Prevalence, management, and outcome of adverse rhythm disorders in takotsubo syndrome: insights from the international multicenter GEIST registry.

One important complication related to takotsubo syndrome (TTS) is adverse rhythm disorders. Our study was conducted to determine the incidence and management of adverse rhythm disorders in TTS and its long-term prognostic impact. We analyzed 906 TTS patients from 9 European centers. Patients were divided into the adverse rhythm disorders group (encompassing ventricular tachycardia, ventricular fibrillation, torsade de pointes, and asystole or complete atrioventricular block) and non-adverse rhythm disorders group. In our study cohort, we identified 67 (7.4%) patients with presence of adverse rhythm disorders. TTS patients were followed up over a period of 2.8 years. In the adverse rhythm disorders group, 18% of patients presented adverse rhythm disorders before hospital admission. Asystole and/or AV block were significantly more presented before admission (13 patients versus 8 patients; p < 0.01), whereas ventricular tachyarrhythmias were more presented in-hospital (4 patients versus 42 patients; p < 0.01). Adverse rhythm disorders patients suffered more frequently from cardiogenic shock (31% versus 7.6%, p < 0.01) and in-hospital death (10.9% versus 3.6%; p < 0.01). Furthermore, the long-term survival was significantly impaired in adverse rhythm disorders patients as compared with non-adverse rhythm disorders patients; (log-rank p < 0.01). Using multivariate Cox regression analysis, cardiogenic shock (HR 2.86, 95% CI 1.1-6.9; p = 0.02) was identified as independent predictors of adverse rhythm disorders. The short- and long-term mortality rate of TTS patients presenting with adverse rhythm disorders was significantly higher than in TTS patients presenting without it. Therefore, TTS patients with adverse rhythm disorders should be carefully monitored during hospital stay and at long-term follow-up.

Malignancies and outcome in Takotsubo syndrome: a meta-analysis study on cancer and stress cardiomyopathy.

Takotsubo syndrome (TTS) can be induced by a large variety of physical/emotional triggers; several cases, however, are related to either an overt or occult malignancy, as shown in retrospective studies and case reports. The aim of this study was therefore to evaluate the clinical outcome of patients with TTS and cancer in a meta-analysis study. In June 2018, a Pubmed systematic research was conducted for studies assessing outcome in patients with TTS and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for adverse events at follow-up. After paper retrieval, four studies were included in the meta-analysis, with a total of 123,563 patients. The prevalence of current or previous malignancy among patients admitted with TTS was 6.7% (8258 patients). When compared to control patients, patients with cancer showed an increased risk of clinical events (RR 3.24, 95% CI 3.04-3.45, p < 0.01). The risk of in-hospital events was significantly higher in the cancer group (RR 2.08 95% CI, 1.50-2.87, p < 0.01) and was mainly due to higher need for respiratory support (RR 1.67, 95% CI, 1.58-1.77, p < 0.01). The risk of adverse events at follow-up was also higher in the cancer group (RR 3.30, 95% CI 3.09-3.51, p < 0.01). Cancer, either history or active, is associated with an increased risk of adverse events in TTS.

Oral anticoagulation in high risk Takotsubo syndrome: when should it be considered and when not?

Standard pharmacological therapy in Takotsubo syndrome (TTS) is still debated and there is a lack of prospective data. In their recent work in BMC Cardiovascular Disorders Abanador-Kamper et al. found that stroke in TTS has an event rate of 2.8% after 30 days and 4.2% after 12 months and they question which patients need oral anticoagulation. According to our clinical data, TTS patients with LV thrombi may be at high risk of stroke. These patients are characterized by apical ballooning pattern, high prevalence of ST-elevation and higher troponin I levels. We have recently proposed a therapeutic algorithm for oral anticoagulation in TTS. In case of apical ballooning pattern and increased admission levels of troponin-I (> 10 ng/mL), oral anticoagulation should be considered, while in case of midventricular/basal ballooning or apical ballooning associated with troponin-I levels < 10 ng/ml, oral anticoagulation should not be considered. A simple combination of echocardiographic parameters (apical ballooning pattern),ECG data (ST-elevation at admission and persistent after 72 h) and laboratory values (troponin serum levels) could be useful for an appropriate therapeutic management of oral anticoagulation in TTS.

"Lambda-wave" ST-elevation is associated with severe prognosis in stress (takotsubo) cardiomyopathy.

BACKGROUND: Persistent ST-segment elevation in acute coronary syndrome is associated with both short and long-term complications. By contrast, there is limited information about ST-elevation and its evolution during takotsubo (stress) cardiomyopathy (TTC). AIM: To evaluate whether persistent downsloping ST-elevation in the early stages of TTC might correlate with short and long-term clinical events. METHODS: One-hundred fifty-eight consecutive subjects with TTC were prospectively enrolled and assessed by electrocardiogram. Patients were classified in two groups according to the presence of downsloping ST-elevation ≥5 mm lasting at least 24 hr ("lambda-wave" ST-elevation group vs. without downsloping ST-elevation) in at least one/two contiguous leads. RESULTS: Five (3.2%) patients, all female with a mean left ventricular ejection fraction 32 ± 5%, were included in the lambda-wave ST-elevation group. These patients were characterized by a higher prevalence of physical stressor (100% vs. 49%, p = 0.04) and higher admission and peak levels of troponin-I levels during hospitalization. Peak of ST-elevation in the lambda-wave ST-elevation group was reached 6 hr after admission and gradually decreased after 24 hr. In-hospital complications were observed in all the patients presenting lambda ST-elevation (100% vs. 23%, p = 0.03, OR: 29.1, p = 0.04); one patient presented endoventricular thrombosis and two died of cardiogenic shock. At long-term follow-up (mean 443 days), adverse events were observed in 80% of patients with lambda-wave ST-elevation (RR of adverse events at follow-up 32, p < 0.01). CONCLUSION: Persistent downsloping lambda-wave ST-elevation during the acute phase of stress cardiomyopathy may be associated with a higher risk of adverse events at short and long-term follow-up.

Right heart strain in arrhythmogenic right ventricular cardiomyopathy: Implications for cardiovascular outcome.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive myocardial dysfunction and associated with an increased risk of major cardiovascular events. AIMS: To determine right heart strain (ventricular and atrial global longitudinal strain (RVGLS and RAGLS)) in patients with definite ARVC and its association with adverse events during follow-up. METHODS: RVGLS and RAGLS were analysed in focused right heart apical views from 70 patients using TomTec ImageArena and association with a composite endpoint (sustained ventricular arrhythmia and cardiovascular death) was determined. RESULTS: Over a median follow-up duration of 4.9 years, 26 (37%) patients met the endpoint. RVGLS was significantly impaired in the event group (-11.5 [-13.3 - -10.2]%) versus the no-event group (-15.8 [-17.1 - -14.5]%, P < 0.001), and so was RAGLS (22.8 [21.4 - 27.4]% vs. 31.5 [25.1 - 39.6]%, respectively, P < 0.001). In Cox regression, RVGLS (HR 1.36, P < 0.001) and RAGLS (HR 0.92, P = 0.002) were associated with higher risk of adverse events. In multivariable Cox regression models, RVGLS and RAGLS remained independent of and were incremental to age, gender, and conventional RV parameters, and model fit was improved when RVGLS and RAGLS were applied together rather than alone. CONCLUSIONS: RVGLS and RAGLS are more impaired in patients with adverse events and associated with adverse events independent of age, gender, and conventional RV parameters. When RVGLS and RAGLS are applied together, prediction models are improved suggesting that right heart strain may form part of the echocardiographic routine protocol in patients with ARVC.

Right atrial strain and cardiovascular outcome in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibro-fatty infiltration of the myocardium and associated with adverse cardiovascular (CV) events. This study aims to examine right atrial (RA) deformation in ARVC and understand its association with CV outcomes. METHODS AND RESULTS: RA strain was determined in 50 patients with definite ARVC, compared with a matched control group of 50 healthy individuals, and analysed for outcome association over a median follow-up duration of 5 years. A subgroup of 30 ARVC patients with normal RA volume (ARVC-N group) was compared with 30 matched controls (Control-N), and the outcome was analysed separately. RA reservoir, conduit, and pump strain were significantly impaired in ARVC vs. control. Similar observations were made in the N-ARVC subgroup. Reservoir strain was associated with an increased risk of atrial arrhythmia (AA) [hazard ratio (HR) 0.88, P < 0.01] and CV events (HR 0.92, P < 0.01). Conduit strain also predicted AA (HR 1.02, P < 0.01), while pump strain predicted CV events (HR 1.09, P = 0.02). Reservoir strain improved the fitness of bivariable models for the association of RV end-diastolic area index, RV fractional area change, and RV global longitudinal strain with CV events. CONCLUSION: ARVC patients display impaired RA strain even when RA volume is normal. Reservoir and pump strain are associated with an increased risk of CV events. Reservoir strain improved model fitness for the association of RVGLS and other echocardiographic parameters with CV events.

Concealed structural heart disease discovered at cardiac magnetic resonance in patients with ventricular extrasystoles from ventricular outflow tract and apparently normal hearts.

BACKGROUND: Outflow tract (OT) premature ventricular contractions (PVCs) are commonly found in clinical practice; in most cases, PVCs are benign and observed in structurally normal hearts, not requiring any therapeutic intervention. In this study, we therefore sought to evaluate with cardiac magnetic resonance (CMR) patients with PVC and apparently normal heart at echocardiographic examination, in order to identify possible substrates linked with higher prevalence of arrhythmias or structural heart disease. METHODS: Thirty-three consecutive patients with frequent PVCs originating from the ventricular OT (right and left) were enrolled in the study and assessed by echocardiography and CMR. All patients had normal baseline electrocardiogram. RESULTS: CMR showed structural changes in 5 patients out of 33; in 3 cases, areas of fibrosis limited in one case to the middle basal segments of the interventricular septum and in two patients to the middle basal segments of the inferior-lateral wall were found. In 2 other cases, however, late gadolinium enhancement showed significant anomalies characterized in one patient by extensive areas of subepicardial fibrosis of the left ventricle, suitable with arrhythmogenic left dominant dysplasia; in another patient, a marked trabeculation of left ventricular medium apical segments suitable with non-compaction myocardium was present. CONCLUSIONS: CMR may identify cases of structural heart disease in subjects with OT PVCs and apparently normal electrocardiogram and echocardiogram examinations. A preliminary screening with CMR may be considered before any further invasive electrophysiology assessment and therapeutic planning.

Incidence and Clinical Impact of Right Ventricular Involvement (Biventricular Ballooning) in Takotsubo Syndrome: Results From the GEIST Registry.

BACKGROUND: The short- and long-term prognosis of Takotsubo syndrome (TTS) presenting with right ventricular (RV) involvement remains poorly understood. RESEARCH QUESTION: What is the incidence and clinical outcome of RV involvement in TTS? STUDY DESIGN AND METHODS: This study analyzed 839 consecutive patients with TTS (758 female subjects and 81 male subjects) in a multicenter registry. RV involvement was defined as wall motion abnormality of the RV free wall, with or without apical involvement. The median long-term follow-up was 2.1 years (interquartile range, 0.3-4.5 years). The primary outcome was in-hospital and out-of-hospital all-cause mortality. The secondary end point was a composite of in-hospital death, thromboembolic events, cardiogenic shock, pulmonary edema, and malignant arrhythmias. RESULTS: The incidence of RV involvement in TTS was 11% (n = 93). More often patients with RV involvement were male compared with patients without RV involvement (P = .02). There was a slight difference in the left ventricular ejection fraction measured in patients with RV involvement vs those patients with isolated left ventricular TTS (38 ± 10% vs 40 ± 10%; P = .03). No major differences in terms of comorbidities were observed between groups except regarding a history of cancer, which was significantly more prevalent in patients with TTS presenting with RV involvement (P = .03). Physical stressors were more prevalent in the RV group (P < .01), whereas emotional stressors were less prevalent (P < .01). Patients with RV involvement had a higher incidence of in-hospital cardiogenic shock (P = .02). The primary outcome (in- and out-of-hospital all-cause mortality) was observed in 12.8% of patients without RV involvement compared with 29% of patients with RV involvement. Although the in-hospital mortality rate was similar in both groups, a higher out-of-hospital all-cause mortality rate (log-rank test, P = .008) was observed in the RV involvement group. The Cox multivariable regression analysis showed that physical triggers were independent predictors of RV involvement. INTERPRETATION: RV involvement defines a high-risk cohort of patients with TTS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04361994; URL: www.clinicaltrials.gov.

Neutrophil/lymphocyte ratio predicts in-hospital complications in Takotsubo syndrome. Results from a prospective multi-center registry.

BACKGROUND: Several hematological indices including subtypes of leukocytes populations have been associated with cardiovascular outcome. Takotsubo syndrome (TTS) is a form of acute heart failure syndrome featured by several in-hospital complications (IHCs). HYPOTHESIS: Hematological indices at admission may predict IHCs in TTS patients. METHODS: One hundred and sixty consecutive patients with TTS were enrolled in a multicenter prospective registry. Clinical data, admission hemogram, and IHCs were recorded. RESULTS: Incidence of IHCs was 37%, including pulmonary edema 9%, cardiogenic shock 9%, need of invasive ventilation 10%, death 8%, stroke 2.5%, and left ventricular thrombi 6%. Patients with IHCs were older, more frequently male, with physical stressor-induced TTS, lower left ventricular ejection fraction at admission. Neutrophil/lymphocyte ratio (NLr) (12 ± 12 vs 7 ± 8, P = .002) and white blood cells/mean platelet volume ratio (1.2 ± 0.5 vs 1.0 ± 0.5, P = .03) at admission were significantly higher in patients with IHCs. NLr values were predictor of IHCs (Odds ratios [OR] 1.07, 95% CI 1.03-1.11, P < .01). When stratified according to NLr into tertiles, the rate of IHCs was from first to third tertile was, respectively, 22%, 31%, and 58%. NLr values in the higher tertile were independent predictors of IHCs even at multivariate analysis (OR 3.7, 95% CI 1.5-9.4, P < .01). NLr values higher than 5 were able to predict IHCs with a sensitivity of 82% and specificity of 58%; negative predictive power was 84% (area under the ROC curve 0.73). CONCLUSIONS: NLr is an independent predictor of IHCs in patients admitted with TTS. Admission hemogram may represent a potential tool for prediction of IHCs in TTS.

Incidence and Clinical Impact of Recurrent Takotsubo Syndrome: Results From the GEIST Registry.

Background Current literature only reports variable information from single-center studies on the recurrence rate, the complications, and the outcome of patients with Takotsubo syndrome ( TTS) experiencing recurrent TTS . Therefore, a detailed description of clinical characteristics, predictors, and the prognostic impact of patients with TTS and recurrences in a multicenter registry is needed. Methods and Results We analyzed 749 patients with TTS from 9 European centers being part of the international, multicenter GEIST (German Italian Stress Cardiomyopathy) Registry. Patients were divided into the recurrence group and the nonrecurrence group. The recurrence rate at a median follow-up of 830 days (interquartile range, 118-1701 days) was 4%. Most recurrences were documented in the first 5 years after the index TTS episode. Up to 2 TTS recurrences were documented in 2 of 30 patients (6%). A variable ballooning pattern (n=6, 0.8%) with, in particular, involvement of the right ventricular occurred in 3 cases (0.4%) at the recurrence event. Except for the higher presence of arterial hypertension (86.7% versus 68.3%; P=0.03) in the recurrence group, no other baseline characteristics were different between groups. Observation of TTS complications during follow-up, including stroke, thromboembolic events, in-hospital death, and cardiogenic shock, revealed no significant differences between groups ( P>0.05), except the higher presence of pulmonary edema in the recurrence group versus the nonrecurrence group (13.3% versus 4.9%; P=0.04). Conclusions The incidence of TTS recurrence is estimated to be 4% in this multicenter TTS registry. A variable TTS pattern at recurrence is common in up to 20% of recurrence cases.

Assessment of the German and Italian Stress Cardiomyopathy Score for Risk Stratification for In-hospital Complications in Patients With Takotsubo Syndrome.

Importance: Takotsubo syndrome (TTS) is an acute, reversible heart failure syndrome featured by significant rates of in-hospital complications. There is a lack of data for risk stratification during hospitalization. Objective: To derive a simple clinical score for risk prediction of in-hospital complications among patients with TTS. Design, Setting, and Participants: In this prognostic study, 1007 consecutive patients were enrolled in the German and Italian Stress Cardiomyopathy (GEIST) registry from July 1, 2007, through December 31, 2017, and identified as the derivation cohort; 946 patients were enrolled in the Spanish Registry for Takotsubo Cardiomyopathy (RETAKO) as the external score validation. An admission risk score was developed using a stepwise multivariable regression analysis from 2 registries. Data analysis was performed from March 1, 2018, through July 31, 2018. Main Outcomes and Measures: In-hospital complications were defined as death, pulmonary edema, need for invasive ventilation, and cardiogenic shock. Four variables were identified as independent predictors of in-hospital complications and were used for the score: male sex, history of neurologic disorder, right ventricular involvement, and left ventricular ejection fraction (LVEF). Results: Of the 1007 patients enrolled in the GEIST registry, 107 (10.6%) were male, with mean (SD) age of 69.8 (11.4) years. Overall rate of in-hospital complications was 23.3% (235 of 1007) (death, 4.0%; pulmonary edema, 5.8%; invasive ventilation, 6.4%; and cardiogenic shock, 9.1%). The GEIST prognosis score was derived by providing 20 points each for male sex and history of neurologic disorders and 30 points for right ventricular involvement and then subtracting the value in percent of LVEF (decimal values between 0.15 and 0.70). Score accuracy on area under the receiver operating characteristic curve analysis was 0.71, with a negative predictive power of 87% with scores less than 20. External validation in the RETAKO population (124 [13.1%] male; mean [SD] age, 69.5 [14.9] years) revealed an area under the curve of 0.73 (P = .46 vs GEIST derivation cohort). Stratification into 3 risk groups (<20, 20-40, and >40 points) classified 316 patients (40.9%) as having low risk; 342 (44.3%) as having intermediate risk, and 114 (14.8%) as having high risk of complications. The observed in-hospital complication rates were 12.7% for low-risk patients, 23.4% for intermediate-risk patients, and 58.8% for high-risk patients (P < .001 for trend). After 2.6 years of follow-up, patients with in-hospital complications had significantly higher rates of mortality than those without complications (40% vs 10%, P = .01). Conclusions and Relevance: The GEIST prognostic score may be useful in early risk stratification for TTS. High-risk patients with TTS may require an intensive care unit stay, and low-risk patients with TTS could be discharged within a few days. In-hospital complications in patients with TTS may be associated with increased risk of long-term mortality.

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.

Inflammatory patterns in Takotsubo cardiomyopathy and acute coronary syndrome: A propensity score matched analysis.

BACKGROUND AND AIMS: Systemic inflammatory activation can be observed in both Takotsubo cardiomyopathy (TTC) and acute coronary syndrome (ACS). The aim of this study was therefore to compare circulating cytokine levels during the acute and subacute phase of TTC and ACS. METHODS: One hundred thirty-six consecutive patients were enrolled in the study; after a propensity score matching, 32 TTC patients were compared with 32 subjects with ACS. Clinical baseline features and circulating levels of interleukin(IL)-1ß, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, MCP1, EGF, VEGF, TNFα were obtained at admission (t0) and after 120 h (t1). RESULTS: At t0, several circulating IL levels were higher in subjects with TTC (IL-2 2 vs. 0.5 pg/ml, IL-4 1.5 vs. 0.82 pg/ml, IL-10 3.34 vs. 1.62 pg/ml, TNF-α 5 vs. 2.3 pg/ml, IFN-γ 0.92 vs. 0.32 pg/ml, EGF 84.8 vs. 10.7 pg/ml, p < 0.05 in all cases), while IL-6 levels were higher in patients with ACS (25.4 vs. 12.4 pg/ml p = 0.03). At t1, IL-2 and EGF levels were still higher in patients with TTC vs. those with ACS (IL-2 4.6 vs. 0.72 pg/ml, p = 0.01; EGF 36.3 vs. 18.5 pg/ml, p = 0.03), while IL-6 serum levels were higher in ACS patients (19.6 vs. 7.35 pg/ml, p = 0.02). CONCLUSIONS: Different inflammatory patterns can be observed during the acute and subacute phase of TTC when compared to ACS. Increased levels of anti-inflammatory interleukins can be found during the acute phase of TTC while ACS is featured by higher levels of IL-6 during the acute and sub-acute phase.

Prognostic value of N-Terminal Pro-B-Type Natriuretic Peptide in Takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TTS), a form of acute transient heart failure, has been associated with severe complications and considerable mortality rates. N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) might serve as a marker to identify high-risk patients but has not yet been investigated regarding prognostic implications in TTS. Aim of this study was to determine the short- and long-term prognostic utility of NT-proBNP in patients with TTS. METHODS: The predictive value of admission NT-proBNP was assessed in an international, multicenter study including 177 consecutive TTS patients. Predefined endpoints were 30-day major adverse cardiac events (MACE) consisting of all-cause death, cardiogenic shock, and pulmonary edema as well as long-term mortality in median 2.3 years after the acute event. RESULTS: Stratification according to median admission NT-proBNP (4511 pg/ml) resulted in significantly higher 30-day MACE [22.5 versus 9.1%; odds ratio (OR) 2.90, 95% confidence interval (CI) 1.20-6.99 p = 0.015] and long-term mortality rates [16.3 versus 9.4%; hazard ratio (HR) 2.72, 95% CI 1.13-6.56 p = 0.021] in patients > median. The best admission NT-proBNP cutoffs to predict 30-day MACE and long-term mortality were determined at 5560 and 8178 pg/ml respectively, with subsequent improved risk stratification for short-term MACE (OR 3.61, 95% CI 1.49-8.72; p = 0.003) and long-term mortality (HR 4.40; 95% CI 1.85-10.44, p < 0.001). Multivariate regression analysis identified admission NT-proBNP as an independent predictor of 30-day MACE (p < 0.001) and long-term mortality (p = 0.012). CONCLUSIONS: Admission NT-proBNP is an independent predictor for short- and long-term adverse events in TTS patients and, therefore, a useful marker for risk stratification immediately at presentation.

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.

Fenofibrate/simvastatin fixed-dose combination in the treatment of mixed dyslipidemia: safety, efficacy, and place in therapy.

Lipids disorder is the principal cause of atherosclerosis and may present with several forms, according to blood lipoprotein prevalence. One of the most common forms is combined dyslipidemia, characterized by high levels of triglycerides and low level of high-density lipoprotein. Single lipid-lowering drugs may have very selective effect on lipoproteins; hence, the need to use multiple therapy against dyslipidemia. However, the risk of toxicity is a concerning issue. In this review, the effect and safety of an approved combination therapy with simvastatin plus fenofibrate are described, with an analysis of pros and cons resulting from randomized multicenter trials, meta-analyses, animal models, and case reports as well.

Dynamic changes of QTc interval and prognostic significance in takotsubo (stress) cardiomyopathy.

BACKGROUND: Prolonged QT corrected (QTc) intervals are associated with adverse cardiovascular outcomes both in healthy and high-risk populations. Our objective was to evaluate the QTc intervals during a takotsubo cardiomyopathy (TTC) episodes and their potential prognostic role. HYPOTHESIS: Dynamic changes of QTc interval during hospitalization for TTC could be associated with outcome at follow-up. METHODS: Fifty-two consecutive patients hospitalized for TTC were enrolled. Twelve-lead electrocardiogram (ECG) was performed within 3 h after admission and repeated after 3, 5, and 7 days. Patients were classified in 2 groups: group 1 presented the maximal QTc interval length at admission and group 2 developed maximal QTc interval length after admission. RESULTS: Mean admission QTc interval was 493 ± 71 ms and mean QTc peak interval was 550 ± 76 ms (P < 0.001). Seventeen (33%) patients were included in group 1 and 35 (67%) patients in group 2. There were no differences for cardiovascular risk factors and in terms of ECG findings such as ST elevation, ST depression, and inverted T waves. Rates of adverse events during hospitalization among patients of group 1 and 2 were different although not significantly (20% vs 6%, P = 0.22). After 647 days follow-up, patients of group 1 presented higher risk of cardiovascular rehospitalization (31% vs 6%, P = 0.013; log-rank, P < 0.01). At multivariate analysis, including age and gender, a prolonged QTc interval at admission was significantly associated with higher risk of rehospitalization at follow-up (hazard ratio: 1.07 every 10 ms, 95% confidence interval: 1.003-1.14, P = 0.04). CONCLUSIONS: Prolonged QTc intervals at admission during a TTC episode could be associated with a higher risk of cardiovascular rehospitalization at follow-up. Dynamic increase of QTc intervals after admission are characterized by a trend toward a better prognosis.

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.

Serum interleukin 6 and 10 levels in Takotsubo cardiomyopathy: Increased admission levels may predict adverse events at follow-up.

BACKGROUND AND AIMS: Systemic inflammation has been hypothesized as a possible mechanism of Takotsubo cardiomyopathy (TTC). Aim of the study was to assess the role of interleukin (IL)-6 and IL-10 in subjects with an episode of TTC. METHODS: Fifty-six consecutive subjects with TTC were prospectively enrolled in the study and followed for a mean of 178 days. Circulating levels of IL-6, IL-10, clinical condition and left ventricular ejection fraction were evaluated at admission. Incidence of death, re-hospitalization and recurrence of TTC during follow-up was also recorded. RESULTS: 23% of patients experienced in-hospital complications while 20% of patients had adverse events at follow-up. IL-6 and IL-10 serum levels at admission were higher in subjects with adverse events at follow-up (120 ± 294 vs. 22 ± 40 pg/ml, p<0.05; 13 ± 35 vs. 2 ± 3 pg/ml, p=0.05, respectively). Increased serum levels of IL-6 and IL-10 were associated with higher adverse events rates at follow-up (Log-Rank p<0.001, <0.05, hazard ratio 8.6, 5.1, respectively) and mortality rates (Log-Rank p<0.001, p<0.05, hazard ratio 20.8, 7.1, respectively). Subjects with both increased IL-6 and IL-10 levels were characterized by an increased risk of adverse events when compared to subjects with only IL-6 or IL-10 increased levels or with values below cutoff values (Log-Rank p<0.01 for any event, <0.001 for death; hazard ratio 1.20 for any event, 1.31 for death), even after correction for age, LVEF and NTproBNP levels in multivariable Cox analysis. CONCLUSIONS: Serum IL-6 and IL-10 admission levels are associated with higher risk of adverse events during follow-up.