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 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

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: 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 CV Disease Normal Hypertension Diabetes Diabetes and Hypertension All Causes Normal Hypertension Diabetes Diabetes and Hypertension

Men

1.00

1.45 (1.23-1.72) 2.06 (1.45-2.93) 2.32 (1.83-2.94) 1.00

1.25 (1.12-1.39) 1.87 (1.48-2.36) 1.97 (1.68-2.32)

Women

1.00

1.89

(1.34-2.66) 2.36

(1.29-4.31) 4.57

(3.06-6.82) 1.00

1.10 (0.91-1.33) 1.64 (1.14-2.36) 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.

EFFECTS OF MENOPAUSAL TRANSITION ON CARDIAC RISK FACTORS

LDL Cholesterol Levels After Menopause Menopause

110 100 90 -24 -18 -12 Months -6 0 6

Jensen J, et al. Influence of menopause on serum lipids and lipoproteins.

Maturitas

1990; 12:321-31

HDL Cholesterol Levels After Menopause

110 100

Menopause

90 -24 -18 -12 Months -6 0 6

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 5 th and 6 th 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-

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.

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.