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          Abstract

          We would like to thank Renin Chang and his collegues for the interest they have expressed in our recently published article ‘Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks’ 1 and the eClinicalMedicine editorial team to give us the opportunity to address their comments. First, Renin Chang et al. concerned about the Neyman bias on the exclusion of patients who died within 30 days of the index date. In the present study, we conducted a 12-month follow-up study of the cohort who survived the first 30 day on the risk of cardiovascular events as well as the survival analyses. 30 days were used as the stratification and at least two visits to healthcare organizations could reduce the bias of loss of follow up and avoid reverse causality. In addition, as suggested by Renin Chang et al., we have performed a sensitivity analysis from the first day after the first occurrence of the index event. The results revealed that the risks of the cardiovascular outcomes and two composite endpoints, major adverse cardiovascular event (HR [95% CI] = 1.702 [1.667–1.738]) and any cardiovascular outcome (HR [95% CI] = 1.514 [1.496–1.533]) were similar with the risks beyond the first 30 d of infection. However, the mortality risks (HR [95% CI] = 2.691 [2.601–2.784]) were inevitably higher than former one (Figure 1 , Table 1 ). Figure 1 Incidence of outcomes among COVID-19 group compared to control subjects (after prosperity score matching). Figure 1 Table 1 Incidence of outcomes among COVID-19 group compared to control subjects (after prosperity score matching). Table 1 Outcome Hazard ratio (95%CI) Original resultsa Renew resultsb Cerebrovascular  Stroke 1.618 (1.545–1.694) 1.496 (1.446–1.548)*  TIA 1.503 (1.353–1.670) 1.451 (1.344–1.567) Arrhythmia  Atrial fibrillation and flutter 2.407 (2.296–2.523) 2.245 (2.171–2.321)*  Tachycardia 1.682 (1.626–1.740) 1.840 (1.797–1.885)*  Bradycardia 1.599 (1.521–1.681) 1.685 (1.628–1.745)*  Ventricular arrhythmias 1.600 (1.535–1.668) 1.698 (1.649–1.748)* Inflammatory heart disease  Pericarditis 1.621 (1.452–1.810) 1.512 (1.401–1.632)  Myocarditis 4.406 (2.890–6.716) 3.767 (2.835–5.007) Ischemic heart disease  Acute coronary disease 2.048 (1.752–2.393) 1.890 (1.702–2.098)  Myocardial infarction 1.979 (1.831–2.138) 1.825 (1.735–1.921)*  Ischemic cardiomyopathy 2.811 (2.477–3.190) 2.289 (2.087–2.509)  Angina 1.707 (1.545–1.885) 1.268 (1.180–1.363)* Other cardiac disorders  Heart failure 2.296 (2.200–2.396) 1.993 (1.934–2.054)*  Cardiomyopathy 2.413 (2.235–2.606) 2.119 (2.005–2.241)*  Cardiac arrest 1.751 (1.526–2.008) 1.864 (1.714–2.026)*  Cardiogenic shock 1.988 (1.599–2.473) 1.594 (1.391–1.826) Thrombotic disorders  Pulmonary embolism 2.648 (2.443–2.870) 2.842 (2.683–3.010)*  Deep vein thrombosis 1.879 (1.751–2.017) 1.949 (1.855–2.047)*  Superficial vein thrombosis 1.592 (1.442–1.756) 1.753 (1.635–1.880)* MACE 1.871 (1.816–1.927) 1.702 (1.667–1.738)* Any cardiac outcome mentioned above 1.552 (1.526–1.578) 1.514 (1.496–1.533)* Mortality 1.604 (1.510–1.703) 2.691 (2.601–2.784)* Note. TIA: Transient Ischemic Attack; MACE: Major Adverse Cardiac Event. *Proportionality (P < 0.001). a Time window was started 30 days after the first occurrence of the index event and ended 395 days after the first occurrence of the index event. b Time window was started 1 days after the first occurrence of the index event and ended 365 days after the first occurrence of the index event. Renin Chang et al. also suggested a self-matched study design. In our cohort, propensity score matching 1:1 by age at index, race, gender, socioeconomic status (SES), comorbidities, blood type, alcohol-related disorders, nicotine dependence, and body mass index (BMI) was used. Furthermore, it was well matched (Std diff <0.1). Propensity score matching has been used increasingly in retrospective analyses of clinical trial data sets, registries, observational studies, electronic medical record analyses, and more. Although the method has some limits, it attempts to adjust post hoc for recognized unbalanced factors at baseline. 2 Renin Chang et al. also refer to inaccuracies of ICD-10 on the diagnosis of the cardiovascular outcomes. We can only agree with this remark as we have noted in our article. There were a lot of population-based studies on the consequences of COVID-19 including cardiovascular outcomes by using ICD-10 as the diagnosis.3, 4, 5 Moreover,most of the cardiovascular diseases were diagnosed according to a comprehensive judgment of clinical manifestations, electrocardiogram and laboratory examinations. In addition, myocarditis that represents a category of diseases need cardiac MRI and endomyocardial biopsy to identify. 6 Thus, ICD10 maybe the proper one at present. Contributors W.J.-W. wrote the draft of the manuscript; S.I.-W. have performed data analysis; James Cheng-Chung Wei revised the manuscript critically. All authors contributed to manuscript revision, read and approved the submitted version. Declaration of interests The authors declare no competing interests.

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          Most cited references6

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          Myocarditis.

          Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study

            Background COVID-19 is a complex disease targeting many organs. Previous studies highlight COVID-19 as a probable risk factor for acute cardiovascular complications. We aimed to quantify the risk of acute myocardial infarction and ischaemic stroke associated with COVID-19 by analysing all COVID-19 cases in Sweden. Methods This self-controlled case series (SCCS) and matched cohort study was done in Sweden. The personal identification numbers of all patients with COVID-19 in Sweden from Feb 1 to Sept 14, 2020, were identified and cross-linked with national inpatient, outpatient, cancer, and cause of death registers. The controls were matched on age, sex, and county of residence in Sweden. International Classification of Diseases codes for acute myocardial infarction or ischaemic stroke were identified in causes of hospital admission for all patients with COVID-19 in the SCCS and all patients with COVID-19 and the matched control individuals in the matched cohort study. The SCCS method was used to calculate the incidence rate ratio (IRR) for first acute myocardial infarction or ischaemic stroke following COVID-19 compared with a control period. The matched cohort study was used to determine the increased risk that COVID-19 confers compared with the background population of increased acute myocardial infarction or ischaemic stroke in the first 2 weeks following COVID-19. Findings 86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2·89 (95% CI 1·51–5·55) for the first week, 2·53 (1·29–4·94) for the second week, and 1·60 (0·84–3·04) in weeks 3 and 4 following COVID-19. When day of exposure was included in the risk period, IRR was 8·44 (5·45–13·08) for the first week, 2·56 (1·31–5·01) for the second week, and 1·62 (0·85–3·09) for weeks 3 and 4 following COVID-19. The corresponding IRRs for ischaemic stroke when day of exposure was excluded from the risk period were 2·97 (1·71–5·15) in the first week, 2·80 (1·60–4·88) in the second week, and 2·10 (1·33–3·32) in weeks 3 and 4 following COVID-19; when day of exposure was included in the risk period, the IRRs were 6·18 (4·06–9·42) for the first week, 2·85 (1·64–4·97) for the second week, and 2·14 (1·36–3·38) for weeks 3 and 4 following COVID-19. In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3·41 (1·58–7·36) and for stroke was 3·63 (1·69–7·80) in the 2 weeks following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6·61 (3·56–12·20) and for ischaemic stroke was 6·74 (3·71–12·20) in the 2 weeks following COVID-19. Interpretation Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19. Funding Central ALF-funding and Base Unit ALF-Funding, Region Västerbotten, Sweden; Strategic funding during 2020 from the Department of Clinical Microbiology, Umeå University, Sweden; Stroke Research in Northern Sweden; The Laboratory for Molecular Infection Medicine Sweden.
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              SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study

              Abstract Objective To investigate the association between SARS-CoV-2 vaccination and myocarditis or myopericarditis. Design Population based cohort study. Setting Denmark. Participants 4 931 775 individuals aged 12 years or older, followed from 1 October 2020 to 5 October 2021. Main outcome measures The primary outcome, myocarditis or myopericarditis, was defined as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Follow-up time before vaccination was compared with follow-up time 0-28 days from the day of vaccination for both first and second doses, using Cox proportional hazards regression with age as an underlying timescale to estimate hazard ratios adjusted for sex, comorbidities, and other potential confounders. Results During follow-up, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male. Of 3 482 295 individuals vaccinated with BNT162b2 (Pfizer-BioNTech), 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted hazard ratio 1.34 (95% confidence interval 0.90 to 2.00); absolute rate 1.4 per 100 000 vaccinated individuals within 28 days of vaccination (95% confidence interval 1.0 to 1.8)). Adjusted hazard ratios among female participants only and male participants only were 3.73 (1.82 to 7.65) and 0.82 (0.50 to 1.34), respectively, with corresponding absolute rates of 1.3 (0.8 to 1.9) and 1.5 (1.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 1.48 (0.74 to 2.98) and the absolute rate was 1.6 (1.0 to 2.6) per 100 000 vaccinated individuals within 28 days of vaccination. Among 498 814 individuals vaccinated with mRNA-1273 (Moderna), 21 developed myocarditis or myopericarditis within 28 days from vaccination date (adjusted hazard ratio 3.92 (2.30 to 6.68); absolute rate 4.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to 6.4)). Adjusted hazard ratios among women only and men only were 6.33 (2.11 to 18.96) and 3.22 (1.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.7 to 4.8) and 6.3 (3.6 to 10.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 5.24 (2.47 to 11.12) and the absolute rate was 5.7 (3.3 to 9.3) per 100 000 vaccinated individuals within 28 days of vaccination. Conclusions Vaccination with mRNA-1273 was associated with a significantly increased risk of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased risk among women. However, the absolute rate of myocarditis or myopericarditis after SARS-CoV-2 mRNA vaccination was low, even in younger age groups. The benefits of SARS-CoV-2 mRNA vaccination should be taken into account when interpreting these findings. Larger multinational studies are needed to further investigate the risks of myocarditis or myopericarditis after vaccination within smaller subgroups.
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                Author and article information

                Journal
                eClinicalMedicine
                EClinicalMedicine
                eClinicalMedicine
                The Author(s). Published by Elsevier Ltd.
                2589-5370
                20 October 2022
                November 2022
                20 October 2022
                : 53
                : 101700
                Affiliations
                [a ]Department of Rheumatology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
                [b ]Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Science, Beijing, China
                [c ]Center for Health Data Science, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
                [d ]Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan
                [e ]Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
                [f ]Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
                [g ]Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
                Author notes
                [* ]Corresponding author at: No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung City 40201, Taiwan.
                Article
                S2589-5370(22)00430-8 101700
                10.1016/j.eclinm.2022.101700
                9583692
                36281441
                e42f0766-5dc9-4207-8eef-524136892529
                © 2022 The Author(s)

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 15 September 2022
                : 27 September 2022
                Categories
                Correspondence

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