Angina Without Obstructive Stenosis: No Longer a ‘Black Box’ Mystery, Say Experts

Microvascular disease can be identified with advanced imaging, but the primary treatment remains old-school: aggressive control of CVD risk factors.

Angina Without Obstructive Stenosis: No Longer a ‘Black Box’ Mystery, Say ExpertsAngina Without Obstructive Stenosis: No Longer a ‘Black Box’ Mystery, Say Experts

Once considered a mysterious “black box” problem, sometimes known as syndrome X, angina without focal obstruction in the large coronary arteries is not a benign condition and should prompt aggressive management of cardiovascular risk factors, according to two new review papers highlighting the phenomenon of microvascular angina.

Because microvascular angina is characterized by angina symptoms in the absence of significant obstructions in the coronary lumen, some patients worked up for coronary artery disease may be inadvertently cleared of heart disease despite being at risk for future cardiovascular events, say experts.  

“It’s now widely recognized that many patients have symptoms [indicative] of ischemic heart disease but we can’t identify a focal obstruction in their coronary arteries,” Marcelo Di Carli, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “In fact, the data suggest that as many as one-third of men and two-thirds of women will have symptoms of chest pain but there’s no focal obstruction on the angiogram. For a long time, those symptoms have been dismissed as not being heart disease. We now know that’s wrong. Many of these patients do indeed have evidence of what we generally call microvascular disease, or heart disease of the small vessels, not readily seen by a coronary angiogram.” 

Di Carli, who co-authored one of the state-of-the-art reviews with Viviany Taqueti, MD (Brigham and Women’s Hospital), said that while coronary artery disease is conventionally defined as obstructive atherosclerosis in the large epicardial vessels, coronary microvascular disease also has a clinical impact on patient outcomes.

“We assumed for a long time that the absence of a focal obstruction in the coronary angiogram was the equivalent of having a relatively good prognosis,” he said. “We now know that many patients who have symptoms and evidence of microvascular disease have worse outcomes than those without microvascular disease. If we can identify who has the disease and who is high risk, we can then figure out how to help them and intervene on the disease, mostly with medical therapy. None of these problems are going to be fixed with a coronary stent.”

Atherosclerosis Evident in Most Patients

In their review, which was published November 19, 2018, in the Journal of the American College of Cardiology, the researchers provide a simplified classification of coronary microvascular disease, noting that the condition may occur without atherosclerosis, with nonobstructive atherosclerosis, and with obstructive atherosclerosis. The vast majority of patients with microvascular disease will have some evidence of atherosclerosis in the large coronary arteries; however, to TCTMD, Di Carli stressed that microvascular disease is widely believed to be the expression of atherosclerosis in the small vessels of the heart.

None of these problems are going to be fixed with a coronary stent. Marcelo Di Carli

“If you think that way, then . . . risk factors that promote atherosclerosis, such as lipids, blood pressure, smoking, obesity, and so on, ought to be treated,” he said. “When you aggressively manage those risk factors, vascular function gets better.”  

K. Lance Gould, MD (McGovern Medical School at UTHealth, Houston, TX), another expert in the coronary physiology of microvascular angina, said that almost without exception, patients with no-stenosis angina will have cardiovascular disease risk factors and these can be treated with guideline-directed medical therapy without the need for further testing.

“However, if a physician or patient wants an explanation—what does the patient have and how bad is it—then the only way to tell is to do a quantitative PET scan or to have an MRI quantitative study,” Gould commented to TCTMD. “But it won’t make any difference to how you treat them.”

In their review, Di Carli and Taqueti provide an algorithm for diagnostic testing strategies in patients with suspected ischemic heart disease. Regardless of whether a functional or anatomic strategy is pursued first, the unexplained angina symptoms merit consideration for testing of coronary microvascular disease with vasomotor testing. They note that invasive coronary angiography can be paired with other catheter-based measures, such as invasive coronary flow reserve, fractional flow reserve, instantaneous wave-free ratio, and wave -intensity analysis, to assess the microvascular coronary physiology.   

“It’s important for patients, especially if we’re telling them, ‘we didn’t find an obstruction, so your symptoms must not be heart disease,’” he said. “We want to prove that this is actually the case so it’s important to test for that.”

Angina Without Focal Obstruction   

Gould, who with Nils Johnson, MD (McGovern Medical School at UTHealth), co-authored the second JACC review paper looking at the physiology and treatment of microvascular angina, said microvascular disease, a term commonly used by the cardiology community, is a misnomer.

“The reason it’s a misnomer is because when you do the proper quantitative [positron emission tomography (PET)] or MR imaging, what you find is that the microvascular function—the ability to dilate and increase flow—is quite good,” said Gould. “That increased flow causes a pressure gradient along the length of the artery without a stenosis, one that has diffuse disease, and that pressure drop at high flow causes subendocardial ischemia and chest pain. Most of what is microvascular angina is actually good microvascular function but angina due to diffuse epicardial narrowing without stenosis.”

Instead, Gould describes the condition more accurately as “angina without focal obstruction” or “no-stenosis angina.”  

In their review of 5,900 sequential PET scans, they identified four distinct subcategories or primary prototypes of no-stenosis angina. The first, which they call subendocardial ischemia, as described above, is characterized by diffuse epicardial narrowing and adequate microvascular function. The second includes overlooked stenoses, such as flush origin occlusions of secondary arterial branches not seen on the angiogram. The third includes diffuse microvascular dysfunction with low coronary flow reperfusion associated with cardiovascular risk factors, subclinical coronary atherosclerosis, endothelial dysfunction, or microvasculopathy from diverse causes. And finally, the rare fourth subtype is no-stenosis angina derived from nonischemic cardiac pain mechanisms.

“What we found was quite surprising, said Gould. “True angina without an explanation is quite rare. In fact, only seven cases out of the 5,900 had to be explained by a different mechanism. All the rest were typically associated with risk factors and some form of coronary atherosclerosis that is not readily imaged by standard technology.”

The bottom line, added Gould, is that the vast majority of these patients have diffuse, epicardial atherosclerosis but no focal stenosis you can see on an angiogram. “This is not a ‘black box’ mystery,” he said. “It’s a common problem, with a common disease, and one that needs to be treated very aggressively with risk-factor control.”

To TCTMD, Di Carli pointed out that several large coronary revascularization studies, such as COURAGE, FREEDOM, FAME, and BARI-2D, have suggested that anywhere from 20% to 50% of patients treated with a stent or a bypass graft continue to have chest pain. “That means that fixing the focal obstruction only solves part of the problem,” he said. “The other part of the problem is what’s downstream of the focal obstruction.”

If a patient presents with chest pain and the coronary angiogram reveals no significant blockages, Di Carli said physicians should not be dismissive of the patient’s symptoms given that this might truly be angina.  

  • Di Carli reports consulting for Sanofi and General Electric.
  • Gould reports 510(k) applications for software related to PET processing, analysis, and flow quantifications (all royalties donated to his institution).
  • Johnson reports an institutional licensing/consulting agreement with Boston Scientific and research support from St. Jude Medical and Volcano/Philips Corporation (all fees donated to his institution).

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