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Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management: A Core Review

Matyal, Robina MD*

doi: 10.1213/ane.0b013e31816f2104
Cardiovascular Anesthesiology: Review Article
Chinese Language Editions

The assumption that males and females are physiologically similar has led to females being clinically evaluated and treated as males. However, there is growing evidence in the literature that, other than the reproductive system, there are other fundamental physiological differences between the two genders. The manifestation of these differences starts soon after puberty and becomes more pronounced with age. The differences in body mass and volume and renal and liver metabolism account for the difference in therapeutic efficacy and side effects of commonly used cardiovascular drugs. Women have smaller coronary arteries, more frequent diastolic dysfunction, present with vague symptoms of coronary artery disease and do worse than men after revascularization procedures. Women also have a shorter cardiac cycle and are more prone to develop arrhythmias and react differently to antiarrhythmic drugs. Most epidemiological trials that have assessed the utility of pharmacological myocardial protection or outcomes after noncardiac surgery have either been performed on men only or women were not identified as a separate group. Recent evidence is suggestive that coronary vasospasm may be the dominant etiology of acute myocardial ischemia in women. This may explain the poor sensitivity and specificity of the routine myocardial perfusion tests. Having considered all this evidence, it has become very essential to view the operative risk stratification as being gender-based. This approach may involve a shift in our present day paradigm of patient management.

From the Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Accepted for publication January 31, 2008.

Address correspondence and reprint requests to Robina Matyal, MD, Instructor in Anesthesia, Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Address e-mail to

Coronary artery disease (CAD), not cancer, is the leading cause of death in women; 1 in 30 women dies of breast cancer, whereas 1 in 6 women dies of CAD.1 Dr. Bernadette Healy in 1991 brought attention to this fact by describing the “Yentl Syndrome.”2 She reported that because of the atypical nature of symptoms, there was a tendency not to recognize CAD in women.2 Yentl, a woman, was the main character in a short story by Isaac Singer, in which she had to dress and act like a man to be able to attend school. This provocative title was a not so subtle reference emphasizing that until quite recently, despite the obvious physiological differences, women had to present themselves as men to receive the same treatment. And, even now if the women do not demonstrate the specific symptoms described in men, they may receive inferior medical care.

This paper will review the major physiological differences between men and women with CAD and discuss the potential ramifications for preoperative screening for CAD. I will review the differences in the perioperative care of women and men undergoing cardiac and noncardiac surgery, which may be responsible for differences in outcome. Finally, I will review current recommendations, as well as needs for further studies regarding gender-specific perioperative cardiovascular risk stratification.

Women’s physiological response to cardiovascular abnormalities is different from men. They have a higher rate of congestive heart failure (CHF), despite normal ejection fraction (EF), than men after myocardial infarction (MI).3 Women also have a higher prevalence of diastolic heart failure.4 Women also tend to develop more severe left ventricular (LV) hypertrophy and maintain normal LV systolic function for a longer time when exposed to higher after-load, e.g., hypertension and aortic stenosis.5,6 The Society of Thoracic Surgery database analysis for the first time revealed that the incidence of postoperative MI, CHF, renal failure, and neurological dysfunction in females after coronary artery bypass surgery was significantly higher than in men.7–10

Female gender is also an independent predictor of adverse outcome (short- and long-term) after combined valve and revascularization procedures, and women have a higher postoperative mortality (7% vs 4%) than men.11 However, there is evidence that the women may have worse prognosis than men in the immediate postoperative period but may have comparable outcomes in the long term.12–14 The likelihood of more frequent postoperative complications is not limited to open revascularization procedures. Women also have an increased incidence of morbidity and mortality (bleeding and vascular complications) after percutaneous coronary interventions and angioplasty for myocardial revascularization than age-matched men.15–17

The likelihood of women demonstrating worse outcomes than men is not unique to cardiac surgical procedures. Women have a lower relative 5-yr survival than men after elective abdominal aortic aneurysm surgery (88% vs 95%) and demonstrate higher mortality after ruptured abdominal aortic surgery (90.2% vs 75.6%).18 There is also a higher risk of stroke after carotid endarterectomy (3.3% vs 2.1%) and a lower incidence of graft patency after peripheral vascular surgery (54% vs 74%).18 The differences in outcome may be due to lack of consideration of unique physiological differences (body size and surface area) in designing therapeutic protocols for women for high-risk noncardiac surgery.19–22

Short-term higher mortality and morbidity in women is probably multifactorial. It can be attributed to a more frequent incidence of CAD presenting acutely and with CHF, and a higher prevalence of comorbidities (diabetes, hypertension, valvular heart disease, and old age) at the time of presentation.11,14,23 But, the inferior cardiovascular morbidity and mortality statistics even after noncardiac surgery18,24–27 are suggestive of more fundamental anatomical and physiological differences. These factors may significantly affect the outcomes after similar degrees of physiological derangement between genders.

Despite being “well established,” the gender-based difference in outcome is not a very well-known fact. And perhaps this apparent ignorance of women as a different patient group is also responsible for lack of development of any gender-based therapeutic protocols. A recent multicenter study comparing the 30-day postoperative morbidity and mortality between Department of Veterans Affairs and private university hospitals after general and vascular surgery did identify women as a separate group in their analysis. But, in the final analysis, they compared men in the Veterans Affairs hospitals with men in the private university hospitals, and a similar comparison between women in the two groups was performed. A morbidity and mortality comparison between men and women in each group or between the two groups was not performed. Also in the final stepwise logistic regression analysis, men were evaluated for more perioperative risk factors than women28–31 (Tables 1 and 2).

Table 1

Table 1

Table 2

Table 2

Similarly, major randomized trials assessing the effects of β-adrenergic blocking drugs, renin-angiotensin enzyme inhibitors, calcium channel blockers, antiarrhythmics, statin drugs, and antiplatelet drugs were performed in males only, or females were not identified as a separate group32–47 (Table 3). Even the trials that have actually demonstrated gender-based differences in the metabolism of drugs have not been translated into a change in the management protocols. Hence, despite this overwhelming evidence in the literature of the inequality between genders, the legacy of the Yentl Syndrome lives on.

Table 3

Table 3

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Gender-Based Differences in the Incidence/Presentation and Diagnosis of CAD

It is generally believed that women are somehow protected against CAD by sex hormones but only during their fertile age, and this protection precipitously fades after menopause. The incidence of CAD increases in both men and women as they age, but that the acceleration or step-up in incidence occurs 10 yr earlier in men than in women.1 In men, the rate of the first major cardiovascular event is 7/1000 between ages 35–44 yr and increases to 68/100 between ages 85–94 yr. However, it has been demonstrated that CAD-related mortality in women has always been higher than that due to malignancies (38% in CAD vs 22% malignancies).48 In Europe, 55% of the women die of CAD annually when compared with 43% of men. Almost a quarter-million women die from CAD every year and “almost every minute, a woman in the United States dies of cardiovascular disease.”49 Another alarming statistic is the progressive increase in the incidence of CAD in older women as opposed to men in whom this incidence is decreasing, especially in younger men, yet CAD is considered a man’s disease.50

Women differ in their clinical manifestation of ischemic heart disease and 43% of women do not demonstrate chest pain as a presenting symptom of angina.51 Traditional diagnostic tests for CAD have different sensitivity and specificity between genders and the seminal Coronary Artery Surgery Study revealed that women were 4.5 times more likely to manifest a false-positive exercise test response even in the presence of normal coronary angiography.52 This finding was recently reconfirmed in the Women’s Ischemia Syndrome Evaluation study, which showed that almost 60% of women investigated for chest pain have no flow-limiting lesions in their coronary arteries, despite evidence of persistent chest pain.53 This reinforces the observation that because of atypical symptoms the women experiencing actual ischemia are not selected for intervention. It is speculated that microvascular coronary involvement is the likely source of misdiagnosis and mistreatment.54

Hence, women seem to differ from men in the etiology, clinical presentation, diagnosis and, above all, the incidence and nature of cardiovascular complications. Despite these obvious differences, there is surprising paucity of literature addressing the potential causes and management strategies tailored specifically for women. The clinical importance of women as a separate group with its own unique physiological response to CAD was further elaborated when the American Heart Association released evidence-based guidelines for the prevention of cardiovascular disease in women. Also, a risk assessment system for women was described based on data specific for women (Tables 4 and 5).55

Table 4

Table 4

Table 5

Table 5

With this background, it is reasonable to state that the assumption of “physiological equality” between the genders is erroneous and at least subject to question.

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Pathophysiologic Differences

The cyclical hormonal changes that females undergo during their lives (menstrual cycle/pregnancy/menopause) may be responsible for the varied cardiovascular physiological responses. Endogenous steroid hormones may have an important role in cardiovascular protection and their absence increases the risk for CAD in older women. It had been believed that the beneficial effects of estrogen were possibly due to its favorable effects on serum cholesterol.56,57 Only in the 1990s it was realized that estrogen receptors were involved in modulating normal endothelial function and also in prevention of atherosclerosis.58,59

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Sex Steroid Hormonal Effects

Estradiol levels are higher in prepubertal girls than boys, and thereafter at puberty the cyclic variation of estrogen and progesterone starts in women and continues for almost four decades.60 The plasma estrogen levels remain at the premenopausal levels in the perimenopausal period but decline precipitously and to only one-tenth the level during menopause.60 Other than modulating menstrual cycle, estrogen has anti-atherosclerotic effects, reduces cellular hypertrophy, and also has antioxidant and antiinflammatory properties.61 Estrogen can cause vasodilatation through an increase in nitric oxide (NO) levels and induction of the NO synthetase gene.62 Vasodilatation and cyclical arterial blood pressure changes can even be appreciated during the normal menstrual cycle with variations in hormonal levels.63,64 This leads to lower systolic blood pressure in premenopausal women when compared with age-matched men. Conversely, a lack of the cyclic vasodilatory effect of estrogen during menopause causes a progressive increase in the incidence of hypertension and increased pulse pressure during menopause.

The role of estrogen in modulating vascular wall elasticity, vasodilatation, and in determining the stability of atherosclerotic plaques in the coronary arteries may explain the differences in pathophysiology of CAD between men and women.65 There is growing evidence that estrogen receptors can mediate cell transduction pathways at the cell membrane level. In the myocardium, these signal cascades control rapid vasodilatation, inhibition of response to cell injury, and control of the size of cellular injury after MI and attenuation of myocardial hypertrophy.66–70

Menopause is also associated with a change in serum lipid profiles, with a rapid decrease in high-density lipoprotein (HDL) levels accompanied by an increase in low-density lipoproteins and triglyceride levels.71,72 It has been shown that hormonal replacement therapy decreases low-density lipoprotein level and increases HDL levels but also increases triglyceride levels. However, the potential benefits of hormonal therapy in optimizing serum lipid profile may be offset by an increased incidence of thromboembolism with the replacement therapy apart from other complications such as an increased risk of breast and uterine cancer.72

In women, the presence of sex hormones leads to attenuated sympathoadrenal activation. Also the sympathoadrenal inhibition is augmented because the pathways regulating the sympathetic nervous system appear to be less sensitive to excitatory stimuli and more sensitive to inhibitory stimuli when compared with men.64,73–75 This protective mechanism is believed to be eliminated with the onset of menopause. However, postmenopausal hormone replacement therapy has not been shown to decrease the incidence of these complications.76–78

With the recent awareness of the Takotsubo syndrome, it is evident that females can develop acute left heart failure with emotional or physical stress in the absence of any occlusive CAD.79,80 This syndrome is predominantly observed in postmenopausal women and the probability of developing this syndrome is increased with a history of diabetes mellitus, hypertension, hyperlipidemia, smoking, and obesity.81 Postmenopausal women presenting with this syndrome have been shown to have higher levels of catecholamine levels in almost 70% of the cases, indicating that it is adrenergic-mediated effect under stress.81 The global issue of hormones and vascular relaxation, coronary atherosclerosis and restenosis, and modulation of catecholamine response deserves further study.

Women also have a higher incidence of undiagnosed diabetes mellitus.82 Diabetes itself increases the risk of CAD to 3%–7% in women when compared with 2%–3% increase in men over and above the other risk factors. The presence of metabolic syndrome in women almost doubles the incidence of CAD.40 The term “metabolic syndrome” is used to define a specific body habitus (abdominal adiposity) along with the presence of two to three risk factors, such as high blood pressure, an increased blood glucose/insulin resistance, and an increase in triglyceride/high-density lipoprotein ratio. This syndrome is associated with a higher incidence of CAD.50 It is more prevalent in women, as almost 45% of the female population meets the criteria of the metabolic syndrome.83,84 The balance of endothelial damage and repair is disrupted in the metabolic syndrome, enhancing arterial atherosclerosis.85,86 It has been shown that the restoration of endothelial function leads to a seven-fold decrease in cardiovascular events in metabolic syndrome.87

The role of hormone therapy for postmenopausal women has been controversial. It has recently been suggested that hormone replacement therapy may be beneficial if initiated between the ages of 50 and 59-yr-of-age or within 10 yr of menopause than after 10 yr of menopause.88–91 This suggests that estrogen may be protective before atherosclerosis sets in the vessels and it may not be beneficial after that.

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LV Hypertrophy and Diastolic Dysfunction

There are very few cardiovascular differences between the genders until the onset of puberty.92 However, shortly after, LV mass increases more rapidly in men and is 15%–30% larger than in women during early adulthood93–98 (Table 6). As opposed to younger men, younger women have a more favorable remodeling of the LV in response to increased after-load with less LV dilation,5,99,100 predisposing them to more severe diastolic dysfunction in later life.101,102 The higher incidence of diastolic dysfunction may be multifactorial, and in addition to the preserved systolic function a combination of hypertension, stiffer aorta and higher total peripheral resistance may also be responsible for increased incidence of diastolic heart failure.5,62,74,75,103,104 Women in general have smaller heart size, smaller end diastolic and end systolic volume, but increased peak and end systolic pressure. Stroke volume is smaller in women, but the cardiac output is normal due to a higher baseline heart rate in women. Initially, women have higher systolic and arterial elastance; later the elastance decreases in arteries and women develop lower diastolic compliance leading to greater loading sensitivity in women despite normal EF.61

Table 6

Table 6

Estrogen favorably affects the collagen synthesis and, through its effects on the rennin-angiotensin system, NO, and calcium handling may be beneficial in preserving diastolic distensiblity in this age group.62 It has been shown that ER-α (estrogen receptor-α) and ER-β (estrogen receptor-β) are upregulated by pressure overload. We need further studies to assess the sex-specific prohypertrophic or antihypertrophic remodeling pathways for deriving future therapies and interventions.

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Coronary Artery Physiology

Women have smaller coronary arteries and lesser collateral circulation than men, thus leading to increased incidence of ischemia during increased myocardial work.105,106 Coronary vessel diameter is independent of body surface area and the smaller coronary diameter cannot be attributed to the smaller body surface area in females.106 Women’s hearts, when transplanted into other females, show little coronary artery changes over time, but when transplanted into men, show progressive coronary enlargement independent of body size and LV hypertrophy.53,107,108 The donor hearts in these studies were from premenopausal women and were transplanted into men and postmenopausal women (both groups with very low estrogen levels). In addition, immunosuppression suppresses estrogen levels.107 The exact mechanism of this phenomena is unknown but appears to be multifactorial.107 Sex hormones, such as estrogen, take part in arterial remodeling and modulating the vasodilatory effects by increasing the NO levels. Also, estrogen causes favorable vascular effects by affecting the vascular collagen synthesis and degradation, inhibiting smooth muscle cell growth, the rennin-angiotensin system, and the aldosterone hormone.62,64

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A finding of particular interest for perioperative management is the observation that baseline heart rate is 4–5 beats higher in women.73 It has been shown to be related to sinus node automaticity. Women have more baroreflex sensitivity; hence, rapid alterations of arterial blood pressure can be controlled better, but with less heart rate response to these blood pressure changes.109 After puberty, the rate-corrected QT interval is prolonged in women along with a shortened sinus node recovery time. The implications of a prolonged QTc are considered further in this article.41,110 The length of the cardiac cycle is longer in men when compared with that in women in whom it varies with the stage of menstrual cycle and is prolonged during menstruation111 (Table 6). Women also develop more pathological tachycardia and atrioventricular nodal reenterant tachycardias than men.109 Men are more than 1.5 times likely to have atrial fibrillation than females in all age groups.112,113 But, since there are twice as many >75-yr-old women than men, the absolute number of women with atrial fibrillation is more than men.109

The above discussion clearly illustrates that the physiological milieu in women is significantly different than men resulting in differing incidences, presentations, and outcomes of cardiovascular disease.

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Preoperative Risk Stratification

Women not only differ in the etiology, pathogenesis, and presenting symptoms of CAD, the accuracy of routine diagnostic tests for cardiovascular risk stratification is also radically different in women. Preoperative risk stratification has to be based on the epidemiological evidence of the existence of gender as a separate risk factor. For an appropriate risk stratification, it is important to identify women with intermediate or high risk factors with appropriate diagnostic criteria and then follow-up with a gender-based preventive approach.114

Chest pain is generally not the typical presenting symptom of angina in women.115 The majority of the women have vague symptoms during angina, such as fatigue, dyspnea, and lack of energy.51 Older women present more commonly as acute coronary syndrome or severe LV failure after physical or mental stress. Since myocardial ischemia is common in the absence of coronary artery narrowing in women, anginal attacks can be confused with depression and mental stress, which is three times more common in women than in men, frequently leading to misdiagnosis and eventually mistreatment.72,116 Almost 50% of women have normal coronary arteries, despite an abnormal myocardial stress test when compared with 17% of men.117

The routine tests for assessment of CAD and risk stratification are geared to diagnose stenotic lesions in the coronary arteries of more than >60% severity. The positive-predictive value of the exercise stress test is lower for women due to earlier fatigue and an impaired ability to reach target heart rate.118,119 In addition, these tests may also have decreased diagnostic accuracy in women because their ischemia is often caused by coronary vasospasm versus flow-limiting coronary artery stenosis.52,53,73,117,120–122 Hence, an apparently negative stress test in the presence of specific risk factors is of little value in the assessment of prognosis. In premenopausal women, endogenous estrogen may have a digoxin-like effect during the stress test leading to ST segment changes, resulting in false positive results.65 The QRS duration on the 12-lead electrocardiogram has been found to be a strong predictor of cardiovascular outcome in women. A wider QRS complex in women with chest pain and preserved systolic function is associated with adverse cardiovascular events independent of CAD severity.123,124

Since the relationship between endothelial dysfunction and CAD has been established, this vascular endothelium dysfunction, e.g., lack of response to vasodilator therapy, may also be used as a prognostic index.122 Furthermore, if the endothelial dysfunction is a prognostic indicator in women, it should be the target for the therapeutic interventions and reversibility should signify improved cardiovascular performance.53 This hypothesis was tested in a study of 400 postmenopausal women with hypertension during the assessment of the response of their brachial artery to chemically mediated vasodilatation.87 The women were followed-up in the ambulatory setting for an average of 6–7 mo and the cardiovascular event rate was seven-fold higher in women in whom the flow-mediated vasodilatation did not improve in the brachial artery by 10%.87 The optimum investigation for the assessment of cardiac performance in women includes ventricular function assessment, regional flow assessment, assessing vessel wall abnormalities, and identifying markers of inflammation (C-reactive protein, amyloid A).53,65

It may be more prudent to use a gender-based preoperative risk stratification approach. Indirect evidence suggests that traditional tests for risk stratification have lower sensitivity and specificity in women than men.65 Thus, it may be more appropriate to develop a prognosis-based approach and identify the culprit patient as opposed to the culprit stenosis.125 It may be important to manage the women with the specific risk factors with a gender-based protocol.

Preoperative clinics may risk-stratify female patients based on the “Aloha approach.”126 According to this protocol, female patients should be identified as high risk if they are >55 yr of age and have history of smoking, hypertension, HDL <40 mg/dL, and a strong family history of CAD. Diabetes mellitus, established atherosclerotic disease, or renal insufficiency should be considered CAD equivalents and women with these comorbidities should be managed appropriately. The exact definition of gender-based appropriate management of these high-risk patients is not well defined. The change in management may involve preoperative risk stratification for women based on the presence or absence of specific risk factors rather than the traditional risk stratification. Because of the vague presentation of CAD, it may be important to have a detailed questionnaire designed specifically for women. Functional capacity in women should be assessed more carefully and objectively because women are more likely to have a sedentary life style. Traditional tests of myocardial function and perfusion should be analyzed in the presence or absence of the already described risk factors. In addition, the failure of the female patients to achieve the predicted heart rate due to either physical exhaustion or inability to increase their heart rate further decreases the utility of these investigations. The presence of a normal EF should not be considered absolute evidence of the normalcy of myocardial function, especially in women, who have a more frequent incidence of diastolic dysfunction. New risk assessment paradigms, such as inflammatory markers and coronary flow reserve (ratio of myocardial blood flow during hyperemia to myocardial blood flow at rest) for myocardial ischemia, may be the future strategies for risk stratification.

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Differences in pharmacokinetic and pharmacodynamics

Women have been known to respond differently to multiple drugs.127–135 For the purposes of this article, I have limited the discussion to a few of the drugs that are routinely used intraoperatively. It is becoming obvious that alteration of dosages to women simply based on their body surface area may not be entirely correct, because it seems that a host of other physiological factors determine the differences in response to these drugs, e.g., antiarrhythmics, and calcium channel blockers which have a different response pattern in females.

Gender-related and hormonal effects on drug distribution and effects have been known for the last 70 yr. However, these discrete differences have not been translated into gender-based therapeutic regimens.136 Different hormonal levels in premenopausal stages affect protein binding, body weight, and fat distribution, leading to a different volume of distribution and relatively decreased glomerular filtration rate. These factors affect drug pharmacokinetics and pharmacodynamics.137 In postmenopausal women, there is larger volume of distribution of lipophilic drugs and their decreased excretion secondary to decrease in renal function. There are also discrete differences in hepatic enzyme activity as well as differences in body fat distribution, plasma volume, protein levels, and gastric emptying time.138,139

Several studies have reported increased serum levels and a more pronounced effect of cardioselective and nonselective β-adrenergic blocking drugs in women.140–142 Women have decreased ability to increase their heart rate, have a prolonged QTc interval, and they are more likely to develop ventricular arrhythmias.111,143,144 Women with a prolonged QTc interval at baseline are more susceptible to develop torsede de pointe with antiarrhythmic drugs, which prolong QTc interval, such as sotalol, quinidine, amiodarone, ibutalide, and certain antimicrobial, antihistamine, and psychiatric drugs.41,145 It is important to keep these physiological characteristics in mind when designing β-adrenergic blocking drug administration protocols, e.g., shorter-acting and smaller dosage.

Gender differences in metabolism and distribution have also been seen for digoxin,146 verapamil,38 and aspirin.147,148 Digitalis has been associated with a higher mortality rate in women due to fatal arrhythmias146 and long-term aspirin use is helpful for stroke prevention but has no preventive effect against cardiovascular thromboembolic events in women.148 Women’s response to thrombolytic therapy has also been associated with more bleeding complications. Even in patients presenting with acute coronary syndrome, the beneficial effect of abciximab is less in women for percutaneous coronary intervention.43 Sexual dimorphism also has an effect on metabolism of angiotensin converting enzyme inhibitors, these drugs being less effective in treating hypertension in older females than in age-matched males.149

Drugs that are commonly used in anesthetic practice, e.g., benzodiazepines111 and methadone,128 have been shown to have gender-related metabolism (Table 7). Higher levels of methadone lead to prolonged analgesic and sedative effects because of decreased clearance in women, and postmenopausal women also have a decreased ability to metabolize alfentinal150 and prednisone.151 Gender differences have been seen in drugs used specifically in anesthetic management. Women are 30%–40% less sensitive than men to propofol for a similar degree of sedation, and hence require higher dosing for the same effect.37,152 Women require 30%–40% less opioid analgesia and k receptor agonists than men for the same degree of pain control.153–155 On the other hand, women are more prone to develop respiratory depression than men, despite smaller dose requirements for pain control.153

Table 7

Table 7

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Anesthetic Implications

Over the years, patient management protocols have been integrated into routine clinical practice that are based on epidemiological studies in which either the gender was never considered as a variable, or research was conducted in males only 32–42,44–47,143 (Table 3). This is despite an accumulating body of evidence to suggest that women have different etiologies, presenting features, response to therapeutics, and outcome.

Women were assumed to be less susceptible to develop CAD due to the protection offered by the sex hormones. This hypothesis was tested by extensive clinical use of replacement hormonal therapy. However, hormonal therapy, which was considered the “gold standard” for prevention of cardiovascular disease in postmenopausal women, is no longer universally recommended for the that purpose.156 Women have been treated differently only as far as adjusting drug dosages based on body weight and surface area. Despite evidence to suggest a different pathophysiology and clinical presentation of CAD in women, we continued to rely on perioperative risk stratification strategies geared to identify men at risk. It is being realized now that the differences between men and women go beyond the obvious differences in reproductive physiology.

It is perhaps a completely different milieu of anatomy and physiology (smaller heart size, narrower coronary arteries, increased heart rate, longer cardiac cycle, different autonomic reflexes, different rennin-angiotensin and aldosterone system, reduced glomerular filtration rate, and volume of distribution of drugs) that may be responsible for the differences in outcome. These differences in outcome have been described primarily after cardiac surgical interventions, and after high-risk noncardiac vascular surgical procedures. No gender-based perioperative protocols have been studied, and we may need to conduct such studies to revise our perioperative management protocols using a gender-based paradigm.

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1. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69–e171
2. Healy B. The Yentl syndrome. N Engl J Med 1991;325:274–6
3. Tofler GH, Stone PH, Muller JE, Willich SN, Davis VG, Poole WK, Strauss HW, Willerson JT, Jaffe AS, Robertson T, et al. Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, particularly black women. J Am Coll Cardiol 1987;9:473–82
4. Kimmelstiel CD, Konstam MA. Heart failure in women. Cardiology 1995;86:304–9
5. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993;72:310–3
6. Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM, McGaughey D, Karp RB. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 1992;86:1099–107
7. Hartz RS, Rao AV, Plomondon ME, Grover FL, Shroyer AL. Effects of race, with or without gender, on operative mortality after coronary artery bypass grafting: a study using The Society of Thoracic Surgeons National Database. Ann Thorac Surg 2001;71:512–20
8. Hannan EL, Bernard HR, Kilburn HC Jr, O’Donnell JF. Gender differences in mortality rates for coronary artery bypass surgery. Am Heart J 1992;123:866–72
9. Suarez EC, Saab PG, Llabre MM, Kuhn CM, Zimmerman E. Ethnicity, gender, and age effects on adrenoceptors and physiological responses to emotional stress. Psychophysiology 2004;41:450–60
10. Vaccarino V, Lin ZQ, Kasl SV, Mattera JA, Roumanis SA, Abramson JL, Krumholz HM. Gender differences in recovery after coronary artery bypass surgery. J Am Coll Cardiol 2003;41:307–14
11. Ibrahim MF, Paparella D, Ivanov J, Buchanan MR, Brister SJ. Gender-related differences in morbidity and mortality during combined valve and coronary surgery. J Thorac Cardiovasc Surg 2003;126:959–64
12. Brandrup-Wognsen G, Berggren H, Hartford M, Hjalmarson A, Karlsson T, Herlitz J. Female sex is associated with increased mortality and morbidity early, but not late, after coronary artery bypass grafting. Eur Heart J 1996;17:1426–31
13. Hirakawa Y, Masuda Y, Kuzuya M, Iguchi A, Kimata T, Uemura K. Impact of gender on in-hospital mortality of patients with acute myocardial infarction undergoing percutaneous coronary intervention: an evaluation of the TAMIS-II data. Intern Med 2007;46:363–6
14. Humphries KH, Gao M, Pu A, Lichtenstein S, Thompson CR. Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004). J Am Coll Cardiol 2007;49:1552–8
15. Vaccarino V, Krumholz HM, Berkman LF, Horwitz RI. Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women? Circulation 1995;91:1861–71
16. Kelsey SF, James M, Holubkov AL, Holubkov R, Cowley MJ, Detre KM. Results of percutaneous transluminal coronary angioplasty in women. 1985–1986 National Heart, Lung, and Blood Institute’s Coronary Angioplasty Registry. Circulation 1993;87:720–7
17. Milcent C, Dormont B, Durand-Zaleski I, Steg PG. Gender differences in hospital mortality and use of percutaneous coronary intervention in acute myocardial infarction: microsimulation analysis of the 1999 nationwide French hospitals database. Circulation 2007;115:833–9
18. Norman PE, Semmens JB, Lawrence-Brown M, Holman CD. The influence of gender on outcome following peripheral vascular surgery: a review. Cardiovasc Surg 2000;8:111–5
19. Cheanvechai V, Harthun NL, Graham LM, Freischlag JA, Gahtan V. Incidence of peripheral vascular disease in women: is it different from that in men? J Thorac Cardiovasc Surg 2004;127:314–7
20. Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Arterial occlusive disease of the lower extremities: do women differ from men in occurrence of risk factors and response to invasive treatment? J Thorac Cardiovasc Surg 2004;127:318–21
21. Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Outcome of carotid endarterectomy on the basis of patient sex: is there a difference? J Thorac Cardiovasc Surg 2004;127:322–4
22. Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Prevalence of abdominal aortic aneurysm and repair outcomes on the basis of patient sex: should the timing of intervention be the same? J Thorac Cardiovasc Surg 2004;127:325–8
23. Blankstein R, Ward RP, Arnsdorf M, Jones B, Lou YB, Pine M. Female gender is an independent predictor of operative mortality after coronary artery bypass graft surgery: contemporary analysis of 31 Midwestern hospitals. Circulation 2005;112: I323–7
24. Belkin M, Conte MS, Donaldson MC, Mannick JA, Whittemore AD. The impact of gender on the results of arterial bypass with in situ greater saphenous vein. Am J Surg 1995;170:97–102
25. Golledge J, Cuming R, Beattie DK, Davies AH, Greenhalgh RM. Influence of patient-related variables on the outcome of carotid endarterectomy. J Vasc Surg 1996;24:120–6
26. Sarac TP, Hertzer NR, Mascha EJ, O’Hara PJ, Krajewski LP, Clair DG, Karafa MT, Ouriel K. Gender as a primary predictor of outcome after carotid endarterectomy. J Vasc Surg 2002;35:748–53
27. Starr JE, Hertzer NR, Mascha EJ, O’Hara PJ, Krajewski LP, Sullivan TM, Beven EG. Influence of gender on cardiac risk and survival in patients with infrarenal aortic aneurysms. J Vasc Surg 1996;23:870–80
28. Fink AS, Hutter MM, Campbell DC Jr, Henderson WG, Mosca C, Khuri SF. Comparison of risk-adjusted 30-day postoperative mortality and morbidity in Department of Veterans Affairs hospitals and selected university medical centers: general surgical operations in women. J Am Coll Surg 2007;204:1127–36
29. Henderson WG, Khuri SF, Mosca C, Fink AS, Hutter MM, Neumayer LA. Comparison of risk-adjusted 30-day postoperative mortality and morbidity in Department of Veterans Affairs hospitals and selected university medical centers: general surgical operations in men. J Am Coll Surg 2007;204:1103–14
30. Hutter MM, Lancaster RT, Henderson WG, Khuri SF, Mosca C, Johnson RG, Abbott WM, Cambria RP. Comparison of risk-adjusted 30-day postoperative mortality and morbidity in Department of Veterans Affairs hospitals and selected university medical centers: vascular surgical operations in men. J Am Coll Surg 2007;204:1115–26
31. Johnson RG, Wittgen CM, Hutter MM, Henderson WG, Mosca C, Khuri SF. Comparison of risk-adjusted 30-day postoperative mortality and morbidity in Department of Veterans Affairs hospitals and selected university medical centers: vascular surgical operations in women. J Am Coll Surg 2007;204:1137–46
32. Alexander KP, Chen AY, Newby LK, Schwartz JB, Redberg RF, Hochman JS, Roe MT, Gibler WB, Ohman EM, Peterson ED. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative. Circulation 2006;114:1380–7
33. Boersma E, Poldermans D, Bax JJ, Steyerberg EW, Thomson IR, Banga JD, van De Ven LL, van Urk H, Roelandt JR. Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001;285:1865–73
34. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906
35. Eidelman RS, Hebert PR, Weisman SM, Hennekens CH. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med 2003;163:2006–10
36. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998;339:489–97
37. Kodaka M, Suzuki T, Maeyama A, Koyama K, Miyao H. Gender differences between predicted and measured propofol C(P50) for loss of consciousness. J Clin Anesth 2006;18:486–9
38. Krecic-Shepard ME, Barnas CR, Slimko J, Jones MP, Schwartz JB. Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol 2000;40:219–30
39. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med 2005;353:349–61
40. Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 1999;66:594–601
41. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590–7
42. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713–20
43. Mehilli J, Ndrepepa G, Kastrati A, Neumann FJ, ten Berg J, Bruskina O, Dotzer F, Seyfarth M, Pache J, Kufner S, Dirschinger J, Berger PB, Schomig A. Sex and effect of abciximab in patients with acute coronary syndromes treated with percutaneous coronary interventions: results from Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial. Am Heart J 2007;154:158.e1–7
44. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999;341:1789–94
45. Raby KE, Brull SJ, Timimi F, Akhtar S, Rosenbaum S, Naimi C, Whittemore AD. The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg 1999;88:477–82
46. Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent. Anesthesiology 1988;68:495–500
47. Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W, Miller D, Mangano DT. Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. Anesthesiology 1998;88:7–17
48. Make Every Mother and Child Count. In: CDC ed. 2005
49. Traynor K. AHA releases heart-disease-prevention guidelines for women. Am J Health Syst Pharm 2004;61:540, 542
50. Olson MB, Shaw LJ, Kaizar EE, Kelsey SF, Bittner V, Reis SE, Smith K, Braunstein GD, Berga SL, Johnson BD, Bairey Merz CN. Obesity distribution and reproductive hormone levels in women: a report from the NHLBI-sponsored WISE Study. J Womens Health (Larchmt) 2006;15:836–42
51. McSweeney JC, Cody M, O’Sullivan P, Elberson K, Moser DK, Garvin BJ. Women’s early warning symptoms of acute myocardial infarction. Circulation 2003;108:2619–23
52. Weiner DA, Ryan TJ, McCabe CH, Kennedy JW, Schloss M, Tristani F, Chaitman BR, Fisher LD. Exercise stress testing. Correlations among history of angina, ST-segment response and prevalence of coronary-artery disease in the Coronary Artery Surgery Study (CASS). N Engl J Med 1979;301:230–5
53. Quyyumi AA. Women and ischemic heart disease: pathophysiologic implications from the Women’s Ischemia Syndrome Evaluation (WISE) Study and future research steps. J Am Coll Cardiol 2006;47:S66–S71
54. Pepine CJ, Balaban RS, Bonow RO, Diamond GA, Johnson BD, Johnson PA, Mosca L, Nissen SE, Pohost GM. Women’s Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2–4, 2002: Section 1: diagnosis of stable ischemia and ischemic heart disease. Circulation 2004;109:e44–e46
55. Mosca L, Appel LJ, Benjamin EJ, Berra K, Chandra-Strobos N, Fabumni RP, Grady D, Haan CK, Hayes SN, Judelson DR, Keenan NL, McBride P, Oparil S, Ouyang P, Oz MC, Mendelsohn ME, Pasternak RC, Pinn VW, Robertson RM, Schenck-Gustafsson K, Sila CA, Smith SC Jr, Sopko G, Taylor AL, Walsh BW, Wenger NK, Williams CL. Summary of the Am Heart Association’s evidence-based guidelines for cardiovascular disease prevention in women. Arterioscler Thromb Vasc Biol 2004;24:394–6
56. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37
57. Mendelsohn ME, Karas RH. Estrogen and the blood vessel wall. Curr Opin Cardiol 1994;9:619–26
58. Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P, Mendelsohn ME. Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 2002;90:1087–92
59. Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, Hodgin J, Shaul PW, Thoren P, Smithies O, Gustafsson JA, Mendelsohn ME. Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002;295:505–8
60. Hayward CS, Kelly RP, Collins P. The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc Res 2000;46:28–49
61. Hayward CS, Knight DC, Wren BG, Kelly RP. Effect of hormone replacement therapy on non-invasive cardiovascular haemodynamics. J Hypertens 1997;15:987–93
62. Regitz-Zagrosek V, Brokat S, Tschope C. Role of gender in heart failure with normal left ventricular ejection fraction. Prog Cardiovasc Dis 2007;49:241–51
63. Anthony M, Berg MJ. Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I. J Womens Health Gend Based Med 2002;11:601–15
64. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583–7
65. Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Wessel TR, Arant CB, Pohost GM, Lerman A, Quyyumi AA, Sopko G. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol 2006;47:S4–S20
66. Bourassa PA, Milos PM, Gaynor BJ, Breslow JL, Aiello RJ. Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 1996;93:10022–7
67. Carlson DL, Lightfoot E Jr, Bryant DD, Haudek SB, Maass D, Horton J, Giroir BP. Burn plasma mediates cardiac myocyte apoptosis via endotoxin. Am J Physiol Heart Circ Physiol 2002;282:H1907–H1914
68. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC, Bender JR. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 2000;87:677–82
69. Kow LM, Pfaff DW. The membrane actions of estrogens can potentiate their lordosis behavior-facilitating genomic actions. Proc Natl Acad Sci USA 2004;101:12354–7
70. Yu HP, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. The PI3K/Akt pathway mediates the nongenomic cardioprotective effects of estrogen following trauma-hemorrhage. Ann Surg 2007;245:971–7
71. Johnson CL, Rifkind BM, Sempos CT, Carroll MD, Bachorik PS, Briefel RR, Gordon DJ, Burt VL, Brown CD, Lippel K, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993;269:3002–8
72. Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, Rabi D, Tremblay J, Alamian A, Barnett T, Cox J, Ghali WA, Grace S, Hamet P, Ho T, Kirkland S, Lambert M, Libersan D, O’Loughlin J, Paradis G, Petrovich M, Tagalakis V. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ 2007;176:S1–S44
73. Burke JH, Goldberger JJ, Ehlert FA, Kruse JT, Parker MA, Kadish AH. Gender differences in heart rate before and after autonomic blockade: evidence against an intrinsic gender effect. Am J Med 1996;100:537–43
74. Perk G, Stessman J, Ginsberg G, Bursztyn M. Sex differences in the effect of heart rate on mortality in the elderly. J Am Geriatr Soc 2003;51:1260–4
75. Hinojosa-Laborde C, Chapa I, Lange D, Haywood JR. Gender differences in sympathetic nervous system regulation. Clin Exp Pharmacol Physiol 1999;26:122–6
76. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000;132:689–96
77. Rossouw JE. Effect of postmenopausal hormone therapy on cardiovascular risk. J Hypertens Suppl 2002;20:S62–S65
78. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33
79. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases]. J Cardiol 1991;21:203–14
80. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J, Longe TF, Maron BJ. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005;111:472–9
81. Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2007;124:283–92
82. Howard BV, Cowan LD, Go O, Welty TK, Robbins DC, Lee ET. Adverse effects of diabetes on multiple cardiovascular disease risk factors in women. The Strong Heart Study. Diabetes Care 1998;21:1258–65
83. Kragelund C, Kober L, Faber J, Steffensen R, Hildebrandt P. Metabolic syndrome and mortality in stable coronary heart disease: relation to gender. Int J Cardiol 2007;121:62–7.
84. Onat A, Hergenc G, Keles I, Dogan Y, Turkmen S, Sansoy V. Sex difference in development of diabetes and cardiovascular disease on the way from obesity and metabolic syndrome. Metabolism 2005;54:800–8
85. Juutilainen A, Kortelainen S, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 2004;27:2898–904
86. Lee WL, Cheung AM, Cape D, Zinman B. Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies. Diabetes Care 2000;23:962–8
87. Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol 2002;40:505–10
88. Mendelsohn ME, Karas RH. HRT and the young at heart. N Engl J Med 2007;356:2639–41
89. Ouyang P, Michos ED, Karas RH. Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions. J Am Coll Cardiol 2006;47:1741–53
90. Ouyang P, Tardif JC, Herrington DM, Stewart KJ, Thompson PD, Walsh MN, Bennett SK, Heldman AW, Tayback MA, Wang NY. Randomized trial of hormone therapy in women after coronary bypass surgery. Evidence of differential effect of hormone therapy on angiographic progression of disease in saphenous vein grafts and native coronary arteries. Atherosclerosis 2006;189:375–86
91. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465–77
92. Malcolm DD, Burns TL, Mahoney LT, Lauer RM. Factors affecting left ventricular mass in childhood: the Muscatine Study. Pediatrics 1993;92:703–9
93. de Simone G, Devereux RB, Daniels SR, Meyer RA. Gender differences in left ventricular growth. Hypertension 1995;26: 979–83
94. Leinwand LA. Sex is a potent modifier of the cardiovascular system. J Clin Invest 2003;112:302–7
95. Blair ML. Sex-based differences in physiology: what should we teach in the medical curriculum? Adv Physiol Educ 2007;31: 23–5
96. Devereux RB. Detection of left ventricular hypertrophy by M-mode echocardiography. Anatomic validation, standardization, and comparison to other methods. Hypertension 1987;9: II19–26
97. Devereux RB, Pickering TG, Alderman MH, Chien S, Borer JS, Laragh JH. Left ventricular hypertrophy in hypertension. Prevalence and relationship to pathophysiologic variables. Hypertension 1987;9:II53–60
98. Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WP. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988;108:7–13
99. Douglas PS, Katz SE, Weinberg EO, Chen MH, Bishop SP, Lorell BH. Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload. J Am Coll Cardiol 1998;32:1118–25
100. Tamura T, Said S, Gerdes AM. Gender-related differences in myocyte remodeling in progression to heart failure. Hypertension 1999;33:676–80
101. Alla F, Al-Hindi AY, Lee CR, Schwartz TA, Patterson JH, Adams KF Jr. Relation of sex to morbidity and mortality in patients with heart failure and reduced or preserved left ventricular ejection fraction. Am Heart J 2007;153:1074–80
102. Grandi AM, Venco A, Barzizza F, Scalise F, Pantaleo P, Finardi G. Influence of age and sex on left ventricular anatomy and function in normals. Cardiology 1992;81:8–13
103. Hundley WG, Kitzman DW, Morgan TM, Hamilton CA, Darty SN, Stewart KP, Herrington DM, Link KM, Little WC. Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796–802
104. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study. Circulation 2005;112:2254–62
105. Cantor WJ, Miller JM, Hellkamp AS, Kramer JM, Peterson ED, Hasselblad V, Zidar JP, Newby LK, Ohman EM. Role of target vessel size and body surface area on outcomes after percutaneous coronary interventions in women. Am Heart J 2002;144: 297–302
106. Sheifer SE, Canos MR, Weinfurt KP, Arora UK, Mendelsohn FO, Gersh BJ, Weissman NJ. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000; 139: 649–53
107. Herity NA, Lo S, Lee DP, Ward MR, Filardo SD, Yock PG, Fitzgerald PJ, Hunt SA, Yeung AC. Effect of a change in gender on coronary arterial size: a longitudinal intravascular ultrasound study in transplanted hearts. J Am Coll Cardiol 2003;41:1539–46
108. Zeier M, Dohler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13:2570–6
109. Villareal RP, Woodruff AL, Massumi A. Gender and cardiac arrhythmias. Tex Heart Inst J 2001;28:265–75
110. Merri M, Benhorin J, Alberti M, Locati E, Moss AJ. Electrocardiographic quantitation of ventricular repolarization. Circulation 1989;80:1301–8
111. Jochmann N, Stangl K, Garbe E, Baumann G, Stangl V. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur Heart J 2005;26:1585–95
112. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–4
113. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–52
114. Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, Ganiats TG, Gomes AS, Gornik HL, Gracia C, Gulati M, Haan CK, Judelson DR, Keenan N, Kelepouris E, Michos ED, Newby LK, Oparil S, Ouyang P, Oz MC, Petitti D, Pinn VW, Redberg RF, Scott R, Sherif K, Smith SC Jr, Sopko G, Steinhorn RH, Stone NJ, Taubert KA, Todd BA, Urbina E, Wenger NK. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481–501
115. Lerman A, Sopko G. Women and cardiovascular heart disease: clinical implications from the Women’s Ischemia Syndrome Evaluation (WISE) Study. Are we smarter? J Am Coll Cardiol 2006;47:S59–S62
116. Hung J, Chaitman BR, Lam J, Lesperance J, Dupras G, Fines P, Bourassa MG. Noninvasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography and exercise thallium myocardial perfusion scintigraphy. J Am Coll Cardiol 1984;4:8–16
117. Bairey Merz N, Bonow RO, Sopko G, Balaban RS, Cannon RO III, Gordon D, Hand MM, Hayes SN, Lewis JF, Long T, Manolio TA, Maseri A, Nabel EG, Desvigne Nickens P, Pepine CJ, Redberg RF, Rossouw JE, Selker HP, Shaw LJ, Waters DD. Women’s Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2–4, 2002: executive summary. Circulation 2004;109:805–7
118. Alexander KP, Shaw LJ, Shaw LK, Delong ER, Mark DB, Peterson ED. Value of exercise treadmill testing in women. J Am Coll Cardiol 1998;32:1657–64
119. Marwick TH, Shaw LJ, Lauer MS, Kesler K, Hachamovitch R, Heller GV, Travin MI, Borges-Neto S, Berman DS, Miller DD. The noninvasive prediction of cardiac mortality in men and women with known or suspected coronary artery disease. Economics of Noninvasive Diagnosis (END) Study Group. Am J Med 1999;106:172–8
120. Nabel EG, Selker HP, Califf RM, Canto JG, Cao JJ, Desvigne-Nikkens P, Goldberg RJ, Finnegan JR Jr, Vaccarino V, Virmani R. Women’s Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2–4, 2002: Section 3: diagnosis and treatment of acute cardiac ischemia: gender issues. Circulation 2004;109:e50–e52
121. Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 1998;105:32S–9S
122. von Mering GO, Arant CB, Wessel TR, McGorray SP, Bairey Merz CN, Sharaf BL, Smith KM, Olson MB, Johnson BD, Sopko G, Handberg E, Pepine CJ, Kerensky RA. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:722–5
123. Triola B, Olson MB, Reis SE, Rautaharju P, Merz CN, Kelsey SF, Shaw LJ, Sharaf BL, Sopko G, Saba S. Electrocardiographic predictors of cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol 2005;46:51–6
124. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. QRS duration and mortality in patients with congestive heart failure. Am Heart J 2002;143:1085–91
125. Bairey Merz CN, Shaw LJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Pepine CJ, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Lerman A, Quyyumi AA, Sopko G. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol 2006;47:S21–S29
126. Mosca L, Appel LJ, Benjamin EJ, Berra K, Chandra-Strobos N, Fabunmi RP, Grady D, Haan CK, Hayes SN, Judelson DR, Keenan NL, McBride P, Oparil S, Ouyang P, Oz MC, Mendelsohn ME, Pasternak RC, Pinn VW, Robertson RM, Schenck-Gustafsson K, Sila CA, Smith SC Jr, Sopko G, Taylor AL, Walsh BW, Wenger NK, Williams CL. Evidence-based guidelines for cardiovascular disease prevention in women. J Am Coll Cardiol 2004;43:900–21
127. Boudikova B, Szumlanski C, Maidak B, Weinshilboum R. Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther 1990;48:381–9
128. de Vos JW, Geerlings PJ, van den Brink W, Ufkes JG, van Wilgenburg H. Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. Eur J Clin Pharmacol 1995;48:361–6
129. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984;61:27–35
130. Sasaki M, Tateishi T, Ebihara A. The effects of age and gender on the stereoselective pharmacokinetics of verapamil. Clin Pharmacol Ther 1993;54:278–85
131. Schwartz JB, Capili H, Daugherty J. Aging of women alters S-verapamil pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1994;55:509–17
132. Thummel KE, O’Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, Wilkinson GR. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1996;59: 491–502
133. Wing LM, Miners JO, Birkett DJ, Foenander T, Lillywhite K, Wanwimolruk S. Lidocaine disposition–sex differences and effects of cimetidine. Clin Pharmacol Ther 1984;35:695–701
134. Xue FS, An G, Liao X, Zou Q, Luo LK. The pharmacokinetics of vecuronium in male and female patients. Anesth Analg 1998;86:1322–7
135. Xue FS, Tong SY, Liao X, Liu JH, An G, Luo LK. Dose-response and time course of effect of rocuronium in male and female anesthetized patients. Anesth Analg 1997;85:667–71
136. Kashuba AD, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 1998;34:203–18
137. Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet 2003;42:107–21
138. Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health 1994;15:619–29
139. Sica DA, Wood M, Hess M. Gender and its effect in cardiovascular pharmacotherapeutics: recent considerations. Congest Heart Fail 2005;11:163–6
140. Propranolol after myocardial infarction. JAMA 1982;248: 2833–4
141. Fletcher A, Beevers DG, Bulpitt C, Butler A, Coles EC, Hunt D, Munro-Faure AD, Newson RB, O’Riordan PW, Petrie JC. Beta adrenoceptor blockade is associated with increased survival in male but not female hypertensive patients: a report from the DHSS Hypertension Care Computing Project (DHCCP). J Hum Hypertens 1988;2:219–27
142. Walle T, Walle K, Mathur RS, Palesch YY, Conradi EC. Propranolol metabolism in normal subjects: association with sex steroid hormones. Clin Pharmacol Ther 1994;56:127–32
143. Kendall MJ, Quarterman CP, Jack DB, Beeley L. Metoprolol pharmacokinetics and the oral contraceptive pill. Br J Clin Pharmacol 1982;14:120–2
144. Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996;94:2535–41
145. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J 2007;153:891–9
146. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403–11
147. Levin RI. The puzzle of aspirin and sex. N Engl J Med 2005;352:1366–8
148. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293–304
149. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ. A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583–92
150. Yun CH, Wood M, Wood AJ, Guengerich FP. Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4. An explanation of the variable elimination clearance. Anesthesiology 1992;77:467–74
151. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995;50:222–39
152. Hoymork SC, Raeder J. Why do women wake up faster than men from propofol anaesthesia? Br J Anaesth 2005;95:627–33
153. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand 2003;47:241–59
154. Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 1996;205:207–9
155. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 1996;2:1248–50
156. Collins P, Rosano G, Casey C, Daly C, Gambacciani M, Hadji P, Kaaja R, Mikkola T, Palacios S, Preston R, Simon T, Stevenson J, Stramba-Badiale M. Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of Eur cardiologists and gynaecologists. Eur Heart J 2007;28:2028–40
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