doi: 10.1161/01.CIR.0000116210.70548.2A
(Circulation. 2004;109:e56-e58.)
© 2004 American Heart Association, Inc.
AHA/NHLBI Conference Proceedings |
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 5: Gender-Related Risk Factors for Ischemic Heart Disease
Key Words: AHA Scientific Statements • women • ischemia • cardiovascular diseases
The concomitant effects of aging, traditional risk factors, and a lack of endogenous estrogen promote the sequelae of arterial dysfunction, inflammation, and atheromatous plaque deposition in women. The challenges for improved diagnosis of coronary artery disease (CAD) in women include the more complex and multifactorial nature of the disease process; small artery size; and vascular and metabolic abnormalities that have yet to be thoroughly elucidated with existing imaging technology. Conditional risk markers, such as high-sensitivity C-reactive protein (hs-CRP), may provide greater insight into the arterial insult and underlying risk burden. Conventional ischemia testing, aimed primarily at detection of obstructive lesions, has provided disappointing results in women. Perhaps as a result of vascular remodeling, symptomatic women more often have nonobstructive atherosclerotic disease and, in some cases, evidence of metabolic or vascular dysfunction. Imaging accuracy in women is also hampered by technical problems and differences in body habitus. In addition, studies assessing diagnostic accuracy of imaging methods have often included small numbers of women subjects. In larger female samples, stress echocardiography and single photon emission computed tomography (SPECT) have yielded positive results in terms of estimating clinical outcomes. Newer technology, such as magnetic resonance spectroscopy (MRS) and perfusion imaging (MRI), has revealed intriguing findings indicating reductions in both subendocardial flow and high-energy phosphates that are suggestive of myocardial ischemia during stress testing in symptomatic women without obstructive CAD. This section reviews the evidence for gender differences in traditional and novel risk factors and explores the use of conventional and innovative myocardial methods to detect myocardial ischemia.
Clinical Application and Evidence
Traditional Risk Factors
The Atherosclerosis Risk In Communities (ARIC) study assessed traditional risks (age, cholesterol, blood pressure, smoking, and diabetes) for CAD events in 15 792 middle-aged, black and white women and men. These traditional risk factors can be integrated into a global risk score to predict 10-year risk of CAD events. Most men and many women have a 10-year CAD risk of greater than 10%. Results from the ARIC study reveal that these risk equations have higher predictive value in women than in men.1 The addition of nontraditional risk factors and subclinical atherosclerosis measures improves prediction in men but not in women.1
Diabetes and Other Metabolic States
Diabetes mellitus negates gender protection and is therefore a CAD risk equivalent. Atherosclerosis begins early in the spectrum of insulin resistance and hyperinsulinemia, with resultant endothelial dysfunction. This process occurs even before the appearance of the metabolic syndrome and often develops in premenopausal women. Excess adiposity and a proinflammatory milieu contribute to these early mechanisms of disease.
Novel Risk Factors
Several novel CAD risk markers have been introduced over the past 10 years, including new forms of lipid particles, metabolites, hemostatic factors, and inflammatory markers.2 These are best classified as risk markers and not risk factors until causal status has been unequivocally established. However, it does appear that these markers reflect and contribute to the underlying pathophysiological processes.3 On the other hand, blood proteins associated with inflammation have proven to be consistent risk factors for CAD in women and men.4 These markers are largely independent of lipid effects but are closely related to insulin resistance and adiposity.5–7 Some medications have large, but often inconsistent, effects on these markers. For example, hormone replacement therapy can increase CRP levels 2- to 3-fold,8 whereas fibrinogen is unaffected by estrogen.9 Although these markers add small independent effects in prediction models, they do summarize much of the risk-based content of traditional risk factors and have been shown to be as predictive as (and in one study more predictive than) LDL cholesterol in hormone replacement therapy users and nonusers.10
Microvascular Abnormalities
It has been proposed that microvascular processes play a greater role in the development of CAD in women than in men as a result of smaller artery size, positive remodeling, and the unexplained higher cardiac event rates in women with established disease. These observations suggest a greater overall atherosclerotic burden for every level of identifiable obstructive disease in women compared with men. Although most studies of microvascular dysfunction have been conducted on small numbers of highly selected patients, data from the ARIC and Beaver Dam Eye Studies, using new computer-assisted measurements of the retinal vasculature,11 report that microvascular processes are more strongly associated with CAD in younger women (43 to 72 years of age) than in similarly aged men. Each standard-deviation decrease in the retinal arteriole-to-venule ratio was associated with a 37% increase in CAD risk.12
Conventional Ischemia Testing
Exercise electrocardiography has a reported lower diagnostic accuracy in women as a result of lower disease prevalence, hormonal fluctuations, lower electrocardiography voltage, and reduced exercise tolerance.13 Accuracy of testing is improved with the addition of an imaging modality. Gated SPECT provides a combination of myocardial perfusion and ventricular function measurements. Factors associated with suboptimal accuracy are small heart size, breast artifact, and the prevalence of single-vessel disease. The use of 99mTc radioisotopes improves SPECT accuracy.14 The prognostic information of SPECT was similar in both men and women in a registry of patients with stable chest pain. Three-year survival ranged from 99% to 85% for 0 to 3 vascular territories with perfusion deficits.15 Stress echocardiography relies on the detection of new or worsening wall motion abnormalities for demonstrable myocardial ischemia.16–18 Diagnostic accuracy is reduced in patients with borderline obstructive lesions and single-vessel CAD.19 Limited acoustic windows that may occur in obese patients or those with lung disease can be improved by using contrast agents to enhance the opacification of the left ventricular cavity. From a registry of 2476 women undergoing stress echocardiography, event-free survival was 97% for those with normal wall motion, compared with 88% for those with inducible wall motion abnormalities.20
Innovative Ischemia Testing
The Women’s Ischemic Syndrome Evaluation (WISE) study used novel testing to measure other markers of arterial dysfunction or myocardial ischemia, including brachial artery flow-mediated dilation, MRI perfusion, coronary flow reserve, coronary artery intravascular ultrasound, and MRS.21 For the WISE women, the detection of myocardial ischemia by conventional stress testing did not confer an adverse prognosis. Preliminary data obtained in a small subset of women without CAD suggest that evidence of ischemia detected by MRS with isometric handgrip stress identifies a cohort with an intermediate event-free survival.22
Cost-Effectiveness Analysis
Cost-effectiveness analysis of diagnostic strategies is challenging, with few clinical trials comparing gender-related differences in stable or acute coronary syndromes.23,24 Decision models have been used to simulate the effects of alternative testing strategies.25–27 The conclusions are sensitive to the limitations of available data, yet these models have provided insights about test use. Decision models suggest that the cost-effectiveness of noninvasive tests for CAD optimally occurs for women with an intermediate pretest probability. Technical improvements in resolution or precision and improvements in risk detection can aid in developing cost-effective testing strategies. However, documentation of a therapeutic benefit resulting in improved survival is critical to establishing cost-effective strategies for the diagnosis of CAD in women.
Section 5 Recommendations
- Global risk prediction models. Future research should focus on the development of evidence that supports the value of serum markers integrated with traditional risk factors, particularly markers amenable to currently available therapeutic interventions. Specifically, a large body of evidence supports the prognostic value of hs-CRP. Clinical trials of therapeutic interventions that reduce hs-CRP should be considered, incorporating investigation of the mechanisms by which hs-CRP increases cardiovascular risk. Also, given the high and rising prevalence of the metabolic syndrome, the role of adipokines as mediators for insulin resistance and inflammation could be explored.
- Simple screening tests for women. There is compelling epidemiological evidence that new risk measures may provide superior identification of women at risk for the development of CAD, including a large body of evidence on the differential risk of generalized retinal arteriolar narrowing. Further research is needed to explore the predictive value of this test as it relates to other measures of small vessel disease and atypical chest pain in women and to other tests for atherosclerosis burden.
- Randomized/controlled clinical trials. On the basis of the findings of the WISE study, there is a continued need for randomized trials comparing conventional testing with innovative testing with regard to the prediction and characterization of adverse cardiac events. As a prelude to randomized trials, there is interest in pooling data from National Heart, Lung and Blood Institute–sponsored and other available datasets. The resultant larger sample sizes of women would facilitate an analysis of symptoms, microvascular disease, and myocardial ischemia testing in relation to existing CAD and subsequent events.
Footnotes
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This paper represents a summary of a scientific conference sponsored by the National Heart, Lung and Blood Institute on October 2–4, 2002. The opinions expressed in this paper are those of the authors and do not necessarily represent those of the editor or the American Heart Association.
The publication of this statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 5, 2003. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0277. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4121, fax 410-528-4264, or e-mail kgray@lww.com. To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.
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