Myocardial Injury and Dysfunction Associated With COVID-19 Vaccination (MIDAVAX)

Evaluation of Myocardial Dysfunction Due to mRNA-based SARS-CoV-2 Vaccines

The overall goal of the study is to investigate the characteristics and potential mechanisms responsible for myocardial injury and dysfunction in patients after COVID-19 vaccination. Cardiac damage will be assessed with cardiac MRI and endomyocardial biopsy (EmBx) histopathology. Myocardial gene expression will be measured in RNA extracted from EmBxs mRNA abundance compared to nonfailing and failing control hearts.

Study Overview

• Status: Completed
• Conditions: COVID-19; Myocardial Injury; Vaccine Reaction

Detailed Description

To determine whether there is microvascular thrombosis-associated myocardial damage and dysfunction vs. inflammation or other changes in patients who, following administration of SARS-CoV-2 mRNA vaccine, develop evidence of myocardial injury typically diagnosed as "myocarditis" based on cardiac MRI findings.

Further, the degree of inflammatory reaction vs. microthrombotic injury to cardiac myocytes from biopsied myocardial tissue will be compared with biopsied myocardial tissue from control hearts. mRNA expression of the ACE2 and ITGA5 binding targets of SARS-Cov-2 Spike protein encoded by mRNA vaccines, as well as expression of other genes that may contribute to post-vaccine pro-thrombotic and pro-inflammatory states including Coagulation Factor 3 (F3, also known as tissue factor), ACE, AGTR1 and AGT) or a dysfunctional cardiac state (NPPB as a marker of pathologic remodeling) will be examined as candidate genes. Additional, global gene expression is being measured by RNA-Seq and microarray.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Ten patients with new symptoms of chest discomfort and biomarkers of myocardial injury that occurred 2-10 days following SARS-CoV-2 mRNA vaccination will be recruited up to 180 days following diagnosis. Patients will have no other known etiology for myocardial injury other than recent mRNA COVID vaccine exposure. Patients may be referred from inpatient or outpatient settings, from across the UCHealth system, but will be recruited in-person at University of Colorado Hospital.

Description

Inclusion Criteria:

1. age ≥18 years;

2. clear evidence of myocardial involvement including:

   1. High Sensitivity Troponin I value of (≥0.05 ng/ml (the 99% upper bound)) OR
   2. an LVEF < 50% OR
   3. ST-T change suggesting STEMI, NSTEMI or myopericarditis in the absence of coronary artery disease, OR
   4. new onset sustained VT or VF
3. Late gadolinium enhancement or edema on cMRI consistent with myocardial injury or inflammation.
4. Documentation of vaccination with mRNA-based COVID-19 vaccine.
5. No history of COVID-19, or a negative SARS-CoV-2 PCR or other FDA approved laboratory test within 1 week of enrollment.
6. Patient and/or legally authorized representative must be competent to understand and agree with informed consent form.

Exclusion Criteria:

1. Hemodynamic instability as evidenced by escalating doses of inotropic agents or vasopressors within the prior 24 hours
2. Respiratory instability as evidenced by increasing oxygen requirements over the 24 hours prior to consent or FiO2 requirement ≥ 60 %.
3. evidence that respiratory failure is the primary reason for myocardial dysfunction;
4. Moderate to severe pulmonary hypertension (mean PAP ≥35 mmHg);
5. INR >1.8 on no anticoagulation or contraindication to withdrawing anticoagulation;
6. platelets <100,000/mm3.
7. History of laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) testing or other commercial or public health assay.
8. Acute or chronic kidney disease with glomerular filtration rate < 30 ml/min.1.72m2

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Patients with evidence of myocardial injury related to vaccination with a SARS-CoV-2 mRNA vaccine; Patients who present with new symptoms of chest pain within 2-10 days following SARS-CoV-2 mRNA vaccination will be recruited up to 180 days following diagnosis. Patients will be screened using multiple methods and then provided informed consent. If patients are unable to consent, health care decision makers of patients who meet initial inclusion criteria will be approached for consent. Following informed consent, a cardiac MRI will be performed (if not performed prior) to assess myocardial function and potential damage. Patients will qualify on the basis of the presence of late-gadolinium enhancement and/or abnormal T1 mapping on MRI. The patient will then be taken to the cardiac catheterization lab where he/she will undergo endomyocardial biopsy and right heart catheterization (RHC) for candidate gene analysis. A blood sample will be collected to analyze circulating biomarkers associated with myocardial injury.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial damage	Initial clinical diagnosis of myocardial injury or myocarditis will be confirmed by cardiac MRI. Specific findings of late gadolinium enhancement and abnormal T1-signals within the myocardium consistent with acute injury, inflammation or edema will be evaluated.	clinical follow up for at least 30 days following endomyocardial biopsy
Histopathological changes assessed by light- and electron-microscopy in myocardial tissue	Determining the histopathologic changes present in the endomyocardial biopsies of patients with COVID-19 vaccine-induced myocardial injury. Assessment of the standard H&E stains will include evaluation for presence and degree of inflammation within the myocardium, presence of microvascular thrombi within vasculature, and evidence of myocardial damage. The trichrome, iron, and Congo red stains will be used to evaluate for the presence of fibrosis, iron, or amyloid, respectively. Electron microscopy will be employed to examine cardiac myocyte and small blood vessel architectures.	clinical follow up for at least 30 days following endomyocardial biopsy
Myocardial mRNA expression	Measure myocardial mRNA expression of candidate genes involved in Spike protein binding and cell entry (ACE2 and ITGA5), the renin-angiotensin system (ACE, AGT, AGTR1), initiation of coagulation (F3/TF) and pathologic myocardial remodeling (NPPB).	clinical follow up for at least 30 days following endomyocardial biopsy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial mRNA expression of additional genes measured by both RNA-Seq and microarray.	Measure mRNA expression of additional candidate and global genes, and compare results to nonfailing and failing controls. Seven candidate genes will be measured by three platforms (qPCR, RNA-Seq and microarray), and global transcripts by RNA-Seq and microarray.	clinical follow up for at least 30 days following endomyocardial biopsy

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); American Heart Association
• Investigators: Principal Investigator: Natasha Altman, MD, University of Colorado, Denver; Principal Investigator: Bristow Michael, MD/PhD, University of Colorado, Denver

Publications and helpful links

General Publications

• Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, Watkinson P, Khunti K, Harnden A, Coupland CAC, Channon KM, Mills NL, Sheikh A, Hippisley-Cox J. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2022 Feb;28(2):410-422. doi: 10.1038/s41591-021-01630-0. Epub 2021 Dec 14.
• Oster ME, Shay DK, Su JR, Gee J, Creech CB, Broder KR, Edwards K, Soslow JH, Dendy JM, Schlaudecker E, Lang SM, Barnett ED, Ruberg FL, Smith MJ, Campbell MJ, Lopes RD, Sperling LS, Baumblatt JA, Thompson DL, Marquez PL, Strid P, Woo J, Pugsley R, Reagan-Steiner S, DeStefano F, Shimabukuro TT. Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021. JAMA. 2022 Jan 25;327(4):331-340. doi: 10.1001/jama.2021.24110.

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2021
• Primary Completion (Actual): December 30, 2024
• Study Completion (Actual): December 30, 2024

Study Registration Dates

• First Submitted: May 2, 2022
• First Submitted That Met QC Criteria: May 2, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: mRNA vaccines; myocardial injury; COVID-19; myocarditis; gene expression
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19
• Other Study ID Numbers: 21-4055; 3UM1AI068614-14S1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No