Severe Myocardium Suppression in Two Congenital Heart Disease Patients After Remdesivir Use

Severe Myocardium Suppression in Two Congenital Heart Disease Patients After Remdesivir Use | 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 Case Report Severe Myocardium Suppression in Two Congenital Heart Disease Patients After Remdesivir Use Yi-Fan Lin, Shih-Yu Fang, Shu-Chien Huang, En-Ting Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4614588/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Nov, 2025 Read the published version in BMC Pediatrics → Version 1 posted 13 You are reading this latest preprint version Abstract Background Remdesivir, the first antiviral agent against SARS-CoV-2 fully approved by the FDA, induces ECG abnormalities and impairs cardiac function. Remdesivir interferes with mitochondrial dynamics in vitro, herein, we report on two pediatric patients with a history of congenital heart disease (CHD) who developed profound cardiogenic shock after remdesivir administration. Patient 1 A 10-year-old boy with hypoplastic left heart syndrome was admitted for SARS-CoV-2 infection with a high viral load. After receiving remdesivir, the patient experienced refractory hypotension and a widening of the QRS duration, followed by cardiac arrest. Despite treatment with multiple inotropes and vasopressors, the patient required venoarterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock and ultimately died of intracranial hemorrhage. Patient 2 A 15-year-old boy with pulmonary atresia and ventricular septal defect after corrective surgeries was admitted for SARS-CoV-2 infection. After receiving remdesivir, the patient developed hypotension, ultimately requiring VA-ECMO due to profound shock and multiorgan failure. Despite stabilization, the patient remained comatose and eventually succumbed to a severe intra-abdominal infection. Conclusion In our proposed model, remdesivir may impair cardiac function, especially at high viral loads, by interfering with mitochondrial quality control and augmenting the cytokine storm. Certain CHDs lead to ventricular overload, rendering cardiomyocytes susceptible to remdesivir-induced mitochondrial dysfunction. Moreover, the sudden onset of shock and the protracted nature of its progression observed in the two patients were in line with the pharmacokinetics of remdesivir. We recommend that remdesivir be used with caution in patients with CHD with right ventricle failure and single-ventricle circulation. Remdesivir SARS-CoV-2 mitochondrial dynamics congenital heart disease Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Since the first outbreak in late 2019, SARS-CoV-2 has inflicted great morbidity and mortality worldwide [ 1 ]. Remdesivir, the first antiviral agent fully approved for use against SARS-CoV-2 by the FDA, reduces mortality, time to recovery, and the need for mechanical ventilation support. Remdesivir is the first-line treatment for hospitalized patients at a high risk of progression to severe disease. Remdesivir is a pro-drug. The intracellular metabolite of remdesivir, an adenosine analog with the ability to inhibit viral RNA-dependent RNA polymerase, purportedly induces ECG abnormalities, such as sinus bradycardia, atrial fibrillation, and complete heart block [ 2 ]. Remdesivir also causes mitochondrial fragmentation in vitro, suppresses mitochondrial respiration, and results in cytotoxicity in cardiomyocytes [ 3 ]. Here, we report the cases of two pediatric patients with a history of congenital heart disease (CHD) who developed profound cardiogenic shock after remdesivir administration. The temporal correlation between the onset of shock and administration of remdesivir could be explained by the pharmacology of remdesivir. We also propose a model of susceptibility to remdesivir-induced mitochondrial dysfunction due to pathological mitochondrial adaptation in patients with severe CHD, based on evidence from basic research as well as our clinical observations. We recommend that remdesivir be used with caution in certain groups of CHD patients. Case Reports Patient 1 This 10-year-old boy with hypoplastic left heart syndrome underwent the initial stage of the Norwood procedure shortly after birth, followed by the creation of a bidirectional Glenn shunt before reaching one year of age. Because of poor family support, he lost follow-up until 2021 when he presented with profound cyanosis with oxygen saturation 60%. He underwent palliative Blablock-Thomas-Taussig shunt (BT shunt) creation to rescue left pulmonary artery hypoplasia. Thereafter, the resting oxygen saturation elevated up to 75–80% and subnormal single ventricle ejection fraction (50%) was documented on echocardiography. In late April 2022, the patient's persistent productive cough escalated to dyspnea, leading to admission. SARS-CoV-2 was ruled out by the RT-PCR test, and chest radiography (CXR) showed no pneumonia but mild cardiomegaly (Fig. 1 ). Empirical treatment with Ampicillin/Sulbactam switched to Teicoplanin due to Methicillin-resistant Staphylococcus aureus in the blood culture. Subsequent blood cultures were negative, and the patient condition was stable. Breakthrough fever occurred on May 6th with blood culture yielded Citrobacter koseri, prompting Piperacillin/Tazobactam administration. Abdominal ultrasound revealed hydrops gallbladder, engorged hepatic vein, and portal vein, suggesting suboptimal right heart function. The abdominal computer tomography (CT) scan showed thick soft tissue infiltrates near the abdominal para-aortic region. Intra-abdominal infection (IAI) was highly suspected. The patient encountered his family member infected with SARS-CoV-2. The cycle threshold in RT-PCR test on May 19th was 18.53. A remdesivir infusion was initiated on the next day. Four hours later, oxygen saturation dropped to 20–30% despite escalation of respiratory support. ECG revealed a widening of the QRS duration. In addition, hypotension gradually developed and was refractory to vasopressor therapy. Subsequently, cardiac arrest occurred. He regained spontaneous circulation after 7 minutes of CPR. Bedside echocardiogram showed global hypokinesia. Central venous pressure (CVP) measured through inferior vena cava was up to 30 mmHg, and mixed venous oxygen saturation was 24%. VA-ECMO was then initiated for cardiogenic shock. Under ECMO support, blood pressure improved, but lactatemia continued to progress. A peritoneal dialysis tube was inserted to relieve abdominal distension. Three days later, lactatemia declined and the echocardiogram showed recovered contractility. Two days later, the patient suffered from intracranial hemorrhage, with both pupils dilated and unresponsive to light. ECMO was withdrawn and the patient passed away. The clinical details and changes in lab data over time in Patient 1 after infection with SARS-CoV-2 and the administration of remdesivir were summarized in Fig. 2 a-c. Patient 2 A 15-year-old boy was born with DiGeorge syndrome, pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries (MAPCAs). He underwent BT shunt creation, unifocalization of the MAPCAs, and complete septation with two-ventricle repair at the age of 11 years. Postoperatively, progressive right ventricle (RV) dilatation with significant residual pulmonary stenosis with pressure gradient up to 36 mmHg, indicating RV failure, was documented on echocardiography. CXR revealed cardiomegaly and patchy infiltrations. (Fig. 3 ) He also had a history of megacolon complicated with necrotizing enterocolitis, for which he had undergone subtotal colectomy with end-to-end ileocolonic anastomosis in his infancy, and early onset scoliosis, for which he had undergone posterior instrumentation with growing rod system. The patient was admitted to the hospital because of SARS-CoV-2 infection and presented with a high fever, sore throat, cough, and loose stools for 3 days since September 28th, 2022. The cycle threshold in the SARS-CoV-2 RT-PCR test was 14.3, and his IL-6 levels had risen to 33,999, indicating high viral load and severe systemic inflammation. Empirical Piperacillin/Tazobactam was given for elevated levels of CRP and procalcitonin, which indicated bacterial co-infection. Remdesivir was administered. Hypotension with poor perfusion developed 2 h after the infusion. His vital signs were as follows: heart rate 134/min, blood pressure, 75/42 mmHg; and CVP, 24 mmHg. The patient was intubated with ventilator support and catecholamine escalation. Blood culture yielded Escherichia coli , and the antibiotics were subsequently upgraded to Amikacin, Teicoplanin and Meropenem. Fluid resuscitation and component therapy were initiated for sepsis and disseminated intravascular coagulation. The second dose of remdesivir was administered the following day. The hypotension and lactatemia persisted and were refractory to inotropes. ECG revealed frequent premature ventricular contractions, the development of left posterior fascicular block, QTc prolongation from 445ms to 510ms, and QRS widening from 138ms to 182ms (Fig. 4 a-b). A bedside ultrasound revealed enlarged RV compressing LV, and decreased LVEF (48%). Owing to profound shock and multiorgan failure, VA-ECMO was initiated. Abdominal computed tomography revealed pneumoperitoneum, indicating IAI and bowel perforation. A PD catheter was inserted for drainage of ascites and peritoneal dialysis. Under strong antibiotic coverage and aggressive fluid resuscitation, his vital signs gradually stabilized, and he could be separated from ECMO 5 days later. The patient remained comatose even when the sedation was withdrawn. In addition, the pneumonia and heart failure worsened. We continued medical treatment, including the escalation of catecholamines and antibiotics. Explorative laparotomy was postponed due to critical condition of the patient. The patient died 28 days after the ECMO removal. The clinical details and changes in lab data over time in Patient 2 after infection with SARS-CoV-2 and the administration of remdesivir were summarized in Fig. 5 a-c. Discussion and Conclusion Here, we briefly summarize the common disease courses. Both had a history of complex CHD and severe IAI simultaneously when they tested positive for SARS-CoV-2 with a high viral load. Before the administration of remdesivir, blood pressure and blood oxygen saturation were maintained. Shock occurred within 3 h after remdesivir infusion and manifested as high CVP, indicating cardiogenic shock in addition to sepsis. Poor heart contractility, high lactatemia, and shock did not respond well to the standard supportive care. In addition, after the administration of remdesivir, both patients had ECG abnormalities, that is, QRS widening. The second patient developed a left posterior fascicular block. Based on the electrophysical changes, clinical course, and temporal correlation between the onset of shock and administration of remdesivir, we hypothesized that remdesivir may have impair cardiac function at high viral loads. As shown in Fig. 6 a, SARS-CoV-2 can inhibit the mitochondrial antiviral signaling pathway in the early stage of infection and prevent host cells from producing type 1 and type 3 interferon, thus delaying the initiation of the antiviral immune response [ 4 , 5 ]. SARS-CoV-2 then rapidly proliferates. SARS-CoV-2 RNA can interfere and hijack mitochondrial biogenetic machinery after entry into mitochondrial matrix from cytosol [ 5 , 6 ]. The mitochondrial redox potential then decreases, leading to the assembly of the mitochondrial permeability transition pore (MPTP). Mitochondrial substances are released into the cytoplasm as potential damage-associated molecular patterns (DAMPs). DAMPs trigger and intensify cytokine storms by binding to pattern-recognition receptors (PRRs) [ 7 ]. By selectively removing dysfunctional mitochondria, mitophagy is the key to mitochondrial quality control. A study showed that SARS-CoV-2 can prevent the formation of autophagosomes and block mitophagy [ 8 , 9 ]. As a result, the infected cells are filled with tiny and dysfunctional mitochondria. Under this premise, remdesivir potentiates mitochondrial dysfunction and leads to cytotoxicity. Remdesivir does not, like anti-HIV nucleoside and nucleotide analogs, directly inhibit mitochondrial DNA polymerase. Remdesivir has weak inhibitory activity toward mitochondrial RNA polymerase [ 10 , 11 ] and therefore does not affect mitochondrial protein homeostasis. Remdesivir, instead, is reported to be a selective, partial agonist for urotensin-II receptor (UTS2R). The half-maximal effective concentration (pEC50) of remdesivir was estimated to be 4.89 ± 0.03 (EC50 = 13 ± 0.9 µM), with the working range of agonistic effects starting at 1 µM based on the response curve [ 12 ]. UTS2R, as a GPCR, in turn activates heterotrimeric G proteins, which leads to dissociation of Gα and Gβγ subunit complexes [ 13 ]. Possibly through impaired regulation of gene expression or trafficking of ERG potassium channels, field potential, which correlates closely with the QT interval, is prolonged [ 12 ]. Remdesivir can also disturb the electrophysiological properties by reducing the spontaneous firing rate, which may lead to disruption in conduction system and development of ventricular premature complex, and the diastolic depolarization rate, which may lead to QRS widening [ 3 ]. In addition, through binding to UTS2R, remdesivir can activate AKT/ERK axis [ 12 ]. Phosphorylation of ERK can in turn phosphorylate mitochondrial fission dynamic-like protein 1 (Drp1) [ 14 ]. Thus, Remdesivir induces mitochondrial fragmentation and dysfunction [ 3 ]. Such effect is not tissue-specific [ 15 ] and is reversed by Mdivi-1, an inhibitor of Drp1 [ 3 ]. Augmented mitochondrial dysfunction can manifest as elevated lactic acid levels, cytokine storm, and poor cardiac contractility, as seen in the two cases above. What makes the hypothesis more convincing is that the pharmacokinetics of remdesivir are well fitted to the temporal correlation between the onset of shock and the administration of remdesivir. Remdesivir undergoes sequential hydrolysis to the nucleoside metabolite GS-441524, which is transmitted intracellularly and converted into the active metabolite remdesivir triphosphate. Remdesivir has a half-life of one hour. Following a single dose of 200 mg of remdesivir administered, the area under the concentration-time curve from 0 to 24 hours (AUC 0 − 24 ) is 4.8 µM•h for remdesivir and 7.7 µM•h for the nucleoside metabolite [ 16 ]. Remdesivir triphosphate has a half-life of up to 43 h [ 11 , 17 ]. Mitochondrial dynamics occur on a timescale of minutes [ 18 ]. The administration of remdesivir can rapidly halt SARS-CoV-2 proliferation and facilitate the resolution of systemic inflammation. Peak concentration of remdesivir is reached within two to three hours after the start of remdesivir infusion. In these two pediatric patients who received usual pediatric dosing of remdesivir, cardiogenic shock occurred two to three hours later, coinciding temporally with the changes in remdesivir concentration. Additionally, based on the AUC 0 − 24 and the working range of UTS2R agonistic effects of remdesivir, we can anticipate that the effect of remdesivir inducing myocardial suppression through the UTS2R signaling pathway can last for at least one day or more. Therefore, the suddenness of onset of shock and the protracted nature of progression observed in the two cases above were possibly due to side effects of remdesivir instead of actual clinical course of COVID-19 or concomitant bacterial septicemia. Moreover, certain CHD can lead to ventricular overload, as shown in Fig. 6 b. Under such chronic stress, the high mitochondrial turnover rate ensures that the quality of mitochondria meets the needs of myocardial metabolism [ 19 ]. Infection with SARS-CoV-2 disrupts compensatory mechanisms [ 20 ]. Thus, cardiomyocytes become increasingly susceptible to remdesivir-induced “metabolic shock.” Several studies have also shown that SARS-CoV-2 can cause elevated pulmonary vascular resistance (PVR) [ 21 – 23 ]. In patients with right heart failure or single ventricle circulation, elevated PVR causes RV afterload and is detrimental to single-ventricle circulation. It is reasonable to assume that the shock in these two patients was caused by intra-abdominal infection; co-infection with SARS-CoV-2 and the administration of remdesivir caused severe myocardial dysfunction due to mitochondrial shock. In summary, Remdesivir should be used with caution in CHD patients with RV failure and single-ventricle circulation. We have admitted that no causal relationship can be directly established with the two cases. More evidence from clinical trials and basic research is required to prove our hypothesis. Declarations Funding This research is supported and sponsored by the Ministry of Science and Technology, Taiwan, R.O.C. under Grant no. 1102314B002090MY3 Competing Interests All authors declare no pertinent conflicts of interest. Author information Authors and Affiliations Department of Education, National Taiwan University Hospital, Taipei 100, Taiwan. Yi-Fan, Lin Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan. Shih-Yu, Fang Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan. Shu-Chien Huang Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan. En-Ting Wu Author Contributions Shih-Yu Fang, Shu-Chien Huang and En-Ting Wu were involved in the clinical decision making and clinical care involved in both cases. Material preparation and analysis were performed by Yi-Fan Lin. The first draft of the manuscript was written by Yi-Fan Lin and En-Ting Wu and all authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript. Correspondence En-Ting Wu. MD, PhD, Department of Pediatrics, National Taiwan University Children’s Hospital, No.8, Chung Shan S. Rd., Zhongzheng Dist., Taipei City 10041, Taiwan (R.O.C.) E-mail address: [email protected] Availability of data and material s The datasets used during the current study available from the corresponding author on reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent has been obtained from the parents of both patients, allowing for the publication of this case report and any accompanying images. Acknowledgement This research is supported and sponsored by the Ministry of Science and Technology, Taiwan, R.O.C. under Grant no. 1102314B002090MY3 References Msemburi W, Karlinsky A, Knutson V, Aleshin-Guendel S, Chatterji S, Wakefield J. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature. 2023;613(7942):130–7. https://doi.org/10.1038/s41586-022-05522-2 . Nabati M, Parsaee H. Potential Cardiotoxic Effects of Remdesivir on Cardiovascular System: A Literature Review. Cardiovasc Toxicol. 2022;22(3):268–72. https://doi.org/10.1007/s12012-021-09703-9 . Kwok M, Lee C, Li HS, Deng R, Tsoi C, Ding Q, et al. Remdesivir induces persistent mitochondrial and structural damage in human induced pluripotent stem cell-derived cardiomyocytes. Cardiovasc Res. 2022;118(12):2652–64. https://doi.org/10.1093/cvr/cvab311 . Li X, Hou P, Ma W, Wang X, Wang H, Yu Z, et al. SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy. Cell Mol Immunol. 2022;19(1):67–78. https://doi.org/10.1038/s41423-021-00807-4 . Bhowal C, Ghosh S, Ghatak D, De R. Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight. Mol Cell Biochem. 2022:1–19. https://doi.org/10.1007/s11010-022-04593-z . Singh KK, Chaubey G, Chen JY, Suravajhala P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol Cell Physiol. 2020;319(2):C258–67. https://doi.org/10.1152/ajpcell.00224.2020 . Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2022;1–15. https://doi.org/10.1038/s41577-022-00760-x . Mehrzadi S, Karimi MY, Fatemi A, Reiter RJ, Hosseinzadeh A. SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: beneficial effects of melatonin. Pharmacol Ther. 2021;224:107825. https://doi.org/10.1016/j.pharmthera.2021.107825 . Hou P, Wang X, Wang H, Wang T, Yu Z, Xu C, et al. The ORF7a protein of SARS-CoV-2 initiates autophagy and limits autophagosome-lysosome fusion via degradation of SNAP29 to promote virus replication. Autophagy. 2023;19(2):551–69. https://doi.org/10.1080/15548627.2022.2084686 . Ciesielska EJ, Kim S, Bisimwa HM, Grier C, Rahman MM, Young CKJ, et al. Remdesivir triphosphate blocks DNA synthesis and increases exonucleolysis by the replicative mitochondrial DNA polymerase, Pol γ. Mitochondrion. 2021;61:147–58. https://doi.org/10.1016/j.mito.2021.09.010 . Bjork JA, Wallace KB. Remdesivir; molecular and functional measures of mitochondrial safety. Toxicol Appl Pharmacol. 2021;433:115783. https://doi.org/10.1016/j.taap.2021.115783 . Ogawa A, Ohira S, Kato Y, Ikuta T, Yanagida S, Mi X, et al. Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction. Commun Biology. 2023;6(1):511. 10.1038/s42003-023-04888-x . Tölle M, van der Giet M. Cardiorenovascular effects of urotensin II and the relevance of the UT receptor. Peptides. 2008;29(5):743–63. https://doi.org/10.1016/j.peptides.2007.08.029 . Serasinghe Madhavika N, Wieder Shira Y, Renault Thibaud T, Elkholi R, Asciolla James J, Yao Jonathon L, et al. Mitochondrial Division Is Requisite to RAS-Induced Transformation and Targeted by Oncogenic MAPK Pathway Inhibitors. Mol Cell. 2015;57(3):521–36. https://doi.org/10.1016/j.molcel.2015.01.003 . Miyazaki K, Yoshimura Y, Miyata N, Sasaki H, Shiba A, Aga M, et al. Acute pancreatitis or severe increase in pancreatic enzyme levels following remdesivir administration in COVID-19 patients: an observational study. Sci Rep. 2022;12(1):5323. https://doi.org/10.1038/s41598-022-09170-4 . Humeniuk R, Mathias A, Kirby BJ, Lutz JD, Cao H, Osinusi A, et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor. Clin Pharmacokinet. 2021;60(5):569–83. 10.1007/s40262-021-00984-5 . Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, et al. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin Transl Sci. 2020;13(5):896–906. https://doi.org/10.1111/cts.12840 . Mitra K, Lippincott-Schwartz J. Analysis of mitochondrial dynamics and functions using imaging approaches. Curr Protoc Cell Biol 2010;Chap 4:Unit 4.25.1-1. https://doi.org/10.1002/0471143030.cb0425s46 . Hwang HV, Sandeep N, Nair RV, Hu DQ, Zhao M, Lan IS, et al. Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular Failure. J Am Heart Assoc. 2021;10(4):e017835. https://doi.org/10.1161/JAHA.120.017835 . Ramachandran K, Maity S, Muthukumar AR, Kandala S, Tomar D, Abd El-Aziz TM, et al. SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics. iScience. 2022;25(1):103722. https://doi.org/10.1016/j.isci.2021.103722 . Halawa S, Pullamsetti SS, Bangham CRM, Stenmark KR, Dorfmüller P, Frid MG, et al. Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective. Nat Reviews Cardiol. 2022;19(5):314–31. https://doi.org/10.1038/s41569-021-00640-2 . Suzuki YJ, Nikolaienko SI, Shults NV, Gychka SG. COVID-19 patients may become predisposed to pulmonary arterial hypertension. Med Hypotheses. 2021;147:110483. https://doi.org/10.1016/j.mehy.2021.110483 . Batah SS, Fabro AT. Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians. Respir Med. 2021;176:106239. https://doi.org/10.1016/j.rmed.2020.106239 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Nov, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 08 Sep, 2025 Reviews received at journal 05 Sep, 2025 Reviewers agreed at journal 05 Sep, 2025 Reviewers agreed at journal 09 Aug, 2025 Reviews received at journal 25 Jul, 2025 Reviewers agreed at journal 05 Jul, 2025 Reviews received at journal 23 Aug, 2024 Reviewers agreed at journal 14 Aug, 2024 Reviewers invited by journal 14 Aug, 2024 Editor invited by journal 28 Jun, 2024 Editor assigned by journal 25 Jun, 2024 Submission checks completed at journal 25 Jun, 2024 First submitted to journal 20 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4614588","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":327810469,"identity":"fa5501cd-e989-4289-a252-092a54075c86","order_by":0,"name":"Yi-Fan Lin","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi-Fan","middleName":"","lastName":"Lin","suffix":""},{"id":327810471,"identity":"c45e06e8-39d4-42bc-91c0-0129bd4dff2d","order_by":1,"name":"Shih-Yu Fang","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shih-Yu","middleName":"","lastName":"Fang","suffix":""},{"id":327810472,"identity":"5c79904d-32c0-4781-8479-96f0470e7833","order_by":2,"name":"Shu-Chien Huang","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shu-Chien","middleName":"","lastName":"Huang","suffix":""},{"id":327810473,"identity":"162e54df-7537-472f-a8ed-86f519b10165","order_by":3,"name":"En-Ting Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYJCCAyCCH0QkFBClgRmiRbIBpMWASC1gYADWSIwWfun+g4cLfh1O3Hx+deKHBwYM8vxiB/BrkZxzmOHwzL7DidtuvN0sAXSY4czZCfi1GNxIZjjM23MbqOXsBpCWBIPbBLTYw7RsnnF28w+itBhIALXw/LiduIG/dxtxtkjcSDY4zNvw33jGDd5tFgkGEoT9wj8j8fFnnj9psv39Zzff/FFhI88vTUALGDC2gewDq5QgQjkY/AHZd4BY1aNgFIyCUTDSAACiDEr1RwEvegAAAABJRU5ErkJggg==","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":true,"prefix":"","firstName":"En-Ting","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2024-06-21 03:23:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4614588/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4614588/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-025-06315-y","type":"published","date":"2025-11-14T15:57:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60633213,"identity":"9c96ed3c-acb5-4e1d-9119-c0ea78869de5","added_by":"auto","created_at":"2024-07-19 01:37:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":416841,"visible":true,"origin":"","legend":"\u003cp\u003eA chest radiograph taken 2 months before the current hospitalization showing enlargement of the cardiac silhouette on the right side.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/c02767d513daace0a5fbc502.png"},{"id":60633215,"identity":"13ba58bd-c90e-442d-9083-bdfe50550f71","added_by":"auto","created_at":"2024-07-19 01:37:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":107029,"visible":true,"origin":"","legend":"\u003cp\u003ea-c. Clinical details and changes in lab data over time in Patient 1 after infection with SARS-CoV-2 and the administration of remdesivir. MAP, mean arterial pressure; CVP, central venous pressure; PD, peritoneal dialysis.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/768622ca4f2eb0b61eb8687b.png"},{"id":60633214,"identity":"fa99c819-2114-4ad9-8c4d-c2061c9ddc11","added_by":"auto","created_at":"2024-07-19 01:37:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":394387,"visible":true,"origin":"","legend":"\u003cp\u003eA chest radiograph taken 1 month before the current hospitalization, showing cardiomegaly and spinal rods implanted for correction of scoliosis.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/d1f0e50a8ec6936c9132bb30.png"},{"id":60633216,"identity":"4a67a6bd-7696-4347-8266-24092259af2a","added_by":"auto","created_at":"2024-07-19 01:37:13","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1438781,"visible":true,"origin":"","legend":"\u003cp\u003ea An electrocardiogram taken upon admission. b. An electrocardiogram taken after two doses of remdesivir were administered. Comparison of ECG before and after the use of remdesivir reveals the development of left posterior fascicular block, QTc prolongation, and QRS widening.\u003c/p\u003e","description":"","filename":"Figure4a.png","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/d370cb1f6f70c9d9ae700a29.png"},{"id":60634145,"identity":"ee937f99-2cf0-4c03-b8bd-e5c799993ca2","added_by":"auto","created_at":"2024-07-19 01:45:13","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":83119,"visible":true,"origin":"","legend":"\u003cp\u003ea-c Clinical details and changes in lab data over time in Patient 2 after infection with SARS-CoV-2 and the administration of remdesivir. MAP, mean arterial pressure; CVP, central venous pressure; PD, peritoneal dialysis.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/dc83e7a9b65aae91d7616db2.png"},{"id":60633218,"identity":"1c05f3fb-3072-432a-a3ac-1092d2430bb3","added_by":"auto","created_at":"2024-07-19 01:37:13","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":297870,"visible":true,"origin":"","legend":"\u003cp\u003ea. Schema of the proposed model elucidating susceptibility to remdesivir-induced mitochondrial dysfunction due to pathological mitochondrial adaptation in patients with congenital heart disease. Adapted from “Coronavirus Replication Cycle”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates. b. Brief summary of the pathophysiology of cardiogenic shock in these two cases based on the model presented in Figure 6a, created with BioRender.com. RdRP, RNA-dependent RNA polymerase; MPTP, mitochondrial permeability transition pore; DAMP, damage associated molecular pattern; Δψm, inner membrane potential; pERK, phosphorylated ERK; pDrp1, phosphorylated Drp1; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; RVOT, right ventricular outflow tract; LV, left ventricle; RV, right ventricle.\u003c/p\u003e","description":"","filename":"Figure6a.png","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/9cdff9ffff285e0c4ea7a182.png"},{"id":96105074,"identity":"34d4303a-d976-4331-a204-f45b1f199e22","added_by":"auto","created_at":"2025-11-17 16:08:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3243683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4614588/v1/a6e8db22-27f3-47d3-89be-b6bfc4a11efd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Severe Myocardium Suppression in Two Congenital Heart Disease Patients After Remdesivir Use","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince the first outbreak in late 2019, SARS-CoV-2 has inflicted great morbidity and mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Remdesivir, the first antiviral agent fully approved for use against SARS-CoV-2 by the FDA, reduces mortality, time to recovery, and the need for mechanical ventilation support. Remdesivir is the first-line treatment for hospitalized patients at a high risk of progression to severe disease. Remdesivir is a pro-drug. The intracellular metabolite of remdesivir, an adenosine analog with the ability to inhibit viral RNA-dependent RNA polymerase, purportedly induces ECG abnormalities, such as sinus bradycardia, atrial fibrillation, and complete heart block [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Remdesivir also causes mitochondrial fragmentation in vitro, suppresses mitochondrial respiration, and results in cytotoxicity in cardiomyocytes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we report the cases of two pediatric patients with a history of congenital heart disease (CHD) who developed profound cardiogenic shock after remdesivir administration. The temporal correlation between the onset of shock and administration of remdesivir could be explained by the pharmacology of remdesivir. We also propose a model of susceptibility to remdesivir-induced mitochondrial dysfunction due to pathological mitochondrial adaptation in patients with severe CHD, based on evidence from basic research as well as our clinical observations. We recommend that remdesivir be used with caution in certain groups of CHD patients.\u003c/p\u003e"},{"header":"Case Reports","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient 1\u003c/h2\u003e \u003cp\u003eThis 10-year-old boy with hypoplastic left heart syndrome underwent the initial stage of the Norwood procedure shortly after birth, followed by the creation of a bidirectional Glenn shunt before reaching one year of age. Because of poor family support, he lost follow-up until 2021 when he presented with profound cyanosis with oxygen saturation 60%. He underwent palliative Blablock-Thomas-Taussig shunt (BT shunt) creation to rescue left pulmonary artery hypoplasia. Thereafter, the resting oxygen saturation elevated up to 75\u0026ndash;80% and subnormal single ventricle ejection fraction (50%) was documented on echocardiography.\u003c/p\u003e \u003cp\u003eIn late April 2022, the patient's persistent productive cough escalated to dyspnea, leading to admission. SARS-CoV-2 was ruled out by the RT-PCR test, and chest radiography (CXR) showed no pneumonia but mild cardiomegaly (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Empirical treatment with Ampicillin/Sulbactam switched to Teicoplanin due to Methicillin-resistant Staphylococcus aureus in the blood culture. Subsequent blood cultures were negative, and the patient condition was stable. Breakthrough fever occurred on May 6th with blood culture yielded Citrobacter koseri, prompting Piperacillin/Tazobactam administration. Abdominal ultrasound revealed hydrops gallbladder, engorged hepatic vein, and portal vein, suggesting suboptimal right heart function. The abdominal computer tomography (CT) scan showed thick soft tissue infiltrates near the abdominal para-aortic region. Intra-abdominal infection (IAI) was highly suspected.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient encountered his family member infected with SARS-CoV-2. The cycle threshold in RT-PCR test on May 19th was 18.53. A remdesivir infusion was initiated on the next day. Four hours later, oxygen saturation dropped to 20\u0026ndash;30% despite escalation of respiratory support. ECG revealed a widening of the QRS duration. In addition, hypotension gradually developed and was refractory to vasopressor therapy. Subsequently, cardiac arrest occurred. He regained spontaneous circulation after 7 minutes of CPR. Bedside echocardiogram showed global hypokinesia. Central venous pressure (CVP) measured through inferior vena cava was up to 30 mmHg, and mixed venous oxygen saturation was 24%. VA-ECMO was then initiated for cardiogenic shock.\u003c/p\u003e \u003cp\u003eUnder ECMO support, blood pressure improved, but lactatemia continued to progress. A peritoneal dialysis tube was inserted to relieve abdominal distension. Three days later, lactatemia declined and the echocardiogram showed recovered contractility. Two days later, the patient suffered from intracranial hemorrhage, with both pupils dilated and unresponsive to light. ECMO was withdrawn and the patient passed away.\u003c/p\u003e \u003cp\u003eThe clinical details and changes in lab data over time in Patient 1 after infection with SARS-CoV-2 and the administration of remdesivir were summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea-c.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient 2\u003c/h3\u003e\n\u003cp\u003eA 15-year-old boy was born with DiGeorge syndrome, pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries (MAPCAs). He underwent BT shunt creation, unifocalization of the MAPCAs, and complete septation with two-ventricle repair at the age of 11 years. Postoperatively, progressive right ventricle (RV) dilatation with significant residual pulmonary stenosis with pressure gradient up to 36 mmHg, indicating RV failure, was documented on echocardiography. CXR revealed cardiomegaly and patchy infiltrations. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) He also had a history of megacolon complicated with necrotizing enterocolitis, for which he had undergone subtotal colectomy with end-to-end ileocolonic anastomosis in his infancy, and early onset scoliosis, for which he had undergone posterior instrumentation with growing rod system.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient was admitted to the hospital because of SARS-CoV-2 infection and presented with a high fever, sore throat, cough, and loose stools for 3 days since September 28th, 2022. The cycle threshold in the SARS-CoV-2 RT-PCR test was 14.3, and his IL-6 levels had risen to 33,999, indicating high viral load and severe systemic inflammation. Empirical Piperacillin/Tazobactam was given for elevated levels of CRP and procalcitonin, which indicated bacterial co-infection.\u003c/p\u003e \u003cp\u003eRemdesivir was administered. Hypotension with poor perfusion developed 2 h after the infusion. His vital signs were as follows: heart rate 134/min, blood pressure, 75/42 mmHg; and CVP, 24 mmHg. The patient was intubated with ventilator support and catecholamine escalation. Blood culture yielded \u003cem\u003eEscherichia coli\u003c/em\u003e, and the antibiotics were subsequently upgraded to Amikacin, Teicoplanin and Meropenem. Fluid resuscitation and component therapy were initiated for sepsis and disseminated intravascular coagulation. The second dose of remdesivir was administered the following day. The hypotension and lactatemia persisted and were refractory to inotropes. ECG revealed frequent premature ventricular contractions, the development of left posterior fascicular block, QTc prolongation from 445ms to 510ms, and QRS widening from 138ms to 182ms (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea-b). A bedside ultrasound revealed enlarged RV compressing LV, and decreased LVEF (48%). Owing to profound shock and multiorgan failure, VA-ECMO was initiated.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAbdominal computed tomography revealed pneumoperitoneum, indicating IAI and bowel perforation. A PD catheter was inserted for drainage of ascites and peritoneal dialysis. Under strong antibiotic coverage and aggressive fluid resuscitation, his vital signs gradually stabilized, and he could be separated from ECMO 5 days later.\u003c/p\u003e \u003cp\u003eThe patient remained comatose even when the sedation was withdrawn. In addition, the pneumonia and heart failure worsened. We continued medical treatment, including the escalation of catecholamines and antibiotics. Explorative laparotomy was postponed due to critical condition of the patient. The patient died 28 days after the ECMO removal.\u003c/p\u003e \u003cp\u003eThe clinical details and changes in lab data over time in Patient 2 after infection with SARS-CoV-2 and the administration of remdesivir were summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea-c.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and Conclusion","content":"\u003cp\u003eHere, we briefly summarize the common disease courses. Both had a history of complex CHD and severe IAI simultaneously when they tested positive for SARS-CoV-2 with a high viral load. Before the administration of remdesivir, blood pressure and blood oxygen saturation were maintained. Shock occurred within 3 h after remdesivir infusion and manifested as high CVP, indicating cardiogenic shock in addition to sepsis. Poor heart contractility, high lactatemia, and shock did not respond well to the standard supportive care. In addition, after the administration of remdesivir, both patients had ECG abnormalities, that is, QRS widening. The second patient developed a left posterior fascicular block.\u003c/p\u003e \u003cp\u003eBased on the electrophysical changes, clinical course, and temporal correlation between the onset of shock and administration of remdesivir, we hypothesized that remdesivir may have impair cardiac function at high viral loads.\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea, SARS-CoV-2 can inhibit the mitochondrial antiviral signaling pathway in the early stage of infection and prevent host cells from producing type 1 and type 3 interferon, thus delaying the initiation of the antiviral immune response [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. SARS-CoV-2 then rapidly proliferates. SARS-CoV-2 RNA can interfere and hijack mitochondrial biogenetic machinery after entry into mitochondrial matrix from cytosol [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The mitochondrial redox potential then decreases, leading to the assembly of the mitochondrial permeability transition pore (MPTP). Mitochondrial substances are released into the cytoplasm as potential damage-associated molecular patterns (DAMPs). DAMPs trigger and intensify cytokine storms by binding to pattern-recognition receptors (PRRs) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. By selectively removing dysfunctional mitochondria, mitophagy is the key to mitochondrial quality control. A study showed that SARS-CoV-2 can prevent the formation of autophagosomes and block mitophagy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As a result, the infected cells are filled with tiny and dysfunctional mitochondria. Under this premise, remdesivir potentiates mitochondrial dysfunction and leads to cytotoxicity. Remdesivir does not, like anti-HIV nucleoside and nucleotide analogs, directly inhibit mitochondrial DNA polymerase. Remdesivir has weak inhibitory activity toward mitochondrial RNA polymerase [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and therefore does not affect mitochondrial protein homeostasis. Remdesivir, instead, is reported to be a selective, partial agonist for urotensin-II receptor (UTS2R). The half-maximal effective concentration (pEC50) of remdesivir was estimated to be 4.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03 (EC50\u0026thinsp;=\u0026thinsp;13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 \u0026micro;M), with the working range of agonistic effects starting at 1 \u0026micro;M based on the response curve [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. UTS2R, as a GPCR, in turn activates heterotrimeric G proteins, which leads to dissociation of Gα and Gβγ subunit complexes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Possibly through impaired regulation of gene expression or trafficking of ERG potassium channels, field potential, which correlates closely with the QT interval, is prolonged [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Remdesivir can also disturb the electrophysiological properties by reducing the spontaneous firing rate, which may lead to disruption in conduction system and development of ventricular premature complex, and the diastolic depolarization rate, which may lead to QRS widening [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In addition, through binding to UTS2R, remdesivir can activate AKT/ERK axis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Phosphorylation of ERK can in turn phosphorylate mitochondrial fission dynamic-like protein 1 (Drp1) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, Remdesivir induces mitochondrial fragmentation and dysfunction [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Such effect is not tissue-specific [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and is reversed by Mdivi-1, an inhibitor of Drp1 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Augmented mitochondrial dysfunction can manifest as elevated lactic acid levels, cytokine storm, and poor cardiac contractility, as seen in the two cases above.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhat makes the hypothesis more convincing is that the pharmacokinetics of remdesivir are well fitted to the temporal correlation between the onset of shock and the administration of remdesivir. Remdesivir undergoes sequential hydrolysis to the nucleoside metabolite GS-441524, which is transmitted intracellularly and converted into the active metabolite remdesivir triphosphate. Remdesivir has a half-life of one hour. Following a single dose of 200 mg of remdesivir administered, the area under the concentration-time curve from 0 to 24 hours (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24\u003c/sub\u003e) is 4.8 \u0026micro;M\u0026bull;h for remdesivir and 7.7 \u0026micro;M\u0026bull;h for the nucleoside metabolite [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Remdesivir triphosphate has a half-life of up to 43 h [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Mitochondrial dynamics occur on a timescale of minutes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The administration of remdesivir can rapidly halt SARS-CoV-2 proliferation and facilitate the resolution of systemic inflammation. Peak concentration of remdesivir is reached within two to three hours after the start of remdesivir infusion. In these two pediatric patients who received usual pediatric dosing of remdesivir, cardiogenic shock occurred two to three hours later, coinciding temporally with the changes in remdesivir concentration. Additionally, based on the AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24\u003c/sub\u003e and the working range of UTS2R agonistic effects of remdesivir, we can anticipate that the effect of remdesivir inducing myocardial suppression through the UTS2R signaling pathway can last for at least one day or more. Therefore, the suddenness of onset of shock and the protracted nature of progression observed in the two cases above were possibly due to side effects of remdesivir instead of actual clinical course of COVID-19 or concomitant bacterial septicemia.\u003c/p\u003e \u003cp\u003eMoreover, certain CHD can lead to ventricular overload, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb. Under such chronic stress, the high mitochondrial turnover rate ensures that the quality of mitochondria meets the needs of myocardial metabolism [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Infection with SARS-CoV-2 disrupts compensatory mechanisms [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Thus, cardiomyocytes become increasingly susceptible to remdesivir-induced \u0026ldquo;metabolic shock.\u0026rdquo;\u003c/p\u003e \u003cp\u003eSeveral studies have also shown that SARS-CoV-2 can cause elevated pulmonary vascular resistance (PVR) [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In patients with right heart failure or single ventricle circulation, elevated PVR causes RV afterload and is detrimental to single-ventricle circulation. It is reasonable to assume that the shock in these two patients was caused by intra-abdominal infection; co-infection with SARS-CoV-2 and the administration of remdesivir caused severe myocardial dysfunction due to mitochondrial shock. In summary, Remdesivir should be used with caution in CHD patients with RV failure and single-ventricle circulation.\u003c/p\u003e \u003cp\u003eWe have admitted that no causal relationship can be directly established with the two cases. More evidence from clinical trials and basic research is required to prove our hypothesis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research is supported and sponsored by the Ministry of Science and Technology, Taiwan,\u0026nbsp;R.O.C. under Grant no.\u0026nbsp;1102314B002090MY3\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no pertinent conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Education, National Taiwan University Hospital, Taipei 100, Taiwan.\u003c/p\u003e\n\u003cp\u003eYi-Fan, Lin\u003c/p\u003e\n\u003cp\u003eDepartment of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.\u003c/p\u003e\n\u003cp\u003eShih-Yu, Fang\u003c/p\u003e\n\u003cp\u003eDepartment of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.\u003c/p\u003e\n\u003cp\u003eShu-Chien Huang\u003c/p\u003e\n\u003cp\u003eDepartment of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan.\u003c/p\u003e\n\u003cp\u003eEn-Ting Wu\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShih-Yu Fang, Shu-Chien Huang and En-Ting Wu were involved in the clinical decision making and clinical care involved in both cases. Material preparation and analysis were performed by Yi-Fan Lin. The first draft of the manuscript was written by Yi-Fan Lin and En-Ting Wu and all authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEn-Ting Wu. MD, PhD,\u003c/p\u003e\n\u003cp\u003eDepartment of Pediatrics, National Taiwan University Children\u0026rsquo;s Hospital,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo.8, Chung Shan S. Rd., Zhongzheng Dist., Taipei City 10041, Taiwan (R.O.C.) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eE-mail address: [email protected]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent has been obtained from the parents of both patients, allowing for the publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research is supported and sponsored by the Ministry of Science and Technology, Taiwan, R.O.C. under Grant no. 1102314B002090MY3\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMsemburi W, Karlinsky A, Knutson V, Aleshin-Guendel S, Chatterji S, Wakefield J. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature. 2023;613(7942):130\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41586-022-05522-2\u003c/span\u003e\u003cspan address=\"10.1038/s41586-022-05522-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNabati M, Parsaee H. Potential Cardiotoxic Effects of Remdesivir on Cardiovascular System: A Literature Review. Cardiovasc Toxicol. 2022;22(3):268\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12012-021-09703-9\u003c/span\u003e\u003cspan address=\"10.1007/s12012-021-09703-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwok M, Lee C, Li HS, Deng R, Tsoi C, Ding Q, et al. Remdesivir induces persistent mitochondrial and structural damage in human induced pluripotent stem cell-derived cardiomyocytes. Cardiovasc Res. 2022;118(12):2652\u0026ndash;64. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/cvr/cvab311\u003c/span\u003e\u003cspan address=\"10.1093/cvr/cvab311\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Hou P, Ma W, Wang X, Wang H, Yu Z, et al. SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy. Cell Mol Immunol. 2022;19(1):67\u0026ndash;78. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41423-021-00807-4\u003c/span\u003e\u003cspan address=\"10.1038/s41423-021-00807-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhowal C, Ghosh S, Ghatak D, De R. Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight. Mol Cell Biochem. 2022:1\u0026ndash;19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11010-022-04593-z\u003c/span\u003e\u003cspan address=\"10.1007/s11010-022-04593-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh KK, Chaubey G, Chen JY, Suravajhala P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol Cell Physiol. 2020;319(2):C258\u0026ndash;67. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1152/ajpcell.00224.2020\u003c/span\u003e\u003cspan address=\"10.1152/ajpcell.00224.2020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2022;1\u0026ndash;15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41577-022-00760-x\u003c/span\u003e\u003cspan address=\"10.1038/s41577-022-00760-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehrzadi S, Karimi MY, Fatemi A, Reiter RJ, Hosseinzadeh A. SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: beneficial effects of melatonin. Pharmacol Ther. 2021;224:107825. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.pharmthera.2021.107825\u003c/span\u003e\u003cspan address=\"10.1016/j.pharmthera.2021.107825\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHou P, Wang X, Wang H, Wang T, Yu Z, Xu C, et al. The ORF7a protein of SARS-CoV-2 initiates autophagy and limits autophagosome-lysosome fusion via degradation of SNAP29 to promote virus replication. Autophagy. 2023;19(2):551\u0026ndash;69. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/15548627.2022.2084686\u003c/span\u003e\u003cspan address=\"10.1080/15548627.2022.2084686\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCiesielska EJ, Kim S, Bisimwa HM, Grier C, Rahman MM, Young CKJ, et al. Remdesivir triphosphate blocks DNA synthesis and increases exonucleolysis by the replicative mitochondrial DNA polymerase, Pol γ. Mitochondrion. 2021;61:147\u0026ndash;58. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.mito.2021.09.010\u003c/span\u003e\u003cspan address=\"10.1016/j.mito.2021.09.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBjork JA, Wallace KB. Remdesivir; molecular and functional measures of mitochondrial safety. Toxicol Appl Pharmacol. 2021;433:115783. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.taap.2021.115783\u003c/span\u003e\u003cspan address=\"10.1016/j.taap.2021.115783\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgawa A, Ohira S, Kato Y, Ikuta T, Yanagida S, Mi X, et al. Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction. Commun Biology. 2023;6(1):511. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s42003-023-04888-x\u003c/span\u003e\u003cspan address=\"10.1038/s42003-023-04888-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eT\u0026ouml;lle M, van der Giet M. Cardiorenovascular effects of urotensin II and the relevance of the UT receptor. Peptides. 2008;29(5):743\u0026ndash;63. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.peptides.2007.08.029\u003c/span\u003e\u003cspan address=\"10.1016/j.peptides.2007.08.029\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerasinghe Madhavika N, Wieder Shira Y, Renault Thibaud T, Elkholi R, Asciolla James J, Yao Jonathon L, et al. Mitochondrial Division Is Requisite to RAS-Induced Transformation and Targeted by Oncogenic MAPK Pathway Inhibitors. Mol Cell. 2015;57(3):521\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.molcel.2015.01.003\u003c/span\u003e\u003cspan address=\"10.1016/j.molcel.2015.01.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyazaki K, Yoshimura Y, Miyata N, Sasaki H, Shiba A, Aga M, et al. Acute pancreatitis or severe increase in pancreatic enzyme levels following remdesivir administration in COVID-19 patients: an observational study. Sci Rep. 2022;12(1):5323. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-022-09170-4\u003c/span\u003e\u003cspan address=\"10.1038/s41598-022-09170-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHumeniuk R, Mathias A, Kirby BJ, Lutz JD, Cao H, Osinusi A, et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor. Clin Pharmacokinet. 2021;60(5):569\u0026ndash;83. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40262-021-00984-5\u003c/span\u003e\u003cspan address=\"10.1007/s40262-021-00984-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHumeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, et al. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin Transl Sci. 2020;13(5):896\u0026ndash;906. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/cts.12840\u003c/span\u003e\u003cspan address=\"10.1111/cts.12840\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitra K, Lippincott-Schwartz J. Analysis of mitochondrial dynamics and functions using imaging approaches. Curr Protoc Cell Biol 2010;Chap 4:Unit 4.25.1-1. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/0471143030.cb0425s46\u003c/span\u003e\u003cspan address=\"10.1002/0471143030.cb0425s46\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHwang HV, Sandeep N, Nair RV, Hu DQ, Zhao M, Lan IS, et al. Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular Failure. J Am Heart Assoc. 2021;10(4):e017835. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/JAHA.120.017835\u003c/span\u003e\u003cspan address=\"10.1161/JAHA.120.017835\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamachandran K, Maity S, Muthukumar AR, Kandala S, Tomar D, Abd El-Aziz TM, et al. SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics. iScience. 2022;25(1):103722. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.isci.2021.103722\u003c/span\u003e\u003cspan address=\"10.1016/j.isci.2021.103722\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHalawa S, Pullamsetti SS, Bangham CRM, Stenmark KR, Dorfm\u0026uuml;ller P, Frid MG, et al. Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective. Nat Reviews Cardiol. 2022;19(5):314\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41569-021-00640-2\u003c/span\u003e\u003cspan address=\"10.1038/s41569-021-00640-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki YJ, Nikolaienko SI, Shults NV, Gychka SG. COVID-19 patients may become predisposed to pulmonary arterial hypertension. Med Hypotheses. 2021;147:110483. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.mehy.2021.110483\u003c/span\u003e\u003cspan address=\"10.1016/j.mehy.2021.110483\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBatah SS, Fabro AT. Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians. Respir Med. 2021;176:106239. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.rmed.2020.106239\u003c/span\u003e\u003cspan address=\"10.1016/j.rmed.2020.106239\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Remdesivir, SARS-CoV-2, mitochondrial dynamics, congenital heart disease","lastPublishedDoi":"10.21203/rs.3.rs-4614588/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4614588/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRemdesivir, the first antiviral agent against SARS-CoV-2 fully approved by the FDA, induces ECG abnormalities and impairs cardiac function. Remdesivir interferes with mitochondrial dynamics in vitro, herein, we report on two pediatric patients with a history of congenital heart disease (CHD) who developed profound cardiogenic shock after remdesivir administration.\u003c/p\u003e\u003ch2\u003ePatient 1\u003c/h2\u003e \u003cp\u003eA 10-year-old boy with hypoplastic left heart syndrome was admitted for SARS-CoV-2 infection with a high viral load. After receiving remdesivir, the patient experienced refractory hypotension and a widening of the QRS duration, followed by cardiac arrest. Despite treatment with multiple inotropes and vasopressors, the patient required venoarterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock and ultimately died of intracranial hemorrhage.\u003c/p\u003e\u003ch2\u003ePatient 2\u003c/h2\u003e \u003cp\u003eA 15-year-old boy with pulmonary atresia and ventricular septal defect after corrective surgeries was admitted for SARS-CoV-2 infection. After receiving remdesivir, the patient developed hypotension, ultimately requiring VA-ECMO due to profound shock and multiorgan failure. Despite stabilization, the patient remained comatose and eventually succumbed to a severe intra-abdominal infection.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn our proposed model, remdesivir may impair cardiac function, especially at high viral loads, by interfering with mitochondrial quality control and augmenting the cytokine storm. Certain CHDs lead to ventricular overload, rendering cardiomyocytes susceptible to remdesivir-induced mitochondrial dysfunction. Moreover, the sudden onset of shock and the protracted nature of its progression observed in the two patients were in line with the pharmacokinetics of remdesivir. We recommend that remdesivir be used with caution in patients with CHD with right ventricle failure and single-ventricle circulation.\u003c/p\u003e","manuscriptTitle":"Severe Myocardium Suppression in Two Congenital Heart Disease Patients After Remdesivir Use","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-19 01:37:08","doi":"10.21203/rs.3.rs-4614588/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-08T06:53:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-05T19:23:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26665329543610721744336102186964124503","date":"2025-09-05T11:50:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7950788698605905129893253920141716533","date":"2025-08-09T11:42:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-25T15:07:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"118664000964678610657847004888557604404","date":"2025-07-05T04:05:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-23T09:57:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"89793987555842442142197748475843902821","date":"2024-08-14T12:06:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-14T11:36:47+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-28T07:04:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-25T10:24:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-25T10:22:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2024-06-21T03:21:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8df81260-ff47-4abe-b9d6-46d513da73cd","owner":[],"postedDate":"July 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T16:01:57+00:00","versionOfRecord":{"articleIdentity":"rs-4614588","link":"https://doi.org/10.1186/s12887-025-06315-y","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2025-11-14 15:57:58","publishedOnDateReadable":"November 14th, 2025"},"versionCreatedAt":"2024-07-19 01:37:08","video":"","vorDoi":"10.1186/s12887-025-06315-y","vorDoiUrl":"https://doi.org/10.1186/s12887-025-06315-y","workflowStages":[]},"version":"v1","identity":"rs-4614588","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4614588","identity":"rs-4614588","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}