cad in women

2016

Phoebe A. Ashley, MD, FACC

VCU Pauley Heart Center

CAD in Women:

Is There Really a

Difference?

Disclosures

• None

Mrs. J.. J56 year old woman• Diabetes

• High Blood Pressure

• High Cholesterol

• Depression

Presents with throat tightness at 1:30 pm

“You have a cold, wait here”

In Radiology at 8:00 pm . . .

The Resuscitation Room . . .

The Rest of the Story . . .

• Status-post a successful intervention of

the right coronary artery.

• Moderately reduced ventricular function

with chronic congestive heart failure

Agenda

• The Truths

• Women Are Not Simply Small Men

• Pathophysiology

• Risk Factors

• Clinical Presentation

The Truths

1.

Coronary Artery Disease in

Women: More to Think About

The Risk

• Coronary Artery Disease:

#1 cause of death

in women and men

in America and in most

industrialized nations

• Stroke:

#4 cause of death

of Americans

The Magnitude of the Problem

• CVD is the leading cause of mortality, morbidity for US women– 1 of 4 US women die from CVD

– Annual CVD morality 2x that of all forms of cancer combined

• An estimated 43 million women in the U.S. are affected by heart disease

• 90% of women have one or more risk factors for developing heart disease

• Despite increases in awareness over the past decade, only 54% of women recognize that heart disease is their number 1 killer

Mosca L, Circulation: Cardiovascular Quality Outcomes 2010

Women and Heart Disease

• Coronary heart disease remains understudied, under diagnosed, and undertreated in women

• Equal prevalence of this disease between the sexes by the age of 40; by the age of 60 more women than men are affected

• Since 1984, the annual CVD mortality rate has remained greater for women than for men

• Almost two-thirds (64%) of women who die suddenly of coronary heart disease have no previous symptoms

Mozaffarian, et al Circulation 2015

Gholizadeh, et al Health Care Women Int 2008

Roger Vl, et al. Circulation 2012

Sex Differences

• Regardless of age, more women than men

die in the first year following an MI (26% vs

19%)

• Within 5 years of a first MI more women will

die (47% vs 36%)

• More women suffer from heart failure

following their first MI (46% vs 22%)

• Women have a higher prevalence of DM, HF,

HTN, depression, and renal dysfunctionMozaffarian, et al Circulation 2015

Cardiovascular Disease Mortality

Trends U.S. 1979-2011

Mozaffarian D et al. Circulation. 2015;131:e29-e322

Our Risk

• Risk of death increases progressively in

older women . . .

Especially after the age of 45 !

• Many heart attacks go unrecognized,

particularly in younger women

Risk Factors at Presentation

0% 20% 40% 60% 80% 100%

Diabetes

Dyslipidemia

Smoking

Obesity

HTN

Men

Women

Dreyer, et al Eur Heart J ACC 2015

Co-morbidities on Presentation

0% 10% 20% 30% 40% 50% 60%

CHF

Renal dysfunction

Lung Disease

CVA/TIA

Cancer

Depression

Men

Women

Dreyer, et al, Eur Heart J, ACC 2015

Young Women with Acute

Myocardial Infarction

• Have more risk factors and more serious

disease than men

• Have more stress, poorer functioning, and

more depression than men


The Presentation

• Women more commonly present with

NSTEMI and non-obstructive CAD

• Women are more likely to have an unusual

pathophysiologic mechanism of CAD

– Spontaneous coronary artery dissection

(SCAD)

– Coronary artery spasm

Hochman, et al NEJM 1999, Hochman, et al JACC 1997, Hasdai, et al AJC 2003,

Bellasi, et al Cleve Clin J Med 2007, Merz, et al JACC 1999, Basso, et al Heart

1996, Demaio, et al AJC 1989, Thompson, et al J Inv Cardiol 2005, Selzer, et al

NEJM 1976

After Revascularization . . .

• Longer hospitalizations

• Higher in-hospital mortality

• More bleeding complications

• 30% more readmissions within 30 d

following their index hospitalization

• Women fail to participate in cardiac rehab

due to significant patient-oriented

biopsychosocial barriersDolor, et al Effective Health Care Program: Comparative Effectiveness Review 2012, Anderson, et al

Circulation 2012, Ahmed, et al Circulation 2013, Poon, et al Am Heart J 2012

The Research

• Women were not enrolled in cardiovascular trials until 1993

• Today women comprise only 24% of participants in all heart related research studies

• Gender specific research is needed to optimize the recognition and treatment of women with heart disease

Challenges in Women

• Delays in symptom recognition and delays in treatment

• Misdiagnoses

• Lower use of angiography, revascularization, aspirin, beta blockers,

statins, and ACE inhibitors*

• Less counseling on risk factor control

• Fewer referrals to cardiac rehab and more “drop-outs”

• Lower adherence to proven guidelines (ACC/AHA, JNC VII, NCEP,

etc)

*Associated with 90% reduction in recurrent major adverse cardiac

events

MORTALITY

Women Are Not Simply

Small Men

2.

The Size Difference

• Our hearts and arteries are proportionately

smaller

Plaque Development in Women is

Often Different

Smooth Lumpy

Coronary Artery Disease

WOMEN• Unstable angina/NSTEMI

• Plaque Erosion

• Microvascular Disease*

• Endothelial Dysfunction*

• Fewer Collaterals

• Single vessel Disease

• More:

• Diabetes

• Dyslipidemia

• Metabolic Syndrome

MEN• MI/Sudden Cardiac Death

• Plaque Explosion

• Epicardial Disease

• Collaterals

• Multi-vessel Disease

• More:

• Smokers

• Hypertension

Pregnancy: A Woman’s First Stress

Test

• Detailed pregnancy history is integral component of risk

assessment for women

• Pregnancy complications: pre-eclampsia, gestational

DM, pregnancy-induced HTN, preterm delivery=early

indicators of CV risk

• Pre-eclampsia, gestational HTN CVD risk

– 3-6x subsequent HTN

– 2x ischemic heart disease, CVA

– Residual endothelial dysfunction, association with CAC

Mosca, Circulation 123:1243, 2011, Fraser, Circulation 125:1367, 2012, Wenger, Am J Cardiol 113:406, 2014, Bellamy, BMJ 335:974, 2007

Ahmed, J Am Coll Cardiol 63:1815, 2014

Pregnancy: A Woman’s First Stress

Test

• Cardiovascular, metabolic stress of

pregnancy potential for early prediction

of future CV risk

• Gestational DM 7x risk of Type 2 DM

Mosca, Circulation 123:1243, 2011, Fraser, Circulation 125:1367, 2012, Wenger, Am J Cardiol 113:406, 2014, Bellamy, BMJ 335:974, 2007 Ahmed, J Am Coll Cardiol

63:1815, 2014

As We Age

• Women’s hearts shrink with age

• Men’s hearts typically grow with age with

increasing ventricular mass

• Ventricular volume decreases in both

sexes, but more precipitously in women

• Increased LV mass associated with higher

blood pressure, increased BMI, and lower

HDL levels

Lima, et al Radiology 2015

Pathophysiology

3.

Universal Classification of MI

Thygesen et al. Third Universal Definition of Myocardial Infarction Circ 2012

Underlying Etiologies of MI

Thygesen et al. Third Universal Definition of Myocardial Infarction Circ 2012

Thrombotic Coronary Occlusions

1. Plaque Rupture

Most common

76% of men 55% of women with fatal MI1

Rare in premenopausal women2

2. Plaque Erosion

Common in younger women3

3. Calcific Nodule

Accounts for ~2-7% of thrombosis in STEMI4

7-32% of women with MI have no angiographicallydemonstrable obstructive CAD (>50%)5, 6, 7, 8

1 Falk, et al EurHeart J 2013, 2 Davies Heart 2000, 3 Farb, et al Circulation 1996,

4Virmani, et al Arterioscler Thromb Vasc Biol 2000,5 Hochman, et al JACC 1997,

6Chokshi, et al Clin Cardiol 2010, 7Berger, et al JAMA 2009, 8Gehrie, et al Am Heart J

2009

Ischemic Heart Disease

Different Types of Vulnerable

Plaque

Scientific Figure on ResearchGate. Available from:

https://www.researchgate.net/figure/259447500 accessed 1/29/16

https://www.researchgate.net/figure/259447500

Plaque Erosions

• Absent or denuded endothelium overlying a plaque

• Downstream microembolization focal myocardial necrosis

• More smooth muscle and proteoglycans, no necrotic core, denuded endothelium leading to thrombosis

• Common cause of ACS

• More likely to be fatal in young women in autopsy studies of MI and SCD

Jia H et al, JACC 2013; Farb A et al, Circulation 1996, Guagliumi et al JACC Intv 2014

Cited in Yamashita A, Asada Y -

J. Biomed. Biotechnol. (2010),

with permission from Sato et al

Coronary Microvascular Disease

• NOT just a small vessel disease problem

• Diffuse atherosclerosis

– Non-obstructive plaque in epicardial vessels

– Abnormal coronary vasoreactivity

– Subendocardial and epicardial ischemia

• More common in women

• Prognosis is poor in women and men

• Multimodality imaging is often required for diagnosis and to guide management

Shaw, LJ, ACC 2013

Ms. F

• 39 y/o female waitress with no known CRFs aside

from stress presents with substernal chest pressure

which developed while at work and was associated

with n/v

• Exam: (-)

• ECG: Normal

• Troponin T: 0.03, 0.09, 0.06

• Angiography: “Ulcerated RCA plaque”

• Severe coronary vasospasm

• Complicated PCI with DES placed in the RCA

3 months later . . .

• Recurrent chest pressure and diaphoresis

• ECG: normal

• Coronary angiography

Coronary Angiography

Spontaneous Coronary Artery Dissection

SCAD

• Should be suspected in any young women without typical atherosclerotic risk factors

• Prevalence– 0.2-4% of patient’s undergoing cardiac cath

– 10.8% in women <50 with ACS or AMI

– ~ 80% women

– ~20% peripartum

• Associated with:– Pregnancy and postpartum status

– Oral contraceptive use

– Exercise

– Connective tissue disorders and vasculitides (including fibromusculardysplasia)

• Familial cases

• STEMI 49%, multi-vessel disease 23%

Vanzetto, et al Eur J Cardiothorac Surg 2009, Nishiguchi, et al Eur Heart J Acute Cardiovasc

Care 2015, Alfonso, et al JACC Cardiovasc Interv 2012, Tweet, et al Circulation 2012,

Michelis JACC 2014, Saw, et al JACC Cardiovasc Interv 2013

SCAD Management

• Diagnosis challenging

• Index of suspicion: young women with no risk factors and no plaque

• Tortuous coronary arteries

• Excess complications with intervention

• Dissection: healing without intervention 60%

• Recurrence: 21% in 10 years

• Survival: >atherosclerotic ACS: 93% at 10 years

Tweet, et al, Circulation 2012; Lettieri, AJC 2015

Coronary Spasm

• May contribute to MI

with or without

atherosclerosis

• Thrombosis likely

plays a role

• With or without

antecedant

vasospastic angina

• Difficult to prove

Coronary Artery Spasm

Medical Treatment Varies

Dependent Upon the ACS Type

ACS

• Plaque Rupture

• Erosion

• Dissection

• Spasm

TREATMENT

• DAPT + statin

• DAPT + statin (?)

• DAPT, no statin

• DAPT + statin + CCB

+ Nitrate

Beta Blocker and ACEI/ARB, dependent upon left

ventricular function

DAPT = Dual antiplatelet therapy CCB= Calcium channel blocker

Risk Factors

4.

Risk Factors

Non-modifiable versus Modifiable

Your #1 Risk Factor:

Family History of Premature Heart Disease

Father with

Heart Disease < age 55

Mother with

Heart Disease < age 65

Need comparable

photo of a man

Non-modifiable Risk Factors

SEX

Non-modifiable Risk Factors

AGE

What About Menopause?

Estrogen

Weight &

Blood

Pressure

HDL

LDL &

Triglycerides

Risk Factors That Can Be Modified

• Diabetes/Glucose Intolerance

• Tobacco

• High Blood Pressure

• Hyperlipidemia

• Obesity

• Metabolic Syndrome

• Obstructive Sleep Apnea

• Lack of Exercise

• Drug Use

• Dental Disease

• Newer Modifiable Risks

– Hostility/Anger

– Stress

– Anxiety/Depression

What’s the Risk of Heart Disease

for People with Diabetes?

For Men:

2-3 times greater

For Women:

4-6 times greater

Tobacco Use

• > 50% of heart attacks in middle-aged women are attributed to tobacco use– Cigarette smoking triples

the MI risk in women

– 25% increased coronary risk among women smokers than men smokers

• Even minimal use elevates risk

• Leads to early menopause

Huxley, et al Lancet 2011

Mrs. B

46 year old woman

Cardiac Risk Factors:

• None

Symptoms:

• Intermittent chest discomfort

– Mid to left side

– Occurs with exertion and at rest

90% Blocked

with Plaque

Mrs. B’s

Coronary Angiogram

• Status post single vessel coronary artery

bypass grafting

• Subsequently diagnosed with high

cholesterol


Hyperlipidemia:

High Cholesterol

The “GOOD” (HDL)

The “BAD” (LDL)

The “UGLY” (Triglycerides)

High Density Lipoprotein:

HDL = Good Cholesterol

Low HDL is BAD

Low Density Lipoprotein:

LDL = Bad Cholesterol

• Better predictor of coronary

artery disease in men than

in women

• Plateaus in men after age 50,

continues to rise in women until at least

age 65

Triglycerides=Ugly

• Underestimation of the association between TG and

disease in a multivariate analysis

• Individual genetic susceptibility may play an important

role in the relationship between plasma TG levels and

CVD

• 76% increase in CVD risk in women

• 31% increased CVD risk in men

(Associated with 1 mmol/L increase in TG levels)

Austin Can J Cardiol. 1998

Ms. P.

• 40 y/o female with hyperlipidemia,

impaired fasting glucose, and elevated

blood pressure is referred for atypical

chest pain.

• SHx: single mother, working fulltime,

nonsmoker, no alcohol or drug use

• ECG: lateral TW inversions


• 95% left circumflex

lesion

• 40% LAD disease

• Small RCA

Characteristics of Metabolic Risk

• Central Obesity

• Insulin Resistance

• Dysproteinemia

• Hypertension

Metabolic Syndrome and CV Risk

• Even in the absence of CVD and diabetes,

individuals with metabolic syndrome have

a significantly higher risk of CAD and all

cause mortality Hu, et al 2004

Ms. Z

• 48 y/o PMP female with RA

• Meds: Prednisone, MTX, Plaquenil

• ECG: RBBB, cannot rule out IMI

• BNP 54, RA 596

• CXR: lung nodule

• CT: incidental coronary artery calcification

Female:Male Ratios in Autoimmune

Diseases• Hashimoto’s thyroiditis 10:1

• Systemic lupus erythematosus 9:1

• Sjogren’s syndrome 9:1

• Antiphospholipid syndrome-secondary 9:1

• Primary biliary cirrhosis 9:1

• Autoimmune hepatitis 8:1

• Graves’ disease 7:1

• Scleroderma 3:1

• Rheumatoid arthritis 2.5:1

• Antiphospholipid syndrome-primary 2:1

• Autoimmune thrombocytopenic purpura 2:1

• Multiple sclerosis 2:1

• Myasthenia gravis 2:1

What is Ms. Z’s risk for Acute MI?

• The odds ratio for AMI:

• RA 1.48

• SLE 2.67

• RA patients have a 59% increase in CAD mortality

• Other disorders to consider:

• Psoriatic Arthritis

• Ankylosing Spondylitis

• Giant Cell ArteritisAARDA, American Autoimmune and Related Diseases Association

Others: Psoriatic Arthritis Ankylosing Spondylitis Giant Cell Arteritis

https://www.aarda.org/autoimmune-information/autoimmune-disease-in-women/ Accessed Nov 29, 2015

Avina-Zubieta JA, Ann Rheum Dis 2012;71:1524-9 Fischer LM, Am J Cardiol. 2004;93(2):198

Cardiac Involvement in

Inflammatory Joint Disease

Nurmohamed, M. T. et al. (2015) Rheumatol. doi:10.1038/nrrheum. Manzi, S. et al. Am. J. Epidemiol. 145, 408–415 (1997)

Paradoxic Effect of Traditional RFs

in RA

• The higher the BMI, the better the survival

• Active inflammation in RA decline in

levels of TC, LDL-C, and HDL-C

compared to individuals without RA

– Lower lipid levels

– Altered lipid structure and function

– Antiatherogenic effects of HDL-C become

proatherogenic

The Emotional Side of

Heart Disease

5.

Stress and Your Heart

How Does Stress

Contribute to Heart Disease ?

Blood Pressure Increases

Cholesterol Increases

Tendency to Overeat

Exercise Less

Smoke, Drink, Take Drugs

Stress Makes

Other Factors Worse

Can cause persistently

elevated levels of

stress hormones

• Adrenaline

• Cortisol

Effects of

Chronic Stress

Changes the way

blood clots, increasing

risk of heart attack

Psychosocial Stress

• Women have higher levels of psychological risk factors such as – Early life adversity

– Post-traumatic stress disorder

– Depression.

• Women are more prone to develop mental problems as a result of stress

• Socioeconomic and psychosocial factors seem to have a higher impact on CAD in women

• Emotional or psychological stress potentially contributes to heart disease in many ways, from influencing heart disease risk factors, to affecting the development of atherosclerosis (hardening of the arteries), to triggering heart attacks

• Young women are especially vulnerable to the negative effects of stress on the heart, which may result in earlier onset of heart disease or more negative health outcomes if the disease is already present


Vaccarino, et al Psychomed Som 2014

Myocardial Infarction and Mental

Stress Study

• Women 50 years or younger had twice the rate of mental

stress induced myocardial ischemia (52 percent versus

25 percent)

– This gender difference was not seen in men and

women over age 50.

Vaccarino, et al Psychomed Som 2014

Marital Stress vs Work Stress

• Marital stress predicts poor prognosis in women aged 30

to 65 years with CHD

• Marital stress was associated with a 2.9-fold increased

risk of recurrent events after adjustment for age,

estrogen status, education level, smoking, diagnosis at

index event, diabetes mellitus, systolic blood pressure,

smoking, triglyceride level, high-density lipoprotein

cholesterol level, and left ventricular dysfunction

• Among working women (n = 200), work stress did not

significantly predict recurrent coronary events

Orth-Gomér, et al JAMA 2000

Depression

• Depression was shown to be an independent risk factor and consequence of CAD

• Depression may be a component of the increased risk of younger women following both MI and CABG procedures 32,44

• Depressive symptoms predicted CAD presence in women aged ≤ 55 years, but not in men aged ≤ 55 years or women aged >55 years.

• Depressive symptoms also predicted increased risk of death in women aged ≤ 55 years, but not in men aged ≤ 55 years and women aged >55 years

Möller-Leimkühler World J Biol Psychiatry2008

Shah, et al J Am Heart Assoc. 2014

Anxiety

• 2280 patients followed for 32 years

• Those with modest anxiety had a 5 fold increased incidence of sudden cardiac death

• Younger adults with ACS with feminine gender are at increased risk of recurrent ACS over 12 months independent of female sex, thought possibly related to increased anxiety

Kawachi et al, Circulation 1994

Pelletier, et al JACC 2016

Stress Mastery

• Change your environment

• Change how you respond to your

environment

Symptoms of Heart

Disease

6.

Professor D.

61 y/o woman

• Cardiac Risk Factors

– Hypertension

– Newly diagnosed high cholesterol

• Symptoms

– Shortness of breath with exertion

– Increasing fatigue

The Widow Maker

Angina Pectoris

Chest Discomfort Equivalents

• Shortness of breath

• Profound fatigue

• Weakness

• Lightheadedness

• Nausea

• Sweating

• Altered mental sensorium

• Fainting

In the absence of chest discomfort

50% of women do not

have typical symptoms

• Extreme Fatigue

• Shortness of Breath

• Indigestion/Nausea

• Dizziness

• Sleep Disturbance50%

Summary

• Heart disease is the #1 killer of women

• Pregnancy and menopause have significant cardiovascular implications

• Women may experience angina in the absence of significant epicardial coronary disease

• Stress is a significant risk factor in women; young women are especially vulnerable to the negative effects of stress on the heart

Be Sure to Stop and Smell the Roses

Thank You

cad in women

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