Patients with Post-COVID-19 Vaccination Myocarditis Have More Favorable Strain in Cardiac Magnetic Resonance Than Those With Viral Myocarditis

doi:10.21203/rs.3.rs-2460008/v1

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Research Article

Patients with Post-COVID-19 Vaccination Myocarditis Have More Favorable Strain in Cardiac Magnetic Resonance Than Those With Viral Myocarditis

https://doi.org/10.21203/rs.3.rs-2460008/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 01 Apr, 2023

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Introduction

There have been reports of myocarditis following vaccination against COVID-19. We sought to describe cardiac magnetic resonance (CMR) findings among pediatric patients.

Methods and Results

Retrospective review at a large academic center of patients clinically diagnosed with post-vaccine myocarditis (PVM) undergoing CMR. Data collected included parametric mapping, ventricular function and degree of late gadolinium enhancement (LGE). Post processing strain analysis was performed using tissue tracking. Strain values, T1/T2 values and ventricular function were compared to age-and gender-matched controls with viral myocarditis using a Wilcoxon Signed Rank test.

Among 12 patients with presumed PVM, 11 were male and 11 presented after the second vaccination dose, typically within 4 days. All presented with chest pain and elevated troponin. 10 met MRI criteria for myocarditis. All had LGE typically seen in the lateral and inferior walls; only five had prolonged T1 values. 10 met criteria for edema based on skeletal muscle to myocardium signal intensity ratio, and only 5 had prolonged T2 mapping values. Patients with PVM had greater short-axis global circumferential and radial strain, right ventricle function and cardiac output when compared to those with viral myocarditis.

Conclusion

Patients with PVM have greater short-axis global circumferential and radial strains compared to those with viral myocarditis. LGE was universal in our cohort. Signal intensity ratios between skeletal muscle and myocardium may be more sensitive in identifying edema than T2 mapping. Overall, the impact on myocardial strain by CMR is less significant in PVM compared to more classic viral myocarditis.

Myocarditis

Cardiac Magnetic Resonance

COVID-19

Pediatric

Vaccination

Following the Food and Drug Administration’s Emergency Use Authorization (EUA) for the Pfizer-BioNTech BNT1262b2 mRNA vaccine in December 2020, scattered reports emerged of myocarditis temporally associated with vaccine administration. This finding was also reported in the pediatric population after the EUA was extended to patients above age 12 in March 2021.^1–14

While there are multiple studies detailing the clinical presentation and course of post-vaccine myocarditis, there is little in the way of comparison of these findings with typical viral myocarditis. Cardiac magnetic resonance (CMR) has been used for years for the diagnosis and management of myocarditis.^15–19 However, detailed CMR data on tissue characterization and ventricular function including strain is lacking, especially in the pediatric population. We hypothesized that vaccine myocarditis may have less effect on ventricular function than routine viral myocarditis. The purpose of the current study was to retrospectively leverage granular CMR data from a large volume academic institution (with consistent imaging protocols and interpretation methodologies for all patients) to compare post-vaccine myocarditis with viral myocarditis.

This study was a retrospective chart review of patients who were clinically diagnosed with myocarditis after vaccination against COVID-19. Inclusion criteria included age under 21 years and presenting within 30 days of a vaccination dose. Patients who presented with an active viral infection were excluded. Each study subject was age (within 6 months) and gender-matched to a control patient diagnosed with presumed viral myocarditis. Potential study subjects with cyanotic and/or symptomatic congenital heart disease, cardiomyopathy, giant cell myocarditis or a plausible alternate explanation for presentation were not selected. Potential controls who presented with fulminant myocarditis requiring extracorporeal membrane oxygenation, intubation or mechanical circulatory support were excluded.

Cardiac magnetic resonance (CMR) for patients with suspected myocarditis include cine steady-state free precession imaging in the 4-chamber, 2-chamber, ventricular short axis, and the left ventricular and right ventricular outflow tract views. Through-plane phase contrast velocity mapping was performed at the aortic root and main pulmonary artery to also assess cardiac output and confirm measurements of ventricular stroke volume. Gadobutrol was used for contrast enhanced imaging. Angiography including coronary imaging was performed with inversion recovery gradient echo imaging using ECG gating with navigators for respiratory motion adaptation. Multiparametric mapping was performed in the short axis projection in the basal, mid and apical views consisting of Modified Look-Locker Inversion recovery sequences for T1 mapping, T2-weighted turbo-inversion recovery magnitude (TIRM) sequences to assess signal intensity ratios of cardiac and skeletal muscle, and T2-prepared single shot steady state free precession sequences for T2 mapping. Late gadolinium enhancement assessment was performed in the 4-chamber, long axis, and short axis views using respiratory motion corrected magnitude and phase sensitive inversion recovery sequences.

Among 12 patients, 11 studies were performed on a 1.5 Tesla Siemens MRI system (Siemens Medical Solutions, Erlangen, Germany) and 1 study was performed on a 3 Tesla Siemens MRI system. CMR analysis was performed using cvi42 software (Circle Cardiovascular Imaging, Calgary, Canada). Per our center’s practice, native T1 values above 1070 ms were considered prolonged and peak regional T2 values above 60 ms were considered abnormal for patients undergoing studies on a 1.5 Tesla scanner.^20,21 Native T1 values above 1149 ms and peak regional T2 values above 62 ms were considered abnormal for studies performed at 3 Tesla.²² CMR studies with evidence of both myocardial edema and non-ischemic myocardial injury were considered positive for myocarditis per published guidelines.¹⁷ Strain analysis was performed with the tissue tracking technique using cines obtained in the short axis, four chamber, two chamber and three chamber views.

Statistical analyses were performed using R version 4.0 (R Foundation, Vienna, Austria) and statistical significance was assessed at the 0.05 level. Strain values, T1 values, extracellular volume, T2 values and ventricular function were compared to age- and gender-matched controls with viral myocarditis using a Wilcoxon Signed Rank test. Spearman’s correlation test was used to determine correlation between strain values, degree of late gadolinium enhancement and parametric mapping. Patient #4 was excluded from correlation analysis between strain values and parametric mapping as their study was performed on a 3 Tesla MRI scanner. The study protocol was approved by the institutional review board.

Baseline Clinical Information

Among 12 patients with presumed post-vaccine myocarditis, 11 were male, ranging from 12 to 17 years old (median 15.5 years, IQR 13–18 years). No patients had a known history of COVID-19 infection. All patients received the BNT1262b vaccine, as the only COVID-19 vaccine approved for this age group (Table 1) at the time of this study. 11 patients presented after their second vaccine dose, and 11 of 12 patients presented within 4 days of receiving the vaccine dose; the remaining patient presented 22 days later without any intervening illness (median = 2.5 days, IQR 1.25–3.75 days). All patients presented with chest pain, and 7 presented with fever or shortness of breath. Patients universally had an elevated troponin, often markedly elevated, and only three patients had mildly elevated B-natriuretic peptide levels. Electrocardiogram (ECG) changes were present in 11 of 12 patients with the most common changes being ST elevation in the inferolateral leads, typically corresponding to regions of late gadolinium enhancement on CMR. Echocardiograms were performed on all patients at the time of admission. 10 patients had normal biventricular ejection. One patient (#6) had mildly depressed left ventricular ejection that normalized two days later and one patient (#5) had mildly depressed left ventricular ejection that was normal 7 days later. No patients had pericardial effusions or wall motion abnormalities.

Table 1

Study Patient Characteristics
Patient	Age (years)	Gender	Vaccine Given	Vaccine Dose	Symptom Onset	Symptoms	Peak Troponin-I	Peak BNP	EKG Changes
1	12	M	BNT1262b2 (Pfizer)	Second	3 days	Chest Pain	5.87	118*	T-wave inversion in inferior leads
2	16	M	BNT1262b2 (Pfizer)	Second	1 day	Chest Pain, Fever, Myalgias, Malaise	14.6	419*	PR depression, Nonspecific T-wave changes
3	13	M	BNT1262b2 (Pfizer)	Second	1 day	Chest Pain, Fever, Headache, Nausea	18.83	35	ST Elevation in Anterolateral and Inferolateral leads
4	17	M	BNT1262b2 (Pfizer)	Second	2 days	Chest Pain, Nausea	25.75	87	None
5	17	M	BNT1262b2 (Pfizer)	Second	3 days	Chest Pain	8.12	30.1	ST Elevation, PR Depression in Inferolateral Leads
6	15	M	BNT1262b2 (Pfizer)	Second	1 day	Chest Pain, Fever, Nausea	88.38	293.4	ST Elevation in Inferolateral Leads
7	14	M	BNT1262b2 (Pfizer)	Second	3 days	Chest Pain, Malaise, Fever, Nausea, Myalgias	1.95	< 10	Nonspecific T-wave Changes
8	16	M	BNT1262b2 (Pfizer)	Second	22 days	Chest Pain	13.13	31	ST Elevation, T-wave inversion in inferolateral leads
9	17	F	BNT1262b2 (Pfizer)	Second	2 days	Chest Pain, Malaise, Fever	7.06	20.2	T wave inversion in inferior leads
10	13	M	BNT1262b2 (Pfizer)	Second	2 days	Chest Pain, Malaise, Fever	15.15	56.6	ST Elevation in Inferolateral Leads, T wave Inversions in Inferior Leads
11	14	M	BNT1262b2 (Pfizer)	First	3 days	Chest Pain, Malaise, Fever	8.48	31.2	ST elevation in Inferolateral Leads
12	16	M	BNT1262b2 (Pfizer)	Second	4 days	Chest Pain	22†	not drawn	Sinus rhythm, premature ventricular complex
* NT-proBNP with listed normal values < 125 pg/mL
† high sensitivity troponin level, with normal values listed as < 14 ng/mL
Troponin-I measured in ng/mL; BNP = Brain natriuretic peptide, in pg/mL

All 12 patients were admitted and were treated with supportive care consisting of nonsteroidal anti-inflammatory drugs. No patients received corticosteroids or intravenous immunoglobulin. No patients required increased support such as inotrope infusion, extracorporeal membrane oxygenation, or heart failure medications. All patients were discharged within 96 hours of admission.

There were 11 male and 1 female control patients, ranging from 13–17 years old (median 15.5 years, IQR 14-16.5 years). All patients presented with chest pain while 9 of 12 had additional symptoms. (Table 2) All 12 patients were admitted and treated with supportive care consisting of NSAIDs. 9 patients had normal ventricular function, 2 patients had mildly depressed function and 1 patient had moderately depressed function. Two patients had wall motion abnormalities. 11 of 12 patients had abnormal EKGs. 7 of 12 patients presented with ST elevation on EKG.

Table 2

Control Patient Characteristics
Patient	Age (years)	Gender	Symptom Onset	Symptoms	Peak Troponin-I	Peak BNP	EKG Changes
1	13	M	2 days	Chest pain, fevers, nausea, fatigue, abdominal pain	45.96	1011.9	ST Elevation in anterolateral leads, nonspecific T wave changes
2	16	M	1 day	Chest pain, Recent gastrointestinal illness	21.42	Not drawn	Nonspecific ST segment and T wave changes
3	14	M	2 days	Chest Pain	6.82	Not drawn	ST Elevation in lateral leads
4	17	M	1 day	Chest pain, Nausea	12.23	93	Nonspecific T wave changes
5	17	M	1 day	Chest pain, Fatigue	33.03	160.5 *	ST Elevation in inferior leads
6	15	M	2 days	Fever, Dizziness, pre-syncopal symptoms	7.73	1233	Nonspecific T wave changes
7	14	M	3 days	Chest pain, Fever, Abdominal pain	28.31	Not drawn	ST Elevation in lateral leads
8	16	M	7 days	Chest pain, Shortness of breath, Headache, Fever	8.27	762.2	ST Elevation and T wave inversion in lateral precordial leads, T wave inversion in inferior leads
9	17	F	1 day	Chest pain	0.14	Not drawn	No abnormalities
10	14	M	1 day	Chest pain	13.60	121.8	ST Elevation in inferior leads
11	14	M	10 days	Chest pain, Headache, Nausea, Dizziness	23.99	36.7	Nonspecific ST changes
12	16	M	2 days	Chest Pain, Dizziness, Nausea, Headache	25.97	100.8	Diffuse ST segment elevation
* NT-proBNP with listed normal values < 100 pg/mL
Troponin-I measured in ng/mL; BNP = Brain natriuretic peptide, in pg/mL

All control patients were discharged home within one week of admission. No patients received intravenous immunoglobulin or steroids, nor did any patients require any mechanical circulatory support, endotracheal intubation or extracorporeal membrane oxygenation. All control patients had normal ventricular function with no wall motion abnormalities at the time of follow up and none had disease that progressed to dilated cardiomyopathy or chronic heart failure.

CMR Findings, Vaccine Myocarditis

CMR was obtained between 4 and 41 days after vaccine administration. (Table 3) Studies met criteria for myocarditis in 10 patients. All patients had normal biventricular size and ejection fraction on CMR. Every patient met criteria for non-ischemic myocardial injury on the basis of late gadolinium imaging (Table 4, Fig. 1–2). While the pattern of late gadolinium enhancement was heterogeneous in our cohort, 9 of 12 patients had enhancement in the inferior or inferolateral wall at various levels (Table 4) and the remaining patients had enhancement across the entire lateral free wall at varying short axis levels. Five patients (#4, 6, 8, 9, 11) also had a prolonged global native T1 time; three patients had a global ECV of 30% or greater. However, six of nine patients with a global ECV less than 30% had regional elevation of the ECV.

Table 3

Cardiac Magnetic Resonance Imaging Findings
Patient	Vaccine to CMR	Global Native T1	Global Contrast Enhanced T1	Hematocrit	Global ECV	Global PC	Peak T2	TIRM Ratio* Base Mid Apex			RV EF	LV EF	Cardiac Output
1	15 days	1010 ms	388 ms	37%	27%§	44%	63.0 ms	2.5	2.0	2.1	70%	80%	4.0
2	18 days	1016 ms	498 ms	49%	25%	49.5%	52.5 ms	3.3	3.6	3.0	67%	69%	4.8
3	4 days	1062 ms	447 ms	40%	30%	50%	63.0 ms	2.8	2.3	2.8	66%	74%	4.9
4†	6 days	1267 ms	552 ms	44%	23% §	42%	47.2 ms	1.8	4.4	4.2	56%	86%	3.7
5	7 days	1003 ms	415 ms	44%	22%	39%	50.4 ms	1.3	1.6	2.1	63%	67%	4.7
6	6 days	1201 ms	463 ms	37%	33%	54%	66.0 ms	2.0	2.3	2.9	58%	59%	4.1
7	9 days	1022 ms	491 ms	39%	28% §	46%	47.0 ms	1.8	1.8	2.0	71%	76%	4.6
8	26 days	1100 ms	427 ms	43%	30%	52%	62.0 ms	0.6	1.9	4.1	58%	61%	4.1
9	41 days	1293 ms	441 ms	40%‡	28% §	45%	46.0 ms	1.1	1.4	1.1	65%	66%	2.4
10	4 days	1033 ms	475 ms	41%	28% §	50%	55.0 ms	2.0	1.8	1.7	72%	78%	5.9
11	6 days	1089 ms	425 ms	34%	27%	41%	61.0 ms	1.4	1.8	2.5	70%	72%	3.8
12	7 days	1019 ms	448 ms	41%	28% §	47%	53.0 ms	1.8	3.2	3.1	59%	57%	4.3
Control 1	N/A	1234 ms	431 ms	31%	37%	52%	67.0 ms	2.1	2.9	3.2	43%	44%	3.0
Control 2	N/A	1028 ms	378 ms	34%	27%	44%	55.7 ms	1.6	1.3	2.1	76%	61%	3.6
Control 3	N/A	1022 ms	455 ms	40%	25%	44%	N/A	2.0	2.4	1.9	68%	56%	3.5
Control 4	N/A	1101 ms	412 ms	43%	32%	53%	N/A	1.0	1.7	2.6	60%	63%	3.5
Control 5	N/A	1013 ms	384 ms	43%	23%	43%	48.6 ms	2.9	2.7	N/A	70%	63%	3.6
Control 6	N/A	1047 ms	435 ms	40%‡	25%	41%	53.5 ms	2.0	3.0	3.0	64%	61%	3.1
Control 7	N/A	1018 ms	438 ms	45%	26% §	48%	N/A	1.6	2.2	2.4	71%	59%	3.6
Control 8	N/A	1173 ms	362 ms	40%	35%	59%	74.5 ms	3.9	4.4	4.1	53%	62%	2.7
Control 9	N/A	1009 ms	369 ms	44%	24%	47%	52.7 ms	2.3	2.4	2.9	66%	65%	2.6
Control 10	N/A	1032 ms	484 ms	42%	30%	52%	N/A	1.8	3.0	3.5	77%	46%	4.8
Control 11	N/A	1022 ms	454 ms	38%	30%	49%	54.1 ms	3.7	2.5	2.2	66%	57%	3.8
Control 12	N/A	1089 ms	411 ms	40%	32%	54%	50.8 ms	2.1	2.6	3.4	66%	47%	3.7
* Ratio of signal intensity on Turbo Inversion Recovery Magnitude Imaging (TIRM) between myocardium and skeletal muscle
† Study performed on a 3 Tesla MRI scanner
‡ Study done with assumed hematocrit of 40%
§ Although global ECV was within normal limits, regional ECV over 30% were noted
CMR = Cardiac Magnetic Resonance, ECV = extracellular volume, PC = partition coefficient, RV = Right Ventricle, LV = Left Ventricle, EF = Ejection Fraction

Table 4

Late Gadolinium Enhancement Findings
Patient	Regions of Enhancement
1	Basal Inferior and Inferolateral Walls
2	Mid to Apical Lateral Wall
3	Basal, Mid and Apical Anterior, Anterolateral, Inferolateral and Inferior Walls; Mid Inferolateral Wall
4	Mid inferolateral and anterolateral walls, apical and basal anterior and lateral walls, tip of apex
5	Mid and Apical Anterolateral and inferolateral extending into the inferior wall
6	Lateral wall from base to apex, basal inferior septum
7	Basal inferior septum
8	Lateral wall of the apex extending to the mid ventricle, Apical inferior wall
9	Lateral wall at the apex
10	Basal inferior lateral wall
11	Mid lateral free wall, extending into the apical and basal lateral free wall
12	Mid to apical anterolateral free wall

Table 5

Cardiac Magnetic Resonance Strain Data
	Study Patients				Control Patients
	SAX Global Circ Strain	SAX Global Radial Strain	LAX Global Long Strain	LAX Global Radial Strain	SAX Global Circ Strain	SAX Global Radial Strain	LAX Global Long Strain	LAX Global Radial Strain
1	-22.7	46.6	-20.8	41.4	-11.2	15.3	-13.5	21.8
2	-21.1	38	-19.3	33.1	-21.6	40.6	-22.9	51.3
3	-21.5	41.6	-20.5	36.6	-20.3	37	-17.6	32.9
4	-21.3	45	-18.6	32.9	-16.7	28	-19.9	37.3
5	-21.1	39.5	-18.4	34.4	-19.6	34.2	-19.9	35.6
6	-18.5	30.6	-15.5	24.2	-19.4	34.6	-15.3	24.3
7	-24.3	52.7	-24.4	55.1	-20.3	37.6	-18.9	34.1
8	-19.3	33.5	-15.7	25.5	-13.4	19.8	-13.5	20.6
9	-22.3	43.1	-19.4	35.4	-17.7	29.2	-17.9	30.8
10	-24.4	55.2	-21.4	41.7	-23.1	47.4	-15.8	35.8
11	-21.3	40.1	-17.3	31.5	-22.2	42.4	-20	36.2
12	-19.8	37.6	-18.9	33	-17.4	29.8	-16.9	27.4
* SAX = Short axis, LAX = Long Axis
† All strain data is expressed in percentages

Table 6

Comparison of Study Patients to Age Matched Controls
	Study Patients Median IQR		Age Matched Controls Median IQR		p value
LV Ejection Fraction	70.5%	63.5, 77.0	66	62.0, 70.5	0.28
RV Ejection Fraction	65.7%	58.0, 69.8	60	51.5, 62.5	0.042
Indexed Cardiac Output	4.2 L/min/m²	3.9, 4.8	3.6	3.1, 3.7	0.024
Short Axis Global Circumferential Strain	-21.3%	-22.5, -20.5	-19.5	-21.0, -17.1	0.006
Short Axis Global Radial Strain	40.9%	37.8, 45.8	34.4	28.6, 39.1	0.007
Long Axis Global Longitudinal Strain	-19.1%	-20.7, -17.9	-17.8	-19.9, -15.6	0.18
Long Axis Global Radial Strain	33.8%	32.2, 39.0	33.5	25.9, 36.0	0.18
Native T1*	1033 ms	1018, 1094	1028	1020, 1068	0.97
Contrast T1*	447 ms	426, 469	431	381, 446	0.10
ECV	28%	25.35, 30.65	30	23.25, 36.75	0.27
Peak T2 (n = 8)	54 ms	41.35, 66.65	49.5	41.75, 57.25	0.44
* Patient 4 was excluded from T1 value analysis as his study was done with a 3.0 Tesla scanner

Table 7

Correlation Between Strain and Parametric Mapping in Study Patients
	Native T1*	Contrast Enhanced T1*	Extracellular Volume	Partition Coefficient	Mass of Myocardium with Late Enhancement	Percentage of Myocardium with Late Enhancement
Short Axis Global Circumferential Strain	r = 0.17 p = 0.67	r = -0.07 p = 0.84	r = 0.11 p = 0.73	r = 0.27 p = 0.40	r = 0.33 p = 0.30	r = 0.14 p = 0.66
Short Axis Global Radial Strain	r = -0.18 p = 0.59	r = 0.03 p = 0.94	r = -0.22 p = 0.49	r = -0.34 p = 0.24	r = -0.22 p = 0.48	r = -0.12 p = 0.72
Long Axis Global Longitudinal Strain	r = 0.33 p = 0.33	r = -0.27 p = 0.42	r = 0.04 p = 0.91	r = 0.05 p = 0.86	r = 0.45 p = 0.14	r = 0.36 p = 0.24
Long Axis Global Radial Strain	r = -0.37 p = 0.26	r = 0.15 p = 0.67	r = -0.10 p = 0.76	r = -0.16 p = 0.62	r = -0.53 p = 0.07	r = -0.44 p = 0.15
* Patient 4 was excluded from T1 value analysis as his study was done with a 3.0 Tesla scanner

Ten patients had signal intensity ratios of cardiac and skeletal muscle equal to or greater than 1.9 on T2 weighted TIRM sequences and five patients had prolonged T2 relaxation values. (Fig. 3) Even using a cutoff of > 55 msec, this finding would not have changed. Two patients, #9 and 10, did not meet criteria for myocardial edema for either TIRM ratio or T2 relaxation times.

One of these patients (#9) underwent her CMR 39 days after the onset of symptoms and was asymptomatic at the time of her study. She did undergo an echocardiogram one day after symptom onset that demonstrated normal biventricular function with no wall motion abnormalities or effusions.

One patient (#4) was incidentally diagnosed with partial anomalous pulmonary venous connection of the left upper pulmonary vein to the innominate vein and right upper pulmonary

vein as well as right middle pulmonary vein to the right superior vena cava; his Qp:Qs was roughly 1.9:1 by CMR. Another patient (#6) had a history of a bicuspid aortic valve; his echocardiogram and CMR demonstrated insignificant aortic insufficiency and stenosis.

CMR Findings, Viral Myocarditis: CMR was obtained within 10 days after symptoms onset in 11 of 12 patients with viral myocarditis. One patient had CMR performed three months later that definitively met criteria for myocarditis. Eleven patients met criteria for myocarditis; one patient was felt to be borderline positive on the basis of very minimal late gadolinium enhancement. Three patients had mildly depressed left ventricular function, though as a whole the left ventricular function was not significantly different from the study cohort. One patient had mildly depressed right ventricular function. Late gadolinium enhancement was universal in the control patients. Six of 12 patients had increased global ECV; one additional patient had a normal global ECV but increased regional ECV. All control patients met criteria for edema on the basis of signal intensity on T2 weighted TIRM sequences. Only two of eight patients who underwent T2 mapping had prolonged T2 values. No patients had any form of congenital heart disease.

Comparison between CMR findings of vaccine and viral myocarditis: Compared to age matched controls with viral myocarditis, patients with post-vaccine myocarditis had a higher right ventricular ejection fraction (RVEF) and cardiac index. (Table 6) They also had more favorable short axis global circumferential and radial strain (Tables 5 and 6). There was no difference between the two cohorts in long axis strain, T1 values and left ventricular function. Amongst patients with post-vaccine myocarditis, there was no correlation between strain values and quantification of late gadolinium enhancement nor strain values and T1 values or extracellular volume (Tables 6 and 7).

In this study comparing pediatric patients with post-vaccine myocarditis and viral myocarditis, we found that patients with post-vaccine myocarditis have more favorable short axis global circumferential and radial strain as well an increased right ventricular ejection fraction and cardiac index. However, there was no correlation of myocardial strain to either the burden of late gadolinium enhancement nor extracellular volume or T1 values.

Post-vaccine myocarditis is a rare phenomenon and has been reported in vaccinations previously, including oral polio, influenza, and smallpox vaccination.^23-25 In cases not directly caused by infection of the myocardium²³, the suspected pathogenesis of post-vaccine myocarditis is “molecular mimicry” between antigens involved in producing vaccination response and those on the myocardium.^24,26

CMR parametric mapping data in cases of pediatric post-COVID-19 vaccine myocarditis in the literature is limited. Shaw et al described two pediatric patients with T1 values, T2 values, and extracellular volume ranging from 1122-1172ms (normal 950-1050ms), 56-74ms (normal < 55ms) and 38 to 42% (normal < 28%), respectively.⁵ Dionne et al described 15 patients, with 4 of 15 patients showing borderline or elevated T1 values, 1 of 15 with borderline elevated T2 values and 2 of 15 with regional hyperintensity on T2 weighted imaging.¹⁴ Vidula et al described an 18 year old who had a T1 time and T2 time of 1089-1097ms, respectively.² McLean et al and Park reported hyperemia and early enhancement, respectively but without reporting T1 values.^1,4 There was no comparison in any of these studies with viral myocarditis.

All 12 patients had late gadolinium enhancement, predominantly in the lateral and inferior walls of the left ventricle. This pattern is consistent with cases of pediatric post-COVID-19 vaccination myocarditis reported in the literature. Similar patterns have also been found after smallpox vaccination.²⁷ Early data suggests that this late gadolinium enhancement may improve over time,¹³ but long-term CMR data and clinical outcomes are still to be determined.

We found that patients with post-vaccine myocarditis had more favorable short axis longitudinal and radial strain compared to patients with viral myocarditis. This finding has not been previously reported in the pediatric population. Myocardial strain can be more sensitive in identifying decreased myocardial deformation than ejection fraction as a normal global ejection fraction can mask diseased and hypokinetic segments. Less favorable strain is associated with adverse events such as all-cause mortality, ventricular tachycardia of longer than 30 seconds and hospitalization for heart failure in adult patients with myocarditis.²⁸ In addition, adult patients with fulminant myocarditis have less favorable strain than those with non-fulminant myocarditis.²⁹ Our study cohort had normal values for strain³⁰ and more favorable strain for previously published strain values in children with myocarditis.³¹ This suggests that post-vaccine myocarditis represents a milder variant of myocarditis.

We failed to find any correlation between parametric mapping values and the amount of discrete fibrosis with strain values. (Table 5) This may be due to our cohort’s small sample size; a larger sample size to determine this would be needed. Previous studies in other diseases such as tetralogy of Fallot has found a correlation between T1 mapping and left ventricular strain, however, DENSE was used to measure myocardial deformation in that study.³²

A relatively low proportion of patients both reported in the literature as well as in this case series have had elevated T2 relaxation times. Using the myocardial to skeletal muscle signal intensity ratio may have increased sensitivity to identify patients with myocardial edema. Alternatively, further work may be needed to identify a more appropriate cutoff for myocardial T2 values to help increase the sensitivity of T2 mapping.

We also found that although the RVEF was normal in both cohorts, patients with post-vaccine myocarditis had a greater RVEF. Previous studies have shown that depressed right ventricular function has been associated with adverse events.³³

Despite the findings in this study, the benefits of vaccination far outweigh the risks.³⁴ The rate of myocarditis is far higher in patients with COVID-19 than in patients receiving the COVID-19 vaccine.³⁵ In addition, children with COVID-19 are at risk for the subsequent multisystem inflammatory syndrome in children (MIS-C), in which children present with severe multi-organ inflammation about 2-6 weeks after the initial infection, sometimes in shock and requiring intensive care with decreased ventricular function.³⁶

This study was limited due to its retrospective nature and relatively small cohort as patients were enrolled from a single center. However, these limitations allow for consistent CMR scanning techniques, sequence analysis and imaging interpretation. Each patient’s diagnosis was felt to be consistent with post-vaccine myocarditis by the clinical providers, but causation cannot necessarily be proved.

Post-vaccine myocarditis has more favorable short axis global circumferential and radial myocardial strain than those with viral myocarditis, lending to the notion that this illness affects ventricular function less than viral myocarditis. Typical CMR findings in our cohort consisted of late gadolinium enhancement in the lateral and free walls of the left ventricle. Measurement of signal intensity ratios between skeletal muscle and myocardium may be more sensitive in identifying myocardial edema compared to T2 mapping at the current normative values used for this study. Overall, the impact on myocardial strain by CMR is less significant in post-vaccine myocarditis compared to more classic viral myocarditis.

Sources of Funding

This project was not funded by any internal or external funds.

Conflicts of interest/Competing interests: The authors declare that they have no conflict of interest.

Ethics approval: This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent: Not obtained due to retrospective study design

Authors' contributions: All authors contributed to the study conception and design. Material preparation and data collection were performed by Danish Vaiyani and Matthew Elias. All authors drafted, read, critically revised, and approved the final manuscript

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No competing interests reported.

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Patients with Post-COVID-19 Vaccination Myocarditis Have More Favorable Strain in Cardiac Magnetic Resonance Than Those With Viral Myocarditis

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