BMJ Open. Does T wave inversion in lead avl predict mid-segment left anterior descending lesion in acute coronary syndrome?

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1 Does T wave inversion in lead avl predict mid-segment left anterior descending lesion in acute coronary syndrome? Journal: Manuscript ID bmjopen-0-00 Article Type: Research Date Submitted by the Author: -Oct-0 Complete List of Authors: Nakanishi, Nobuto; Ise Red Cross Hospital, Department of Cardiology Goto, Tadahiro; Massachusetts General Hospital, Emergency medicine Ikeda, Tomoya ; Ise Red Cross Hospital, Department of Cardiology Kasai, Atsunobu ; Ise Red Cross Hospital, Department of Cardiology <b>primary Subject Heading</b>: Emergency medicine Secondary Subject Heading: Cardiovascular medicine, Diagnostics Keywords: T wave inversion, electrocardiography, acute coronary syndrome, left anterior descending lesion : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

2 Page of Does T wave inversion in lead avl predict mid-segment left anterior descending lesion in acute coronary syndrome? ABSTRACT Objectives:Recent studies have reported that T wave inversion in lead avl is associated with mid-segment left anterior descending (MLAD) lesion. However, limited data is available regarding the predictive value of electrocardiographic T wave inversion in lead avl for MLAD lesion among patients with acute coronary syndrome (ACS). Setting: Retrospective single-centre study, using a prospectively-collected coronary angiography database. Participants: We included consecutive adult patients with suspected ACS who underwent emergency percutaneous coronary intervention within h after arriving at the hospital. We excluded patients who met the following criteria: ) patients who did not undergo an ECG before PCI, ) patients with complete occlusion of the left main trunk and proximal-segment left anterior descending artery and ) patients diagnosed with vasospastic angina. Primary and secondary outcome measures: The primary outcome was MLAD lesion >0%. The other outcome of interest was MLAD lesion as the cause for ACS. We calculated the sensitivity, specificity, and predictive values for each outcome, with stratification of the presence of isolated T wave inversion. Results: T wave inversion in lead avl had a sensitivity of.%, specificity of.%, positive predictive value of.%, and negative predictive value of.% for predicting MLAD lesion. However, isolated T wave inversion in lead avl had a sensitivity of.%, specificity of.%, positive predictive value of 0.%, and negative predictive value of.% for predicting MLAD : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

3 Page of lesion. These diagnostic values did not change materially with focusing on patients with MLAD lesion as the cause. Conclusions: In our study, T wave inversion in lead avl had low sensitivity and specificity for predicting MLAD lesion. However, isolated T wave inversion in lead avl had a high specificity. Our inferences underscore the importance of a cautious interpretation of T wave inversion in lead avl among patients with ACS. ( Words) Strengths and limitations of this study This is the first study to evaluate the diagnostic value of T wave inversion in lead avl for mid-segment left anterior descending (MLAD) lesion among patients with acute coronary syndrome. Although previous studies demonstrated that the usefulness of diagnostic values of T wave inversion in lead avl for MLAD lesion, our observation did not show the usefulness among ACS patients. Because this study is a single-centre, retrospective study, the generalizability of our inferences might be limited. Our inferences underscore the importance of a cautious interpretation of T wave inversion in lead avl among patients with ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

4 Page of INTRODUCTION The -lead electrocardiogram (ECG) is a fundamental tool to diagnose acute coronary syndrome (ACS) because ST-T changes in ECG reflect myocardial ischemia. Based on the diagnosis and prediction of ischemic lesions using ECG, cardiologists can provide early therapeutic intervention for patients with ACS.[] T wave inversion in lead avl has been reported to be a reciprocal change of inferior wall infarctions, mostly caused by right coronary artery lesions.[, ] However, several recent, small studies have suggested that T wave inversion in lead avl is associated with mid-segment left anterior descending (MLAD) lesion.[-] For example, a prospective observational study reported that the T wave inversion in lead avl was significantly associated with MLAD lesion >0% among patients with chronic stable angina.[] Another retrospective study from the US, using data of patients who underwent percutaneous coronary intervention (PCI), reported that the sensitivity of isolated T wave inversion in lead avl for predicting MLAD lesion >0% was.%, and the specificity was.%.[] However, these studies were conducted in limited population samples (e.g., single-centre studies, including non-emergency PCI), thereby limiting the generalizability of their inferences for patients with suspected ACS. Despite the clinical significance of T wave inversion in lead avl for the early detection of ischemic lesions, the association between T wave inversion in lead avl and MLAD lesion >0% among patients with ACS is yet to be elucidated. To address this gap in the current literature, we aimed to investigate the diagnostic value of T wave inversion in lead avl for MLAD lesion among patients who underwent emergency PCI for ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

5 Page of METHODS.. Study Design and Settings This is a retrospective analysis using data from the coronary angiography (CAG) database at the Ise Red Cross Hospital from January 0 to December 0. The Ise Red Cross Hospital had beds (medical and surgical), with approximately,000 outpatients and 0,000 admissions in 0. There were,000 emergency department visits, and 00 PCI were performed annually (including 0 cases of emergency PCI for ACS). Since, all CAG and PCI data has been prospectively collected for the CAG database. All data including patient s demographics, ECG findings, CAG findings, and treatment data, were registered by cardiologists. This study was approved by the clinical research ethics committee at the Ise Red Cross Hospital... Study Population We included consecutive adult patients who underwent emergency PCI. Emergency PCI was defined as PCI performed for patients with suspected ACS within h after arriving at the hospital.[, ] We excluded patients who met the following criteria: ) patients who did not undergo an ECG before PCI, ) patients with complete occlusion of the left main trunk and proximal-segment left anterior descending artery (i.e., we could not evaluate the MLAD lesion), and ) patients diagnosed with vasospastic angina... T wave inversion Based on a joint recommendation of the American Heart Association (AHA), the American College of Cardiology Foundation (ACCP), and the Heart Rhythm Society (HRP),[] we defined the T wave inversion as T wave 0. mv, compared with the baseline from the end : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

6 Page of of the T wave to the beginning of the P wave. The T wave inversion in lead avl was measured by cardiologists who were blinded to the results. In addition, we defined isolated T wave inversion as the presence of T wave inversion only in lead avl regardless of ST elevation in other leads, using a previously described classification scheme for isolated T wave inversion.[, ].. Outcome and Measured Variables The primary outcome was MLAD lesion >0%. MLAD was defined as the first septal branch to the point where left anterior descending artery forms an angle in right anterior oblique view.[0] The other outcome of interest was the MLAD lesion as the cause for ACS. The MLAD lesion as the cause for ACS was defined as ) the MLAD lesion where PCI was performed or ) the MLAD lesion diagnosed as the cause by the PCI operator. Data on patient demographics, including age, sex, smoking, family history of coronary artery diseases, hypertension, history of myocardial infarction, diabetes mellitus, and dyslipidaemia, were collected from the database and medical charts of our hospital... Statistical Analyses Continuous data were presented as the median (interquartile ranges [IQR]), whereas categorical data were expressed as number (%), with differences analysed using the chi-square test or Fisher s exact test as appropriate. We calculated the sensitivity, specificity, and predictive values of T wave inversion in lead avl for predicting MLAD lesion (positive predictive value [PPV] and negative predictive value [NPV]) with stratification by the presence of isolated T wave inversion. For sensitivity analysis, we repeated the analysis after excluding the patients : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

7 Page of with left ventricular hypertrophy and bundle branch block because these are associated with T wave inversion.[, ] Data analyses were conducted using R statistical software version.0. (R Development Core Team, Vienna, Austria). All statistical tests were two-tailed, and the chosen type error rate was p < : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

8 Page of RESULTS A total of patients underwent PCI at the Ise Red Cross Hospital from January 0 to December 0. Among these, patients underwent emergency PCI. Of patients who did not meet the inclusion criteria, patients did not undergo ECG before PCI, and patients had complete occlusion of the left main trunk or proximal-segment left anterior descending artery; therefore, patients were eligible for analysis (Figure ). The median age of the patients was ( ) years, and patients were male (%, Table ). The most common coronary risk factors were hypertension (%), dyslipidaemia (%), and smoking (0%). Of patients, (%) patients were diagnosed with ST-elevation myocardial infarction (Table ). The right coronary artery was the site of the most frequent causative lesion, followed by the left anterior descending artery. Single-vessel disease was diagnosed in approximately half of the patients. Among patients, patients had MLAD lesion >0% (Table ). T wave inversion in lead avl had a sensitivity of.% (% confidence interval [CI],.%.%), specificity of.% (% CI,.%.%), positive predictive value of.% (% CI,.0%.%), and negative predictive value of.% (% CI,.%.%) for predicting MLAD lesion. By contrast, isolated T wave inversion in lead avl had a sensitivity of.% (% CI,.%.%), specificity of.% (% CI, 0.0%.0%), positive predictive value of 0.% (% CI,.%.%), and negative predictive value of.% (% CI,.%.%) for predicting MLAD lesion. Focusing on patients with the MLAD lesion as the cause, T wave inversion in lead avl had a sensitivity of.% (% CI,.%.%), specificity of.% (% CI,.%.%), positive predictive value of.% (% CI,.%.%), and negative predictive value of.% (% CI,.%.%) for predicting MLAD lesion as the cause. By : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

9 Page of contrast, isolated T wave inversion in lead avl had a higher specificity of.% (% CI, 0.% 0.%) for predicting the MLAD lesion as the cause. In sensitivity analysis after excluding patients with left ventricular hypertrophy and bundle branch block, the performance of the T wave inversion in lead avl for predicting MLAD lesion did not change materially (Table ). Focusing on patients with the MLAD lesion as the cause, isolated T wave inversion in lead avl had a higher specificity of.% (% CI,.%.%) for predicting the MLAD lesion as the cause : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

10 Page of DISCUSSION In this retrospective study using data from the CAG database at the Ise Red Cross Hospital from January 0 to December 0, we found that, among patients with ACS, the diagnostic value of T wave inversion in lead avl for predicting MLAD lesion was unsatisfactory. However, isolated T wave inversion in lead avl had high specificity for predicting MLAD lesion, even after excluding patients with left ventricular hypertrophy and bundle branch block. To the best of our knowledge, this is the first study to evaluate the diagnostic value of T wave inversion in lead avl for MLAD lesion among patients who underwent emergency PCI for ACS. T wave inversion in ECG is vital to the early diagnosis and detection of ischemic lesion for patients with suspected ACS. Reciprocal changes in ECG are recognized earlier than the ST elevation as the reflection of the ischemic lesion in ACS,[, ] and % of ACS patients had only reciprocal changes without ST elevation.[] To date, several studies have focused on the diagnostic values of T wave inversion for predicting MLAD lesion.[,, ] Among patients with chronic stable angina, the odds ratio of T wave inversion in lead avl for predicting MLAD lesion was..[] In another study, T wave inversion in leads avl and I had a sensitivity of.% and specificity of.% for predicting MLAD lesion.[] However, in our study, T wave inversion in lead avl had a low sensitivity of.% and a specificity of.% for predicting MLAD lesion. The reasons for the disparities in the diagnostic values among studies are likely multifactorial. First, although the definition of T wave inversion was unclear in previous studies,[,, ] we clearly defined T wave inversion according to the AHA definition[]; therefore, our findings were less likely to be subject to information bias. Second, a previous study used a combination of T wave inversion in lead avl and lead I to estimate the diagnostic : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

11 Page 0 of values.[] Third, the disparities in the diagnostic values may be attributable to the differences in study population, settings, or any combination of these factors. For example, the study by Farhan et al. that reported the effectiveness of T wave inversion in lead avl in diagnosing coronary artery disease was limited to patients with chronic stable angina.[] Another study included patients who underwent non-emergency PCI (i.e., elective PCI).[] Fourth, multivessel lesions cause complicated ECG changes, thereby the differences in the proportions of multivessel lesions compared with previous studies may have been influential.[] Indeed, the previous two studies had more multivessel lesions than our study, (.% in our study vs..% in Farhan s study, p = 0.; and vs. 0.% in Hassen s study, p < 0.0).[, ] Although we did not show the diagnostic usefulness of T wave inversion in lead avl accompanying T wave inversion in other leads, isolated T wave inversion in lead avl (i.e., the presence of T wave inversion only in lead avl) had a high specificity of.% for predicting MLAD lesion. Because treatment strategy and complications depend on the infarction site,[] isolated T wave inversion in lead avl might help to predict the site of the ischemic lesion, resulting in improved patient outcome. Moreover, in agreement with the study reported that approximately % of physicians missed an isolated T wave inversion,[] our findings underscore the importance of cautious interpretation of T wave inversion as a clue to predict the ischemic lesion : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

12 Page of Limitations Our study has several potential limitations. First, because this study is a single-centre study, the generalizability of our inferences is limited. Nevertheless, we analysed the consecutive data during 0 0 with the definition of T wave inversion based on AHA guidelines.[] Moreover, all T wave inversions were evaluated by cardiologists who were blinded to the results of PCI. Second, as with any other observational studies focused on patients with ACS, we could not differentiate whether the MLAD lesion had newly occurred or not. However, our inferences were not changed materially among patients with ACS caused by the MLAD lesion as the cause. Finally, we included patients who underwent PCI. Therefore, our inferences should be used for predicting the ischemic lesion, and not for diagnosing ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

13 Page of CONCLUSIONS In our study, T wave inversion in lead avl based on the guidelines, had low sensitivity and specificity for predicting MLAD lesion. However, isolated T wave inversion in lead avl had high specificity. Our inferences underscore the importance of a cautious interpretation of T wave inversion in lead avl, particularly for the isolated T wave inversion in lead avl. Our findings facilitate further studies to validate the diagnostic values of T wave inversion in lead avl for predicting ischemic lesions : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

14 Page of Acknowledgement The authors acknowledge to Japanese Emergency Medicine Network (JEMNet) and cardiologist in Ise Red Cross Hospital for designing and helping this research. Competing interests None. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Contributors NN was involved in study concept and design, analysis and interpretation of the data and drafting of the manuscript. TG took part in study concept and design, analysis and interpretation of the data and drafting of the manuscript. TK was involved in acquisition of the data. AK took part in analysis and interpretation of the data and critical revision of the manuscript for important intellectual content. Ethics approval Ise Red Cross Hospital. Data sharing statement No additional data are available : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

15 Page of REFERENCES. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 00;:-0.. Kracoff OH, Adelman AG, Marquis JF, et al. Twelve-lead electrocardiogram recording during percutaneous transluminal coronary angioplasty. Analysis of reciprocal changes. J Electrocardiol 0;:-.. Kracoff OH, Adelman AG, Oettinger M, et al. Reciprocal changes as the presenting electrocardiographic manifestation of acute myocardial ischemia. Am J Cardiol ;:-.. Hassen GW, Costea A, Smith T, et al. The neglected lead on electrocardiogram: T wave inversion in lead avl, nonspecific finding or a sign for left anterior descending artery lesion? J Emerg Med 0;:-0.. Farhan HL, Hassan KS, Al-Belushi A, et al. Diagnostic Value of Electrocardiographic T Wave Inversion in Lead avl in Diagnosing Coronary Artery Disease in Patients with Chronic Stable Angina. Oman Med J 00;:-.. Hassen GW, Talebi S, Fernaine G, et al. Lead avl on electrocardiogram: emerging as important lead in early diagnosis of myocardial infarction? Am J Emerg Med 0;:-.. O'Gara PT, Kushner FG, Ascheim DD, et al. 0 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 0;:e-.. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med 00;0: : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

16 Page of Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation 00;:e Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation ;:-0.. Hayden GE, Brady WJ, Perron AD, et al. Electrocardiographic T-wave inversion: differential diagnosis in the chest pain patient. Am J Emerg Med 00;0:-.. Hassen GW, Costea A, Carrazco C, et al. Isolated T Wave Inversion in Lead avl: An ECG Survey and a Case Report. Emerg Med Int 0;0: : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

17 Page of FIGURE LEGEND Figure. Flowchart of patients included in this study : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

18 Page of Table. Baseline characteristics of patients who underwent emergency percutaneous coronary intervention Variables Overall (n=) Age, median (IQR) ( ) Male sex () Type of coronary risk factors Smoking 0 (0) Family history of coronary artery diseases () Hypertension () History of myocardial infarction () Diabetes mellitus () Dyslipidaemia () Hyper triglyceride (TG) () Hyper low-density lipoprotein (LDL) () Low high-density lipoprotein (HDL) () Abbreviation; IQR, interquartile range Data were expressed as n (%) unless otherwise indicated - : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

19 Page of Table. Angiographic data of patients who underwent emergency percutaneous coronary intervention Variables Overall (n=) ST-elevation myocardial infarction () Causative lesion Right coronary artery 0 () Left main trunk () Left anterior descending artery () Left circumflex artery () High lateral branch () Coronary lesions Single-vessel disease 0 () Double-vessel disease (0) Triple-vessel disease () No of lesions in left anterior descending artery* 0 () 0 () () () Data were expressed as n (%) *No of lesions in left anterior descending artery doesn't include diagonal branch - : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

20 Page of Table. Performance of T wave inversion in lead avl for predicting mid-segment left anterior descending lesion MLAD lesion MLAD >0% MLAD 0% Overall (n=) p value n = n = T wave inversion in lead avl* () () () < 0.0 Isolated T wave inversion in lead avl () (0) () 0. MLAD lesion as the cause Overall (n=) Cause (+) n = Cause (-) n = p value T wave inversion in lead avl () () () < 0.0 Isolated T wave inversion in lead avl () () () 0.0 Data were expressed as n (%) Abbreviation; ECG, electrocardiogram; MLAD, mid-segment left anterior descending artery; CI, confidence interval * Sensitivity.% (% CI,.%.%), specificity.% (% CI,.%.%), positive predictive value.% (% CI,.0%.%), and negative predictive value.% (% CI,.%.%). Sensitivity.% (% CI,.%.%), specificity.% (% CI, 0.0%.0%), positive predictive value 0.% (% CI,.%.%), and negative predictive value.% (% CI,.%.%). Sensitivity.% (% CI,.%.%), specificity.% (% CI,.%.%), positive predictive value.% (% CI,.%.%), and negative predictive value.% (% CI,.%.%). Sensitivity.% (% CI, 0.%.%), specificity.% (% CI, 0.% 0.%), positive predictive value.% (% CI, 0.%.%), and negative predictive value.% (% CI,.%.%). - : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

21 Page 0 of Table. Performance of T wave inversion in lead avl for predicting mid-segment left anterior descending lesion, after excluding patients with left ventricular hypertrophy and bundle branch block MLAD lesion Overall (n=) MLAD >0% n = MLAD 0% n = T wave inversion in lead avl* () () () 0.0 Isolated T wave inversion in lead avl () () () 0.0 MLAD lesion as the cause Overall (n=) Cause (+) n = Cause (-) n = p value p value T wave inversion in lead avl () () () < 0.0 Isolated T wave inversion in lead avl () () () 0. Data were expressed as n (%) Abbreviation; ECG, electrocardiogram; MLAD, mid-segment left anterior descending artery; CI, confidence interval * Sensitivity.0% (% CI,.%.%), specificity.0% (% CI, 0.%.%), positive predictive value.% (% CI,.% 0.%), and negative predictive value.% (% CI,.%.%). Sensitivity.% (% CI,.%.0%), specificity.% (% CI,.%.%), positive predictive value.% (% CI,.%.%), and negative predictive value 0.% (% CI,.0%.0%). Sensitivity.% (% CI,.%.%), specificity.% (% CI,.% 0.%), positive predictive value.% (% CI,.%.0%), and negative predictive value.% (% CI,.% 0.%). Sensitivity.% (% CI, 0.%.%), specificity.% (% CI,.%.%), positive predictive value.% (% CI, 0.%.0%), and negative predictive value.% (% CI,.%.%). - : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

22 Page of Figure. Flowchart of patients included in this study. x0mm ( x DPI) - : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

23 Page of STARD checklist for reporting of studies of diagnostic accuracy (version January 00) Section and Topic Item On page # # TITLE/ABSTRACT/ Identify the article as a study of diagnostic accuracy (recommend MeSH KEYWORDS heading 'sensitivity and specificity'). INTRODUCTION State the research questions or study aims, such as estimating diagnostic accuracy or comparing accuracy between tests or across participant groups. METHODS Participants The study population: The inclusion and exclusion criteria, setting and locations where data were collected. Participant recruitment: Was recruitment based on presenting symptoms, results from previous tests, or the fact that the participants had received the index tests or the reference standard? Participant sampling: Was the study population a consecutive series of participants defined by the selection criteria in item and? If not, specify how participants were further selected. Data collection: Was data collection planned before the index test and reference standard were performed (prospective study) or after (retrospective study)? Test methods The reference standard and its rationale. Technical specifications of material and methods involved including how and when measurements were taken, and/or cite references for index tests and reference standard. Definition of and rationale for the units, cut-offs and/or categories of the - results of the index tests and the reference standard. 0 The number, training and expertise of the persons executing and reading the index tests and the reference standard. Whether or not the readers of the index tests and reference standard were blind (masked) to the results of the other test and describe any other clinical information available to the readers. Statistical methods Methods for calculating or comparing measures of diagnostic accuracy, - and the statistical methods used to quantify uncertainty (e.g. % confidence intervals). Methods for calculating test reproducibility, if done. n.a. RESULTS Participants When study was performed, including beginning and end dates of recruitment. Clinical and demographic characteristics of the study population (at least information on age, gender, spectrum of presenting symptoms). The number of participants satisfying the criteria for inclusion who did or did not undergo the index tests and/or the reference standard; describe why participants failed to undergo either test (a flow diagram is strongly recommended). Test results Time-interval between the index tests and the reference standard, and n.a. any treatment administered in between. Distribution of severity of disease (define criteria) in those with the target condition; other diagnoses in participants without the target condition. A cross tabulation of the results of the index tests (including indeterminate and missing results) by the results of the reference standard; for continuous results, the distribution of the test results by the results of the reference standard. 0 Any adverse events from performing the index tests or the reference n.a. standard. Estimates Estimates of diagnostic accuracy and measures of statistical uncertainty - (e.g. % confidence intervals). How indeterminate results, missing data and outliers of the index tests n.a. were handled. Estimates of variability of diagnostic accuracy between subgroups of participants, readers or centers, if done. Estimates of test reproducibility, if done. n.a. DISCUSSION Discuss the clinical applicability of the study findings : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

24 Does T wave inversion in lead avl predict mid-segment left anterior descending lesion in acute coronary syndrome? : a retrospective study Journal: Manuscript ID bmjopen-0-00.r Article Type: Research Date Submitted by the Author: 0-Dec-0 Complete List of Authors: Nakanishi, Nobuto; Ise Red Cross Hospital, Department of Cardiology Goto, Tadahiro; Massachusetts General Hospital, Emergency medicine Ikeda, Tomoya ; Ise Red Cross Hospital, Department of Cardiology Kasai, Atsunobu ; Ise Red Cross Hospital, Department of Cardiology <b>primary Subject Heading</b>: Emergency medicine Secondary Subject Heading: Cardiovascular medicine, Diagnostics Keywords: T wave inversion, electrocardiography, acute coronary syndrome, left anterior descending lesion : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

25 Page of Does T wave inversion in lead avl predict mid-segment left anterior descending lesion in acute coronary syndrome? : a retrospective study AUTHORS:, MD ; Tadahiro Goto, MD ; Tomoya Ikeda, MD ; Atsunobu Kasai, MD, PhD AFFILIATIONS:. Department of Cardiology, Ise Red Cross Hospital, Mie, Japan. Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States. CORRESPONDING AUTHOR: Dr.. Address: Department of Cardiology, Ise Red Cross Hospital, -- Funae, Ise, Mie, -, Japan. nobuto_nakanishi@ise.jrc.or.jp. Tel: Fax: +--- RUNNING HEAD: Diagnostic value of T wave inversion in lead avl KEY WORDS: T wave inversion, electrocardiography, acute coronary syndrome, left anterior descending lesion Word count: word : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

26 Page of ABSTRACT Objectives: Limited data is available regarding the predictive value of electrocardiographic T wave inversion in lead avl for mid-segment left anterior descending (MLAD) lesion among patients with acute coronary syndrome (ACS). Setting: Retrospective single-centre study, using a prospectively-collected coronary angiography database from January 0 to December 0. Participants: We included consecutive adult patients with ACS who underwent urgent percutaneous coronary intervention (PCI) within h after arriving at the hospital. We excluded patients who did not undergo an ECG before PCI, patients with proximal MLAD occlusion, and patients diagnosed with vasospastic angina. Primary and secondary outcome measures: The primary outcome was MLAD lesion >0%. The other outcome of interest was MLAD lesion as the cause for ACS. First, we evaluated the diagnostic values of T wave inversion in lead avl regardless of other T wave changes for each outcome. Second, we evaluated the diagnostic values of isolated T wave inversion in lead avl. Results: Overall, patients were eligible for the analysis. T wave inversion in lead avl regardless of other T wave changes had a sensitivity of.%, specificity of.%, positive predictive value of.%, and negative predictive value of.% for predicting MLAD lesion. Isolated T wave inversion in lead avl had a sensitivity of.%, specificity of.%, positive predictive value of 0.%, and negative predictive value of.% for predicting MLAD lesion. These diagnostic values did not change materially with focusing on patients with MLAD lesion as the cause. Conclusions: While T wave inversion in lead avl regardless of other T wave changes had low diagnostic values for predicting MLAD lesion, isolated T wave inversion in lead avl had a high : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

27 Page of specificity. Our inferences underscore the importance of a cautious interpretation of T wave inversion in lead avl among patients with ACS. Strengths and limitations of this study This is the first study to evaluate the diagnostic value of T wave inversion in lead avl for mid-segment left anterior descending (MLAD) lesion among patients with acute coronary syndrome. Although previous studies demonstrated that the usefulness of diagnostic values of T wave inversion in lead avl for MLAD lesion, our observation did not show the usefulness among ACS patients. Because this study is a single-centre, retrospective study, the generalizability of our inferences might be limited. Our inferences underscore the importance of a cautious interpretation of T wave inversion in lead avl among patients with ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

28 Page of INTRODUCTION The -lead electrocardiogram (ECG) is a fundamental tool to diagnose acute coronary syndrome (ACS) because ST-T changes in ECG reflect myocardial ischemia and myocardial necrosis after myocardial ischemia. Based on the diagnosis and prediction of ischemic lesions using ECG, cardiologists can provide early therapeutic intervention for patients with ACS.[] T wave inversion in lead avl has been reported to be a reciprocal change of inferior wall infarctions, mostly caused by right coronary artery lesions.[, ] However, several recent, small studies have suggested that T wave inversion in lead avl is associated with mid-segment left anterior descending (MLAD) lesion.[-] For example, a prospective observational study reported that the T wave inversion in lead avl was significantly associated with MLAD lesion >0% among patients with chronic stable angina.[] Another retrospective study from the US, using data of patients who underwent percutaneous coronary intervention (PCI), reported that the sensitivity of isolated T wave inversion in lead avl for predicting MLAD lesion >0% was.%, and the specificity was.%.[] However, these studies were conducted in limited population samples (e.g., single-centre studies, including non-urgent PCI), thereby limiting the generalizability of their inferences for patients with suspected ACS. Despite the clinical significance of T wave inversion in lead avl for the early detection of ischemic lesions, the association between T wave inversion in lead avl and MLAD lesion >0% among patients with ACS is yet to be elucidated. To address this gap in the current literature, we aimed to investigate the diagnostic value of T wave inversion in lead avl for MLAD lesion among patients who underwent urgent PCI for ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

29 Page of METHODS.. Study Design and Settings This is a retrospective analysis using data from the coronary angiography (CAG) database at the Ise Red Cross Hospital from January 0 to December 0. The Ise Red Cross Hospital had beds (medical and surgical), with approximately,000 outpatients and 0,000 admissions in 0. There were,000 emergency department visits, and 00 PCI were performed annually (including 0 cases of urgent PCI for ACS). Since, all CAG and PCI data has been prospectively collected for the CAG database. All data including patient s demographics, ECG findings, CAG findings, and treatment data, were registered by cardiologists. This study was approved by the clinical research ethics committee at the Ise Red Cross Hospital... Study Population We included consecutive adult patients who underwent urgent PCI. Urgent PCI was defined as PCI performed for patients with suspected ACS within h after arriving at the hospital.[, ] In patients with suspected non-st elevation myocardial infarction, board-certificated cardiologists assessed the need for coronary angiography based on the information on patient s symptoms, laboratory findings, ECG findings, and ultrasonographic findings. We excluded patients who met the following criteria: ) patients who did not undergo an ECG before PCI, ) patients with complete occlusion of the left main trunk and proximal-segment left anterior descending artery (i.e., we could not evaluate the MLAD lesion), and ) patients diagnosed with vasospastic angina... T wave inversion : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

30 Page of Based on a joint recommendation of the American Heart Association (AHA), the American College of Cardiology Foundation (ACCP), and the Heart Rhythm Society (HRP),[] we defined the T wave inversion as T wave 0. mv, compared with the baseline from the end of the T wave to the beginning of the P wave (Supplemental Figure a and b). The T wave inversion in lead avl was measured by cardiologists who were blinded to the results. In addition, we defined isolated T wave inversion as the presence of T wave inversion only in lead avl regardless of ST elevation in other leads, using a previously described classification scheme for isolated T wave inversion (Supplemental Figure a and b).[, ].. Outcome and Measured Variables The primary outcome was MLAD lesion >0%. MLAD was defined as the first septal branch to the point where left anterior descending artery forms an angle in right anterior oblique view.[0] The other outcome of interest was the MLAD lesion as the cause for ACS. The MLAD lesion as the cause for ACS was defined as ) the MLAD lesion where PCI was performed or ) the MLAD lesion diagnosed as the cause by the PCI operator in the case with multi-vessel disease. Data on patient demographics, including age, sex, smoking, family history of coronary artery diseases, hypertension, history of myocardial infarction, diabetes mellitus, and dyslipidaemia, were collected from the database and medical charts of our hospital... Statistical Analyses Continuous data were presented as the median (interquartile ranges [IQR]), whereas categorical data were expressed as number (%), with differences analysed using the chi-square test or Fisher s exact test as appropriate. We calculated the sensitivity, specificity, and predictive : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

31 Page of values of T wave inversion in lead avl for predicting MLAD lesion (positive predictive value [PPV] and negative predictive value [NPV]). First, we examined the association between T wave inversion in lead avl regardless of other T wave changes and MLAD lesion. Second, we repeated the analysis focusing on isolated T wave inversion.[] For sensitivity analysis, we repeated the analysis after excluding the patients with left ventricular hypertrophy and bundle branch block because these are associated with T wave inversion.[, ] Data analyses were conducted using R statistical software version.0. (R Development Core Team, Vienna, Austria). All statistical tests were two-tailed, and the chosen type error rate was p < : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

32 Page of RESULTS A total of patients underwent PCI at the Ise Red Cross Hospital from January 0 to December 0. Among these, patients underwent urgent PCI. Of patients who did not meet the inclusion criteria, patients did not undergo ECG before PCI, and patients had complete occlusion of the left main trunk or proximal-segment left anterior descending artery; therefore, patients were eligible for analysis (Figure ). The median age of the patients was ( ) years, and patients were male (%, Table ). The most common coronary risk factors were hypertension (%), dyslipidaemia (%), and smoking (0%). Of patients, (%) patients were diagnosed with ST-elevation myocardial infarction and leaving (%) patients were non ST-elevation myocardial infarction (Table ). The right coronary artery was the site of the most frequent causative lesion, followed by the left anterior descending artery. Single-vessel disease was diagnosed in approximately half of the patients. Among patients, a total of patients had T wave inversion in lead avl regardless of other T wave changes and patients had isolated T wave inversion in lead avl (Table ). There was no difference in the time from symptom onset to initial ECG between patients with T wave inversion and those without ( [-] min vs. [-] min; p=0.). Overall, patients had MLAD lesion >0%. T wave inversion in lead avl regardless of other T wave changes had a sensitivity of.% (% confidence interval [CI],.%.%), specificity of.% (% CI,.%.%), positive predictive value of.% (% CI,.0%.%), and negative predictive value of.% (% CI,.%.%) for predicting MLAD lesion. By contrast, isolated T wave inversion in lead avl had a sensitivity of.% (% CI,.%.%), specificity of.% (% CI, 0.0%.0%), positive predictive value of 0.% (% : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

33 Page of CI,.%.%), and negative predictive value of.% (% CI,.%.%) for predicting MLAD lesion. Focusing on patients with the MLAD lesion as the cause, T wave inversion in lead avl regardless of other T wave changes had a sensitivity of.% (% CI,.%.%), specificity of.% (% CI,.%.%), positive predictive value of.% (% CI,.%.%), and negative predictive value of.% (% CI,.%.%) for predicting MLAD lesion as the cause. By contrast, isolated T wave inversion in lead avl had a higher specificity of.% (% CI, 0.% 0.%) for predicting the MLAD lesion as the cause. In sensitivity analysis after excluding patients with left ventricular hypertrophy and bundle branch block, the performance of the T wave inversion in lead avl regardless of other T wave changes for predicting MLAD lesion did not change materially (Table ). Focusing on patients with the MLAD lesion as the cause, isolated T wave inversion in lead avl had a higher specificity of.% (% CI,.%.%) for predicting the MLAD lesion as the cause : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

34 Page 0 of DISCUSSION In this retrospective study using data from the CAG database at the Ise Red Cross Hospital from January 0 to December 0, we found that, among patients with ACS, the diagnostic value of T wave inversion in lead avl regardless of other T wave changes for predicting MLAD lesion was unsatisfactory. However, isolated T wave inversion in lead avl had high specificity for predicting MLAD lesion, even after excluding patients with left ventricular hypertrophy and bundle branch block. To the best of our knowledge, this is the first study to evaluate the diagnostic value of T wave inversion in lead avl for MLAD lesion among patients who underwent urgent PCI for ACS. T wave inversion in ECG is vital to the early diagnosis and detection of ischemic lesion for patients with suspected ACS. Reciprocal changes in ECG are recognized earlier than the ST elevation as the reflection of the ischemic lesion in ACS,[, ] and % of ACS patients had only reciprocal changes without ST elevation.[] To date, several studies have focused on the diagnostic values of T wave inversion for predicting MLAD lesion.[,, ] Among patients with chronic stable angina, the odds ratio of T wave inversion in lead avl for predicting MLAD lesion was..[] In another study, T wave inversion in leads avl and I had a sensitivity of.% and specificity of.% for predicting MLAD lesion.[] However, in our study, T wave inversion in lead avl regardless of other T wave changes had a low sensitivity of.% and a specificity of.% for predicting MLAD lesion. The reasons for the disparities in the diagnostic values among studies are likely multifactorial. First, although the definition of T wave inversion was unclear in previous studies,[,, ] we clearly defined T wave inversion according to the AHA definition[]; therefore, our findings were less likely to be subject to information bias. Second, a previous : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

35 Page of study used a combination of T wave inversion in lead avl and lead I to estimate the diagnostic values.[] Third, the disparities in the diagnostic values may be attributable to the differences in study population, settings, or any combination of these factors. For example, the study by Farhan et al. that reported the effectiveness of T wave inversion in lead avl in diagnosing coronary artery disease was limited to patients with chronic stable angina.[] Another study included patients who underwent non-urgent PCI (i.e., elective PCI).[] Fourth, in general multivessel lesions cause complicated ECG changes, thereby the differences in the proportions of multivessel lesions compared with previous studies may have been influential.[] Indeed, the previous two studies had more multivessel lesions than our study, (.% in our study vs..% in Farhan s study, p=0.; and vs. 0.% in Hassen s study, p<0.0).[, ] Although we did not show the diagnostic usefulness of T wave inversion in lead avl regardless of other T wave changes, isolated T wave inversion in lead avl (i.e., the presence of T wave inversion only in lead avl) had a high specificity of.% for predicting MLAD lesion. Because treatment strategy and complications depend on the infarction site,[] isolated T wave inversion in lead avl might help to predict the site of the ischemic lesion, resulting in improved patient outcome. Moreover, previous studies reported that approximately % of physicians missed an isolated T wave inversion in lead avl and that the best single lead for the emergency detection of ACS was lead avl.[, ] In agreement with these literature, our findings underscore the importance of cautious interpretation of T wave inversion in lead avl as a clue to predict the ischemic lesion in ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.

36 Page of Limitations Our study has several potential limitations. First, because this study is a single-centre study, the generalizability of our inferences is limited. Nevertheless, we analysed the consecutive data during 0 0 with the definition of T wave inversion based on AHA guidelines.[] Moreover, all T wave inversions were evaluated by cardiologists who were blinded to the results of PCI. Second, this sudy is limited by the small sample size. In particular, isolated T wave inversion was observed in only % of patients; therefore, our observartions should be validated by larger study. Third, in this analysis, we did not measure the association between T wave inversion and diagonal lesions.[] However, to maintain the consistency with the previous literature,[, ] we focused on the association between T wave inversion in lead avl and MLAD lesion regardless of the presence of diagonal lesions. Fourth, as with any other observational studies focused on patients with ACS, we could not differentiate whether the MLAD lesion had newly occurred or not. However, our inferences were not changed materially among patients with ACS caused by the MLAD lesion as the cause. Finally, we included patients who underwent PCI. Therefore, our inferences should be used for predicting the ischemic lesion, and not for diagnosing ACS : first published as 0./bmjopen-0-00 on February 0. Downloaded from on March 0 by guest. Protected by copyright.