-1980 Women 1988-1994 American Heart Association.

2002 Heart and Stroke Statistical Update.

2001

40

Overweight and Obesity in US Adults

56.3

Overweight Obese 52 60 50 40 30 20 10 0 18.7

25.6

Men Women Overweight defined as >25 BMI; obese defined as >30 BMI.

American Heart Association.

2002 Heart and Stroke Statistical Update.

2001

41

Moderate or Vigorous Physical Activity in US Adults

Men Women 50 40 30 20 10 0 Non Hispanic white men Non Hispanic black men BMI <25 Mexican American men BMI 25-29 Non Hispanic white women BMI 30+ Non Hispanic black women Mexican American women American Heart Association.

2002 Heart and Stroke Statistical Update.

2001

Physical Inactivity

• Lack of exercise is a proven risk factor for heart disease – A lack of regular physical exercise is a growing epidemic in the US • Heart disease is twice as likely to develop in inactive people than in those who are more active • Physical activity helps maintain weight, blood pressure, and diabetes • Women should exercise to increase heart rate for 20-30 minutes a day, 3-5 times per week 42

43

CAD Risk Factors: Goals

Risk Factor Hypertension (mm Hg) High cholesterol (mg/dL) Diabetes Cigarette smoking Minimal Goal Systolic <140 Diastolic <90 LDL-C 100-129 Serum TC 160-199 HDL-C 45 (men) HDL-C 55 (women) Near-normal fasting glucose (HbA1c <7%) Complete cessation Optimal Goal Systolic <120 Diastolic <80

Primary:

LDL-C 100

Secondary:

TG <200 HDL-C >35, Same Same Grundy SM, et al.

Circulation.

1999. American Heart Association Consensus Panel.

Circulation.

1995; The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the National High Blood Pressure Education Program Coordinating Committee.

Arch Intern Med.

1997

44

Major Risk Factors

• • • • • • • Diabetes mellitus – CHD risk equivalent Cigarette smoking Hypertension (blood pressure >140/90 mm Hg or on anti-hypertensive medications) Low HDL cholesterol (<40 mg/dL) Family history premature CHD (in male first relative <55 years; in female first relative <65 years) Age (men >45 years; women >55 years) High LDL cholesterol (>160 mg/dL)

Risk Categories

CHD or risk equivalent (DM, ASHD) 2+ risk factors 0-1 risk factor

LDL Goal

<100 <130 <160 • CHD risk equivalent = 20% - city of Nashville households w/ female adults (n = 500,000) Shaw LJ.

Am J Managed Care.

2001 National Heart, Lung, and Blood Institute

Menopause, Estrogen, and Hormone Replacement Therapy (HRT)

45

46

Hormonal Effects on Ischemia and Disease Prevalence

• Premenopause – Estrogen has digoxin-like effect:  ST  • Post-menopause effect on HRT –  ST  - vasodilatory effects of HRT – Increase exercise duration/decrease chest pain • Women with intact uterus take progestin to protect against uterine malignancies – Estrogen and medroxyprogesterone attenuate this effect Lloyd GW, et al.

Heart.

2000; Webb CM, et al.

Lancet

. 1998; Morise AP, et al.

Am J Cardiol.

1993; Rosano GM, et al.

J Am Coll Cardiol.

2000

Hormonal Effects on Ischemia and Disease Prevalence

• Estrogen modulates chest pain syndromes • Premenopausal CAD: angina/ischemia variation by menstrual cycle –

Early follicular phase

estradiol and progesterone levels - low < time to ischemia onset –

Mid-cycle

estrogen levels - highest > time to ischemia onset 47 Lloyd GW, et al.

Heart.

2000; Webb CM, et al.

Lancet

. 1998; Morise AP, et al.

Am J Cardiol.

1993; Rosano GM, et al.

J Am Coll Cardiol.

2000

Postmenopausal Hormone Therapy and Cardioprotection

• First randomized trial • HERS trial (Heart and Estrogen/Progestin Replacement Study) – Secondary CAD prevention trial – Randomized trial of placebo vs estrogen and medroxyprogesterone – Follow-up = 4 years – N = 2,763 women with an intact uterus – Outcome measures • Primary: nonfatal MI or cardiac death • Secondary: unstable angina, coronary revascularization, congestive heart failure 48 HERS trial.

JAMA.

1998.

Is There a Role for HRT?

• Secondary prevention – 1998: HERS • 4 years of treatment with conjugated estrogen plus medroxyprogesterone acetate • No reduction in the risk of MI and coronary death in women with established CAD 49 HERS trial.

JAMA.

1998.

Is There a Role for HRT?

• Secondary prevention – 3/2000: Estrogen Replacement and Atherosclerosis trial (ERA) • 309 postmenopausal women with CAD • Placebo vs conjugated estrogen (.625 mg/day) vs conjugated estrogen (.625 mg/day) with medroxyprogesterone acetate (2.5 mg/day) • Angiographic analysis of the diameter of the coronary arteries at the start of the study and 3 years later • ERA trial results at follow-up angiography – The progression of coronary atherosclerosis was unchanged in the women randomized to either of the estrogen groups 50 ERA trial.

J Am Coll Cardiol.

2001

Is There A Role for HRT?

• Primary prevention – Women’s Health Initiative • 160,000 women:1991-2005 • Initial results: no cardioprotection attributed to HRT in women on HRT • American Heart Association: HRT not recommended for primary or secondary cardioprotection 51

Conclusions

Risk Factor Management 52

53

Conclusions: Risk Factor Management

• CVD begins in childhood and is strongly associated with major risk factors for heart disease • Multiple risk factors require more aggressive management • Aggressive risk-factor modification (often with multiple medications) is the most effective strategy for reducing the consequences of heart disease Berenson GS, et al.

N Engl J Med.

1998. Neaton JD, et al.

Arch Intern Med.

1992. Kannel WB. in

Atherosclerosis and Coronary Artery Disease.

1996. Grundy SM, et al.

Circulation.

1999

Gender Differences in CAD Risk Factors

• Increasing recognition that athersosclerosis is an inflammatory process • Ridker PM, et al: A prospective case controlled study among 28,263 postmenopausal women – Among 12 markers of inflammation, C reactive protein was the strongest univariate predictor of the risk of CV events 54 Ridker PM, et al.

N Engl J Med.

2000

Diagnosis and Management of CAD in Women

• Gender differences: presentation, manifestation, and diagnosis of CAD • Gender differences in mortality – 63% of women who die suddenly from CAD had no prior warning symptoms – 42% of women vs 24% of men will die within 1 year after MI • Thus, early recognition of symptoms and accurate diagnosis of CAD is of great importance 55

Heart Disease in Women: Lessons From the Past Decade

• The importance of studying gender-specific aspects of CAD have helped in the following clinical dilemmas: – Presentation of CAD: women are older than men – Less specific clinical manifestations of CAD in women – Greater difficulty in diagnosis: women > men – More severe consequences on MI when it occurs in women 56