Elevated Sera sST2 Is Associated With Heart Failure in Men ≤50 Years Old With Myocarditis
Open accessAbstract
Background: Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST 2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results: Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST 2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST 2 levels were higher in healthy men ( P =8×10 −6 ) and men with myocarditis ( P =0.004) compared with women. sST 2 levels were elevated in patients with myocarditis and New York Heart Association class III ‐ IV heart failure ( P =0.002), predominantly in men ( P =0.0003). Sera sST 2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r =0.231, P =0.0006), but not in women ( r =0.172, P =0.57). Sera sST 2 levels were also significantly higher in male mice with myocarditis ( P =0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P <0.001), but not estradiol ( P =0.32), increased sera sST 2 levels in male mice with myocarditis. Conclusions: We show in a well‐characterized subset of heart failure patients with clinically suspected and biopsy‐confirmed myocarditis that elevated sera sST 2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.
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Pre-COVID myocarditis occurs more often in young men under 50 years, with a sex ratio of 2 to 4:1 men to women.
“Myocarditis pre-COVID is known to occur more often in young men under the age of 50 years, with a sex ratio of 2 to 4:1 men to women”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [115]
The Results section reports a 3.5:1 male-to-female ratio among the study’s myocarditis patients, within the claimed range, and shows that most patients aged ≤50 were men. These are findings from the study sample, not evidence that myocarditis generally occurred at that rate in the pre-COVID population. (LLM, conf=0.87)
Experimental — accuracy not yet measuredWomen are more likely to develop myocarditis after menopause.
“while women are more likely to develop myocarditis after menopause, which is reviewed in previous studies. 64,113-117”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [115]
The Results section reports that 59 of 67 women with myocarditis in this study were over 50, but this distribution does not establish that women are more likely to develop myocarditis after menopause. The Methods and Discussion state that menopause status was not obtained and age 50 was used only as a surrogate; the paper does not report a menopause-specific risk of developing myocarditis. (LLM, conf=0.77)
Experimental — accuracy not yet measuredIL-1β levels in the heart correlate to the severity of inflammation in male BALB/c mice with autoimmune CVB3 myocarditis.
“IL-1 β levels in the heart correlate to the severity of inflammation in male BALB/c mice with autoimmune CVB3 myocarditis. 115,129”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [115]
The Results sections report that serum sST2 correlates with cardiac inflammation and, separately, with cardiac IL-1β in BALB/c mice with CVB3 myocarditis. The Discussion says cardiac IL-1β is elevated in male mice, but our copy does not report the claimed direct correlation between cardiac IL-1β levels and inflammation severity or identify this model as autoimmune. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIL-18 strongly drives Th1 immune responses, but in BALB/c mice, this produces a mixed Th1/Th2 response that promotes fibrosis and DCM rather than a classical STAT-driven Th1 response.
“IL-18, originally named IFNγ -inducing factor, strongly drives Th1 immune responses, 143-145 but in BALB/c mice, this produces a mixed Th1/Th2 response that promotes fibrosis and DCM rather than a classical STAT-driven Th1 respo nse. 115,146,160,165”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [115]
The Discussion (page unavailable) says IL-18 contributes to extracellular-matrix remodeling, a step in progression from myocarditis to DCM, and reports elevated cardiac IL-18 in male mice with CVB3 myocarditis. It does not say IL-18 produces a mixed Th1/Th2 response in BALB/c mice or contrast that response with STAT-driven Th1 signaling; its discussion of Th1 and Th2 responses concerns IL-33/ST2. (LLM, conf=0.82)
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References 54 · Cited by 99
Research works printed but not linked: 5
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- Authors
- Coronado, M. J., Bruno, K. A., Blauwet, L. A., Tschöpe, C., Cunningham, M. W., Pankuweit, S., van Linthout, S., Jeon, E., McNamara, D. M., Krejčí, J., Bienertová‐Vašků, J., Douglass, E. J., Abston, E. D., Bucek, A., Frisancho, J. A., Greenaway, M. S., Hill, A. R., Schultheiss, H., Cooper, L. T., & Fairweather, D.
- Affiliations
- Johns Hopkins University (US)
- Mayo Clinic (US)
- Charité – Universitätsmedizin Berlin (DE)
- University of Oklahoma Health Sciences Center (US)
- Universitätsklinikum Gießen und Marburg (DE)
- Department of Cardiology and Berlin‐Brandenburg Center for Regenerative Medicine Campus Virchow Klinikum Charite‐ Universitaetsmedizin Berlin Berlin Germany
- Samsung Medical Center (KR)
- University of Pittsburgh (US)
- Masaryk University (CZ)
- Department of Pathological Physiology and the Research Center for the Toxic Compounds in the Environment Faculty of Sciences Masaryk University Brno Czech Republic
- Mayo Clinic in Florida (US)
- Institut Kardiale Diagnostik und Therapie (DE)
- Corresponding author
- Fairweather, DeLisa
- ORCID
- Venue
- Journal of the American Heart Association
- Published
- 2019-01-22
- Volume
- 8
- Issue
- 2
- Pages
- e008968-e008968
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC6497352
- OpenAlex
- W2910815323
- Cited by
- 99
- References
- 54
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 20 · 2023: 17 · 2022: 21 · 2021: 5 · 2020: 16 · 2019: 3 · 2018: 1
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Heart, Lung, and Blood Institute (R01HL087033, R01HL135165, R01HL111938, R01HL056267)
- National Institute of Environmental Health Sciences (R21ES024414, T32ES007141)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Takotsubo Cardiomyopathy and Associated Phenomena
- Keywords
- myocarditis, heart failure, soluble ST2, sex differences, young men, testosterone, gonadectomy, hormone replacement therapy, cardiac inflammation, biomarkers, NYHA functional class
- MeSH terms
- Interleukin-1 Receptor-Like 1 Protein, Adult, Age Factors, Animals, Biopsy, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Heart Failure, Humans, Male, Mice, Inbred BALB C, Middle Aged, Myocarditis, Myocardium, Prognosis, Retrospective Studies, Sex Factors, Biomarkers, Mice
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