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Accuracy of Non-Invasive Stress Testing in Women and Men with Angina in the Absence of Obstructive Coronary Artery Disease☆

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Accuracy of Non-Invasive Stress Testing in Women and Men with Angina in the Absence of Obstructive Coronary Artery Disease☆ International Journal of Cardiology 282 (2019) 7–15 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Accuracy of non-invasive stress testing in women and men with angina in the absence of obstructive coronary artery disease☆ Vedant S. Pargaonkar a, Yuhei Kobayashi a, Takumi Kimura a, Ingela Schnittger a,EricK.H.Chowb, Victor F. Froelicher a, Ian S. Rogers a, David P. Lee a, William F. Fearon a, Alan C. Yeung a, Marcia L. Stefanick c, Jennifer A. Tremmel a,⁎ a Division of Cardiovascular Medicine, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA b The Quantitative Sciences Unit, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA c Stanford Prevention Research Center, Stanford School of Medicine, Stanford, CA, USA article info abstract Article history: Objective: While N20% of patients presenting to the cardiac catheterization laboratory with angina have no Received 28 February 2018 obstructive coronary artery disease (CAD), a majority (77%) have an occult coronary abnormality (endothelial Received in revised form 17 September 2018 dysfunction, microvascular dysfunction (MVD), and/or a myocardial bridge (MB)). There are little data regarding Accepted 22 October 2018 the ability of noninvasive stress testing to identify these occult abnormalities in patients with angina in the ab- Available online 23 October 2018 sence of obstructive CAD. Methods: We retrospectively evaluated 155 patients (76.7% women) with angina and no obstructive CAD who Keywords: underwent stress echocardiography and/or electrocardiography before angiography. We evaluated Duke tread- Electrocardiography Echocardiography mill score, heart rate recovery (HRR), metabolic equivalents, and blood pressure response. During angiography, Coronary artery disease patients underwent invasive testing for endothelial dysfunction (decrease in epicardial coronary artery diameter Angina N20% after intracoronary acetylcholine), MVD (index of microcirculatory resistance ≥25), and intravascular ultra- sound for the presence of an MB. Results: Stress echocardiography and electrocardiography were positive in 58 (43.6%) and 57 (36.7%) patients, respectively. Endothelial dysfunction was present in 96 (64%), MVD in 32 (20.6%), and an MB in 83 (53.9%). On multivariable logistic regression, stress echo was not associated with any abnormality, while stress ECG was associated with endothelial dysfunction. An abnormal HRR was associated with endothelial dysfunction and MVD, but not an MB. Conclusion: Conventional stress testing is insufficient for identifying occult coronary abnormalities that are frequently present in patients with angina in the absence of obstructive CAD. A normal stress test does not rule out a non-obstructive coronary etiology of angina, nor does it negate the need for comprehensive invasive testing. © 2018 Elsevier B.V. All rights reserved. 1. Introduction anginal symptoms [1]. Several occult coronary abnormalities can be identified in these patients, including endothelial dysfunction, micro- More than 20% of patients undergoing coronary angiography (CA) vascular dysfunction (MVD), and/or a myocardial bridge (MB), which have no significant obstructive coronary artery disease (CAD) despite may explain their symptoms [2]. Previous studies have reported worse outcomes in this patient population [3], with a higher burden of hospitalization, repeat CA, and higher healthcare cost [4,5]. Current clin- Abbreviations: CA, coronary angiography; CAD, coronary artery disease; DTS, duke ical practice guidelines are also not helpful in the management of these fl treadmill score; ECG, electrocardiogram; FFR, fractional ow reserve; HRR, heart rate patients since current diagnostic criteria for CAD are not met [6]. Inva- recovery; IMR, index of microcirculatory resistance; IVUS, intravascular ultrasound; METs, metabolic equivalents; MVD, microvascular dysfunction; MB, myocardial bridge; sive cardiac catheterization including endothelial function testing, coro- NPV, negative predictive value; PPV, positive predictive value; SNS, sympathetic nervous nary physiology measurements, and intravascular ultrasound (IVUS) system; Tmn, mean transit time; WMSI, wall motion score index. are suggested to be the gold standard tests for identifying these occult ☆ All authors take responsibility for all aspects of the reliability and freedom from bias of coronary abnormalities [7–9]. the data presented and their discussed interpretation. Stress echocardiography (echo) and stress electrocardiography ⁎ Corresponding author at: 300 Pasteur Drive, Room H2103, MC 5218, Stanford, CA 94305, USA. (ECG) are non-invasive tests considered integral in the evaluation of pa- E-mail address: [email protected] (J.A. Tremmel). tients with known or suspected CAD [10]. The diagnostic value of these https://doi.org/10.1016/j.ijcard.2018.10.073 0167-5273/© 2018 Elsevier B.V. All rights reserved. 8 V.S. Pargaonkar et al. / International Journal of Cardiology 282 (2019) 7–15 tests has been proven in identifying obstructive CAD, but little data are obstructive CAD (stenosis b50%) on CA. Patients were electively referred to the cardiac available regarding their ability to evaluate the source of angina in pa- catheterization for CA because of a clinical suspicion of coronary ischemia based on persis- tent anginal symptoms for at least three months despite medical therapy with or without tients with non-obstructive CAD. A previous study by Cassar et al. re- an abnormal stress test. A baseline coronary angiogram was performed via the femoral ar- ported that noninvasive stress tests have limited diagnostic accuracy tery to rule out obstructive CAD in the right and left coronary arteries. These patients for identifying coronary vasomotor dysfunction in patients with no additionally underwent invasive testing to evaluate for an underlying coronary patho- obstructive CAD [11]. Specifically, they found that stress echo, stress physiology as a cause of their angina, including endothelial dysfunction, MVD, or an MB [2]. We excluded those with an acute coronary syndrome, prior heart transplantation, ECG, and stress nuclear imaging were not helpful in identifying coronary artery bypass grafting, renal insufficiency (creatinine N1.5 mg/dL), EF b55%, or fl endothelium-dependent dysfunction (decrease in coronary blood ow another likely explanation of angina such as pulmonary hypertension, hypertrophic car- ≤50% after intracoronary acetylcholine (Ach)), as well as endothelium- diomyopathy, or valvular heart disease. independent dysfunction (coronary flow reserve (CFR) ≤2.5 after Stress tests were ordered at the discretion of the treating physician as an evaluation intracoronary adenosine). This study has never been replicated, nor for angina. The stress tests included an exercise or dobutamine stress echo, or an exercise treadmill test, according to standard laboratory protocols. All stress tests were performed has it been evaluated using more contemporary invasive methods and before invasive coronary testing. All patients ultimately underwent CA, either because of a more comprehensive non-invasive measures. positive stress test or because of persistent anginal symptoms despite a negative stress Our aim was to investigate the diagnostic value of comprehensive test. The study was approved by the Stanford Institutional Review Board, and informed, noninvasive stress testing, including stress echo, stress ECG, and non- written consent was obtained from all patients. ECG stress testing parameters in identifying symptomatic women and men with non-obstructive CAD who underwent contemporary invasive 2.2. Invasive coronary testing testing for an occult coronary abnormality as a cause of their angina. After CA, patients underwent further invasive evaluation for endothelial dysfunction, MVD, and an MB, as described previously [2]. In brief, we tested coronary endothelial func- 2. Methods tion by administering up to 200 μg of intracoronary Ach into the left main coronary artery. Endothelial dysfunction was diagnosed if the epicardial coronary artery diameter de- 2.1. Study population creased by N20% compared with baseline on quantitative coronary angiography [12]. Next, we measured the index of microcirculatory resistance (IMR) in the left anterior We retrospectively analyzed 155 adult patients (133 stress echo, 22 exercise treadmill descending artery (LAD) using a pressure-temperature sensor guidewire (Certus Pressure tests) with typical (64.9%) or atypical (35.1%) angina who had been found to have non- Wire, St. Jude, St. Paul, MN). Resting mean transit time (Tmn) and hyperemic Tmn were Fig. 1. Demonstrative example of occult coronary abnormalities in patients with angina in the absence of obstructive CAD. (A) Coronary angiogram with diffuse vasoconstriction after 100 μg intracoronary acetylcholine demonstrating diffuse epicardial endothelial dysfunction. (B) Coronary physiology measurements demonstrating microvascular dysfunction with an IMR of 32.7. (C) Still frame of intravascular ultrasound (IVUS) inside a myocardial bridge. Arrows point to characteristic echolucent half-moon sign (halo), with a thickness of 0.45 mm. V.S. Pargaonkar et al. / International Journal of Cardiology 282 (2019) 7–15 9 calculated by administering 3 ml of intracoronary saline. Maximal hyperemia was channel blocker usage [23,26]. A p-value b0.05 was considered significant. Statistical anal- achieved using intravenous adenosine. Simultaneous measurements
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