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Recent data suggest the Yentl syndrome
is alive and well. In angina and ACS (top)
relatively more men are chosen for coronary
angiography, which reveals a majority of men
with obstructive CAD (upper middle left)
compared with women with MCD
(upper middle right). Medical therapy follows
according to male- and female-pattern disease.
This produces undertreatment of at-risk women
and men with female-pattern disease - and results
in a higher death/MI rate in women than in men.
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The editorial was written by Noel Bairey Merz, a cardiologist from Cedars-Sinai Medical Center in Los Angeles, California, who has spent her career trying to unlock the female physiology of heart disease. And among her findings is that women are more prone than men to microvascular coronary dysfunction, a condition affecting the pre-capillary coronary arterioles, which branch from the epicardial coronary arteries, but occur before the capillaries. On Sunday, Bairey Merz told a symposium that cardiologists should consider microvascular coronary dysfunction (MCD) when investigating women for chest pain.
She told ESC Congress News: “Since the late 1950s, when coronary angiography was first developed, cardiologists have focused on the large epicardial coronaries that can be seen outside the heart muscle. They have been trained to think that as soon as they see coronary arteries that are not obstructed, the case is closed. This mind-set needs to be changed to consider the microvasculature.” The major difficulty, she added, is that the pre-capillary coronary arterioles are very small (40-280 microns) such that their anatomy and function are not evident on routine angiograms.
Much of our understanding of the physiological differences in women with CVD comes from the Women’s Ischemic Syndrome Evaluation (WISE) study, sponsored by the National Heart and Lung Institute in the USA. In this study Bairey Merz and colleagues followed up 936 women referred for coronary angiography for suspected ischemia between 1996 and 2000. The results of angiograms, published in JACC in 2006, showed that only one-third of the subjects actually had obstructive blockages in their coronary arteries (in similar groups of men three-quarters would have had blockages); the remaining two-thirds had no blockages but more than half demonstrated low blood flow to the heart. It is from the data of the WISE study that investigators have estimated that around three million women in the USA suffer from ischemic heart disease in the absence of any obstructive CAD.
MCD is not caused by obstructive CAD, but is a condition where small vessels lose their ability to dilate and increase blood flow; the WISE study suggested dysfunction in up to four mechanistic pathways. Two of these pathways involve abnormalities of the vascular endothelial cells, which are unable to produce enough nitric oxide leading to suboptimal dilatation; the third is a non-endothelial auto-regulation of the micro vasculature, and the fourth abnormal smooth muscle contraction in the epicardial coronary arteries.
Symptoms are remarkably similar to atherosclerosis. “Which makes perfect sense,” said Bairey Merz, “because, when myocardial tissue is starved of oxygen, symptoms will be the same whatever the cause. The main difference is that MCD patients can have prolonged episodes of chest pain at rest without evidence of myocardial infarction.”
Risk factors include age, hypertension, cigarette smoking, dyslipidaemia, and visceral obesity. “Our WISE study suggests that there is also likely to be a genetic element involved,” she said.
Far from being harmless, MCD points to long-term dangers. The WISE study found that 13% of the women who experienced angina symptoms without obstructive CAD had died within seven years. “This translates to a 2.5 % total risk of dying in any given year,” explains Bairey Merz. While this is half that of obstructive CAD, it is still 2.5 times higher than in asymptomatic control subjects. Bairey Merz added that one quarter of the deaths are sudden cardiac death, one quarter acute MI, one quarter ischemic stroke and one quarter heart failure.
Such statistics, she said, highlight an urgent need to identify and treat women with MCD. To this end, cardiologists might routinely check coronary flow reserves in all patients with chest pain but no evidence of obstructive CAD. She recommends that these patients should be offered provocative coronary testing with a two-step diagnostic test where first adenosine is injected into the coronary arteries and blood flow measured, then acetylcholine is injected and blood flow measured. If either test shows decreased blood flow to the myocardium, a diagnosis of MCD may be made.
Women diagnosed with MCD, says Bairey Merz, require aggressive risk factor management, along with anti-anginal/anti-ischemic treatments such as beta blockers, ACE, exercise training, tricyclic antidepressants (used as a visceral analgesic) and ranolazine. Much to Bairey Merz’s chagrin, ACC/AHA guidelines to date have awarded treatment of MCD Level II b evidence, although revised guidelines incorporating new data are under consideration.
The WISE study group is currently planning the WISE-ISCHEMIA trial to investigate whether mortality is influenced in women diagnosed with MCD and treated with anti-atherosclerotic and anti-anginal medications. “If we show a positive trial outcome,” she said, ”we should get guidelines for treatment of MCD raised to Level I evidence.“