Treadmill exercise stress testing is a widely available, cost-effective method to identify coronary microvascular dysfunction (CMD) in patients with angina and confirmed nonobstructive coronary arteries, new research suggests. The analysis, published online Monday and in the Jan. 16 issue of the Journal of the American College of Cardiology, noted that that while exercise electrocardiographic stress testing (EST) has historically been validated against obstructive coronary artery disease, it is also highly effective in detecting CMD in patients without obstructive coronary artery disease. “It is important to remember that the accuracy of EST has historically been assessed and validated against its ability to detect the presence of obstructive coronary artery disease (CAD), with the reference standard being visual diameter stenosis on coronary angiography,” said the authors, led by Aish Sinha, MBBS, BSc, from the British Heart Foundation Center of Excellence and National Institute for Health Research Biomedical Research Center at King’s College London. “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.” Study details Sinha and colleagues assessed the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in 102 patients (65% women, mean age 60 years) with angina with nonobstructive coronary arteries (ANOCA) who underwent invasive coronary physiological assessment using adenosine and acetylcholine. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography, said the authors, adding that the study was powered to detect specificity of ≥91% and that CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. The team reported that 32 patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (non-ischemic group). There were no differences in gender, age, body mass index, cardiovascular risk factors, Canadian Cardiovascular Society angina grade, and New York Heart Association functional class between the two groups, said the team. However, patients in the ischemic group had a higher percentage of typical angina (91% vs 73%; P = 0.043) and lower hemoglobin levels (130 g/L vs 137 g/L; P = 0.008) than those in the non-ischemic group, they added. Furthermore, analysis showed that all patients in the ischemic group had CMD, compared with 66% of patients in the non-ischemic group (P < 0.001). There were no differences in coronary flow reserve or hyperemic (minimal) microvascular resistance between the two groups; however, patients in the ischemic group had lower acetylcholine flow reserve (1.2 vs 1.5; P < 0.001), as well as higher peak heart rate (145 beats/min vs 136 beats/min; P = 0.015) and rate-pressure product (27,662 mm Hg beats/min vs 24,678 mm Hg beats/min; P = 0.039) during exercise. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. “In recent years, there has been a paradigm shift in our understanding of ischemic heart disease, with the emphasis moving away from detecting obstructive CAD to confirming a physiological substrate for myocardial ischemia in the setting of chronic coronary disease,” said the team. “However, the diagnostic accuracy of traditional non-invasive tests has not been systematically re-evaluated against contemporary standards of assessing ischemia.” Challenging the false-positive belief Sinha and colleagues noted that when using comprehensive coronary physiology as the reference standard, ischemic ECG changes during exercise were highly specific for CMD in the patient cohort. “This is an important finding that highlights the limitations of using obstructive CAD as a reference standard to assess the accuracy of non-invasive imaging modalities,” they said, noting that the specificity and positive predictive value of EST are much higher when assessed against comprehensive physiological evaluation of the coronary circulation, in contrast to validation against the frequency of obstructive epicardial CAD. “The findings challenge the traditional belief that EST has a high false positive rate,” offering new insights into the diagnostic process for myocardial ischemia, added Sinha and colleagues, noting that treadmill exercise stress testing is a widely available, cost-effective method to identify CMD in patients with angina and confirmed nonobstructive coronary arteries. Indeed, writing in an accompanying editorial, John F. Beltrame, BMBS, PhD, Sarena La, BSc, and Jessica Marathe, MBBS, PhD, from the University of Adelaide and the Central Adelaide Local Health Network, Australia, noted that the new study emphasizes that the EST is an indicator of myocardial ischemia, not a “rule-in” investigation for obstructive CAD. “Moreover, when a patient with suspected angina and no obstructive CAD on coronary imaging (either CTCA [computed tomography coronary angiography] or invasive coronary angiography) has an ischemic EST result, the clinician should diagnose the patient with ANOCA or INOCA [ischemia with nonobstructive coronary arteries] and consider coronary physiological testing to identify the mechanism(s) responsible for the ischemia,” they said. Sources: Sinha A, Dutta U, Demir OM, et al. Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function. J Am Coll Cardiol 2024;83:291-299. Beltrame JF, La S, Marathe J. Clinical Utility of the Humble Exercise ECG Stress Test. J Am Coll Cardiol 2024;83:300-302. Image Credit: zinkevych – stock.adobe.com