stress-induced cardiomyopathy)

Clinical correlates and prognostic significance of electrocardiographic abnormalities in apical ballooning syndrome (Takotsubo/stress-induced cardiomyopathy) Chadi Dib, MD, a Samuel Asirvatham, MD, FACC, b Ahmad Elesber, MD, c Charanjit Rihal, MD, FACC, b Paul Friedman, MD, FACC, b and Abhiram Prasad, MD, FRCP, FESC, FACC b Rochester, MN; and Ashland, KY

Background Apical ballooning syndrome (ABS) is a unique transient cardiomyopathy that mimics an acute myocardial infarction. The relative frequency of ST-segment elevation on the 12-lead electrocardiogram (ECG) and its prognostic significance is unknown. The aims of this study were to evaluate the frequency and the clinical correlates of ST- and T-wave abnormalities on the admission ECG in patients with ABS. Methods

Patients were retrospectively identified from the cardiac catheterization database—those who underwent coronary and left ventricular angiography and fulfilled the Mayo criteria for ABS during the period January 1988 to November 2006. They were divided into 3 groups according to the presence of (1) ST-segment elevation (N1 mm in 2 contiguous lead) or new left bundle branch block, (2) T-wave inversion (N3 mm in 3 contiguous leads) but no ST shift, and (3) nonspecific ST-T abnormalities or normal ECG at the time of admission. Clinical and echocardiographic findings were compared between groups.

Results

Among the 105 patients, 36 (34.2%), 32 (30.4%), and 37 (35.2%) patients were in the three respective groups. There were no differences in the clinical characteristics, ejection fraction, and outcomes between the 3 groups. Over a median follow-up of 2.5 years, there was no difference in the 5-year recurrence rate of ABS between the 3 groups (13%, 5%, 17% patients, respectively, P = .25). The 5-year mortality was similar in the 3 groups (24%, 7.3%, 10.8%, P = .58).

Conclusions

ST-segment elevation is absent in two thirds of patients with ABS. Thus, the cardiomyopathy may mimic either ST-elevation or non–ST-elevation myocardial infarction. The ECG abnormalities at presentation do not correlate with the magnitude of ventricular dysfunction or outcomes. (Am Heart J 2009;157:933-8.)

Apical ballooning syndrome (ABS), also known as Takotsubo or stress-induced cardiomyopathy and broken heart syndrome, is an acute reversible cardiomyopathy. Apical ballooning syndrome is characterized by transient regional wall motion abnormalities of the left ventricular mid segments with or without apical involvement and hyperkinesis of the basal segments.1 Patients with ABS frequently present with acute onset chest pain and dyspnea associated with mild myonecrosis. Thus, the condition mimics an acute coronary syndrome (ACS) and is an important differential

From the aDepartment of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, bThe Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN, and cKing's Daughter Medical Center, Ashland, KY. Submitted October 21, 2008; accepted December 18, 2008. Reprint requests: Abhiram Prasad, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected] 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.12.023

diagnosis of myocardial infarction.2 Recent guidelines on the management of non–ST-elevation ACS from the American College of Cardiology (ACC) /American Heart Association (AHA)3 as well as the European Society of Cardiology4 have included ABS among the differential diagnoses, but as yet, ABS has not been included in the guidelines for ST-segment elevation myocardial infarction.5 Early reports from Japan and around the world suggested that most patients with ABS presented with ST-segment elevation on the electrocardiogram (ECG).6,7 This fact has therefore been incorporated into recent, widely quoted review articles on the subject.1,8 However, apart from the study by Tsuchihashi et al,6 the data have been derived from very small case series. Based on the increasing experience of diagnosing and treating ABS at our institution, we hypothesized that there is considerable heterogeneity in the ECG characteristics of these patients. Thus, the aim of the study was to evaluate the frequency of ST-segment elevation and other ECG abnormalities among patients with the

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Table I. Patient characteristics ST elevation/new LBBB (n = 36)

T-wave inversion (n = 32)

Normal ECG/nonspecific changes/ old LBBB (n = 37)

P

66 ± 15 33 F, 3 M 18 (50%) 2 (6%) 14 (39%) 9 (25%)

67 ± 12 32 F 19 (59%) 2 (6%) 7 (22%) 6 (18%)

64 ± 11 35 F, 2 M 17 (46%) 1 (3%) 12 (32%) 6 (16.2%)

.75 .27 .53 .76 .32 .36

28 (78%) 17 (47%) 16 (44.4%) 12 (33%)

23 (72%) 17 (53%) 17 (53.1%) 11 (34%)

24 (65%) 22 (59%) 18(48.6%) 9 (24%)

.47 .58 .7 .60

25 (69.4%) 4 (11.11%) 25 (69.4%) 17 (47.2%)

25 (78.1%) 2 (6.25%) 16 (50%) 15 (46.8 %)

31 2 23 13

.8 .7 .2 .49

5 (13.8%) 4 (11.1%)

4 (12.5%) 1 (3.1%)

Age Sex Hypertension Diabetes mellitus Hyperlipidemia Current smoker Medications on admission Aspirin β-Blockers ACE-inhibitors Statins Symptom at presentation Chest pain Dyspnea Precipitating factor Congestive heart failure during hospitalization Intubation IABP use

(83.7%) (5.4%) (62.1%) (35.1%)

1 (2.7%) 2 (5.4%)

.15 .39

ACE, Angiotensin-converting enzyme; IABP, intra-aortic balloon pump.

cardiomyopathy and correlate them with the clinical characteristics and outcomes.

Methods Patients To identify potential patients with the ABS, we retrospectively searched the Mayo Clinic cardiac catheterization database from January 1988 to October 2006 for inpatients with acute cardiac illness who underwent both coronary and left ventricular angiography. Our initial search was restricted to all patients with coronary artery diameter stenoses b40% and hypokinesis, akinesis or dyskinesis of the mid and/or apical left ventricular segments with sparing of the basal segments. This search yielded 549 cases, of which 421 were excluded because they had been diagnosed with chronic conditions such as dilated cardiomyopathy, valvular heart disease, ischemic cardiomyopathy, or congenital heart disease or because they had wall motion abnormalities resulting from a paced rhythm. One hundred seven patients met the Mayo Clinic criteria for ABS,2 and repeat echocardiograms showed complete resolution of the left ventricular dysfunction. Of those 107 patients, 105 gave informed consent and formed the study population. The data were obtained from the clinical records of each patient after obtaining the approval for the study from the Mayo Clinic Institutional Review Board. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study; all study analyses, the drafting and editing of the manuscript, and its final contents.

Electrocardiogram analysis The ECG was recorded at a paper speed of 25 mm/s with a 10mm/mV amplification scale. Hard copies of the ECG were

analyzed simultaneously by two investigators, who were blinded to the patients' clinical and echocardiographic characteristics. ST-segment elevation was measured 80 mm following the J point using hand calipers. The patients were divided into 3 groups according to the findings on the ECG at presentation. The three groups were those who had ST-segment elevation (N1 mm in at least 2 contiguous leads or new onset of left bundle-branch block [LBBB]), T-wave inversion (inverted T-wave amplitude N3 mm in at least 3 precordial or inferior leads) without ST shift, and other findings (nonspecific ST-T wave abnormalities, normal ECG, old LBBB).

Clinical follow up Follow-up was performed through return visits and telephone interviews. Recurrence of ABS was defined as a subsequent episode of a reversible cardiomyopathy fulfilling the Mayo Clinic diagnostic criteria. Data on mortality and morbidity was collected using available clinical information from the medical records and by reviewing death certificates.

Statistical analysis All data were expressed as mean ± SD. Categorical factors were compared among the 3 groups using the χ2 test for independence. Analysis of variance test was used to compare continuous variables among the three groups. Overall mortality and the recurrence were estimated using the Kaplan-Meier method. The curves were compared between the groups using log-rank tests. A P value of less that .05 was considered significant.

Results Baseline characteristics There was no difference in age, sex, and prevalence of conventional risk factors for atherosclerosis, medications on admission, or the presence of a precipitating stressor

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Table II. ECG, troponin and ejection fraction according to ECG findings

QTc at presentation Maximum QTc Peak troponin level (ng/mL) Ejection fraction at presentation (%) Regional wall motion score index at presentation Ejection fraction at follow-up (%) Median time to follow ejection fraction (interquartile range) (d) Length of hospitalization

ST elevation/new LBBB (n = 36)

T-wave inversion (n = 32)

Normal ECG/nonspecific changes/old LBBB (n = 37)

P

449.8 ± 47.22 512.1 ± 48.86 1.09 ± 0.82 42 ± 12 1.95 ± 0.34 64 ± 7 401 (29.2-346.5)

484.6 ± 51.12 546.4 ± 68.39 0.71 ± 0.97 38 ± 14 1.93 ± 0.47 60 ± 5 393 (36-240)

434.2 ± 29.84 473.8 ± 55.24 0.55 ± 0.41 36 ± 14 2.03 ± 0.46 61 ± 7 618 (9-469.5)

b.01 b.01 .11 .37 .8 .01 .6

7 ± 4 (3-24)

Figure 1

6 ± 3(2-16)

5 ± 2 (2-13)

.03

Figure 2

Kaplan-Meier estimate of survival free of recurrence at 5 years in the 3 groups.

Frequency of ECG abnormalities at presentation in patients with ABS.

between the three groups (Table I). The peak troponin level and ejection fraction at presentation were also similar in the 3 groups (Table II). None of the patients had spontaneous coronary spasm, embolism, thrombus, or plaque rupture on the angiogram performed during the acute presentation.

ECG findings Of the 105 patients identified with ABS, 35 (33%) had ST-segment elevation on the ECG at admission and 1 (0.9%) had new onset of LBBB, 32 (30%) had T-wave inversions, 34 (32%) had nonspecific ST-T abnormalities, and 3 (2.8%) had existing LBBB (Figure 1). Data regarding the time from symptom onset to when the ECG was performed was available in 65 patients (n = 24 patients, n = 16, and n = 25, in groups I, II, and III,

respectively). There was no difference in the duration of symptom onset to the admission ECG between the three groups (group I: 615 ± 237 min, group II: 698 ± 290 min, group III: 581 ± 232 min, P = .95). Corrected QT-interval (QTc) at presentation and max QTc were significantly longer among patients with Twave inversion (Table II).

Clinical outcomes There was no difference between the three groups with regard to the frequency of congestive heart failure, need for intubation, or placement of an intraaortic balloon pump. Ejection fraction at presentation was equally decreased in the three groups (P = .37) and normalized in all patients at follow-up. Patients who presented with ST-segment elevation had longer hospitalization (7 ± 4 days) compared to patients with T-wave inversions (6 ± 3 days) or nonspecific ST-T wave abnormalities (5 ± 2 days) (P = .03). In-hospital mortality was 0%, 3%, and 2.7% (P = .42) in the three respective groups.

936 Dib et al

Figure 3

Kaplan-Meier estimate of survival at 5 years in the 3 groups.

Over a median follow-up of 2.5 years, with a range extending from 1 month to 17 years, 31 patients had recurrent episodes of chest pain, of which 6 initially presented with ST elevation, 11 with T-wave inversions, 13 with nonspecific ST-T abnormalities, and 1 with LBBB. The 5-year Kaplan-Meier recurrence rate estimates were 13%, 5% and 17% respectively (P = .25) (Figure 2). The 5-year Kaplan-Meier mortality estimates in groups I, II and III were 24%, 7.3% and 10.8%, respectively (P = .58) (Figure 3).

Discussion The major findings of this study are that (1) ABS may present with or without ST-segment elevation on the ECG, and (2) the clinical and echocardiographic characteristics as well as the outcomes of those with or without ST elevation are similar. Our findings suggest that approximately one third of patients with ABS present with ST-segment elevation, one third with significant T-wave inversion and the remainder with nonspecific features on the ECG. These conclusions are derived from one of the largest cohorts published to date and highlight the importance of including the differential diagnosis of ABS for all patients presenting with a myocardial infarction and not just those with STsegment elevation.9 The observation that two thirds of patients with ABS mimic a non–ST-elevation myocardial infarction contrasts with the original series by Tsuchihashi et al6 which reported the presence of ST-segment elevation in 90% of their patients. The difference between the present study and that by Tsuchihashi et al may, in part, be due to an increasing awareness among physicians about the cardiomyopathy and, hence, more cases being diagnosed. In addition, an invasive strategy for the treatment of non–ST-elevation ACS is now more widely applied in current practice resulting in early imaging of

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the coronary arteries and left ventricle during the course of the presentation, which is required for diagnosing and differentiating ABS from an ACS. Our findings are consistent with a recent report from Sharkey et al10 in which ST-segment elevation was detected in only 56% of their cohort. The patients in the present study were typical for ABS in that 95% were postmenopausal women. There were no differences in the baseline clinical characteristics of the patients within each of the three ECG groups. Similarly, the outcomes such as the occurrence of congestive heart failure, need for intubation or intraaortic balloon counterpulsation, and inhospital and longterm mortality were not different between the groups. Thus, the ECG in patients with ABS does not provide significant prognostic information. This is in contrast to patients with myocardial infarction in whom those with ST-elevation are younger and have a higher in-hospital morbidity and mortality compared to those who suffer a non–ST-elevation myocardial infarction.11,12 In addition to the limited utility for prognostication, we have also previously reported that the ECG has limited diagnostic utility in differentiating ABS from ST-elevation myocardial infarction.13 Deep T waves with QTc prolongation after an acute illness is most often associated with neurogenic stunning in patients with intracranial bleeding.14 One third of the patients in this study presented with this pattern, highlighting the similarity between neurogenic stunning and ABS.15 In general, deep T-wave inversion and QTc prolongation has been thought to be an evolutionary finding in ABS, occurring during the recovery phase in the hospital.14 However, our data suggest that it may also be the presenting feature. The duration from symptom onset to ECG was similar in all 3 groups, making it less likely that this group represented patients who presented late. Patients with deep T-wave inversion also had longer maximum QTc interval during the hospitalization compared to those with ST-elevation or nonspecific findings. Despite the potential increased risk of ventricular arrhythmias, the outcomes in this group were not worse. Kono et al16 have reported that among patients with subarachnoid hemorrhage who develop neurogenic stunning, a condition related to ABS, the presence of ST-segment elevation was associated with much greater left ventricular systolic dysfunction compared to patients without ST-segment shift. In the present study, we did not observe any difference in the magnitude of left ventricular dysfunction at presentation, measured as ejection fraction and regional wall motion score index, between those with and without ST-segment elevation. Thus, differences in the magnitude of wall motion abnormality did not appear to account for the variable ECG appearances. At follow-up, the ejection fraction recovered to a normal value in all 3 groups,

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though intriguingly, it was statistically higher in those with ST-segment elevation. We believe that this is unlikely to be a biologically significant difference, although it is conceivable that more prompt and aggressive early medical therapy for potential coronary thrombosis due to the presence of ST-segment elevation on the ECG may have contributed to better myocardial salvage.

Limitations This is a retrospective analysis that is subject to the limitations of such analyses and does not allow us to establish the mechanism for the presence or absence of ST-segment elevation. It is possible that ST-segment elevation is present in all patients early in the course of ABS, and that its absence and deep T-wave inversion in some patients represent later evolutionary findings. However, this is not supported by the fact that the duration from symptom onset to the first ECG was similar in all the three groups for the patients in whom this data was available (n = 65). The relatively small number of patients in the study is due to the low incidence of ABS; nevertheless, it is one of the largest series on ABS.

4.

5.

6.

Conclusion Apical ballooning syndrome is an increasingly diagnosed acute cardiomyopathy that can mimic ACS at presentation. The cardiomyopathy should be considered in the differential diagnosis of both ST-segment and non–ST-segment elevation myocardial infarction. By most estimates, approximately 1% to 2% of all patients presenting with an initial primary diagnosis of myocardial infarction have ABS7,9 Since there are approximately 732,000 hospital discharges with a primary diagnosis of an acute myocardial infarction in the Unites States each year,17 a conservative estimate of the annual rate of ABS may be 7,000 to 14,000 cases. Moreover, our data indicate that the ECG features at presentation do not correlate with the magnitude of left ventricular dysfunction nor do they predict long-term outcomes.

7.

8.

9.

10.

11.

References 1. Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141: 858-65. 2. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408-17. 3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/ non–ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on

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Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/ Non–ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50: e1-e157. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of non–ST-segment elevation acute coronary syndromes of the European Society of Cardiology. Eur Heart J 2007;28:1598-660. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117: 296-329. Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol 2001;38:11-8 [see comment]. Bybee KA, Prasad A, Barsness GW, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol 2004;94:343-6. Gianni M, Dentali F, Grandi AM, et al. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27:1523-9. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol 2007;99:182-5. Sharkey SW, Lesser JR, Menon M, et al. Spectrum and significance of electrocardiographic patterns, troponin levels, and thrombolysis in myocardial infarction frame count in patients with stress (tako-tsubo) cardiomyopathy and comparison to those in patients with ST-elevation anterior wall myocardial infarction. Am J Cardiol 2008;101:1723-8. Liebson PR, Klein LW. The non-Q wave myocardial infarction revisited: 10 years later. Prog Cardiovasc Dis 1997;39:399-444. Wiviott SD, Morrow DA, Frederick PD, et al. Application of the Thrombolysis in Myocardial Infarction Risk Index in non–ST-segment elevation myocardial infarction: evaluation of patients in the National Registry of Myocardial Infarction. J Am Coll Cardiol 2006; 47:1553-8. Bybee KA, Motiei A, Syed IS, et al. Electrocardiography cannot reliably differentiate transient left ventricular apical ballooning syndrome from anterior ST-segment elevation myocardial infarction. J Electrocardiol 2007;40:38.e1-6. Burch GE, Meyers R, Abildskov JA. A new electrocardiographic pattern observed in cerebrovascular accidents. Circulation 1954; 9:719-23.

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15. Lee VH, Connolly HM, Fulgham JR, et al. Tako-tsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: an underappreciated ventricular dysfunction. J Neurosurg 2006;105: 264-70. 16. Kono T, Morita H, Kuroiwa T, et al. Left ventricular wall motion abnormalities in patients with subarachnoid hemorrhage:

neurogenic stunned myocardium. J Am Coll Cardiol 1994;24: 636-40. 17. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69-e171.

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