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The Three Paradoxes
• 1. Women have a higher prevalence of angina compared to men, yet have an overall lower prevalence of atherosclerosis and obstructive coronary artery disease
• 2. Symptomatic women undergoing coronary angiography have less extensive and severe CAD, despite being older with a greater risk factor burden, compared to men
• 3. Despite relatively less CAD, women have a more adverse prognosis compared to men
Bairey Merz, C. N. Women and Ischemic Heart Disease. JACC: Cardiovascular
Imaging Vol 4, No 1, 2011.
Presentation: 45 year-old woman in the Emergency Department
• Exhaustion• Throat and jaw discomfort• Palpitations• Shortness of Breath
Canto et al. Association of Age and Sex with Myocardial Symptom Presentation; Gender
Differences in Symptoms of Myocardial Ischemia
E.J.
• 59 year old woman with history of dyslipidemia was playing poker in Las Vegas when she felt a “clinching” substernal discomfort for about 10 minutes. The discomfort radiated to her teeth. 2 days later while sleeping, she felt cold/clammy for 3 hours, which resolved with rest. She felt a loss of appetite and energy.
• There was no resolution with Pepto-Bismol or acid reducer
E.J.’s story
• Family History: Brother with DM2, Father died suddenly of abdominal aortic aneurysm at 82, Mother has hypertension, diabetes, hyperlipidemia
• PE: 5’7” 137#, waist circ. 34• 98/56, pulse 62. Normal cardiopulmonary
exam
E.J.’s trip to the hospital
• Total cholesterol 223; Triglycerides 243; HDL 34; LDL 124
• EKG with ST elevation• Troponin I: peak of 9.3 (normal <0.5)• Cath with LAD lesion of 20-30% stenosis• Echo normal• Cardiac CT normal• Thrombolysis was given
Gender and MI Triggers
• Women reported emotional stress prior to MI– Marital stress was reported to be more
problematic in women– Work stress was more problematic for men
• Men reported heavy physical activity prior to MI
Sex and Gender Aspects in Clinical Medicine p. 18
Ischemia symptoms in women: “atypical”
• fatigue• right or left arm and
shoulder pain• indigestion• epigastric pain• neck pain• syncope• nausea• abdominal pain
• dyspnea• dizziness• palpitations• interscapular pain• weakness• vomiting• throat and jaw pain
• asymptomatic
Differences in Symptoms: Hypotheses of origin
• Parasympathetic nerves innervate the posterior and inferior surfaces of the heart
• Women and men are more likely to have right dominant coronary systems
• Women have a predominance of parasympathetic influence on heart rate regulation
• Theory: ischemia of those areas stimulates the vagus nerve– causes discomfort in locations also innervated by the
vagus nerveEvans, J. Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes. J Applied Phys
Dec. 1, 2001. Vol 91, No.6, 2611-2618.
Atherosclerosis Risk Factors with Greater Detriment in Women
• Smoking• Depression• Metabolic syndrome• Diabetes• Hypertension
Yusuf, S. Effectt of potentially modifiable risk factors associated with myocardial
infarctionin 52 countries. Lancet 2004; 364: 937-52.
Relative Risk (95% CI) for mortality in subjects with hypertension, diabetes, or both adjusted for age,
center, BMI, smoking and cholesterol.DECODE study
Men Women
CV Disease
Normal 1.00 1.00
Hypertension 1.45 (1.23-1.72) 1.89 (1.34-2.66)
Diabetes 2.06 (1.45-2.93) 2.36 (1.29-4.31)
Diabetes and Hypertension 2.32 (1.83-2.94) 4.57 (3.06-6.82)
All Causes
Normal 1.00 1.00
Hypertension 1.25 (1.12-1.39) 1.10 (0.91-1.33)
Diabetes 1.87 (1.48-2.36) 1.64 (1.14-2.36)
Diabetes and Hypertension 1.97 (1.68-2.32) 2.22 (1.74-2.83)
Endothelial function and diabetes
• Estrogen usually helps improve endothelial function
• Diabetes negates the protective sex differences in endothelial function and nitric oxide effect
Steinberg. Type II diabetes abrogates sex differences in endothelial function in
premenopausal women. Circ 101. 2040-2046 (2000).
Atherosclerosis Risk Factors Unique to Women
• Climacteric symptoms- peri and early post menopausal symptoms are not associated with cardiovascular disease
• Persistent or late-onset hot flashes are associated with heart disease
• Hypertensive events during pregnancy• Hyperglycemic events during pregnancy• Acceleration of the prevalence of heart
disease after menopause
Other Risk Factors Under investigation
• Systemic autoimmune disease greatly increases risk of cardiovascular disease
• Higher prevalence of autoimmune disease in women
Frostegard, J. Autoimmunity, oxidized LDL and cardiovascular disease. Autoimmunity Reviews Vol1, Issue 4, August 1, 2002. pp
233-237.
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LDL Cholesterol Levels After Menopause
Menopause
Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31
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HDL Cholesterol Levels After Menopause
Menopause
Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31
Estrogen’s effects on vessels
• Estrogen effects– Improve response to nitric oxide– Allow for endothelial compliance– Increase coagulation factors
• Estrogen withdrawal decreases vascular repair
Endothelial Cell Layers in Healthy Postmenopausal and Premenopausal Women
• Postmenopausal cells show evidence of endothelial cell death, denudation, and RBC, platelet, and protein attachment, as well as fractured basal membranes, and loss of intercellular junctions
• Premenopausal cells show tight connections, a continuous layer of endothelial cells, and thick plasma membranes
Differences in Coronary Vascular Plaque Pathology
Female• Continuous endothelial
plaque deposition• Outward remodeling• Present in small distal
arteries• More endothelial
dysfunction
Male• Localized endothelial
plaque deposition• Invades lumen diameter• Present in medium-sized
arteries
Burke. Effect of risk factors on the mechanism of acute thrombosis and
sudden death in women. circ. 1998;97: 2110-2116.
Differences in Ischemia Testing for non-obstructive disease
Less effective• Treadmill• Percutaneous Coronary
Angiography• CT angiogram
More effective• Nuclear stress echo• Cardiac Magnetic
Resonance Imaging
Angiography Differences
• Of women with chest pain or an abnormal stress test, only 40% had flow-limiting stenosis on angiography
• Women are more likely to have single vessel disease
• Sex differences in vascular obstructions on angiography disappear with advancing age
Prigione p23.
The triad of microvascular dysfunction
• Angina• Abnormal stress testing• No obstruction on angiography
Samim, A. Treatment of Angina and Microvascular Coronary Dysfunction.
Current Treatment Options in Cardiovascular Medicine. (2010) 12:355-
364.
Coronary Differences
• Anatomical differences: Women have smaller coronary arteries
• Women may experience endothelial dysfunction more commonly– Abnormal stress test
New insights into ischemi heart disease in women.
ccjm.org/content/74/8/585.full.pdf
Impact of age on innervation in women
• Cardiac innervation undergoes a sympathetic surge between the 5th and 6th decades of life in women
Sakata. Physiological Changes in Human Cardiac Sympathtic Innervation and Activity
Assessed by 123I-Metaiodobenzylguanidine (MIBG) Imaging.
Circulation Journal Vol. 73. Feb. 2009.
Sex Differences in Plaque Disturbance
Women• Superficial plaque erosion
with thrombus formation
Men• Plaque rupture
Arbustini; Prigione p 23.
Biomarkers in Acute Coronary Syndrome
Women• CRP• BNP
Men• Troponin• Creatine kinase
Bairey Merz- Proceedings 2010; Wiviott. Differential expression of cardiac
biomarkers by gender in patients with unstable angina/non-ST elevation
myocardial infarction. Circ. 2004;109:580-586.
Thrombolysis
• Fibrinolyic therapy in (TIMI)-II– Higher rates of death and reinfarction in women at
6 weeks and one year• Fibrinolytic therapy in (ExTRACT-TIMI)-25
– Higher incidence of death after reperfusion in women
Comparisons of revascularization procedures
• Equally effective when performed in similar time frames– Percutaneous coronary intervention– Coronary Artery Bypass Grafting
• Women tend to bleed more often with antiplatelet therapy
• Women have greater mortality after CABG
Prigione p 20.; Mortensen, OS. Gender differences in health-related quality of life following ST-elevation myocardial infarction: women and men do not benefit from primary percutaneous coronary intervention to the same degree. Eur J Cardiovasc Prev
Rehab. 2007 Feb;14(1):37-43.
Differences in Ischemia Mortality
• Women without chest pain have higher in-hospital mortality– Especially under 65 years of age in the 30 days
after hospitalization• Higher rates of in-hospital mortality, death, or
myocardial (re)infarction• More frequent hospitalizations with
nonobstructive disease
Bridging the Gender Gap; Canto; Prigione p 20.
• Figure- Sex differences in acute myocardial infarction outcomes. Vaccarino. N Engl J Med 1999; 341:217-225.
Sex-Specific Recommendations by ACC/AHA practice guidelines
• Women with high-risk features, recommendations for invasive strategy are similar to men
• Women with low-risk features, initial non-invasive strategy is recommended
AHA practice guidelines
Sex Differences in Risk Factor Impact After Infarction
• Diabetic women are 3x more likely to die after a cardiac event than diabetic men
• Women who smoke experience more complications in the 6 months following an MI– Repeat myocardial infarction– Heart-related hospitalization– Revascularization procedure
Howe,M. Role of Cigarette Smoking and Gender in Acute Coronary Syndrome
Events. Am J Cardiol 2011;108:1382-1386.
Differences in evidence for secondary prevention therapy
• Statin- equally effective• Aspirin- equally effective• Nitrates- equally effective• ACE inhibitors- equally effective• Beta blockers- equally effective• Aldosterone inhibitors- equally effective
• GPIIb/IIIIa inhibitor- may be less effective in women Inhibition of platelet glycoprotein IIb/IIIa
with eptifibatide in patients with acute coronary syndromes. PURSUIT trial.
Treatment for Microvascular Coronary Dysfunction
• Statins, angiotensin-converting enzyme inhibitors, and aspirin
• B-blockers, calcium channel blockers, nitrates
Samim. Treatment of Angina and Microvascular Coronary Dysfunction.
Emotional Impact of MI on the Sexes
• Women are less likely to involve spouses in the recovery process
• Women suffer from depression and anxiety after MI than men
• Receiving health information from practitioners resulted in less depression
• Sex after MI occurs less often in almost half of men and nearly 60% of women
Prigione p 21. Stewart. Gender differences in health information needs and decisional preferences in patients recovering from an acute ischemic coronary event. Psychosom Med 2004 Jan-Feb;66(1):42-8. People ‘needlessly avoid sex after heart
attacks’ PubMed Health Thu May 10 2012.
• Estrogen therapy after plaque is present conveys no benefit to the endothelium
• Estrogen therapy for secondary prevention of coronary artery disease is discouraged
HERS and ERA trials- Mosca in AHA Scientific Statement. circulation 2001.
CME Questions
1. Anginal symptoms are similar between younger men and women. F- younger women tend to have less chest pain and more atypical symptoms.
2. Catheterization is the best study to evaluate microvascular disease. F- Microvascular disease is best found with cardiac MRI or functional testing.
3. Atherosclerosis treatments are more effective in women. F- they appear to be equally effective.
4. The hormone changes with menopause decrease HDL and increase LDL.