Purpose: The aim of this study was to evaluate right ventricle (RV) dyssynchrony and its relation with mortality using speckle tracking echocardiography (STE) in patients with acute inferior myocardial infarction (IMI). Methods: One hundred and fifty-eight consecutive patients with acute IMI treated with primary percutaneous coronary intervention and 44 healthy subjects were included. RV myocardial involvement (RVMI) was defined as an elevation greater than 1 mm in V1 or V4R and/or the presence of a culprit lesion at the proximal portion of the first RV marginal branch after reviewing coronary angiography. Patients were followed for three years to determine the cardiovascular mortality. Results: Overall, 70 patients with IMI had RVMI. IMI patients had significantly higher RV peak systolic longitudinal strain dyssynchrony (PLSSD) index, lower peak longitudinal systolic strain (PLSS), longer time to PLSS and time to PLSS differences compared to healthy controls while the patients with RVMI had significantly worse values compared to patients without RVMI and healthy controls. Twenty-seven patients (17.1%) died within two years. RVMI was more prevalent in mortality group and they had significantly higher RV PSSD index, whereas they had lower RV free wall PLSS and longer time to PLSS differences. ROC analysis revealed that a RV PLSSD index > 65 ms predicted mortality with a sensitivity of 88.9% and specificity of 71.8,% in IMI patients. Conclusions:Intra- and interventricular dyssynhcrony may develop in patients with acute IMI, especially in those with RV involvement, which might have a negative effect on the prognosis of these patients.
Despite advancement in therapy and management, left ventricular thrombus (LVT) after anterior myocardial infarction (MI) is sporadically encountered and remains associated with a very high risk of major cardiovascular events and mortality. Cardiac magnetic resonance (CMR) is considered the gold standard technique for LVT detection, but it is a time consuming and expensive test not available in all centers, especially when repeated exams are necessary. Transthoracic echocardiography represents a useful tool to screen for LVT and to identify predictors of high risk of developing LVT. The advances in ultrasound technology and the use of contrast agents may potentially help clinicians to identify LVT and the use of sequential echocardiography for each patient with acute MI complicated by LVT may provide an opportunity to quantify regression and its correlation with outcomes to tailor the management of these patients. Hence, this narrative review focuses on the added value of echocardiographic-guided LVT management in patients with recent anterior MI to reduce mortality and morbidity excess related to LVT based on current evidence.
Background: Although diastolic dysfunction is common among patients treated with cancer therapy, no clear evidence has been shown that it predicts systolic dysfunction. This study evaluated the correlation of longitudinal diastolic strain time (Dst) with the routine echocardiography diastolic parameters and to estimated its role in the early detection of cardiotoxicity among patients with active breast cancer. Methods: Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling all adult patients referred to the cardio-oncology clinic. All patients with breast cancer, planned for Doxorubicin therapy were included. Echocardiography, including Global longitudinal systolic strain (GLS) and Dst, was assessed at baseline before chemotherapy (T1), during Doxorubicin therapy (T2) and after the completion of Doxorubicin therapy (T3). Cardiotoxicity were determined by GLS relative reduction of ≥15%. Dst was assessed as the time measured (ms) of the myocardium lengthening during diastole. =diastolic time (ms) measured. Results: Among 69 patients, 67 (97.1%) were females with a mean age 52±13years. Diastolic strain timeDst measurement was significantly associated with the standard routine diastolic parameters. Significant GLS reduction was observed in 10 (20%) patients at T3 . Both in a univariate and a multivariate analyses the change in Ds basal time from T1 to T2 emerged to be significantly associated with GLS reduction at T3 (p<0.04). Conclusions: Among breast cancer patients, Dst time showed high correlation to standard the routine diastolic echocardiography parameters. Relative reductionChange in Ds basal time emerged associated with clinically significant systolic dysfunction as measured by GLS reduction.
Background: Right ventricular failure (RVF) following Left Ventricular Assist Device (LVAD) implantation is associated with worse outcomes. Prediction and early identification of RVF with speckle-tracking echocardiography (STE) has been proposed. Methods: We queried multiple databases for articles reporting on pre-operative/intraoperative global longitudinal strain (GLS) and free-wall strain (FWS) in LVAD recipients. We performed a systematic review and meta-analysis of published literature. The standard mean difference (SMD) in GLS and FWS in patients with and without RVF postoperatively was pooled using random effects model. Results: Fifteen studies, with a total of 967 LVAD recipients were included. There was statistically significant difference in GLS among patients who did and did not develop RVF; SMD= -3.09 (95% CI: -4.62 to -1.57; p-value <0.0001). There was significant difference in FWS between two groups; SMD: -2.75 (95% CI: -3.72 to -1.79; p-value <0.0001). Upon subgroup analysis of imaging modality, transthoracic echocardiography (TTE)-derived GLS and FWS remained predictive for RVF with SMD of -3.97 (95% CI: -5.40 to -2.54; p-value <0.001) and -3.05 (95% CI: -4.11 to -1.99; p-value <0.001), respectively. However, there was no significant difference between RVF and non-RVF groups upon using transesophageal echocardiography (TEE) to assess GLS and FWS. Conclusion: GLS and FWS assessment of the RV by STE is a useful tool to predict postoperative RVF in LVAD recipients. While the predictive role of TTE was robust, the TEE-derived measures seemed to be less predictive. Future studies need to specify the strain cut-off value that can predict the adverse outcome of RVF
Our case was initially admitted with presumptive diagnosis of Non-ST elevated myocardial infarction in congestive heart failure and was later found to have large left atrial (LA) mass. Apart from complete echocardiography study, we took help of multimodality imaging to better characterise this LA mass.However we did not have a confirmed diagnosis. Cardiac surgery was performed and surprisingly revealed large LA mass with pockets of fresh blood inside LA. Pathological specimen confirmed the presence of hematoma ruling out other atrial neoplasms. Though contrast echocardiography and cardiac magnetic resonance imaging were closest to intra-operative diagnoses, In the absence of any pre-disposing factors, final diagnosis was made at surgery and histopathological diagnosis.
Diagnosis of anomalous origin of the right subclavian artery (AORSA) from the right pulmonary artery (RPA) is usually made using CT or invasive angiography. We report a patient diagnosed using transthoracic echocardiography (TTE). A newborn girl prenatally known to have d-TGA presented with cyanosis sparing the right hemithorax and arm. Oxygen saturations on the right hand were persistently higher than on the right ear and other extremities. Repeat TTE using a modified echocardiographic imaging plane allowed for full visualization of the entire subclavian artery course, revealing AORSA from RPA. We discuss further the approach to echocardiographic diagnosis and surgical implications.
Objective: To evaluate the role of peak atrial longitudinal strain (PALS) through speckle tracking 2D echocardiography for the assessment of structural and functional left atrial (LA) remodelling in a type 2 diabetes mellitus (T2DM) population. Methodology: We conducted a cross-sectional study during a 9-month period. Were included T2DM adults aged 18 and above. The variables assessed during the study include age and gender of participants, diabetes characteristics, cardiovascular risk factors, clinical anthropometric and haemodynamic parameters, standard echocardiographic parameters, volume-derived LA functions and 2D PALS. Results: We included a total of 102 patients. The mean age was 58±11.7 years and the M/F sex ratio was 1:1.5. Coexistent arterial hypertension (HTN) was observed in more than half (59.8%) of the population sample. Mean 2D PALS was 29.2±8.9% with 58.8% (95% CI:50.0–68.6) of subjects having a reduced LA strain (i.e.<32%). Reservoir and pump functions were the most altered LA volumetric phasic functions. Mean indexed LA maximal volume was 22.2±6.8 ml/m². There was a significant association between abnormal PALS and age, Body mass index (BMI), indexed LA volume, E/E’ ratio, LA active ejection fraction (pump function) and LA expansion index (reservoir function). Conclusion: LA remodelling is a recurrent condition in adult T2DM Cameroonians. The Reservoir and pump LA functions were the most affected. Assessment of LA global strain allows early detection of LA remodelling with comparison to LA size standard analyses. Age, BMI, indexed LA volume, E/E’ ratio, reservoir and pump LA functions were associated to 2D LA global strain impairment.
Introduction: The right ventricle (RV) strain measured by speckle tracking (RVS) is a novel method of assessing RV function. We compared RVS to RV fractional area change (FAC%), tricuspid annular peak systolic excursion (TAPSE) and Doppler tissue imaging-derived peak systolic velocity (S’) in the assessment of right ventricular (RV) systolic function measured using cardiac magnetic resonance imaging (MRI). Methods: We enrolled consecutive patients who underwent cardiac MRI between Jan 2012- Dec 2017 and a transthoracic echocardiogram (TTE) within 1 month of the MRI with no interval event. Baseline clinical characteristics and MRI parameters were extracted from chart review. Echocardiographic parameters were measured prospectively. TTE parameters including RVS, TAPSE, S’ and FAC% were tested for accuracy to identify impaired RV EF (EF <45% & <30%) using receiver operator curves. Results: The study cohort included 500 patients with mean age 55 yr ± 18 and right ventricular systolic pressure 33.7 ± 13.6 mmHg. The area under ROC for RVS was 0.69 (95% CI 0.63 – 0.75) and 0.78 (95% CI 0.70 – 0.88) to predict RVEF <45% & RVEF <30% respectively. The RV FAC % had second highest accuracy of predicting RVEF among all the TTE parameters tested in study. Conclusion: Right ventricular strain is the most accurate echocardiographic method to detect impaired right ventricular systolic function when using MRI as the gold standard.
We present a late presentation of saddle pulmonary embolism and thrombus-in-transit straddle the patent foramen on patient who successfully recovered from severe acute respiratory syndrome coronavirus-2 (COVID-19) pneumonia. Seven days post-discharge (i.e. 28 days after initial COVID-19 symptom onset), she was readmitted to hospital for severe dyspnea. Computer tomography angiogram and echocardiography confirmed the diagnosis. Severe pro-inflammatory and pro-thrombotic states with endothelial involvement have been reported associated with severe COVID-19 infection. However the duration of hypercoagulable state has not yet known. This case highlights the risk of thromboembolic phenomena for prolonged periods of times after recovering from COVID-19 pneumonia.
Correlation between AHI and right ventricular diastolic function in patients with obstructive sleep apnea syndromeJunfang Li 1, MD, PhD, Changhong Lu2, MD, Zhibin Wang 1, MD, PhD1, Department of Echocardiography, Qingdao University Affiliated Hospital, Qingdao, 266001,China2, Department of Heart Center, Qingdao Fuwai Cardiovascular Hospital, Qingdao, 266034,ChinaCorresponding author: Zhibin Wang, Department of Echocardiography, Qingdao UniversityAffiliated Hospital, No. 16, Jiangsu Road, Qingdao 266001, China
Aim Doppler echocardiography has become the standard imaging modality for diastolic function and provide pathophysiological insight into systolic and diastolic heart failure. In this study we aimed to obtain normal echocardiographic Doppler parameters of healthy Turkish population. Methods Among 31 collaborating institutions from all regions of Turkey, 1154 healthy volunteers were enrolled in this study. Predefined protocols were used for all participants during echocardiographic examination and The American Society of Echocardiography and European Association of Cardiovascular Imaging recommendations were used for echocardiographic Doppler measurements. Results A total of 967 healthy participants were enrolled in this study after applying exclusion criteria. Echocardiographic examination was obtained from all subjects following predefined protocols. Mitral E wave velocity and E/A ratio were higher in females and decreased progressively in advancing ages. E wave deceleration time and A wave velocity were increased with aging. Assessment of tissue Doppler velocities showed that left ventricular lateral e’, septal e’ and septal s’ were higher in younger subjects and in females. E/e’ ratio was increased progressively with advancing decades. Right ventricular e’and s’ were decreased but a’ was increased with increasing age. Septal e’ lower than 8 cm/s was 1.9% in the fifth decade and 13.7% in ages older than 50-years. The E/e’ ratio greater than 15 (and also 13) was not found. Conclusion This study, for the first time, provides echocardiographic reference ranges for normal cardiac Doppler data in healthy Turkish population which will be useful in routine clinical practice as well as in future clinical trials.
B-LINES IN COVID-19: “UNSPECIFICITY” IS NOT “MEANINGLESS”Luigi Vetrugno1,2 MD, Prof, Tiziana Bove1,2 MD, Prof, Daniele Orso1 MD, Federico Barbariol2 MD, Flavio Bassi2 MD, Enrico Boero3 MD, Giovanni Ferrari4 MD, Robert Kong5MD, FRCA, EDIC,1Department of Medicine, University of Udine, ItalyAnesthesia and Intensive Care ClinicVia Colugna n° 50, 33100 Udine, Italy2University-Hospital of Udine, ItalyDepartment of Anesthesia and Intensive CareP.le S. Maria della. Misericordia n° 15, 33100 Udine, Italy3Anesthesia and Intensive Care, San Giovanni Bosco Hospital, Torino, Italy4SC Pneumologia ad Indirizzo Semi Intensivo, Azienda Ospedaliera Ordine Mauriziano. Largo Turati 62 – Torino, Italy5 Cardiac Anaesthesia & Intensive Care, Brighton & Sussex University Hospital, Brighton BN2 5BE United KingdomShort title: lung ultrasound and B-lines*Corresponding author:Prof. Luigi Vetrugno, MDDepartment of Medicine, University of Udine, ItalyAnesthesia and Intensive Care ClinicVia Colugna n° 50, 33100 Udine, ItalyPhone: +39 0432 559509Fax: +39 0432 559502Financial Support and Sponsorship: None.Conflict of Interest: Luigi Vetrugno received travel support for Congress Lecture by Cook Medical.The other authors declare no conflict of interest.Key works: Lung Ultrasound; interstitial syndrome, COVID-19, B-lines.Authors’ contributions LV and DO concept, design and drafting the manuscript. TB, FB, EB, FB, GF critical revision of the manuscript for important intellectual content. RK critical review and editing the manuscript. All authors read and approved the final manuscript.We thank Prof. Trovato and Dr Sperandeo for commenting on our article.1 We agree with them that lung ultrasound (LU) imaging is useful and our aim was to provide readers with a succinct overview of how LU was used in the care of COVID-19 patients at two centres in Italy.2 The frequent finding in COVID-19 patients of lung consolidation at the inferior and basal regions means that one of the limitations of LU, which is to perform a complete assessment of the periphery of the lungs, is mitigated, as affected regions are not obscured by the scapula. Other authors have shown that in COVID-19 patients, LU provided results similar to those of computed tomography (CT) of the lung and superior to those of standard chest x-rays.3-5 Therefore, LU provides clinicians with another mode of lung imaging that can be performed non-invasively and without the logistic challenges of obtaining CT lung scan in these patients, as is well-known to centers who have been faced with a large caseload.6 As stated in our article, we have not identified an LU finding that is pathognomonic of COVID-19.1-7 However, the presence of B lines in several different clinical situations does not decrease their significance. In medicine, many signs are frequent in various diseases, like fever, but this is not a good reason to underestimate or not consider them at all. Furthermore, emerging ultrasound image analysis based on artificial intelligence and deep learning has the potential to further enhance the utility of LU.8-9 Although caution is needed in terms of exaggerating the power of LU, we hope it will continue to be used widely after the pandemic.ReferencesSperandeo M, Trovato G. Usefulness of lung ultrasound imaging in Covid-19 pneumonia: the persisting need of safety and evidences. Echocardiography. in press (ECHO-2020-0386)Vetrugno L, Bove T, Orso D, et al. Our Italian experience using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with COVID-19. Echocardiography. 2020;37:625‐627. doi:10.1111/echo.14664Huang Y, Wang S, Liu Y. A Preliminary Study on the Ultrasonic Manifestations of Peripulmonary Lesions of Non-Critical Novel Coronavirus Pneumonia (COVID-19). SSRN. 2020. doi: 10.21203/rs.2.24369/v1Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7:4. doi: 10.1186/s40779-020-0233-6Convissar D, Gibson LE, Berra L, Bittner EA, Chang MG. Application of Lung Ultrasound during the COVID-19 Pandemic: A Narrative Review [published online ahead of print, 2020 Apr 30]. Anesth Analg. 2020;10.1213/ANE.0000000000004929. doi:10.1213/ANE.0000000000004929Wang E, Mei W, Shang Y, et al. Chinese Association of Anesthesiologists Expert Consensus on the Use of Perioperative Ultrasound in Coronavirus Disease 2019 Patients [published online ahead of print, 2020 Apr 10]. J Cardiothorac Vasc Anesth. 2020;S1053-0770(20)30325-6. doi:10.1053/j.jvca.2020.04.002Vetrugno L, Bove T, Orso D, Bassi F, Boero E, Ferrari G. Lung Ultrasound and the COVID-19 ”Pattern”: Not All That Glitters Today Is Gold Tomorrow [published online ahead of print, 2020 May 8]. J Ultrasound Med. 2020;10.1002/jum.15327. doi:10.1002/jum.15327Corradi F, Brusasco C, Vezzani A, et al. Computer-aided quantitative ultrasonography for detection of pulmonary edema in mechanically ventilated cardiac surgery patients. Chest 150:640‐651, 2016 doi:10.1016/j.chest.2016.04.013Gullett J, Donnelly JP, Sinert R, et al. Interobserver agreement in the evaluation of B-lines using bedside ultrasound. J Crit Care. 2015;30:1395-1399 doi:10.1016/j.jcrc.2015.08.021
Objective:Identification of patients who are nonresponders to cardiac resynchronization therapy (CRT) with the use of simple and objective parameters may be helpful in tailoring treatment. The aim of this study is to investigate whether E/(Ea×Sa) could be a predictor of CRT nonresponders (E=early diastolic transmitral velocity, Ea=early diastolic mitral annular velocity, Sa=systolic mitral annular velocity). Methods:In total, 53 heart failure patients were evaluated for this study, and 33 patients were included according to the study criteria. Before and six months after CRT-D(CRT with a defibrillator) implantation, E, Ea, and Sa were determined at the medial and lateral mitral annular sites, and the average values were obtained. E/(Ea×Sa) was calculated (medial, lateral, average). The patients were followed for six months to monitor their CRT response. A responder was defined as a patient with a reduction in end-systolic volume of <15% and an increase in six-minute walking distance of 50 meters. Results:At a six-month follow-up, 24(72.7%) of the 33 patients responded to CRT. At the six-month follow-up, in the responder group, the E/Ea ratio, lateral mitral, and average E/(Ea×Sa) indices were significantly reduced (p<0.01 for all). The baseline lateral mitral, medial mitral, and average E/(Ea×Sa) indices were significantly lower in the responder group than in the nonresponder group (p≤0.01 for all). The ROC analysis showed that all the E/(Ea×Sa) indices predict the CRT nonresponder patients. The AUC values were 0.89(lateral E/(Ea×Sa)), 0.85(average E/(Ea×Sa)), and 0.77(medial E/(Ea×Sa))(p≤0.01 for all). Conclusion:We found that the E/(Ea×Sa) index is a novel predictor of CRT nonresponder patients.
We present a case of a 66-year-old male with dyspnea and bilateral lower-extremity edema. Pericardiotomy and biopsy were performed and reported malignant mesothelioma. Primary pericardial mesothelioma is a highly malignant tumor that has unfavorable prognosis, and is extremely rare, even among heart tumors. In our case, despite the large amount of pericardial effusion of the first echocardiography, the infiltrated like pericardium was still detected. In addition, cytology after pericardiocentesis reported suspicion of malignancy, which followed by pericardiotomy and biopsy, lead to our timely diagnosis.
We report a case of a 17-year-old healthy male presenting with multisystem hyperinflammatory shock temporally associated with COVID-19. Cardiac involvement was suspected based on evidence of significant cardiac injury (elevated cardiac biomarkers, electrocardiographic and echocardiographic abnormalities). Cardiac magnetic resonance imaging was performed demonstrating global biventricular systolic dysfunction, as well as a small area of T2 hyperintensity and mid wall late gadolinium enhancement. This case discusses the varied cardiac involvement in pediatric patients with COVID-19 infection and highlights that cardiac injury is not just limited to hyperinflammatory syndrome related global dysfunction but a more focal myocarditis can also be seen.
Diastolic dysfunction (DD) is reported to affect up to 35% of the adult general population. The consequence of progressive DD is heart failure with preserved ejection fraction (HFpEF). Coronary microvascular dysfunction (CMD) has been suggested as one of the pathologic mechanisms leading to HFpEF. We investigated whether there was an association between coronary microvascular function and echocardiographic indices of left ventricular diastolic function in patients with chest pain and unobstructed coronary arteries (CPUCA). This retrospective observational study recruited patients referred to cardiology clinics assessment of chest pain who subsequently underwent assessment via CT coronary angiogram (CTA). Coronary microvascular dysfunction was determined by myocardial blood flow reserve (MBFR; <2.0) using myocardial contrast echocardiography. Echocardiographic indices of diastolic function (septal mitral annular e’; septal mitral annular E/e’) were measured from baseline transthoracic echocardiogram. 149 patients (52% men) with a mean age 59.7(9.5) years were recruited. Mean (standard deviation) MBFR was 2.2 (0.51). 37% (55/149) had MBFR<2.0. Median [interquartile range] septal mitral annular e’ velocity and septal mitral annular E/e’ were 7.6 cm/s [6.2, 8.9] and 9.5 [7.5, 10.8] respectively. Univariate regression analysis showed only age was a significant predictor of increasing septal mitral annular E/e’ (=+0.20 95% CI 0.13, +0.28, p<0.001) but not MBFR. Multivariable analysis also showed no association between these septal mitral annular E/e’ and MBFR after adjustment for cardiovascular risk factors. There was no relationship found between echocardiographic indices of left ventricular diastolic function and coronary microvascular function.
To the Editor:We enjoyed reading the case, authored by Janus and Hoit, of a 67-year-old woman with a subarachnoid hemorrhage (SAH) who presented with three different variants of takotsubo (TT).[i] We congratulate the authors on their interesting contribution to the literature. We would like to share some comments and questions on the chronology and management of the events between the first two episodes, which occurred a few days apart. Although fascinating, this is not the first case of TT with a rapidly evolving pattern. We previously described a case of mid-ventricular takotsubo which replaced apical ballooning in 6 hours.[ii] A recent meta-analysis showed that almost 80% of TT recurrences exhibit a ballooning pattern different from the first presentation.[iii] In this regard, regional cardiac sympathetic innervation remodeling or denervation could hypothetically justify why the same territory is usually spared from further relapses. Even though images were not provided, the authors stated that “echocardiographic wall motion abnormalities quickly resolved after each acute stressor”. One could therefore argue that this was not a case of multiple TT variants during the same episode, as noted by Madias,iii but rather an example of early recurrences. Additionally, if cardiac innervation remodeling were responsible for the different locations of the ballooning, we believe that the change in pattern would have taken longer to manifest. This would not support the observation of two distinct ballooning patterns emerging within days, let alone hours.i, ii In this case, a short-term change from the mid-ventricular to apical pattern could be reasonably explained by different β adrenergic-receptor (β-AR) subtype downregulation. We know that norepinephrine can downregulate β1-AR after a few hours. Beta1-ARs are markedly lower on biopsied patients with acute TT compared to healthy controls,[iv] whilst in the same study β2-ARs expression—which is predominant in the apical and mid-ventricular segments and thought to be involved in typical takotsubo pathogenesis[v]—was equivalent to normal. Thus, the sequence of events could be interpreted as a relative local β2 prevalence due to dynamic β1 downregulation (β1:β2 mismatch), following a base:mid-ventricle, and ultimately a mid-ventricle:apex progression. What do the authors think about this theory? Is it possible that multi-faceted presentations might simply be under-recognized? Should this be the case, how do they think we could better understand this phenomenon in a noninvasive fashion? Could dobutamine stress echocardiography have utility to identify areas of β-AR downregulation and sympathetic denervation? It would also be interesting to know more about the patient’s medical therapy. Did she receive nonselective β-blockers, such as labetalol or carvedilol, usually prescribed after SAH? If so, this might indicate that β-blockers do not prevent recurrences,[vi] but rather create a maladaptive imbalance in regional β1:β2 distribution favoring early relapse(s), as this case suggests.References[i] Janus SE, Hoit BD. The three faces of takotsubo cardiomyopathy in a single patient. Echocardiography. 2020 Jan;37(1):135-138. doi: 10.1111/echo.14560. Epub 2019 Dec 16.[ii] Casavecchia G, Zicchino S, Gravina M, et al. Fast 'wandering' Takotsubo syndrome: atypical mixed evolution from apical to mid-ventricular ballooning. Future Cardiol. 2017 Nov;13(6):529-532. doi: 10.2217/fca-2017-0018. Epub 2017 Oct 12.[iii] Madias JE. Comparison of the first episode with the first recurrent episode of takotsubo syndrome in 128 patients from the world literature: Pathophysiologic connotations. Int J Cardiol. 2020 Mar 3. pii: S0167-5273(20)30215-1. doi: 10.1016/j.ijcard.2020.03.003.[iv] Nakano T, Onoue K, Nakada Y, et al. Alteration of β-Adrenoceptor Signaling in Left Ventricle of Acute Phase Takotsubo Syndrome: a Human Study. Sci Rep 8, 12731 (2018). https://doi.org/10.1038/s41598-018-31034-z.[v] Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012 Aug 7;126(6):697-706. doi: 10.1161/CIRCULATIONAHA.112.111591. Epub 2012 Jun 25.[vi] Santoro F, Ieva R, Musaico F, et al. Lack of efficacy of drug therapy in preventing takotsubo cardiomyopathy recurrence: a meta-analysis. Clin Cardiol. 2014 Jul;37(7):434-9. doi: 10.1002/clc.22280. Epub 2014 Apr 3.