Exercise ECGs Highly Specific for Coronary Microvascular Dysfunction

Exercise electrocardiographic (ECG) stress tests appeared to reliably indicate that some patients with angina with nonobstructive coronary arteries (ANOCA) actually had coronary microvascular dysfunction (CMD), preliminary evidence showed.

A standard Bruce-protocol exercise test showed 100% specificity for CMD, verified against invasive coronary assessment as reference, with all patients showing ischemic ECG changes during the exercise test also having confirmed CMD. Using endothelium-independent and endothelium-dependent CMD as the reference standard, the false-positive rate of the exercise tests was 0% in a small cohort, reported Haseeb Rahman, PhD, BMBCh, of St. Thomas’ Hospital in London, and colleagues.

Therefore, with these basic exercise tests, patients with ANOCA could be provided with an explanation for their symptoms and a mechanism for myocardial ischemia in the absence of obstructive disease.

“In patients with ANOCA, ischemia on EST [exercise ECG stress testing] was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false-positive rate,” Rahman’s group concluded in the Journal of the American College of Cardiology.

A simple noninvasive testing modality, exercise ECG stress testing has fallen out of favor in recent years due to frequent false positives when used for detecting obstructive coronary artery disease (CAD) as validated against visual diameter stenosis on coronary angiography.

“However, we now know that myocardial ischemia can, and indeed in nearly one-third of cases does, occur in the absence of obstructive CAD due to CMD. Therefore, it is conceivable that historical false-positive EST results were due not to the poor specificity of EST as a diagnostic test but rather to the limitations of obstructive CAD as a reference standard for myocardial ischemia,” the study authors explained.

“Our results show that a positive result on EST is highly specific for (and suggestive of) the presence of an ischemic substrate, but as this does not distinguish the relative contributions of the epicardial and microvascular compartments, EST will always have to be combined with a test that specifically evaluates the epicardial coronary arteries, namely, invasive or noninvasive coronary angiography,” they added.

The London group suggested keeping coronary CT angiography as the first-line assessment for patients presenting with chest pain that might be consistent with inducible ischemia. The exercise ECG would be a second-line test “to expedite the diagnosis of CMD in a large proportion of patients and streamline the use of (less widely available and more costly) tests, such as invasive physiology and/or stress perfusion cardiac [MRI].”

Whether this strategy works would need further testing, the researchers acknowledged.

“This proposed approach requires further studies to assess its utility in clinical practice, as ANOCA may also arise from epicardial coronary artery spasm, which was not addressed in the present study,” wrote a trio led by John Beltrame, BMBS, PhD, of the University of Adelaide in Australia, in an accompanying editorial.

“As with any diagnostic investigation, the clinician must address the purpose for undertaking an investigation in each patient. If the clinical question is to identify the presence of obstructive CAD, then clearly CT coronary angiography is the optimal noninvasive technique,” the group wrote. “In contrast, the EST is not designed to assess coronary artery anatomy but is a simple, inexpensive, noninvasive technique to detect the presence of myocardial ischemia in appropriate patients.”

In this study, Rahman’s team made the case for exercise testing with a cohort of consecutive patients presenting with angina who were referred for further assessment. There were 262 individuals with stable angina screened for eligibility, of whom 160 made it to coronary angiography with physiological assessment and 102 who were ultimately included in the final analysis. Inclusion criteria included ANOCA (fractional flow reserve >0.80) and preserved left ventricular ejection fraction (>50%). The final cohort had a mean age of 60 years, and 65% were women.

Participants underwent exercise stress tests a median 29 days after invasive coronary angiography with physiological assessment using adenosine and acetylcholine.

All 32 patients who developed ischemia during testing had CMD, while their 70 nonischemic peers had CMD in 66% of cases (P<0.001).

The ischemic group tended to have lower acetylcholine flow reserve (AChFR), indicating endothelium-dependent microvascular dysfunction. AChFR ≤1.5 — not coronary flow reserve — was the strongest predictor of ischemic ECG changes during exercise.

“This reiterates the physiological relevance of acetylcholine testing in the evaluation of patients with ANOCA … [AChFR] is likely to be a better surrogate for the physiological flow-mediated vasodilatation that occurs during exercise, as it assesses the functionality of both the endothelial and vascular smooth muscle pathways,” Rahman and colleagues stressed.

They nevertheless acknowledged that their observations were based on a single-center study with a relatively small sample size, and may not apply to patients without angina symptoms.

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