key: cord-0730777-jwy7c9uu authors: Ahmed, S. K.; Mohamed, M. G.; Essa, R. A.; Ahmed Rashad, E. A.; Mohamed, S. A.; Khdir, A. A. title: Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: First systematic review and meta-analysis date: 2022-04-19 journal: nan DOI: 10.1101/2022.04.16.22273937 sha: d100f98c21bbbc64511a14da96b48e708129fa26 doc_id: 730777 cord_uid: jwy7c9uu Background and aims Concerns have been raised recently about takotsubo cardiomyopathy after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines. Methods From inception until March 10, 2022, a systematic literature search was conducted in PubMed and Google Scholar. The study included individuals who developed cardiac takotsubo cardiomyopathy as a result of receiving COVID-19 vaccinations, regardless of the type of vaccine or dose. Results Eight studies, including 8 cases, participated in the current systematic review. The median age was 61.6 years; 87.5% were female, while 12.5% were male. 75% of the patients received the mRNA COVID-19 vaccines, while 25% received other types. In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.2 days, and all cases recovered from their symptoms. Conclusion Takotsubo (stress) cardiomyopathy complications that are associated with COVID-19 vaccination are rare, they can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who had received a second dose of the vaccine in the last 3 days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT-proBNP. All of cases completely recovered. The coronavirus (COVID)-19 pandemic, which was caused by the severe acute respiratory Takotsubo cardiomyopathy (TCM) is a type of heart disease that is frequently triggered by strong physical and/or emotional stress. Although the pathophysiology of this condition is not fully understood, studies have suggested that it may be caused by activation of central autonomic neurons expressing oestrogen receptors, coronary vasospasm, increased sensitivity to a surge in circulating catecholamines and metabolic dysfunction [1] . Catecholamine levels have been found to be higher in TTC than in STEMI [2, 3] . TTC cases have risen from 1.5% to 7.8% as a result of the COVID-19 pandemic [4] . TTC has already been linked to a 'cytokine storm' of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa), which causes hyperinflammation in COVID-19-patients [5, 6] . Individuals who presented without COVID-19 infection or other notable risk factors may have been infected with TTC due to the psychological stress of living in a pandemic [1] . TTC is more likely to occur in people who have a history of mental illness before the outbreak of the pandemic [5, [7] [8] [9] . Moderna mRNA1273 and Pfizer BioNTech BNT1626b2 (COVID19 mRNA vaccines) induce innate immunity, cytotoxic and helper T cell responses, and in particular B cell responses [10] . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022. ; https://doi.org/10.1101/2022.04. 16.22273937 doi: medRxiv preprint Pain, erythema, swelling, fever, headache, and myalgia were the most common systemic or local reactions reported [11] . However, acute myocardial infarction, pulmonary embolism, stroke, and venous thromboembolism are all possible complications of mRNA based COVID19 vaccines [12] [13] [14] . There have been reports of takotsubo cardiomyopathy following the COVID-19 vaccination, particularly following the messenger RNA (mRNA) vaccines [1, [15] [16] [17] [18] [19] [20] [21] . We are aware of no systematic review that has been conducted specifically for COVID-19 vaccines induced stress cardiomyopathy. Given the rarity of adverse takotsubo cardiomyopathy associated with COVID19 vaccination, the majority of the peer reviewed and published papers are case reports. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines. In this study, the primary goal is to clarify the possibility of takotsubo cardiomyopathy associated with COVID-19 vaccination and to elaborate on the demographic and clinical characteristics of COVID-19 vaccinated individuals who develop takotsubo cardiomyopathy. The review follows the PRISMA 2020 guidelines for reporting systematic reviews and metaanalyses [22] . The review protocol was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022316515. Additionally, the AMSTAR-2 checklist was used to assess the quality of this review, which was found to be of high quality [23] . No ethical approval was required for this review article. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 19, 2022 2. In this review, narrative and systematic reviews, as well as papers with insufficient data, were excluded. Furthermore, articles written in languages other than English were excluded. Every step of the data extraction process from the original source was guided by PRISMA 2020, which was used to guide the process. Three independent authors (SKA, RAE, and MGM) used the Rayyan website to screen abstracts and full-text articles based on inclusion and exclusion criteria [24] . Disagreements between the three independent authors were resolved by discussion. The data extraction process was carried out using predefined forms in Microsoft Office Excel. A total of the following information was extracted from each research study: author names, year of publication, age, gender, type of COVID-19 vaccine, dose, troponin levels, days to symptoms onset, symptoms, length of hospital stay/days, ECG, LVEF < 50% or LVEF > 50%, treatment and their outcomes. We used the Joanna Briggs Institute's critical appraisal tool for case reports to evaluate all included studies [25] . Each article was evaluated independently by three authors (SKA, MGM, and RAE). . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 19, 2022 The paper evaluation disagreements were resolved either through discussion or by the first author (SKA). The results of our systematic review were evaluated using the AMSTAR 2 criteria [23] . The overall quality of our systematic review was rated "moderate" by the AMSTAR 2 tool. The data from all the articles included in this systematic review were extracted and pooled. This included (author names, year of publication, age, gender, type of COVID-19 vaccine, dose, troponin levels, days to symptoms onset, symptoms, length of hospital stay/days, ECG, LVEF <50% or LVEF >50%, treatment and their outcomes). We collected this information from the findings of eligible studies. Statistical analysis will be performed using the Statistical Package for the Social Sciences (SPSS) 25.0 software program (SPSS Inc, Chicago, IL, USA). Categorical data will be expressed as proportions (%), and numerical data will be expressed as mean ± standard deviation (SD). We pooled the results of the studies into one table. The major databases (PubMed and Google Scholar) yielded 189 articles relevant to our search criteria on March 10,2022. The references were then organized using a citation manager tool (Mendeley), and seven articles were automatically eliminated because they were duplicate. Then, a final check was performed on 182 articles to ensure that their titles, abstracts, and full texts were accurate. There were 169 articles that were rejected because they did not meet the requirements to be included. Aside from that, 13 articles were submitted for retrieval, with five of them being rejected because they did not meet our inclusion criteria. Finally, our systematic review included only 8 articles (Fig 1) . Case report details are shown in ( Table 1) . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022 In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 ± 2.19 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.20 ± 3.96 days, and all cases recovered from their symptoms. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022 Vaccines are one of the most effective treatments to combat COVID19, saving millions of lives each year. However, the ideal option is a vaccine that is effective, safe, and does not cause serious side effects. Due to the lack of a viable and approved COVID19 treatment, competition for vaccine development began and the 259 COVID19 vaccine project began on November 11, 2020. The rapid development of vaccines raises the potential for vaccine-related safety concerns. Many countries are developing vaccines to protect the population after the COVID 19 pandemic [27] . Many vaccines were available earlier than planned due to urgent needs. New technologies are also helping to develop much more effective vaccines. However, those potential adverse effects must be considered [28] . The COVID-19 pandemic has seen the largest global vaccination program in history with over 11.3 billion vaccination doses administered from December 2020 to December 2021. With increasing populations being vaccinated daily, we are seeing an increase in reports of associated side effects. The most common side effects reported are pain, swelling, and redness around the injection site. Systemic effects such as fever, fatigue, myalgia, and headache can also occur in around one in four. A higher prevalence of these systemic effects has been noted in women, individuals [29] . Moreover, severe side effects have been reported and are under current monitoring: thrombocytopenic thrombosis, anaphylaxis, Bell's palsy, and capillary leak syndrome [30] . Although the pathophysiology of takotsubo syndrome after Covid19 vaccination is not well established, the proposed hypotheses are Stunning changes in ischemia-induced myocardium secondary to microvessel or multi vascular vasospasm; Direct myocardial injury due to surge currents. Animal studies modelling the octopus trap showed high serum epinephrine levels and high apical-basal levels. Pleiotropic b2-adrenergic receptor gradient in the context of apical myocardial depression, consistent with typical echocardiographic findings of takotsubo syndrome [31] . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022. ; https://doi.org/10.1101/2022.04.16.22273937 doi: medRxiv preprint Also, the mechanism behind this is a controversy for which the decisive mechanism has not yet been identified. Some authors develop cytokine storms, cause systemic inflammatory response syndrome (SIRS), cause broken heart syndrome, and, despite aggressive treatment, cause heart failure that is difficult to withdraw from the ventilator [32] . Acute emotional or physical stressors induce increased levels and bioavailability of catecholamines and cortisol in the blood that mediate multiple pathways Pericardial coronary artery spasm, microvascular dysfunction, and direct muscle cell injury, are all Key findings of TTS. References to the essential role of catecholamines in TTS include, for example high plasma levels in affected patients and subsequent induction of TTS-like disease, administration of epinephrine or norepinephrine [33] . While producing catecholamines positive inotropic effects of Gs-coupling proteins, they activate 2 adrenergic receptors. The heart tissue is different if high levels of epinephrine (but no epinephrine) are present once secreted, the 2ad receptor switches from Gs to Gi coupling. This switch to Gi is predominant at the apex of heart tissue and is intended to be limited in the degree of myocardial injury during catecholamine surge induced by cardiotoxic activation of 1 and 2 adrenergic receptors Gs pathway [34] . The release of several inflammatory cytokines such as interleukin6 and tumor necrosis factor in the cytokine storm accompanying during a few days' post vaccinations is multifactorial and mediated by direct effects of cytokine storm and microvascular dysfunction. It is not clear, however, why a high incidence of TTS has been reported during a specific time post-vaccine. Moreover, TTS cases have been reported also following COVID19 vaccinations. It should be noted that disease-induced stress and catecholamine surge may also aggravate these pathways, and such an overlap in mechanisms seems reasonable. Elevated levels of catecholamines have been in aortic roots and coronary sinuses in patients with COVID 19 vaccine and TTS [35, 36] . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. [15] . Patients with symptoms of acute coronary syndrome such as chest pain or dyspnea including changes in the electrocardiogram and release of troponin, etc. Myocardial enzymes and in the absence of serious obstructive coronary artery disease meet the Takotsubo syndrome Mayo Clinic criteria [37] . All patients underwent coronary angiography to eliminate significant obstruction coronary heart disease. Demographics; Symptoms at the time of presentation; ECG, and transthoracic echocardiographic findings; cardiac enzymes, including creatine, Troponin I, and creatine phosphokinase were recorded during hospitalization. In the selected cases, magnetic resonance imaging (CMRI) was performed [38] . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022. ; https://doi.org/10.1101/2022.04.16.22273937 doi: medRxiv preprint murmur of Levine 2/6 at the second left sternal border, clear lung sounds, and no leg edema. On admission, electrocardiography (ECG) newly revealed atrial fibrillation with a normal axis, negative T-waves in I, aVL, and V3-6, and a prolonged QTc interval of 495 ms [17] . The clinical results of patients ultimately, Takotsubo cardiomyopathy is not benign the condition is associated with a 5.6% per patient year death 9.9% per patient risk of serious cardiac adverse events. This index of possible ChAdOx1nCov19 Cardiomyopathy indicates the need for vigilance when the assessment of acute coronary syndrome after ChAdOx1 nCov19 vaccination [2] . Supportive cardiac care-optimal management of myocardial injury post-COVID 19 vaccines has not yet been established. Therefore, for the management of patients with myocardial disorders, including patients with suspected TTS, support measures such as angiotensin receptor inhibitor and angiotensin converting enzyme (ACE) inhibitor. Includes, treatment of arrhythmias, and avoidance of heart toxins, alternatively, angiotensin receptor blockers (ARBs), which are used to reduce ejection fraction and treat heart failure [41] . Medical management for Takotsubo cardiomyopathy is based on the presence or absence of hemodynamic stability and other complications. Patients have complications such as acute heart failure without LV outflow tract obstruction should receive diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers, and beta-blockers [42] . However, in contrast to the mortality benefit realized in other types of heart failure, therapy with beta-blockers and ACE inhibitors do not discuss significant survival benefits in patients with Takotsubo cardiomyopathy. In addition, only ACE inhibitors were shown to help prevent the recurrence of takotsubo induced cardiomyopathy [43] . The role of aldosterone antagonists has not been well-established, but they have been hypothesized to be potentially cardioprotective due to anticatecholamine effects [44] . . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022 Guidelines on the duration of treatment are lacking, but patients are typically treated for 4 weeks until improvement of LVEF is seen. There are no studies that have evaluated the role of goaldirected medical therapy on atypical variant takotsubo [18] . Patients with takotsubo syndrome generally have a good prognosis. An outcomes study assessing trends of hospitalized patients with takotsubo cardiomyopathy demonstrated an in-hospital mortality rate of 1.3% [95% confidence interval (CI) 1.1-1.6], hospital discharge rate to the home of 73.6% (95% CI 72.7-74.6), and 1-year mortality of 6.9% (95% CI 6.4-7.5) [45] . Consistent with the prior case experiences of post-DCCV takotsubo syndrome, and was discharged home without the need for post-acute care services. Repeat TTE at 2 months showed complete global and regional restoration of LV function [46] . We found more than half of the patients length of hospital stay Mean ± SD were 10.20 ± 3.96 days and all of them recovered without any complications. Her follow-up CMR showed resolving myocardial oedema in the apex and septum. Repeat TTE showed normal left ventricular (LV) systolic function and resolution of previously noted wall motion abnormalities [47] . While takotsubo cardiomyopathy after covid-19 vaccine pathogenesis is incompletely understood, catecholamine excess mediated myocardial stunning is favoured, with excess release precipitated by a physical or emotional triggering event. Primarily seen in ageing women, the diagnosis of takotsubo of presentation and triggers, characteristic imaging and exclusion of acute coronary . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022. ; https://doi.org/10.1101/2022.04.16.22273937 doi: medRxiv preprint syndrome and myocarditis. Cytokine storm has been described with an excessive and uncontrolled inflammatory response, and there is a feedback loop between catecholamines and cytokines [48] . We recognize that our systematic review has some limitations, which include; we only involved case reports and case series, due to the limited numbers of original studies published on the takotsubo cardiomyopathy after taken COVID-19 vaccines so the results should be interpreted with some caution. Moreover, we do not have any data about the previous history of COVID-19, which may affect the results, since COVID-19 can also cause cardiac complications. There is no conflict to be declared. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022 This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. All relevant data are within the manuscript and its supporting information files. Not commissioned, externally peer-reviewed Acknowledgments Not applicable . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 19, 2022 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 19, 2022 Discharged Discharged Discharged Discharged Discharged Discharged Discharged Discharged . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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