Cardiac arrest (CA) is relatively rare but lethal complication of takotsubo cardiomyopathy (TTC). In most instances, patients are diagnosed with TTC after CA, making it difficult to distinguish if TTC is the precipitant or the consequence of the index event. In this systematic review, patient-level data were obtained to seek out the characteristics of patients in whom the underlying cause of CA is TTC. A comprehensive search of 4 major databases (Embase, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to the last week of September 2014. Of 186 citations, 62 case studies were included in the analysis, providing patient-level data on 77 patients. In 60 patients (78%), the diagnosis of TTC was made after CA. Patients presenting with CA were younger (mean age 49.5 ± 16 vs 64.9 ± 11 years, p <0.0001) and had relatively shorter corrected QT interval (mean 530 ± 101 vs 616 ± 140 ms) on electrocardiography. TTC-related hypotension was the major cause of CA in the acute phase, while a long corrected QT interval triggered CA in the subacute (24- to 72-hour) phase. In 11 patients, CA was not directly instigated by TTC despite a left ventricular appearance matching TTC. In conclusion, in TTC, CA typically develops within the first 3 days of presentation and is the result of long corrected QT interval–induced polymorphic ventricular tachycardia. Secondary TTC, in which patients present with typical left ventricular features after CA, likely represents a distinct cohort in which identifiable inheritable arrhythmias or structural heart disease should be sought.
Takotsubo cardiomyopathy (TTC) is an increasingly recognized cardiac condition, which predominantly affects aging women and leads to profound but transient left ventricular systolic dysfunction. The short- and long-term prognoses of patients with TTC are relatively benign compared with those with acute myocardial infarction. Nonetheless, shock and cardiac arrest (CA) can complicate TTC, resulting in morbidity and mortality. Our understanding of the mechanisms of acute complications related to TTC, in particular CA, is still lacking. Indeed, a paucity of CA events in an already rare disorder is 1 of the main hindrances to conducting appropriate mechanistic and follow-up studies. This is further complicated by the fact that in most such cases, CA is the primary presentation and TTC is diagnosed subsequently. Thus, to obtain sufficient events of CA in patients with TTC, we conducted a systematic review of the available published research and obtained patient-level data to determine the clinical characteristics, underlying causes, and currently used management strategies. We also aimed to understand if the clinical characteristics of patients who are diagnosed with TTC after CA resuscitation differed from those patients diagnosed with TTC who then subsequently experienced CA. For the purpose of this study, we defined the first group as “secondary TTC” and the second group of patients as “primary TTC.”
Methods
A comprehensive search strategy was developed to find all the published reports on TTC and CA. A thorough computer-based search was performed using Ovid MEDLINE, Embase, Google Scholar, and PubMed. No limit to the start date was applied, and the search was conducted up to September 30, 2014. We hand-searched the references cited in the previous reviews and important reports on TTC.
We included comparative studies of any design (randomized control trials, cohort, case-control, cross-sectional, single case reports, case studies, case series). Eligible studies had to provide documentation on the mode of CA in patients diagnosed with TTC. Studies with any number of patients were considered eligible as long as they provided basic clinical data on the patients who experienced CA. Inclusion was restricted to publications in the English language or when translations of foreign-language publications were provided. When data were reported from overlapping study samples (e.g., multiple publications from the same group), the most recent study or the 1 with the highest number of patients was included in the analysis.
Two reviewers (KS and KC) screened all titles and abstracts independently. This was followed by full-text review of the selected reports by the same 2 reviewers. One reviewer (KS) extracted data independently from selected studies using a standardized, pilot-tested extraction template. The following data were extracted: study characteristics (author, country, study design, study population, number of participants, and objective of the study), participant characteristics (age and gender), clinical characteristics (acute coronary syndrome type for TTC, predisposing physical and/or emotional stressors, development of TTC before or after CA, presence of chest pain or dyspnea before CA, hypotension development before CA, the left ventricular ejection fraction, type of CA, and clinical outcome), and management of cases (electrophysiologic [EP] studies, insertion of pacemaker or defibrillator).
Data are expressed as mean ± SD unless otherwise stated. Comparisons between normally distributed data were performed using nonpaired Student’s t tests, while Wilcoxon’s tests were used for skewed data and chi-square tests for proportional data. Linear regression was used for univariate comparisons. GraphPad Prism version 6 (GraphPad Software, San Diego, California) and SPSS version 17 (SPSS, Inc., Chicago, Illinois) were the statistical software packages used.
Results
The search for published research on TTC and CA yielded 186 citations ( Figure 1 ). Titles and abstracts were reviewed for all the short-listed citations, and 118 reports were chosen for full-text review. Of the 118 full-text reports reviewed for eligibility, 62 met all the inclusion and exclusion criteria ( Table 1 ). All studies were observational single-patient case reports or case series of patients.
| No. | Author | Year | Country | Patient Number | CA before TTC | Chest pain before TTC diagnosis | Type of arrest | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| VT | PMVT | VF | PEA | Asystole | |||||||
| 1 | Finsterer | 2014 | Austria | 1 | 1 | 1 | 1 | 1 | |||
| 2 | S-Pasiarska | 2014 | Poland | 1 | 1 | 1 | 1 | ||||
| 3 | Siegfried | 2014 | USA | 1 | 0 | 1 | 1 | ||||
| 4 | Lisi | 2014 | Italy | 1 | 1 | 1 | 1 | ||||
| 5 | Harika | 2014 | USA | 1 | 1 | 0 | 1 | ||||
| 6 | Peters | 2014 | Germany | 1 | 1 | 0 | 1 | 1 | 1 | ||
| 7 | Cakici | 2014 | Turkey | 1 | 0 | 1 | 1 | ||||
| 8 | Bleser | 2013 | Germany | 1 | 1 | 0 | 1 | ||||
| 9 | Nascimento | 2013 | USA | 1 | 0 | 1 | 1 | ||||
| 10 | Ritchie | 2013 | USA | 1 | 1 | 1 | 1 | ||||
| 11 | Tran | 2013 | Australia | 1 | 1 | 0 | 1 | 1 | |||
| 12 | Russell | 2013 | USA | 1 | 1 | 0 | 1 | ||||
| 13 | Liang | 2013 | USA | 1 | 1 | 0 | 1 | ||||
| 14 | Kawagoe | 2013 | Japan | 1 | 1 | 0 | 1 | ||||
| 15 | Schimpf | 2013 | Germany | 1 | 1 | 0 | 1 | ||||
| 16 | Struzkova | 2013 | Czech Republic | 1 | 1 | 0 | 1 | ||||
| 17 | Cvorovic | 2013 | Serbia | 1 | 1 | 0 | 1 | ||||
| 18 | Chadha | 2013 | USA | 1 | 1 | 0 | 1 | ||||
| 19 | Singh | 2013 | Australia | 3 | 3 | 0 | 1 | ||||
| 20 | Aregullin | 2013 | USA | 1 | 1 | 0 | 1 | ||||
| 21 | Tachotti | 2012 | Brazil | 2 | 2 | 0 | 1 | ||||
| 22 | Bortnik | 2012 | Italy | 1 | 1 | 0 | 1 | ||||
| 23 | Caudron | 2012 | France | 1 | 1 | 0 | 1 | ||||
| 24 | Cunnington | 2012 | UK | 1 | 1 | 0 | 1 | ||||
| 25 | Hasdemir | 2013 | Turkey | 1 | 1 | 0 | 1 | ||||
| 26 | Cho | 2012 | Korea | 1 | 1 | 1 | 1 | ||||
| 27 | Lieb | 2012 | USA | 1 | 1 | 0 | 1 | ||||
| 28 | Bomann | 2011 | New Zealand | 1 | 1 | 0 | 1 | ||||
| 29 | Ahn | 2011 | Korea | 1 | 0 | 1 | 1 | ||||
| 30 | Peters | 2012 | Germany | 1 | 1 | 0 | 1 | ||||
| 31 | S Kaźmirska | 2010 | Poland | 1 | 1 | 0 | 1 | ||||
| 32 | Verdier | 2011 | France | 2 | 2 | 0 | 1 | ||||
| 33 | Basselin | 2011 | France | 1 | 1 | 0 | NA | ||||
| 34 | M-Shakin | 2011 | USA | 1 | 0 | 1 | 1 | ||||
| 35 | Madias | 2011 | USA | 8 | 2 | NA | 1 | ||||
| 36 | Bartoli | 2011 | USA | 1 | 1 | 0 | 1 | 1 | |||
| 37 | Hassid | 2010 | USA | 1 | 1 | 1 | 1 | ||||
| 38 | Vernick | 2010 | USA | 1 | 1 | 0 | 1 | 1 | |||
| 39 | Pepe | 2011 | Italy | 1 | 0 | 1 | 1 | ||||
| 40 | Boes | 2011 | Germany | 1 | 1 | 0 | 1 | ||||
| 41 | Kurisu | 2010 | Japan | 2 | 2 | 1 | 1 | ||||
| 42 | Shimokawahara | 2009 | Japan | 1 | 1 | 0 | 1 | ||||
| 43 | Olivotti | 2010 | Italy | 1 | 0 | 0 | 1 | 1 | 1 | ||
| 44 | Kalra | 2009 | USA | 1 | 1 | 0 | 1 | ||||
| 45 | Kwon | 2009 | Korea | 1 | 1 | 1 | 1 | ||||
| 46 | Zaman | 2009 | Australia | 1 | 1 | 0 | 1 | ||||
| 47 | Gotyo | 2009 | Japan | 1 | 0 | 0 | 1 | ||||
| 48 | Suzuki | 2010 | Japan | 1 | 1 | 0 | 1 | ||||
| 49 | Mathew | 2009 | USA | 2 | 1 | 2 | 1 | ||||
| 50 | Freitas | 2011 | Brazil | 1 | 1 | 1 | 1 | ||||
| 51 | Suk | 2009 | Korea | 1 | 1 | 0 | 1 | ||||
| 52 | Facciorusso | 2008 | Italy | 1 | 1 | 0 | 1 | ||||
| 53 | Mahida | 2009 | UK | 1 | 0 | 1 | 1 | ||||
| 54 | Cruvinel | 2008 | Brazil | 1 | 1 | 0 | 1 | ||||
| 55 | Cabaton | 2008 | France | 1 | 1 | 0 | 1 | ||||
| 56 | Bahlmann | 2008 | Germany | 1 | 1 | 0 | 1 | ||||
| 57 | Dib | 2008 | USA | 4 | 2 | 2 | 1 | ||||
| 58 | Makaryus | 2008 | USA | 1 | 1 | 1 | 1 | ||||
| 59 | Furushima | 2008 | Japan | 1 | 1 | 0 | 1 | ||||
| 60 | D’Amato | 2008 | Italy | 1 | 1 | 1 | 1 | ||||
| 61 | Raddino | 2007 | Italy | 1 | 1 | 0 | 1 | ||||
| 62 | Flam | 2014 | Sweden | 1 | 0 | 1 | 1 | ||||
A total of 77 patients were diagnosed with TTC and CA. The mean age of patients was 52.8 ± 16.2 years. As with other cohorts of TTC, women constituted the majority of patients, making up 83% of the cohort. The classic left ventricular apical ballooning appearance of TTC was described in 76% of the patients, and the rest of the patients had nonapical variants (midventricular and basal variants) of TTC. The mean left ventricular ejection fraction was 33 ± 11% at presentation. ST-segment elevation was documented on electrocardiography in 42% of the patients. The average increases in troponin and creatine kinase levels were 5.7 ± 10.8 mg/dl and 888 ± 1,357 U/L, respectively. The mean increase in brain natriuretic peptide level was 4,604 ± 4,377 pg/ml. TTC was precipitated by identifiable physical stressors in 39 patients and by emotional stressors in 16 patients, and no identifiable stressors could be identified in 15 patients. In 7 studies, information on physical or emotional stressors was not available.
The mode of CA was ventricular fibrillation in 36 patients, monomorphic ventricular tachycardia in 19 patients, polymorphic ventricular tachycardia (PMVT) in 15 patients, asystole in 12, and pulseless electrical activity in 2 patients. Seven patients had recurrent episodes of CA. In 31 patients with reported systolic blood pressure measurements, 22 experienced episodes of hypotension before the onset of CA. In 20 patients (26%), episodes of CA occurred during general anesthesia for noncardiac surgery. Length of the corrected QT (QTc) interval on electrocardiography at the time of CA was available for 31 patients; the mean duration was 559 ± 121 ms. In 11 patients (14%), there were other known causes of CA along with TTC. Subarachnoid hemorrhage (SAH), arrhythmogenic right ventricular dysplasia (ARVD), and known QTc prolongation syndrome (medication related, electrolyte imbalance, and genetic causes) were the most common causes of CA. Eleven patients underwent placement of automated implantable cardiac defibrillators (AICDs), 4 had permanent pacemakers, 2 wore wearable cardioverter defibrillators, and 4 underwent EP studies. The rest of the patients were discharged without EP studies or AICD placement. No arrhythmia was induced on EP study.
In 60 patients (78%), the diagnosis of TTC was made after CA (secondary TTC), and in the remaining 17 patients (22%), TTC was diagnosed before CA (primary TTC) ( Table 2 ). In primary TTC, 12 patients (20%) reported dyspnea and/or chest pain, triggered by emotional stressors, before CA. In the primary TTC group, the average time between TTC diagnosis and CA was 3.6 ± 4.4 days. Only 1 patient had CA after the first week of diagnosis (15th day). Exclusion of that patient in calculation of the duration of CA after TTC diagnosis reduced the average to 2.3 ± 1.8 days. Patients with primary TTC had longer QTc intervals at the time of CA (mean 616 ± 140 ms), with PMVT being the most commonly reported arrhythmia ( Table 3 ).
| Secondary Takotsubo Cardiomyopathy | Primary Takotsubo Cardiomyopathy | P value | |
|---|---|---|---|
| Number | 60 | 17 | |
| Men | 10 | 3 | NS |
| Women | 50 | 14 | NS |
| Age (years) | 49.5 ± 16 | 64.9 ± 11 | <0.0001 |
| PMVT | 7 | 8 | 0.001 |
| VT | 17 | 2 | NS |
| VF | 31 | 5 | NS |
| Asystole and PEA | 12 | 2 | NS |
| LVEF (%) | 28 ± 15 (53) ∗ | 29 ± 16 (17) ∗ | NS |
| Troponin (mg/dl) | 5.6 ± 11 (40) ∗ | 1.4 ± 1.7 (6) ∗ | 0.03 |
| QTc (ms) during CA | 530 ± 101 (20) ∗ | 616 ± 140 (11) ∗ | NS |
| Longest QTc (ms) | 583 ± 84 (9) ∗ | 640 ± 126 (9) ∗ | NS |
| ST elevation on ECG | 37 | 8 | NS |
| Death | 11 | 2 | NS |
∗ Numbers appearing in brackets represents the number of patients for whom the relevant information was available.
| Number | Author | Women | Age (yrs) | Alive | PMVT | LVEF (%) | Emotional stress | QTc Interval (ms) | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Longest | At the time of cardiac arrest | Follow-up | ||||||||
| 1 | Cakici | 1 | 67 | 1 | 1 | 40 | 1 | 680 | 680 | 390 |
| 2 | Nascimento | 1 | 57 | 1 | 1 | 20 | 0 | 883 | 883 | 520 |
| 3 | Ahn | 1 | 78 | 1 | 1 | 35 | 1 | 720 | 720 | NA |
| 4 | Madias | 1 | 53 | 1 | 0 | 55 | 1 | 568 | 568 | 404 |
| 0 | 78 | 1 | 1 | 35 | 0 | 725 | 725 | 492 | ||
| 0 | 81 | 1 | 1 | 40 | 0 | 547 | 547 | 442 | ||
| 1 | 74 | 1 | 1 | 28 | 0 | 529 | 529 | 405 | ||
| 1 | 73 | 1 | 1 | 35 | 1 | 480 | 480 | 395 | ||
| 1 | 61 | 1 | 1 | 35 | 0 | 626 | 626 | 454 | ||
| 5 | Mahida | 1 | 55 | 1 | 1 | NA | 0 | NA | >510 | 490 |
| 6 | Dib | 1 | 74 | 0 | 0 | 40 | NA | NA | 399 | NA |
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