Natural History of Myocardial Injury After COVID-19 Vaccine-Associated Myocarditis.

BACKGROUND: Acute myocarditis is a rare complication of mRNA-based COVID-19 vaccination. Little is known about the natural history of this complication.
METHODS: Baseline and convalescent (≥ 90 days) cardiac magnetic resonance (CMR) imaging assessments were performed in 20 consecutive patients meeting Updated Lake Louise Criteria for acute myocarditis within 10 days of mRNA-based vaccination. CMR-based changes in left ventricular volumes, mass, ejection fraction (LVEF), markers of tissue inflammation (native T1 and T2 mapping), and fibrosis (late gadolinium enhancement [LGE] and extracellular volume [ECV]) were assessed between baseline and convalescence. Cardiac symptoms and clinical outcomes were captured.
RESULTS: Median age was 23.1 years (range 18-39 years), and 17 (85%) were male. Convalescent evaluations were performed at a median (IQR) 3.7 (3.3-6.2) months. The LVEF showed a mean 3% absolute improvement, accompanied by a 7% reduction in LV end-diastolic volume and 5% reduction in LV mass (all P < 0.015). Global LGE burden was reduced by 66% (P < 0.001). Absolute reductions in global T2, native T1, and ECV of 2.1 ms, 58 ms, and 2.9%, repectively, were documented (all P ≤ 0.001). Of 5 patients demonstrating LVEF ≤ 50% at baseline, all recovered to above this threshold in convalescence. A total of 18 (90%) patients showed persistence of abnormal LGE although mean fibrosis burden was < 5% of LV mass in 85% of cases. No patient experienced major clinical outcomes.
CONCLUSIONS: COVID-19 mRNA vaccine-associated myocarditis showed rapid improvements in CMR-based markers of edema, contractile function, and global LGE burden beyond 3 months of recovery in this young patient cohort. However, regional fibrosis following edema resolution was commonly observed, justifying need for ongoing surveillance.

INTRODUCTION

The rapid development, regulatory approval, and global distribution of mRNA-based vaccination against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) virus or COVID-19 is considered one of the greatest contributions to public health in modern history. As of March 1st, 2022 more than 10 billion vaccine doses have been administered across 184 countries. In this context, several case series2, 3, 4, 5, 6, 7, 8, 9, 10 have reported rare occurrences of acute myocarditis early following vaccination, particularly among younger males11, 12, 13. These observations have led to expanding interest and concern regarding the downstream sequelae of this potentially serious complication.

CMR imaging provides highly reproducible evaluations of chamber volumetry, mass, function, and tissue injury in the setting of acute myocarditis. Water-sensitive T2 (edema) imaging and fibrosis-sensitive late gadolinium enhancement (LGE) imaging can be complemented by parametric T1 and T2 mapping to permit the serial quantification of acute myocardial injury. Pre-pandemic CMR cohort studies of community-acquired acute myocarditis collectively suggest the acute inflammatory stage of myocarditis to resolve over a 3-month period, at which time parametric markers of tissue edema normalize and permit the reasonable evaluation of residual fibrosis15, 16, 17, 18. However, COVID-19 vaccine associated myocarditis is postulated to be related to an over-aggressive immune response to host-cell manufactured mRNA nucleosides . Whether this unique and iatrogenic mechanism of immune-mediated cytotoxic injury carries similar natural history to active viral myocarditis is unknown.

In this study we recruited 20 consecutive patients presenting with acute myocarditis within 10 days of mRNA-based COVID-19 vaccination. All patients underwent baseline and ≥3-month convalescent assessments inclusive of clinical evaluation and comprehensive CMR imaging, the latter facilitating serial quantitative analysis of myocardial injury. Tissue injury findings were evaluated in the context of chamber remodelling, contractile recovery, symptom burden, and major clinical outcomes.

METHODS

Twenty adult (≥18-year-old) patients diagnosed with acute myocarditis within 10 days of receiving an mRNA-based COVID-19 vaccine between June 2021 and December 2021 were enrolled. Patients were required to have a high clinical suspicion of acute myocarditis based upon the European Society of Cardiology Diagnostic Criteria and meet CMR-based diagnostic criteria for acute myocarditis by the Updated Lake Louise Criteria. All subjects underwent CMR imaging, baseline blood collection, 12-lead ECG, chest x-ray and clinical evaluations. A detailed health questionnaire inclusive of demographics, current cardiac symptoms, prior history of inflammatory disease and comorbid illnesses was completed. Patients were then asked to undergo repeat CMR imaging, questionnaires, and a review of medical records at a minimum 3-months of convalescence. Informed patient consent was obtained under the Cardiovascular Imaging Registry of Calgary (CIROC, NCT04367220).

CMR imaging was performed using 3 Tesla scanners (Prisma or Skyra, Siemens Healthineers, USA). The imaging protocol included balanced steady state-free precession (bSSFP) cine imaging in sequential short and long-axis planes followed by native T1mapping using a modified lock-locker inversion recovery (MOLLI) technique, T2 mapping using a T2-prepared gradient echo (GRE) technique, and black blood T2-weighted imaging using a spectral attenuated inversion recovery (SPAIR) technique prior to contrast infusion of 0.15 mmol/kg gadolinium (Gadovist, Bayer Inc. Canada). Ten minutes following contrast administration, late gadolinium enhancement (LGE) imaging was performed in short and long axis views using a phase-sensitive inversion recovery (PSIR) pulse sequence, followed by repeat T1 mapping for the estimation of extracellular volume (ECV) fraction.

Image post-processing was performed using commercial software (cvi42TM version 5.13.5, Circle Cardiovascular Imaging, Calgary, Canada). Baseline and follow up studies were analyzed by trained core laboratory personnel blinded to clinical data. Analysis was conducted in accordance with recommendations of the Society of Cardiovascular Magnetic Resonance . Semi-automated contours were applied to short-axis cine images to obtain biventricular end-diastolic and end-systolic volumes, ejection fraction, and LV mass. Volumetric analyses were indexed to body surface area using the Mosteller formula. LGE images were analyzed using the signal threshold versus reference myocardium (STRM) technique at 5 standard deviations (5SD) above reference myocardium. Regional patterns of LGE were scored as subepicardial, mid-wall patchy, mid-wall striae, diffuse, RV insertion site and subendocardial. The presence of regional edema (signal ≥2-fold skeletal muscle) was identified from T2-weighted SPAIR imaging. Finally, native T1 and T2 maps were analyzed for the basal, mid, and apical views. Segmental values were generated for the 16-segment AHA model with global values provided as the average of all segments. Identical methods were applied to reconstructed ECV maps.

Minor and Major Cardiovascular Outcomes

At convalescent assessments all patients were interviewed, and medical records reviewed to identify clinical evidence of major and minor clinical outcomes. Major clinical outcomes were defined as cardiac hospitalization, new-onset heart failure requiring diuretic use, atrial fibrillation, or ventricular arrhythmia. Minor clinical outcomes were defined as persistent chest pain or need for escalation in medical therapy.

Statistical Analysis

Descriptive statistics were provided as percentages for discrete variables and mean (standard deviation) or median (range or interquartile range) for continuous variables. Paired t-test or Wilcoxon-Rank-Sum tests were used to compare baseline to follow up CMR parameters, depending on normality of variable distributions. A two-sided p-value of < 0.05 was considered for statistical significance. All analyses were performed using IBM SPSS Statistics for Windows, version 28 (IBM Corp., Armonk, N.Y., USA).

RESULTS

Clinical Characteristics

Patient characteristics are summarized in Table 1 . All patients were under 40 years of age with a majority (85%) being male. Sixteen (80%) patients presented following a second mRNA vaccination within 6 days (range: 2-6 days), while four presented following first mRNA vaccination within 10 days (range: 2-10 days). Of the former group, four received a second dose of BNT162b2 [Pfizer-BioNTech], 12 (60%) a second dose of mRNA-1273 [Moderna]. Of the latter group, two received a single dose of BNT162b2 [Pfizer-BioNTech], while two a first dose of mRNA-1273 [Moderna]. Four patients described prior (>6 month) history of a mild, PCR-confirmed COVID-19 infection without chest pain or hospitalization. Nineteen (95%) patients presented with chest pain with one describing as upper epigastric pain, and none had any antecedent viral respiratory symptoms. No patient had a history of rheumatologic or connective tissue disease. A single patient reported prior history of myocarditis 10 years prior.

Table 1

Baseline clinical characteristics of patients with COVID-19 vaccine associated myocarditis (n=20)

Variable	N (%)
Baseline Clinical Characteristics
Age, median (IQR) years	23.1(20.3-29.4)
Male sex	17 (85)
BMI (kg/m2), median (IQR)	25 (23.2-27.6)
Diabetes	0 (0)
Hypertension	0 (0)
Dyslipidemia	0 (0)
Current smoker	0 (0)
Presenting symptomatologyChest painDyspneaMyalgiasSweatingEpigastric discomfort	19 (95)2 (10)1 (5)1 (5)1 (5)
HospitalizedCCU admission	18 (90)3 (15)
In-hospital clinical complicationsHypotensionHeart failureRespiratory failure / IntubationAtrial arrhythmiaVentricular arrhythmia	0 (0)0 (0)0 (0)0 (0)0 (0)
Length of hospital stay, median (IQR) days	3 (2-3)
Peak hs-troponin T (ng/L), mean (SD)	958 (627)
Peak NT-proBNP (ng/L), median (IQR) days	576 (211-931)(N=4 patients)
Peak CRP (mg/L), mean (SD)	35.0 (24.1)
Leukocytosis (WBC>11,000 per mm3)	1 (5)
ECG at presentationNormalST elevation (diffuse or regional)PR depression	9 (45)11 (55)4 (20)
Coronary artery angiographyAbnormalNormalNot performed	0 (0)2 (10)18 (90)
Medications at dischargeColchicineNSAIDsSteroidsACEiBeta blockerSpironolactone	19 (95)15 (75)0 (0)5 (25)4 (20)1 (5)

The results of non-CMR diagnostic testing are summarized in Table 1. All had negative PCR testing for COVID-19. Elevations in high-sensitive Troponin-T were confirmed in all patients (peak levels 42-2320 ng/L; normal 0-13 ng/L) while 18 (90%) had elevation in C-reactive protein (10.5-96.2 mg/L, normal 0-8 mg/L). ST elevation was observed on the initial ECG in 11 (55%) patients. All chest x-ray results were normal.

Eighteen (90%) patients were hospitalized during their acute illness and were discharged without in-patient cardiac complications [median (IQR) length of hospital stay: 3 (2-3) days]. All but one patient was treated with colchicine, this combined with nonsteroidal anti-inflammatory drugs in 75%. Five patients, all having an LVEF <55%, were prescribed angiotensin converting enzyme inhibitors (ACEi), four additionally a beta-blocker, and one additionally spironolactone. No patient was prescribed steroids. All patients reported >50% symptom improvement within 48 hours of first colchicine dose.

Clinical Outcomes

Convalescent evaluations were conducted at a median (range, IQR) of 111 days (92-224, 99-186 days) from day of diagnosis. At this time 4 (20%) patients reported a minor outcome due to ongoing chest pain, for which all were receiving extended colchicine and NSAIDs therapy without steroids. No major clinical outcome was documented.

Cardiovascular Magnetic Resonance Findings

All patients completed baseline and follow-up CMR imaging. All studies were of diagnostic quality.

Baseline CMR imaging findings are summarized in Table 2 . All patients met Updated Lake Louise Criteria for acute myocarditis with typical findings, as shown in Fig. 1 and 2 . LV ejection fraction was below reference normal values (i.e., ≤56%) in 10 (50%) patients with 5 (25%) having an LV ejection fraction <50%. Regional elevation in T2 signal on SPAIR imaging was identified in 19 (95%) patients. All patients showed sub-epicardial pattern LGE involving the inferolateral and/or lateral wall segments; two patients (10%) being incrementally coded with mid-wall patchy LGE. Abnormal T1 and T2 signal elevation was commonly identified in segments without visible LGE, suggesting global myocardial edema. Post-contrast analyses identified a mean global LGE burden of 8.6 +/- 5.3% of the LV mass. Regionally matched elevations in ECV were observed (Table 2, Fig. 2 and 3 ).

Table 2

Comparison of baseline and follow Cardiovascular Magnetic Resonance (CMR) quantitative markers in COVID-19 vaccine-associated myocarditis

CMR variables	Baseline	Follow up	P value
LVEDVi, ml/m2	81.7 (73.9, 89.6)	75.8 (71.15, 84.9)	0.015
LVESVi, ml/m2	34.9 (31.4, 42.0)	32.6 (29.3, 34.8)	0.006
LVEF, %, mean (SD)	54.7 (5.94)	57.7 (3.48)	0.014
LVMI, g/m2	51.1 (45.8, 57,4)	48.4 (43.3, 51.7)	0.002
RVEDVi, ml/m2	79.4 (70.0, 79.4)	82.1 (72.9, 90.0)	0.093
RVESVi, ml/m2	36.4 (28.6, 43.7)	39 (34.0, 42.7)	0.048
RVEF, %, mean (SD)	53.8 (5.91)	54 (4.67)	0.004
LAVI-biplane, ml/m2	31.7 (26.4, 37.9)	31.9 (26.5, 34.6)	0.411
LGE mass (g, ≥5SD)	7.4 (3.24, 12.1)	1.7 (0.62, 3.16)	<0.001
Global LGE (% of LV mass, ≥5SD) , mean (SD)	8.6 (5.30)	2.9 (2.01)	<0.001
Global T2 (msec), mean (SD)	39.7 (2.39)	37.6 (1.89)	0.001
Global native T1 (msec), mean (SD)	1261.9 (45.5)	1203.9 (28.2)	<0.001
Global ECV, %	32.9 (30.9, 37.0)	30.0 (28.6, 32.0)	0.001

Data presented as median (IQR) unless otherwise specified

Abbreviations: IQR, interquartile range; LAVI, left atrial volume indexed to body surface area. LGE, late gadolinium enhancement; LV, left ventricle; LVEDVi, left ventricular end-diastolic volume indexed to body surface area; LVESVi, left ventricular end-systolic volume indexed to body surface area; LVEF, left ventricular ejection fraction; LVMI, indexed left ventricular mass; RV, right ventricle; RVEDVi, right ventricular end-diastolic volume indexed to body surface area; RVESVi, right ventricular end-systolic volume indexed to body surface area; RVEF, right ventricular ejection fraction. SD, standard deviation.

Figure 1

Baseline and convalescent Cardiac Magnetic Resonance (CMR) findings in an 18-year-old male with acute myocarditis 3 days following a second dose of mRNA-based vaccine. Top panel: Arrows indicate regional elevations in all tissue markers consistent with acute myocarditis. Bottom panel: Substantial improvement observed at 105 days follow-up with mild persistent fibrosis seen on LGE imaging in the basal inferior wall (arrows). SPAIR: spectral attenuated inversion recovery ECV: extracellular volume, LGE: late gadolinium enhancement

Figure 2

Cardiac Magnetic Resonance (CMR) quantitative imaging parameters measured at baseline and ≥3 months follow-up. LVEF: left ventricular ejection fraction; LGE, late gadolinium enhancement; ECV: extracellular volume

Figure 3

Comparison of baseline and follow-up mean segmental values of T2 mapping, native T1 mapping, extracellular volume (ECV) fraction, and late gadolinium enhancement (LGE) fibrosis burden using a 5 standard deviation threshold. Data are presented according to the American Heart Association (AHA) 16-segment model. Normal local reference values for T2, native T1, and ECV are 36-48msec, 1103-1263msec, and 23-31%, respectively.

The findings of convalescent CMR imaging are summarized in Table 2 and are graphically displayed in Fig. 2 and 3. Significant reductions in LVEDV (7.2% relative, p=0.015) and LVESV (6.6% relative, p=0.006) were observed, these associated with a significant 3% absolute increase in mean LV ejection fraction (p=0.014). A 5.2% relative reduction in LV mass was seen (p=0.002). Five out of 10 (50%) patients showing abnormal LV ejection fraction at baseline experienced normalization to normal values in convalescence. The remaining 5 patients had LV ejection fraction values between 52 and 55%. A single patient experienced an absolute drop in LV ejection fraction of 7%, however remained within the normal range (Fig. 3).

Global measures of native T1 and T2 decreased significantly on convalescent imaging with respective mean global reductions of 58 msec (p≤0.001) and 2.1 msec (p=0.001). Based upon local laboratory-specific reference values for each pulse sequence, no patient demonstrated a persistent elevation in global native T1 or T2 (i.e., >2SD reference mean). T2 SPAIR imaging was also reported as normal in all subjects. Mean global ECV decreased by an absolute value of 2.9% (p=0.001) while 5 patients (25%) demonstrated a persistent elevation above the >2SD upper limit of normal (31%) for our laboratory (range 32.0 to 36.2%). LGE analysis showed a 66% relative reduction in the global enhanced myocardial mass (p<0.001). Any residual LGE was visually coded in 18 (90%) patients, its distribution consistently representing a reduced volume of injury observed at baseline.

The results of segmental LGE and tissue mapping-based analyses are shown in Fig. 3, these demonstrating robust resolution of tissue edema and mild persistent fibrosis of the inferolateral segments. A trivial pericardial effusion was observed in two patients. No patient showed pericardial thickening.

Patients with a baseline LVEF <50% did not demonstrate a significantly higher burden of LGE at follow up versus those with LVEF ≥50% (p=0.75). Of the four patients with persistent chest pain at time of convalescent evaluation, no statistically significant change in any CMR-based marker was observed.

DISCUSSION

This study assessed the natural history of myocardial tissue injury associated with mRNA-based COVID-19 vaccination among a cohort of symptomatic hospitalized patients with CMR-confirmed disease. In this clinical population we documented no short-term major clinical adverse outcomes. At a median follow-up of 111 days, marked improvements were observed in all quantitative CMR-based measures of tissue injury and contractile function, with normalization of tissue markers related to myocardial edema. At this convalescent stage we observed a 66% reduction in the volume of injured myocardium as assessed by LGE quantification; however, 90% of patients demonstrated evidence of residual myocardial fibrosis. These results support the natural history of COVID-19 vaccine-associated myocarditis to be transient with prompt resolution of myocardial inflammation when treated with standard medical therapy. However, the observed persistence of regional myocardial fibrosis in the majority of patients provides justification for long-term surveillance in this young patient population.

The incidence of acute myocarditis associated with the administration of mRNA-based vaccines to the SARS-CoV2 virus is estimated to be between 1.4 and 2.7 cases per 100,000 exposures 23, 24, 25, although increased rates have been observed in younger males , , . Several studies to date have described short-term estimates of major cardiovascular complications, these consistently identifying a low incidence rate , , , , . Despite this, concern has persisted given the potential for residual myocardial injury to become a nidus for downstream complications, including heart failure or ventricular arrhythmias28, 29, 30. The mechanism of myocardial injury following mRNA-based vaccination remains uncertain, however, is postulated to reflect over-aggressive T-cell activation following host-cell manufacturing of modified mRNA nucleosides of the SARS-CoV-2 virus, this subsequently leading to myocardial injury through molecular mimicry. Whether this iatrogenic catalyst of myocardial injury results in a similar duration and cumulative burden of inflammatory injury as compared to community-acquired viral myocarditis was previously unknown. Recently, a single case series of 5 subjects was published casting preliminary insights from convalescent CMR-based findings following mRNA COVID-19 vaccination induced injury. In this study by Cavalcante, et al., all 5 patients showed LVEF normalization and resolution of myocardial edema (by T2 mapping) after a median follow up of 106 days. Similar to our reported larger cohort study, persistent fibrosis was seen on LGE imaging in 4 (80%) of these patients following the complete resolution of edema. The extent of injury encountered during vaccine-associated myocarditis was recently studied by Hanneman, et al., in 21 patients and compared to the burden of injury observed in a historic myocarditis cohort. This study suggested a lower mean burden of LGE may be encountered in this setting versus historic community-acquired myocarditis. However, in our study we identified a mean acute LGE burden of 8.6 +/- 5.3% using a >5SD threshold, this being identical to that which we observed in a historic acute myocarditis cohort series of 100 patients studied at our institution using identical core laboratory-based analysis techniques (8.5 +/- 9.2% at >5SD threshold) . In addition, versus the 65% reduction in global LGE burden we observed at 12-months in this historic cohort, we identified an identical 66% reduction at ≥ 3-month duration of follow-up. Further supporting this hypothesis is that all objective markers of tissue edema were normalized at our pre-selected ≥90 day period of convalescence. While this suggests extended follow-up beyond this period is unlikely to yield further reductions in LGE burden, we feel this requires confirmation and accordingly plan to re-assess this patient population at 12-months.

The presence of persistent fibrosis in the absence of edema has been described to be a predictor of long-term outcomes in patients with non-COVID acute myocarditis. A sub-cohort analysis of the Italian Study in Myocarditis (ITAMY) registry studying those patients who underwent repeat imaging at 6-months, demonstrated that persistent of LGE following resolution of edema was associated with a 4.5-fold increased risk (p=0.008) of death, ventricular arrhythmia or heart failure hospitalization in long-term follow-up. Accordingly, despite our current and prior studies , demonstrating significant involution of tissue injury volume following edema resolution, any degree of residual fibrosis may indicate need for long-term surveillance.

Limitations

This study is recognized to have limitations given its modest sample size and available duration of clinical surveillance. We chose a minimum duration of 3-months to define convalescence based upon prior studies describing satisfactory resolution of tissue mapping markers of edema at this time in community-acquired myocarditis15, 16, 17, 18. Supporting this time period, we observed a normalization of T2 mapping values and T2-weighted black blood imaging findings in all subjects. While supporting a state of post-injury recovery, we recognize the potential for incremental injury involution and remodelling to occur beyond this period, warranting studies of longer duration for the evaluation of tissue remodelling in this population. Histologic confirmation of acute myocarditis was not performed given a low suspicion for alternative diagnoses, and lack of clinical indication based upon contemporary recommendations , , . Finally, convalescent sampling of serum biomarkers was not undertaken in this study, limiting serial comparisons of imaging and serum-based markers of injury.

CONCLUSIONS

Acute myocarditis following COVID-19 mRNA vaccination is associated with a prompt resolution in myocardial edema, reduction in tissue injury volume, and improvement in systolic function when treated with standard medical therapy. However, a dominant proportion of patients show residual fibrosis following the resolution of edema, this being previously recognized as a risk marker of future cardiovascular outcomes in non-COVID community-acquired myocarditis. Future studies evaluating long-term clinical outcomes in this patient population are required.