Takotsubo cardiomyopathy (TC) is a reversible cardiomyopathy with a benign short-term prognosis but is associated with recurrence rate of 10%. Clinical variables that predict long-term mortality and recurrence are unknown; 56 consecutive patients presenting to a single urban medical center who fulfilled the Mayo Clinic criteria for the diagnosis of TC were included. Patients were followed with 100% completeness; >60 clinical factors were analyzed, including presentation, treatment, electrocardiogram, and echocardiographic, angiographic, and demographic variables. Survival analysis was performed using the Kaplan-Meier function and Cox proportional hazards regression models. There were 15 deaths during follow-up: 5 in-hospital, 4 before 90 days, and 6 after 90 days. Mean survival was 4.47 years (95% confidence interval 3.81 to 5.13). All short-term survivors had repeat ejection fraction evaluation demonstrating improvement; 45 of 56 patients were women and 96% were postmenopausal. The nonfatal recurrence rate was 1.8%. QTc interval at presentation was the factor most strongly predictive of overall outcome, after intubation. All patients with mortality had QTc intervals between 400 and 550 ms. In conclusion, this study demonstrates the prognostic significance of QTc prolongation at presentation in TC. Because the cause of TC involves intense catecholamine release and hyperadrenergic tone, the QTc may reflect the individual impact on myocardial repolarization and the balance between sympathetic innervation and parasympathetic compensation. In conclusion, in this series, TC was associated with an 8.9% in-hospital mortality, an additional 17.9% mortality after discharge, and a nonfatal recurrence rate of 1.8%. Moreover, the QTc on presentation with TC was predictive of outcome.
Takotsubo cardiomyopathy (TC) is a transient, reversible form of cardiomyopathy. The severity of left ventricular dysfunction is variable; the crucial criterion in making the diagnosis is the presence of a profound regional abnormality of midventricular LV segments, typically with akinesis or dyskinesis of the apex. The most common clinical presentation is that of an acute myocardial infarction (MI), including electrocardiographic changes and the release of troponin and other myocardial enzymes, in the absence of significant obstructive coronary artery disease. TC most commonly affects postmenopausal women, with an incidence estimated at 5.2 per 100,000 women and 0.6 per 100,000 men, although its prevalence was reported to be 1% to 2% from a registry with troponin-positive acute coronary syndrome. The LV dysfunction is temporary but of intense severity and is managed with supportive therapy. The in-hospital mortality rate ranges from 0% to 8% in reported series. The longest follow-up was 4.4 years, with a recurrence rate of 11.4%, and repeat episodes between 8 days and 4 years after the initial event. There was also a 17% mortality rate over this follow-up period. The purpose of this investigation was to characterize short- and long-term prognosis in TC and to identify clinical and laboratory variables predictive of in-hospital and long-term outcomes.
Methods
Fifty-six consecutive patients presenting to a single urban medical center with TC comprised the study group. The Institutional Review Board approved the study protocol and data analysis. No external funding was used for this study. The International Classification of Diseases, Ninth Revision ( ICD code 429.83), was used to identify patients, aged ≥18 years, who were discharged with a diagnosis of TC. The charts of identified patients who presented from 2004 to 2014 were reviewed for the diagnostic criteria of TC. Those who were incorrectly coded were excluded.
Inclusion into the study group was determined by satisfying the Mayo Clinic criteria. This includes: (1) transient severe hypokinesis, akinesis, or dyskinesis of the left ventricular midsegments with or without apical involvement; (2) the regional wall motion abnormalities typically extend beyond a single epicardial coronary artery distribution; (3) a stressful trigger, either psychological or medical, should often, but not always, be present; (4) an absence of obstructive coronary disease or angiographic evidence of acute plaque as seen during cardiac catheterization; and (5) there should be new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin. The patient should not have the diagnosis of pheochromocytoma or myocarditis. The exclusion criteria were (1) patients who did not meet the earlier mentioned criteria, (2) presence of a ≥50% stenosis of the left anterior descending artery, or (3) incomplete evaluation for TC, including coronary angiography.
Demographics, laboratory investigations, and echocardiographic and angiographic information were collected from the electronic medical records; >60 different variables were obtained and analyzed including medications like antibiotics, antiemetics, intravenous catecholamines, and laboratory values like electrolyte disturbances, which can affect QT intervals. Patients were followed with 100% completeness. Information regarding follow-up was obtained by contacting the patients or the power of attorney for health care. A prespecified questionnaire was used to gather information. Communication was by telephone, e-mail, or paper mail. The questions ascertained if the patient was admitted for similar complaints after the index hospitalization, if they were diagnosed with TC again and, if so, the circumstances leading to it. If a patient was admitted at a different center, consent was obtained for release of health care information, and the medical records were reviewed for investigations and recurrence of TC, if any. Patients who were reported to be deceased were confirmed with the national database using their social security numbers.
Regional wall motion and EF were estimated from the echocardiogram; 12-lead electrocardiogram (ECG) performed at a paper speed of 25 mm/s and an amplification of 10 mm/mV was used for the analysis of ST segments, T waves, and QT intervals. Digitized ECGs acquired by the Philips Pagewriter TC70 series were used and then manually checked for accuracy. The first ECG that was obtained on presentation (in the emergency room) was used for the analysis. ECG obtained 48 hours after admission was also used for the analysis. ST-segment elevation was coded if ECG criteria of the universal definition of myocardial infarction were satisfied. QT intervals were measured in all cases by the digital system and then manually checked in lead II by standard methods; the corrected QT (QTc) intervals were calculated using Bazett’s formula (QTc = QT/√RR interval). Rhythm analysis and T-wave changes were noted as data points as well.
Descriptive statistics for clinical characteristics are presented as means and SDs for continuous data and as counts and percentages for dichotomous and categorical data. Survival curves were created for 90-day and 6-year survival. Relevant clinical variables were assessed for their independent contribution in survival outcome using Cox regression modeling. Statistically significant predictors in the univariate analysis were included in the multivariate model. Analyses were performed using SPSS 22.0 for Windows (IBM Corp., Armonk, New York), and statistical significance was determined at p ≤0.05.
Results
The clinical characteristics of the study patients are listed in Table 1 . Intubation and mechanical ventilation occurred in 10.7% of subjects. Deep T-wave inversion was the most common abnormal finding on electrocardiography (57.1%). ST elevation was also noted in 7 patients (12.5%). Mean initial LVEF was 33.2 ± 7.9% and 57.6 ± 7.4% for repeat LVEF. Mean time to repeat echo was 21.6 ± 37.6 weeks. Mean troponin (6.47 ± 13.57) was elevated in all patients. Mean length of stay was 8.7 ± 8.1 days ( Table 2 ). Most patients (91.1%) were discharged on >1 cardiac medication (3.0 ± 1.2 medications).
| Variable | Total (n = 56) | Deceased (n= 15) | Alive (n = 41) |
|---|---|---|---|
| Female | 45 (80.4%) | 10 (66.7%) | 35 (85.4%) |
| Age at Incidence | 65.8 ±14.12 | 69.2 ±12.81 | 64.6 ±14.52 |
| Hypertension | 32 (57.1%) | 7 (46.7%) | 25 (61.0%) |
| Dyslipidemia | 21 (37.5%) | 3 (20.0%) | 18 (43.9%) |
| Diabetes mellitus | 14 (25%) | 4 (26.7%) | 10 (24.4%) |
| Tobacco Use | 20 (35.7%) | 6 (40.0%) | 14 (34.1%) |
| Clinical Scenario | |||
| Non Identifiable | 3 (5.4%) | 0 (0%) | 3 (7.3%) |
| Physical | 44 (78.6%) | 15 (100.0%) | 29 (70.7%) |
| Emotional | 9 (16.1%) | 0 (0%) | 9 (22.0%) |
| Heart Failure at Presentation | 16 (28.6%) | 3 (20.0%) | 13 (31.7%) |
| Mechanical Ventilation | 6 (10.7%) | 5 (33.3%) | 1 (2.4%) |
| Intraortic Balloon Pump | 0 (0%) | —- | —- |
| Electrocardiogram | |||
| ST Elevation | 7 (12.5%) | 2 (13.3%) | 5 (12.2%) |
| Deep TWI | 32 (57.1%) | 9 (60.0%) | 23 (56.1%) |
| Non Specific ST-T | 16 (28.6%) | 4 (26.7%) | 12 (29.3%) |
| Left Bundle Branch Block | 1 (1.8%) | 0 (0%) | 1 (2.4%) |
| Coronary Angiogram | |||
| Initial Ejection Fraction | 33.2 ±7.9 | 32.7 ±8.0 | 33.4 ±7.9 |
| Left Ventricular end diastolic pressure | 23.5 ± 6.5 | 22.5 ± 5.9 | 23.8 ± 6.7 |
| Follow Up Ejection Fraction | 57.6 ±7.4 | 57.5 ± 8.0 | 57.7 ± 7.4 |
| Time to Repeat Echo | 21.6 ±37.6 | 13.0 ± 11.8 | 23.2 ± 40.7 |
| Maximal serum creatinine (mg/dl) | 1.8 ± 0.7 | 1.0 ± 0.4 | 1.2 ± 0.7 |
| Troponin 25th, 75th IQ | 0.76, 4.90 | 0.72, 10.72 | 0.77, 4.69 |
| Total (n = 56) | Deceased (n= 15) | Alive (n = 41) | |
|---|---|---|---|
| Length of Stay (days) | 8.7 ± 8.1 | 9.6 ± 8.4 | 8.4 ± 8.1 |
| Discharge Medications | |||
| Aspirin | 41 (73.2%) | 8 (53.3%) | 33 (80.5%) |
| Beta Blockers | 46 (82.1%) | 10 (66.7%) | 36 (87.8%) |
| ACE Inhibitors | 47 (83.9%) | 10 (66.7%) | 37 (90.2%) |
| Statins | 38 (67.9%) | 7 (46.7%) | 31 (75.6%) |
All short-term survivors had repeat LVEF evaluation demonstrating improvement to normal in EF. Fifteen deaths (26.8%) occurred over a period of 2.3 ± 1.8 years; the mean age at time of death was 70.1 ± 12.9 years ( Table 2 ). The majority of these deaths (60%) occurred within the first 90 days from hospital admittance ( Figure 1 ). There were 5 in-hospital deaths (8.9%), 4 died before 90 days, and 6 after 90 days (19.6% mortality of those that survived initial hospitalization). Mean survival was 4.47 years (95% confidence interval [CI] 3.81 to 5.13; Figure 1 ). The causes of death included congestive heart failure, arrhythmia, sepsis, and noncardiac causes ( Figure 1 ). The nonmortal recurrence rate was 1.8% (n = 1). TC contributed to death in the majority of those who died in hospital; all deaths after discharge were unrelated to cardiac illness.
Relevant clinical variables were assessed for their independent contribution in survival outcome. None of these variables were univariate predictors and were not included in the multivariate model. The QTc interval at 48 hours after admission and the trend in QTc interval compared with admission were not statistically significant. Neither heart rate nor uncorrected QT interval were multivariate predictors.
Intubation, QTc per 50 ms, and medications at discharge (beta blockers, angiotensin converting enzyme inhibitors, Aspirin, and statins) were included in the multivariate model ( Table 3 ). Of these, only 2 variables remained statistically significant predictors in the multivariate model: intubation (hazard ratio 4.68, 95% CI 1.17 to 18.72, p = 0.029) and QTc per 50 ms (hazard ratio 0.43, 95% CI 0.18 to 1.00, p = 0.051).
