Vaccine-associated myocarditis with cardiac scarring
A walkthrough of a new preprint
Reading time:
short story - novelette - novella 1- novel - PhD thesis - War and Peace - U.S. Tax Code
Also available with translator, 🇫🇷 🇪🇸 🇩🇪 🇯🇵 etc
I have changed to underlined hyperlinks for legibility and the color blind.
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I am in the final stages of drafting “Magnesium deficiency and associated pathologies: Part 2”, but just like the origins of this Substack back in 2022 occasionally there is an interesting paper to report, and in this case, two have just gone to print.
The second paper I will walk through separately is “A Case Report of Acute Lymphoblastic Leukaemia (ALL)/Lymphoblastic Lymphoma (LBL) Following the Second Dose of Comirnaty®: An Analysis of the Potential Pathogenic Mechanism Based on of the Existing Literature”.
Both papers need transcribing from pdf’s and bear in mind that they are preprints, not final peer-reviewed papers (which unfortunately doesn’t mean what it should).
Emphasis in bold is mine throughout.
TL;DR: Post-vax myocarditis was not “mild” for a third of the patients in the study. The long term prognosis is unknown.
This preprint was published on medRxiv on 22nd March ‘24 by Warren et al.
For background also see “Nuclear medicine: 18F-FDG PET/CT for the detection of vaccine-induced pathologies”.
Background
What is myocardial fibrosis?
Myocardial fibrosis is scarring of the heart muscles due to a sudden or chronic heart injury. “Fibrosis” is the medical term for scarring, and “myocardial” refers to the muscle of your heart.
Producing scar tissue is your body’s way of quickly healing from an injury, but new scar tissue lacks the contractile properties of healthy heart tissue.
Myocardial fibrosis can lead to heart failure. Heart failure occurs when your heart can’t pump enough blood to meet your body’s needs.
Larger amounts of scarring are linked to an increased risk of heart failure.
…Types of myocardial fibrosis
Doctors generally divide myocardial fibrosis into two types: replacement and interstitial. Replacement fibrosis happens when scar tissue forms in response to the death of muscle cells. Interstitial fibrosis occurs when scar tissue forms in the space between muscle cells but isn’t directly related to muscle cell death.
Interstitial fibrosis can be subdivided into two other categories: reactive and infiltrative. Reactive interstitial fibrosis occurs when scar tissue forms in response to pressure or blood volume overload, and it’s seen in aging conditions such as diabetes or high blood pressure.
Infiltrative fibrosis occurs when the heart lays down proteins and a group of molecules called “glycosphingolipids.” This kind of fibrosis is seen in Anderson-Fabry disease and amyloidosis.
It’s possible to have replacement and interstitial fibrosis at the same time.
…The leading cause of myocardial fibrosis is myocardial infarction (heart attack). A heart attack occurs when part of your heart doesn’t receive adequate blood flow because of a blockage in your arteries.
The lack of blood flow leads to the death of heart cells. Fibrosis develops when scar tissue replaces dead muscle cells.
…A type of MRI scan called a “cardiovascular magnetic resonance (CMR) scan” is the current imaging technique of choice for diagnosing myocardial fibrosis. A CMR uses magnetic waves and radiowaves to assess the structure of your heart and blood vessels.
Two CMR image-enhancing techniques play an important role in identifying fibrosis. Late gadolinium enhancement is a CMR method that can be used to look for replacement fibrosis. T1 mapping and extracellular volume fraction is a CMR technique that can be used to look for interstitial fibrosis.
…Myocardial fibrosis outlook
Myocardial fibrosis is a complication of many different heart conditions and can range in severity from mild to severe. The outlook for people with myocardial fibrosis tends to be better for people with minor scarring.
Research suggests that interstitial fibrosis may be reversible with early treatment, but myocardial fibrosis is a predictor of poor outlook for people with chronic heart failure.
In a 10-year study from 2018, researchers found a 27% increased risk of cardiovascular death in people who received aortic valve replacement with fibrosis compared with people without fibrosis.
From: “Everything You Need to Know About Myocardial Fibrosis“ (2023)
https://www.healthline.com/health/heart-disease/myocardial-fibrosis#takeaway
Word count of the full paper: 4638
Key takes from “Improved diagnosis of COVID-19 vaccine-associated myocarditis with cardiac scarring identified by cardiac magnetic resonance imaging.”1 (2024)
Abstract
Background
Myocarditis is a rare but potentially serious complication of COVID-19 vaccination. Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging can identify cardiac scar, which may improve diagnostic accuracy and prognostication.
Objectives
To define the incidence of long-term LGE post COVID-19 vaccine-associated myocarditis (C-VAM) and to establish the additive role of CMR in the diagnostic work-up.
Methods
Patients with Brighton Collaboration Criteria Level 1 (definite) or Level 2 (probable) C-VAM were prospectively recruited from the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC) database to undergo CMR at least 12 months after diagnosis. As there were limited patients with access to baseline CMR, prior CMR results were not included in the initial case definition. The presence of LGE on follow-up CMR was then integrated into the diagnostic algorithm and the reclassification rate (definite vs. probable) was calculated.
Results
Sixty-seven patients with C-VAM (mean age 30 ± 13 years, 72% male) underwent CMR evaluation. Median time from vaccination to CMR was 548 (range 398-603) days. Twenty patients (30%) had persistent LGE, most frequently found in the basal inferolateral segment (n = 11). At diagnosis, nine patients (13%) were classified as definite and 58 (87%) as probable myocarditis. With integration of CMR LGE data, 16 patients (28%) were reclassified from probable to definite myocarditis.
Conclusion
Persistent LGE on CMR occurs in one third of patients with C-VAM. Without CMR at diagnosis, almost one third of patients are misclassified as probable rather than definite myocarditis.
Abbreviations
CMR Cardiac Magnetic Resonance Imaging
COVID-19 Coronavirus disease of 2019
C-VAM COVID-19 vaccine-associated myocarditis
LGE Late gadolinium enhancement
MRI Magnetic Resonance Imaging
TTE Transthoracic echocardiography
SAEFVIC Surveillance of Adverse Events Following Vaccination In the Community
True incidence may be as high as 3 cases per 100, as with the smallpox vaccine and according to several case reports at the time, such as in schools and cycling clubs:2 3 4
Myocarditis is a rare but important complication of COVID-19 vaccination, with an incidence of approximately 2 cases per 100,000(2). Although the clinical course of COVID-19 vaccine-associated myocarditis is usually benign and self-limiting(3, 4), previous studies evaluating the use of cardiac magnetic resonance imaging (CMR) in the acute setting have found imaging abnormalities are common. These findings include late gadolinium enhancement (LGE), which reflects myocardial fibrosis and scarring (seen in up to 90% of cases) and elevated myocardial T2 relaxation time, which is indicative of myocardial oedema (in up to 80% of cases)(5, 6).
The true case count was much higher due to misclassification:
The Brighton Collaboration Case Definition(7) for the diagnosis of Level 1 (definite) myocarditis requires either histological evidence of myocarditis, or the combination of elevated myocardial biomarkers in association with diagnostic imaging features on either CMR or transthoracic echocardiography (TTE). Endocardial biopsies were rarely undertaken in Australia to confirm a C-VAM diagnosis, and due to barriers with funding and access, most patients did not undergo evaluation with CMR at the time of diagnosis, which meant diagnostic classification and therefore risk stratification depended primarily on clinical and echocardiographic characteristics alone. This may have resulted in both diagnostic uncertainty and the potential failure to identify those at higher long-term risk of cardiac complications.
Whilst little is known about the longer-term sequelae of this condition, specifically the impact on cardiac function and its clinical correlation, it is particularly crucial to define as COVID-19 vaccine-associated myocarditis is predominantly a disease of the young and healthy(8). Current evidence is limited to only a few small cohort studies with a relatively short follow up period.
Thus, we present our study evaluating long-term CMR findings in a cohort of 67 adolescents and adults with COVID-19 vaccine-associated myocarditis, which is, to our knowledge, the largest such study with the longest follow up period. In addition, we sought to highlight the critical role of CMR in the work up of this condition by defining the reclassification rate of probable to definite myocarditis with the addition of CMR with LGE imaging to baseline clinical and echocardiographic assessment.
Participants were recruited from the Australian equivalent of VAERS. This, in itself, will have a significant underreporting factor:
All participants were prospectively recruited from a centralised surveillance database containing patients who received a diagnosis of COVID-19 vaccine-associated myocarditis between August 2021 and March 2022.
I disagree that “all” A/E’s are reported. This kind of reporting can give your career a very poor prognosis:
All adverse vaccine related events in Victoria, Australia are reported to SAEFVIC (Surveillance of Adverse Events Following Vaccination In the Community), the state-wide vaccine safety service. SAEFVIC has been operating since 2007 and comprises central reporting enhanced passive and active surveillance systems for all vaccine adverse events following immunisation. All identified reports of myocarditis or myopericarditis were systematically followed up to obtain clinical information to allow independent categorisation of COVID-19 vaccine-associated myocarditis according to the Brighton Criteria (see below)(7). Based on available information, all myocarditis cases were categorised as Level 1 (definite) or Level 2 (probable) and were included in this study.
Exclusion criteria were reasonable:
Exclusion criteria prohibiting enrolment for follow up CMR included severe renal impairment (estimated glomerular filtration rate <30ml/min/1.73m2 ), allergy to gadolinium contrast, pregnancy, current breastfeeding and any other contraindication to magnetic resonance imaging (MRI).
On the other hand, the Brighton Criteria excluded or misclassified a lot of cases:
According to the Brighton Criteria, the diagnosis of COVID-19 vaccine-associated myocarditis requires symptom onset within two weeks of COVID-19 vaccination.
A diagnosis of Level 1 (definite) myocarditis requires either histological evidence of myocarditis on endomyocardial combination of elevated myocardial biomarkers (troponin I or T) and diagnostic imaging features on either CMR or TTEbiopsy, or the (7).
Diagnostic CMR findings include the presence of either patchy myocardial oedema on T2 mapping or LGE on T1 weighted images involving >1 segments in a non-coronary distribution. Diagnostic TTE findings include new right or left ventricular dysfunction (either global or segmental), new regional wall motion abnormalities, new left ventricular diastolic dysfunction, ventricular dilatation, or change in ventricular wall thickness.
Level 2 (probable) myocarditis is defined as the combination of cardiac symptoms (including chest pain, palpitations, dyspnoea, diaphoresis or sudden death) and either elevated cardiac biomarkers (troponin I or T, or CK-myocardial band), diagnostic TTE findings or new abnormalities on ECG (including ST-segment or T-wave abnormalities, evidence of atrial or ventricular arrhythmia, or conduction disease)(7).
Retrospective re-examination and reclassification of historic cases that were missed:
For our initial case definition, we divided our cohort into baseline Brighton Criteria Level 1 or 2 on the basis of clinical and echocardiographic data alone. We believed this best reflected the current clinical practice given access to CMR at the time of diagnosis was limited in Australia. We then included follow up CMR data into reclassification, specifically the presence of LGE, which can be assumed in the absence of prior cardiac events to represent scarring from prior vaccine myocarditis. This enabled an evaluation of the additive role of CMR in the diagnosis and classification of COVID-19 vaccine-associated myocarditis.
30 years old ± 13 isn’t that young:
Results
A total of 67 patients underwent CMR evaluation following a diagnosis of COVID-19 vaccine-related myocarditis.
The baseline and treatment characteristics are summarised in Table 1. The mean age was 30 ± 13 years and the majority of patients were male (72%). Most patients (55 of 67 patients, 82%) developed myocarditis following the Comirnaty® BNT162b2 COVID-19 (Pfizer-BioNTech) vaccine. Ten patients (15%) had the Spikevax® mRNA-1273 (Moderna) vaccine prior to symptoms, while two patients received a diagnosis of myocarditis following the Vaxzevria ChAdOx1-S (AstraZeneca) vaccine (3%). The second COVID-19 vaccine dose was the most common precipitant for myocarditis in this cohort, in 47 patients (70%). Most patients received a single type of vaccine (n = 63, 94%), while a small proportion (n = 4, 6%) received a combination of types (all four cases received two doses of AstraZeneca, followed by a dose of Pfizer).
Any cases 14 days or more after the vax would have been excluded by the Brighton Criteria. Reduced left ventricular ejection fraction is associated with a poor prognosis.5
All 67 patients were hospitalised. The median time from vaccination to hospitalisation was five days (interquartile range (IQR) 3-16 days). The length of hospitalisation was usually brief, with a median duration of two days (IQR 1-3 days). Only three patients (4%) required intensive care admission. Abnormal ECG findings were seen in 29 (43%) patients at presentation, with the most common abnormality being diffuse ST-segment elevation, which was present in 21 patients. The mean peak troponin was 4072 ± 7256 µg/L. A total of 10 (15%) patients had abnormal echocardiographic changes at presentation, seven of whom had reduced left ventricular ejection fraction (LVEF <50%). Four patients had regional wall motion abnormalities (two without associated reduced LVEF) and two patients had left ventricular dilation (one without other associated abnormalities on TTE). A further 13 patients (19%) had a trivial or small pericardial effusion.
“Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis.”6
Only 13% of patients were classified as “definite myocarditis”:
Approximately half the patients received colchicine as initial therapy (51%), with 42 patients (63%) treated with non-steroidal anti-inflammatory agents. Only three patients (4%) received corticosteroids. No patients required inotropic support, mechanical ventilation, or extra-corporeal membrane oxygenation. On baseline assessment (without CMR), nine patients (13%) were classified as definite myocarditis, while the remaining 58 patients (87%) were classified as probable myocarditis.
The median time for follow-up CMR was 548 days (18 months):
Table 2 contains the CMR results. Of the 67 patients had CMR, 60 studies were performed at >12 months post vaccination. A total of 44 prospective CMR scans were performed on adults who either had no initial CMR or an abnormal baseline CMR. A further 16 prospective CMR scans were performed on adolescents (aged <18) for the same reason. Seven patients had a CMR performed as part of their initial workup that was normal, so in these patients follow up CMR was not performed. The median time from vaccination to follow up CMR was 548 days (IQR 398-603).
LGE reflects myocardial fibrosis and scarring. This firmly puts to rest the narrative that COVID-19 vaccine-associated myocarditis (C-VAM) was somehow “transient and mild”:
The disease course of myocarditis following COVID-19 vaccination is typically transient and mild, with resolution of symptoms within 1 to 3 weeks in most patients.
…Disclosure
Dr K. Hanneman has received speaker’s honorarium from Sanofi-Genzyme, Amicus, and Medscape. Dr P. Thavendiranathan has received speaker’s honorarium from Amgen, Boehringer Ingelheim-Lilly, and Takeda. Dr J.A. Udell has served as a consultant or speaker for AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, Janssen, Merck, Novartis, and Sanofi and has received research grants from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim-Lilly, and Janssen.
From: “Myocarditis Following COVID-19 Vaccination” (2023)
Almost a third of patients (n = 20, 30%) had evidence of persistent myocardial late gadolinium enhancement, and the common territory containing LGE was the basal inferolateral wall (n = 11) (Figure 1). The pattern of LGE was most commonly subepicardial (n = 13), followed by midwall (n = 7) and then subendocardial (n = 2). Two patients had left ventricular regional wall motion abnormalities which corresponded to the territory of LGE. Eight patients had low-normal ejection fraction (LVEF 50-54%) on follow up CMR, two of whom had mild or moderately reduced LVEF on baseline echocardiogram. The remaining five patients with reduced LVEF on TTE had normalisation of their ejection fraction on follow up CMR. All patients had a normal T1 and T2 time on follow up CMR. The mean T1 time was 992 ± 89ms and the mean T2 time was 48 ± 6ms. A total of eight patients (12%) had a pericardial effusion, all of which were trivial or small and of no haemodynamic significance.
16 patients (28%) classified as “probable” had their classification changed to “definite”, with LGE, and four (44%) of “definites” had LGE on follow-up:
Four patients (44%) who were originally classified as definite myocarditis had LGE on follow up CMR. Sixteen patients (28%) who were originally classified as probable myocarditis had LGE, which resulted in re-classification to definite myocarditis (Figure 2). There was no significant difference in the rate of LGE between those who were originally classified as definite or probable myocarditis (44% vs. 28%, p = 0.30).
“Late gadolinium enhancement is the technique of choice for detecting myocardial fibrosis.”7
Table 3 demonstrates the results of baseline and follow up CMR for the 20 patients who underwent serial studies. The median time from vaccination to baseline CMR was 48 days (range 14-143) and the median time from baseline to follow up CMR was 457 days (range 400-556). On baseline CMR, 19 (95%) patients had late gadolinium enhancement. Eight patients (20%) had evidence of myocardial oedema identified by hyperintensity on T2- weighted imaging. Two patients had an elevated T1 time. Five patients had low-normal ejection fraction (LVEF 50-54%). Of the 19 patients with LGE at baseline, 10 patients had resolution of the LGE on follow up CMR, five patients had persistent LGE but to a lesser extent and four patients had unchanged LGE on follow up CMR. No patients had progression of LGE on follow up CMR.
Highlights from the discussion:
We found that the incidence of persistent myocardial fibrosis is high, seen in almost a third of patients at >12 months post diagnosis, which could have implications for the management and prognosis of this predominantly young cohort. Furthermore, our findings highlight the critical role played by CMR in the diagnosis and risk-stratification of this condition. Without CMR, almost a third of patients were misclassified as probable rather than definite myocarditis.
Despite the clinical course being “mild” 30% had signs of fibrosis and scarring:
Consistent with previous studies, our study population was comprised of mostly younger male patients in whom the clinical course of myocarditis was relatively mild. Nonetheless, incidence of LGE was high, seen in 30% of the total cohort. The long-term clinical implications of LGE in this condition are as yet unknown, but LGE has been demonstrated to confer worse prognosis in non-COVID-19 vaccine-associated myocarditis(9, 10), especially if it persists beyond six months(11).
LGE was a stronger predictor of long-term mortality than reduced LVEF:
Furthermore, a study of 222 patients with biopsy-proven myocarditis identified that LGE on CMR was the strongest predictor of long-term mortality (hazard ratio 8.4 for all-cause mortality, hazard ratio 12.8 for cardiac mortality), and carried more prognostic significance than LVEF, degree of LV dilation and New York Heart Association functional status(12).
The prognosis may not improve with time, and regular clinical reviews are recommended due to the risk of deterioration and fatal ventricular arrhythmia:
This prognostic impact persists at 10-year follow up(13). Concerningly, left ventricular fibrosis is also a nidus for ventricular arrhythmia in chronic cardiomyopathies(14-16). As such, the identification of LGE on CMR in patients with a history of COVID-19 vaccine-associated myocarditis should at a minimum prompt regular clinical review, to allow for periodic monitoring for arrhythmias and deterioration in cardiac function.
A recent study had similar findings, although the CMR studies were conducted earlier. These cases weren’t outliers:
A recent study of 12-month follow-up CMR in 40 adolescents with C-VAM found a comparable incidence of persistent LGE to our study, with a rate of 37.5%(17) (seen in 15 out of 40 patients). Researchers similarly found a predilection of LGE for the lateral LV segments. We describe a lower incidence of LGE than a previous study of 16 adolescents with a history of C-VAM who underwent serial CMR evaluation at diagnosis and between three and eight months post(6). Investigators found persistent LGE in 68% of patients, although they observed a significant reduction in the burden of LGE in all subjects. In this prior study, the follow-up CMR scans were performed at a very early time interval post-diagnosis, and it is possible that there may have been lower incidence of LGE if the CMR studies were performed >12 months.
After the obligatory praising of these unsafe and ineffective “vaccines” the authors go on to claim that C-VAM isn’t as lethal as viral myocarditis (as per the earlier pharma-conflicted study).
I dispute this conclusion by saying it is too early to know as they lack any longer-term data; mortality rates in the young from COVID-19 were near zero; and we need investigations into the cardiovascular effects of breakthrough and other viral infections, with increased viral loads due to impaired immunity through igG4 class switching, etc:
Furthermore, a recent study by Lai et al indicates a favourable medium-term prognosis of C-VAM compared to viral myocarditis. Only one death was observed in a cohort of 104 patients with C-VAM, which conferred a 92% lower mortality risk than viral myocarditis(4). Of note, however, this study did not include CMR data, which prevented exploration of CMR predictors of adverse outcome (such as LGE).
Limitations include the small sample size, and they acknowledge the lack of longer-term studies:
Although this is the largest cohort study to date evaluating follow-up CMR in patients with COVID-19 vaccine-associated myocarditis, our study is nonetheless limited by its small sample size. Additionally, it does not contain clinical follow up to ascertain correlation between CMR findings and symptoms or adverse events. For this reason, even longer-term follow up studies are required to define the prognostic significance of LGE in this condition.
Tenous, unless they had smallpox vaccine in the interim…
We did not collect clinical data on the development of interval cardiac events between vaccination and follow up CMR, therefore it is technically possible that the LGE observed could have been related to a different cardiac condition. Finally, participation in our study was voluntary, which may have resulted in selection bias and impacted the accuracy of the overall incidence of long-term LGE.
Not “transient and mild”. This is not good, especially considering the numbers affected and are undiagnosed or misclassified:
In conclusion, long-term myocardial fibrosis is a common finding in patients with COVID-19 vaccine-associated myocarditis. CMR enables accurate diagnostic assessment and risk stratification of patients with this condition and is critical to a comprehensive work up and long-term follow up strategy.
Full paper:
https://www.medrxiv.org/content/10.1101/2024.03.20.24304640v1.full.pdf
To conclude, studies into radiation-induced heart disease (RIHD) and Radiation-induced myocardial fibrosis (RIMF) provide clues to the long-term prognosis for more acute cases that were undiagnosed and untreated.
Key takes from “New therapeutic insights into radiation-induced myocardial fibrosis“8 (2019) by Ma et al:
Abstract
Radiation therapy (RT) for the treatment of thoracic tumors causes radiation-induced heart disease (RIHD). Radiation-induced myocardial fibrosis (RIMF) is both an acute and chronic stage of RIHD, depending on the specific pathology, and is thought to be a major risk factor for adverse myocardial remodeling and vascular changes. With the use of more three-dimensional conformal radiation regimens and early screenings and diagnoses for RIMF, the incidence of RIHD is declining, but it still must be carefully investigated to minimize the mortality and morbidity of patients with thoracic malignancies after RT treatment. Effective methods for preventing RIMF involve a decrease in the direct radiation dose in the heart, and early screening and diagnosis. Medications remain as a useful adjunct for preventing or treating RIMF. This review mainly discusses the cellular and molecular mechanisms underlying RIMF, and new therapeutic drugs that can potentially be developed from this knowledge.
Keywords: miRNA, prevention and treatment of RIMF, radiation therapy, radiation-induced myocardial fibrosis (RIMF)
Also see Accelerated atherosclerosis: a warning from history for pathologies overlapping with radiation-induced heart disease, such as ROS generation caused by Spike binding ACE2.
Radiation-induced heart disease (RIHD) is the leading cause of noncancer-related death, and may not present until several years after patients have undergone thoracic radiation therapy (RT). RIHD mainly manifests as asymptomatic myocardial ischemia, pericarditis (both acute and chronic forms), coronary artery disease (such as accelerated atherosclerosis), conduction abnormalities, valvulitis, myocarditis, and heart failure.
Radiation-induced myocardial fibrosis (RIMF) has both acute and chronic stages of RIHD, based on the specific pathology, and is thought to be a major risk factor for myocardial remodeling and vascular changes. Although patients may initially be asymptomatic, 10 years after RT, RIMF can subsequently result in restrictive or constrictive pericarditis and heart failure, which are lethal cardiovascular events. Thus, studies that include RIMF as an endpoint may contribute to the early prevention and diagnosis of radiation-induced heart toxicity.
All these are associated with synthetic mRNA/LNP administration too:
RIMF is the result of a multifactorial interaction. Many studies have demonstrated that miRNAs, fibroblasts, transforming growth factor beta (TGF-β) and peroxisome proliferator-activated receptor (PPAR) alpha are implicated in the pathological processes of RIMF.
There is hope, provided you get diagnosed and treated early.
Being gaslit, sent home with paracetamol, and told you are “stressed” just doesn’t cut it:
In fact, several existing drugs can reverse RIMF, at least partially. Recent research has shown that miRNAs may be a new therapeutic modality for RIHD, and new therapeutic approaches will be gradually discovered for the prevention and treatment of RIMF.
Early stages of RIMF include acute inflammation ~6 h after radiation in small and medium-sized arteries, with neutrophilic infiltration throughout the heart:
In the first few minutes, the endothelial cells of myocardial capillaries that are exposed to radiation are activated with increased permeability, thus inducing early acute endothelial inflammation,14 that may adversely transfer to the nonirradiated surrounding cells15; subsequently, neutrophils are recruited, and inflammatory cytokines, such as monocyte chemotactic factor, tumor necrosis factor (TNF), and interleukins (IL-1, IL-6, and IL-8), are released, which then leads to increased levels of neutrophil and lymphocyte infiltration.16 After a few hours of irradiation, monocytes differentiate into the M2 subset of macrophages that secretes transforming growth factor β (TGF-β), which is responsible for the differentiation of fibroblasts into myofibroblasts.17 In addition to the acute inflammatory responses, there are immediate expressions of proto-oncogenes, including c-myc and c-jun, which may contribute to late fibrotic changes.18 These prior studies in other organ systems suggest that similar changes may also occur in the irradiated heart.
The latent phase begins approximately 2 days after radiation and involves the mild progression of fibrosis with the progressive injury of endothelial cells in the myocardial capillaries of the healthy pericardium and myocardium, which then results in stenosis of the lumen, thrombosis formation, myocardial cell death, and fibrosis.
The late phase occurs approximately 70 days after radiation and involves extensive fibrosis in experimental animal models.13 The chronic effects of radiation on tissues of the heart lead to RIMF, and, eventually, result in a decrease in elasticity and distensibility, thus leading to a reduction in ejection fraction and cardiac failure.16
This relates more to my earlier Substack:
Radiation-induced accelerated atherosclerosis is also a side effect of thoracic radiation therapy. In this situation, the exposure of macrophages to radiation produces inflammatory signals and induces the ingestion of lipids to transform into foam cells in the intima of the vessel wall. In the media, smooth muscle cells differentiate into myofibroblasts that secrete collagen and extracellular matrix, with these myofibroblasts subsequently entering the intima and leading to the formation of inflammatory plaques with high collagen and fibrin contents.20 Moreover, plaque formation that is induced by radiation may be more prone to rupture and intraplaque hemorrhage, with notably increased levels of macrophages and granulocytes and without elevated levels of systemic inflammatory markers, in the intima of mice. Lipid cores have been observed to be larger in female mice and slightly smaller in male mice.21 Moreover, the mid and distal left anterior descending arteries are primarily involved in RIMF.22
RIMF is usually asymptomatic - you don’t even know you are ill:
Early radiation-induced heart toxicity is usually asymptomatic, but pathological damage still progresses. The early screening and diagnosis of RIMF is crucial for patients with thoracic tumors after RT. Serum cardiac biomarkers, including both troponin I (TnI) and brain natriuretic peptide (BNP) (which are markers of other forms of injury in the heart, such as necrosis or myocardial cell death), may be useful for assessing radiation-induced cardiac damage, and seem to be superior to the use of echocardiography.23
Markers for myocardial damage persist for a long time, and again we have case reports indicating overlapping pathologies:
2. CASE HISTORY
A 77‐year‐old Japanese woman presented to our hospital with generalized fatigue, 7 days after receiving the second dose of the BNT162b2 COVID‐19 vaccine. Her medical history was notable for dyslipidemia without heart disease, and there was no family history of cardiovascular disease.
Her brain natriuretic peptide (BNP), troponin T, creatine kinase (CK), CK‐MB, and C‐reactive protein levels were elevated to 1661 pg/ml, 8.4 ng/ml, 532 U/L, 71 U/L, and 6.6 mg/L, respectively. The results of her COVID‐19 polymerase chain reaction testing were negative. Further, investigation results for parvovirus B19, mycoplasma, Epstein–Barr virus, adenovirus, influenza virus, and herpes simplex viruses 1 and 2 were also negative.
From: “A case of BNT162b2 COVID‐19 vaccine‐associated fulminant myocarditis in a very elderly woman“ (2022)
BNP levels do not become significantly elevated until 1 month after radiation, and these levels begin to decrease at 12 months after radiation in breast cancer patients.24,25 Furthermore, BNP levels have been observed to be associated with radiation-induced cardiac damage in 5-year breast cancer survivors after radiotherapy.26 The levels of BNP/NT-proBNP (typically >100 pg/ml/>300 pg/ml) indicate the risk of adverse events in all patients who are at risk for heart disease.27
Medications remain a useful adjunct to prevent or treat RIMF. miRNAs and cell therapies appear to be highly promising as novel therapeutic targets for the mitigation or prevention of RIMF, and clinical trials will be required to test the potential interventions for radiation-induced heart disease.
Full paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689916/
References
Warren J, Cheng D, Crawford NW, et al. Improved diagnosis of COVID-19 vaccine-associated myocarditis with cardiac scarring identified by cardiac magnetic resonance imaging. Published online March 22, 2024. doi:10.1101/2024.03.20.24304640
Eckart RE, Love SS, Atwood JE, et al. Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination1. Journal of the American College of Cardiology. 2004;44(1):201-205. doi:10.1016/j.jacc.2004.05.004
Ahlborg B, Linroth K, Nordgren B. ECG-Changes without Subjective Symptoms after Smallpox Vaccination of Military Personnel. Acta Medica Scandinavica. 1966;180(S464):127-134. doi:10.1111/j.0954-6820.1966.tb05079.x
Times TB. Doctors advise against intensive sport after Covid vaccination. Accessed March 29, 2024. https://www.brusselstimes.com/181660/doctors-advise-against-intensive-sport-after-covid-vaccination
Curtis JP, Sokol SI, Wang Y, et al. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. Journal of the American College of Cardiology. 2003;42(4):736-742. doi:10.1016/S0735-1097(03)00789-7
Pappritz K, Lin J, El-Shafeey M, et al. Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis. ESC Heart Fail. 2022;9(2):925-941. doi:10.1002/ehf2.13845
Magnetic Resonance Imaging of Cardiovascular Fibrosis and Inflammation: From Clinical Practice to Animal Studies and Back - PMC. Accessed March 29, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766566/
Ma CX, Zhao XK, Li YD. New therapeutic insights into radiation-induced myocardial fibrosis. Ther Adv Chronic Dis. 2019;10:2040622319868383. doi:10.1177/2040622319868383
It would be remiss of me not to bring magnesium into the discussion:
Magnesium enhances cardiomyocyte proliferation and suppresses cardiac fibrosis induced by chronic ACTH exposure in rats
Jelena Petrović et al. Magnes Res. 2021.
"...Our results show, for the first time, that administration of Mg in rats was effective in ameliorating the development of ACTH-evoked cardiac fibrosis, while facilitating cardiomyocyte proliferation. Furthermore, we propose that Mg supplementation attenuates ACTH-induced HPA axis hyperactivity, as one of the underlying plausible mechanisms, which may contribute to its cardioprotective effects."
https://pubmed.ncbi.nlm.nih.gov/34463274/
I used to think that fibrosis was permanent and irreversible, until I was corrected by a cardiologist. If you leave it too long then it can be due to remodelling, but there are some drugs that, if given early, can mitigate some of the damage or inhibit the process:
Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction (2022)
"4.4.1. Renin–Angiotensin–Aldosterone System (RAAS) Inhibitors RAAS inhibitors are widely used to target cardiac fibrosis. Drugs such as lisinopril, losartan, amlodipine, and spironolactone have proven their anti-fibrotic effect on cardiomyocytes [23,99,100]. A recent study demonstrated that a new first-in-class angiotensin receptor inhibitor, sacubitril/valsartan, can suppress the effect of RAAS during cardiac remodeling by blocking angiotensin II type 1 receptors and activating vasoactive peptides through the inhibition of the neprilysin enzyme, which is responsible for their degradation [101]. Sacubitril/valsartan prevented maladaptive cardiac fibrosis and dysfunction by blocking cardiac fibroblast activation and proliferation in a mouse model of pressure overload–induced hypertrophy [102]."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496565/