Contrary to Expectations, Study Finds No Sex Difference in Coronary Microvascular Dysfunction

Among angina patients without obstructive CAD, men and women have similar microvascular function on the index of microcirculatory resistance (IMR), but coronary flow reserve (CFR) is lower in women, according to a study published in the September 2015 issue of JACC: Cardiovascular Interventions.

Take Home: Contrary to Expectations, Study Finds No Sex Difference in Coronary Microvascular DysfunctionResearchers led by Jennifer A. Tremmel, MD, MS, of Stanford University Medical Center (Stanford, CA), prospectively enrolled 157 patients (mean age 53.7 years; 74.5% women) who were referred for catheterization due to suspected ischemia based on angina. First, patients underwent angiography to rule out obstructive CAD (defined as >50% diameter stenosis) in the right and left coronary arteries. In patients without obstructive CAD, further evaluation of the LAD was done using CFR, IMR, FFR, QCA, and IVUS.

Atherosclerosis was minimal, with mean 23.2% diameter stenosis by QCA. Women were more likely than men to have hypertension and a family history of early-onset CAD. Vessel size on QCA and IVUS was consistently smaller in women than in men, but lumen size was similar in both sexes due to less epicardial disease in women.

IMR—defined as mean distal coronary pressure at hyperemia multiplied by hyperemic mean transit time—was similar between women and men (20.7 vs 19.1; P = .45). In contrast, CFR—defined as resting mean transit time divided by hyperemic mean transit time—was lower in women (3.8 vs 4.8; P = .004), a difference mostly arising from a shorter resting mean transit time in women (1.05 vs 1.31 seconds; P = .005). Hyperemic mean transit time was 0.29 seconds in both men and women (P = .79).

Ten women (8.5%) and no men had CFR ≤ 2.0 (P = .048), whereas IMR ≥ 25 was seen in 28.2% and 15% of women and men, respectively (P = .10). Regardless of patient sex, shorter resting times correlated with shorter hyperemic times while longer resting times correlated with longer hyperemic times.

On multivariate analysis, female sex was an independent predictor of lower CFR (P = .011) and shorter resting mean transit time (P = .004).

WISE Comparisons

“These findings strongly suggest that resting flow status has a major effect on CFR, and that previous reports on sex differences in CFR may reflect higher resting flow in women rather than more significant microvascular disease,” write Dr. Tremmel and colleagues. “In our study, IMR, a direct measure of the microvasculature that is not dependent on resting flow, was not different between the sexes, suggesting that there is no sex difference in coronary microvascular dysfunction.”

The WISE study showed that women with angina without obstructive CAD typically have lower CFR values, which likely stem from significant microvascular dysfunction, the authors explain. “But the WISE study only evaluated women, so little is known about similarly presenting men or differences between the sexes,” they say.

It is unclear why women had higher resting coronary flow in the current study, the authors continue, as they did not find any associations with age or hormonal status. That finding in women may be “secondary to a lower resting vascular tone, which has been shown to differ between women and men,” they suggest, adding that since hyperemic mean transit time and IMR were similar between the sexes, “poor augmentation of coronary flow from rest to hyperemia is unlikely an explanation for lower CFR in women.”

Misconceptions of ‘Syndrome X’

The “conundrum” of angina without obstructive CAD is often called “Syndrome X,” according to Kishore J. Harjai, MD, of Geisinger Wyoming Valley Medical Center (Wilkes-Barre, PA). He told TCTMD in an email that this presentation is more prevalent in women and generally is “felt to be related to greater microvascular dysfunction in women,” yet this study dispels that commonly held belief.

“Men as well as women with Syndrome X respond well to coronary vasodilators, such as calcium blockers and nitrates,” he said. “This study does not change how we treat patients with Syndrome X, but it questions the notion that women have more microvascular dysfunction.”

Due to design flaws and “certain pertinent findings,” Dr. Harjai said he is not ready to fully accept the findings of this study. Because fewer women than men had abnormal stress tests before going to angiography, more data should have been obtained on those with abnormal results. “It is entirely possible that the burden of microvascular dysfunction in women was underestimated, because 1 in 3 women subjects had no documented ischemia,” he suggested.

Additionally, “I would have liked to see the coronary physiology tested in the distribution of the artery associated with the stress test abnormality,” he said. “It is possible that microvascular dysfunction is indeed more prevalent in women, but exists in a non-LAD vessel.”

Looking forward, “if future studies continue to dispel sex differences in the prevalence of microvascular dysfunction, then we may have to consider other explanations for the greater prevalence of Syndrome X in women,” noted Dr. Harjai. “Maybe the perception or description of pain is different in women compared to men. Perhaps stress tests are overcalled more often in women because of breast shadow; if so, noncardiac pain can get labeled as ‘ischemia.’ Left ventricular hypertrophy and LV diastolic dysfunction cannot be left out of such analyses.”

A ‘Unifying’ Paper

In an accompanying editorial, Alexandra J. Lansky, MD, and Cody Pietras, of Yale University School of Medicine (New Haven, CT), say the study sheds “important new light on the pathobiology of ischemic heart disease in women in whom vascular dysfunction was thought to be central.”

The historical “emphasis on microvascular dysfunction as the primary cause of the sex differences in angina symptoms in the absence of obstructive CAD may have been misguided,” they write. “Based on these new data, it appears unlikely that the fundamental pathophysiology of ischemic heart disease is different between the sexes; rather, sex-based disparities in the prevalence and combination of known risk factors result in different manifestations of disease in women compared with men.”

Robert Schwartz, MD, of the Minneapolis Heart Institute Foundation (Minneapolis, MN), told TCTMD in a telephone interview that the study is “unifying” but does not offer major clinical implications. “It’s 1 more stepping stone on the path to being able to understand and eventually to treat patients who have angina without obstructive CAD,” he said. “That’s critical because the standard clinical impression now is to throw up our hands and say, ‘We can’t do anything with this.’”

1. Kobayashi Y, Fearon WF, Honda Y, et al. Effect of sex differences on invasive measures of coronary microvascular dysfunction in patients with angina in the absence of obstructive coronary artery disease. J Am Coll Cardiol Intv. 2015;8:1433-1441.
2. Lansky AJ, Pietras C. Coronary microvascular dysfunction: does sex matter [editorial]? J Am Coll Cardiol Intv. 2015;8:1442-1444.

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  • The study was supported by the NIH.
  • Dr. Tremmel reports receiving honoraria from Boston Scientific, Medtronic, ReCor, St. Jude Medical, and Terumo.
  • Drs. Harjai, Lansky, and Schwartz and Mr. Pietras report no relevant conflicts of interest.