Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function

Abstract

Background: Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease.

Objectives: The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA).

Methods: Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. 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. The study was powered to detect specificity of ≥91%.

Results: A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. 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%.

Conclusions: In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

Keywords: acetylcholine flow reserve; coronary flow reserve; coronary microvascular dysfunction; coronary physiological assessment; exercise stress test; false positive rate.

Graphical abstract

Figure 1

Consolidated Standards of Reporting Trials Diagram Demonstrating Study Flow This diagram demonstrates the number of patients assessed for eligibility and the reasons for exclusion. Overall, 262 patients with stable angina were assessed for eligibility, of whom 102 were excluded because of nonanginal symptoms or absence of symptoms. A total of 160 patients underwent coronary angiography with physiological assessment, of whom 38 were excluded. A total of 122 patients with comprehensive coronary physiological assessment (in response to both adenosine and acetylcholine [ACh]) underwent the mandated exercise ECG stress test, of whom 102 were included in the final analysis. BBB = bundle branch block; CAD = coronary artery disease; LBBB = left bundle branch block.

Figure 2

Coronary Physiological Assessment Protocol This is our standard clinical protocol that is used in all patients with angina and nonobstructive coronary arteries to identify an ischemic substrate. All patients undergo coronary angiography followed by intravenous (IV) adenosine assessment. Only patients with fractional flow reserve (FFR) >0.80 were included in this study. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic average peak velocity (APV) in response to adenosine (140 μg/kg/min) and resting APV, with a value of <2.5 used to diagnose endothelium-independent microvascular dysfunction. Patients then underwent assessment with intracoronary (IC) acetylcholine (ACh) infusion (18 μg/mL), and ACh flow reserve (AChFR) was calculated as the ratio of volumetric coronary blood flow (CBF) during ACh infusion and CBF during rest. Volumetric CBF, in turn, was calculated as 0.5 × APV × cross-sectional area 5 mm distal to the Doppler sensor. AChFR ≤1.5 was diagnostic of endothelium-dependent microvascular dysfunction. Patients with CFR <2.5 and/or AChFR ≤1.5 were defined as having coronary microvascular dysfunction (CMD).

Central Illustration

Exercise Electrocardiographic Stress Testing in the Contemporary Era Assessing the specificity of exercise electrocardiographic (ECG) stress testing against the contemporary gold standard of comprehensive coronary physiological assessment.