Y Does X Make A Difference
Myocardial Ischemia
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
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
SEX AND GENDER DIFFERENCES IN
MYOCARDIAL INFARCTION
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 nerve
Evans, 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:
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
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)
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)
CV Disease
All Causes
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-
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
EFFECTS OF MENOPAUSAL
TRANSITION ON CARDIAC RISK
FACTORS
LDL Cholesterol Levels After Menopause
% of level at -6 months before menopause
Menopause
110
100
90
-24
-18
-12
-6
0
6
Months
Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31
HDL Cholesterol Levels After Menopause
% of level at -6 months before menopause
110
100
Menopause
90
-24
-18
-12
-6
0
6
Months
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:
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-
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.
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
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 inhospital 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 noninvasive 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
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•
•
•
•
•
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.
Lifestyle Impact on Women
• Moderate alcohol consumption is more
protective to women
Yusuf. Lancet;
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.