Resolution of Refractory COVID-19 Vaccine-Induced Myopericarditis with Adjunctive Rapamycin
Main Article Content
Nicolas Hulscher, MPH
http://orcid.org/0009-0008-0677-7386
Alexander Vickery
http://orcid.org/0009-0007-7257-0693
Peter A. McCullough, MD, MPH
http://orcid.org/0000-0002-0997-6355
http://orcid.org/0009-0008-0677-7386
Alexander Vickery
http://orcid.org/0009-0007-7257-0693
Peter A. McCullough, MD, MPH
http://orcid.org/0000-0002-0997-6355
Abstract
COVID-19 vaccine-induced myopericarditis is now commonly encountered in clinical practice. The mainstay of clinical management involves vaccine Spike protein detoxification and colchicine for 12 months or longer. Herein, we present a case of a previously healthy 23-year-old male with autism spectrum disorder who developed COVID-19 vaccine-induced myopericarditis and class II heart failure. He was treated with Spike detoxification, which is the combined use of over-the-counter nattokinase, bromelain, and curcumin, in addition to colchicine. While transient heart failure resolved, his chest discomfort persisted and at times was debilitating. Serial electrocardiograms indicated persistent global ST segment elevation. We describe the successful addition of off-label oral rapamycin to arrest inflammatory processes, extirpate ST elevation, and significantly improve quality of life. We summarize existing research that provided a rationale for the use of rapamycin. Concisely, these include targeting autophagy, mRNA translation, and immune activity modulation. We propose that mTOR inhibitors should be investigated as a potential disease-modifying interim treatment for COVID-19 vaccine induced cardiac injury.
Keywords:
COVID-19 vaccination, cardiomyopathy, heart failure, molecular mimicry, rapamycin, drug repurposing
Article Details
How to Cite
HULSCHER, Nicolas; VICKERY, Alexander; MCCULLOUGH, Peter A..
Resolution of Refractory COVID-19 Vaccine-Induced Myopericarditis with Adjunctive Rapamycin.
Medical Research Archives, [S.l.], v. 12, n. 11, nov. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6099>. Date accessed: 12 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i11.6099.
Section
Case Reports
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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25. Huang HC, Lai YJ, Liao CC, et al. Targeting conserved N-glycosylation blocks SARS-CoV-2 variant infection in vitro. EBioMedicine. 2021;74:10 3712. doi:10.1016/j.ebiom.2021.103712
26. Whitby K, Pierson TC, Geiss B, Lane K, Engle M, Zhou Y, Doms RW, Diamond MS. Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J Virol. 2005 Jul;79(14):8698-706. doi: 10.1128/JVI.79.14.8698-8706.2005.
27. Garcia G Jr, Sharma A, Ramaiah A, et al. Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication. Cell Rep. 2021;35(1):108940. doi:10. 1016/j.celrep.2021.108940
28. Casas-Sanchez, Aitor et al. “Inhibition of Protein N-Glycosylation Blocks SARS-CoV-2 Infection.” mBio vol. 13,1 (2021): e0371821. doi:10.1128/mbio.03718-21
29. Khan N. mTOR: A possible therapeutic target against SARS-CoV-2 infection. Arch Stem Cell Ther. 2021;2(1):5-7.
30. Gu J, Hu W, Song Z-P, Chen Y-G, Zhang D-D and Wang C-Q (2016) Rapamycin Inhibits Cardiac Hypertrophy by Promoting Autophagy via the MEK/ERK/Beclin-1 Pathway. Front. Physiol. 7:104. doi: 10.3389/fphys.2016.00104
31. Maeda K, Shioi T, Kosugi R, et al. Rapamycin ameliorates experimental autoimmune myocarditis. Int Heart J. 2005;46(3):513-530. doi:10.1536/ihj.46.513
32. Maisch B. SARS-CoV-2, vaccination or autoimmunity as causes of cardiac inflammation. Which form prevails?. SARS-CoV-2, Impfung oder Autoimmunität als Ursachen für Herzentzündungen. Welche Form überwiegt?. Herz. 2023;48(3):195-205. doi:10.1007/s00059-023-05182-6
33. Kanduc, Darja. “From SARS-CoV-2 to Myocarditis and Sudden Death via Molecular Mimicry and Immunologic Memory,” Current Practice in Medical Science Vol. 4 (2022): 129-138. doi:10.9734/bpi/cpms/v4/3200B
34. Nunez-Castilla J, Stebliankin V, Baral P, Balbin CA, Sobhan M, Cickovski T, Mondal AM, Narasimhan G, Chapagain P, Mathee K, Siltberg-Liberles J. Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins. Viruses. 2022 Jun 28;14(7): 1415. doi: 10.3390/v14071415
35. Angeli F, Reboldi G, Trapasso M, Zappa M, Spanevello A, Verdecchia P. COVID-19, vaccines and deficiency of ACE2 and other angiotensinases. Closing the loop on the "Spike effect". Eur J Intern Med. 2022 Sep;103:23-28. doi: 10.1016/j.ejim. 2022.06.015
36. Krämer LM, Brettschneider J, Lennerz JK, et al. Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis. Sci Rep. 2018;8(1):16594. Published 2018 Nov 9. doi:10.1038/s41598-018-34808-7
37. Gao G, Chen W, Yan M, Liu J, Luo H, Wang C, Yang P. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Int J Mol Med. 2020 Jan;45(1):195-209. doi: 10.3892/ijmm. 2019.4407
38. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008 Sep;8(3):224-36. doi: 10.1016/j.cmet. 2008.07.007
39. Madison BB. Srebp2: A master regulator of sterol and fatty acid synthesis. J Lipid Res. 2016 Mar;57(3):333-5. doi: 10.1194/jlr.C066712
40. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293. doi:10.1016/j.cell.2012.03.017
41. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35. doi:10.1038/nrm3025
42. Groenman AP, Schweren LJ, Dietrich A, Hoekstra PJ. An update on the safety of psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Drug Saf. 2017;16(4):455-464. doi:10.1080/14740338. 2017.1301928
2. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med. 2020;383(20): 1920-1931. doi:10.1056/NEJMoa2022483
3. Mead M, Seneff S, Rose J, et al. COVID-19 Modified mRNA “Vaccines”: Lessons Learned from Clinical Trials, Mass Vaccination, and the Bio-Pharmaceutical Complex, Part 2. International Journal of Vaccine Theory, Practice, and Research. 2024; 3(2), 1275-1344. doi: 10.56098/w66wjg87
4. Yasmin F, Najeeb H, Naeem U, et al. Adverse events following COVID-19 mRNA vaccines: a systematic review of cardiovascular complication, thrombosis, and thrombocytopenia. Immun Inflamm Dis. 2023; 11:e807. doi:10.1002/iid3.807
5. United States Department of Health and Human Services (DHHS), Public Health Service (PHS), Centers for Disease Control (CDC) / Food and Drug Administration (FDA), Vaccine Adverse Event Reporting System (VAERS) 1990 - 08/30/2024, CDC WONDER On-line Database. Accessed at http://wonder.cdc.gov/vaers.html on Sep 23, 2024
6. Rose J, Hulscher N, McCullough PA. Determinants of COVID-19 vaccine-induced myocarditis. Ther Adv Drug Saf. 2024;15:20420986 241226566. Published 2024 Jan 27. doi:10.1177/2 0420986241226566
7. Hulscher N, Hodkinson R, Makis W, McCullough PA. Autopsy findings in cases of fatal COVID-19 vaccine-induced myocarditis. ESC Heart Fail. Published online January 14, 2024. doi:10.1002 /ehf2.14680
8. Hulscher, N., Cook, M. J., Stricker, R. B., McCullough, P. A. Excess Cardiopulmonary Arrest and Mortality after COVID-19 Vaccination in King County, Washington. J Emerg Med OA. 2024; 2(1), 01-11.
9. Hulscher N, Procter BC, Wynn C, McCullough PA. Clinical Approach to Post-acute Sequelae After COVID-19 Infection and Vaccination. Cureus. 2023;15(11):e49204. Published 2023 Nov 21. doi:10.7759/cureus.49204
10. Behbahani-Nejad O, Mikolich B, Morgenstern D, Mikolich JR. Myocarditis response to colchicine therapy based on cardiac MRI diagnostic criteria. J Am Coll Cardiol. (2021) 77(18_Supplement_1): 1432. doi: 10.1016/S0735-1097(21)02790-X
11. Valore L, Junker T, Heilmann E, et al. Case report: mRNA-1273 COVID-19 vaccine-associated myopericarditis: Successful treatment and re-exposure with colchicine. Front Cardiovasc Med. 2023;10:1135848. Published 2023 Apr 17. doi:10.3389/fcvm.2023.1135848
12. McCullough, P.; Hulscher, N. Risk Stratification for Future Cardiac Arrest after COVID-19 Vaccination. Preprints 2024, 2024080821. doi:10. 20944/preprints202408.0821.v1
13. Faksova K, Walsh D, Jiang Y, et al. COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals. Vaccine. 2024;42(9):2200-2211. doi:10. 1016/j.vaccine.2024.01.100
14. Parry PI, Lefringhausen A, Turni C, et al. 'Spikeopathy': COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA. Biomedicines. 2023;11(8):2287. Published 2023 Aug 17. doi:10.3390/biomedicines11082287
15. Baumeier C, Aleshcheva G, Harms D, et al. Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series. Int J Mol Sci. 2022;23(13):6940. Published 2022 Jun 22. doi:10.3390/ijms23136940
16. Wu N, Joyal-Desmarais K, Ribeiro PAB, et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir Med. 2023;11(5): 439-452. doi:10.1016/S2213-2600(23)00015-2
17. Castruita JAS, Schneider UV, Mollerup S, et al. SARS-CoV-2 spike mRNA vaccine sequences circulate in blood up to 28 days after COVID-19 vaccination. APMIS. 2023;131(3):128-132. doi:10. 1111/apm.13294
18. Brogna C, Cristoni S, Marino G, et al. Detection of recombinant Spike protein in the blood of individuals vaccinated against SARS-CoV-2: Possible molecular mechanisms. Proteomics Clin Appl. 2023;17(6):e2300048. doi:10.1002/prca.202 300048
19. Yu CK, Tsao S, Ng CW, et al. Cardiovascular Assessment up to One Year After COVID-19 Vaccine-Associated Myocarditis. Circulation. 2023; 148(5):436-439. doi:10.1161/CIRCULATIONAHA.1 23.064772
20. Fürst T, Šourek P, Krátká Z, Janošek J. Batch-dependent safety of COVID-19 vaccines in the Czech Republic and comparison with data from Denmark. Eur J Clin Invest. 2024;54(10):e14271. doi:10.1111/eci.14271
21. Schmeling M, Manniche V, Hansen PR. Batch-dependent safety of the BNT162b2 mRNA COVID-19 vaccine. Eur J Clin Invest. 2023;53(8):e13998. doi:10.1111/eci.13998
22. Jablonowski K, Hooker B. Batch-dependent safety of the BNT162b2 mRNA COVID-19 vaccine in the United States. Science, Public Health Policy and the Law. 2024 Sep 26; v5.2019-2024
23. Knoll F. How Bad is My Batch? [Online]. GitHub; 2024 [cited 2024 Oct 25]. Available at: https://knollfrank.github.io/HowBadIsMyBatch/HowBadIsMyBatch.html
24. Hulscher, N.; McCullough, P. A. Delayed Fatal Pulmonary Hemorrhage Following COVID-19 Vaccination: Case Report, Batch Analysis, And Proposed Autopsy Checklist. Preprints 2024, 2024 021096. doi:10.20944/preprints202402.1096.v1
25. Huang HC, Lai YJ, Liao CC, et al. Targeting conserved N-glycosylation blocks SARS-CoV-2 variant infection in vitro. EBioMedicine. 2021;74:10 3712. doi:10.1016/j.ebiom.2021.103712
26. Whitby K, Pierson TC, Geiss B, Lane K, Engle M, Zhou Y, Doms RW, Diamond MS. Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J Virol. 2005 Jul;79(14):8698-706. doi: 10.1128/JVI.79.14.8698-8706.2005.
27. Garcia G Jr, Sharma A, Ramaiah A, et al. Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication. Cell Rep. 2021;35(1):108940. doi:10. 1016/j.celrep.2021.108940
28. Casas-Sanchez, Aitor et al. “Inhibition of Protein N-Glycosylation Blocks SARS-CoV-2 Infection.” mBio vol. 13,1 (2021): e0371821. doi:10.1128/mbio.03718-21
29. Khan N. mTOR: A possible therapeutic target against SARS-CoV-2 infection. Arch Stem Cell Ther. 2021;2(1):5-7.
30. Gu J, Hu W, Song Z-P, Chen Y-G, Zhang D-D and Wang C-Q (2016) Rapamycin Inhibits Cardiac Hypertrophy by Promoting Autophagy via the MEK/ERK/Beclin-1 Pathway. Front. Physiol. 7:104. doi: 10.3389/fphys.2016.00104
31. Maeda K, Shioi T, Kosugi R, et al. Rapamycin ameliorates experimental autoimmune myocarditis. Int Heart J. 2005;46(3):513-530. doi:10.1536/ihj.46.513
32. Maisch B. SARS-CoV-2, vaccination or autoimmunity as causes of cardiac inflammation. Which form prevails?. SARS-CoV-2, Impfung oder Autoimmunität als Ursachen für Herzentzündungen. Welche Form überwiegt?. Herz. 2023;48(3):195-205. doi:10.1007/s00059-023-05182-6
33. Kanduc, Darja. “From SARS-CoV-2 to Myocarditis and Sudden Death via Molecular Mimicry and Immunologic Memory,” Current Practice in Medical Science Vol. 4 (2022): 129-138. doi:10.9734/bpi/cpms/v4/3200B
34. Nunez-Castilla J, Stebliankin V, Baral P, Balbin CA, Sobhan M, Cickovski T, Mondal AM, Narasimhan G, Chapagain P, Mathee K, Siltberg-Liberles J. Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins. Viruses. 2022 Jun 28;14(7): 1415. doi: 10.3390/v14071415
35. Angeli F, Reboldi G, Trapasso M, Zappa M, Spanevello A, Verdecchia P. COVID-19, vaccines and deficiency of ACE2 and other angiotensinases. Closing the loop on the "Spike effect". Eur J Intern Med. 2022 Sep;103:23-28. doi: 10.1016/j.ejim. 2022.06.015
36. Krämer LM, Brettschneider J, Lennerz JK, et al. Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis. Sci Rep. 2018;8(1):16594. Published 2018 Nov 9. doi:10.1038/s41598-018-34808-7
37. Gao G, Chen W, Yan M, Liu J, Luo H, Wang C, Yang P. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Int J Mol Med. 2020 Jan;45(1):195-209. doi: 10.3892/ijmm. 2019.4407
38. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008 Sep;8(3):224-36. doi: 10.1016/j.cmet. 2008.07.007
39. Madison BB. Srebp2: A master regulator of sterol and fatty acid synthesis. J Lipid Res. 2016 Mar;57(3):333-5. doi: 10.1194/jlr.C066712
40. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293. doi:10.1016/j.cell.2012.03.017
41. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35. doi:10.1038/nrm3025
42. Groenman AP, Schweren LJ, Dietrich A, Hoekstra PJ. An update on the safety of psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Drug Saf. 2017;16(4):455-464. doi:10.1080/14740338. 2017.1301928