Adverse Cardiovascular Outcomes in Women with Ischemic Heart Disease

Abraham Bornstein, MD, FACC
Weill Cornell Medical College
New York, NY
Have Women Been Historically Shortchanged?

The problems and paradoxes related to establishing the diagnosis of ischemic heart disease in women have persisted in terms of magnitude, complexity and severity. Variable symptoms of angina in the absence of clinically obstructive coronary artery disease (CAD) constitute a relatively common clinical scenario in women and remain a source of confusion for physicians caring for such patients. Until recently, the prognosis of women with signs and symptoms suggestive of myocardial ischemia in the absence of obstructive CAD had been thought to be benign based on early cohort studies. Clinically, such women have been offered little more than reassurance that they do not have cardiac disease, or when symptoms persist, are offered anxiolytics as well as antidepressants instead of appropriately targeted cardiac primary prevention. Nevertheless, when these symptoms persist, women have not only had to endure a host of various noninvasive cardiac tests, repeated hospitalizations, as well as invasive coronary angiography. More recently, the concept of the benign nature of this clinical scenario has been challenged, with more recent evidence demonstrating that women with cardiac symptoms in the setting of normal or nonobstructive coronary arteries still have an unacceptably high risk of future cardiac events.

Chest pain and other equivalent cardiac symptoms that may be suggestive of myocardial ischemia, even in the absence of obstructive CAD, have important functional, economic, and prognostic implications for women in general and society at large. A recent retrospective study of men and women with suspected ischemia resulting in referral for angiography showed that women were far more often found to have angiographically normal coronary arteries. Yet, these same women were 4 times more likely to be readmitted for chest pain or for an acute coronary syndrome within the next 180 days. Data from the Women's Ischemia Syndrome Evaluation (WISE) study estimate that, among the approximately 500,000 US women who undergo coronary angiography annually, 50% have had no demonstrable obstructive coronary lesions (where obstruction is considered 50% narrowing in any coronary artery) in contrast to 7% to 17% of men who undergo angiography.

As previously mentioned, in light of this high rate of nonobstructive coronary angiograms, until recently such women were usually offered little in terms of treatment, despite recurrent symptoms requiring hospitalization, repeated procedures, functional disabilities, and future cardiac events that result in a heavy economic burden with average lifetime costs estimated to be greater than $750,000. Despite being a common clinical scenario with important public health consequences, the prevalence of chest pain in the absence of obstructive CAD has not declined since initially reported.

Concomitantly, this has led to an increase in poor cardiac outcomes and an increase in cardiovascular mortality in women. Historically speaking, research and management in ischemic heart disease has traditionally focused on men, which had resulted in an unproven yet accepted assumption that what has been proven true for men must also probably be true for women. The more appropriate realization among medical researchers and academicians should have focused on the fact that actually, there are large deficiencies in the established knowledge base of ischemic heart disease, particularly related to patient gender. Over the course of the most recent decade, researchers have finally realized that the important clinical question that need to be answered was how clinically significant is ischemic heart disease in women, and why are there such discrepant diagnostic and management issues in women with ischemic heart disease when compared to men; specific related concerns should have focused on the following questions: is ischemic heart disease in women a different disease than ischemic heart disease in men?; what are the variant pathophysiologic mechanisms of angina in women as opposed to men?; what is the significance of the increased morbidity and mortality, age-related or otherwise, seen in women compared to men?; are the different manifestations of ischemic heart disease in men vs. women more a function of gender-related referral and treatment bias or an actual expression of a different pathophysiologic disease process.

Cardiovascular disease is the leading cause of death in both women and men. Although the number of cardiovascular deaths in the United States has declined in men, over the past decade, it has actually increased in women. Most of this increase has been attributed to primarily ischemic heart disease and ischemic stroke. Specifically, coronary heart disease, which includes coronary atherosclerotic disease, myocardial infarction, acute coronary syndromes, and angina, makes up the largest subset of this mortality, with more than 240,000 women dying annually from the disease. Unfortunately, this ominous trend is primed to continue, because not only is our population aging, but it is simultaneously being ravaged by the epidemics of obesity, metabolic syndrome, and diabetes, all of which disproportionately affect women. Considering both the outpatient and inpatient aspects of the problem, annual cost projections for the management of cardiovascular disease are approaching about $400 billion annually. Clearly, this is an important medical and public health issue which may not be fiscally sustainable.

Historically, gender specific differences in cardiovascular disease mortality provides further confirmatory evidence supporting the lack of comparable progress in population-based risk reduction efforts for women.  Ever since 1984, the total number of deaths from cardiovascular disease has been greater for women than for men.  In 2000, approximate 60,000 more women than men died from cardiovascular disease.  Further evidence has confirmed substantial delays in healthcare seeking behavior, less intensive resource utilization patterns, and longer times to diagnose for women as compared to men. Of the 1.1 million hospitalizations for acute myocardial infarctions each year, more men are admitted regardless of age group (721,000 in men vs. 410,000 women).  Despite more male admissions, the rate of reinfarctions and one year death rates are still higher in women. Furthermore, women have a less favorable midterm outcome after my career revascularization procedures than do their male counterparts.  A well-designed and effective diagnostic strategy is critical in women at risk for coronary heart disease because up to 40% of initial cardiac events are fatal.

On the other hand, more recently, there has been significant progress in the identification and treatment of risk factors for coronary artery disease, as well as advances in the diagnosis and treatment of ischemic heart disease, which have resulted in a decline in mortality in the United States. The recent National Health Statistics and Center for Disease Control data has shown a reduction in coronary heart disease age-adjusted death rates for women of 26.9% since 1999.  Despite this significant improvement coronary heart disease remains the leading cause of death of US women claiming the lives of over 210,000 in 2005. Since sudden cardiac death is often the first manifestation of coronary artery disease in a high proportion of women (52%) compared with men (42%), early identification of women at risk for ischemic heart disease is critical.

The appropriate and accurate evaluation of chest discomfort in women is the critical first step leading to the effective care and appropriate management of women with heart disease. Historically, this has been the point at which women have been more likely to be underdiagnosed, undertreated, or at least treated differently from men, especially when a definitive diagnosis had not yet been firmly established. In population studies of coronary heart disease over the years, women have often been either almost totally excluded from clinical trials, or at least significantly underrepresented.  As a result of this, current practice recommendations are thus inadvertently based on a model of heart disease developed from signs and symptoms most often seen in men with much of the new data on coronary heart disease in women, often confounded, questioned, or on occasion, entirely ignored.

Further complicating the problem, current established diagnostic tools and testing, focused on the classic model of chest pain caused by significant macrovascular coronary obstruction characteristically seen in men, are often limited in their efficacy in establishing a definitive diagnosis of obstructive coronary artery disease as the etiology for chest pain in women. Current diagnostic tools used to evaluate coronary artery disease derived their diagnostic utility based on the concept that cardiac ischemia is caused by "significant" vascular obstruction in any branch of a major coronary artery (greater than 50% stenosis by angiography).  However, of the 450,000 women undergoing cardiac catheterization and coronary angiography each year, more than 50% are found to have non-obstructive coronary lesions or normal coronary arteries, once again reflecting the fact that gender specific issues arise with each diagnostic modality in the assessment of chest pain and coronary artery disease in women. Another example of problem is reflected by the use of the ECG treadmill test, one of the most widely utilized coronary artery disease risk stratification tool, consistently demonstrates lower sensitivity and specificity and women (60% to 70%) when compared to men (~ 80%). This may in part reflect a lower pretest probability and/or prevalence of obstructive coronary artery disease in women; however other reasons, including conditions such as microvascular angina, mitral valve prolapse and/or coronary artery vasospasm may also play a role. Further observations that women are more limited in their ability to achieve maximal target levels of exercise, and that they demonstrate lower QRS voltage further detracts from the test's diagnostic accuracy. More recently, investigators have found that other information obtained from an exercise treadmill test besides ST depression, such as exercise duration, exercise capacity, and METS achieved, can also be utilized to supplement and therefore enhance prognostication. Researchers have subsequently discovered that the key to accurate diagnosis using exercise testing data in women is to include factors other than ST segment depression. 2 measures integrating multiple parameters from exercise testing have been found to dramatically improve diagnostic and prognostic accuracy of testing for women. These include an assessment of the simple          Δ ST/Δ heart rate index and or the Duke Treadmill score (calculated as: exercise time - (5 × ST segment deviation) + (4 × chest pain [1 = non-limiting, 2 = limiting]).  Okin and Kligfield reported an improvement in test sensitivity in women compared with men, using the simple Δ ST/Δ heart rate index; these investigators found 33% to 35% improvement in test sensitivity for detection of significant, 3-vessel coronary disease in women after adjusting for amount of exercise-induced ST segment depression by change in heart rate. In terms of stress SPECT myocardial perfusion imaging, the average sensitivity and specificity are 81% and 66%, respectively.  These results are similar for stress echocardiography with a sensitivity of 84% and a specificity of 76%. In microvascular angina and/or endothelial dysfunction, more commonly seen in female patients, the currently guideline-established stress testing modalities may be of lesser utility.  Nevertheless, research continues to report underrecognition and underdiagnosis of ischemic heart disease as a major contributing factor to the consistently higher mortality rates seen in women. For instance, recent evidence-based practice program reports from the Agency for Healthcare Research and Quality continue to find a paucity of women enrolled in cardiovascular diagnostic research studies. On the other hand, timely and accurate diagnosis has been shown to significantly reduce cardiovascular disease mortality for women. In fact, once the diagnosis is established, it appears that current therapeutic interventions are equally effective in decreasing risk in both women and men.

Ischemic Heart Disease Symptoms in Women and Their Associated Prognostic Value

Chest pain is the most common symptom suggestive of coronary artery disease, prompting subjects to seek attention from physicians. As previously mentioned, women are far more likely to have nonspecific chest pain symptoms than are men, which may contribute to missed diagnoses, loss of treatment and or intervention opportunities, and therefore increased risk of acute events associated with poor clinical outcomes. Patients with atypical symptoms have approximately twice the delay before hospital admission, and are less likely to receive appropriate therapy, therefore at risk of suffering higher mortality rates. In the past, research on coronary symptoms in women and their relationship with clinical outcomes has inadvertently focused on women with luminal obstructive coronary artery disease. In a study published in 2006, entitled Persistent Chest Pain Predicts Cardiovascular Events in Women without Obstructive Coronary Artery Disease. In the NIH-NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study, a recent four-center, NHLBI study that evaluated approximately 1,000 women with suspected ischemia referred for elective diagnostic coronary angiography, the objectives were to investigate new and diagnostic pathophysiologic mechanisms and to better characterize outcomes in the absence of flow-limiting stenoses by angiography.  Almost all of these women had chest discomfort. Angiographic findings of this cohort of women showed that only 38% of the women had 50% or greater stenosis. This confirmed several prior studies that found the majority of women presenting with symptoms and/or signs suggesting ischemic heart disease had no stenosis or <50% stenosis. It is this subgroup that was of particular interest. The investigators looked at women with non-obstructive coronary artery disease and were able to demonstrate that different symptom profiles were associated with different long-term outcomes.  The authors evaluated 412 patients without obstructive coronary artery disease, using 261 women with significant obstructive coronary artery disease to serve as controls. Whereas 54% of these patients had complete resolution of symptoms after discharge, 46% of the 412 patients continued to experience episodes of chest pain for more than a year.  Unexpectedly, the rate of the most serious cardiovascular outcomes was unusually high in this purported low-risk population. The combined endpoints of death, myocardial infarction, stroke, and heart failure were almost twice as high in the women (14.4%) who experience persistent chest pain, as opposed to the men (8.5%). These most recent findings continue to refute the notion that normal or near normal coronary angiography implies a benign prognosis, once again, prompting renewed debate about the proper strategy and public health efforts targeting early atherosclerosis, particularly in women.

Over the past decade, there has been more comprehensive data confirming significant gender differences in the presentation, diagnosis, and ultimately, the most effective treatment of chest pain due to coronary insufficiency in women as opposed to men. When compared to men, women have more in the way of atypical chest pain symptoms, such as chest pain that occurs during rest, or awakens the patient from sleep, or chest pain that is associated with periods of emotional stress. Women are also more likely to have accompanying symptoms such as neck and shoulder discomfort, nausea, vomiting, dyspnea, and or severe fatigue, symptoms which are far less characteristic in men who present with clinical coronary artery disease. It is therefore quite apparent that ischemia in women produces a significantly different pattern of clinical symptomatology. However, what we have learned from more recent trials is that while chest pain in women may be atypical, occurring at rest or presenting with other associated atypical symptoms beyond angina, this does not decrease the likelihood of coronary heart disease or adverse cardiac events as it might in men.

Therefore, it seems quite apparent that women who present with nonspecific chest pain and normal or near normal coronary angiograms do not have a benign prognosis nor a favorable outcome.  Among these patients, there is a significant number who can be shown to be suffering from cardiac pain of a presumed ischemic nature.  Most of these patients are women who complain of chest discomfort and suffer disability for years, ultimately resulting in significant morbidity and mortality.  Recent findings have demonstrated that some of these patients, mostly women, are at increased risk of myocardial infarction, as well as cardiac death.  Significant coronary plaque burden can be present despite an apparent normal or near normal coronary lumen, thus providing a link between a seemingly benign normal coronary angiogram and an unanticipated associated increased risk of a major future cardiac event.

It has also been demonstrated that physicians who astutely tried to utilize good clinical judgment in order to optimally triage patients down the appropriate path of diagnostic assessment, and optimal treatment, are often inadvertently influenced by their own gender biases. For the most part, guidelines and recommendations to prevent coronary artery disease in women do not differ much from those in men.  Nevertheless, women are less likely prescribed aspirin, beta blockers, as well as lipid lowering therapy as either primary or secondary prevention measures when compared to men. It has also been observed that women are treated less aggressively and referred for cardiac catheterization less frequently than their male counterparts. During the evaluation of the acute coronary syndrome such as occurs in the emergency room setting, women were less likely to receive heparin, angiotensin converting enzyme inhibitors, aspirin, and glycoprotein IIb/IIIa inhibitors, while being more likely to be discharged from the emergency room.

Finally, a general lack of awareness among women and physicians alike may also play a role in the gender disparities that have been well defined. For instance, only 55% of women surveyed in 2006 indicated heart disease as the leading killer in women.  In contrast, 63.1% of women identified heart disease as the leading cause of death in men. Women with appropriately healthy levels of risk factors also tended to underestimate their own personal risk for cardiovascular disease. Sadly, less than 20% of physicians interviewed were acquainted with the fact that annually, more women than men died of cardiovascular disease by a factor of 50,000.

The Unique Vascular Pathophysiology of Women with Ischemic Heart Disease

Over the past several years, a growing volume of experimental and clinical data indicate that gender associated with their inherent sex hormones may well play an important part in the heterogeneous and variable cardiovascular physiology and pathophysiology seen between men and women. New data from the Women’s Ischemia Syndrome Evaluation (WISE) on vascular findings in women with ischemic heart disease (IHD) and how these findings differ from those in men have corroborated these differences. For instance, a number of common vascular disease-related conditions are either unique to women (e.g., pregnancy related hypertensive disorders, gestational diabetes, peripartum dissection, polycystic ovarian syndrome, etc.) or more frequently seen in women (e.g., migraine, coronary spasm, lupus, vasculitis, Raynaud’s phenomenon, etc.) than in men. Post-menopausal women more frequently have many traditional vascular disease risk conditions (e.g., hypertension, diabetes, obesity, inactivity, and so on), and these conditions cluster more frequently in them than men. Many of these conditions have been linked with oxidative stress, endothelial dysfunction, inflammation, insulin resistance, defective angiogenesis, and dyslipidemia. Perhaps these conditions explain, at least in part, some non-genetic factors in a family history of CV disease that might a play a role in the lifelong risk for IHD in women.

Women’s coronary vessels, which are inherently structurally smaller in size (independent of body size), when pathologically impacted, appear to contain more diffuse atherosclerosis, and their microvasculature appear to be more frequently dysfunctional compared to men. Functionally, women’s vessels frequently show impaired vasodilator responses. A better understanding of these findings should provide direction for new algorithms to improve diagnostic evaluation, prognostic risk assessment, as well as more appropriate management of the vascular dysfunction underlying IHD in women.

Microvascular structural damage secondary to aging, hypertension, diabetes, left ventricular hypertrophy, and other processes is also likely to be important in ischemic heart disease in women as reflected by retinal microvascular abnormalities linked to blood pressure, inflammation, and endothelial dysfunction. Such microvascular abnormalities predict IHD outcomes in women but not men. Thus, retinal microvascular structural alterations allow a fairly easily obtained non-invasive assessment of systemic vascular pathology.

Risk Conditions for Vascular Dysfunction Seen in Women with IHD versus Men

  • Traditional risk factors
  • Higher prevalence in postmenopausal women
  • More frequent clustering (the metabolic syndrome)
  • When present, higher level (e.g., if hypertensive, higher BP, higher LDL, etc.)
  • Older age
  • More frequent vasculitis (e.g., lupus, temporal arteritis, Takayasu’s, etc.)
  • Conditions unique to women
  • Peripartum
  • Hypertensive disorders of pregnancy
  • Gestational diabetes
  • Delivering a thin baby
  • Coronary or aortic root dissection
  • Polycystic ovarian syndrome
  • Hypoestrogenemia of hypothalamic origin
  • Hormone replacement therapy
  • Others

BP = blood pressure; IHD = ischemic heart disease; LDL = low-density lipoprotein.

Considerable data has begun to accumulate supporting the fact that gender most likely associated with sex hormone differences between men and women has a very important influence on cardiovascular physiology and pathology. Much of this data has been corroborated by the Women’s Ischemia Syndrome Evaluation (WISE) Study, on vascular findings related to ischemic heart disease (IHD) in women and how these findings differ from those in men. The hypothesis of this study is that women with IHD have evidence for a more severe and/or different form of vascular disease compared with men.

A link between arterial size and sex hormones is supported by studies of transsexuals where brachial artery size in genetic men taking estrogens is smaller compared with control men. Genetic women taking androgens have larger arteries than control women. Androgen-deprivation therapy in genetic men is associated with smaller artery size compared with control men. These findings imply that sex hormones have different effects on arterial remodeling. Positive remodeling may be a marker of underlying vascular injury, which could explain the high event rate observed among women with non-obstructive coronary angiographic findings in the WISE Study.

Structural changes in large arteries from aging and atherosclerosis also increase arterial stiffness. In diabetic women, but not men, age-related stiffening of the aorta commonly occurs. Alterations in large artery stiffness were observed in a sample of women from the WISE Study compared with age-matched and body mass index-matched control women. In other postmenopausal women with CAD, increased brachial pulse pressure, another measure of arterial stiffness, was associated with CAD progression, independent of risk factors or hormone replacement. In the WISE Study, pulse pressure was an independent predictor of CAD severity and clinical outcomes. Non-invasive measures of arterial stiffness may be useful to estimate the atherosclerotic-induced structural consequences in post-menopausal women and may therefore, provide insight into the effect of various therapies on stiffness as well as adverse outcomes.

Coronary Structure and Function Underlying Vascular Dysfunction Seen in Women with IHD versus Men

  • Structural findings
  • Macrovessels and microvessels
  • Smaller size
  • Increased stiffness (fibrosis, remodeling, and so on)
  • More diffuse disease, erosion > rupture
  • Microemboli, rarefaction (drop out), disarray, and so on
  • Functional findings
  • Macro- and microvessels
  • Endothelial dysfunction
  • Smooth muscle dysfunction (Raynaud’s, migraine, CAS)
  • Inflammation
  • Plasma markers
  • Vasculitis (Takayasu’s, rheumatoid, SLE, CNSV, giant cell, etc)

CAS = coronary artery spasm; CNSV = central nervous system vasculitis; IHD = ischemic heart disease; SLE = systemic lupus erythematosus.

Women also have somewhat different clinical findings that relate to pathophysiology of IHD than male counterparts. The woman with IHD often is older, has a greater risk factor burden, and more functional disability.  Aging attenuated many estrogen-related potentially beneficial vascular responses including endothelial progenitor cells (EPCs) and coronary microvascular function in the WISE Study. Experimental models have linked sex hormones and other risk conditions (e.g., hypertension, diabetes, and so on) to IHD in women. Briefly, high estrogen levels before menopause and decreasing estrogen and progesterone levels after menopause are believed to influence IHD in women. Estrogen exerts effects via receptors abundant in vascular tissue to transduce signals regulating gene expression, but also has non-genomic actions. Variations in plasma sex hormones and receptor genes, acting with endothelial and vascular smooth muscle factors, are all potential links to the differences in vascular structure and function that contribute to both heterogeneity among women as well as gender differences in the manifestations of IHD.

Functional alterations as changes in vascular reactivity also suggest a more severe disease in women implicating both endothelium and smooth muscle. Sex hormones exert effects on vascular reactivity via endothelium and also directly on smooth muscle. Various mechanisms are involved, ranging from gender-specific or hormonal influences on nitric oxide synthase gene to sex-hormone related differences in L-type voltage-gated Ca2+-activated K+ channels and also include effects on vascular repair. Because women, during their lifetime, spend considerable time under widely fluctuating hormonal influences (e.g., puberty, pregnancy, peripartum, and menopause), their vessels may be naturally programmed for more robust functional alterations when compared to men.

Role of Coronary Endothelial Dysfunction

More than half the women tested with acetylcholine in the WISE had coronary endothelial dysfunction, which independently predicted adverse outcomes. The risk conditions present in women, alone or in clusters, increase oxidative stress to injure endothelium of both large and small vessels in varying degrees. In large arteries of women presenting with chest discomfort, endothelial dysfunction is a marker for early atherosclerosis before structural changes to the vessel wall are ever appreciated by you coronary angiography. Vascular injury resulting in endothelial dysfunction has been linked to positive remodeling of large coronary arteries without flow-limiting lesions. Endothelial dysfunction of the microvasculature has the potential to limit myocardial perfusion. Normal endothelial repair processes may be adequate for this injury, but over time, repair processes may deteriorate for many reasons (e.g., loss of estrogen, overwhelming oxidative stress as associated with metabolic syndrome, hypertension, obesity, aging, etc). Recent evidence indicates that bone-marrow–derived EPCs (endothelial progenitor cells) are important in vascular repair, and estrogen increases these circulating EPCs by antiapoptotic properties. Circulating EPCs become depleted in individuals with multiple risk conditions and aging, which may be why women present with ischemic heart disease approximately 10 or more years later in life than men.  This occurs at time when aging likely has powerful effects on supply and quality of EPCs. Thus women, at this later stage of life, would be less capable of vascular repair, which could explain poor outcomes compared with men whose coronary vessels were preconditioned at an age when they were more capable of vascular repair.

Role of Vascular Smooth Muscle Dysfunction

As previously mentioned manifestations suggesting alterations of vascular smooth muscle function are more frequent in women than men (e.g., coronary artery spasm, Raynaud’s phenomenon, and migraine), and both coronary spasm and migraine have been linked with IHD. Impaired smooth muscle relaxation has also been suggested as a marker for atherosclerosis. Coronary flow reserve attenuation with intracoronary adenosine, as observed in many of the WISE women, seems indicative of impaired microvascular smooth muscle relaxation. Positron emission tomographic scanning results in a WISE subgroup without epicardial CAD suggest that the distribution of this microvascular defect is heterogeneous, and P31 cardiac magnetic spectroscopy results document high-energy phosphate depletion as seen with ischemia. But atherosclerosis risk conditions account for <20% of the variability in coronary flow reserve, indicating that other unidentified factors are also influencing microvascular function.

Previous studies have also documented gender-related differences in skin flow responses to provocative maneuvers and in endothelial nitric oxide production in skin microvasculature. Estrogen improves endothelial function, but menopause is associated with abnormal endothelial function in the coronary microvasculature. Estrogens, but not progestogens, antagonize the effect of menopause. So women are primed to have microvascular dysfunction, which has been suggested as a cause for ischemia without flow-limiting epicardial vessel stenoses. Also, microvascular spasm may cause ischemia, and most of these patients are women. These examples indicate that microvascular dysfunction has the potential to evoke angina-like symptoms, induce cardiac ischemia, and is linked to adverse clinical outcomes.

Relative Roles of Endothelial Versus Smooth Muscle Dysfunction and Large Vessels versus Microvessels

Considerable evidence implicates the coronary microcirculation, along with large vessel atheroma, to explain findings of ischemic heart disease in women. This includes wide variability in effort tolerance over time (a frequent finding in women), large scatter between stenosis severity and flow reserve, reduced flow responses to stress in regions perfused by non-stenotic vessels, as well as variability in outcome after successful percutaneous coronary intervention.  It is also of interest that in 25% of women with acute coronary syndrome (ACS) who were subsequently proven not to have any flow-limiting stenosis, brain natriuretic peptide (BNP) and C-reactive protein (CRP) were predictive of adverse clinical outcomes and pathologic findings of plaque erosion with microvascular embolization is often found in women who suffer cardiovascular mortality.

In summary, considerable evidence indicates that the large and small coronary vessels of women with IHD may be more diseased compared to men. In such women, an area of induced ischemic injury may not be limited because usual vasorelaxation required for collateral function is abnormal. This hypothesis could help explain why women tolerate ACS poorly compared with men and why subsequent heart failure, for example, is not only more frequent but also more lethal in women than men.

A summary of the four-year, risk-adjusted outcomes by extent of coronary disease confirmed a 9.4% death or MI rate (or about 2.7% annually) in the subgroup with no or minimal disease by angiography. This is an unacceptably high event rate. Another summary then estimated lifetime cost of care for cardiovascular disease by the angiographic extent of disease. Even women with no disease by angiography have in excess of $750,000 for lifetime costs for care. In an era of shrinking health care resources, such a finding also is disconcerting. Of particular interest was a subgroup of women without apparent angiographic obstruction. In a WISE substudy, the arteries of these women were examined using intravascular ultrasound (IVUS). The findings confirmed that >80% of women with so-called 'normal angiograms' have diffusely distributed plaque lesions by IVUS and the vast majority have multiple lesions. These data should be the foundation for the development of potential new gender specific algorithms to improve detection and management of ischemic heart disease in women at any stage.

Sex Specific Challenges in Diagnostic and Prognostic Testing for Coronary Artery Disease: Outcomes Research and Cost-Effectiveness Analysis for Cardiac Diagnostic Imaging

Technological advances in cardiac imaging have led to dramatic increases in test utilization and in cardiovascular health care costs. Over the past 10 years, cardiac imaging has become one of the major factors contributing to rising healthcare costs. For instance, more than 9.3 million myocardial perfusion procedures were performed in 2002 in the United States with a growth of 40% over the subsequent three years. Some of the newer testing methodologies are more expensive but also more accurate than traditional exercise ECG testing.  The problem is the paucity of information that exists to date that could be used to guide the clinician about which test order or to inform policymakers about which tests represent the best value.  Despite several meta-analyses based primarily on observational studies, there continues to be limited comparative diagnostic as well as prognostic data in similar at-risk populations. Significant cost saving could be realized if rational healthcare policies, based on both clinical outcomes and cost-effectiveness data, allocated limited resource use more efficiently in appropriate at-risk populations.  One of the greatest challenges in choosing cost-effective and accurate diagnostic testing strategies for disease detection and risk stratification, involves the appropriate selection of candidates primarily on the basis of their pretest cardiovascular risk assessment such as patients who are at intermediate to moderate risk of disease. Cost-effective and accurate noninvasive cardiac testing becomes much more difficult in populations with a low prevalence of disease. For instance, coronary artery disease is less prevalent in premenopausal women and its incidence tends to lag anywhere from 10 to 15 years behind that of men until approximately the seventh decade of life.  Therefore, risk factors and chest pain history in women, utilizing clinically established risk prediction algorithms, should play a significant role in determining the pretest likelihood of the presence of ischemic heart disease as well as disease-related prognosis, in terms of future cardiovascular events. This type of information would be extremely valuable in guiding clinical decision-making and therapeutically effective risk reduction strategies. Healthcare advances such as new drugs, devices, or screening and diagnostic tests must demonstrate safety and efficacy to be approved for clinical use. However, in the face of rising healthcare costs and limited budgets, questions persist regarding their value.  Cost-effectiveness analysis is one approach to determining value and refers to a method for assessing the costs and health benefits of an intervention or diagnostic test. Assuming that health budgets cannot meet all of the possible demand, cost-effectiveness evaluation can assist decision-makers in appropriately allocating resources to maximize the net public health benefit from choosing among options in the care of patients. On the basis of current guidelines, exercise stress testing is considered the primary standard reference test to investigate the cause of chest discomfort presumed to be of coronary origin. Stress imaging, utilizing either stress echocardiography or stress myocardial perfusion imaging, are both considered second choices.  Coronary angiography has been relegated to third choice.  However, while the cost of exercise EKG testing is lower, the accuracy of other imaging modalities has been reported to be higher. An economic evaluation could be quite helpful in choosing the appropriate diagnostic algorithm, sense, from a clinical standpoint, it is not enough if a test is marginally better than another to justify its use; the extra value should be proportional to the extra cost and any potentially associated extra risk.

As cost-effectiveness analysis is primarily an approach to evaluating competing diagnostic tools or therapies, it cannot answer all questions regarding the available diagnostic strategies to detect ischemic heart disease and is by no means the only approach that healthcare economists use. Thus, cost-effectiveness analysis in and of itself cannot answer questions such as how many patients will be helped, how much will it cost society, and how will it be paid for. By no means does cost-effectiveness analysis suggest that larger societal questions are somehow irrelevant, however, cost-effectiveness analysis may help inform decisions, thus helping society make choices offering better value.

Cost-effectiveness analysis is an approach that can be used to extend the understanding of efficacy data, which often come from clinical trials. Despite its many limitations, when appropriately applied, it is more valuable than comparisons of cost alone, sometimes called cost-minimization studies, which implicitly suggest equivalence of efficacy. Consumers that utilize this information (i.e., guideline committees, policy makers, and health insurers) should be quite familiar with its strengths and limitations. Obviously, efficacy alone can never be the sole criterion by which a diagnostic modality should be evaluated; many other issues may limit the value of the new diagnostic modality being tested, including safety, adverse effects, and issues as to whether the therapy can be practically and widely applied.  Similarly, no one would reasonably argue that cost-effectiveness should be the sole criterion for deciding whether a therapy should be implemented or covered by health insurance. Cost-effectiveness analysis is a method for describing the efficiency by which any new diagnostic modality or therapy leads to improved health. Many other factors should be considered in rendering such decisions.

As an example, the future use of cardiac CT and MRI depends not only on their sensitivity and specificity in diagnosing ischemic heart disease and their ability to predict acute cardiac events, but also on their cost-benefit ratio.  To date, limited data is available on the cost-effectiveness of cardiac CT and MRI. A few studies have suggested that, in patients with low to intermediate pretest probability of CAD, coronary artery calcium scanning as the initial non-invasive test can be a more cost-effective pathway for identifying patients in need of invasive coronary angiography to identify significant coronary stenoses than traditional diagnostic pathways, especially those beginning with exercise treadmill exercise testing. Similarly, absence of coronary artery calcium on CT scanning may save costs by reliably identifying patients who do not need expensive invasive coronary angiography despite suggestive history and stress testing.

Among patients with risk factors for CAD, detection of subclinical CAD by coronary artery calcium scanning may allow focusing intensive primary risk factor modification with expensive pharmacologic agents on those patients who are at highest risk of developing advanced vascular disease. Initial detection of subclinical CAD could potentially decrease the cost of cardiovascular morbidity and mortality to society by identifying patients in whom disabling acute coronary events may be prevented or postponed by risk factor modification. Instead of serial coronary artery calcium scanning, use of MCG, which is significantly less costly might aid in this approach by monitoring the effect of lifestyle modification or pharmacologic intervention in delaying ischemic heart disease progression. Such potential unproven benefits must be weighed against the cost of broad population-based application of using MCG, cardiac CT or MRI, especially if performed conjointly.

A number of studies have demonstrated for instance, that stress echocardiography in women, offers additional prognostic data beyond that provided by clinical or exercise treadmill testing alone, and therefore may be more cost effective.  For example, the low specificity of exercise ECG testing especially in young and middle-aged women could potentially lead to a higher rate of unnecessary coronary angiography with its associated inherent increased expense.  Additionally, the results of several studies indicate that stress echocardiography may be a cost efficient tool in diagnosing suspected coronary artery disease in women with an intermediate pretest likelihood of coronary disease.

In terms of cardiac radionuclide imaging, SPECT imaging has been the most commonly performed stress imaging modality in the United States.  Of the estimated 7.8 million patients who underwent perfusion imaging in 2002, approximately 40% were women. Exercise myocardial perfusion imaging, however, has been reported to have technical limitations especially in women where, for instance, where there may be a significant incidence of false positive results related to breast attenuation as well as small left ventricular cavity size. Because of the older age of most women undergoing stress myocardial perfusion imaging for the diagnosis of coronary artery disease, advanced age and the growing prevalence of obesity, both, often associated with decreased exercise capacity, may produce a higher incidence of false negative results necessitating the use of pharmacological stress SPECT imaging.

Ultimately, the aim of the cardiac diagnostic workup is to establish or rule out the diagnosis of ischemic heart disease, and/or coronary artery disease with optimal accuracy. In the diagnostic evaluation of patients, however, calculating diagnostic sensitivity and specificity is more often than not hampered by verification work-up bias in which women with abnormal test results are referred for cardiac catheterization, resulting in enhanced diagnostic sensitivity, but at the cost of diminished specificity. In terms of long-term prognosis based on the results of imaging tests to define false negative and false positive results, most recent data has been shown to be reliable and helpful in predicting the risk of cardiac events. The availability and utilization of this prognostic information encourages a change from an anatomy-based to a risk-based treatment strategy on the basis of the interpretation of these noninvasive test results, which should prove quite beneficial to the management of women with heart disease, especially in symptomatic women in whom non-obstructive coronary disease is prevalent.

In summary therefore, most of the factors that impact the accuracy of diagnostic stress testing in women include the following issues. 1) There is a lower overall prevalence of coronary artery disease in general, and obstructive coronary disease in particular, in women, with a higher prevalence of single vessel disease; 2) There is a higher prevalence of atypical chest discomfort presumed secondary to unusual etiologies including microvascular disease, coronary spasm or cardiac syndrome X, and even mitral valve prolapse associated chest pains. 3) Symptomatology in women has been inherently less predictive in conjunction with being less well analyzed. 4) Due to age at initial diagnosis or obesity, women have demonstrated limited exercise capacity. 5) The response to exercise in women is different than that seen in men in a number of ways including, limited exercise capacity, lower peak exercise values, less increase in left ventricular ejection fraction, increased cardiac output by enhancing end-diastolic volume, and inappropriate catecholamine release. 6) The estrogenic hormonal milieu in women can produce digitalis-like false positive ECG changes. 7) Lastly, anatomical differences between men and women that can affect myocardial perfusion cardiac imaging results include smaller coronary size in women, diminished left ventricular chamber size in women, and female breast attenuation artifact.

From the complexity of the gender-specific data accumulated to date, certain observations can be made, which make certain hypotheses plausible.  Firstly, symptoms of chest discomfort in women may in and of themselves be an independent predictor of cardiovascular events.  Secondly, symptomatic women have poorer clinical outcomes and prognoses despite the absence of obstructive macrovascular coronary artery disease. Finally, it is highly likely that a significant number of women with cardiac symptoms have true myocardial ischemia due primarily to microvascular coronary disease and/or inducible endothelial dysfunction involving the coronary vascular system as has been previously demonstrated in a subset of women from the WISE Study. Therefore, the appearance of normal coronary arteries during traditional coronary angiography may actually be misleading and not truly reflective of either coronary arteriolar pathology or overall plaque burden.

Every year, 5 billion imaging studies are performed worldwide, with 50% of them being cardiovascular examinations.  In the past 5 years since the introduction of 64-detector row cardiac computed tomography angiography (CCTA), there has been an exponential growth in the quantity of scientific evidence to support the feasibility of its use in the clinical evaluation of individuals with suspected coronary artery disease (CAD). Since then, there has been considerable debate as to where CCTA precisely fits in the algorithm of evaluation of individuals with suspected CAD.  Proponents of CCTA contend that the quality and scope of the available evidence to date support the replacement of conventional methods of CAD evaluation by CCTA, whereas critics assert that clinical use of CCTA is not yet adequately proven and should be restricted, if used at all. Coincident with the scientific debate underlying the clinical utility of CCTA, there has developed a perception by many that the rate of growth in cardiac imaging is disproportionately high and unsustainable. In this respect, all noninvasive imaging modalities and, in particular, more newly introduced ones, have undergone a higher level of scrutiny for demonstration of clinical and economic effectiveness. We herein describe the latest available published evidence supporting the potential clinical and cost efficiency of CCTA, drawing attention not only to the significance but also the limitations of such studies. These points may trigger discussion as to what future studies will be both necessary and feasible for determining the exact role of CCTA in the workup of patients with suspected CAD.

Of the previously mentioned 5 billion imaging studies performed worldwide each year, of which 50% are cardiovascular examinations, 30 to 50% of all these studies may be partially or totally inappropriate according to recent estimates.  This represents potential harm for the patient undergoing the imaging procedure (who experiences all of the acute risks of the procedure and/or contrast study without any commensurable benefit), an excessive and unnecessary cost for society, often associated with long delays in the waiting lists for other patients needing the examination.  Economic induction, medico-legal concern, and specialist guidelines, which have not routinely weighed the potential benefits against the risks of a given procedure, boost inappropriateness of these imaging techniques. In case of ionizing tests, the reduction of useless imaging testing would improve the quality of care also through abatement of long-term risks, which are linked to the dose employed. The radiation dose equivalent of common cardiological imaging examinations corresponds to more than 1000 chest X-rays for a thallium scan and to more than 500 chest X-rays for a multislice computed tomography.  Although a direct evaluation of incidence of cancer in patients undergoing these procedures is not available, the estimated risk (often ignored by cardiologists) of cancer according to the latest 2005 Biological Effects of Ionizing Radiation Committee VII is about 1 in 500 exposed patients for cardiac thallium scintigraphy, and 1 in 750 for a CT scan. This level of risk is probably not acceptable when a scintigraphic or radiological procedure is utilized for cardiovascular screening (when the risk side of the risk-benefit equation is not fully considered) or when similar information can be obtained by other means associated with less risk exposure. By contrast, the cost may be fully acceptable in appropriately selected groups as a filter to more invasive, risky, and costly procedures (for instance, coronary angiography and anatomy-driven revascularization).  At this point in time, the cardiological community, that faces the reality of limited resources, needs to take responsibility for this inappropriate testing in order to minimize it, since the frequency of these tests precipitate a dramatic increase in health care costs with no derived health benefit, probable exposure to harm, and an overall reduction in the quality of care.

Where Do We Go From Here?

There are a number of important steps that need to be taken to bring this situation under control and ensure that female patients are also receiving the highest quality of care possible. First, educational and community supportive programs need to be created to increase awareness among women about their risk of heart disease. Second, we must educate, or re-educate physicians that ischemic heart disease, whether or not associated with obstructive coronary lesions is quite prevalent in women and carries a poor prognosis. Clinicians therefore need to pay more attention to even atypical symptoms associated with apparently normal test findings in women. Society, in general, must appreciate that there is a 'female pattern' of ischemia-related symptoms distinct from that seen in men, but just as deleterious. Physicians must come to grips with the fact that an apparently 'clean' coronary angiogram in a symptomatic woman does not mean a benign long-term prognosis. More research needs to be done looking at issues such as concealed plaque (e.g., remodeling), evidence of inflammation involving the vasculature, the prognostic utility of novel blood markers, and the roles of endothelial dysfunction, as well as microvascular pathology. Finally, it is absolutely imperative that we apply evidence-based preventive strategies to stem the tide of hypertension, obesity, and diabetes in all patients.

The ultimate goal of improved cardiovascular care in women requires more comprehensive risk assessment necessitating a more selective and gender-specific approach to the use of noninvasive cardiovascular studies as well as the appropriate institution of preventive interventions such as lipid lowering, aspirin, and/or ACE inhibition.  It must be clearly understood that an abnormal noninvasive test result in an intermediate-risk, asymptomatic person should be interpreted as yet another risk factor for a future cardiovascular event and not as a mandate for establishing the presence or absence of angiographically obstructive coronary artery disease.  Finally, it should be clear that the use of cardiovascular tests to improve assessment of prognosis should not be confused with the use of such tests for coronary disease diagnosis.