Virus and Vaccine-Induced Cardiomyopathy: Beyond Troponin, and Myocarditis Beyond COVID-19 Vaccines, Key References

An Examination of Etiology, Biomarkers, and Clinical Implications

There is little remaining room for doubt that myocarditis and pericarditis are among the adverse events one can expect from COVID-19 mRNA shots. At the end of this article is a list of related articles on that issue. Today’s question is: what indicators, used in combination with Troponin, might be useful in identifying “subclinical” or “not clinically significant” myocarditis and preventing sudden death in afflicted young adults? And what evidence exists of the risk of heart damage from other vaccines?

Introduction

Troponin, a critical cardiac biomarker, is instrumental in diagnosing myocardial infarction or heart attacks (Thygesen et al., 2018). This protein, found in cardiac muscle cells, spills into the blood when heart tissue damage occurs. Our focus will be the varied causes behind elevated troponin, with special attention given to a unique intersection — virus- and vaccine-induced cardiomyopathy.

Elevated Troponin: A Closer Examination

"Elevated" is a relative term in medicine. Factors such as patient characteristics, the specific troponin assay used, and clinical judgment help define what's considered 'elevated' troponin (Thygesen et al., 2018). Although commonly linked to myocardial infarction, elevated troponin can also signify different forms of cardiac injury.

Cardiomyopathy: An Overview

Cardiomyopathy refers to a group of diseases affecting the heart muscle. These diseases may lead to heart failure, irregular heart rhythms, or even sudden cardiac arrest (Bozkurt et al., 2016). The interplay between elevated troponin and cardiomyopathy presents a complex puzzle that physicians must piece together.

Virus-Induced Cardiomyopathies

Virus-induced cardiomyopathies result from viral infections of the heart muscle. These infections trigger an inflammatory response that could evolve into chronic cardiomyopathy (Kindermann et al., 2008; Bowles et al., 2003; Kuhl et al., 2005). The exact mechanisms behind this transition involving the body's immune response are varied but involve cell death.

Vaccine-Induced Cardiomyopathy: Real Beyond COVID-19 Vaccine, But Underappreciated

Recent attention has turned towards vaccines, particularly COVID-19 vaccines, as potential triggers for cardiomyopathy. This novel and less-understood occurrence has been associated with mRNA and adenoviral vector-based vaccines (Montgomery et al., 2021; Bozkurt et al., 2021).

According to Brambatti et al., 2017, the distribution of causes leading to hypersensitivity eosinophilic myocarditis (EM) would be as follows:

1. Antibiotics: 36.5% of cases (notably minocycline and beta-lactam antibiotics)

2. Central nervous system agents: 21.1% (primarily clozapine followed by carbamazepine)

3. Vaccines: 7.7%

4. Anti-tubercular agents: 1.9%

5. Other agents: 32.8%

6. In 14.7% of cases, data about drugs potentially involved were not available.

This distribution underlines the wide range of exposures that can lead to hypersensitivity EM and emphasizes the importance of a comprehensive patient history and diligent investigation in identifying the causative agent.

CardioEosinophilia and Immune Signaling

Infiltrating eosinophils can play a significant role in the immunological response which can contribute to heart cell damage in myocarditis. Eosinophils are white blood cells that respond to specific signals during an immune response, and their recruitment to the heart tissue can indicate an ongoing inflammatory process.

The recruitment of eosinophils is a highly regulated process involving a range of cytokines and chemokines. Interleukin-5 (IL-5) is a cytokine of particular interest. IL-5 plays a crucial role in eosinophils' maturation, activation, and survival, making it central to their accumulation in tissues (Rothenberg & Hogan, 2006).

Other significant cytokines and chemokines include eotaxin (CCL11), a potent chemoattractant for eosinophils. Eotaxin directs eosinophils to the site of inflammation, often in response to an allergen or parasite but also potentially in response to injury or infection, including that which may occur in myocarditis (Rothenberg et al., 1997).

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Case Reports

Exploring real-world reports of vaccine-induced cardiomyopathy provides valuable insights. Some cases feature infiltrating eosinophils, immune cells indicating an allergic or autoimmune reaction. However, not all cases show this infiltration, suggesting a complex interplay of factors in vaccine-induced cardiomyopathy (Montgomery et al., 2021).

Additional Biomarkers of Heart Cell Death

Beyond troponin, other biomarkers like Creatine Kinase-MB (CK-MB), Myoglobin, and B-type natriuretic peptide (BNP) serve as key indicators of cardiac injury (Vasile et al., 2008). These molecules are released into the bloodstream following damage to the heart muscle and can provide valuable diagnostic information.

Some of these must be measured within a few days’ time for accuracy for immediate effects; thus, if heart tissue damage is suspected post-vaccination, it may be thought that the measurements may have to be made shortly thereafter. However, given the chronicity of the nature of COVID-19 vaccine myocarditis, vaccinated athletes could be screened for monitoring for post-vaccine myocarditis to avoid crises associated with intensive physical activity. It is critical to stress that while troponin is a cornerstone in diagnosing myocardial damage, the absence of clinically significant elevation should not lead to complacency. Troponin levels are just one piece of the puzzle. If there is a simultaneous elevation in other biomarkers indicative of cardiac tissue damage, these signs may point toward underlying myocardial injury that warrants further investigation, especially in virus or vaccine-induced myocarditis scenarios (Sandoval et al., 2020).

Diagnostic and Therapeutic Implications

The evolving landscape of vaccine-induced cardiomyopathy necessitates a re-evaluation of our diagnostic and therapeutic approaches. Clinicians must adapt to new findings, ensuring effective individualized treatment strategies for patients. Missed diagnoses of ongoing heart injury due to “non-clinically significant troponin” levels may be missed leading to cardiac crises and deaths.

Conclusion

The multifaceted causes behind elevated troponin weave a rich tapestry of clinical challenges, including vaccine-induced cardiomyopathy. Further probing into this complex interplay deepens our understanding, potentially leading to improved patient outcomes.

The interconnectedness of these various cardiac indicators emphasizes the need for a comprehensive, patient-centric approach to diagnostic and therapeutic strategies. Clinicians must remain vigilant and avoid complacency, even in cases where troponin levels might not present as clinically significant. There is an undeniable need for further research and exploration into the complex landscape of cardiac biomarkers to ensure improved patient outcomes and the evolution of cardiological practices.

Annotated References

Bozkurt B, Colvin M, Cook J, et al. "Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement from the American Heart Association." Circulation. 2016;134(23):e579-e646.

This scientific statement from the American Heart Association provides an overview of the current strategies for diagnosing and treating various specific forms of dilated cardiomyopathies.

Bozkurt B, Kamat I, Hotez PJ. "Myocarditis With COVID-19 mRNA Vaccines." Circulation. 2021;144(6):471-484.

This article discusses the occurrence of myocarditis following the administration of mRNA COVID-19 vaccines. It offers insight into potential causes and clinical management of this condition.

Bowles NE, Ni J, Kearney DL, et al. "Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults." J Am Coll Cardiol. 2003;42(3):466-72.

This research investigates the role of adenovirus as a common cause of myocarditis in children and adults. It employs PCR techniques to detect viral genomes in myocardial tissues.

Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, Ammirati E. "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes." Journal of the American College of Cardiology. 2017;70(19):2363-2375.

This article provides an in-depth exploration of eosinophilic myocarditis, looking at its characteristics, treatment strategies, and patient outcomes. Eosinophilic myocarditis is a specific type of myocarditis where eosinophils infiltrate the myocardial tissue, and it can be associated with a variety of causes including drug hypersensitivity, systemic diseases, and parasitic infections.

Kindermann I, Kindermann M, Kandolf R, et al. "Predictors of outcome in patients with suspected myocarditis." Circulation. 2008;118(6):639-48.

This study identifies factors that can predict the outcome of patients with suspected myocarditis, potentially informing treatment strategies and patient management.

Kuhl U, Pauschinger M, Noutsias M, et al. "High prevalence of viral genomes and multiple viral infections in the myocardium of adults with 'idiopathic' left ventricular dysfunction." Circulation. 2005;111(7):887-93.

The research explores the significant prevalence of viral genomes in adults diagnosed with 'idiopathic' left ventricular dysfunction, suggesting a possible link between viral infections and certain cardiac conditions.

Montgomery J, Ryan M, Engler R, et al. "Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military." JAMA Cardiol. 2021;6(10):1202-1206.

This article documents cases of myocarditis following the administration of mRNA COVID-19 vaccines among members of the U.S. military, providing real-world evidence of vaccine-associated myocarditis.

Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147-74.

Based on this, the article "The eosinophil" by Rothenberg and Hogan is a comprehensive review of the biology of eosinophils, a type of white blood cell. The authors challenge the traditional view of eosinophils as end-stage cells primarily involved in host protection against parasites. Instead, they propose that eosinophils are multifunctional leukocytes with roles in various inflammatory responses and in modulating both innate and adaptive immunity.

The review examines the products derived from eosinophils, including granule constituents and mechanisms for releasing their diverse mediators. The authors highlight eosinophils' roles in homeostatic functions such as developmental biology and immune responses, emphasizing their interactions with mast cells and T cells.

The article also outlines the molecular steps involved in eosinophil development and trafficking, focusing on the transcription factor GATA-1, the eosinophil-specific cytokine IL-5, and the eotaxin family of chemokines.

The authors then review the role of eosinophils in various disease processes, including infections, asthma, and gastrointestinal disorders, and discuss recent findings from studies using genetically engineered eosinophil-deficient mice. The review concludes with a discussion of strategies for targeted therapeutic intervention in eosinophil-mediated diseases.

This in-depth examination of eosinophils provides invaluable insights into the complex roles these cells play in health and disease.

Rothenberg ME, Luster AD, Leder P. Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression. Proc Natl Acad Sci U S A. 1995;92(19):8960-4.

This study examines the role of eotaxin, a chemokine involved in attracting eosinophils, a type of white blood cell.

The authors cloned the mouse eotaxin gene and analyzed its structure and biological function. They found that eotaxin, first identified in guinea pigs and linked to asthma, is a distinct member of the Cys-Cys chemokine family. The murine eotaxin gene is located on mouse chromosome 11, an area that encodes other Cys-Cys chemokines.

The researchers found that the eotaxin protein directly attracts eosinophils. The eotaxin gene is widely expressed in normal mice and is strongly induced in cultured endothelial cells in response to interferon-gamma. Additionally, eotaxin is locally induced in response to the transplantation of interleukin 4-secreting tumor cells, suggesting it contributes to the recruitment of eosinophils and the antitumor effect of interleukin 4.

These findings suggest that eotaxin could play a role in various inflammatory conditions by regulating eosinophil migration and activity.

Sandoval Y, Januzzi JL Jr, Jaffe AS. "Cardiac Troponin for Assessment of Myocardial Injury in COVID-19: JACC Review Topic of the Week." J Am Coll Cardiol. 2020;76(10):1244-1258.

This review examines the use of cardiac troponin as a biomarker to assess myocardial injury, particularly in the context of COVID-19.

Thygesen K, Alpert JS, Jaffe AS, et al. "Fourth Universal Definition of Myocardial Infarction (2018)." J Am Coll Cardiol. 2018;72(18):2231-2264.

This article provides the fourth universal definition of myocardial infarction, outlining the diagnostic criteria and usage of biomarkers such as troponin in clinical settings.

Vasile VC, Babuin L, Giannitsis E, Katus HA, Jaffe AS. "Relationship of MRI-determined infarct size and cTnI measurements in patients with ST-elevation myocardial infarction." Clin Chem. 2008;54(3):617-9.

This research investigates the relationship between myocardial infarction size (as determined by MRI) and cardiac troponin I measurements in patients with ST-elevation myocardial infarction.

COVID vaccines increase risk of serious cardiac events by 18X

Myocarditis after Pfizer and Moderna mRNA technology based gene injection vaccine (Larson et al.); describes 8 patients who were hospitalized with chest pain and who were diagnosed with myocarditis

Elevated risk of myocarditis after COVID-19 vaccination (Pfizer booster), Patone et al.: "Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex"