Likely features of female coronary artery disease

Background

While women appear to be at lower risk for coronary artery disease the search for "coronary artery disease in women" in the pubmed database revealed 50 publications in 1980, 500 in 1995 and nearly 1000 in 2013. Many of these publications have shown that the process is delayed by 10 years, rather than avoided. Initiatives such as Women at Heart aimed at increasing awareness that cardiovascular disease is the cause of death in 55% of women compared to 43% of men.
Aspects such as clinical course features, symptoms, main pathogenetic mechanisms, effects of pharmaceutical substances have been proven to a certain extent gender-specific and differences should be taken into account during primary and secondary prevention of coronary artery disease (CAD). Fertile age, menopause, oral contraceptives, hormonal and metabolic disorders during pregnancy, labor and therapeutic abortion as well as physiological differences are specific to women (1,2,3).

1 - Risk factors

During post-menopausal years traditional risk factors in woman tend to become very present and increase a woman's risk for coronary artery disease.
In women, and relative to their male counterparts:

• Arterial hypertension - Arterial hypertension is detected more often at age 65 years and older and increases with age. The most widespread form is isolated systolic which, over the age of 60, increases more rapidly (4).
• Diabetes - Diabetes increases risk of CAD by twofold in comparison to men.
• Obesity - Fat tissue in obesity tends to be pear-shaped rather than concentrating in the abdomen; a marker of CAD in women is the abdominal obesity type. 
• Smoking - According to a study of risk factors for congestive heart failure in men and women, smoking carries a 300% greater risk of CAD, and a risk of chronic heart failure 88% greater (in men it is only 45% greater) compared to a woman who has never smoked. (5)
• Lipids - Blood plasma cholesterol levels and CAD risk in general is lower (6). Conversely, it is well known that high density lipoproteins (HDL) levels are  5-10 mg/dL higher during her fertile years and the Framingham study demonstrated that young women have lower cholesterol levels. At 50-55 years, however, cholesterol levels increase and exceed men’s.
  Blood plasma low density lipoproteins and triglyceride concentrations increase during menopause and at the 65 years mark exceed men's. We also know that high triglycerides levels have a greater impact on CAD development (7). 

Female centered findings: 

• Obesity - Obesity in the Nurses’ Health Study was shown to increase CAD risk two to three-fold compared to woman of normal weight. Correction of other risk factors didn’t decrease cardiovascular mortality (8). 
• Early diagnosis - When the first CAD symptoms occur in young age, women frequently develop myocardial infarction and sudden cardiac death.  
• Diabetes - Diabetes blocks estrogen protection in the preclimacterium period and increases risk of CAD 5.4 times more than in diabetes-free women. Cardiac death risk in women suffering from diabetes is three times greater than in those who do not (9).
• Anamnestic record - Women whose parents have had a myocardial infarction under the age of 60 years have a 5 times greater CAD mortality risk compared to the general population, yet women tend not to know their history regardng CAD.
• Lipids - It is believed that hormonal changes and menopause onset cause reduced HDL levels. Below 1.25 mmol/L HDL, increased sudden cardiac death is shown. HDL levels also significantly correlate with angiography detected coronary atherosclerosis and with the manifestation rate and the number of stenotic arteries. This correlation is preserved in women with cholesterol levels less than 5.2 mmol/L.  

B) Other risk factors
Psychosocial factors, anatomical characteristics and atherosclerosis pathogenetic mechanisms are also important.
Relative to their male counterparts:

• Psychosocial factors - Psychosocial factors have been demonstrated in numerous investigations to have a probable impact of on development of coronary artery disease. Cardiovascular diseases' incidence is inversely related to income level, education and social and economic status. Depression and anxiety levels heighten after a confirmed CAD diagnosis, physical and social activity are lower after cardiovascular events (myocardial infarction, surgery).
• Anatomical characteristics and atherosclerosis pathogenesis - They can determine clinical course features and CAD symptoms. Indeed, angiographic and autopsy results show a smaller left and anterior inferior coronary artery diameter regardless of body surface area. Intravascular ultrasound investigation results proved the presence of these characteristics, explaining susceptibility to vessel occlusion. Myocardial collateral vessels known to be a cause for rapid CAD progression are smaller in number and diameter (10).
• Plaque erosion - Acute coronary syndrome often occurs as a result of erosion of atherosclerotic plaque, and less frequently from the rupture of the fibrous cap as it often is case in men. 
• Death at one year - According to the American Heart Association 38% of women die over the course of the first year after confirmed myocardial infarction whereas 25% of men do. According to the Framingham study, the first symptom of CAD is angina in 56.5% of women whereas early angina concerns 40.7 % of males.
• Mental problems - More neurosis, vegetative and anxiety-depressive disorders, and doctor visit for chest pain are noted. 
• Symptoms - A meta-analysis of international variations across 31 countries has found that women have an "atypical" course of coronary artery disease, i.e without classical pain syndrome typical for angina, nor frequent attacks at night and with a satisfactory condition during the daytime (vasospastic angina) and painless myocardial ischemia.
• Treatment - Women rarely receive rest ECG and stress tests, nor coronary angiography. They are often prescribed tranquilizers (11,12).
• ST-elevation - Unstable angina and acute myocardial infarction in women frequently occur without ST-segment elevation. The high frequency of microvascular changes, endothelial dysfunction and non-stenotic atherosclerosis can explain the rare appearance of ST-segment elevation during acute coronary syndrome.

• Estrogen - Postmenopausal CAD development is an indicator of the protective role of estrogen. Estrogen deficiency is known to contribute to deterioration of arteries’ elastic properties, renin and angiotensin II increases in blood plasma, and decreasing plasma levels of endothelin I, insulin resistance and insulin sensitivity, which generate nitric oxide and its bioavailability. 
• Surgical risk - Surgical risk of CAD in menopause is twice as high as in same age premenopausal women. 
• Endothelial dysfunction - Endothelial dysfuntion in menopausal and postmenopausal women refers to the development of microvascular CAD form which in turn exacerbates the course of atherosclerosis. Estrogens alter the stability of atherosclerotic plaques, affecting the mechanisms of inflammation. 
• Hormone replacement therapy - The results of clinical trials (HERS, WHI and others) have shown that there is no reduction in CAD risk from hormone replacement therapy use (13,14).
• Late diagnosis - Clinical manifestations of coronary heart disease explain the late diagnosis of the disease. 
• Myocardial infarction - 65% of MI is non-ST elevation, 21% is macrofocal and 14% is transmural.
• The prevalence of myocardial infarction is determined by the coronary perfusion characteristics (oxygen "impoverishment" of subendocardial departments) and small coronary arteries affection. Morphological studies indicate lesions of the coronary arteries' intramural branches.
• The high frequency of microvascular changes, endothelial dysfunction and non-stenotic atherosclerosis can explain the rare appearance of ST-segment elevation during acute coronary syndrome 

2 - Testing

Coronary artery disease diagnostics in women are challenging because a typical course will be to show "atypical" pain syndrome and intact coronary arteries (15).
The following investigations apply to diagnostics of CAD: rest ECG, stress tests (treadmill test, bicycle ergometry), pharmacologic tests, Holter ECG, rest and stress echocardiography, radionuclide techniques, coronary angiography, MRI, positron emission tomography, blood biomarkers identification. 
Relative to their male counterparts:

• Exercise stress tests give a false positive result more often in women (20-50% of cases) than in men (8% of cases). 
• Ischemic ST-segment depression occurs in 16-24% of healthy women of all ages but in only 2-14% of men. 

Female centered findings:

• The typical clinical manifestation of angina with a positive exercise stress test indicates CAD with a high degree of probability. 
• A randomised clinical study involving comparison of the results of myocardial perfusion imaging in MRI and treadmill test with symptoms of stable angina showed no additional significance of expensive testing. Horizontal ST-segment depression ≥ 1.5 mm while small capacity physical exercise (500 kgm/min) and long-term persistence during restitution are considered to be the most reliable signs of myocardial ischemia.
• Holter ECG transient myocardial ischemia is diagnosed in the case of ischemic type ST-segment depression of 1 mm or more, with the duration of ST-segment depression of at least 1 min and the time between separate episodes of at least 1 min. 
• "Silent" myocardial ischemia is frequently diagnosed in CAD and can be considered as an unfavorable diagnostic and a prognostic sign.
• Radioisotope stress testing has some limitations due to the perfusion defect in the anterior-septal area caused by the radiation signal attenuation owing to the breast tissue. Simultaneous stress testing and myocardial imaging are recommended to improve the predictive value of the method.

3 - Treatment

The same non-pharmacological, and pharmacological interventions are used in the treatment of both women and men with CAD.
Nevertheless, relative to their male counterparts:

• Lifestyle changes and risk factor modification affect the prognosis of the disease more greatly in women. 
• The same drugs can be administered according to the type of CAD. Special attention is paid to anti-atherosclerotic statin therapy of which effectiveness in reducing the coronary mortality (36%) and risk of ischemic events has been proven in many clinical studies (4S, HPS, AFCAPS / TexCAPS, WOSCOPS, CARE, LIPID , MIRACL, AVERT).  
• Some calcium channel blockers (nifedipine, amlodipine) are known to have gender specific features - women have higher clearance and lower serum drug concentration than men (16).
• Sex hormones affect the regulation of myocardial β-adrenergic sensitivity: β-receptors functional activity is observed due to lower estrogen levels. When using β-blocker metoprolol women show higher plasma drug levels and therefore a more evident heart rate and blood pressure reduction.  

Regarding endovascular and surgical treatment of CAD, intervention in women has some distinct features:

1. The Coronary Artery Surgery Study showed that women, compared to men
   
   • after coronary artery bypass surgery (CABG) had a 4.5 % mortality compared with 1.9%
   • were older when surgery was performed and had been diagnosed with severe or unstable angina, hypertension, diabetes and dyslipidemia more frequently
   • had worse clinical signs, high in-hospital mortality, high vascular dissection risk and less successful angioplasty
   • had a lesser survival of grafts, lesser degree of symptom improvement in the postoperative period, frequent postoperative myocardial infarction, more frequent heart occurrence and more likely required reoperation within 5 years after CABG.
2. In TIMI III, women's, mortality during 6 months follow-up after angioplasty was 0.8 %, similar to men (17).

• Female physiological characteristics may affect the pharmacokinetics of drugs in treatment. Alterations in the levels of sex hormones during the menstrual cycle may alter the concentration of water and electrolytes (18).

Regarding secondary prevention of CAD:

1. Simvastatin: The 4S study aimed at among 4,444 participants, 19% were women aged 35-70 years. The goal of treatment was to reduce and maintain cholesterol levels within 3.0-5.2 mmol/L in patients receiving simvastatin 20-40 mg per day.
   • In 77 % of patients the goal was reached, and the lipid-lowering effects of simvastatin were noted irrespective of sex. 
   • Total mortality and coronary mortality did not significantly change, whereas coronary events were reduced up to 34% and nonfatal myocardial infarction by 36 % (19).  
2. Statins: The HPS study included elderly women. The positive effects of statin therapy in women was a one third risk decline in myocardial infarction and stroke. In this study requirement for revascularisation did not depend on gender, age and baseline total cholesterol (20).
3. Rovustatin: The JUPITER study of 6,800 women older than 60 years with increased cardiovascular risk treated with rosuvastatin showed that the anti-atherosclerotic drug reduced the risk of cardiovascular events by 46% compared with placebo in patients without identified cardiovascular risk (21). Treatment of dyslipidemia with elevated triglycerides and low HDLshould include fibrates and nicotinic acid.
4. Aspirin: Aspirin reduces the incidence of myocardial infarction, stroke and cardiovascular death by 25% in men and women. NHS epidemiological study found a significant reduction in risk of myocardial infarction in women taking aspirin 6 times a week. Women are known to have higher bioavailability, lower clearance, longer half-life of aspirin compared with men. Aspirin actively effects platelet aggregation in men due to the influence of testosterone. Women frequently show aspirin resistance.
5. Glycoprotein IIb / IIIa inhibitor abciximab: Anticoagulant therapy including glycoprotein IIb / IIIa inhibitor abciximab during invasive procedures for CAD in women has similar clinical effects in as in men. However women develop a higher level of complications taking standard doses prescribed for men (22).

Conclusions 

Gender differences in the structure of organs, physiological reactions, and hormonal background determine certain peculiarities in clinical manifestations, course of the disease in women and men. As in men, symptoms specific to CAD in women need prompt recognition for determination of risk groups and development of preventive measures. The full range of diagnostic measures should be put in place for women taking into account the low sensitivity and specificity of non-invasive methods, according to the latest guidelines on management of coronary artery disease.
Women have been underrepresented in cardiovascular clinical trials, especially in the field of coronary artery disease (23). Clinical trials enrolling a significant proportion of women will allow for pre-specified gender analysis and those performed in women only will also better address their specific needs. The iPOWER study for example will include 2,000 women with suspected CAD and CAD who will be followed for 5 years for cardiovascular outcomes. The study will provide information on methods to diagnose coronary microvascular dysfunction and determine the prognostic value of routine non-invasive assessment of microvascular function.