Myocardial Injury and Altered Gene Expression Associated With SARS-CoV-2 Infection or mRNA Vaccination

Abstract

SARS CoV-2 enters host cells via its Spike protein moiety binding to the essential cardiac enzyme angiotensin-converting enzyme (ACE) 2, followed by internalization. COVID-19 mRNA vaccines are RNA sequences that are translated into Spike protein, which follows the same ACE2-binding route as the intact virion. In model systems, isolated Spike protein can produce cell damage and altered gene expression, and myocardial injury or myocarditis can occur during COVID-19 or after mRNA vaccination. We investigated 7 COVID-19 and 6 post-mRNA vaccination patients with myocardial injury and found nearly identical alterations in gene expression that would predispose to inflammation, coagulopathy, and myocardial dysfunction.

Keywords: ACE, angiotensin I–converting enzyme gene; ACE2, angiotensin-converting enzyme 2 gene; AGT, angiotensinogen gene; AGTR1, angiotensin II receptor type 1 gene; ANG II, angiotensin II; BNP, B-type natriuretic peptide; CMR, cardiac magnetic resonance; COVID-19; EM, electron microscopy; F3, coagulation factor III (tissue factor) gene; ITGA5, integrin subunit alpha 5 gene; IVS, interventricular septum; LGE, late gadolinium enhancement; LM, light microscopy; LV, left ventricular; LVEF, left ventricular ejection fraction; NDC, nonischemic dilated cardiomyopathy; NPPB, natriuretic peptide B gene; RV, right ventricular; S, SARS-CoV-2 Spike; TnI, troponin I; gene expression; mRNA vaccines; myocardial injury; myocarditis.

Graphical abstract

Figure 1

Endomyocardial Biopsies of a COVID-19 Patient and a Post–mRNA Vaccine Case COVID-19 patient 7: (A) Endomyocardial biopsy (EmBx) demonstrating infiltrating inflammatory cells with associated myocyte injury (arrows) (×200); (B) higher-power view of myocyte injury, characterized by fragmentation of myocytes and early necrosis (arrows) (×400); (C) electron microscopy (EM) showing myocyte damage characterized by myocytolysis and decreased contractile elements (arrow) with adjacent unremarkable mitochondria (arrowhead). Post–mRNA vaccine case 3: (D) EmBx with small-caliber vessels exhibiting microvascular thrombosis (arrows) (×600); (E) trichrome stain highlighting microvascular thrombosis (arrows) (×600); (F) EM with nonocclusive platelet-rich thrombus (arrow) interacting with endothelial cells of an interstitial vessel with adjacent red blood cells (asterisks).

Figure 2

Cardiac Magnetic Resonance Imaging of Post–mRNA Vaccine Cases (A) Case 1, 4-chamber (4C) images, initial study shown top left: short T2 inversion recovery (STIR) imaging specifically identifies increased interstitial space from either myocyte loss or edema, showing increased signal in the lateral left ventricular (LV) wall suggesting acute myocardial edema. This is less obvious on follow-up imaging (top right) conducted 57 days later. Shown in the bottom panels are initial (left) and follow-up (right) post–gadolinium contrast phase-sensitive inversion recovery (PISR) 4C images. Note that the initial focal punctate late gadolinium enhancement (LGE) areas in the lateral wall (arrows) are less prominent on follow-up. (B) Case 3, initial STIR imaging shown in the top left panel, with follow-up study conducted 35 days later on the right. Note the septal, apical, and lateral foci of increased signal for edema (arrows) with a decreased signal on the follow-up study . Shown in the center panels are (left) initial LGE punctate foci in the lateral wall in 2 places and LV apex (arrows). Follow-up study (center right) shows a single less prominent LGE focus. The bottom panel images are T1 mapping native relaxation times showing 1 septal, 2 lateral anterior, and 3 lateral posterior values from regions of interest. Note that (left) initial values are ∼1,105-1,230 ms for all 3 regions suggesting increased interstitial space, whereas in (right) the follow-up study the T1 values are normal (<1,050 ms) except region 2 (1,085 ms), which was abnormal on the LGE images (center right) of the lateral wall.

Figure 3

Box and Whisker Plots for mRNA Abundance Box (median and [Q1, Q3]) and whisker plots for mRNA abundance as 2^−ΔCt (2^∆-dCt) referenced to GAPDH^22,48 for explanted heart interventricular septum (nonfailing [NF]: n = 20; failing [F]: n = 25 [15 nonischemic dilated cardiomyopathy, 10 ischemic cardiomyopathy]), 17 endomyocardial biopsy (EmBx) NF control samples from the BORG study,^, 33 F nonischemic cardiomyopathy (NDC) patients from BORG, 6 COVID-19 subjects, and 4 post-vaccine myocardial injury subjects. ACE2/ACE from the BORG study is calculated from microarray fluorescence units that are log2 transformed. Significance levels are indicated above or below box plot: ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; NS (nonsignificant): P ≥ 0.05. ACE, angiotensin I–converting enzyme gene; ACE2, angiotensin-converting enzyme 2 gene; AGT, angiotensinogen gene; AGTR1, angiotensin II receptor type 1 gene; ITGA5, integrin subunit alpha 5 gene; F3, coagulation factor III (tissue factor) gene; NPPB = natriuretic peptide B.

Figure 4

Scatterplot of Linear Discriminant Analysis by Group, Defined by mRNA Abundance of 7 Candidate Gene Transcripts The 4 mRNA vaccine (VAX) patients classified with the 6 patient COVID-19 group with 97.7% ± 2.2% posterior probability. The probabilities for being classified with the nonfailing (n = 18) or failing (n = 25) explanted heart group are, respectively, 0.2% ± 0.3% and 2.1% ± 2.1% (Table 3). In the nonfailing group, 2 of the 20 hearts are not represented, because mRNA abundance of AGTR1 was too low to be measured and expression of all 7 genes was required for the linear discriminant analysis.