, Malissa J. Wood2 and Malissa J. Wood3
(1)
Harvard Medical School Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
(2)
Harvard Medical School, Boston, USA
(3)
MGH Heart Center Corrigan Women’s Heart Health Program, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Abstract
Worldwide, 8.6 million women will die from cardiovascular (CV) disease each year [1]. Similarly in the US, CV disease is the number one killer of women [2]. In 2007, the Centers for Disease Control reported 1.2 million deaths among US women, 370,000 (30 %) of which were attributable to CV disease (heart disease and stroke). To compare, 293,000 (24 %) were attributable to all forms of cancer combined [2].
Abbreviations
AAA
Abdominal aortic aneurysm
ACC
American College of Cardiology
ACE
Angiotensin Converting Enzyme
Afib
Atrial fibrillation
AHA
American Heart Association
AR
Aortic regurgitation
ARB
Angiotensin Receptor Blocker
AS
Aortic stenosis
ASD
Artial septal defect
AVNRT
Atrioventricular nodal reentrant tachycardia
BMI
Body mass index
CAD
Coronary artery disease
CHF
Congestive heart failure
Cigs
Cigarettes
CV
Cardiovascular
CVA
Cerebral vascular accident
DVT
Deep vein thrombosis
EF
Ejection fraction
ESRD
End stage renal disease
GI
Gastrointestinal
HDL
High density lipoprotein
HELLP
Hemolysis elevated liver enzymes, low platelet count
HITT
Heparin induced thrombocytopenia and thrombosis
HOCM
Hypertropic obstructive cardiomyopathy
HR
Hazard ratio
HTN
Hypertension
IMT
Intima media thickness
IUGR
Intra-uterine growth retardation
LDL
Low density lipoprotein
LV
Left ventricle
LVEF
Left ventricular ejection fraction
MI
Myocardial infarction
Mins
Minutes
MR
Mitral regurgitation
MS
Mitral stenosis
PAC
Premature atrial complex
PAD
Peripheral artery disease
PCI
Percutaneous coronary intervention
PDA
Patent ductus arterosis
PE
Pulmonary embolism
PVC
Premature ventricular complexes
RCT
Randomized controlled trial
RR
Relative risk
SERM
Selective estrogen-receptor modulators
TC
Total cholesterol
VSD
Ventricular septal defect
Wk
Week
Cardiovascular Disease in Women
Worldwide, 8.6 million women will die from cardiovascular (CV) disease each year [1]. Similarly in the US, CV disease is the number one killer of women [2]. In 2007, the Centers for Disease Control reported 1.2 million deaths among US women, 370,000 (30 %) of which were attributable to CV disease (heart disease and stroke). To compare, 293,000 (24 %) were attributable to all forms of cancer combined [2].
Eight million US women are currently living with CV disease and 435,000 will have a heart attack this year [1]. However, while only 24 % of men die within 1 year of their heart attack, 42 % of women do [1]. For women under 50, their first heart attack is twice as likely to be fatal [1]. On average, CV disease presents 10 years later in men than women [3].
Risk Factors for Cardiovascular Disease in Women
Traditional Framingham risk factors (cholesterol, hypertension (HTN), smoking, diabetes and family history) apply differently to women [4]
Elevated Cholesterol
14.6 % of Americans >20 years old have elevated total cholesterol [5]
For men, total cholesterol (TC) and low density lipoprotein (LDL) are the most predictive
For women, the TC/ high density lipoprotein (HDL) ratio is more accurate (ratio should be ≥4) and for women >65 years of age, HDL and triglycerides (TG) appear are more significant [6]
Primary Prevention
Recent meta-analysis of over 18 randomized controlled trials (RCT) with N = 121,235 showed that statins decrease CV events and all-cause mortality in men and women; therefore statin therapy should be used in appropriate patients regardless of gender [7]
Benefit to treating low HDL with statin, even with normal LDL, in postmenopausal women
AFCAPS/TexCAPS Study [8]: In men/postmenopausal women with normal TC and LDL but low HDL, statin decreased incidence of first myocardial infarction (MI) by 46 % in women, 37 % in men
No data to support statin use in premenopausal women without history of coronary artery disease (CAD) or multiple risk factors [4]
Secondary Prevention
Benefit from statins with history of MI and normal cholesterol
CARE Study [9]: men/women with normal cholesterol but history of MI, statin decreased death/MI 46 % in women, 26 % in men
Hypertension
30 % of Americans >20 years old have HTN [5]
Women with HTN have 3.5 times greater risk of CV disease than women with normal blood pressure (BP) [1]
Women are less likely to be aware of HTN, less likely to be treated and less likely to be at goal once on treatment [6]
Women’s Health Initiative: Only 36 % of women with HTN, on meds, achieved goal BP, control is worse with older women [10]
Treatment Options
Thiazides: enhance bone density (decrease urinary excretion of calcium), showed best results as monotherapy in Women’s Health Initiative
Angiotensin Converting Enzyme (ACE) Inhibitors/Angiotensin Receptor Blockers (ARB): some suggest that they may be less effective in women because of low plasma renin activity
Meta-Analysis of diuretics and ACE/ARB show no difference in effectiveness when used as monotherapy [11]
Beta Blockers: less effective BP medication
Smoking
Smoking erases a woman’s estrogen protection [1]
Heavy Smokers (>20 cigs/day) have two to fourfold increased CV risk [12]
Light Smokers (1–4 cigs/day) still have two to threefold increased risk [12]
Women who smoke have first MI 19 years earlier, on average, than nonsmokers [1]
Mechanism [13]
Linear relationship between number of cigarettes smoked and cholesterol
Chronic smokers have higher serum insulin levels but are insulin resistant
Smoking causes wall damage and accelerated plaque formation
Smoking + contraceptive use accelerates thrombogenesis
Smoking Cessation Decreases Risk
Nurses Health’s Study [14]: 30 % decrease in CAD after 2 years of cessation
Continued improvement in CV health for 10–15 years, after which risk is equivalent to nonsmoker
Diabetes
Most powerful predictor of CV risk in women
Eliminates the 10-year “gender gap”
Hyperglycemia decreases estradiol-mediated nitric oxide production, causes endothelial dysfunction and promotes platelet aggregation [15]
Hyperglycemia creates a “hypercoagulable” state by increasing levels of fibrinogen, factor VII and fibrinopeptide A [16]
Over the age 40, more women than men have diabetes
Presentation of Heart Disease in Women
In contrast to men, women do not present with typical angina [6]
Women are more likely to present with atypical symptoms such as [6]:
Shoulder/neck pain
Abdominal pain
Profound fatigue
Dyspnea without pain
2/3 of deaths from MI occur in women with no history of chest pain [1]
71 % of women do experience early warning symptoms of MI but they are atypical and often involve no chest pain
American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for Risk Factor Management in Women [4]
Risk Stratification
High Risk (>20 % chance of CV event in the next 10 years)
≥1 of the following: Known CAD, history of cerebral vascular accident (CVA), peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), end stage renal disease (ESRD), diabetes
Intermediate Risk (10–20 % chance of CV event in the next 10 years)
≥1 of the following: Smoking, HTN, Hyperlipidemia, obesity, poor diet, physical inactivity, poor exercise capacity, family history in first degree relative, coronary calcification, thick intima media thickness (IMT), autoimmune disease, preeclampsia, gestational diabetes, gestational hypertension
Low Risk (<10 % chance of CV event in the next 10 years)
All of the following: TC < 200 mg/dL, BP < 120/80 mmHg, Fasting glucose <100 mg/dL, body mass index (BMI) <25 kg/cm2, nonsmoker, 150 min/week of moderate exercise or 75 min/week of intense exercise, healthy/DASH-like diet
Lifestyle Intervention
Smoking: Encourage cessation
Physical Activity: Minimum 30 min/day on most if not all days
Cardiac Rehab: For all women after acute coronary syndrome (ACS)
Diet: Encourage fruits/vegetables, grains, low/non fat dairy, lean protein; limit saturated fat <10 % of calories, cholesterol <300 mg/day and trans fatty acid intake
In high risk women, limit saturated <7 % of calories, cholesterol <200 mg/day and limit trans fats as much as possible
Omega-3-Fatty Acids: Only as adjunct therapy in high risk women
Weight: BMI 18.5–24.9
Psychosocial: Women with CV disease should be evaluated/treated for depression (Table 12-1)
Table 12-1
Therapeutic interventions
High risk
Intermediate risk
Low risk
Blood pressure
Treat all women with BP > 140/90 mmHg
Goal:
Treat all diabetics with BP > 130/85 mmHg
<120/80 mmHg
Use thiazide diuretic in all, unless contraindicated
Lipids
Statin: Start when LDL > 100 mg/dL
Statin: Start when LDL ≥ 130 mg/dL
0–1 risk factor: Consider statin when LDL ≥ 190 mg/dL
Goal:
Continue (regardless of LDL) unless contraindicated
>1 risk factor: Consider statin when LDL ≥ 160 mg/dL
LDL < 100 mg/dL
HDL >50 mg/dL
TG < 150 mg/dL
Niacin/fibrate: Start when HDL <40 mg/dL
Niacin/fibrate: Start when HDL is <40 mg/dL after LDL is at goal
Consider niacin/fibrate if HDL <40 mg/dL once LDL is at goal
Diabetes
Use all lifestyle and pharmacologic options to maintain HbA1c <7 %
Goal:
HbA1c <7 %
Specific Medications
Aspirin
High Risk: Use 75–162 mg aspirin or clopidogrel, unless contraindicated
Intermediate Risk: Consider 75–162 mg aspirin if blood pressure is controlled and risks of gastrointestinal (GI) bleeding do not outweigh risk
Low Risk: Routine aspirin use not recommended
Beta Blockers
Used in all women, indefinitely, with history of MI or chronic ischemic syndrome
ACE Inhibitors
Used in all high risk women, unless contraindicated
ARB
Used for high risk women with evidence of heart failure or ejection fraction (EF) <40 % who are intolerant of ACE inhibitors
Atrial Fibrillation/Stroke Prevention
Warfarin: All women with chronic/paroxysmal atrial fibrillation (goal INR 2–3), unless they are low risk (CHADS-2 score 0–1, <1 %/year risk) or are at high risk for bleeding
Aspirin: All women with chronic/paroxysmal atrial fibrillation with CHADS-2 score of 0–1 (risk <1 %/year) or women in whom warfarin is contraindicated
Medications that are Contraindicated for Prevention
Hormone therapy and selective estrogen-receptor modulators, selective estrogen-receptor modulators (SERM), (Class III, Level A)
Antioxidants, Vitamins E, C and beta carotene, (Class III, Level A)
Folic Acid, with or without Vitamin B6/B12 (Class III, Level A)
Aspirin for women >65 years old– routine use not recommended to prevent MI (Class III, Level B)
Stress Testing
Exercise ECG’s are less accurate in women than men
Sensitivity/specificity 61 %/70 % (compared to 72 %/77 % in men)
Accuracy improved by adding tests: Duke Treadmill Test, heart rate recovery, maximal exercise capacity
Stress Echocardiography
No effect of gender on test outcome of test
Mean sensitivity in women 81 %, specificity 86 %
May be the most cost-effective way to diagnose CAD in women with “indeterminate” likelihood of disease
Perfusion Imaging
Has special features in women such as smaller hearts and breast tissue
Use of higher count isotope 99mTc and less attenuation minimizes breast attenuation
Useful in women who cannot exercise (i.e. stress echocardiography)
Vasodilator perfusion imaging is more accurate than exercise stress imaging
SPECT imaging provides gradation of risk (rather than dichotomous presence of disease)
CT/MRI
Data is emerging but at present, there does not appear to be a significant difference in diagnostic accuracy between men and women
Benefits
Risks
Improves lipid profile
Breast cancer (RR = 1.35 weeks/>10 years)
Decreases insulin resistance
Endometrial cancer (RR = 8.22 weeks/>8 years)
May improve body fat distribution
DVT/PE (RR = 2)
Inhibits intimal hyperplasia
Gallbladder disease (RR = 2)
Potentiates endothelium –derived-relaxing factor
Increases prostacyclin production
Decreases fibrinogen
Calcium channel blocking effect
Antioxidant effects
Observational Data
Nurses’ Health Study [17]: Significant reduction in MI/death
RCT Data
HERS Study [19]: Estrogen + Progesterone vs. Placebo in high risk post menopausal women – showed no difference in rate of nonfatal MI/death but 52 % increase in CV events during first year of therapy
ERA Study [20]: Neither Estrogen + Progesterone nor Estrogen only showed angiographic benefit on disease
WHI Study [21]: 16,000 postmenopausal women – trial stopped early because of hazard ratio (HR) = 1.24 for coronary heart disease among hazard ratio patients. Study concluded that hormone therapy did not provide protective benefit and may cause harm
WHI (Estrogen Only Arm) [22]: Also stopped early because hormone replace increased risk of CVA and did not decrease risk of heart disease
Conclusion
Based on data from observational/randomized trials, Estrogen + Progesterone or Estrogen only therapy should not be used for primary or secondary prevention
Further research into this area is warranted given the somewhat controversial nature of the current literature
Evaluation of Cardiac Disease in Women
Differences from Men
Women are more likely to have single-vessel disease
Women are more likely to have non-obstructive disease
Decreased accuracy of diagnostic testing in women
Higher rate of false positives
Referral and Treatment Outcomes in Women
Referral for Intervention
Early data from Gusto IIB [23] suggested women were referred less often for percutaneous coronary intervention (PCI)
However, later data suggests that when adjusted for disease burden, there is no difference in the rate of referral between men and women
Hospitalization
Women have more complications (shock, congestive heart failure [CHF], pain, cardiac rupture, stroke)
Mortality is the same, once adjusted for age/baseline risk
Reinfarction rates were also similar
Primary PCI
Referral rates are now the same for women/men
Women/men have similar procedural success rates
PCI improves survival and decreases hemorrhage risk, compared to thrombolytics
Women have higher 30-day mortality and more complications
This is likely due to differences in baseline risk: later presentation, more challenging initial diagnosis, older age, more comorbidities
Thrombolytics
Early Study (Gusto I) [24] – similar artery patency, similar early mortality reduction but women’s 30-day mortality rates are twice that of men
No weight based dosing led to higher cerebral hemorrhage rates in women
Later Study (TIMI II) [25] – similar mortality benefit for women and men with thrombolytics
Heart Failure in Women
Risk Factors in Women
HTN and diabetes are most significant for women, compared to CAD for men
Diabetic women have higher risk of developing post-MI CHF
Gender Specific: Postpartum cardiomyopathy and Takatsubo’s
Differing structural response of heart tissue may predispose to left ventricular (LV) hypertrophy
Gender Specific CardiomyopathiesGet Clinical Tree app for offline access
Postpartum: see section “Cardiovascular Disease in Pregnancy”
Takatsubo Cardiomyopathy: stress cardiomyopathy or apical ballooning syndrome
Clinical Presentation [26–28]
Suggestive of acute MI (chest pain, ST-segment elevation, cardiac biomarker release, and LV dysfunction) and the absence of significant CAD
Associated with regional systolic dysfunction of the mid and apical LV and hyperkinesis of the basal segments.
More prevalent in post menopausal women following a period of extreme emotional or physical stress.
Pathophysiology
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