Nonobstructive CAD and Her Heart:
A Diagnostic Dilemma

Ischemic heart disease (IHD) in women is an important problem that is difficult to identify early because understanding of early-stage symptoms and mechanisms is lacking.¹ The presentation of IHD in women is more complex and multifactorial than that in men.² Traditional diagnostic tests that focus on identifying obstructive disease are not as effective in women as in men.² Up to 50% of women undergoing catheterization show nonobstructive coronary artery disease (CAD).³ Therefore, the need to effectively work up chest pain symptoms in women is paramount.³ This issue of Know Her Heart examines the issue of nonobstructive CAD in women and the need for improved screening in this population.

Microvascular Ischemia in Women: A Clinical Challenge

Persistent anginal symptoms in women without angiographic CAD—that is, no demonstrated obstruction—present a challenge in terms of diagnosis and treatment.⁴ According to the landmark WISE^a study, microvascular ischemia is frequently associated with such symptoms in women with nonobstructive coronary arteries.⁵ Reis et al reported that, in a subset of 159 women from the WISE study with chest pain in the absence of obstructive CAD, 47% were found to have subnormal (<2.5) coronary flow velocity reserve suggestive of microvascular dysfunction.⁶

Such vascular dysfunction plays a central role in the genesis of symptoms and ischemia in women, as well as in the estimation of outcome.² WISE study investigators suggest that ischemia in the setting of vascular dysfunction places women at relatively higher risk than their male counterparts for any amount of obstructive coronary disease.²

^a Women's Ischemia Syndrome Evaluation study.

Pathophysiology of IHD in Women: New Hypotheses

Gender-specific differences in response to atherosclerotic risk burden may affect the development of IHD in women.² Endogenous and exogenous sex hormones influence²:

Differences in inflammatory response and estrogen deficiency in premenopausal women may be etiologic in differences in IHD presentation, pathophysiology, and responses to treatment.²

In women, symptoms may occur in stressful settings due to impaired flow reserve and endothelial dysfunction in vessels with a relatively smaller arterial lumen, resulting in myocardial ischemia.² This may be further exacerbated in the presence of insulin resistance, metabolic syndrome, or hypertension with diastolic dysfunction.²

Need for Nonobstructive Disease Recognition and Risk Assessment

The WISE study showed that women without obstructive CAD but with abnormal nuclear magnetic resonance spectroscopy (MRS) results consistent with ischemia may have a similar cardiovascular event risk as women with overt CAD.⁴ Freedom-from-cardiovascular-event rates were similar between women with no CAD but abnormal MRS (57%) and those with CAD (52%), with both being significantly lower than rates in women with no CAD and normal MRS (87%; P=.009 vs no CAD/abnormal MRS, and P<.0001 vs CAD) (Figure 1).⁴
 

Figure 1. Freedom From Events by Diagnostic Category

MRS = magnetic resonance spectroscopy.
Adapted from Johnson et al. Circulation. 2004;109:2993-2999.
 

Therefore, effective workup of women's chest pain symptoms is of paramount importance.³ Women with angina not attributable to obstructive CAD are often diagnosed with noncardiac chest pain, but a diagnosis of coronary microvascular dysfunction should be considered in such patients.⁶

Because of the level of diagnostic uncertainty, additional risk assessment measures may be of relatively greater importance in women than in men, including²:

• Blood inflammatory markers (SOR: C)
• Evidence of plaque burden (SOR: C)
• Evidence of ischemia (SOR: C)

Tests such as cardiac magnetic resonance, MRS, and invasive coronary vasomotor testing may be promising approaches for diagnosis and management of women with microvascular disease.³ Additionally, vascular function assessment with intracoronary acetylcholine and nitroglycerin can provide a prognostic tool for coronary events in women.⁷ Finally, coronary flow velocity reserve response to pharmacologic stress may also be a feasible and reliable tool to measure microvascular function in patients with chest pain and no obstructive CAD.³ Referral to a cardiologist may be warranted to determine appropriate testing.

Improving Management

Women with microvascular ischemia consistently have less symptom relief with current therapies, mainly because the pathophysiology is not well understood.²

Microvascular ischemia in women is often concomitant with abnormal endothelial function, and prudent management should include aggressive medical therapy directed at improving endothelial function, atherosclerosis, and established risk factors, which includes⁵:

• Statin lipid lowering (SOR: A for high-risk women; SOR: B for low-risk women)
• Angiotensin-converting enzyme inhibitors (SOR: A)
• Aspirin (SOR: A for high-risk women; SOR: B for other women)

Improved management of subclinical disease may help improve outcomes. Once clinical cardiovascular disease develops in women, their prognosis appears to be worse than that of their male counterparts.⁸

Get WISE

The WISE study has been the source of much of the most important information about nonobstructive coronary disease in women. To read more about this landmark clinical trial, see the following WISE articles:

• Johnson BD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute–sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation. 2004;109(24):2993-2999. View abstract
• Pepine CJ. Ischemic heart disease in women. J Am Coll Cardiol. 2006;47(3 suppl S):1S-3S. View abstract
• Shaw LJ, et al. Insights from the NHBLI-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(3 suppl S):4S-20S. View abstract
• Bairey Merz CN, et al. Insights from the NHBLI-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(3 suppl S):21S-29S. View abstract
• Pepine CJ, et al. Some thoughts on the vasculopathy of women with ischemic heart disease. J Am Coll Cardiol. 2006;47(3 suppl S):30S-35S. View abstract
• Shaw LJ, et al. The value of estimated functional capacity in estimating outcome: results from the NHBLI-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. 2006;47(3 suppl S):36S-43S. View abstract
• Handberg E, et al. Impaired coronary vascular reactivity and functional capacity in women: results from the NHBLI-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. 2006;47(3 suppl S):44S-49S. View abstract
• Gierach GL, et al. Hypertension, menopause, and coronary artery disease risk in the Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. 2006;47(3 suppl S):50S-58S. View abstract
• Lerman A, et al. Women and cardiovascular heart disease: clinical implications from the Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. 2006;47(3 suppl S):59S-62S. View abstract
• Jacobs AK. Women, ischemic heart disease, revascularization, and the gender gap: what are we missing? J Am Coll Cardiol. 2006;47(3 suppl S):63S-65S. View abstract
• Quyyumi AA. Women and ischemic heart disease: pathophysiologic implication from the Women's Ischemia Syndrome Evaluation (WISE) study and future research steps. J Am Coll Cardiol. 2006;47(3 suppl S):66S-71S. View abstract

References
1. Pepine CJ. Ischemic heart disease in women. J Am Coll Cardiol. 2006;47(3 suppl S):1S-3S. 2. Bairey Merz CN, Shaw LJ, Reis SE, et al. 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(3 suppl S):21S-29S. 3. Ahmed B, Bairey Merz CN, Sopko G. Are we 'WISE'r? Findings from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation study. Womens Health. 2006;2(1):57-64. 4. Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health - National Heart, Lung, and Blood Institute - sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation. 2004;109(24):2993-2999. 5. 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(3 suppl S):59S-62S. 6. Reis SE, Holubkov R, Smith AJC, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001;141(5):735-741. 7. Quyyumi AA. Women and ischemic heart disease: pathophysiologic implication from the Women's Ischemia Syndrome Evaluation (WISE) study and future research steps. J Am Coll Cardiol. 2006;47(3 suppl S):66S-71S. 8. Sibley C, Blumenthal RS, Bairey Merz CN, Mosca L. Limitations of current cardiovascular disease risk assessment strategies in women. J Womens Health. 2006;(1):54-56.