1. Discuss issues related to the prevalence of CVD in women.

2. Discuss testing modalities for CVD in women.

3. Assess and recognize a woman’s risk for CVD.

4. Discuss data supporting long-term consequences of preeclampsia.

5. Identify pregnant women at risk for CVD.

Clinical Challenges in Women’s Heart Health
Pamela Paulsen, MD, Interventional Cardiologist, North Memorial Heart Center, Robbinsdale, MN; Medical Director, North Memorial Women’s Heart Clinic, Plymouth, MN

General considerations: cardiovascular disease (CVD) leading cause of death for women in United States; more women than men have died from CVD annually in last 20 to 25 yr; dramatic reduction in risk for CVD deaths in last 6 to 8 yr likely result of national campaigns increasing awareness of heart disease in women; significant increase in incidence and mortality in age range of 60s; ways in which CVD mortality impacted in women—awareness of providers; atypical presentation; accepted medications used less in women; algorithms for risk stratification and absence in clinical trials (women comprise only ≈19% of participants in clinical trials); risk for CVD increases with age; presentation ≈10 yr later for women than men; prevalence equivalent in men and women at 65 yr of age; prevalence higher in women >75 yr of age

CVD risk factors: young women—20% to 30% have CVD; family history accounts for ≈10% of risk profile; family history more powerful risk factor in women than men; polycystic ovary syndrome (PCOS); preeclampsia; gestational diabetes; more frequent vasculitis; more aortic root dissection; older women—stress cardiomyopathy (takotsubo syndrome or broken heart syndrome); 99.5% of cases in postmenopausal women; characterized by high adrenalin and catecholamines, electrocardiographic (ECG) changes suggestive of myocardial infarction (MI), and abnormal wall motion with normal coronary angiography; assessment of risk-profile limitations—even patients assessed at low risk have CVD; Framingham global risk score and National Cholesterol Education Program (NCEP) underestimate risk in women (50% of patients presenting with MI had risk <5%-10%); Framingham does not take into account body mass index (BMI), waist circumference, and triglycerides; annual assessment of risk recommended in all women >20 yr of age, with focused attention at perimenopause and menopause; history—symptoms, family history, lipid profile, and blood pressure (BP); physical examination—abdominal obesity, waist circumference (<35 in for women), carotid examination (listen for bruits); atherosclerosis develops over time; evidence of arterial blockage in 70% of people <35 yr of age

Signs and symptoms of CVD in women: atypical presentation; 80% of women presenting with coronary artery disease (CAD) report chest discomfort or heaviness; ask about symptoms of heaviness, pressure, or discomfort, rather than pain (women often have higher pain threshold); shortness of breath (SOB), shoulder pain, fatigue, weakness, nausea, vomiting, diaphoresis, and anxiety; not all symptoms indicative of CVD; suspect CVD if patient reports sudden onset of symptoms with usual activity; heart palpitations and fluttering in perimenopausal period not sign of MI or ischemic heart disease

Angina pectoris: most predominant symptom in women before presenting with CVD; ≈25% of women presenting with classic chest discomfort, ECG changes, and elevation of cardiac enzymes do not have obstructive or severe CAD; ≈1 million women annually present with symptoms warranting evaluation; Women’s Ischemia Syndrome Evaluation (WISE)—showed 50% of women with angina with no significant CAD had abnormal coronary blockage; 50% with endothelial dysfunction; vasodilation in response to stress or exercise slightly reduced in postmenopausal women (estrogen plays role in vasodilation); abnormal vasodilatation often a problem in women with classic angina; imaging studies suggest more diffuse problem than focal problem

Diagnostic testing: stress ECG ≈65% accurate for detecting CAD; stress echocardiography or stress thallium (nuclear scan) ≈80% to 90% accurate; standard noninvasive tests do not reveal blockage until artery 70% to 80% blocked; detection of earlier disease requires invasive testing modality; electron beam computed tomography (CT) detects early formation of CAD; exercise testing in women—functional capacity reduced in women compared to men; heart rate (HR) goes up faster with exercise in women and declines faster after exercise; detection of ischemia missed in approximately one-third of patients if unable to exercise to 5 metabolic equivalents (METS; 5 to 6 min on standard treadmill test); ST depression on ECG common in women, not good predictor of ischemia; ≈50% of women evaluated for chest discomfort, SOB, or shoulder pain have symptoms on treadmill; noninvasive testing misses 1 of 10 significant findings; reevaluate if symptoms persist without explanation; probability of disease lower where testing less sensitive, especially in younger women; more single-vessel disease than multivessel disease in women; process more diffuse and less likely to show up on stress test; many women unable to reach maximum aerobic capacity with treadmill testing; ≈4.4-fold increase in cardiac mortality if woman cannot achieve 5 METS; activity status—Duke Activity Status Index predicts functional capacity using 12 questions about level of activity; even patient with symptoms participating in aggressive athletic activity has lower overall mortality than patient unable to perform any activities; exercise results in WISE trial—only 12% of women achieved good level of exercise (>9 or 10 METS); two-thirds achieved target HR; review exercise component of treadmill test as well as imaging results when assessing risk for death from CVD; functional capacity associated with impaired vascular function

Exercise echocardiography: identifies cardiac structure and function at same time; high sensitivity and specificity; results based on subjective interpretation; avoids ionizing radiation; ejection fraction (EF) may not increase in women as it does in men after exercise; poor images in 10% to 15% of women; rapid decline in HR in women after exercise decreases sensitivity (abnormalities seen only at higher HR); left bundle branch block (LBBB) pattern can look like anterior wall abnormality

Nuclear stress testing: assesses post-exercise EF and myocardial perfusion; easier to combine with pharmacologic test; more sensitive but less specific than stress echocardiography; more likely to identify abnormality; breast attenuation can give false-positive test result; woman with normal scan has <1% chance per year of major cardiac event if symptoms remain unchanged; assesses symptoms only at time of test; 7% chance of dying from CVD in next year with severely abnormal scan; instruct patient that reevaluation needed if symptoms change or new symptoms develop; factors in choosing stress test—local expertise; woman’s ability to exercise; patient’s body size; presence of LBBB; more difficult to detect new abnormality in woman with history of MI or heart failure (perfusion study more appropriate); consider angiography if stress ECG abnormal

MI without coronary disease: WISE trial data showed 20% of women with chest pain did not have blockage, but magnetic resonance spectroscopy (MRS) showed abnormal blood flow; hypothesis for abnormal MRS—greater reliance on anaerobic metabolism in response to exercise; usual strategies often ineffective; chest pain with normal epicardial coronary arteries—patients with >1 coronary risk factor; average age 50 yr; more common in women; persistent chest pain; blockage tends to be more diffuse in women, compared to men (harder to detect with testing)

Pathophysiology of angina and normal coronaries: reduced coronary flow reserve; blood vessels in absence of estrogen do not dilate; role of estrogen in CVD unclear; abnormal autonomic control of coronary artery tone; adrenergic hyperactivity; different perception of pain than men; angiography in women—women twice as likely as men to have nonobstructive coronary disease; detects only blockage of >50% (do not tell patient with normal angiography that they do not have blockage); risk reduction and analysis important tools; outcomes with normal or minimal CAD— approximately one-third had perfusion abnormalities; two-thirds of patients had continued symptoms with medication; ≈10% required hospitalization; outcomes with significant CAD—more unstable angina; more MIs and worse prognosis than men; interventions for women with chest pain and normal coronary angiography—recognition; aggressive risk factor modification; clinical challenge, with no consensus on treatment; imipramine sometimes helpful in lessening pain perception, but does not treat ischemia or atherosclerosis; L-arginine

MI in women: atypical presentation; late arrival at hospital; less likely to be triaged rapidly; less likely to receive aggressive treatment; women <50 yr of age more likely to die from first MI; marital stress, not job stress, major factor in women with CVD; treatment of chest pain in women—treat obstructive CAD same as men; do not tell woman with nonobstructive disease that symptoms not from CVD; aggressive medical therapy recommended to improve endothelial function and BP

Preeclampsia: What Are the Future Risks?
Christopher Robinson, MD, Assistant Professor of Obstetrics and Gynecology, Medical University of South Carolina, Charleston

Preeclampsia and CVD: hypothesis for risk marker—metabolic stress of pregnancy causes underlying potential for vascular disease to manifest as preeclampsia; woman returns to subclinical and normotensive state postpartum; over time, woman with history of preeclampsia may be pushed above clinical threshold for disease manifested as CVD; similarities between preeclampsia and CVD—similar risk markers, clinical picture, and pathology; nonmodifiable risk markers—age, family history; modifiable risk markers—hypertension, diabetes, renal disease, obesity

Pathology: acute atherosis—characteristic lesions in preeclampsia; affects uteroplacental arteries; characterized by endothelial dysfunction; fibroid necrosis of arterial wall; infiltration of perivascular space by mononuclear cells; accumulation of lipid-laden macrophages and lipoprotein(a) [Lp(a)] deposition; resultant plaque can occlude placental vessel; clinical presentation— preeclampsia characterized by metabolic changes in mother; hyperlipidemia, reduced high-density lipoprotein (HDL), elevated triglycerides, elevated free fatty acids, increased insulin resistance, increased coagulation; is pregnancy a stress test?—increased cardiac output and increased volume during pregnancy; women presenting with history of alterations of components of metabolic syndrome may exceed clinical threshold; propensity for CVD and metabolic disease later in life recognized; pregnancy provides opportunity for obstetrician to identify CVD in subclinical stage; vascular risk factors related to gestational hypertension, preeclampsia, gestational diabetes, or thrombosis may be revealed during pregnancy in woman with preeclampsia, then recur later in life

Evidence supporting association: DeWolf describes pathognomonic placental lesion of preeclampsia; Chesley described group of women with previous eclampsia who did not die of CVD; Mann showed 2.8-fold increased risk for MI with history of preeclampsia; complications reported include stillbirth, abruption, normotensive intrauterine growth restriction (IUGR), ischemic heart disease, or stroke (some studies looked at deep venous thromboembolism); death secondary to ischemic heart disease—population-based study of 7500 women in Iceland; 42-yr follow-up; showed 50% increased risk for death secondary to ischemic heart disease in women with hypertension in pregnancy; 90% in women with preeclampsia; women with eclampsia had 2.6-fold increased risk; findings of study looking at measures of CVD—increased risk for hypertension (2.4-fold); increased risk for MI (2.3-fold); increased risk for chronic ischemia; increased risk for angina pectoris, ischemic heart disease, and venous thromboembolism; pregnancy complications and maternal risk of dying from ischemic heart disease—data show 90% risk for woman having baby in bottom 20% of birthweight quintile; risk increased 80% if woman had preterm birth in index pregnancy; 2-fold increased risk if woman had preeclampsia; associations additive if woman had all 3 classifiers in previous pregnancy (7-fold risk); long-term mortality of mothers and fathers after preeclampsia—population-based study from Norwegian Birth Registry; risk increased 10% with history of preeclampsia; 2.7-fold increased risk with history of preeclampsia resulting in preterm birth; 8-fold increased risk with mortality from CVD in preeclampsia and preterm birth; no significant association with CVD in paternal arm of study; cardiovascular and thromboembolic events following hypertensive pregnancy—2.8-fold increased risk for acute MI with gestational hypertension; 2.2-fold increased risk with mild preeclampsia; 3.3-fold increased risk with severe preeclampsia; 2.3-fold increased risk for deep venous thromboembolism in women with severe preeclampsia

Cardiovascular health after maternal-placental syndrome (CHAMPS study): population-based retrospective cohort study of women free from CVD before first documented delivery; maternal placental syndrome (MPS)—preeclampsia, gestational hypertension, placental abruption, and placental infarction; study showed increased length of hospitalization for women with MPS; mean age at index delivery, 28 yr; average age at which CV event occurred, 38 yr; incidence of CVD 500 per million person-years in women who had had MPS, compared with 200 per million in women who had not; risk for maternal premature CVD after MPS in index pregnancy—2-fold increased risk for CVD after controlling for prepregnancy risk factors; 2-fold increased risk for CAD, ≈2-fold increased risk for cerebrovascular disease and 3-fold increased risk for peripheral artery disease; risk for maternal premature CVD according to type of MPS —risk increased 70% with placental abruption or placental infarction; risk increased 80% with gestational hypertension; preeclampsia, 2.1-fold increased risk; 3-fold increased risk with poor fetal growth; 4.4-fold increased risk with MPS and intrauterine fetal death; risk for premature CVD associated with previous MPS in presence of traditional risk factors for CVD—significantly increased in women with prepregnancy hypertension, diabetes, and obesity; no significant risk with dyslipidemia alone, but significantly increased risk with dyslipidemia and MPS; significantly increased risk with 3 to 4 symptoms of metabolic syndrome; increased risk with tobacco use

Conclusion: more severe the index case of preeclampsia, greater the future risk for premature CVD; diagnosis of MPS may identify group of women who should be targeted for reduction of CVD risk factors; no published evidence-based guidelines for long-term management of women with previous MPS; prevention of CVD—early recognition of risk; Framingham risk stratification misses one-third of women at risk; identification of women with history of MPS may identify risk group for intervention; educate women at risk about early lipid screening and lifestyle modification; American Heart Association recommendations for reduction of CVD in women—smoking cessation, heart-healthy diet, physical activity, weight reduction (achieve BMI of 18.5 to 24.9); evidence-based 2007 guidelines for CVD prevention in women—recognize preeclampsia/eclampsia may be early indicator of CVD; pregnancy provides unique opportunity to identify women at risk for CVD; preeclampsia research—magnesium vs labetalol trial (LAMPET); sildenafil (Viagra); vascular endothelial growth factor-121 (VEGF-121) replacement; Digibind (FAB fragment, antidigoxin antibody); vitamins C and E; DEEP02; artificial neural networks for prediction of preeclampsia; proteomic profiling for elucidation of plasma markers of preeclampsia