More than half of men and women with suspected coronary artery disease (CAD) have microvascular dysfunction even with the absence of an abnormal stress test, according to a study published online April 30, 2014, ahead of print in Circulation. In addition, the presence of microvascular dysfunction is a strong predictor of major adverse events and thus may eventually be a useful target for therapeutic interventions, the authors say.

Investigators led by Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital (Boston, MA), used coronary flow reserve (CFR) to detect microvascular dysfunction in 405 men and 813 women referred to their institution for evaluation of suspected CAD. None of the participants had a history of CAD, and there was no visual evidence of CAD on rest or stress positron emission tomography (PET).

Microvascular Dysfunction Common

Microvascular dysfunction, defined as CFR < 2.0, was detected in more than half of both men and women. Even among a subgroup without evidence of coronary artery calcification on CT imaging, the prevalence of microvascular dysfunction was almost as high (table 1).

Table 1. Presence of Microvascular Dysfunction by Sex

At a median follow-up of 1.3 years, the presence of microvascular dysfunction was associated with a higher rate of MACE  (cardiac death, MI, revascularization after 90 days, and hospital admission for CHF). Most of the individual endpoints were also linked with microvascular dysfunction (table 2).

Table 2. Clinical Outcomes by Microvascular Dysfunction Status

Sex had no effect on outcomes associated with microvascular dysfunction.

The presence of microvascular dysfunction was a powerful incremental predictor of MACE in both men and women (HR 0.80; 95% CI 0.75-0.86 per 10% increase in CFR (P < .001). Including CFR in risk analysis resulted in a favorable net reclassification improvement, a measure of predictive performance, (OR 0.280 (95% CI 0.049-0.512), after adjustment for clinical risk and ventricular function.

Important Risk Factor in Both Sexes

In an accompanying editorial, John W. Petersen, MD, and Carl J. Pepine, MD, both of the University of Florida (Gainesville, FL), say the study data confirm the authors’ prior findings about the high prevalence of microvascular dysfunction and extend the association with adverse outcomes to men. They observe that the findings are “highly relevant for clinical trials evaluating therapeutic agents as this field lacks evidence-based data to inform patient management. Future study is also necessary to determine if [microvascular dysfunction] significantly strengthens the prediction of adverse outcomes beyond that provided by traditional risk models, such as the Framingham risk score.”

In an email with TCTMD, Kishore J. Harjai, MD, of Geisinger Wyoming Valley Medical Center (Wilkes-Barre, PA), called microvascular dysfunction “a powerful but underappreciated risk factor for major adverse cardiovascular events.” However, he added, “it is unclear whether [microvascular dysfunction] occurs independently of established risk factors or is an epiphenomenon resulting from other risk factors. Lack of easy screening tools has limited its use in clinical practice and hindered meaningful research.”

Dr. Harjai observed that there are many unanswered questions that could potentially be explained by invoking microvascular dysfunction, such as why some people with minimal or no risk factors develop ventricular arrhythmias or have coronary events. “The field of microvascular dysfunction is ripe for clinical investigation and randomized trials,” he concluded.

How to Treat Remains Unclear

However, a barrier to clinical use of microvascular dysfunction is thelack of data on how best to treat the condition, said Robert Schwartz, MD, of the Minneapolis Heart Institute Foundation (Minneapolis, MN), in a telephone interview with TCTMD. “We don’t understand yet what microvascular dysfunction is or where it comes from…. But we know where to look for it, so now we can start trying to characterize it better,” he noted.

Despite some lingering questions, he said the data are now strong enough in women to include microvascular dysfunction as part of risk stratification for coronary events, although confirmation is still required to do the same for men.

“We probably should [also] develop better diagnostic tools,” he added. “PET is okay, but it’s not as sensitive or specific as it could be. So, the gauntlet has been laid down to make better diagnoses, and once that’s done, to make better therapies.”

1. Murthy VL, Naya M, Taqueti VR, et al. Effects of gender on coronary microvascular dysfunction and cardiac outcomes. Circulation. 2014;Epub ahead of print.
2. Petersen JW, Pepine CJ. The prevalence of microvascular dysfunction, its role among men, and links with adverse outcomes: non-invasive imaging reveals the tip of the iceberg [editorial]. Circulation. 2014;Epub ahead of print.

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