Angina, ischemia, infarct with open arteries: a women’s problem

We can no longer ignore myocardial ischemia in the absence of obstructive coronary arteries, particularly when our patient is a woman.

Current clinical care patterns document the tendency to disregard patients with “normal” or nonobstructive coronary angiography who are predominantly women in the setting of chest pain symptoms. New data demonstrate that this is no longer appropriate.

Specifically, patients with chest pain and normal or near normal coronary angiograms are a group in which the prognosis is not as benign as previously reported and represent missed opportunities for preventive therapies.

Prevalence

“Normal,” defined as no visible disease, or nonobstructive coronary disease (luminal irregularities <50% judged visually) at coronary angiography is present in 10% to 25% of women presenting with acute coronary syndrome/ST-segment elevation myocardial infarction compared to 6% to 10% in men. There are an estimated 1.4 million patients discharged from U.S. hospitals following an acute coronary syndrome annually and among these 600,000 are women.

C. Noel Bairey Merz

Among those women for whom angiographic data are available, this 10% to 25% “normal” coronary angiography rate translates into 60,000 to 150,000 women with acute coronary syndrome/MI with nonobstructive coronary disease annually in the United States alone. This number is far greater in magnitude than other health conditions that affect women, such as uterine cancer (36,100), ovarian cancer (23,100), cervical cancer (12,800), and death due to breast cancer (40,800).

Prognosis

The short-term prognosis of patients with unstable angina and nonobstructive coronary artery disease includes 2% of death and MI at 30 days follow-up. Recent data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study document that women with nonobstructive coronary disease and evidence of myocardial ischemia have a poor prognosis compared to women with nonobstuctive coronary disease and no myocardial ischemia.

Specifically, an adverse event rate of 14% that included cardiac death, nonfatal infarction and revascularization procedures during more than four years of follow-up was observed in these women, rivaling rates observed in women with obstructive coronary disease.

Additionally, more than 40% of these women are rehospitalized for chest pain more than once, and 30% underwent repeat coronary angiography despite demonstration of “normal” coronary arteries on prior angiography.

What does this mean? When carefully performed stress testing demonstrates ischemia in the setting of normal or nonobstructive coronary arteries, we can no longer call these “false positive” tests and ignore the ischemia.

The pathophysiology of women with angina and “normal” angiograms is not homogeneous and includes at least three groups: patients with chest pain of noncardiac origin; patients with chest pain of cardiac but nonischemic origin; and patients with chest pain due to myocardial ischemia related to coronary vascular abnormalities. All groups may have disability due to chest pain, but the prognosis and therapeutic targeting may be different across the groups.

Chest pain of noncardiac origin

Patients without evidence of ischemia using a sensitive measure such as stress perfusion imaging are more likely to have noncardiac chest pain, due to a variety of conditions including gastrointestinal.

These patients are often reassured following coronary angiography, do not have recurrent symptoms, and are less likely to be rehospitalized or undergo repeat coronary angiography. Referral for noncardiac evaluation, such as workup for esophageal or other gastrointestinal disorders, is appropriate.

Cardiac but nonischemic origin

A number of women with recurrent and persistent chest pain and normal coronary angiograms, including those with ischemic-appearing exercise electrocardiograms, may have exaggerated or abnormal cardiac pain perception. Increased pain perception is more common in women compared to men, although the reason or reasons remain poorly understood. Prior reports have not found significant relationships between pain perception and psychologic disorders.

Imipramine improves the symptoms of patients with abnormal cardiac pain perception and normal coronary angiograms, possibly through a visceral analgesic effect. Imipramine also has anticholinergic and alpha antagonist effects demonstrated in the coronary as well as peripheral circulation, which may be relevant in the modulation of the coronary microcirculation.

Cardiac and ischemic origin

Among the cardiac ischemic group, a minority of patients (2% to 3%) have variant angina caused by coronary artery spasm. This may or may not be demonstrated during stress testing and can require provocative testing during coronary angiography for a definitive diagnosis.

The much larger group of the cardiac ischemic etiology includes the patients with myocardial ischemia due to vascular dysfunction. Recent data demonstrate that a majority of these patients have an impaired coronary flow reserve, defined as an impairment in blood flow in response to exercise, metabolic or pharmacological stimulation, which can precipitate ischemia during periods of increased myocardial oxygen demand.

Coronary flow reserve can be measured by coronary sinus thermodilution, gated-single photon emission computed tomography (SPECT), positron emission tomography, intra-coronary Doppler velocity, or most recently by myocardial perfusion by magnetic resonance imaging (MRI).

There are likely a number of causes for impairment of coronary flow reserve in patients with nonobstructive coronary angiograms. Subjects with decreased endothelium-dependent vasodilatation responses, by definition, have decreased coronary flow reserve. Conversely, impaired coronary flow reserve does not necessarily mean endothelial vascular dysfunction because the abnormality could reside in the endothelium-independent response and in the microvascular coronary arteries.

Functional derangements of the microvascular arteries with no, or minor, endothelial dysfunction can occur in conditions such as hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, and systemic collagen diseases. Abnormalities in coronary microvascular response alone to adenosine do not appear to be predictive of adverse outcomes in patients with chest pain and normal angiograms.

Conversely, when impaired coronary flow reserve is accompanied by coronary endothelial dysfunction, as assessed by provocative coronary acetylcholine testing, it predicts an unfavorable outcome. Treatment for this patient group should include beta-adrenergic blockers to reduce myocardial oxygen consumption and symptoms. Exercise training has also been demonstrated to be of benefit.

Aggressive therapy with statins and ACE inhibitors should be used in patients who qualify for this treatment by the presence of risk factors, and/or evidence of atherosclerosis, and/or evidence of endothelial dysfunction. Persistence or deterioration of symptoms despite aggressive medical therapy in women with endothelial dysfunction is associated with coronary disease progression, and repeat coronary angiography is appropriate.

Future directions

While experimental, clinical and epidemiological studies show associations and potential links between oxidative stress, endothelial dysfunction and early reversible atherogenetic processes, there is a substantial need for further studies to be performed in this area. Large-scale collaborative clinical trials are also needed to determine the effectiveness of symptomatic treatment, as well as treatment of coronary endothelial dysfunction, and to test whether change in endothelial function relates to changes in outcomes.

Future study should also be directed at determining the value of less invasive methods of endothelial function measurement. While we work on these studies, however, we can no longer ignore myocardial ischemia in the absence of obstructive coronary arteries, particularly when our patient is a woman.

C. Noel Bairey Merz, MD, is director of the Preventive and Rehabilitative Cardiac Center at Cedars-Sinai Medical Center. She is also Holder of the Women’s Guild Chair in Women’s Health and Medical Director of Women’s Health at Cedars-Sinai and professor of medicine at the University of California, Los Angeles School of Medicine. Bairey Merz is an editorial board member of Cardiology Today’s Preventive Cardiology section.

For more information:

• Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: A changing philosophy. JAMA 2005;293:477-484.