Cardiac troponin and creatine kinase-MB (CK-MB) remain the core routine biomarkers of myocardial injury in FM^[17,18]. Their practical value lies in their accessibility and rapid turnaround time. In particular, troponin directly reflects cardiomyocyte damage and is therefore central to the initial laboratory assessment of suspected FM. CK-MB, although less specific, still contributes to the conventional injury profile and may be useful in routine emergency evaluation where extended molecular assays are not available.

These injury markers should not be overinterpreted. Elevated troponin levels may also occur in other acute cardiovascular conditions, particularly acute coronary syndromes^[19,20]. Therefore, in FM, abnormal troponin or CK-MB values are best understood as evidence of substantial myocardial injury within the appropriate clinical context, rather than as independent proof of a FM diagnosis. Their major role is to support suspicion, quantify the extent of injury, and prompt timely integration with electrocardiographic, hemodynamic, and imaging findings^[17,18].

Natriuretic peptides, including B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), complement myocardial injury markers by reflecting ventricular wall stress and acute hemodynamic load^[17,18]. In FM, BNP and NT-proBNP are often elevated because fulminant disease is frequently accompanied by rapidly evolving ventricular dysfunction, circulatory instability, and heart failure physiology. As a result, natriuretic peptide elevation may provide useful information on the stress imposed on the failing ventricle, especially when interpreted together with troponin rather than in isolation.

As with troponin, natriuretic peptides are not specific for FM. Their levels may also rise in acute heart failure and other settings of ventricular dysfunction^[21,22]. Their value in FM therefore lies less in etiologic discrimination than in physiologic characterization. A combined pattern of marked myocardial injury and ventricular stress may be more informative than any single conventional marker alone, because it better reflects the coexistence of inflammatory myocardial damage and acute hemodynamic decompensation that typifies fulminant presentation.

The discriminatory value of routine biomarkers may increase when they are interpreted together with bedside physiologic and organ-injury variables. In a retrospective study of adults, discrimination between fulminant and non-FM improved when routine admission variables were analyzed in combination rather than separately^[23]. The final model included mean arterial pressure, creatinine, blood urea nitrogen, aspartate aminotransferase, troponin I, and ventricular wall motion abnormality^[23]. This observation is conceptually important because it suggests that FM is often recognized more accurately as a combined syndrome of myocardial injury, hemodynamic compromise, and systemic organ stress than as an isolated elevation in a single cardiac biomarker.

This composite approach is best viewed as a clinical discrimination model rather than a molecular biomarker panel. Its main value is pragmatic: it may help identify which patients with suspected myocarditis are more likely to have a fulminant presentation using information already available at admission^[23]. In this context, routine injury- and stress-related biomarkers also show measurable but nonspecific discriminatory value. In a young-adult acute myocarditis cohort, troponin I discriminated FM with an area under the curve (AUC) of 0.772 at a cutoff of 0.48 ng/mL, whereas NT-proBNP showed stronger performance, with an AUC of 0.969 at a cutoff of 256 pg/mL, 96% sensitivity, and 80% specificity^[24]. NT-proBNP also remained an independent predictor of FM in multivariable analysis. These findings support the value of natriuretic peptides for reflecting hemodynamic stress, whereas troponin should be interpreted mainly as a sensitive but nonspecific marker of myocardial injury. However, these markers do not establish etiology and should not be interpreted as substitutes for subsequent multimodal evaluation^[24]. Additional validation in larger and prospectively adjudicated FM cohorts is still needed. Routine injury- and stress-related markers also provide limited insight into the immune intensity that underlies fulminant progression, which warrants separate consideration of inflammation-related biomarkers.

C-reactive protein (CRP) remains one of the simplest and most widely available inflammatory markers in the evaluation of suspected FM^[17,18]. In clinical practice, its value lies in indicating that severe myocardial injury is occurring in an inflammatory milieu rather than in a purely ischemic or hemodynamic setting^[25]. When interpreted together with troponin, natriuretic peptides, clinical presentation, and hemodynamic findings, CRP may therefore strengthen suspicion that the syndrome is inflammatory rather than purely mechanical in nature.

Its limitations, however, are substantial. CRP may also increase in infection^[26], sepsis^[27], and other inflammatory states^[28]. Accordingly, CRP should be regarded as a supportive marker of inflammatory context rather than a discriminator of FM etiology or a standalone determinant of fulminant presentation.

Routine blood count-derived inflammatory indices provide a simple and readily available approach to inflammatory assessment in FM. The systemic immune-inflammation index (SII) and the systemic inflammatory response index (SIRI) are attractive because they can be calculated rapidly after admission and do not require new assays^[29,30]. In pediatric and young-adult myocarditis cohorts, SII and SIRI demonstrated potential diagnostic value for FM. In one pediatric cohort, SII showed an AUC of 0.760 with a cutoff value of 1,050, whereas SIRI showed an AUC of 0.640 with a cutoff value of 1.9. In a young-adult myocarditis cohort, SII showed stronger diagnostic performance, with an AUC of 0.911 at a cutoff value of 1020, 91% sensitivity, and 83% specificity, and remained an independent predictor of FM^[29]. Across available studies, reported SII performance varied, with AUC values ranging from approximately 0.760 to 0.920, cutoff values from 1,020 to 1,378, sensitivity from 68.8% to 91%, and specificity from 83% to 94.4%. Similarly, SIRI showed variable diagnostic performance, with reported AUC values from approximately 0.640 to 0.710 and cutoff values from 1.9 to 2.058. These variations suggest that age group, cohort design, sampling time, and differences in FM definitions may influence the observed diagnostic performance of these inflammatory indices^[29]. The main appeal of SII and SIRI is not molecular specificity but bedside immediacy: they translate a routine complete blood count into an estimate of systemic immune activation at essentially no additional cost. This makes them especially relevant in settings where advanced biomarker assays are unavailable or delayed.

These indices should nonetheless be interpreted cautiously. Their biological plausibility in FM is strong because fulminant disease is often accompanied by marked innate immune activation^[31,32], but they are not myocarditis-specific tools. They may also rise in sepsis^[33], infective endocarditis^[34], and other inflammatory conditions. SII and SIRI are therefore better framed as inflammatory enrichment markers or triage aids rather than as disease-specific FM biomarkers. In the current literature, SII appears more promising than SIRI, but both still require broader validation across more rigorously phenotyped FM cohorts^[35]. Accordingly, reported AUC values for SII and SIRI should be interpreted as preliminary cohort-specific estimates rather than stable diagnostic thresholds ready for routine clinical use.

S100A8/A9 is the most compelling inflammation-related protein biomarker currently studied in FM. S100A8 and S100A9 are calcium-binding S100 family proteins that form the heterodimeric complex calprotectin and are mainly expressed by activated neutrophils and monocytes/macrophages^[36]. Extracellular S100A8/A9 can function as an alarmin and amplify innate immune responses through pattern-recognition receptors such as Toll-like receptor 4 and the receptor for advanced glycation end products^[37]. Plasma proteomic studies identified S100A8/A9 as a candidate biomarker and possible therapeutic target^[37]. In validation analyses, admission S100A8/A9 distinguished FM from non-FM, acute myocardial infarction, and acute decompensated heart failure^[37]. This is clinically important because these conditions are common acute-care mimics of FM.

In a two-center validation cohort, plasma S100A8/A9 measured at admission differentiated FM from non-FM with an AUC of 0.923, from acute myocardial infarction with an AUC of 0.892, and from acute decompensated heart failure with an AUC of 0.978^[37]. The heterodimer also performed better than S100A8 or S100A9 alone, supporting the view that the combined signal is biologically and diagnostically more informative than either subunit measured separately.

S100A8/A9 was also associated with disease severity. Higher levels were linked to lower left ventricular ejection fraction and greater inflammatory burden^[37]. These findings suggest that S100A8/A9 may reflect both the intensity of myocardial injury and the strength of the inflammatory response. Its biological relevance further supports its candidacy, because S100A8/A9, also known as calprotectin, functions within a damage-associated molecular pattern pathway. In the same clinical dataset, higher S100A8/A9 expression was accompanied by higher circulating IL-1, IL-2R, IL-6, and IL-10 levels, reinforcing the view that this marker tracked a broader hyperinflammatory state rather than isolated tissue injury alone^[37]. Experimental evidence has further strengthened this candidate. In a coxsackievirus B3-induced FM model, blockade of the S100A8/A9 pathway improved survival, reduced inflammatory cell infiltration, and improved cardiac function^[37]. Pharmacologic blockade with ABR-238901 reduced mortality and mitigated the decline in cardiac function in myocarditis mice, thereby providing interventional support for a mechanistic role rather than a purely associative signal^[37]. Thus, S100A8/A9 may represent more than a passive inflammatory biomarker. Experimental intervention studies suggest that it can act as an active inflammatory mediator in FM, partly through Toll-like receptor 4 and receptor for advanced glycation end products signaling. However, whether S100A8/A9 is causally involved in human FM remains unproven. It should therefore be regarded as a mechanistically plausible biomarker and potential therapeutic target, rather than a clinically validated causal factor.

Overall, S100A8/A9 currently represents a high-priority translational candidate among inflammation-related biomarkers in FM, because its evidence spans discovery proteomics, human diagnostic validation, association with functional severity and cytokine activation, and experimental therapeutic rescue. However, it should not yet be regarded as a clinically established diagnostic marker. Further prospective multicenter studies are needed to validate its diagnostic cutoffs, clarify the influence of sampling time and assay platform, and determine whether S100A8/A9 adds incremental value beyond conventional inflammatory and myocardial injury markers.

Beyond S100A8/A9, additional inflammation-linked protein candidates have emerged in recent literature. In a cytokine-focused investigation, plasma Siglec-5 and CD163 were reported to have diagnostic and severity-related associations with FM^[38]. Siglec-5 is an inhibitory sialic acid-binding immunoglobulin-like lectin expressed mainly on myeloid cells^[39], whereas CD163 is a scavenger receptor predominantly expressed on monocytes and macrophages and is commonly regarded as a marker of macrophage activation^[40]. These biological features provide a rationale for evaluating circulating Siglec-5 and CD163 as inflammation-related biomarkers in FM. However, compared with S100A8/A9 and sST2, the available evidence remains less mature, and independently validated predictive metrics, stable cutoffs, and externally confirmed sensitivity or specificity estimates are still limited. Their levels were also negatively correlated with left ventricular ejection fraction^[38]. These findings are noteworthy because both molecules are biologically consistent with dysregulated innate immune activation and macrophage-related inflammatory responses. Unlike S100A8/A9, however, these candidates remain supported mainly by early exploratory datasets rather than by layered validation across independent cohorts and mechanistic intervention studies. Siglec-5 and CD163 are therefore best presented at this stage as hypothesis-generating inflammatory protein candidates rather than established clinical biomarkers for FM^[38].

The inflammation-related biomarker landscape in FM thus shows a clear gradient of maturity: CRP, SII, and SIRI are accessible but nonspecific; S100A8/A9 is biologically anchored and comparatively well validated; and Siglec-5/CD163 remain promising but preliminary. This layered interpretation is more informative than treating all inflammatory markers as equivalent signals. Even so, inflammation-related markers do not fully capture disease dynamics, short-term prognosis, or multiorgan injury, thereby motivating interest in novel molecular biomarkers.

Among currently studied molecular biomarkers, sST2 remains one of the most compelling protein biomarker candidates in FM^[17,41]. sST2 is the soluble isoform of the interleukin-1 receptor family protein ST2 and can act as a circulating decoy receptor for IL-33. Recent mechanistic evidence in FM further suggests that CCR2-positive macrophage-derived sST2 may be internalized by cardiomyocytes through the insulin-like growth factor 2 receptor and contribute to mitochondrial dysfunction^[41]. Earlier studies also showed that circulating sST2 increased markedly during the acute phase of FM and declined during recovery^[17]. This dynamic pattern suggested that sST2 may reflect disease activity over time rather than simply a fixed baseline abnormality. Additional clinical work supported its diagnostic value. In children with suspected viral myocarditis, one retrospective study showed that sST2 was associated with FM and had good diagnostic performance, with an area under the curve of 0.865^[42]. The validation confirmed that sST2 also correlated with markers of cardiac stress and cardiac dysfunction^[42].

Later work strengthened the clinical case for sST2. In one prospective cohort, a plasma threshold of 58.39 ng/mL showed high diagnostic accuracy for FM^[17]. Evidence from this cohort indicated that sST2 distinguished FM from other acute hemodynamically unstable conditions with an AUC of 0.96 and outperformed cardiac troponin I (cTnI) and NT-proBNP in differential diagnosis, while the same cutoff also achieved high specificity and sensitivity in prospective validation^[17]. More recent translational work has further suggested that sST2 may carry prognostic significance^[41]. Admission plasma sST2 above 600 ng/mL predicted 30-day death or ECMO requirement and performed better than NT-proBNP and cTnI for that outcome^[41].

Experimental data have provided unusually strong mechanistic validation for this marker. A recent study showed that sST2 was derived predominantly from infiltrating CCR2-positive macrophages, entered cardiomyocytes via the insulin-like growth factor 2 receptor, altered YY1 localization, and suppressed mitochondrial electron transport chain gene expression^[41]. Neutralizing sST2 restored mitochondrial function, improved cardiac performance, and increased survival in FM models^[41]. These findings indicate that sST2 may be linked not only to severity, but also to disease progression itself. In this context, sST2 is best viewed as a multifunctional biomarker in FM: it may support diagnosis at admission, reflect disease dynamics during recovery, identify patients at higher short-term risk, and point to a targetable pathogenic pathway.

The current evidence still has practical limitations. Most available sST2 studies remain single-center or modest in size, and serial sampling has not been standardized across cohorts. Nevertheless, sST2 is one of the most mature FM biomarker candidates and deserves translational priority because it integrates diagnostic, prognostic, dynamic, and mechanistic evidence. Future studies should validate disease- and outcome-specific cutoffs, standardize sampling windows and assay platforms, and test whether sST2 provides incremental value beyond troponin, natriuretic peptides, echocardiography, and hemodynamic variables.

cfDNA represents a distinct direction in FM biomarker research because it may reflect not only myocardial injury but also the multisystem damage that frequently accompanies fulminant disease^[43]. Recent work using genome-wide cfDNA methylation profiling suggested that plasma cfDNA could trace the tissue origins of injury and identify early multiorgan involvement in myocarditis^[43]. In the reported cohort, cfDNA showed potential for early risk stratification and appeared to outperform several conventional biochemical indicators in identifying severe organ injury patterns^[43].

The conceptual value of cfDNA is considerable. Although cfDNA methylation profiling may provide tissue-of-origin information and early multiorgan injury assessment, current FM evidence remains exploratory. Standardized FM-specific diagnostic cutoffs, externally validated sensitivity and specificity estimates, and prospectively tested risk-prediction metrics have not yet been established. Therefore, cfDNA should be presented as a tissue-injury mapping and risk-stratification research tool rather than as a clinically validated diagnostic biomarker.

Non-coding RNA biomarkers in FM, including tiRNAs^[44], microRNAs^[45,46], and circular RNAs^[47], remain exploratory but are of interest because they may reflect tightly regulated inflammatory and injury-response programs rather than nonspecific tissue damage alone. Among these, tiRNA-Gln-TTG-001 was reported to be elevated during the acute phase of pediatric FM, to decrease during recovery, and to correlate with hs-cTnT, CRP, and procalcitonin^[44]. However, available studies mainly report differential expression and correlation analyses rather than validated FM-specific AUC, cutoff, sensitivity, specificity, odds ratio, hazard ratio, or C-index estimates. Circulating microRNA candidates, including hsa-miR-21, were also associated with FM severity or prognosis in pediatric cohorts^[48], while circRNA profiling identified dysregulated inflammatory signaling networks and highlighted candidates such as hsa_circ_0064338^[47]. Collectively, these studies suggest that RNA-based biomarkers may provide mechanistically informative molecular signatures in FM.

The ncRNA literature is still limited by small sample sizes, heterogeneous study designs, and incomplete validation in clinically relevant control populations. Accordingly, tiRNAs, microRNAs, and circRNAs are better regarded as innovative molecular candidates than as clinically deployable biomarkers for current FM practice.

Metabolomic signals are biologically relevant to FM because fulminant disease is characterized by profound inflammatory activation, energetic stress, and frequent multiorgan dysfunction^[2,49,50]. In principle, these features make metabolic profiling an attractive approach for capturing the systemic consequences of fulminant progression. However, the current literature has not yet produced a validated circulating metabolite panel with clear bedside utility for FM. For this reason, metabolomics should presently be discussed mainly as a discovery-oriented tool that may help identify perturbed pathways and generate mechanistic hypotheses, rather than as an established clinical biomarker strategy for FM.

Overall, the novel biomarker landscape in FM shows a clear gradient of maturity. sST2 is currently the most biologically and clinically substantiated candidate. For most other non-coding RNA and metabolomic candidates, the available evidence remains at the discovery or early translational stage. These studies typically report differential expression, pathway enrichment, correlation with injury or inflammatory markers, or candidate regulatory networks, but do not yet provide externally validated FM-specific predictive metrics such as AUC, C-index, hazard ratio, odds ratio, standardized cutoffs, sensitivity, or specificity. These biomarkers should therefore be interpreted as hypothesis-generating molecular signals rather than clinically actionable diagnostic tools.

Immune checkpoint inhibitor (ICI)-associated myocarditis provides a clear example of the context-dependent value of etiologically informative biomarkers in FM. In patients with recent exposure to ICIs, abnormalities in routine laboratory markers may be interpreted more specifically in light of the exposure history. Troponin elevation, often together with creatine kinase elevation, may raise suspicion for myocarditis in this case^[51]. Even so, these markers are not subtype-specific in a strict sense. Their principal value lies in supporting etiologic suspicion in the context of a known trigger, rather than serving as a dedicated diagnostic biomarker panel for ICI-associated FM^[52].

The available ICI myocarditis literature further suggests that inflammatory indices such as neutrophil-to-lymphocyte ratio (NLR) and CRP may have adjunctive prognostic value, whereas emerging candidates such as selected microRNAs remain preliminary^[53]. However, these markers have not yet been validated as FM subtype-defining biomarkers with reproducible cutoffs or robust predictive metrics. Their interpretation remains highly dependent on ICI exposure history, concurrent myositis or skeletal muscle injury, cancer status, and the broader clinical context. Deep immune profiling has also identified expansion of cytotoxic CD45RA (TEMRA) CD8-positive T cells with clonal enrichment and inflammatory CXCL9/CXCL10-positive macrophage programs, but these findings have not yet established a routine circulating biomarker panel for bedside use^[51,52]. Accordingly, in ICI-associated FM, biomarker interpretation still depends more on exposure context and integrated clinical suspicion than on any validated subtype-defining blood signature.

For eosinophilic myocarditis and giant cell myocarditis, the current circulating biomarker landscape is even less mature. There is no specific evidence supporting a validated standalone blood biomarker that reliably identifies giant cell myocarditis at presentation. Accordingly, no robust circulating AUC, cutoff, sensitivity, specificity, odds ratio, hazard ratio, or C-index can currently be recommended for blood-based identification of giant cell myocarditis in the FM setting. Instead, giant cell myocarditis is usually suspected from a particularly high-risk clinical phenotype, especially refractory ventricular arrhythmias or advanced conduction disease^[54]. Likewise, eosinophilic myocarditis may show peripheral eosinophil-related signals, but these findings mainly suggest a possible cause rather than serving as definitive biomarkers^[55].

This distinction is important for the review narrative. In these subtypes, currently available blood abnormalities function more as etiologic clues than as true diagnostic biomarkers, and their interpretation remains inseparable from the broader clinical picture. These entities should therefore be discussed briefly and cautiously in a biomarker review: their importance is unquestionable, but the biomarker evidence remains limited.

Viral myocarditis remains one of the major etiologic substrates of FM^[31], yet the current literature still does not support a mature blood-based biomarker that can independently distinguish active viral FM from other inflammatory or noninflammatory acute cardiac syndromes^[31,32]. In the available literature, tissue virology remains more informative than circulating markers, and PCR-based evaluation of myocardial viral load remains important for distinguishing active viral replication from post-viral inflammatory disease^[31]. Blood biomarkers in viral FM should therefore be understood as supportive rather than definitive etiologic tools.

More broadly, the main lesson from etiologic biomarker studies is not that subtype-specific plasma markers are already clinically established, but that different FM subtypes may possess distinct immune programs that could guide future biomarker discovery. The immune-profiling findings in ICI-associated myocarditis and the growing interest in viral myocarditis-associated ncRNAs support this direction, but they have not yet translated into robust bedside assays for routine etiologic classification. Overall, other biomarkers and etiologic clues in FM remain limited in both maturity and scope. Their present value lies mainly in narrowing the likely cause in selected clinical settings—particularly when exposure history, eosinophilia, refractory arrhythmia, or other distinctive features have already focused suspicion. They are not yet reliable as primary tools for early diagnosis, severity stratification, or prognosis in most acute-care presentations of FM.