Prognostic role of neoplastic markers in Takotsubo syndrome.

Takotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9-14.8, HR = 7.8 95% CI 2.4-25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6-52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE.

A simple procedure in a complex patient: perioperative takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TTC) is a rare but life-threatening condition that is still not completely understood. Characterised by rapidly reversible ventricular dysfunction without any prior coronary artery disease, it can imitate a myocardial infarction and lead to death if not managed appropriately. This report examines a case of intraoperative cardiac arrest in a patient with no previous cardiac disease, and discusses the factors that may have precipitated this event, as well as the ways of distinguishing the cause of the arrest based on clinical course and investigations, eventually leading to a diagnosis of TTC.

Dor torácica na emergência: quando pensar em síndrome de Takotsubo? / Emergency chest pain: when to think about Takotsubo syndrome?

A síndrome de Takotsubo é uma cardiomiopatia induzida por estresse, caracterizada por disfunção transitória do ventrículo esquerdo. Essa disfunção pode ser confundida com infarto agudo miocárdio na sala de emergência por ter características clínicas semelhantes ­ principalmente a dor torácica. A fisiopatologia ainda não é bem definida, mas está associada à deficiência de estrogênio e ao aumento de catecolaminas que estimulam o acoplamento dos receptores beta-2 do coração, o que resulta em atividade inotrópica negativa, levando à disfunção contrátil do ventrículo esquerdo. As enzimas cardíacas alteradas dificultam ainda mais o diagnóstico da síndrome de Takotsubo. O exame padrão-ouro, que diferencia a síndrome de Takotsubo do infarto agudo do miocárdio, é a angiografia coronariana. Uma das opções na emergência é o ecocardiograma na beira do leito. Além disso, os critérios de Mayo devem ser usados para diagnosticar a síndrome de Takotsubo. É importante, para o profissional que trabalha no pronto-socorro, ter a síndrome de Takotsubo como diagnóstico diferencial na dor torácica.

Takotsubo syndrome is a stress-induced cardiomyopathy characterized by a transient left ventricular dysfunction. This dysfunction can be confused with acute myocardial infarction in the emergency room as it has similar clinical characteristics, especially chest pain. Its pathophysiology is not yet well defined, but is associated with estrogen deficiency and increased catecholamines that stimulate the coupling of cardiac beta-2 receptors, resulting in negative inotropic activity and leading to contractile dysfunction of the left ventricle. Altered cardiac enzymes make the diagnosis of Takotsubo syndrome even more difficult. The gold standard exam that will differentiate Takotsubo syndrome from acute myocardial infarction is coronary angiography. One of the options in the emergency room is bedside echocardiography. In addition, Mayo criteria should be used to diagnose Takotsubo syndrome. Professionals working in the emergency room shall have Takotsubo syndrome as a differential diagnosis in chest pain.

Systemic Inflammatory Response Syndrome Is a Major Determinant of Cardiovascular Outcome in Takotsubo Syndrome.

BACKGROUND: Recent insights have emphasized the importance of inflammatory response in takotsubo syndrome (TTS). We sought to evaluate the predictors of systemic inflammatory response syndrome (SIRS) and its impact on cardiovascular mortality after TTS.Methods and Results:The 215 TTS patients were retrospectively included between September 2008 and January 2018. SIRS was diagnosed in 96 patients (44.7%). They had lower left ventricular ejection fraction (LVEF) on admission (34.5% vs. 41.9%; P<0.001) and higher peak brain natriuretic peptide and troponin. At a median follow-up of 518 days, SIRS was associated with increased in-hospital mortality (14.6% vs. 5.0%; P=0.019), overall mortality (29.4% vs. 10.8%; P=0.002), and cardiovascular mortality (10.6% vs. 2.1%; P=0.026). A history of cancer (OR, 3.36; 95% CI: 1.54-7.31; P=0.002) and LVEF <40% at admission (OR, 2.31; 95% CI: 1.16-4.58; P=0.017) were identified as independent predictors of SIRS. On multivariate Cox regression analysis, SIRS (HR, 12.8; 95% CI: 1.58-104; P=0.017), age (HR, 1.09; 95% CI: 1.02-1.16; P=0.01), and LVEF <40% at discharge (HR, 9.88; 95% CI: 2.54-38.4; P=0.001) were independent predictors of cardiovascular death. CONCLUSIONS: SIRS was found in a large proportion of TTS patients and was associated with enhanced myocardial damage and adverse outcome in the acute phase. At long-term follow-up, SIRS remained an independent factor of cardiovascular death.

Biomarkers in patients with Takotsubo cardiomyopathy compared to patients with acute anterior ST-elevation myocardial infarction.

Background: Takotsubo cardiomyopathy (TTC) is a syndrome of acute non-coronary heart failure with similar symptoms and electrocardiograms to acute anterior ST-elevation myocardial infarction (STEMI). Little is known about the pathophysiology of TTC. We assessed admission plasma concentrations of biomarkers reflecting neuroendocrine response (copeptin, mid-regional-pro-adrenomedullin, pro-atrial-natriuretic-peptide, soluble thrombomodulin (sTM), syndecan-1) and inflammation (suppression-of-tumorigenicity 2 (ST2), high-sensitive C-reactive-protein) in TTC patients and compared to patients with acute anterior STEMI.Materials and methods: Twenty TTC patients were matched with 40 STEMI patients by age, gender and left ventricular ejection fraction. Blood was sampled upon hospital admission immediately before acute coronary angiography.Results: The groups had similar comorbidities. TTC patients had higher plasma concentrations of sTM: 7.94 (5.89;9.61) vs. 6.42 (5.50;7.82)ng/ml, p = 0.04 and ST2 (53 (32;157) vs. 45 (31;55)ng/ml, p = 0.008) and higher heart rate: 101 ([Formula: see text]33) vs. 76([Formula: see text]14)bpm, p = 0.0001, but lower concentrations of copeptin (10.4 (7.6;39) vs. 92.3 (13;197)pmol/l, p < 0.05) and troponin T (348 (98;759) vs. 1190 (261;4105)ng/l, p = 0.04).Conclusion: TTC patients had higher plasma concentrations of sTM and ST2, higher heart rate and lower copeptin and troponin T concentrations compared to acute anterior STEMI patients. This study contributes to the hypothesis that TTC patients have endothelial cell damage and are hemodynamically more stable than patients with acute anterior STEMI on admission.

Sex-dependent differences in clinical characteristics and in-hospital outcomes in patients with takotsubo syndrome.

INTRODUCTION: Takotsubo syndrome (TTS) is an acute reversible left ventricular dysfunction, which occurs mainly in postmenopausal women. OBJECTIVES: The goal of this study was to compare the course of the disease and prognoses in men and women with TTS in 2 large Polish university hospitals. PATIENTS AND METHODS: The analysis included 232 patients (211 women and 21 men) hospitalized at the 1st Chair and Department of Cardiology at the Medical University of Warsaw and at the 1st Department of Cardiology at the Medical University of Gdansk. RESULTS: Men who developed TTS were more likely to live alone than women. Physical stress triggered TTS more often in men than in women. There were no differences in the prevalence of risk factors and comorbidities, except for a higher prevalence of smoking in men. With regard to the cardiac biomarkers, both admission and peak levels of N­terminal prohormone of brain natriuretic peptide were higher in women. ST­segment depression was found more frequently in men than in women (25% vs 6.2%). Despite the same length of hospitalization, ejection fraction at discharge was lower in men than in women (50% vs 60%). In­hospital outcomes (arrhythmias, mechanical complications, cardiogenic shock, mortality rate) were similar in both groups. ß-Adrenolytics and statins were more often prescribed to women than to men (74.5% vs 52.4% and 68.3% vs 38.1%). Moreover, there was a tendency toward more frequent use of P2Y12 inhibitors in men than in women (23.8% vs 10.4%). CONCLUSIONS: Differences occurred in the clinical course of TTS between men and women. However, in­hospital outcomes were similar in both groups.

Cardiac Transplantation Using Hearts With Transient Dysfunction: Role of Takotsubo-Like Phenotype.

BACKGROUND: The impact of different types of regional wall motion abnormalities (RWMAs), including the Takotsubo syndrome-like (TTS-like) phenotype, on posttransplant outcomes when using donor hearts with transient left ventricular systolic dysfunction (LVSD) is unknown. We evaluated the prevalence, clinical characteristics, and prognostic association of different RWMAs including TTS-like hypokinesis and posttransplant outcomes when using donor hearts with transient LVSD. METHODS: From all adult (≥18 years) heart transplants in United Network of Organ Sharing between January 2007 and September 2015, we identified 472 donor hearts with improving or transient LVSD, defined as left ventricular ejection fraction ≤ 40% on initial transthoracic echocardiogram (TTE) that improved to ≥50% on follow-up TTE during donor evaluation. These improved LVSD donors were then subdivided into 3 groups based on RWMAs on the initial TTE, TTS-like (49, 10.38%), non-TTS RWMAs (74, 15.68%), and diffuse global hypokinesis (349, 73.94%), and compared for baseline characteristics and posttransplant outcomes with follow up until June 2018. RESULTS: Donors with TTS-like LVSD were older and more likely to be female. The type of RWMA on initial TTE (including TTS-like) of transient LVSD donor hearts was not associated with 1-year or 5-year posttransplant mortality. Posttransplant functional status scores of recipients (at 1 year) and donor left ventricular ejection fraction (at median follow-up of 3.6 years) improved in all 3 subgroups. Rates of stroke or pacemaker predischarge were also similar. CONCLUSIONS: In the largest analysis of transplanted donor hearts with transient LVSD, 1 in 4 had RWMAs on the initial TTE, but this was not associated with adverse posttransplant outcomes. Donor hearts with initial LVSD should be pursued irrespective of TTS-like hypokinesis or other RWMAs.

Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy.

BACKGROUND: Acute stress-induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable with that of myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. METHODS: In a multicenter study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age-, sex-, and comorbidity-matched control subjects. During the index event and at the 5-month follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging, including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched control subjects underwent investigation at a single time point. RESULTS: Subjects were predominantly middle-aged (64±14 years) women (90%). Compared with control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 milliseconds versus 10.5±0.9 milliseconds; P<0.001) and nonballooning (12.9±0.6 milliseconds versus 10.5±0.9 milliseconds; P=0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 pg/mL versus 6.5±5.8 pg/mL; P<0.001) and chemokine (C-X-C motif) ligand 1 (1903±168 pg/mL versus 1272±177 pg/mL; P=0.01) concentrations and classic CD14++CD16- monocytes (90±0.5% versus 87±0.9%; P=0.01) were also increased whereas intermediate CD14++CD16+ (5.4±0.3% versus 6.9±0.6%; P=0.01) and nonclassic CD14+CD16++ (2.7±0.3% versus 4.2±0.5%; P=0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium, although persistent elevations in serum interleukin-6 concentrations ( P=0.009) and reductions in intermediate CD14++CD16+ monocytes (5.6±0.4% versus 6.9±0.6%; P=0.01) remained. CONCLUSIONS: We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets, and an increase in systemic proinflammatory cytokines. Many of these changes persisted for at least 5 months, suggesting a low-grade chronic inflammatory state. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02897739.

Takotsubo cardiomyopathy in a young adult with transplanted heart: what happened to denervation?

This manuscript describes the first report of takotsubo cardiomyopathy in a young heart transplant recipient following angry debate. Our patient is a 21-year-old woman with cardiac transplant performed owing to right ventricular failure in congenital heart disease. Positive echocardiography with typical asymmetry of regional function, positive enzymes, and negative biopsy and angiography met the criteria for the diagnosis of takotsubo cardiomyopathy. Patient was discharged after 1 week in good clinical conditions and fully recovered cardiac function. The development of takotsubo cardiomyopathy in transplanted heart suggests that re-innervation occurs, thus representing a target for catecholamine-induced cardiac dysfunction.

Comprehensive assessment of sex hormones in Takotsubo syndrome.

BACKGROUND: The detailed pathomechanism of Takotsubo syndrome (TS) is still elusive. Due to the predominance of postmenopausal females, a potential role of sex hormones has been suggested. However, the limited available data are contradictory. The aim of this study was to comprehensively assess the role of sex hormone levels in a large cohort of TS patients. METHODS: Serum samples of 57 female TS patients and 57 female patients with myocardial infarction (MI), matched for age (±2years) and repolarization disturbances were analyzed for estradiol (E2), estrone (E1), testosterone and androstenedione using liquid chromatography-tandem mass spectrometry. RESULTS: There was no difference concerning the concentrations of E1 [pmol/l (IQR): 89.1 (62.5, 132.0) vs. 98.8 (63.3, 156.0), p=0,441], testosterone [nmol/l (IQR): 0.67 (0.46, 1.00) vs. 0.80 (0.49, 1.08), p=0.382] and androstenedione [nmol/l (IQR): 2.03 (1.57, 3.11) vs. 2.98 (1.48, 5.27), p=0.244] between female TS and MI patients. Regarding E2, the majority of patients demonstrated concentrations below the detection limit of 30pmol/l (TS: n=41/54, 75.9%; MI: n=32/53, 60.4%; p=0.078). The remaining individuals with detectable E2 concentrations did not show a significant difference between TS and MI patients [pmol/l (IQR): 40.5 (33.0, 53.3) vs. 54.1 (37.9, 60.9); p=0.20]. CONCLUSIONS: Altered sex hormone levels, especially an estradiol deficiency, could not be identified as a risk factor for TS.

Pathophysiology of Takotsubo Syndrome.

Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment-elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.

Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome.

BACKGROUND: Matrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity. METHODS AND RESULTS: In 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0-186.3) (median (interquartile range)), TTC 115.7 (94.3-137.7) and controls 80.9 (73.2-90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13-0.51) from decreased EF<50% at 0.08 (0.05-0.20), (p = 0.04) in TTC, but not in ACS. CONCLUSIONS: Even with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment.

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.

Impact of Malignancies in the Early and Late Time Course of Takotsubo Cardiomyopathy.

BACKGROUND: Although the relationship between malignancies and catecholamine-induced myocardial stunning remains largely speculative, it has been suggested that the presence of cancer may lower the threshold for stress stimuli and/or may aggravate cardiac adrenoreceptor sensitivity. We sought to investigate whether associations exist between a previous or current diagnosis of malignancy, diagnostic parameters during hospitalization and death in takotsubo. METHODS AND RESULTS: The 154 takotsubo patients were retrospectively identified between May 2008 and December 2014. Previous history of malignancy was identified in 44 patients (28.5%). Cardiac arrest was present at admission in 13 patients (8.4%). Intra-aortic balloon pump was inserted in 16 patients (10.4%). In patients with malignancy, higher B-type natriuretic peptide (BNP), leukocyte and C-reactive protein (CRP) peaks could be observed during the hospital phase. Initial impairment of left ventricular ejection fraction was negatively related to BNP, leukocyte, and CRP peaks. At a median follow-up of 364 days, all-cause death occurred in 41 patients (26.6%) and cardiac death in 12 patients (7.7%). Multivariate Cox regression analysis identified malignancy (hazard ratio 4.77 (1.02-22.17), leukocyte peak and age as independent predictors of cardiac death. Malignancy (2.62 (1.26-5.44), leukocyte peak (1.05 (1.01-1.08) and initial cardiac arrest (6.68 (2.47-18.01) were identified as independent predictors of overall mortality. CONCLUSIONS: In the present takotsubo patients, the prevalence of malignancy was high and may have affected cardiovascular outcomes through the activation of inflammatory and neurohormonal mechanisms. (Circ J 2016; 80: 2192-2198).