Acute myocarditis represents an inflammatory cardiomyopathy marked by immune-mediated myocardial damage triggered by diverse etiologies including viral infections, autoimmune disorders, toxic exposures, and pharmacological agents. Clinical outcomes range from spontaneous resolution to progression toward dilated cardiomyopathy or sudden cardiac death (1–3). Among the adolescent population, it has become the main cause of sudden cardiac death, surpassing the incidence of ischemic heart disease. Current epidemiological data indicate that the incidence of acute myocarditis is 10 to 22 per 100,000 and is on the rise (3, 4). The clinical manifestations of myocarditis are heterogeneous, ranging from mild symptoms such as chest pain and palpitations to life-threatening cardiogenic shock and ventricular arrhythmias. There exists a critical need for validated prognostic biomarkers to facilitate early risk stratification and guide therapeutic interventions in this heterogeneous patient population.

Pathological manifestations of myocarditis include myocyte necrosis, fibrosis, and edema, driven by innate and adaptive immune responses (5). While the exact pathogenic mechanisms remain elusive, contemporary research highlights neutrophils as key mediators of myocardial injury in acute myocarditis (6, 7). Clinical studies demonstrate that elevated neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) correlate with prolonged hospitalization in myocarditis patients (8). The neutrophil percentage-to-albumin ratio (NPAR) synergistically combines acute-phase (neutrophils) and chronic-phase (albumin) inflammatory markers, offering a more integrated evaluation of inflammatory status (9). Systemic Immune Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI) as sensitive indicators of inflammatory immune homeostasis, show strong prognostic value in various inflammatory diseases (10). Among acute coronary syndrome patients receiving percutaneous coronary intervention (PCI), both SIRI and aggregate index of systemic inflammation (AISI) independently predict major adverse cardiovascular events (11, 12).

These integrated inflammatory indices provide a clinically feasible and methodologically robust framework for risk stratification. When incorporated with conventional clinical parameters, they enable the development of multidimensional prediction algorithms that optimize both prognostic accuracy and therapeutic decision-making. This study specifically aims to validate the clinical utility of four novel inflammatory indices (NPAR, SII, SIRI, and AISI) for early severity assessment in acute myocarditis patients.

The baseline clinical characteristics of the total cohort (N=183) are detailed in Table 2 . The majority of myocarditis patients are men, however fulminant myocarditis is more common in women. Compared to the mild myocarditis group, the fulminant myocarditis group had higher age, NYHA scores, Neutrophil, cardiac troponin I (cTnI), CK-MB, BNP, CRP, lactic acid (Lac), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (sCr), NPAR, SII, SIRI and AISI. But lower heart rate, ejection fraction, blood pressure, lymphocyte counts, Monocytes counts (all P < 0.05).

For patients with myocarditis, Spearman correlation analysis showed significant relationships between the NYHA score at admission and the values of NPAR, SII, SIRI, and AISI (r = 0.370, 0.296, 0.284, and 0.246, P < 0.01). Patients with worse cardiac function (NYHA score > III) nonetheless had higher levels of NPAR, SII, SIRI and AISI than patients with comparatively better cardiac function (NYHA score < II) ( Figure 1 ).

The differences in NPAR, SII, SIRI, and AISI between patients with mild acute myocarditis and those with fulminant myocarditis are compared in Figure 2 . The mild patient group had lower levels of NPAR, SII, SIRI, and AISI than the severe patient group (P < 0.05).

With an AUC of 0.774 (95% CI 0.6854 - 0.8620, P < 0.05), ROC analysis ( Figure 3 ) revealed that the critical value of NPAR was 1.753, indicating a sensitivity of 0.848 and a specificity of 0.560 for diagnosing acute myocarditis. The critical value of SII for discriminating mild from severe cases was 1169, with a sensitivity of 0.783 and a specificity of 0.529, and an AUC of 0.667 (95% CI 0.5599 - 0.7749; P < 0.05). The cutoff value of SIRI was 2.058, with a sensitivity of 0.549 and a specificity of 0.852, and an AUC of 0.710 (95% CI 0.6201 - 0.8000, P < 0.05). The threshold value of AISI was 446, with a sensitivity of 0.570 and a specificity of 0.735, with an AUC of 0.663 (95% CI 0.5677 - 0.7587, P < 0.05).

To investigate if higher NPAR, SII, SIRI, and AISI were independent risk markers for patients with fulminant myocarditis, variables with P < 0.05 during the binary logarithmic analysis were included in the multivariate analysis ( Table 3 ). High NPAR (OR = 5.67, 95%CI: 1.81 ~ 16.36, P < 0.05), SII (OR = 1.01, 95%CI: 1.01 ~ 1.01, P < 0.05), SIRI(OR = 1.21 95%CI: 1.06 ~ 1.37, P < 0.05), and AISI(OR = 1.01, 95%CI: 1.01 ~ 1.01, P < 0.05) were found to be independently linked with the probability of fulminant myocarditis in multivariate logistic regression analysis.

Current diagnostic approaches for myocarditis remain nonspecific, primarily dependent on established clinical criteria rather than definitive biomarkers (13). Although the exact pathophysiological mechanisms remain incompletely understood, immune cells emerge as central orchestrators of myocardial inflammation. The inflammatory cascade in acute myocarditis involves coordinated actions of multiple immune lineages - neutrophils, monocytes, macrophages, and T/B lymphocytes (5, 16–18). Neutrophils, the most abundant circulating immune cells, serve as the first line of defense against pathogens and play a critical role in innate immune responses. Notably, their activity is amplified in acute myocarditis, exacerbating inflammatory cascades (6, 19). Experimental models demonstrate neutrophil chemotactic leadership, with these cells preceding monocyte infiltration and facilitating subsequent myeloid recruitment to inflamed myocardium (20). Treg cells play an important protective role in the occurrence of myocarditis (21). It was found that Treg cell abundance was negatively correlated with myocarditis severity (22, 23). Consistent with this paradigm, our cohort revealed marked lymphopenia in fulminant cases compared to moderate presentations, suggesting compromised immunoregulatory capacity. Oxidative stress plays an important role in the course of the disease in acute myocarditis, and serum albumin is the most abundant antioxidant in the whole blood (24). Albumin can combine lipopolysaccharides and other bacterial products (lipophosphomic acid and peptidoglycan), reactive oxygen species, nitric oxide and other nitrogen-reactive substances, and prostaglandins to regulate inflammation (25). Its levels fluctuate rapidly during acute inflammation due to extracellular metastasis (26). Therefore, hypoalbuminemia plays an important role in the development and progress of cardiovascular diseases (27). Our results also demonstrate that patients with fulminant myocarditis have lower serum albumin levels than those with mild myocarditis.

A meta-analysis by Ghulam et al. (28) identifies CRP as a dual-purpose biomarker for myocarditis diagnosis and outcome prediction. Emerging inflammatory indices combine practical advantages (cost-effectiveness, rapid assessment) with comprehensive immune-inflammation profiling, demonstrating independent prognostic value across multiple disease states (29–31). Recent researches find novel inflammatory biomarkers as significant predictors of both disease onset and adverse outcomes in cardiovascular conditions including CAD and hypertension (32–34). Cui et al. identified elevated NPAR at admission as an independent predictor of in-hospital mortality in ST-segment elevation myocardial infarction (STEMI) patients (35). Population-level research demonstrates significant associations between SII and SIRI with cardiovascular disease prevalence and all-cause mortality (36). Jiang et al. (12) revealed that elevated AISI levels in acute myocardial infarction (AMI) patients correlate with increased cardiovascular mortality risk, suggesting its utility as an early prognostic indicator. These findings collectively establish systemic inflammation biomarkers as critical tools for cardiovascular disease stratification and outcome prediction.

While NLR and MLR have established associations with myocarditis severity (8), the prognostic potential of novel composite inflammatory indices - NPAR, SII, SIRI, and AISI - remains underexplored. Nevertheless, research on compound inflammatory markers such NPAR, SII, SIRI, and AISI is lacking. This study provides the first analysis linking these advanced inflammatory indices to disease severity in acute myocarditis. Our findings reveal correlations between NPAR, SII, SIRI, and AISI levels with both cardiac dysfunction metrics and clinical severity stratification. Moreover, univariate and multivariate binary logistic regression results show that NPAR, SII, SIRI, and AISI are independently linked to patients’ risk of developing fulminant myocarditis. To our knowledge, this represents the inaugural investigation establishing NPAR, SII, SIRI, and AISI as clinically significant biomarkers for acute myocarditis severity assessment.

Our results indicate that elevated NPAR, SII, SIRI, and AISI levels at admission correlate with reduced cardiac function and heightened fulminant myocarditis risk. These indices may thus facilitate risk-stratified therapeutic strategies and serve as practical clinical tools for evaluating disease progression and potential complications.

In conclusion, we are the first investigation to apply NPAR, SII, SIRI, and AISI as clinically significant biomarkers for acute myocarditis severity stratification. NPAR, SII, SIRI, and AISI indicators will provide theoretical support for early intervention in patients with acute myocarditis. These findings provide reference for the implementation of risk-adapted treatment options and early targeted interventions that promote acute myocarditis management.