Tobias Graf

Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences.

Despite increasing research efforts, the prognostic consequences of takotsubo cardiomyopathy (TTC) remain largely unknown. The aim of this study was therefore to compare the long‐term mortality rate of TTC patients with high‐risk patients presenting with ST‐segment elevation myocardial infarction (STEMI).

Management of arrhythmias in patients with Takotsubo cardiomyopathy: Is the implantation of permanent devices necessary?

BACKGROUND Arrhythmias are frequent in Takotsubo cardiomyopathy (TTC) and a major determinant of outcome. OBJECTIVE The purpose of this study was to provide a rationale for management strategies, particularly for permanent device implantation given the reversible nature of TTC. METHODS Treatment strategies of arrhythmias including ventricular fibrillation (VF), ventricular tachycardia (VT), asystole, pulseless electrical activity, and complete atrioventricular (AV) or sinoatrial block were assessed in a bicentric cohort of consecutive patients with TTC (n = 286) with a mean follow-up period of 3.3 ± 2.4 years. RESULTS The prevalence of arrhythmias during the acute phase of TTC was 12.2% (n = 35), consisting predominantly of VT (n = 16 [5.6%]), VF (n = 7 [2.4%]), and complete AV block (n = 8 [2.8%]). Seven patients received a permanent pacemaker because of complete AV (n = 6) or sinoatrial (n = 1) block. Regular device checkups were available in 2 patients and demonstrated ongoing high-degree AV block despite recovery of left ventricular function. Three patients with transient bradyarrhythmias who did not receive devices died shortly after hospital discharge from unknown causes. One patient received an implantable cardioverter-defibrillator after resuscitation for VF and did not require device interventions during 2-year follow-up. Patients with polymorphic VT (n = 7), monomorphic VT (n = 6), or VF (n = 2) who were discharged from hospital survived or died of noncardiac reasons, with the cause of death remaining unclear in 1 patient with monomorphic sustained VT. CONCLUSION Our data suggest that bradyarrhythmias in the acute setting of TTC may require permanent pacemaker implantation. In contrast, polymorphic ventricular arrhythmias might be managed with a temporary approach (eg, wearable cardioverter-defibrillators) until recovery of repolarization time and left ventricular function.

Prevalence and prognostic relevance of atrial fibrillation in patients with Takotsubo syndrome

BACKGROUND Takotsubo syndrome (TTS) is associated with a considerable risk of complications during the acute phase and substantial long-term mortality rates. Concomitant atrial fibrillation may have an impact on outcome in these patients. Aim of this study was to assess the prevalence and prognostic relevance of atrial fibrillation in TTS. METHODS We performed an international, multicenter study including 387 TTS patients consecutively enrolled at 3 centers. Atrial fibrillation was defined as known history before admission or documented episodes during hospital stay. Long-term mortality was evaluated in median 2.9years after the acute event. RESULTS Atrial fibrillation was found in 97 TTS patients (25.1%) and was associated with older age (p<0.01), less emotional triggers (p=0.03), higher incidence of cardiogenic shock (p<0.01), lower left ventricular ejection fraction (p<0.01), and a prolonged hospital stay (p<0.01). Determinants of atrial fibrillation at admission (n=34 patients; 9.0%) in multivariate logistic regression analysis were age (p=0.001) and cardiogenic shock (p=0.013). Long-term mortality was significantly higher in TTS patients with as compared to patients without atrial fibrillation (35.2% versus 15.3%; hazard ratio 3.02, 95% confidence interval 1.90-4.78; p<0.001). In multivariate Cox regression analysis atrial fibrillation was identified as an independent determinant of outcome even after adjustment for clinical variables, left ventricular functional parameters (ballooning pattern, ejection fraction), and cardiogenic shock. CONCLUSIONS In TTS patients, atrial fibrillation is frequent and associated with increased long-term mortality rates. Furthermore, our study identifies atrial fibrillation as an independent predictor of outcome and a potential tool for risk stratification in TTS.

Impact of persistent ST elevation on outcome in patients with Takotsubo syndrome. Results from the GErman Italian STress Cardiomyopathy (GEIST) registry

BACKGROUND Potential predictors of clinical complications of Takotsubo syndrome (TTS) are poorly known. Persistent ST-segment elevation (PSTE) may have an impact on outcome similar as previously reported in acute coronary syndrome. The aim of this study was to assess the prevalence and prognostic relevance of PSTE in patients with TTS. METHODS Two-hundred-sixty-nine consecutive patients were enrolled in an international multicenter registry. PSTE was defined as the documentation of ST-elevation at least for the first 48h of hospitalization. Long-term mortality was evaluated in median 1.9years after the acute event. RESULTS PSTE was found in 52 TTS patients (19%). Patients with PSTE were characterized by higher admission levels of troponin-I (23±12 vs 8±49ng/L, p<0.001), experienced a longer hospitalization (10±5 vs 8±3days, p=0.02) and a higher rate of in-hospital complications (31% vs 17% p=0.03). At multivariate analysis including PSTE, age, male sex, admission ejection fraction, PSTE (odds ratio [OR] 4.2; 95% confidence interval [CI] 1.4-13; p=0.01), age (OR 1.05; 95%CI 1.00-1.10; p=0.03) and admission ejection fraction (OR 0.93; 95%CI 0.87-0.99; p=0.02) were independent predictors of in-hospital complications. At long-term follow-up no significant differences in terms of mortality were observed between patients with and without PSTE (19% vs 15%; p=0.5). However, PSTE was a predictor of major cardiac adverse events (MACE) at follow-up (HR 2.32, 95% CI 1.02-5.31, p 0.045). CONCLUSIONS In TTS patients, PSTE is a common finding, represents an independent predictor of in-hospital complications and could be associated with MACE at follow-up.

Optical Coherence Tomography to Evaluate Plaque Burden and Morphology in Patients With Takotsubo Syndrome

Background Disrupted atherosclerotic plaques in the left anterior descending coronary artery are discussed controversially as a potential pathophysiological mechanism in Takotsubo syndrome (TTS). Therefore, the aim of the present study was to assess plaque burden and morphology by using optical coherence tomography in patients with TTS. Methods and Results A total of 23 consecutive TTS patients were included in this single‐center study and underwent optical coherence tomography imaging of the left main coronary artery and the left anterior descending coronary artery at acute presentation. All patients fulfilled the established diagnostic criteria for TTS and the diagnosis was confirmed with a multimodality imaging approach including cardiac magnetic resonance in 16 patients (69.6%). Atherosclerotic plaques located in the left anterior descending coronary artery or both the left anterior descending coronary artery and the left main coronary artery were detected in 16 TTS patients (69.6%), with 6 patients exhibiting multiple plaque types. In addition to the predominant fibrocalcific (52.2%) and lipid‐rich plaques (30.4%), thin‐cap fibroatheromas were also found in 6 patients (26.1%). However, ruptured plaques or intracoronary thrombi were not observed. Vessel stenosis >50% was found in 3 patients (13.0%) by analyzing cross‐sectional areas. Clinical characteristics and cardiac magnetic resonance findings did not differ significantly between TTS patients with and without atherosclerotic plaques. Conclusions Using optical coherence tomography, the present study revealed a high prevalence of atherosclerotic plaques in patients with TTS, including a considerable number of highly vulnerable thin‐cap fibroatheromas. However, ruptured plaques or intracoronary thrombi were not observed and are therefore most likely not the underlying mechanism of TTS.

Prevalence and long‐term prognostic impact of malignancy in patients with Takotsubo syndrome

Takotsubo syndrome (TTS) is an acute and transient myocardial dysfunction of the left and/or right ventricle. The acute presentation is indistinguishable from that of an acute coronary syndrome, whereas no culprit lesion responsible for the distinct wall motion abnormality can be found on coronary angiography.1 Growing evidence suggests that the long-term prognosis of TTS is much worse than expected.1 Non-cardiovascular events including cancerrelated deaths contribute considerably to the increased mortality of TTS patients.2 Consequently, there is increasing speculation about a potential pathophysiological connection between cancer and TTS and some evidence that malignancies significantly influence the clinical course of TTS.3–5 The aim of this study was therefore to investigate the exact prevalence of malignancy and to assess its clinical consequences, including long-term survival, in a large cohort of TTS patients. A total of 286 TTS patients were included between February 2004 and April 2014. The diagnosis of TTS was confirmed using the revised Mayo Clinic criteria. The study was conducted in compliance with the Helsinki Declaration. Informed consent for the use of medical data for research purposes was obtained. The medical records of all patients were screened. Data were supplemented by telephone interviews to determine the prevalence of malignancy. Follow-up was also conducted using standardized telephone interviews. Statistical analyses were performed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA). A two-sided P-value of ≤0.05 was considered to indicate statistical significance. Data were presented as the mean ± standard deviation (SD)

Prevalence and Prognostic Impact of Diabetes in Takotsubo Syndrome: Insights From the International, Multicenter GEIST Registry

OBJECTIVE In view of low prevalence rates, diabetes is discussed as a protective factor for the occurrence of Takotsubo syndrome (TTS). Furthermore, it was associated with improved outcome in a small single-center analysis. Therefore, this study assessed the prevalence and prognostic relevance of concomitant diabetes in TTS. RESEARCH DESIGN AND METHODS A total of 826 patients with TTS were enrolled in an international, multicenter, registry-based study (eight centers in Italy and Germany). All-cause mortality was compared between patients with diabetes and patients without diabetes, and the independent predictive value of diabetes was evaluated in multivariate regression analysis. RESULTS The prevalence of diabetes was 21.1% (n = 174). TTS patients with diabetes were older (P < 0.001), were more frequently male (P = 0.003), had a higher prevalence of hypertension (P < 0.001), physical triggers (P = 0.041), and typical apical ballooning (P = 0.010), had a lower left ventricular ejection fraction (P = 0.008), had a higher rate of pulmonary edema (P = 0.032), and had a longer hospital stay (P = 0.009). However, 28-day all-cause mortality did not differ between patients with diabetes and patients without diabetes (6.4% vs. 5.7%; hazard ratio [HR] 1.11 [95% CI 0.55–2.25]; P = 0.772). Longer-term follow-up after a median of 2.5 years revealed a significantly higher mortality among TTS patients with diabetes (31.4% vs. 16.5%; P < 0.001), and multivariate regression analysis identified diabetes as an independent predictor of adverse outcome (HR 1.66 [95% CI 1.16–2.39]; P = 0.006). CONCLUSIONS Diabetes is not uncommon in patients with TTS, is associated with increased longer-term mortality rates, and is an independent predictor of adverse outcome irrespective of additional risk factors.

Transient left atrial dysfunction is a feature of Takotsubo syndrome

BackgroundTakotsubo syndrome (TTS) is characterized by a transient left and/or right ventricular dysfunction as a consequence of a distinctive pattern of regional wall motion abnormalities. However, a systematic evaluation of the left atrial (LA) function in patients with TTS is lacking. The aim of the present study was therefore to comprehensively assess LA performance indexes and function in patients with TTS.MethodsWe compared LA function assessed by volumetric indexes derived from fractional volume changes in cardiovascular magnetic resonance (CMR) between 125 TTS patients and 125 patients with anterior ST-segment elevation myocardial infarction (STEMI). Furthermore, recovery of LA performance was evaluated in a subgroup of 20 TTS patients with follow-up CMR data.ResultsPatients with TTS demonstrated a significantly lower total LA emptying fraction (EF) [44% (interquartile range (IQR) 34–53%) versus 51% (IQR 42–56%); p < 0.01], passive LA-EF [21% (IQR 14–30%) versus 24% (IQR 20–29%); p = 0.03] and active LA-EF [29% (IQR 20–38%) versus 35% (28–42%); p < 0.01] compared to patients with anterior STEMI. Among the 20 TTS patients with serial CMR data, the total LA-EF significantly improved from 42% (IQR 29–48%) at the acute stage to 51% (IQR 46–59%) at follow-up (p < 0.01). Similarly, active LA-EF (p < 0.01) and passive LA-EF (p = 0.02) improved significantly as well.ConclusionCompared to anterior STEMI, TTS patients demonstrated a significantly decreased LA function during the acute/subacute phase of the disease. However, impairment of LA performance seems to be transient in TTS with recovery during follow-up.

Classical apical ballooning with significant stenosis of the left anterior descending coronary artery: is cardiac magnetic resonance imaging the solution for this diagnostic dilemma?

Takotsubo cardiomyopathy (TTC) is characterized by an acute, but transient myocardial dysfunction with distinct left ventricular wall motion abnormalities (WMAs), mimicking an acute coronary syndrome (ACS). The current pathophysiologic hypothesis postulates a major role of catecholamine excess and enhanced sympathetic activity [1]. About 1–2 % of patients with ACS turn out to be affected by TTC [2]. Initially, the absence of significant coronary artery disease (CAD) was a prerequisite for the diagnosis of TTC. However, in the revised Mayo Clinic diagnostic criteria for TTC, the presence of CAD in vessels not supplying dysfunctional myocardium is no longer an exclusion criterion to establish the diagnosis [3]. According to recent reports, the prevalence of various degrees of CAD in patients with TTC ranged from 10 to 60 % [1, 4, 5]. This increased recognition of the coexistence of CAD and TTC, however, comprises diagnostic and therapeutic challenges. Herein, we present two cases of TTC with typical transient apical ballooning, which do not apply to the initially, in 2004, proposed Mayo Clinic criteria because of a coexisting significant stenosis of the left anterior descending (LAD) coronary artery. An 88-year-old woman was admitted to our emergency unit with acute dyspnea and weakness. An emotional stressful event (family argument) preceded the admission. The electrocardiogram showed no significant ST-segment elevations in leads V4–V6. Troponin T was elevated with 451 ng/l (normal \14 ng/l). Creatine kinase (CK) was elevated with 351 U/l (normal\170 U/l) with a CK-MB of 33 U/l (normal \25 U/l). The subsequent coronary angiography showed a coronary one-vessel disease with a high-grade stenosis of the LAD (Fig. 1a), which was treated with two drug eluting stents (DES). Notably, the affected vessel outreached the left ventricular apex (LAD recurrent segment, wrap-around LAD). Levocardiography revealed a left ventricular ejection fraction (LVEF) of 43 % with apical and midventricular akinesia accompanied by basal hyper-contractility in terms of a typical apical ballooning (Fig. 1b). Two days after the acute event, cardiac magnetic resonance imaging (CMR) confirmed the distinct WMA (Fig. 1c) and demonstrated myocardial edema without late gadolinium enhancement (LGE) (Fig. 1d) in the area of left ventricular dysfunction. Five months after the acute event, follow-up echocardiogram and CMR confirmed complete recovery of the LVEF. A 78-year-old man was admitted to our emergency unit with progressive dyspnea, worsening of general condition, vertigo and recurrent collapses. A preceding stressful event could not be detected. The electrocardiogram showed atrial fibrillation without repolarization disturbances. Troponin T was elevated with 487 ng/l (normal \14 ng/l). CK was elevated with 789 U/l (normal\190 U/l) due to the rhabdomyolysis as a result of the recurrent collapses and drops. CK-MB remained normal. Again, coronary angiography demonstrated a wrap-around LAD with a high-grade stenosis (Fig. 2a), which was treated with one DES. Levocardiography showed typical apical ballooning with an LVEF of 28 % which was confirmed via CMR 9 days after the acute event (Fig. 2b, c). Again, CMR detected edema in the area of WMA without any signs of LGE & Christian Möller christian.moeller@uksh.de

Left Ventricular Thrombi in Takotsubo Syndrome: Incidence, Predictors, and Management: Results From the GEIST (German Italian Stress Cardiomyopathy) Registry

Background Left ventricular (LV) thrombi during Takotsubo syndrome represent a potential complication and can be associated with cerebrovascular embolic events. The aim of this study was to evaluate the exact incidence, predictors, and management strategies of LV thrombi in patients with Takotsubo syndrome. Methods and Results We enrolled 541 consecutive patients in a multicenter international registry. Clinical features and echocardiographic data at admission, during hospitalization, and after 3 months were evaluated. Survival rates for long‐term follow‐up (mean 984±908 days) were recorded. Twelve Takotsubo syndrome patients (2.2%) developed LV thrombi (all female presenting with apical ballooning pattern). All patients with LV thrombi were treated with oral anticoagulation therapy; however, 2 (17%) had a stroke before treatment initiation. These patients were characterized by a higher prevalence of ST‐elevation (56% versus 16%; P<0.001) and higher troponin I levels (10.8±18.3 ng/mL versus 3.5±4.3 ng/mL; P=0.001) as compared with those without LV thrombi. At multivariate analysis including age, sex, LV ejection fraction, ST‐elevation at admission, and apical ballooning pattern, troponin I level >10 ng/mL was the only predictor for LV thrombosis (hazard ratio 6.6, confidence interval, 1.01–40.0; P=0.04). After 3 months all LV thrombi disappeared. Oral anticoagulation therapy was interrupted in all patients except 1. At long‐term follow‐up, the survival rate was not different between patients with and without LV thrombi (84% versus 85%; P=0.99). Conclusions LV thrombi have a relatively low incidence among patients with Takotsubo syndrome and were detected in female patients with apical ballooning pattern and increased troponin levels. Oral anticoagulation therapy for 3 months seems reasonable in these high‐risk patients.