Coronary Abnormalities May Explain Angina in Patients Without Obstructive Disease

More than three-quarters of patients with angina but no obstructive CAD have occult coronary abnormalities such as endothelial dysfunction or microvascular impairment, according to a study published online February 20, 2015, ahead of print in Circulation. In 23%, no coronary explanation for angina was found.Take Home: Coronary Abnormalities May Explain Angina in Patients Without Obstructive Disease

“[P]atients with chest pain who undergo a coronary angiogram that appears normal often have other coronary causes for their chest pain beyond the classic epicardial coronary stenosis,” said William F. Fearon, MD, of Stanford University Medical Center (Stanford, CA), in an email with TCTMD. “These abnormalities can be detected at the time of the angiogram reasonably safely and quickly by performing additional invasive testing.”

Between August 2007 and November 2012, Dr. Fearon and colleagues invasively evaluated 139 patients (mean age 54 years; 77% female) with angina in the absence of obstructive CAD by testing endothelial function and performing physiological assessments (n = 137) and IVUS examinations (n = 120). There were no significant procedure-related complications.

All patients had stable angina, 72% had an abnormal stress test prior to angiography, and 24% were referred for angiography despite at least 1 normal stress test due to persistent and concerning symptoms.

High Rate of Occult Abnormalities Seen

Overall, 76.3% of patients had some degree of coronary abnormalities on invasive testing. These included endothelial dysfunction (decrease in luminal diameter of > 20% vs baseline after intracoronary acetylcholine) in 43.9%, microvascular impairment (index of microcirculatory resistance 25) in 21.2%, myocardial bridge in 57.9%, and FFR 0.80 in 5.1%. Additionally, all patients had at least some evidence of atherosclerosis of the LAD on IVUS.

Only 1 occult abnormality was observed in most patients, but when more were present, the most common combination was endothelial dysfunction and myocardial bridging.

No coronary explanation for angina could be found in 23% of patients. These patients tended to have less atherosclerotic burden on IVUS examination of the LAD compared with those with abnormalities.

Interestingly, 77% of patients with at least 1 coronary circulatory abnormality had an abnormal stress test, while 44% of those with no abnormality had a normal stress test (P = .10).

On multivariable logistic regression analysis, diabetes was the only independent predictor of endothelial dysfunction, age the only independent predictor of microvascular dysfunction, and homocysteine level the only independent predictor of low FFR. No predictors emerged for myocardial bridging.

Although additional invasive testing incurs extra time and health care expenditures, the study authors say, these may be offset by reducing the need for further unnecessary testing or treatment and potentially decreasing recurrent hospital visits while improving quality of life.

As for the patients with no abnormalities, Dr. Fearon and colleagues say they are likely to “do well without any specific cardiac medical therapy and alternative noncardiac etiologies for their symptoms should be pursued.” Furthermore, low event rates on long-term follow-up in these patients would further emphasize the need to distinguish them from those with abnormal coronary circulation.

“One of the limitations of the current paper is that it does not include outcome data,” Dr. Fearon said. “Hopefully, this will be forthcoming. To that end, this paper does not likely change perception regarding the prognosis of patients with 1 or more of these other coronary causes for chest pain, but it does raise awareness regarding the high prevalence of these abnormalities.”

Comprehensive Evaluation Needed

An accompanying editorial by Carl J. Pepine, MD, MACC, of the University of Florida (Gainesville, FL), suggests the finding that three-quarters of patients with nonobstructive CAD have coronary abnormalities is “likely an underestimate.”

Because many additional mechanisms—both coronary and noncoronary—beyond epicardial stenosis can contribute to angina and ischemia, Dr. Pepine advises clinicians to recognize multiple processes in combination as explanations for angina. As an example, he says although endothelial dysfunction alone may not be responsible for angina in some patients, “in combination with another coronary abnormality the probability for an additional effect would very likely increase.”

Not relying solely on the angiogram for guidance is an important message of this and other recent studies, he adds.

“The ‘less than very good’ outcomes of these patients with angina and no obstructive CAD, described recently by many groups, must be recognized so that a near-normal or ‘normal’ angiogram does not drive diagnostic and therapeutic complacency,” Dr. Pepine says. “Importantly, given the impaired prognosis for such patients, the search for cause(s) of ischemic symptoms and signs (even troponin elevation as with nonST-segment elevation myocardial infarction) must be much more comprehensive than simply a 10-minute diagnostic angiogram performed as part of ‘usual care.’”

According to Dr. Fearon, a comprehensive evaluation is the best way to look beyond the angiogram for coronary circulatory causes for chest pain other than obstructive epicardial disease.

“One has to balance what can be done safely and reasonably quickly and still provide as much information as possible,” he said. “We found that the protocol used in this study satisfies those conditions.”


1. Lee B-K, Lim H-S, Fearon WF, et al. Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease. Circulation. 2015;Epub ahead of print.
2. Pepine CJ. Multiple causes for ischemia without obstructive CAD: not a short list [editorial]! Circulation. 2015;Epub ahead of print. 


  • Dr. Fearon reports receiving research support from St. Jude Medical and honoraria from Medtronic.
  • Dr. Pepine reports no relevant conflicts of interest.

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