Cardiac Safety of COVID-19 Vaccines: A Longitudinal Study of Health Checkup Subjects Using Multi-Modal Imaging

Cardiac Safety of COVID-19 Vaccines: A Longitudinal Study of Health Checkup Subjects Using Multi-Modal Imaging | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cardiac Safety of COVID-19 Vaccines: A Longitudinal Study of Health Checkup Subjects Using Multi-Modal Imaging Mayuko Sorimachi, Osamu Manabe, Kazuya Shizukuishi, Hiroshi Shibata, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6901350/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The aim of this study was to assess myocardial metabolic activity and cardiac function in asymptomatic health checkup subjects before and after vaccination COVID-19 vaccination. Materials and methods We retrospectively analyzed clinical records of 67 asymptomatic subjects who underwent whole-body FDG PET/CT before and after COVID-19 vaccination. Cardiac metabolic activity was assessed using myocardial standardized uptake value (SUVmax). Echocardiography and cardiac MRI, including cine-based strain analysis, were used to evaluate cardiac function. The Wilcoxon signed-rank test and Bland-Altman plots were applied to assess changes between pre- and post-vaccination data. Results No significant differences in myocardial FDG uptake (SUVmax: 3.29 [IQR: 2.84–6.45] vs. 3.21 [IQR: 2.76–7.25], P = 0.63) was observed. Similarly, echocardiographic parameters, including LVEF, LVEDV, and LVESV, remained unchanged. MRI-based circumferential strain also showed no significant alterations (-21.27 ± 3.63 vs. -21.90 ± 3.60, P = 0.088). Conclusions This study, the first to systematically evaluate myocardial FDG uptake alongside MRI strain analysis in the same subjects pre- and post-vaccination, demonstrates no significant impact of COVID-19 vaccination on myocardial metabolic activity or cardiac function. These findings support the cardiac safety of COVID-19 vaccination and provide a robust basis for future research in broader populations. positron emission tomography fluorodeoxyglucose COVID-19 vaccine ejection fraction circumferential strain Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has significantly impacted global health, with widespread vaccination emerging as a primary strategy to reduce infection rates and prevent severe illness 1 . COVID-19 vaccines have been effective in mitigating the impact of the virus 2 ; however, understanding their broader effects on health remains essential. Common side effects include localized pain at the injection site, headache, joint and muscle pain, fatigue, chills, and fever, which are generally mild and transient. However, rare but severe adverse reactions have also been reported, including shock, anaphylaxis, myocarditis, and pericarditis. Among these, the potential impact on cardiac health is particularly notable, as myocarditis and pericarditis, although rare, are serious conditions that require careful monitoring and further investigation to ensure the safety and well-being of vaccine recipients. 3 , 4 . In imaging studies, 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is instrumental in assessing metabolic activity, with FDG uptake in the myocardium being of particular interest. FDG is physiologically accumulated in myocardial tissue, reflecting glucose metabolism; however, increased FDG uptake may also indicate pathological conditions such as ischemia or inflammation 5 . This dual capacity of FDG to reveal both physiological and pathological myocardial activity highlights its potential as a sensitive marker for detecting subclinical myocardial inflammation or ischemic changes that might emerge post-vaccination. Cardiac magnetic resonance imaging (MRI), particularly cine MRI, is a valuable tool for cardiac function assessment due to its high spatial and temporal resolution. Strain analysis derived from cine MRI images enables precise quantification of myocardial deformation, providing detailed insights into early, subclinical cardiac dysfunction that might not be detectable with conventional metrics 6 . Nakahara et al. conducted a study comparing myocardial FDG uptake in asymptomatic COVID-19-vaccinated and nonvaccinated individuals, finding increased FDG uptake in vaccinated subjects 7 . A key limitation of their study, however, is its cross-sectional design, which compares different groups rather than evaluating changes within the same individuals before and after vaccination. This approach introduces variability, limiting the ability to attribute changes in myocardial FDG uptake specifically to vaccination. Our study addresses this limitation by assessing both myocardial FDG uptake and cardiac function, using strain analysis from cine MRI, in the same asymptomatic subjects before and after COVID-19 vaccination. This within-subject design enables us to more accurately detect subtle metabolic and functional changes attributable to vaccination. Combining FDG PET/CT with MRI-based strain analysis provides a comprehensive assessment of early cardiac effects, offering insights that could enhance monitoring protocols and vaccine safety recommendations, particularly for individuals with preexisting cardiac risk. To date, no studies have systematically evaluated myocardial FDG uptake alongside, echocardiography and strain analysis using MRI in the same asymptomatic health checkup subjects before and after COVID-19 vaccination. This research uniquely focuses on examining the same subjects pre- and post-vaccination, providing critical insights into potential cardiac effects attributable to vaccination. By assessing changes in myocardial FDG uptake and cardiac function using cine MRI-based strain analysis and FDG PET/CT imaging, this study aims to identify whether vaccination is associated with detectable alterations in myocardial strain or metabolic activity. Materials and methods Patients This study retrospectively reviewed the clinical records of subjects who underwent whole-body FDG PET/CT between September 2021 and March 2022 as after vaccination PET/CT results. We included subjects with a documented history of two or three COVID-19 vaccinations. Their characteristics, including age, gender, height, body weight, blood pressure, heart rate, and fasting plasma glucose (FPG) levels on the same day as the PET/CT, were obtained from electronic medical records. In total 96 patients were initially considered as inclusion. We excluded patients without vaccine information (n = 5), without PET/CT study before vaccination (n = 17), with data before PET/CT scanner update (before Jan/31/2017) (n = 5), with surgery within 6 months (n = 1), or with low cardiac function (echocardiography: EF < 50%) (n = 1) (Fig. 1 ). This study was approved by the Institutional Review Board, which waived the requirement for written informed consent. PET/CT acquisition protocol PET/CT imaging was performed using a Discovery IQ scanner (GE Healthcare, Japan), which integrates a helical 16-slice CT scanner with a bismuth germanium oxide (BGO) scintillator detector PET scanner. All participants fasted for at least 12 hours before the scan, and fasting blood glucose (FBG) levels were measured prior to FDG administration. An intravenous dose of approximately 2.5 MBq/kg of FDG was administered with the subjects at rest. A low-dose CT scan was conducted first for attenuation correction, using parameters of Auto mAs, 120 kV tube voltage, 3.75 mm slice thickness, and 3.26 mm increments. Whole-body PET imaging was then performed, covering the region from the head to the thighs, approximately one hour after FDG injection, with a scan time of 3 minutes per bed position. The scan duration and coverage were adjusted based on the scanner's capabilities and the patient's condition. PET scanning was conducted with a fixed axial field of view (500 × 500 mm). Data were reconstructed into an image matrix of 192 × 192 pixels (pixel size: 2.60 × 2.60 mm) using Fourier rebinning and time-of-flight list-mode ordered subsets expectation maximization, with a PET slice thickness of 3.75 mm. Both PET and CT images were acquired with the subjects in a supine position during free breathing. MRI acquisition protocol Cardiac MRI was performed using an Ingenia CX 3.0T scanner (Philips, Japan) with the patient in a supine position during breath-holding to minimize motion artifacts. The imaging parameters were optimized according to the scanner's capabilities and the patient's condition. Standard electrocardiographic (ECG) gating was utilized to synchronize image acquisition with the cardiac cycle. Multi-plane localizer scans were first acquired to ensure accurate planning and positioning of the cardiac imaging planes. Cine imaging was then performed using steady-state free precession (SSFP) sequences in the standard short-axis view. The typical acquisition parameters for cine imaging included a repetition time (TR) of 3.3 ms, an echo time (TE) of 1.65 ms, a flip angle of 50°, a slice thickness of 10 mm with a 10 mm interslice gap, a matrix size of 128 × 128, and a field of view (FOV) of 380 mm × 380 mm. PET/CT imaging analysis Two nuclear medicine physicians (MS and OM), blinded to clinical information, imaging reports, and each other's interpretations, independently reviewed the FDG PET/CT images. Following the method of previous studies, cardiac FDG uptake was visually assessed and scored semi-quantitatively (score 0–3) 7 . Figure 2 gives representative cases of each score (Fig. 2 ). Intra-examiner reproducibility was assessed after a 5-month interval by one physician (MS). Subsequently, an experienced nuclear medicine physician (OM) conducted a detailed review of the PET images and measured the maximum standardized uptake value (SUVmax) of the myocardium to evaluate glucose metabolic activity. Additionally, cardiac metabolic volume (CMV) and cardiac metabolic activity (CMA) were measured. Following previous studies, CMV is determined by assessing myocardial FDG uptake relative to blood pool uptake, which serves as a reference threshold 8 , 9 . The CMV represents the volume of myocardial tissue with FDG uptake, thus highlighting areas with potentially increased metabolic activity. CMA is calculated by multiplying the CMV (the volume of myocardium above the SUV threshold) by the mean standardized uptake value (SUVmean) within this volume. Echocardiography An echocardiographic examination was performed by an experienced cardiologist or sonographers, and reviewed their findings without knowledge of the PET data. Left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were measured from apical 2-chamber and 4-chamber views using the biplane disk-summation method according to American Society of Echocardiography Committee recommendations. MRI cine imaging analysis Circumferential strain (CS) was estimated from cine images using feature tracking with Ziostation 2 and REVORAS (Ziosoft, Inc., Tokyo, Japan), which automatically defined the left ventricular region of interest. Statistical analyses Continuous variables are presented as medians with interquartile ranges (IQR), while categorical variables are presented as absolute counts with percentages. The Wilcoxon signed-rank test was used to analyze continuous variables, and Fisher’s exact test was applied for comparisons of categorical data. Kappa statistics were calculated to assess intra- and inter- observer agreement in FDG PET/CT image interpretation. Reproducibility of semi-quantitative visual scores were assessed by the linearly weighted Cohen κ coefficient. Repeatability and reproducibility of myocardial SUVmax was assessed by Bland-Altman plot and Spearman correlation coefficient. FDG uptake and MRI-derived parameters before and after vaccination were assessed using Bland-Altman plots to evaluate agreement. Statistical significance was defined as P < 0.05. All data analyses were performed using JMP version 17.1.0 (SAS Institute, Cary, NC). Results Characteristics of the subjects This study included 67 subjects with both pre- and post-vaccination FDG PET/CT results available (mean age 61.9 years, 42 male). Patient characteristics are summarized in Table 1. There were no significant changes in weight (65.4 [IQR, 56.4–72.2] vs. 65.0 [IQR, 56.3–72.7] kg, P = 0.68) n or blood pressure, including systolic (120 [IQR, 110–134] vs. 121 [IQR, 108–133] mmHg, P = 0.82) and diastolic measurements (75.0 [IQR, 66.0–81.0] vs. 75.0 [IQR, 66.5–81.0] mmHg, P = 0.51), before and after vaccination. Plasma glucose levels also remained unchanged (97.2 ± 19.2 vs. 97.2 ± 21.4, P = 0.83). FDG PET/CT findings The median interval between FDG PET/CT and vaccination was 3 months. There was no significant difference in FBG levels between the two PET/CT scans (92 [IQR, 84–104] vs. 94 [IQR, 84–105] mg/dl, P = 0.83). For the visual assessment, the correlation of intra-examiner measurements after a 5-month interval was high (before vaccination: R = 0.99, P < 0.001; after vaccination: R = 0.96, P < 0.001). The Spearman’s correlation coefficients assessing reproducibility were R = 1.00 (P < 0.001) before vaccination and R = 0.99 (P < 0.001) after vaccination as reproducibility between two examiners. Intra-examiner reproducibility of SUVmax after 5 months was shown to be weighted κ = 0.85 ([95% CI 0.76–0.93], P < 0.001) before vaccination and weighted κ = 0.95 ([95% CI 0.90-1.00], P < 0.001) after vaccination. Reproducibility between the two examiners was weighted κ = 0.74 ([95% CI 0.65–0.83], P < 0.001) before vaccination and κ = 0.77 ([95% CI 0.68–0.86], P < 0.001) after vaccination. Visual assessment was not significantly changed between two scans (Mann-Whitney U test, P = 0.77) (Fig. 3 ). Myocardial SUVmax did not significantly change before and after vaccination (3.29 [IQR, 2.84–6.45] vs. 3.21 [IQR, 2.76–7.25], P = 0.63) (Table 2, Fig. 4 A). No significant changes were observed when analyzed separately by gender. For females, SUVmax was 3.28 [IQR, 2.79–8.54] before vaccination and 4.06 [IQR, 2.64–10.17] after vaccination (P = 0.57). Similarly, for males, SUVmax was 3.32 [IQR, 2.84–5.99] before vaccination and 3.16 [IQR, 2.76–5.08] after vaccination (P = 0.33). CMV (2.34 [IQR, 0-112.51] vs. 0.57 [IQR, 0-93.8] mL, P = 0.81) and CMA (5.78 [IQR, 0-454.83] vs. 1.71 [IQR, 0-392.48] mL, P = 0.94) also showed no significant differences (Table 2, Fig. 4 B, 4 C). Figure 5 presents typical examples of cases with decreased uptake and unchanged uptake after COVID-19 vaccination (Fig. 5 ). Interval analysis Myocardial FDG uptake was analyzed based on the interval between vaccination and the PET/CT examination. Subjects were divided into 2 groups according to the interval; (a) less than 4 months (N = 37, 1.78 ± 0.93 months) and (b) 4 months or longer (N = 30, 5.57 ± 1.36 months). Difference of SUVmax values before and after vaccine were assessed at each group. No significant differences in SUVmax were observed in either group; (a) 3.29 [2.74–8.96] vs. 3.28 [2.89–5.93], P = 0.76, and (b) 3.36 [2.79–9.49] vs. 3.16 [2.76–5.06], P = 0.22 (Fig. 6 ). Echocardiography findings Echocardiography data from 63 patients were available. There were no significant changes in LVEF (67.0 [62.0–72.0] vs. 68.0 [62.0–72.0] %, P = 0.72), LVEDV (92.5 [IQR, 78.6-107.5] vs. 87.7 [IQR, 78.6-107.5] mL, P = 0.46), or LVESV (30.7 ± 10.3 vs. 29.6 [22.3–35.0] mL, P = 0.55) before and after vaccination (Table 2, Fig. 7 A). MRI findings Cardiac MRI data before and after vaccination were available for 49 out of 67 patients. All post-vaccination MRI scans were performed within 6 days before or after the corresponding PET/CT scans. Circumferential strain (CS) showed no significant difference before and after vaccination (-21.27 ± 3.63 vs. -21.90 ± 3.60, P = 0.088) (Table 2, Fig. 7 B). Discussion This study represents the first to systematically evaluate myocardial FDG uptake alongside, echocardiography and strain analysis using MRI in the same asymptomatic health checkup individuals before and after COVID-19 vaccination. By focusing on the same subjects pre- and post-vaccination, we were able to provide a unique and precise assessment of potential cardiac effects attributable to vaccination. Our findings demonstrated no significant changes in myocardial FDG uptake between the pre- and post-vaccination states, suggesting that vaccination does not cause detectable alterations in myocardial metabolic activity. Similarly, cardiac function, as assessed by echocardiography and MRI—including key parameters such as LVEF, LVEDV, LVESV, and circumferential strain—showed no significant differences. Our study yielded findings that differ from those of previous research 7 . Earlier studies reported increased myocardial FDG uptake in vaccinated patients compared to non-vaccinated patients, suggesting a potential inflammatory response in the myocardium following COVID-19 vaccination 7 . The discrepancy between our findings and those of previous studies may be explained by several factors. First, prior studies primarily utilized a cross-sectional design, comparing vaccinated individuals with non-vaccinated individuals, rather than evaluating longitudinal changes within the same subjects. This approach could introduce variability due to interindividual differences. In contrast, our study analyzed FDG uptake in the same individuals before and after vaccination, thereby minimizing interindividual variability. This within-subject analysis showed no significant differences in myocardial FDG uptake between the two scans. Furthermore, subgroup analyses stratified by sex yielded consistent results, with no significant changes in FDG uptake observed before and after vaccination. In our study, we also measured volume-based parameters such as Cardiac Metabolic Volume (CMV) and Cardiac Metabolic Activity (CMA), which had not been evaluated in previous research. SUVmax, which assesses only the maximum uptake at a single point, is susceptible to noise and has limitations, particularly when myocardial uptake is lower than that of the blood pool, making it difficult to determine the appropriate area for analysis. However, volume-based parameters provide a more robust assessment by integrating both the extent and intensity of FDG uptake (ref). This offers a measure of the overall metabolic activity within the myocardium, enabling a more comprehensive evaluation of myocardial health and potential pathological changes. These findings suggest that, in our cohort, COVID-19 vaccination did not result in a detectable increase in myocardial metabolic activity. Second, differences in FDG PET/CT protocols, fasting conditions, or study populations may also account for variations in findings. In our study, the subjects were individuals undergoing health checkups, ensuring that the pre-examination preparation was consistent across all cases. Furthermore, the interval between vaccination and FDG PET/CT imaging may influence the results, as inflammatory responses might be transient or vary based on individual immune reactions. El-Sayed H. Ibrahim et al. reported that strain parameters were significantly reduced in patients with myocarditis or suspected myocarditis caused by COVID-19 infection 10 . In contrast, a prospective cohort study by Ming-Yen Ng et al. found no significant changes in myocardial imaging parameters, including global native T1, T2, extracellular volume, left and right ventricular EF, global longitudinal strain, and late gadolinium enhancement, after COVID-19 vaccination 11 . Similarly, the echocardiography and MRI analyses in our study showed no significant differences in myocardial functional parameters before and after vaccination. This aligns with our findings that cardiac function remained unchanged post-vaccination in our cohort. The absence of significant changes in both FDG uptake and myocardial strain suggests that COVID-19 vaccination does not have a measurable impact on myocardial metabolic activity or functional parameters in asymptomatic individuals. These results provide additional evidence supporting the cardiac safety of the vaccine, particularly in the context of routine FDG PET/CT and MRI evaluations in a low-risk population. The primary limitation of this study is the relatively small sample size, which may affect the generalizability of our findings. However, the study’s strength lies in its within-subject design, allowing for the assessment of each individual’s myocardial FDG uptake and strain parameters both before and after vaccination. This design minimizes variability and provides a more reliable evaluation of potential changes attributable to the vaccine, lending significance to our results despite the limited sample size. Further research with larger, more diverse populations is needed to validate these findings and investigate whether factors such as vaccine type, dosage, or individual susceptibility might influence the myocardial metabolic response post-vaccination. In conclusion, our study, which uniquely evaluated the same asymptomatic health checkup subjects before and after COVID-19 vaccination, demonstrated that vaccination does not adversely impact myocardial metabolic activity or cardiac function. These findings highlight the robustness of our approach and provide valuable evidence supporting the cardiac safety of COVID-19 vaccination in this cohort. Declarations Ethical Statement: Approval from our institutional ethics review board was obtained, and the requirement for informed consent was waived for this retrospective study. Author contributions: MS and OM conceived and designed the study. The material preparation, data collection, and analyses were performed by MS and OM. MS and OM wrote the first draft of this manuscript. All authors commented on the previous versions of the manuscript. All the authors have read and approved the final version of the manuscript. Data availability : The datasets used and/or analyzed in the current study are available from the corresponding author upon request. Acknowledgments: None. References Crook H, Raza S, Nowell J, et al. Long covid-mechanisms, risk factors, and management. BMJ . 2021;374:n1648. Gao P, Liu J, Liu M. Effect of COVID-19 Vaccines on Reducing the Risk of Long COVID in the Real World: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health . 2022;19. Florek K, Sokolski M. Myocarditis Associated with COVID-19 Vaccination. Vaccines (Basel) . 2024;12. Choi Y, Lee JS, Choe YJ, et al. Myocarditis and Pericarditis are Temporally Associated with BNT162b2 COVID-19 Vaccine in Adolescents: A Systematic Review and Meta-analysis. Pediatr Cardiol . 2024. Manabe O, Kikuchi T, Scholte AJHA, et al. Radiopharmaceutical tracers for cardiac imaging. J Nucl Cardiol . 2018;25:1204-1236. Pan J, Ng SM, Neubauer S, et al. Phenotyping heart failure by cardiac magnetic resonance imaging of cardiac macro- and microscopic structure: state of the art review. Eur Heart J Cardiovasc Imaging . 2023;24:1302-1317. Nakahara T, Iwabuchi Y, Miyazawa R, et al. Assessment of Myocardial. Radiology . 2023;308:e230743. Manabe O, Ohira H, Hirata K, et al. Use of. Eur J Nucl Med Mol Imaging . 2019;46:1240-1247. Hirata K, Kobayashi K, Wong KP, et al. A semi-automated technique determining the liver standardized uptake value reference for tumor delineation in FDG PET-CT. PLoS One . 2014;9:e105682. Ibrahim EH, Rubenstein J, Sosa A, et al. Myocardial Strain for the Differentiation of Myocardial Involvement in the Post-Acute Sequelae of COVID-19-A Multiparametric Cardiac MRI Study. Tomography . 2024;10:331-348. Ng MY, Tam CH, Lee YP, et al. Post-COVID-19 vaccination myocarditis: a prospective cohort study pre and post vaccination using cardiovascular magnetic resonance. J Cardiovasc Magn Reson . 2023;25:74. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6901350","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":472347680,"identity":"c69edee9-d8ce-44f6-a726-09f8b31eb02c","order_by":0,"name":"Mayuko Sorimachi","email":"","orcid":"","institution":"Dokkyo Medical University Saitama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mayuko","middleName":"","lastName":"Sorimachi","suffix":""},{"id":472347681,"identity":"29216a60-71dd-4f5f-8375-48ed1d0a60b1","order_by":1,"name":"Osamu Manabe","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYLACxgYGOcZmBjaGBDD3AHFajEnXktjAANRCFOAXO/zswc8dNunN7czPHjxgsJNnYDyL3xrJ2Wnmhr1n0nIbm9nMDRIYkg0bGM4l4NVicDvBTIK37TBQCw+bRAIDM1D5GQMCWtK/Sf5t+5/OCNFST4yWHDNp3rYDCVAthwlrkZydUyYteybZEOgXM4kEg+OGbYT8wi+dvk3y7Q47ecP+w88kf1RUy/NLEAgxOACGFMidwNiROEOcDgZ5hMU9RGoZBaNgFIyCkQIAjN1BvmOndZgAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8518-8441","institution":"Jichi Medical University Saitama Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Osamu","middleName":"","lastName":"Manabe","suffix":""},{"id":472347682,"identity":"6da2b2d1-2f8b-451c-aee2-da0b32602c50","order_by":2,"name":"Kazuya Shizukuishi","email":"","orcid":"","institution":"Saitama Central Clinic","correspondingAuthor":false,"prefix":"","firstName":"Kazuya","middleName":"","lastName":"Shizukuishi","suffix":""},{"id":472347683,"identity":"71611276-8f4c-49f8-b89b-5c40cdc8fc15","order_by":3,"name":"Hiroshi Shibata","email":"","orcid":"","institution":"Saitama Central Clinic","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Shibata","suffix":""},{"id":472347684,"identity":"99b032fb-2729-4a43-ab39-5aefbd63169a","order_by":4,"name":"Kazunori Kubota","email":"","orcid":"","institution":"Dokkyo Medical University Saitama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kazunori","middleName":"","lastName":"Kubota","suffix":""},{"id":472347685,"identity":"3625dc4b-b8e8-412d-a992-e91cd1b47aea","order_by":5,"name":"Noriko Oyama-Manabe","email":"","orcid":"","institution":"Jichi Medical University Saitama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"","lastName":"Oyama-Manabe","suffix":""}],"badges":[],"createdAt":"2025-06-16 04:00:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6901350/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6901350/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85363624,"identity":"3336cde2-577b-4d71-96d4-750f946c24bd","added_by":"auto","created_at":"2025-06-25 06:24:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40365,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow diagram of study criteria.\u003c/p\u003e\n\u003cp\u003eA total of 96 patients underwent PET/CT imaging after vaccination, and 67 patients met the study criteria. Of those, 49 patients underwent cardiac MRI, and 63 patients underwent echocardiography before and after vaccination.\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/ceb06ac37a4068efa0c8f388.png"},{"id":85363628,"identity":"7c5a73cd-c36e-437d-bb6f-b1d28ce6e790","added_by":"auto","created_at":"2025-06-25 06:24:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":81767,"visible":true,"origin":"","legend":"\u003cp\u003eThe representative images of visual myocardial score are shown. The gray scale of images was fixed from SUV = 0.00 to SUV = 6.00. The myocardial uptake was evaluated by the score of zero to three.\u003c/p\u003e","description":"","filename":"Figure21.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/05857158b8a425110f42ee26.png"},{"id":85364429,"identity":"1452987a-5cc5-4178-8902-4eeba3adb6da","added_by":"auto","created_at":"2025-06-25 06:32:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":17748,"visible":true,"origin":"","legend":"\u003cp\u003eVisual assessment of myocardial FDG uptake before and after vaccination.\u003c/p\u003e\n\u003cp\u003eThe myocardial FDG uptake, assessed using a visual scoring system (score range: 0–3), showed no significant difference between groups (Mann-Whitney U test, P = 0.77).\u003c/p\u003e","description":"","filename":"Figure31.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/5c796c0b49507f64e2a30af5.png"},{"id":85364426,"identity":"05db5442-94dd-4628-a970-8d237dc1f5ee","added_by":"auto","created_at":"2025-06-25 06:32:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":60802,"visible":true,"origin":"","legend":"\u003cp\u003eSemi-quantitative assessment of myocardial FDG uptake before and after vaccination.\u003c/p\u003e\n\u003cp\u003eA. Bland-Altman Plot for Myocardial FDG Uptake (SUVmax), B. for Cardiac Metabolic Volume (CMV), and C. for Cardiac Metabolic Activity (CMA). No significant difference was observed in myocardial FDG uptake, represented by SUVmax (3.29 [IQR: 2.84–6.45] vs. 3.21 [IQR: 2.76–7.25], P = 0.63), CMV (IQR: 2.34 [0-112.51] vs. 0.57 [0-93.8], P = 0.81), and CMA (IQR: 5.78 [0-454.83] vs. 1.71 [0-392.48], P = 0.94). The horizontal line indicates the mean difference between the two measurements, while the dashed lines represent the upper and lower limits of agreement (mean ± 1.96 × standard deviation).\u003c/p\u003e","description":"","filename":"Figure41.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/4ca69e5f886b5650991cbf63.png"},{"id":85364433,"identity":"4ea3ee83-abb6-463e-a496-fbff8eb45ed9","added_by":"auto","created_at":"2025-06-25 06:32:30","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":196855,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative cases\u003c/p\u003e\n\u003cp\u003eFDG PET/CT images of maximum intensity projection (MIP) image (above) and axial myocardial image (below). A-1 Image of a male in his 50s before vaccination. Myocardial visual score was 2 and myocardial uptake was SUVmax = 7.35, CMV = 223.5 mL and CMA = 852.9 mL. A-2 Image after vaccination (14 months from A). Visual score was 0 and myocardial uptake decreased to SUVmax = 2.73, CMV = 0.0 mL and CMA = 0.0 mL. B-1 Image of a female in her 40s before vaccination. Myocardial visual score was 0 and myocardial uptake was SUVmax = 2.19, CMV = 0.0 mL and CMA = 0.0 mL. B-2 Image after vaccination (12 months from C). Left axilla uptake appeared due to the vaccination (black arrow). Visual score remained 0 and myocardial uptake was SUVmax = 2.26, CMV = 0.0 mL and CMA = 0.0 mL.\u003c/p\u003e","description":"","filename":"Figure51.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/6a2cabf56b43ba9ac3e68791.png"},{"id":85363606,"identity":"fc0b13fe-c7d7-4141-8612-4b0551a80677","added_by":"auto","created_at":"2025-06-25 06:24:29","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":90269,"visible":true,"origin":"","legend":"\u003cp\u003eInterval-Based Comparison of Myocardial FDG Uptake Before and After Vaccination\u003c/p\u003e\n\u003cp\u003eBland-Altman plots illustrating changes in myocardial SUVmax before and after vaccination in two groups: (a) \u0026lt; 4 months (N = 37, 3.29 [2.74–8.96] vs. 3.28 [2.89–5.93], P = 0.76), and (b) ≥ 4 months (N = 30, 3.36 [2.79–9.49] vs. 3.16 [2.76–5.06], P = 0.22). The solid line indicates the mean difference, while dashed lines represent the limits of agreement (mean ± 1.96 × SD). No significant differences were observed in either group.\u003c/p\u003e","description":"","filename":"Figure61.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/612c11953f020b3226fb5491.png"},{"id":85363613,"identity":"b7f98b35-eba4-4c01-8970-192c9cefa9d7","added_by":"auto","created_at":"2025-06-25 06:24:29","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":92080,"visible":true,"origin":"","legend":"\u003cp\u003eEvaluation of cardiac function before and after vaccination\u003c/p\u003e\n\u003cp\u003eA. Bland-Altman Plot for LVEF (Left Ventricular Ejection Fraction) from Echocardiography, and B. Circumferential Strain (CS) from Cardiac MRI: No significant differences were noted in LVEF measurements (67.0 [62.0–72.0] vs. 68.0 [62.0–72.0] %, P = 0.72) or in CS values (-21.27 ± 3.63 vs. -21.90 ± 3.60, P = 0.088).\u003c/p\u003e","description":"","filename":"Figure71.png","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/294b226bc577320b96f0420b.png"},{"id":85812977,"identity":"29f11358-d864-481c-9d20-483afd56f38c","added_by":"auto","created_at":"2025-07-02 04:22:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1235812,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6901350/v1/bb65bc9a-9b7f-4ca2-9181-9c0f3b612b71.pdf"}],"financialInterests":"","formattedTitle":"Cardiac Safety of COVID-19 Vaccines: A Longitudinal Study of Health Checkup Subjects Using Multi-Modal Imaging","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has significantly impacted global health, with widespread vaccination emerging as a primary strategy to reduce infection rates and prevent severe illness \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. COVID-19 vaccines have been effective in mitigating the impact of the virus \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e; however, understanding their broader effects on health remains essential. Common side effects include localized pain at the injection site, headache, joint and muscle pain, fatigue, chills, and fever, which are generally mild and transient. However, rare but severe adverse reactions have also been reported, including shock, anaphylaxis, myocarditis, and pericarditis. Among these, the potential impact on cardiac health is particularly notable, as myocarditis and pericarditis, although rare, are serious conditions that require careful monitoring and further investigation to ensure the safety and well-being of vaccine recipients. \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn imaging studies, \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is instrumental in assessing metabolic activity, with FDG uptake in the myocardium being of particular interest. FDG is physiologically accumulated in myocardial tissue, reflecting glucose metabolism; however, increased FDG uptake may also indicate pathological conditions such as ischemia or inflammation \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. This dual capacity of FDG to reveal both physiological and pathological myocardial activity highlights its potential as a sensitive marker for detecting subclinical myocardial inflammation or ischemic changes that might emerge post-vaccination.\u003c/p\u003e \u003cp\u003eCardiac magnetic resonance imaging (MRI), particularly cine MRI, is a valuable tool for cardiac function assessment due to its high spatial and temporal resolution. Strain analysis derived from cine MRI images enables precise quantification of myocardial deformation, providing detailed insights into early, subclinical cardiac dysfunction that might not be detectable with conventional metrics \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNakahara et al. conducted a study comparing myocardial FDG uptake in asymptomatic COVID-19-vaccinated and nonvaccinated individuals, finding increased FDG uptake in vaccinated subjects \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. A key limitation of their study, however, is its cross-sectional design, which compares different groups rather than evaluating changes within the same individuals before and after vaccination. This approach introduces variability, limiting the ability to attribute changes in myocardial FDG uptake specifically to vaccination.\u003c/p\u003e \u003cp\u003eOur study addresses this limitation by assessing both myocardial FDG uptake and cardiac function, using strain analysis from cine MRI, in the same asymptomatic subjects before and after COVID-19 vaccination. This within-subject design enables us to more accurately detect subtle metabolic and functional changes attributable to vaccination. Combining FDG PET/CT with MRI-based strain analysis provides a comprehensive assessment of early cardiac effects, offering insights that could enhance monitoring protocols and vaccine safety recommendations, particularly for individuals with preexisting cardiac risk.\u003c/p\u003e \u003cp\u003eTo date, no studies have systematically evaluated myocardial FDG uptake alongside, echocardiography and strain analysis using MRI in the same asymptomatic health checkup subjects before and after COVID-19 vaccination. This research uniquely focuses on examining the same subjects pre- and post-vaccination, providing critical insights into potential cardiac effects attributable to vaccination. By assessing changes in myocardial FDG uptake and cardiac function using cine MRI-based strain analysis and FDG PET/CT imaging, this study aims to identify whether vaccination is associated with detectable alterations in myocardial strain or metabolic activity.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis study retrospectively reviewed the clinical records of subjects who underwent whole-body FDG PET/CT between September 2021 and March 2022 as after vaccination PET/CT results. We included subjects with a documented history of two or three COVID-19 vaccinations. Their characteristics, including age, gender, height, body weight, blood pressure, heart rate, and fasting plasma glucose (FPG) levels on the same day as the PET/CT, were obtained from electronic medical records. In total 96 patients were initially considered as inclusion. We excluded patients without vaccine information (n\u0026thinsp;=\u0026thinsp;5), without PET/CT study before vaccination (n\u0026thinsp;=\u0026thinsp;17), with data before PET/CT scanner update (before Jan/31/2017) (n\u0026thinsp;=\u0026thinsp;5), with surgery within 6 months (n\u0026thinsp;=\u0026thinsp;1), or with low cardiac function (echocardiography: EF\u0026thinsp;\u0026lt;\u0026thinsp;50%) (n\u0026thinsp;=\u0026thinsp;1) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This study was approved by the Institutional Review Board, which waived the requirement for written informed consent.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePET/CT acquisition protocol\u003c/h3\u003e\n\u003cp\u003ePET/CT imaging was performed using a Discovery IQ scanner (GE Healthcare, Japan), which integrates a helical 16-slice CT scanner with a bismuth germanium oxide (BGO) scintillator detector PET scanner. All participants fasted for at least 12 hours before the scan, and fasting blood glucose (FBG) levels were measured prior to FDG administration. An intravenous dose of approximately 2.5 MBq/kg of FDG was administered with the subjects at rest.\u003c/p\u003e \u003cp\u003eA low-dose CT scan was conducted first for attenuation correction, using parameters of Auto mAs, 120 kV tube voltage, 3.75 mm slice thickness, and 3.26 mm increments. Whole-body PET imaging was then performed, covering the region from the head to the thighs, approximately one hour after FDG injection, with a scan time of 3 minutes per bed position. The scan duration and coverage were adjusted based on the scanner's capabilities and the patient's condition.\u003c/p\u003e \u003cp\u003ePET scanning was conducted with a fixed axial field of view (500 \u0026times; 500 mm). Data were reconstructed into an image matrix of 192 \u0026times; 192 pixels (pixel size: 2.60 \u0026times; 2.60 mm) using Fourier rebinning and time-of-flight list-mode ordered subsets expectation maximization, with a PET slice thickness of 3.75 mm. Both PET and CT images were acquired with the subjects in a supine position during free breathing.\u003c/p\u003e\n\u003ch3\u003eMRI acquisition protocol\u003c/h3\u003e\n\u003cp\u003eCardiac MRI was performed using an Ingenia CX 3.0T scanner (Philips, Japan) with the patient in a supine position during breath-holding to minimize motion artifacts. The imaging parameters were optimized according to the scanner's capabilities and the patient's condition. Standard electrocardiographic (ECG) gating was utilized to synchronize image acquisition with the cardiac cycle.\u003c/p\u003e \u003cp\u003eMulti-plane localizer scans were first acquired to ensure accurate planning and positioning of the cardiac imaging planes. Cine imaging was then performed using steady-state free precession (SSFP) sequences in the standard short-axis view. The typical acquisition parameters for cine imaging included a repetition time (TR) of 3.3 ms, an echo time (TE) of 1.65 ms, a flip angle of 50\u0026deg;, a slice thickness of 10 mm with a 10 mm interslice gap, a matrix size of 128 \u0026times; 128, and a field of view (FOV) of 380 mm \u0026times; 380 mm.\u003c/p\u003e\n\u003ch3\u003ePET/CT imaging analysis\u003c/h3\u003e\n\u003cp\u003eTwo nuclear medicine physicians (MS and OM), blinded to clinical information, imaging reports, and each other's interpretations, independently reviewed the FDG PET/CT images. Following the method of previous studies, cardiac FDG uptake was visually assessed and scored semi-quantitatively (score 0\u0026ndash;3) \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e gives representative cases of each score (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIntra-examiner reproducibility was assessed after a 5-month interval by one physician (MS). Subsequently, an experienced nuclear medicine physician (OM) conducted a detailed review of the PET images and measured the maximum standardized uptake value (SUVmax) of the myocardium to evaluate glucose metabolic activity. Additionally, cardiac metabolic volume (CMV) and cardiac metabolic activity (CMA) were measured. Following previous studies, CMV is determined by assessing myocardial FDG uptake relative to blood pool uptake, which serves as a reference threshold \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The CMV represents the volume of myocardial tissue with FDG uptake, thus highlighting areas with potentially increased metabolic activity. CMA is calculated by multiplying the CMV (the volume of myocardium above the SUV threshold) by the mean standardized uptake value (SUVmean) within this volume.\u003c/p\u003e\n\u003ch3\u003eEchocardiography\u003c/h3\u003e\n\u003cp\u003eAn echocardiographic examination was performed by an experienced cardiologist or sonographers, and reviewed their findings without knowledge of the PET data. Left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were measured from apical 2-chamber and 4-chamber views using the biplane disk-summation method according to American Society of Echocardiography Committee recommendations.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMRI cine imaging analysis\u003c/h2\u003e \u003cp\u003eCircumferential strain (CS) was estimated from cine images using feature tracking with Ziostation 2 and REVORAS (Ziosoft, Inc., Tokyo, Japan), which automatically defined the left ventricular region of interest.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eContinuous variables are presented as medians with interquartile ranges (IQR), while categorical variables are presented as absolute counts with percentages. The Wilcoxon signed-rank test was used to analyze continuous variables, and Fisher\u0026rsquo;s exact test was applied for comparisons of categorical data. Kappa statistics were calculated to assess intra- and inter- observer agreement in FDG PET/CT image interpretation. Reproducibility of semi-quantitative visual scores were assessed by the linearly weighted Cohen κ coefficient. Repeatability and reproducibility of myocardial SUVmax was assessed by Bland-Altman plot and Spearman correlation coefficient.\u003c/p\u003e \u003cp\u003eFDG uptake and MRI-derived parameters before and after vaccination were assessed using Bland-Altman plots to evaluate agreement. Statistical significance was defined as P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All data analyses were performed using JMP version 17.1.0 (SAS Institute, Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the subjects\u003c/h2\u003e \u003cp\u003eThis study included 67 subjects with both pre- and post-vaccination FDG PET/CT results available (mean age 61.9 years, 42 male). Patient characteristics are summarized in Table\u0026nbsp;1. There were no significant changes in weight (65.4 [IQR, 56.4\u0026ndash;72.2] vs. 65.0 [IQR, 56.3\u0026ndash;72.7] kg, P\u0026thinsp;=\u0026thinsp;0.68) n or blood pressure, including systolic (120 [IQR, 110\u0026ndash;134] vs. 121 [IQR, 108\u0026ndash;133] mmHg, P\u0026thinsp;=\u0026thinsp;0.82) and diastolic measurements (75.0 [IQR, 66.0\u0026ndash;81.0] vs. 75.0 [IQR, 66.5\u0026ndash;81.0] mmHg, P\u0026thinsp;=\u0026thinsp;0.51), before and after vaccination. Plasma glucose levels also remained unchanged (97.2\u0026thinsp;\u0026plusmn;\u0026thinsp;19.2 vs. 97.2\u0026thinsp;\u0026plusmn;\u0026thinsp;21.4, P\u0026thinsp;=\u0026thinsp;0.83).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eFDG PET/CT findings\u003c/h2\u003e \u003cp\u003eThe median interval between FDG PET/CT and vaccination was 3 months. There was no significant difference in FBG levels between the two PET/CT scans (92 [IQR, 84\u0026ndash;104] vs. 94 [IQR, 84\u0026ndash;105] mg/dl, P\u0026thinsp;=\u0026thinsp;0.83).\u003c/p\u003e \u003cp\u003eFor the visual assessment, the correlation of intra-examiner measurements after a 5-month interval was high (before vaccination: R\u0026thinsp;=\u0026thinsp;0.99, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; after vaccination: R\u0026thinsp;=\u0026thinsp;0.96, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The Spearman\u0026rsquo;s correlation coefficients assessing reproducibility were R\u0026thinsp;=\u0026thinsp;1.00 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) before vaccination and R\u0026thinsp;=\u0026thinsp;0.99 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after vaccination as reproducibility between two examiners. Intra-examiner reproducibility of SUVmax after 5 months was shown to be weighted κ\u0026thinsp;=\u0026thinsp;0.85 ([95% CI 0.76\u0026ndash;0.93], P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) before vaccination and weighted κ\u0026thinsp;=\u0026thinsp;0.95 ([95% CI 0.90-1.00], P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after vaccination. Reproducibility between the two examiners was weighted κ\u0026thinsp;=\u0026thinsp;0.74 ([95% CI 0.65\u0026ndash;0.83], P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) before vaccination and κ\u0026thinsp;=\u0026thinsp;0.77 ([95% CI 0.68\u0026ndash;0.86], P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after vaccination. Visual assessment was not significantly changed between two scans (Mann-Whitney U test, P\u0026thinsp;=\u0026thinsp;0.77) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMyocardial SUVmax did not significantly change before and after vaccination (3.29 [IQR, 2.84\u0026ndash;6.45] vs. 3.21 [IQR, 2.76\u0026ndash;7.25], P\u0026thinsp;=\u0026thinsp;0.63) (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). No significant changes were observed when analyzed separately by gender. For females, SUVmax was 3.28 [IQR, 2.79\u0026ndash;8.54] before vaccination and 4.06 [IQR, 2.64\u0026ndash;10.17] after vaccination (P\u0026thinsp;=\u0026thinsp;0.57). Similarly, for males, SUVmax was 3.32 [IQR, 2.84\u0026ndash;5.99] before vaccination and 3.16 [IQR, 2.76\u0026ndash;5.08] after vaccination (P\u0026thinsp;=\u0026thinsp;0.33). CMV (2.34 [IQR, 0-112.51] vs. 0.57 [IQR, 0-93.8] mL, P\u0026thinsp;=\u0026thinsp;0.81) and CMA (5.78 [IQR, 0-454.83] vs. 1.71 [IQR, 0-392.48] mL, P\u0026thinsp;=\u0026thinsp;0.94) also showed no significant differences (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e presents typical examples of cases with decreased uptake and unchanged uptake after COVID-19 vaccination (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eInterval analysis\u003c/h2\u003e \u003cp\u003eMyocardial FDG uptake was analyzed based on the interval between vaccination and the PET/CT examination. Subjects were divided into 2 groups according to the interval; (a) less than 4 months (N\u0026thinsp;=\u0026thinsp;37, 1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93 months) and (b) 4 months or longer (N\u0026thinsp;=\u0026thinsp;30, 5.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.36 months). Difference of SUVmax values before and after vaccine were assessed at each group. No significant differences in SUVmax were observed in either group; (a) 3.29 [2.74\u0026ndash;8.96] vs. 3.28 [2.89\u0026ndash;5.93], P\u0026thinsp;=\u0026thinsp;0.76, and (b) 3.36 [2.79\u0026ndash;9.49] vs. 3.16 [2.76\u0026ndash;5.06], P\u0026thinsp;=\u0026thinsp;0.22 (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEchocardiography findings\u003c/h2\u003e \u003cp\u003eEchocardiography data from 63 patients were available. There were no significant changes in LVEF (67.0 [62.0\u0026ndash;72.0] vs. 68.0 [62.0\u0026ndash;72.0] %, P\u0026thinsp;=\u0026thinsp;0.72), LVEDV (92.5 [IQR, 78.6-107.5] vs. 87.7 [IQR, 78.6-107.5] mL, P\u0026thinsp;=\u0026thinsp;0.46), or LVESV (30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3 vs. 29.6 [22.3\u0026ndash;35.0] mL, P\u0026thinsp;=\u0026thinsp;0.55) before and after vaccination (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMRI findings\u003c/h2\u003e \u003cp\u003eCardiac MRI data before and after vaccination were available for 49 out of 67 patients. All post-vaccination MRI scans were performed within 6 days before or after the corresponding PET/CT scans. Circumferential strain (CS) showed no significant difference before and after vaccination (-21.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.63 vs. -21.90\u0026thinsp;\u0026plusmn;\u0026thinsp;3.60, P\u0026thinsp;=\u0026thinsp;0.088) (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eB).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study represents the first to systematically evaluate myocardial FDG uptake alongside, echocardiography and strain analysis using MRI in the same asymptomatic health checkup individuals before and after COVID-19 vaccination. By focusing on the same subjects pre- and post-vaccination, we were able to provide a unique and precise assessment of potential cardiac effects attributable to vaccination. Our findings demonstrated no significant changes in myocardial FDG uptake between the pre- and post-vaccination states, suggesting that vaccination does not cause detectable alterations in myocardial metabolic activity. Similarly, cardiac function, as assessed by echocardiography and MRI\u0026mdash;including key parameters such as LVEF, LVEDV, LVESV, and circumferential strain\u0026mdash;showed no significant differences.\u003c/p\u003e \u003cp\u003eOur study yielded findings that differ from those of previous research \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Earlier studies reported increased myocardial FDG uptake in vaccinated patients compared to non-vaccinated patients, suggesting a potential inflammatory response in the myocardium following COVID-19 vaccination \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The discrepancy between our findings and those of previous studies may be explained by several factors. First, prior studies primarily utilized a cross-sectional design, comparing vaccinated individuals with non-vaccinated individuals, rather than evaluating longitudinal changes within the same subjects. This approach could introduce variability due to interindividual differences. In contrast, our study analyzed FDG uptake in the same individuals before and after vaccination, thereby minimizing interindividual variability. This within-subject analysis showed no significant differences in myocardial FDG uptake between the two scans. Furthermore, subgroup analyses stratified by sex yielded consistent results, with no significant changes in FDG uptake observed before and after vaccination. In our study, we also measured volume-based parameters such as Cardiac Metabolic Volume (CMV) and Cardiac Metabolic Activity (CMA), which had not been evaluated in previous research. SUVmax, which assesses only the maximum uptake at a single point, is susceptible to noise and has limitations, particularly when myocardial uptake is lower than that of the blood pool, making it difficult to determine the appropriate area for analysis. However, volume-based parameters provide a more robust assessment by integrating both the extent and intensity of FDG uptake (ref). This offers a measure of the overall metabolic activity within the myocardium, enabling a more comprehensive evaluation of myocardial health and potential pathological changes. These findings suggest that, in our cohort, COVID-19 vaccination did not result in a detectable increase in myocardial metabolic activity. Second, differences in FDG PET/CT protocols, fasting conditions, or study populations may also account for variations in findings. In our study, the subjects were individuals undergoing health checkups, ensuring that the pre-examination preparation was consistent across all cases. Furthermore, the interval between vaccination and FDG PET/CT imaging may influence the results, as inflammatory responses might be transient or vary based on individual immune reactions.\u003c/p\u003e \u003cp\u003eEl-Sayed H. Ibrahim et al. reported that strain parameters were significantly reduced in patients with myocarditis or suspected myocarditis caused by COVID-19 infection \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In contrast, a prospective cohort study by Ming-Yen Ng et al. found no significant changes in myocardial imaging parameters, including global native T1, T2, extracellular volume, left and right ventricular EF, global longitudinal strain, and late gadolinium enhancement, after COVID-19 vaccination \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Similarly, the echocardiography and MRI analyses in our study showed no significant differences in myocardial functional parameters before and after vaccination. This aligns with our findings that cardiac function remained unchanged post-vaccination in our cohort. The absence of significant changes in both FDG uptake and myocardial strain suggests that COVID-19 vaccination does not have a measurable impact on myocardial metabolic activity or functional parameters in asymptomatic individuals. These results provide additional evidence supporting the cardiac safety of the vaccine, particularly in the context of routine FDG PET/CT and MRI evaluations in a low-risk population.\u003c/p\u003e \u003cp\u003eThe primary limitation of this study is the relatively small sample size, which may affect the generalizability of our findings. However, the study\u0026rsquo;s strength lies in its within-subject design, allowing for the assessment of each individual\u0026rsquo;s myocardial FDG uptake and strain parameters both before and after vaccination. This design minimizes variability and provides a more reliable evaluation of potential changes attributable to the vaccine, lending significance to our results despite the limited sample size. Further research with larger, more diverse populations is needed to validate these findings and investigate whether factors such as vaccine type, dosage, or individual susceptibility might influence the myocardial metabolic response post-vaccination.\u003c/p\u003e \u003cp\u003eIn conclusion, our study, which uniquely evaluated the same asymptomatic health checkup subjects before and after COVID-19 vaccination, demonstrated that vaccination does not adversely impact myocardial metabolic activity or cardiac function. These findings highlight the robustness of our approach and provide valuable evidence supporting the cardiac safety of COVID-19 vaccination in this cohort.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Statement:\u003c/strong\u003e Approval from our institutional ethics review board was obtained, and the requirement for informed consent was waived for this retrospective study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e MS and OM conceived and designed the study. The material preparation, data collection, and analyses were performed by MS and OM. MS and OM wrote the first draft of this manuscript. All authors commented on the previous versions of the manuscript. All the authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e: The datasets used and/or analyzed in the current study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e None.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCrook H, Raza S, Nowell J, et al. Long covid-mechanisms, risk factors, and management. \u003cem\u003eBMJ\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2021;374:n1648.\u003c/li\u003e\n\u003cli\u003eGao P, Liu J, Liu M. Effect of COVID-19 Vaccines on Reducing the Risk of Long COVID in the Real World: A Systematic Review and Meta-Analysis. \u003cem\u003eInt J Environ Res Public Health\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2022;19.\u003c/li\u003e\n\u003cli\u003eFlorek K, Sokolski M. Myocarditis Associated with COVID-19 Vaccination. \u003cem\u003eVaccines (Basel)\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2024;12.\u003c/li\u003e\n\u003cli\u003eChoi Y, Lee JS, Choe YJ, et al. Myocarditis and Pericarditis are Temporally Associated with BNT162b2 COVID-19 Vaccine in Adolescents: A Systematic Review and Meta-analysis. \u003cem\u003ePediatr Cardiol\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2024.\u003c/li\u003e\n\u003cli\u003eManabe O, Kikuchi T, Scholte AJHA, et al. Radiopharmaceutical tracers for cardiac imaging. \u003cem\u003eJ Nucl Cardiol\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2018;25:1204-1236.\u003c/li\u003e\n\u003cli\u003ePan J, Ng SM, Neubauer S, et al. Phenotyping heart failure by cardiac magnetic resonance imaging of cardiac macro- and microscopic structure: state of the art review. \u003cem\u003eEur Heart J Cardiovasc Imaging\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2023;24:1302-1317.\u003c/li\u003e\n\u003cli\u003eNakahara T, Iwabuchi Y, Miyazawa R, et al. Assessment of Myocardial. \u003cem\u003eRadiology\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2023;308:e230743.\u003c/li\u003e\n\u003cli\u003eManabe O, Ohira H, Hirata K, et al. Use of. \u003cem\u003eEur J Nucl Med Mol Imaging\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2019;46:1240-1247.\u003c/li\u003e\n\u003cli\u003eHirata K, Kobayashi K, Wong KP, et al. A semi-automated technique determining the liver standardized uptake value reference for tumor delineation in FDG PET-CT. \u003cem\u003ePLoS One\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2014;9:e105682.\u003c/li\u003e\n\u003cli\u003eIbrahim EH, Rubenstein J, Sosa A, et al. Myocardial Strain for the Differentiation of Myocardial Involvement in the Post-Acute Sequelae of COVID-19-A Multiparametric Cardiac MRI Study. \u003cem\u003eTomography\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2024;10:331-348.\u003c/li\u003e\n\u003cli\u003eNg MY, Tam CH, Lee YP, et al. Post-COVID-19 vaccination myocarditis: a prospective cohort study pre and post vaccination using cardiovascular magnetic resonance. \u003cem\u003eJ Cardiovasc Magn Reson\u003c/em\u003e.\u003cem\u003e \u003c/em\u003e2023;25:74.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"positron emission tomography, fluorodeoxyglucose, COVID-19, vaccine, ejection fraction, circumferential strain","lastPublishedDoi":"10.21203/rs.3.rs-6901350/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6901350/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe aim of this study was to assess myocardial metabolic activity and cardiac function in asymptomatic health checkup subjects before and after vaccination COVID-19 vaccination.\u003c/p\u003e\u003ch2\u003eMaterials and methods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed clinical records of 67 asymptomatic subjects who underwent whole-body FDG PET/CT before and after COVID-19 vaccination. Cardiac metabolic activity was assessed using myocardial standardized uptake value (SUVmax). Echocardiography and cardiac MRI, including cine-based strain analysis, were used to evaluate cardiac function. The Wilcoxon signed-rank test and Bland-Altman plots were applied to assess changes between pre- and post-vaccination data.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNo significant differences in myocardial FDG uptake (SUVmax: 3.29 [IQR: 2.84\u0026ndash;6.45] vs. 3.21 [IQR: 2.76\u0026ndash;7.25], P\u0026thinsp;=\u0026thinsp;0.63) was observed. Similarly, echocardiographic parameters, including LVEF, LVEDV, and LVESV, remained unchanged. MRI-based circumferential strain also showed no significant alterations (-21.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.63 vs. -21.90\u0026thinsp;\u0026plusmn;\u0026thinsp;3.60, P\u0026thinsp;=\u0026thinsp;0.088).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study, the first to systematically evaluate myocardial FDG uptake alongside MRI strain analysis in the same subjects pre- and post-vaccination, demonstrates no significant impact of COVID-19 vaccination on myocardial metabolic activity or cardiac function. These findings support the cardiac safety of COVID-19 vaccination and provide a robust basis for future research in broader populations.\u003c/p\u003e","manuscriptTitle":"Cardiac Safety of COVID-19 Vaccines: A Longitudinal Study of Health Checkup Subjects Using Multi-Modal Imaging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 06:24:24","doi":"10.21203/rs.3.rs-6901350/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe0282d2-c960-4145-ab05-96f9aa9b1977","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-02T04:14:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 06:24:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6901350","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6901350","identity":"rs-6901350","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}