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Acute electrocardiographic differences between Takotsubo cardiomyopathy and anterior ST elevation myocardial infarction
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ScienceDirect Journal of Electrocardiology xx (2014) xxx – xxx www.jecgonline.com
Acute electrocardiographic differences between Takotsubo cardiomyopathy and anterior ST elevation myocardial infarction☆ Giacomo Mugnai, MD, a,⁎ Giulia Pasqualin, MD, a Giovanni Benfari, MD, a Livio Bertagnolli, MD, a Francesca Mugnai, b Francesca Vassanelli, MD, a Giuseppe Marchese, MD, a Gabriele Pesarini, MD, PhD, a Giuliana Menegatti, MD a a
Division of Cardiology, University Hospital of Verona, Verona Italy b Medicine and Surgery, University of Siena, Siena Italy
Abstract
Background: The aim of this study was to compare ECG findings between anterior ST elevation myocardial infarction (STEMI) and Takotsubo cardiomyopathy (TC) in a similar sample of postmenopausal women. Methods: Between 2008 and 2011, 27 patients with TC were retrospectively enrolled and matched with 27 STEMI patients with the same age and sex taken from the prospective database of our laboratory. Results: The absence of abnormal Q waves, the ST depression in aVR and the lack of ST elevation in V1 were significantly associated with TC (respectively: 52% vs 18%, p = 0.01; 47% vs 11%, p = 0.01; 80% vs 41%, p = 0.01). The combination of these ECG findings identified TC with a specificity of 95% and a positive predictive value of 85.7%. Conclusions: The ECG on admission may be useful to distinguish TC from anterior STEMI. The combination of three ECG findings identifies patients with TC with high specificity and positive predictive value. © 2014 Elsevier Inc. All rights reserved.
Keywords:
Takotsubo cardiomyopathy; Anterior STEMI; Myocardial infarction; ECG
Introduction Takotsubo cardiomyopathy (TC) is a transient syndrome commonly triggered by physical or emotional stress. It is characterized by transient left ventricular (LV) dysfunction with chest pain, electrocardiographic impairments (ECG) and clinical features resembling an anterior acute myocardial infarction with occlusion of left anterior descending (LAD) coronary artery [1–5]. Patients with TC have either normal coronary arteries or slight luminal irregularities. Since TC generally occurs in postmenopausal women, the differential diagnosis between TC and acute myocardial infarction is very challenging especially in these selected patients. The diagnosis is particularly challenging for those patients with TC exhibiting ST segment elevation. Some electrocardiographic characteristics have been previously proposed to distinguish the two conditions on admission [6–10]. The 12☆
No conflicts of interest to declare. ⁎ Corresponding author at: Division of Cardiology, Department of Medicine, University Hospital of Verona, P.le A. Stefani, 1–37126, Verona, Italy. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2014.11.001 0022-0736/© 2014 Elsevier Inc. All rights reserved.
lead ECG represents a very simple, noninvasive, widely available initial diagnostic test which may address the physician to the correct clinical and therapeutic management. Our aim was to analyze and compare ECG findings between acute ST elevation myocardial infarction (STEMI) and TC in a sample with a prevalence of postmenopausal women to identify the most reliable ECG parameters for the differential diagnosis.
Methods Between January 2008 and December 2011, 27 consecutive patients with a diagnosis of TC according to the Mayo Clinic criteria [11] were retrospectively enrolled in our study (mean age 64.6 ± 13.5 years, 26 females). Each patient with TC was matched with one patient randomly extracted from a group of anterior STEMI patients with the same age and sex taken from the prospective electronic database of our catheterization laboratory. The diagnosis of anterior STEMI was based on typical symptoms and ST elevation ≥ 2 mm in men, or ≥ 1.5 mm in women in leads V2–V3 and/
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or ≥ 1 mm in other leads [12]. Patients with idiopathic dilated cardiomyopathy, prior myocardial infarction and with a symptoms onset-to-admission time greater than 12 hours were excluded. All patients underwent coronary and left ventricular angiography in the acute phase. Informed consent for coronary angiogram was obtained from all patients before the procedure. A LAD obstructive disease was found in all patients with acute anterior STEMI. The proximal tract of LAD was involved in 20 patients, the middle tract in 13 patients and the distal one in 2 patients. Clinical characteristics (age, sex, cardiovascular risk factors, comorbidities, possible physical or emotional triggers) and physical examinations were gathered. Peak values of cardiac enzymes (CKMBm) were gathered from medical records. During the hospital stay, the trans-thoracic 2D echocardiography (TTE) was routinely performed in all patients on admission and before discharge. The standard follow-up time for echocardiography after discharge in our hospital was 3 or 6 months. The first admission ECG of all patients with Takotsubo cardiomyopathy and anterior STEMI was reviewed. At the time of admission, standard 12-lead ECGs were recorded at a paper speed of 25 mm/s and an amplification of 10 mm/mV. Standard ECG parameters were assessed: heart rate, PR interval, QRS axis, QRS duration, QT interval and QT corrected using Bazett's formula, QT dispersion (QTd), STT abnormalities, abnormal Q waves. The following ST segment characteristics were analyzed in both groups: the maximal ST segment elevation and leads involved, the presence of depressions in leads II, III, and aVF and the ST depression in aVR. ST segment elevation was assessed at the J-point, according to European Society of Cardiology guidelines [12]. The following parameters cut-offs were considered in our analysis: ST segment elevation ≥ 1.0 mm, negative T wave ≥ 0.5 mm, Q-wave amplitude ≥ 2 mm and duration ≥ 0.02 s in leads V2 and V3 or ≥ 0.03 s in II, aVF; I, aVL; V4–V6 [13]. The sum of ST segment elevation in leads V1–V3 and V4–V6 was calculated and then the ratio of ST elevation in leads V 4–V6 to ST elevation in leads V1-V3 was determined. QT interval was measured from the onset of the QRS to the end of the T wave, defined as a return to the T-P baseline. If U waves were present, the QT interval was measured to the nadir of the curve between the T and U waves. Three consecutive cycles were evaluated for each lead. The QTd was measured as the difference between the maximum and the minimum QT on the standard 12-lead ECG. All ECG measurements were made by two cardiologists blinded to angiographic and clinical data. In case of disagreement, a third physician was consulted. Continuous variables are expressed as mean ± SD and, if appropriate, were compared using the Student's t-test. Categorical variables are expressed as numbers and percentages and, if appropriate, were compared with the chi-square analysis. A p value b 0.05 was deemed statistically significant. Statistical analysis was performed using IBM SPSS Statistics 18 (SPSS, Inc., Chicago, Illinois, USA).
Results The mean age of both groups was 64.6 ± 13.5 years (median 66) and females were 26 (96%). Chest pain was the most common presenting symptom (23/27, 85%). In 16 patients (59%) with TC a possible triggering event was identified: emotional in 9 patients (33%), physical stress (exercise, acute illnesses, surgery, and trauma) in 7 (26%). Patients with anterior STEMI had similar demographic characteristics and cardiovascular risk factors compared with those with TC (Table 1). Creatine kinase-MB peak (μg/L) was significantly greater in patients with anterior STEMI (502.5 ± 471.8 vs 16.8 ± 17.6; p b 0.0001). Left ventricular ejection fraction (LVEF) assessed on admission was similar in both groups (44.5 ± 7.6% in TC group vs 46.5 ± 7.9% in STEMI group; p = 0.4). In the anterior STEMI group, initial TIMI flow measured during coronary angiography resulted “1” in 8 patients (30%) and “0” in 19 patients (70%); otherwise, all patients with Takotsubo presented an initial TIMI flow of “3”. Two typical ECG presentations of TC and anterior STEMI are illustrated in the Fig. 1. In patients with TC, three distinct patterns were found: 1) convex ST segment elevation (1.6 ± 1.3 mV), predominantly in leads V2–V4 in 15 patients (56%), associated with negative T wave in the same leads in 8 patients on admission, and positive T wave with evolution to negative in the remaining patients; 2) isolated T-wave inversion, mainly in I (50%), aVL (80%) and precordial leads (70%), becoming more prominent and deeper over time (n = 10, 37%); 3) no ST-segment or T wave changes on admission in 2 patients (7%) with subsequent negative and diffuse T wave inversion in precordial leads. All ST elevations resolved by the time of hospital discharge in all 15 patients. In the acute phase, new Q waves developed in 5 patients (18%), usually in V1–V3 (n = 3, 60%), and these persisted after hospital discharge in two patients (40%). No significant changes in the amplitudes of the QRS complexes were observed between the “admission” ECG and subsequently recorded ECGs, as previously reported by other works [14,15].
Table 1 Demographic and clinical characteristics of patients with Takotsubo cardiomyopathy and anterior STEMI. Variable
Takotsubo
Myocardial infarction
P-value
Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Smoking, n (%) Family history for coronary artery disease, n (%) Creatine kinase-MB peak (μg/L) Left ventricular ejection fraction (%) [admission] Left ventricular ejection fraction (%) [before discharge] Pain to ECG (hours)
15 (56%) 15 (56%) 4 (15%) 1 (4%) 5 (19%)
13 (48%) 9 (33%) 3 (11%) 5 (19%) 4 (15%)
16.8 ± 17.6 44.5 ± 7.6
502.5 ± 471.8 46.5 ± 7.9
b0.001 0.4
54.7 ± 4.5
46.8 ± 6.5
b0.01
6.2 ± 2.1
3.8 ± 2.1
b0.001
0.6 0.1 0.7 0.08 0.7
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Fig. 1. A – A typical ECG during acute anterior STEMI. The ST segment elevation involves all precordial leads, including V1, and is maximal in the leads V2− V3. Reciprocal ST depression can be observed II, III and aVF. Abnormal Q waves are clear in leads V1− V4. B – In this ECG, some of typical characteristics of TC can be observed. The ST elevation is less prominent and only involves V2− V3; reciprocal ST depression is absent in II, III and aVF. Abnormal Q waves can be observed only in aVL.
All anterior STEMI patients had ST elevation in at least one of the 12 ECG leads. Fourteen patients exhibited T wave inversion (52%) on admission, especially in aVL (n = 7,50%) and II, III, and aVF (n = 5, 36%), but not in those leads involved in ST segment elevation; after the acute phase, all the leads with ST segment elevation developed T wave inversion. Fourteen patients (52%) presented new Q waves on admission, especially in precordial leads (n = 7, 54%) and in III and aVF (n = 5, 38%). Table 2 shows the comparison of the ECG findings between patients with TC and those with anterior STEMI. No differences in heart rate, PR interval, T wave inversion and QRS axis were found. Corrected QT intervals were longer in TC than in anterior STEMI patients, but not significantly (470.7 ± 36.4 vs 456.3 ± 32.1 ms, p = 0.7). Also QT dispersion was higher in patients with TC, without any statistical significance (59.4 ± 17.1 vs 40.5 ± 19.9 ms, p = 0.7). QRS duration was significantly greater in STEMI patients compared with TC group (100.0 ± 26.0 vs 90.9 ± 15.5; p = 0.01) and also the abnormal Q waves were considerably more frequent in patients with anterior STEMI (52% vs 18%; p = 0.01). Mean ECG findings did not significantly differ between patients with symptom onset to ECG N 6 hours compared with those with symptom onset to ECG N 6 hours, in both groups (Table 3). Table 4 shows the comparison of ECG findings between patients with TC presenting ST elevations and those with anterior STEMI. Reciprocal ST depression in II, III and aVF was similarly found in both groups (27% vs 33%, p = 0.6). On the other hand, TC patients had ST segment depression in
lead aVR more frequently than patients with anterior STEMI (47% vs 11%, p = 0.01) and also the lack of ST elevation in lead V1 was considerably more frequent in patients with TC presenting ST elevation than those with anterior STEMI (80% vs 41%, p = 0.01). The number of leads involved in ST elevation was very similar between two groups but ST segment amplitudes were higher in patients with anterior STEMI. In fact, the maximal ST amplitude was markedly greater in STEMI group compared with TC patients (3.9 ± 2.4 mm vs 1.6 ± 1.3 mm; p = 0.04). The sum of ST segment elevation amplitudes was significantly higher in patients with anterior STEMI both in V4–V6 and in V1–V3
Table 2 ECG Findings for Takotsubo cardiomyopathy and anterior STEMI. Variable
Takotsubo
Myocardial infarction P-value
Heart rate (bpm) PR interval (ms) QRS duration (ms) QT interval (ms) QTc Bazett (ms) QT dispersion (ms) Maximal ST elevation (mm) Number of leads involved by ST elevation Abnormal Q waves, n (%) T wave inversion, n (%) QRS axis (°)
80.4 ± 16.8 165.2 ± 27.7 90.9 ± 15.5 414.7 ± 45.5 470.7 ± 36.4 59.4 ± 17.1 1.6 ± 1.3
80.6 ± 19.8 163.9 ± 24.5 100.0 ± 26.0 401.5 ± 51.1 456.3 ± 32.1 40.5 ± 19.9 3.9 ± 2.4
0.3 0.8 0.01 0.8 0.7 0.7 0.04
4.6 ± 2.8
4.5 ± 1.4
0.9
5 (18%) 20 (74%) 16.2 ± 48.2
14 (52%) 14 (52%) 2.1 ± 45.8
0.01 0.09 0.3
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Table 3 Comparison of ECG findings in both groups stratifying by time from symptom onset to recording ECGs N6 hours vs b 6 hours. Variable
Heart rate (bpm) PR Interval (ms) QRS duration (ms) QT Interval (ms) QTc Bazett (ms) QT dispersion (ms) Maximal ST elevation (mm) Abnormal Q waves, n (%)
Takotsubo
P
b 6 hours
N6 hours
83.4 ± 19.8 160.8 ± 30.4 89.4 ± 23.9 402.3 ± 48.2 461.3 ± 22.1 56.4 ± 10.2 2.6 ± 1.4 2 (40%)
78.5 ± 21.1 169.3 ± 36.5 97.2 ± 18.6 420.7 ± 39.5 475.7 ± 26.2 60.2 ± 20.1 1.2 ± 0.4 3 (60%)
compared with TC group (respectively: 7.2 ± 6.1 vs 2.5 ± 2.2 mm, p = 0.007; 3.9 ± 3.4 vs 1.3 ± 1.9 mm, p = 0.01); the ratio of ST elevation in leads V4–V6 to ST elevation in leads V1–V3 was similar in both groups (0.63 ± 0.51 vs 0.55 ± 0.84, p = 0.7). As the Fig. 2 shows, in patients with anterior STEMI, the ST segment elevation more frequently involved the precordial leads, especially V2 and V3 (100% of cases), and never involved the inferior leads. Moreover, the lead V1 was often involved by the ST elevation (16/27, 59%). Also TC patients exhibited ST segment elevation particularly in V2 and V3 (14/15, 93% of cases) but they sometimes presented ST elevation in the inferior leads, especially in II (5/15, 33%); interestingly, the lead V1 was sporadically involved in ST elevation (3/15, 20%). In TC patients with ST elevation, the lack of ST elevation in lead V1 identified TC with 80% sensitivity and 60% specificity, with a positive predictive value of 80% for a test accuracy of 68.6% (Table 5). The absence of abnormal Q waves similarly identified TC. ST segment depression in lead aVR was able to recognize TC with 90% specificity and 77.8% positive predictive value but with lower sensitivity values (46.7%); this ECG finding was found to have the best accuracy (71.4%). The combination of all these ECG findings (lack of ST elevation in lead V1 + absence of abnormal Q waves + ST segment depression in lead aVR) identified TC with 95% specificity and 85.7% positive predictive value at the expense of sensitivity which collapsed to 40% (Table 5). The intra-observer intraclass correlation coefficient for TpTe was 0.95 (95% CI, 0.90–0.97) and the inter-observer intraclass correlation coefficient was 0.89 (95% CI, 0.86–0.95).
Table 4 ST elevation characteristics in patients with Takotsubo cardiomyopathy presenting ST elevation and those with anterior STEMI. ECG finding
Takotsubo (n = 15)
Anterior STEMI (n = 27)
P-value
Reciprocal changes, n (%) ST depression-aVR, n (%) No ST elevation-V1, n (%) ST elevation V1–3 (mm) ST elevation V4–6 (mm) ST elevation V4–6/ST elevation V1–3
4 (27%) 7 (47%) 12 (80%) 2.5 ± 2.2 1.3 ± 1.9 0.55 ± 0.84
9 (33%) 3 (11%) 11 (41%) 7.2 ± 6.1 3.9 ± 3.4 0.63 ± 0.51
0.6 0.01 0.01 0.007 0.01 0.7
ns ns ns ns ns ns ns ns
Myocardial infarction
P
b 6 hours
N 6 hours
86.2 ± 19.4 155.9 ± 34.1 104.2 ± 13.2 395.8 ± 32.1 453.4 ± 40.1 38.5 ± 21.2 4.4 ± 2.8 5 (36%)
79.3 ± 28.1 177.4 ± 38.2 98.8 ± 20.3 405.1 ± 45.1 466.3 ± 30.2 45.2 ± 15.1 3.4 ± 2.0 9 (64%)
ns ns ns ns ns ns ns ns
Discussion In our study we sought to compare acute ECG characteristics between TC and anterior STEMI in two similar small populations to evaluate the usefulness of the ECG in distinguishing them. The main findings in this study are the following: 1) three distinct patterns were observed in TC patients: ST segment elevation with or without T wave inversion, isolated T wave inversions and no ST segment or T wave abnormalities; 2) in patients with anterior STEMI, ST segment elevation was considerably higher in precordial leads; 3) the combination of three ECG findings (lack of ST elevation in lead V1, the absence of abnormal Q waves and ST depression in lead aVR) was able to identify the TC with a specificity of 95% and a positive predictive value of 85.7%. Similar demographic characteristics and cardiovascular risk factors were found between TC and STEMI patients except for smoking which was more prevalent in the STEMI group. Although the population sample was relatively small and predominantly represented by women, this finding is surprising given the different pathophysiologies of both conditions. However, these results should not be generalized because of the small number of patients in our study. The distinct patterns observed in patients with TC might be related to different symptoms onset-to-admission time; although in our study all patients had a symptoms onset-toadmission time lower than 12 hours, ST elevation might have disappeared within a few hours from the onset. Previous studies have showed higher ST elevation amplitudes in patients with anterior STEMI compared with TC patients and our data confirm these findings [6,8–10]; in fact, the sum of ST segment elevation amplitudes was significantly greater in patients with anterior STEMI both in V4–V6 and in V1–V3. Although some studies have reported different results [6,8], in our work the ratio of ST elevation in leads V4–V6 to ST elevation in leads V1–V3 was similar in both groups. Of note, in our study ST elevation was assessed at the J point, according to European Society of Cardiology guidelines and similarly to some recently published works [10,16]; previously, some studies had evaluated the ST segment elevation 80 ms after the J point [6,17]. In the presence of increased T wave amplitude in the acute phase, a noticeable amount of patients might exhibit ST-segment elevation when the magnitude is measured 80 ms after the J point despite the absence of ST-segment elevation when the magnitude is measured at the J point. The
G. Mugnai et al. / Journal of Electrocardiology xx (2014) xxx–xxx
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Fig. 2. Above – Prevalence of ST elevation in patients with anterior STEMI. In precordial leads, high rates of segment ST elevation were found in leads V2–V4. The prevalence of ST elevation was considerable in V1 and gradually decreased in V5− V6. No inferior leads were involved by ST segment elevation. Below – Prevalence of ST elevation in patients with TC. Higher rates of ST segment elevation were found in leads V2− V3. The prevalence of ST elevation in V1 was markedly lower in patients with TC than those with anterior STEMI. Moreover, patients with TC presented in a moderate proportion of cases (20–33%) an involvement of the inferior leads.
presence or absence of ST-segment elevation could thus be considerably affected by the point used to assess ST-segment deviation as well as by the cut-off values of ST segment elevation [8]. Further studies are needed to identify the optimal cut-off values of ST-segment elevation for the differential diagnosis between TC and anterior STEMI. Our data are consistent with some previously published studies which have reported a considerable amount of TC patients with ST elevation in the inferior leads (20–50%) [8]. In fact, in our study ST elevation in the inferior leads was observed in 3–5 patients (n = 3 in III, n = 4 in aVF, n = 5 in II) for a percentage ranging from 20% to 33%. On the contrary, no patients with anterior STEMI exhibited ST elevation in the inferior leads. We also confirm a lower prevalence of ST elevation in lead V1 in TC patients (3/15, 20%) compared with STEMI patients (16/27, 59%; p = 0.01). This finding is very interesting especially as the
significant proportion of cases with mid or distal LAD involvement (n = 15) might have led to a decreased percentage of patients with ST elevation in lead V1 among STEMI patients. In fact, the different locations of LAD occlusion responsible for anterior STEMI may lead to different ST deviation patterns, both in frontal and tin precordial leads, based on the differences in orientation of the ST vector [18,19] Abnormal Q waves were more frequently found in patients with anterior STEMI (52% vs 18%; p = 0.02). The absence of pathological Q waves in patients with TC may be explained by the absence of true myocardial necrosis [6]; on the contrary, in STEMI patients, pathological Q waves often appear within 12 hours from the onset and may be related to either initial myocardial necrosis or local intramyocardial conduction delays secondary to myocardial ischemia in regions supplied by the proximal LAD [20]. In
Table 5 Sensitivity, specificity, accuracy and predictive values of some ECG characteristics in distinguishing Takotsubo cardiomyopathy from anterior STEMI.
Lack of ST elevation in V1 No abnormal Q waves ST depression in aVR The presence of 2 out of 3 ECG parameters The combination of all the parameters
Sensitivity
Specificity
PPV
NPV
Accuracy
80% 81.4% 46.7% 60% 40%
60% 50% 90% 75% 95%
80% 68.7% 77.8% 64.3% 85.7%
60% 66.7% 69.2% 71.4% 67.8%
68.6% 68.1% 71.4% 68.6% 71.4%
PPV: positive predictive value; NPV: negative predictive value.
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patients with TC, ST elevation very often has been described to occur in lead − aVR facing the apical and inferolateral regions resulting in ST depression in the opposing lead aVR [8]. In the anterior STEMI, the prevalence of ST elevation in − aVR (and the consequent ST depression in aVR) might occur in proximal occlusions with anterolateral involvement in which the ST vector points anywhere between − 60 and + 120 degrees [18]. In our study, ST depression in aVR was found more frequently in TC patients (p = 0.01) and this marker identified TC with high specificity and positive predictive values (90% and 77.8%, respectively) but very low sensitivity (46.7%). The lack of ST elevation in lead V1 and the absence of abnormal Q waves had individually similar sensitivity, specificity and predictive values (Table 5). The combination of these 3 ECG findings hugely enhanced both the specificity (95%) and the positive predictive value (85.7%) with a decrease of the sensitivity (40%). Therefore, the contemporary presence of all these markers very precisely identified those patients with TC. Many studies have found the absence of reciprocal ST depression in II, III and aVF as a peculiar ECG marker of TC [6–10,21]. In our study, the frequency of ST depression in the inferior leads did not differ between the two groups; this may be explained by the low percentage of reciprocal ST depression in leads II, III, and aVF in anterior STEMI (33%) attributable to the considerable amount of patients with mid or distal LAD occlusion in our case series. As expected, patients with anterior STEMI presented markedly higher levels of creatine kinase-MB compared with TC patients (b 0.0001). Of note, QRS duration was significantly more prolonged in STEMI patients; this might be explained by intramyocardial conduction delays due to a greater myocardial ischemia caused by the proximal LAD occlusion. On the other hand, QTc and QT dispersion were mildly higher in TC patients, consistent with data from the literature [6–10]; generally, the repolarization times and the dispersion of ventricular repolarization in TC are mildly prolonged on admission and they enormously increase in the subacute phase [22]. The most important limitations of this study are related to its retrospective and single-center design. The sample size is small and results of this study should be confirmed by larger prospective studies.
Conclusions In conclusion, our study sought to retrospectively analyze the ECG differences between TC and anterior STEMI in a similar sample with a prevalence of postmenopausal women. Patients with TC exhibited on admission three distinct ECG patterns: ST segment elevation with or without T wave inversion, isolated T wave inversions and no ST segment-T wave abnormalities. Patients with anterior STEMI presented higher ST segment elevation in precordial leads without involvement of the inferior leads. The combination of three ECG findings (lack of ST elevation in lead V1, the absence of abnormal Q waves and ST depression in lead aVR) was able to differentiate the TC with a specificity of 95% and a positive predictive value of 85.7%.
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ScienceDirect Journal of Electrocardiology xx (2014) xxx – xxx www.jecgonline.com
Acute electrocardiographic differences between Takotsubo cardiomyopathy and anterior ST elevation myocardial infarction☆ Giacomo Mugnai, MD, a,⁎ Giulia Pasqualin, MD, a Giovanni Benfari, MD, a Livio Bertagnolli, MD, a Francesca Mugnai, b Francesca Vassanelli, MD, a Giuseppe Marchese, MD, a Gabriele Pesarini, MD, PhD, a Giuliana Menegatti, MD a a
Division of Cardiology, University Hospital of Verona, Verona Italy b Medicine and Surgery, University of Siena, Siena Italy
Abstract
Background: The aim of this study was to compare ECG findings between anterior ST elevation myocardial infarction (STEMI) and Takotsubo cardiomyopathy (TC) in a similar sample of postmenopausal women. Methods: Between 2008 and 2011, 27 patients with TC were retrospectively enrolled and matched with 27 STEMI patients with the same age and sex taken from the prospective database of our laboratory. Results: The absence of abnormal Q waves, the ST depression in aVR and the lack of ST elevation in V1 were significantly associated with TC (respectively: 52% vs 18%, p = 0.01; 47% vs 11%, p = 0.01; 80% vs 41%, p = 0.01). The combination of these ECG findings identified TC with a specificity of 95% and a positive predictive value of 85.7%. Conclusions: The ECG on admission may be useful to distinguish TC from anterior STEMI. The combination of three ECG findings identifies patients with TC with high specificity and positive predictive value. © 2014 Elsevier Inc. All rights reserved.
Keywords:
Takotsubo cardiomyopathy; Anterior STEMI; Myocardial infarction; ECG
Introduction Takotsubo cardiomyopathy (TC) is a transient syndrome commonly triggered by physical or emotional stress. It is characterized by transient left ventricular (LV) dysfunction with chest pain, electrocardiographic impairments (ECG) and clinical features resembling an anterior acute myocardial infarction with occlusion of left anterior descending (LAD) coronary artery [1–5]. Patients with TC have either normal coronary arteries or slight luminal irregularities. Since TC generally occurs in postmenopausal women, the differential diagnosis between TC and acute myocardial infarction is very challenging especially in these selected patients. The diagnosis is particularly challenging for those patients with TC exhibiting ST segment elevation. Some electrocardiographic characteristics have been previously proposed to distinguish the two conditions on admission [6–10]. The 12☆
No conflicts of interest to declare. ⁎ Corresponding author at: Division of Cardiology, Department of Medicine, University Hospital of Verona, P.le A. Stefani, 1–37126, Verona, Italy. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2014.11.001 0022-0736/© 2014 Elsevier Inc. All rights reserved.
lead ECG represents a very simple, noninvasive, widely available initial diagnostic test which may address the physician to the correct clinical and therapeutic management. Our aim was to analyze and compare ECG findings between acute ST elevation myocardial infarction (STEMI) and TC in a sample with a prevalence of postmenopausal women to identify the most reliable ECG parameters for the differential diagnosis.
Methods Between January 2008 and December 2011, 27 consecutive patients with a diagnosis of TC according to the Mayo Clinic criteria [11] were retrospectively enrolled in our study (mean age 64.6 ± 13.5 years, 26 females). Each patient with TC was matched with one patient randomly extracted from a group of anterior STEMI patients with the same age and sex taken from the prospective electronic database of our catheterization laboratory. The diagnosis of anterior STEMI was based on typical symptoms and ST elevation ≥ 2 mm in men, or ≥ 1.5 mm in women in leads V2–V3 and/
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or ≥ 1 mm in other leads [12]. Patients with idiopathic dilated cardiomyopathy, prior myocardial infarction and with a symptoms onset-to-admission time greater than 12 hours were excluded. All patients underwent coronary and left ventricular angiography in the acute phase. Informed consent for coronary angiogram was obtained from all patients before the procedure. A LAD obstructive disease was found in all patients with acute anterior STEMI. The proximal tract of LAD was involved in 20 patients, the middle tract in 13 patients and the distal one in 2 patients. Clinical characteristics (age, sex, cardiovascular risk factors, comorbidities, possible physical or emotional triggers) and physical examinations were gathered. Peak values of cardiac enzymes (CKMBm) were gathered from medical records. During the hospital stay, the trans-thoracic 2D echocardiography (TTE) was routinely performed in all patients on admission and before discharge. The standard follow-up time for echocardiography after discharge in our hospital was 3 or 6 months. The first admission ECG of all patients with Takotsubo cardiomyopathy and anterior STEMI was reviewed. At the time of admission, standard 12-lead ECGs were recorded at a paper speed of 25 mm/s and an amplification of 10 mm/mV. Standard ECG parameters were assessed: heart rate, PR interval, QRS axis, QRS duration, QT interval and QT corrected using Bazett's formula, QT dispersion (QTd), STT abnormalities, abnormal Q waves. The following ST segment characteristics were analyzed in both groups: the maximal ST segment elevation and leads involved, the presence of depressions in leads II, III, and aVF and the ST depression in aVR. ST segment elevation was assessed at the J-point, according to European Society of Cardiology guidelines [12]. The following parameters cut-offs were considered in our analysis: ST segment elevation ≥ 1.0 mm, negative T wave ≥ 0.5 mm, Q-wave amplitude ≥ 2 mm and duration ≥ 0.02 s in leads V2 and V3 or ≥ 0.03 s in II, aVF; I, aVL; V4–V6 [13]. The sum of ST segment elevation in leads V1–V3 and V4–V6 was calculated and then the ratio of ST elevation in leads V 4–V6 to ST elevation in leads V1-V3 was determined. QT interval was measured from the onset of the QRS to the end of the T wave, defined as a return to the T-P baseline. If U waves were present, the QT interval was measured to the nadir of the curve between the T and U waves. Three consecutive cycles were evaluated for each lead. The QTd was measured as the difference between the maximum and the minimum QT on the standard 12-lead ECG. All ECG measurements were made by two cardiologists blinded to angiographic and clinical data. In case of disagreement, a third physician was consulted. Continuous variables are expressed as mean ± SD and, if appropriate, were compared using the Student's t-test. Categorical variables are expressed as numbers and percentages and, if appropriate, were compared with the chi-square analysis. A p value b 0.05 was deemed statistically significant. Statistical analysis was performed using IBM SPSS Statistics 18 (SPSS, Inc., Chicago, Illinois, USA).
Results The mean age of both groups was 64.6 ± 13.5 years (median 66) and females were 26 (96%). Chest pain was the most common presenting symptom (23/27, 85%). In 16 patients (59%) with TC a possible triggering event was identified: emotional in 9 patients (33%), physical stress (exercise, acute illnesses, surgery, and trauma) in 7 (26%). Patients with anterior STEMI had similar demographic characteristics and cardiovascular risk factors compared with those with TC (Table 1). Creatine kinase-MB peak (μg/L) was significantly greater in patients with anterior STEMI (502.5 ± 471.8 vs 16.8 ± 17.6; p b 0.0001). Left ventricular ejection fraction (LVEF) assessed on admission was similar in both groups (44.5 ± 7.6% in TC group vs 46.5 ± 7.9% in STEMI group; p = 0.4). In the anterior STEMI group, initial TIMI flow measured during coronary angiography resulted “1” in 8 patients (30%) and “0” in 19 patients (70%); otherwise, all patients with Takotsubo presented an initial TIMI flow of “3”. Two typical ECG presentations of TC and anterior STEMI are illustrated in the Fig. 1. In patients with TC, three distinct patterns were found: 1) convex ST segment elevation (1.6 ± 1.3 mV), predominantly in leads V2–V4 in 15 patients (56%), associated with negative T wave in the same leads in 8 patients on admission, and positive T wave with evolution to negative in the remaining patients; 2) isolated T-wave inversion, mainly in I (50%), aVL (80%) and precordial leads (70%), becoming more prominent and deeper over time (n = 10, 37%); 3) no ST-segment or T wave changes on admission in 2 patients (7%) with subsequent negative and diffuse T wave inversion in precordial leads. All ST elevations resolved by the time of hospital discharge in all 15 patients. In the acute phase, new Q waves developed in 5 patients (18%), usually in V1–V3 (n = 3, 60%), and these persisted after hospital discharge in two patients (40%). No significant changes in the amplitudes of the QRS complexes were observed between the “admission” ECG and subsequently recorded ECGs, as previously reported by other works [14,15].
Table 1 Demographic and clinical characteristics of patients with Takotsubo cardiomyopathy and anterior STEMI. Variable
Takotsubo
Myocardial infarction
P-value
Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Smoking, n (%) Family history for coronary artery disease, n (%) Creatine kinase-MB peak (μg/L) Left ventricular ejection fraction (%) [admission] Left ventricular ejection fraction (%) [before discharge] Pain to ECG (hours)
15 (56%) 15 (56%) 4 (15%) 1 (4%) 5 (19%)
13 (48%) 9 (33%) 3 (11%) 5 (19%) 4 (15%)
16.8 ± 17.6 44.5 ± 7.6
502.5 ± 471.8 46.5 ± 7.9
b0.001 0.4
54.7 ± 4.5
46.8 ± 6.5
b0.01
6.2 ± 2.1
3.8 ± 2.1
b0.001
0.6 0.1 0.7 0.08 0.7
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Fig. 1. A – A typical ECG during acute anterior STEMI. The ST segment elevation involves all precordial leads, including V1, and is maximal in the leads V2− V3. Reciprocal ST depression can be observed II, III and aVF. Abnormal Q waves are clear in leads V1− V4. B – In this ECG, some of typical characteristics of TC can be observed. The ST elevation is less prominent and only involves V2− V3; reciprocal ST depression is absent in II, III and aVF. Abnormal Q waves can be observed only in aVL.
All anterior STEMI patients had ST elevation in at least one of the 12 ECG leads. Fourteen patients exhibited T wave inversion (52%) on admission, especially in aVL (n = 7,50%) and II, III, and aVF (n = 5, 36%), but not in those leads involved in ST segment elevation; after the acute phase, all the leads with ST segment elevation developed T wave inversion. Fourteen patients (52%) presented new Q waves on admission, especially in precordial leads (n = 7, 54%) and in III and aVF (n = 5, 38%). Table 2 shows the comparison of the ECG findings between patients with TC and those with anterior STEMI. No differences in heart rate, PR interval, T wave inversion and QRS axis were found. Corrected QT intervals were longer in TC than in anterior STEMI patients, but not significantly (470.7 ± 36.4 vs 456.3 ± 32.1 ms, p = 0.7). Also QT dispersion was higher in patients with TC, without any statistical significance (59.4 ± 17.1 vs 40.5 ± 19.9 ms, p = 0.7). QRS duration was significantly greater in STEMI patients compared with TC group (100.0 ± 26.0 vs 90.9 ± 15.5; p = 0.01) and also the abnormal Q waves were considerably more frequent in patients with anterior STEMI (52% vs 18%; p = 0.01). Mean ECG findings did not significantly differ between patients with symptom onset to ECG N 6 hours compared with those with symptom onset to ECG N 6 hours, in both groups (Table 3). Table 4 shows the comparison of ECG findings between patients with TC presenting ST elevations and those with anterior STEMI. Reciprocal ST depression in II, III and aVF was similarly found in both groups (27% vs 33%, p = 0.6). On the other hand, TC patients had ST segment depression in
lead aVR more frequently than patients with anterior STEMI (47% vs 11%, p = 0.01) and also the lack of ST elevation in lead V1 was considerably more frequent in patients with TC presenting ST elevation than those with anterior STEMI (80% vs 41%, p = 0.01). The number of leads involved in ST elevation was very similar between two groups but ST segment amplitudes were higher in patients with anterior STEMI. In fact, the maximal ST amplitude was markedly greater in STEMI group compared with TC patients (3.9 ± 2.4 mm vs 1.6 ± 1.3 mm; p = 0.04). The sum of ST segment elevation amplitudes was significantly higher in patients with anterior STEMI both in V4–V6 and in V1–V3
Table 2 ECG Findings for Takotsubo cardiomyopathy and anterior STEMI. Variable
Takotsubo
Myocardial infarction P-value
Heart rate (bpm) PR interval (ms) QRS duration (ms) QT interval (ms) QTc Bazett (ms) QT dispersion (ms) Maximal ST elevation (mm) Number of leads involved by ST elevation Abnormal Q waves, n (%) T wave inversion, n (%) QRS axis (°)
80.4 ± 16.8 165.2 ± 27.7 90.9 ± 15.5 414.7 ± 45.5 470.7 ± 36.4 59.4 ± 17.1 1.6 ± 1.3
80.6 ± 19.8 163.9 ± 24.5 100.0 ± 26.0 401.5 ± 51.1 456.3 ± 32.1 40.5 ± 19.9 3.9 ± 2.4
0.3 0.8 0.01 0.8 0.7 0.7 0.04
4.6 ± 2.8
4.5 ± 1.4
0.9
5 (18%) 20 (74%) 16.2 ± 48.2
14 (52%) 14 (52%) 2.1 ± 45.8
0.01 0.09 0.3
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Table 3 Comparison of ECG findings in both groups stratifying by time from symptom onset to recording ECGs N6 hours vs b 6 hours. Variable
Heart rate (bpm) PR Interval (ms) QRS duration (ms) QT Interval (ms) QTc Bazett (ms) QT dispersion (ms) Maximal ST elevation (mm) Abnormal Q waves, n (%)
Takotsubo
P
b 6 hours
N6 hours
83.4 ± 19.8 160.8 ± 30.4 89.4 ± 23.9 402.3 ± 48.2 461.3 ± 22.1 56.4 ± 10.2 2.6 ± 1.4 2 (40%)
78.5 ± 21.1 169.3 ± 36.5 97.2 ± 18.6 420.7 ± 39.5 475.7 ± 26.2 60.2 ± 20.1 1.2 ± 0.4 3 (60%)
compared with TC group (respectively: 7.2 ± 6.1 vs 2.5 ± 2.2 mm, p = 0.007; 3.9 ± 3.4 vs 1.3 ± 1.9 mm, p = 0.01); the ratio of ST elevation in leads V4–V6 to ST elevation in leads V1–V3 was similar in both groups (0.63 ± 0.51 vs 0.55 ± 0.84, p = 0.7). As the Fig. 2 shows, in patients with anterior STEMI, the ST segment elevation more frequently involved the precordial leads, especially V2 and V3 (100% of cases), and never involved the inferior leads. Moreover, the lead V1 was often involved by the ST elevation (16/27, 59%). Also TC patients exhibited ST segment elevation particularly in V2 and V3 (14/15, 93% of cases) but they sometimes presented ST elevation in the inferior leads, especially in II (5/15, 33%); interestingly, the lead V1 was sporadically involved in ST elevation (3/15, 20%). In TC patients with ST elevation, the lack of ST elevation in lead V1 identified TC with 80% sensitivity and 60% specificity, with a positive predictive value of 80% for a test accuracy of 68.6% (Table 5). The absence of abnormal Q waves similarly identified TC. ST segment depression in lead aVR was able to recognize TC with 90% specificity and 77.8% positive predictive value but with lower sensitivity values (46.7%); this ECG finding was found to have the best accuracy (71.4%). The combination of all these ECG findings (lack of ST elevation in lead V1 + absence of abnormal Q waves + ST segment depression in lead aVR) identified TC with 95% specificity and 85.7% positive predictive value at the expense of sensitivity which collapsed to 40% (Table 5). The intra-observer intraclass correlation coefficient for TpTe was 0.95 (95% CI, 0.90–0.97) and the inter-observer intraclass correlation coefficient was 0.89 (95% CI, 0.86–0.95).
Table 4 ST elevation characteristics in patients with Takotsubo cardiomyopathy presenting ST elevation and those with anterior STEMI. ECG finding
Takotsubo (n = 15)
Anterior STEMI (n = 27)
P-value
Reciprocal changes, n (%) ST depression-aVR, n (%) No ST elevation-V1, n (%) ST elevation V1–3 (mm) ST elevation V4–6 (mm) ST elevation V4–6/ST elevation V1–3
4 (27%) 7 (47%) 12 (80%) 2.5 ± 2.2 1.3 ± 1.9 0.55 ± 0.84
9 (33%) 3 (11%) 11 (41%) 7.2 ± 6.1 3.9 ± 3.4 0.63 ± 0.51
0.6 0.01 0.01 0.007 0.01 0.7
ns ns ns ns ns ns ns ns
Myocardial infarction
P
b 6 hours
N 6 hours
86.2 ± 19.4 155.9 ± 34.1 104.2 ± 13.2 395.8 ± 32.1 453.4 ± 40.1 38.5 ± 21.2 4.4 ± 2.8 5 (36%)
79.3 ± 28.1 177.4 ± 38.2 98.8 ± 20.3 405.1 ± 45.1 466.3 ± 30.2 45.2 ± 15.1 3.4 ± 2.0 9 (64%)
ns ns ns ns ns ns ns ns
Discussion In our study we sought to compare acute ECG characteristics between TC and anterior STEMI in two similar small populations to evaluate the usefulness of the ECG in distinguishing them. The main findings in this study are the following: 1) three distinct patterns were observed in TC patients: ST segment elevation with or without T wave inversion, isolated T wave inversions and no ST segment or T wave abnormalities; 2) in patients with anterior STEMI, ST segment elevation was considerably higher in precordial leads; 3) the combination of three ECG findings (lack of ST elevation in lead V1, the absence of abnormal Q waves and ST depression in lead aVR) was able to identify the TC with a specificity of 95% and a positive predictive value of 85.7%. Similar demographic characteristics and cardiovascular risk factors were found between TC and STEMI patients except for smoking which was more prevalent in the STEMI group. Although the population sample was relatively small and predominantly represented by women, this finding is surprising given the different pathophysiologies of both conditions. However, these results should not be generalized because of the small number of patients in our study. The distinct patterns observed in patients with TC might be related to different symptoms onset-to-admission time; although in our study all patients had a symptoms onset-toadmission time lower than 12 hours, ST elevation might have disappeared within a few hours from the onset. Previous studies have showed higher ST elevation amplitudes in patients with anterior STEMI compared with TC patients and our data confirm these findings [6,8–10]; in fact, the sum of ST segment elevation amplitudes was significantly greater in patients with anterior STEMI both in V4–V6 and in V1–V3. Although some studies have reported different results [6,8], in our work the ratio of ST elevation in leads V4–V6 to ST elevation in leads V1–V3 was similar in both groups. Of note, in our study ST elevation was assessed at the J point, according to European Society of Cardiology guidelines and similarly to some recently published works [10,16]; previously, some studies had evaluated the ST segment elevation 80 ms after the J point [6,17]. In the presence of increased T wave amplitude in the acute phase, a noticeable amount of patients might exhibit ST-segment elevation when the magnitude is measured 80 ms after the J point despite the absence of ST-segment elevation when the magnitude is measured at the J point. The
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Fig. 2. Above – Prevalence of ST elevation in patients with anterior STEMI. In precordial leads, high rates of segment ST elevation were found in leads V2–V4. The prevalence of ST elevation was considerable in V1 and gradually decreased in V5− V6. No inferior leads were involved by ST segment elevation. Below – Prevalence of ST elevation in patients with TC. Higher rates of ST segment elevation were found in leads V2− V3. The prevalence of ST elevation in V1 was markedly lower in patients with TC than those with anterior STEMI. Moreover, patients with TC presented in a moderate proportion of cases (20–33%) an involvement of the inferior leads.
presence or absence of ST-segment elevation could thus be considerably affected by the point used to assess ST-segment deviation as well as by the cut-off values of ST segment elevation [8]. Further studies are needed to identify the optimal cut-off values of ST-segment elevation for the differential diagnosis between TC and anterior STEMI. Our data are consistent with some previously published studies which have reported a considerable amount of TC patients with ST elevation in the inferior leads (20–50%) [8]. In fact, in our study ST elevation in the inferior leads was observed in 3–5 patients (n = 3 in III, n = 4 in aVF, n = 5 in II) for a percentage ranging from 20% to 33%. On the contrary, no patients with anterior STEMI exhibited ST elevation in the inferior leads. We also confirm a lower prevalence of ST elevation in lead V1 in TC patients (3/15, 20%) compared with STEMI patients (16/27, 59%; p = 0.01). This finding is very interesting especially as the
significant proportion of cases with mid or distal LAD involvement (n = 15) might have led to a decreased percentage of patients with ST elevation in lead V1 among STEMI patients. In fact, the different locations of LAD occlusion responsible for anterior STEMI may lead to different ST deviation patterns, both in frontal and tin precordial leads, based on the differences in orientation of the ST vector [18,19] Abnormal Q waves were more frequently found in patients with anterior STEMI (52% vs 18%; p = 0.02). The absence of pathological Q waves in patients with TC may be explained by the absence of true myocardial necrosis [6]; on the contrary, in STEMI patients, pathological Q waves often appear within 12 hours from the onset and may be related to either initial myocardial necrosis or local intramyocardial conduction delays secondary to myocardial ischemia in regions supplied by the proximal LAD [20]. In
Table 5 Sensitivity, specificity, accuracy and predictive values of some ECG characteristics in distinguishing Takotsubo cardiomyopathy from anterior STEMI.
Lack of ST elevation in V1 No abnormal Q waves ST depression in aVR The presence of 2 out of 3 ECG parameters The combination of all the parameters
Sensitivity
Specificity
PPV
NPV
Accuracy
80% 81.4% 46.7% 60% 40%
60% 50% 90% 75% 95%
80% 68.7% 77.8% 64.3% 85.7%
60% 66.7% 69.2% 71.4% 67.8%
68.6% 68.1% 71.4% 68.6% 71.4%
PPV: positive predictive value; NPV: negative predictive value.
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patients with TC, ST elevation very often has been described to occur in lead − aVR facing the apical and inferolateral regions resulting in ST depression in the opposing lead aVR [8]. In the anterior STEMI, the prevalence of ST elevation in − aVR (and the consequent ST depression in aVR) might occur in proximal occlusions with anterolateral involvement in which the ST vector points anywhere between − 60 and + 120 degrees [18]. In our study, ST depression in aVR was found more frequently in TC patients (p = 0.01) and this marker identified TC with high specificity and positive predictive values (90% and 77.8%, respectively) but very low sensitivity (46.7%). The lack of ST elevation in lead V1 and the absence of abnormal Q waves had individually similar sensitivity, specificity and predictive values (Table 5). The combination of these 3 ECG findings hugely enhanced both the specificity (95%) and the positive predictive value (85.7%) with a decrease of the sensitivity (40%). Therefore, the contemporary presence of all these markers very precisely identified those patients with TC. Many studies have found the absence of reciprocal ST depression in II, III and aVF as a peculiar ECG marker of TC [6–10,21]. In our study, the frequency of ST depression in the inferior leads did not differ between the two groups; this may be explained by the low percentage of reciprocal ST depression in leads II, III, and aVF in anterior STEMI (33%) attributable to the considerable amount of patients with mid or distal LAD occlusion in our case series. As expected, patients with anterior STEMI presented markedly higher levels of creatine kinase-MB compared with TC patients (b 0.0001). Of note, QRS duration was significantly more prolonged in STEMI patients; this might be explained by intramyocardial conduction delays due to a greater myocardial ischemia caused by the proximal LAD occlusion. On the other hand, QTc and QT dispersion were mildly higher in TC patients, consistent with data from the literature [6–10]; generally, the repolarization times and the dispersion of ventricular repolarization in TC are mildly prolonged on admission and they enormously increase in the subacute phase [22]. The most important limitations of this study are related to its retrospective and single-center design. The sample size is small and results of this study should be confirmed by larger prospective studies.
Conclusions In conclusion, our study sought to retrospectively analyze the ECG differences between TC and anterior STEMI in a similar sample with a prevalence of postmenopausal women. Patients with TC exhibited on admission three distinct ECG patterns: ST segment elevation with or without T wave inversion, isolated T wave inversions and no ST segment-T wave abnormalities. Patients with anterior STEMI presented higher ST segment elevation in precordial leads without involvement of the inferior leads. The combination of three ECG findings (lack of ST elevation in lead V1, the absence of abnormal Q waves and ST depression in lead aVR) was able to differentiate the TC with a specificity of 95% and a positive predictive value of 85.7%.
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