American Heart Association Consensus Panel. Circulation. ..

1
Women and Coronary Artery Disease (CAD)

• Module 2 Risk Factors and Gender Differences

2
Supported by an unrestricted educational grant
from Fujisawa Healthcare, Inc.
3
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
4
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
5
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

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 lt50 years
• Plaque rupture most frequent mode of coronary
  thrombosis in women gt50 years and correlated with
  elevated serum total cholesterol

Burke AP, et al. Circulation. 1998
7
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

Burke AP, et al. Circulation. 1998
8
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)

9
Warning Signs and Symptoms of CAD
10
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)

11
Gender Differences in Emergency Department
Presentation for CAD Without Chest Pain
Milner KA, et al. Am J Cardiol. 1999
12
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

13
Women and CAD

• Which Risk Factors Predispose Women to CAD?

14
Major Risk Factorsfor Heart Disease
Grundy SM, et al. Circulation. 1998 Grundy SM.
Circulation. 1999 Braunwald E. N Engl J Med.
1997 Grundy SM, et al. J Am Coll Cardiol. 1999
15
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 lt0.9, coronary Ca2

16
Correlation of Electron-Beam Tomography (EBT)
Calcium and Low Density Lipoprotein (LDL)
Cholesterol
r 0.06, P 0.49
Hecht. J Am Coll Cardiol. 2001
17
US Adults With High Blood Pressure (1988-1994)
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
18
Predicted Cardiac Survival by Peak Systolic
Blood Pressure
Shaw LJ. AHA abstract. 2000
19
US Adults With LDL Cholesterol of 130 mg/dL or
Higher (1988-1994)
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
20
Diabetes and CAD in Women
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
22
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
23
Lowest Survival Rates for Diabetic Women
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 lt4 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
Geiss LS, et al. Diabetes in America (2nd ed).
1995
26
Diabetes High Blood Sugar

• Diabetes is a abnormally high level of blood
  sugar (or glucose) indicating the bodys
  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

27
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 ? 3-
  to 7-fold increase in risk of a CV event
• 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 gt
  male diabetics (may be a factor in the less
  favorable outcome of women)

28
Diabetes A Major Risk Factor for Heart Disease

• 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
29
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

30
Clinical Identification of the Metabolic Syndrome

• Abdominal obesity
• Men gt102 cm (gt40 in)
• Women gt88 cm (gt35 in)
• Triglycerides (TG) gt150 mg/dL
• HDL cholesterol
• Women lt50 mg/dL
• Men lt40 mg/dL
• Blood pressure gt130/gt85 mm Hg
• Fasting glucose gt110 mg/dL

National Heart, Lung, and Blood Institute
31
Impact of Triglyceride Levels on Relative Risk
of CAD
Castelli WP. Can J Cardiol. 1988
32
Women and CAD Risk Factors

• Higher prevalence of avoidable risk factors1
• ? blood cholesterol
• ? physical inactivity
• ? overweight (body mass index, 25.0-29.9)
• Diabetes is a more powerful risk factor for CAD2
• 3- to 7-fold in women vs 2- to 3-fold in men
• ? HDL cholesterol levels more predictive of CAD2
• Women counseled less about nutrition, exercise,
  and weight control2

1. American Heart Association. 1999 Heart and
Stroke Statistical Update. 1998 2. Mosca L, et
al. Circulation. 1999
33
Comparison of NCEP ATP-III Scores by EBT Calcium
Scores
Hecht HS. J Am Coll Cardiol. 2001
34
MI or Death Often First Sign of CAD
Levy D, et al. Textbook of Cardiovascular
Medicine. 1998
35
Impact of Cholesterol Levels on Risk of Death
Neaton JD, et al. Arch Intern Med. 1992
36
Simvastatin Survival StudySignificant Event
Reduction in Men and Women
0
-10
-20
Percent risk reduction
P lt .00001
P .01
-30
Women
-34 Men n 3,617
-35 Women n 827
Men
-40
-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
37
Lovastatin Reduced the Risk of First Acute Major
Coronary Events in the AFCAPS Trial
38
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

39
Overweight
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
40
Overweight and Obesity in US Adults
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
41
Moderate or Vigorous Physical Activity in US
Adults
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
42
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

43
CAD Risk Factors Goals
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 gt140/90 mm Hg or on
  anti-hypertensive medications)
• Low HDL cholesterol (lt40 mg/dL)
• Family history premature CHD (in male first
  relative lt55 years in female first relative lt65
  years)
• Age (men gt45 years women gt55 years)
• High LDL cholesterol (gt160 mg/dL)
• Risk Categories LDL Goal
• CHD or risk equivalent (DM, ASHD) lt100
• 2 risk factors lt130
• 0-1 risk factor lt160
• 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
45
Menopause, Estrogen, and Hormone Replacement
Therapy (HRT)
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
47
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 lt time to ischemia
  onset
• Mid-cycle estrogen levels - highest gt time to
  ischemia onset

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
48
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

HERS trial. JAMA. 1998.
49
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

HERS trial. JAMA. 1998.
50
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

ERA trial. J Am Coll Cardiol. 2001
51
Is There A Role for HRT?

• Primary prevention
• Womens Health Initiative
• 160,000 women1991-2005
• Initial results no cardioprotection attributed
  to HRT in women on HRT
• American Heart Association HRT not recommended
  for primary or secondary cardioprotection

52
Conclusions

• Risk Factor Management

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
54
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

Ridker PM, et al. N Engl J Med. 2000
55
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

56
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 gt men
• More severe consequences on MI when it occurs in
  women