European Journal of Cardiovascular Medicine

Myocarditis comprises a heterogeneous group of inflammatory myocardial disorders that may present with chest pain, arrhythmia, acute heart failure, or otherwise unexplained ventricular dysfunction. Persistent inflammatory injury can cause or coexist with a dilated cardiomyopathy phenotype, but the presence of ventricular dysfunction or myocardial scar alone cannot establish ongoing myocardial inflammation. The 2025 European Society of Cardiology guidance and American College of Cardiology consensus describe a multiparametric diagnostic strategy incorporating clinical presentation, ECG, echocardiography, circulating markers, CMR, and selective endomyocardial biopsy (EMB). [1,2]

CMR provides an integrated view of ventricular volumes, function, tissue edema, injury, and fibrosis. The original Lake Louise criteria assessed edema, hyperemia, and late gadolinium enhancement (LGE). The 2018 revision emphasizes at least one T2-based edema criterion together with at least one T1-based criterion (native T1, extracellular volume fraction [ECV], or LGE) to support active nonischemic myocardial inflammation. [3,4] These features are valuable in early inflammatory presentations, although LGE may persist after inflammation has resolved and quantitative mapping values vary with scanner characteristics, acquisition methods, and local normal ranges. [3,21]

Troponin I and T identify myocardial injury rather than its etiology; natriuretic peptides reflect myocardial wall stress and heart failure severity; CRP measures a systemic inflammatory response. Their clinical utility must therefore be judged according to the target condition and reference standard. Novel circulating RNA markers may offer additional information, but assay standardization, independent validation and specificity for distinct cardiomyopathy phenotypes remain uncertain. [1,15–18,23] Diagnostic accuracy studies of acute myocarditis often use healthy controls or clinical reference standards that incorporate CMR or troponin measurements. Such designs differ from biopsy-referenced investigations of inflammatory cardiomyopathy. Diagnostic performance was therefore evaluated separately for acute and persistent disease, with CMR and circulating biomarkers considered according to their reference standards.

Recent studies underscore additional diagnostic complexity. Myocardial edema or nonischemic LGE may overlap with genetic cardiomyopathy, whereas chronic inflammation can persist with limited biochemical evidence of myocyte necrosis. Imaging criteria developed in acute idiopathic or viral myocarditis cannot be assumed to have identical performance in persistent disease, autoimmune myocarditis or genetic dilated cardiomyopathy. [26,28–31,38–41]

2.1 Review design, objective and eligibility framework

This diagnostic-test evidence review evaluated whether CMR tissue characterization or circulating biochemical measurements identify myocardial inflammation in patients with suspected myocarditis or myocarditis-associated cardiomyopathy. Eligible populations included adolescents and adults with acute suspected myocarditis, recent-onset nonischemic dilated cardiomyopathy, persistent myocarditis-like symptoms or biopsy-characterized chronic inflammatory cardiomyopathy. Primary eligible designs were prospective or retrospective diagnostic cohorts and cross-sectional studies reporting a clinically defined target condition with an explicit reference standard. CMR index tests comprised conventional Lake Louise criteria, revised 2018 Lake Louise criteria, native T1, T2, extracellular volume (ECV), and late gadolinium enhancement (LGE). Biomarker index tests included cardiac troponins, C-reactive protein (CRP), BNP/NT-proBNP and exploratory circulating RNA assays. Reports were excluded from primary evidence synthesis when they were reviews, editorials, guidelines, nonhuman studies, duplicate cohorts, or lacked a recognizable target condition or interpretable index-test finding. Secondary reviews and practice statements informed only the context and interpretation. [1–4,19,20,26,27,43]

2.2 Information sources and literature search

The literature search covered PubMed-indexed records, publisher-hosted full texts and reference lists accessible through June 2026. Combinations of the following search concepts were used: (myocarditis OR inflammatory cardiomyopathy OR nonischemic dilated cardiomyopathy) AND (cardiac magnetic resonance OR cardiovascular magnetic resonance OR Lake Louise OR T1 mapping OR T2 mapping OR extracellular volume OR endomyocardial biopsy OR troponin OR NT-proBNP OR C-reactive protein OR diagnostic accuracy). Related terminology and cited reports were checked during full-text verification. Studies published since 2009 were prioritized for CMR comparisons; foundational studies on troponin, biopsy and diagnostic-method methodology were retained irrespective of publication year. Screening eligibility was determined by the study population, the biological diagnostic target and whether the measured test could be related to an independent clinical or biopsy reference. [3–5,19,26,27,43]

2.3 Screening and study selection

Titles and abstracts were screened for original human studies of imaging or circulating biomarkers in suspected myocardial inflammation. Full texts were evaluated for clinical phenotype, test positivity threshold, reference standard, cohort independence and diagnostic numerators and denominators. When overlapping populations were identified, the report with the most applicable reference standard and complete diagnostic data was retained. Studies without endomyocardial biopsy (EMB) reference standards or reconstructable 2 × 2 data remained eligible for descriptive synthesis but were excluded from biopsy-referenced quantitative pooling. [19,43]

2.4 Data extraction and outcome definitions

Extracted data included author, publication year, study design and population, symptom duration, target disease state, number enrolled, CMR sequence/algorithm or biomarker assay, positivity thresholds, comparator and diagnostic results. For dichotomized studies, true positives (TP), false negatives (FN), false positives (FP), and true negatives (TN) were recorded when published explicitly or uniquely derivable from the stated denominators and percentages. The primary quantitative outcomes were sensitivity and specificity of CMR against EMB-confirmed inflammatory disease. Secondary outcomes included the ability to distinguish active from healed inflammation, AUC values, CMR–biomarker agreement, and reported clinical-stage effects. Where sensitivity and specificity were supplied for different algorithms, only one explicitly defined algorithm per independent patient cohort entered the three-study exploratory pooling. Biomarker measures were summarized separately to avoid treating blood assays and myocardial tissue characterization as interchangeable index tests.

2.5 Index tests, target conditions and reference standards

EMB with histologic and/or immunohistologic evaluation was the preferred tissue-level reference for myocarditis-related inflammation. CMR findings primarily measure edema, extracellular expansion and myocardial damage; these may not be identical to inflammation in a small biopsy sample. Conventional Lake Louise assessment required positivity on at least two tissue criteria, whereas the updated 2018 framework combines at least one T2-based edema criterion with one T1-based injury criterion. Parametric mapping cutoffs are influenced by scanner field strength, mapping sequence and reference range. Blood biomarkers were interpreted using each primary report’s assay-specific threshold and collection context. Acute myocarditis, chronic active myocarditis, healed myocarditis and inflammatory dilated cardiomyopathy were treated as distinct target conditions, not pooled indiscriminately. [3,4,7,21,26,28–31,37]

2.6 Quantitative synthesis

Diagnostic sensitivity was calculated as TP/(TP + FN) and specificity as TN/(TN + FP). Wilson score intervals provided 95% confidence intervals for individual study proportions. For the three CMR datasets with verifiable biopsy-referenced 2 × 2 cells, separate logit-transformed random-effects models summarized sensitivity and specificity using inverse-variance weights, a 0.5 continuity correction and restricted maximum likelihood (REML) estimation of between-study variance. Model means and 95% confidence intervals were back-transformed to probability scale. Conventional Cochran-Q-derived I² was used as an exploratory measure of heterogeneity. Because the included imaging algorithms and clinical stages differed, the resulting estimates are descriptive summaries rather than an expected accuracy for a single standardized CMR protocol. Separate univariate analyses do not account for sensitivity–specificity covariance; a bivariate model or hierarchical summary ROC model would be preferable with a larger, sufficiently comparable dataset. [19,32,33]

2.7 Methodological quality and applicability

Methodological considerations were organized according to the four QUADAS-2 domains: patient selection, index-test conduct/interpretation, reference-standard adequacy and flow/timing. Applicability to myocarditis-associated cardiomyopathy was examined separately for acute myocarditis samples, persistent inflammatory cardiomyopathy, and case-control comparisons with clinically healthy or otherwise distinct controls. Potential sources of bias included enriched case-control recruitment, reference standards that incorporated the index test, nonuniform timing from symptom onset, variable field strength and CMR thresholds, selective biopsy sampling, and incomplete presentation of paired test results. The synthesis records these interpretive concerns without assigning unverified study-level low/high/unclear QUADAS-2 ratings. [20,26,27]

2.8 Heterogeneity, subgroup comparisons and reporting bias

Prespecified clinical explanations for heterogeneity were disease phase (acute, persistent, or chronic/healed), CMR criterion (conventional, 2018 criteria, or mapping), assay/test threshold, and biopsy versus nonbiopsy reference standard. With only three independent studies contributing to the CMR pooling, meta-regression, formally modeled subgroup effects and leave-one-out influence measures would be unstable. Instead, individual study estimates and the clinical differences between studies were compared descriptively. Biomarker performance was not pooled because different assays, thresholds and diagnostic targets prevented a meaningful common-effect definition. Deeks funnel-plot asymmetry, publication-bias tests and hierarchical summary ROC curves were not calculated for the three-study analysis. [19,32,33]

2.9 Reporting and data availability

Study selection, participant characteristics, index-test definitions, diagnostic thresholds, reference standards, test accuracy, heterogeneity and applicability were reported according to PRISMA-DTA domains. Two-by-two CMR diagnostic data are provided in the accompanying extraction dataset. No protocol registration number was available. [19,43]

3.1 Study selection

A total of 136 records were identified, comprising 124 database and register records and 12 records from other methods. After removal of 26 duplicates, 110 records underwent title and abstract screening, of which 82 were excluded. Twenty-eight reports were sought for retrieval; two could not be retrieved. Of the 26 full-text reports assessed for eligibility, 18 were excluded: six reviews, guidelines or editorials; four with unsuitable reference standards; five without extractable diagnostic data; two overlapping cohorts; and one with nonhuman or irrelevant outcomes. Eight studies were included in the descriptive synthesis, and three contributed biopsy-referenced CMR data to the meta-analysis.

3.2 Included study characteristics

Eight primary diagnostic studies addressed acute suspected myocarditis, recent-onset dilated cardiomyopathy, active versus healed myocarditis, and circulating RNA biomarkers. Seven evaluated CMR accuracy or CMR–biomarker concordance; one primarily investigated a circulating RNA marker. Reference standards were heterogeneous: several studies used EMB-based tissue definitions, whereas Luetkens et al. applied a clinical reference standard and Blanco-Domínguez et al. compared acute myocarditis with other clinical conditions. Acute and persistent inflammatory phenotypes were assessed separately. [5–11,15]

Table 1. Primary diagnostic evidence and relevance to myocarditis-associated cardiomyopathy

3.3 Three-study exploratory meta-analysis of biopsy-referenced CMR

Three biopsy-referenced CMR cohorts included 229 participants, of whom 137 were EMB-positive and 92 EMB-negative. Diagnostic criteria differed across studies: two conventional CMR features in recent-onset dilated cardiomyopathy, the 2018 Lake Louise criteria in acute suspected myocarditis, and T1/T2 mapping thresholds in a mixed clinical population. [6,9,10]

The denominators for the three studies were 42, 73 and 114 participants, respectively. Across studies, 137 participants met the biopsy reference definition for inflammation and 92 did not. Šramko et al. used two conventional CMR findings in recent-onset dilated cardiomyopathy (TP 10, FN 5, FP 4, TN 23), Li et al. applied the 2018 criteria in acute suspected myocarditis (TP 41, FN 2, FP 4, TN 26), and Zainal et al. used T1/T2 mapping positivity in a mixed chronicity sample (TP 41, FN 38, FP 23, TN 12). The substantial disagreement in their individual specificities (85.2%, 86.7% and 34.3%) indicates an important threshold- and population-related source of heterogeneity. [6,9,10]

Table 2. Two-by-two diagnostic data for the exploratory CMR meta-analysis

The pooled CMR sensitivity was 74.9% (95% CI 37.9–93.6; I²=87.5%) and pooled specificity was 70.9% (95% CI 33.7–92.1; I²=90.8%). The wide intervals and pronounced heterogeneity reflect divergent phenotypes and positivity definitions. In the 2013 recent-onset cardiomyopathy cohort, sensitivity and specificity were 66.7% and 85.2%; in the acute 2021 cohort, they were 95.3% and 86.7%; and in the 2024 mixed chronicity cohort, 51.9% and 34.3%. These data should not be interpreted as a pooled 2018 Lake Louise criteria estimate. [6,9,10]

3.4 Stage-dependent diagnostic utility of CMR

The older biopsy-referenced study by Lurz et al. demonstrated that conventional two-of-three CMR criteria were less informative after more than 14 days of symptoms: in acute suspected myocarditis sensitivity was 81% and specificity 71%, compared with 63% and 40% in chronic symptoms. The MyoRacer trial likewise found that native T1 and T2 mapping performed best during acute presentations, whereas T2 mapping retained useful discrimination in chronic symptoms. [5,7]

Additional imaging studies, without matching 2 × 2 biopsy data suitable for the main model, support this stage dependence. Ferreira and colleagues established the value of native T1 mapping for acute myocarditis, while Thavendiranathan and Luetkens reported that quantitative edema-sensitive imaging can improve recognition of myocardial involvement. Differences in scanning field strength, diagnostic reference, chosen cutoffs and time after symptom onset limit direct transportability of their estimates to persistent cardiomyopathy. [28–31]

By contrast, the 2024 prospective study that directly compared biopsy-proven chronic lymphocytic myocarditis against healed myocarditis found that T2 elevation in three or more segments correctly identified 51 of 53 active cases and 44 of 50 healed cases. Its sensitivity was 96.2%, specificity 88.0%, and total accuracy 92.2%. Global T2 elevation had 81.1% sensitivity and 86.0% specificity; LGE and T1 mapping showed poorer discrimination between active and healed stages. This emphasizes that the optimal tissue marker and diagnostic threshold depend on the particular clinical question. [11]

3.5 Circulating cardiac biomarkers

Cardiac troponin and inflammatory biomarkers offered inconsistent discrimination against EMB-defined disease across cohorts. In the 114-patient study by Zainal et al., high-sensitivity troponin T at >13.9 ng/L was positive in 40 of 79 EMB-positive patients and 18 of 35 EMB-negative patients (sensitivity 50.6%, specificity 48.6%). Despite this poor biopsy concordance, troponin correlated with CMR native T1, T2 and CRP, supporting its role as a measure of active myocyte injury. [10]

In the prospective chronic-versus-healed myocarditis study, troponin elevation >57 ng/L was present in 27/53 active and 3/50 healed cases (sensitivity 50.9%, specificity 94.0%); NT-proBNP >300 ng/L was present in 35/53 active and 15/50 healed cases (sensitivity 66.0%, specificity 70.0%). Adding elevated troponin or CRP to a T2-based CMR rule improved specificity but could decrease sensitivity. These observations cannot be generalized to other troponin assay thresholds or used to diagnose the etiology of cardiomyopathy without imaging and clinical evaluation. [11]

Table 3. Biopsy-referenced circulating biomarker results in contemporary cohorts

The earlier 42-patient inflammatory cardiomyopathy cohort found high-sensitivity troponin T diagnostically inadequate for identifying biopsy inflammation, despite its association with adverse clinical events. Likewise, troponin elevation has long been documented in myocarditis, but it can reflect ischemic and nonischemic injury. [6,17,18] The investigational circulating RNA candidate described by Blanco-Domínguez et al. achieved an AUC of 0.927 against acute myocardial infarction in a defined comparison, but questions about the molecular identity and independent validation of the analyte have been raised; this signal is therefore not a clinically established substitute for CMR or EMB. [15,16]

Overall, the circulating biomarker evidence did not support a single pooled diagnostic accuracy value. Troponin identifies cardiomyocyte injury rather than inflammatory etiology; patients with long-standing infiltrative inflammation may have negative results, whereas myocardial infarction and other myocardial injury states can produce positive findings. NT-proBNP reflects hemodynamic burden, and CRP reflects systemic inflammation. The circulating RNA signal described by Blanco-Domínguez et al. represents a different diagnostic contrast (acute myocarditis versus infarction or other clinical controls) and cannot be numerically equated with biopsy-confirmed inflammatory cardiomyopathy. [15–18,25,37]

3.6 Findings in published diagnostic meta-analyses

Diagnostic meta-analyses of acute myocarditis have generally reported higher accuracy than biopsy-referenced cohorts with mixed clinical phenotypes, although they frequently included clinically adjudicated cases and healthy or noncardiac controls. Pan et al. pooled 17 studies involving 867 myocarditis cases and 441 controls and reported 74% sensitivity and 86% specificity for the original Lake Louise criteria, with 85% sensitivity for native T1 mapping. Jia et al. pooled 10 studies and reported sensitivity/specificity of 84%/86% for T1 mapping, 77%/83% for T2 mapping, and 69%/77% for extracellular volume. [12,13]

Giri et al. analyzed 11 studies involving 677 participants and reported sensitivity/specificity of 83%/86% for native T1, 81%/86% for T2, and 71%/81% for extracellular volume. These estimates pertain predominantly to acute myocarditis and cannot be generalized to biopsy-defined persistent inflammatory cardiomyopathy without accounting for differences in the disease stage and reference standard. [14]

Table 4. Selected published meta-analytic estimates for acute myocarditis (context only)

3.7 Risk of bias and applicability of included evidence

Patient selection and index-test interpretation varied substantially among the eight studies. Luetkens et al. used a clinical reference definition, whereas other cohorts assessed EMB-defined inflammation. The acute population studied by Li et al. differed from the mixed or persistent disease populations evaluated by Zainal et al. and Brendel et al. Selective biopsy sampling, disease-stage differences, and discrepancies between conventional CMR, quantitative mapping, and biomarker targets limited applicability across studies. Comparisons involving healthy or clinically distinct controls were less directly applicable to differentiating active from healed inflammatory cardiomyopathy. [5–11,15,20]

Table 5. Diagnostic target and primary applicability consideration for the eight included investigations

3.8 Between-study heterogeneity and additional analyses

Both pooled diagnostic measures exhibited very substantial between-study heterogeneity (sensitivity I² = 87.5%; specificity I² = 90.8%). The widest divergence occurred in the mapping-based mixed-chronicity cohort, whose sensitivity was 51.9% and specificity 34.3%, compared with 95.3% and 86.7% in the acute 2018 Lake Louise cohort. In the 42-patient recent-onset dilated cardiomyopathy cohort, the conventional criteria gave 66.7% sensitivity and 85.2% specificity. These discordant findings are consistent with disease-stage and threshold effects; no credible common stage-specific summary can be derived from one or two studies per stratum. [6,9,10]

Study-level sensitivity and specificity estimates showed broad variation, and both univariate REML pooled measures had wide confidence intervals. Differences in 2018 Lake Louise criteria and mapping thresholds limited comparability. A bivariate summary receiver operating characteristic model, formal publication-bias analysis, and meta-regression were not performed because only three clinically discordant biopsy-referenced cohorts contributed diagnostic 2 × 2 data. [19,32,33]

3.9 Reporting bias, evidence certainty and sensitivity considerations

Publication or selective-reporting bias cannot be quantified reliably from three eligible CMR 2 × 2 tables. An independent certainty-of-evidence rating was not available for the pooled CMR endpoints. The limited number of studies, different diagnostic definitions, uncertainty in EMB as a reference, and large between-study variability reduce confidence in any generalizable pooled estimate. The biomarker data are more appropriately described by assay and clinical target than summarized in an overall forest plot. An additional robustness consideration is that the small-cohort weight and any single study’s criteria can materially affect a three-study random-effects result; no numeric leave-one-out effect is claimed without a prespecified re-analysis.

3.10 Integrated diagnostic interpretation

Current guidelines and consensus documents favor clinical assessment, injury and inflammatory biomarkers, electrocardiography, echocardiography and multiparametric CMR as complementary elements of evaluation. Troponin and NT-proBNP are not stand-alone confirmatory tests for inflammatory cardiomyopathy. EMB is especially relevant when progressive dysfunction, high-grade arrhythmia or a potentially treatable etiologic subtype makes tissue-level diagnosis consequential. [1,2,21–23,26,27,37]

Diagnostic performance varied markedly by disease stage and reference standard. In three biopsy-referenced CMR cohorts, pooled sensitivity and specificity were imprecise, with I² values above 85% for both measures. The acute cohort assessed using the 2018 Lake Louise criteria demonstrated greater accuracy than the mixed-chronicity cohort using mapping-based thresholds. Among patients with recent-onset dilated cardiomyopathy, focal or low-grade myocardial inflammation may not produce sufficient CMR-detectable edema to meet a binary criterion. [6,9,10]

CMR evaluates tissue consequences of inflammation, whereas EMB evaluates sampled myocardial cells and interstitium. Because inflammation is spatially heterogeneous, both tests may miss relevant disease, and neither is an error-free reference. CMR can identify subepicardial and midmyocardial abnormalities beyond the spatial reach of right-ventricular endomyocardial sampling. Conversely, diffuse inflammation with minimal edema, or persisting scar after resolution of inflammation, can limit CMR specificity for an active inflammatory process. The poor agreement found in Zainal et al. should therefore not be interpreted simply as failure of one modality; rather, it suggests that imaging and histopathology interrogate overlapping but nonidentical biological phenomena. [10,21,22]

In acute inflammatory presentations, quantitative native T1 and T2 mapping improve diagnostic sensitivity, and the 2018 Lake Louise criteria reflect the importance of combining injury and edema signs. In chronic disease, this pattern shifts. LGE is often retained as fibrosis after inflammation subsides, while T2 can remain a more direct marker of active edema. The chronic-versus-healed study by Brendel et al. is particularly relevant to myocarditis-associated cardiomyopathy because it used biopsy-defined disease activity, not simply healthy controls, as the diagnostic target. Its high performance with a segmental T2 threshold requires external confirmation across centers, scanner vendors, cardiomyopathy etiologies, and different inflammatory cell patterns. [3,7,8,11]

The broader literature reinforces this distinction. Multiple observational and meta-analytic investigations support the diagnostic contribution of T1/T2 mapping in acute presentations, while chronic disease involves different pathophysiology and may overlap with genetically mediated dilated cardiomyopathy. The strength of an imaging-positive finding therefore depends upon the pretest probability, alternative cardiomyopathy etiologies, and whether the reference is EMB, clinically adjudicated myocarditis, or a healthy comparison group. [26,28–31,36,38–41]

The blood tests studied are pathobiologically complementary but not interchangeable. Troponin is sensitive to myocyte injury under appropriate timing and assay selection but is not myocarditis-specific. A low or normal troponin concentration cannot reliably exclude chronic inflammatory cardiomyopathy because active leukocytic infiltration may coexist with relatively little ongoing myocyte necrosis. NT-proBNP is valuable in identifying and grading heart failure and wall stress, yet it rises in many noninflammatory cardiomyopathies. CRP can support evidence of inflammatory activity but lacks organ specificity. An integrated approach can improve confidence when several signals are concordant, although it must not be assumed that simply adding positive markers always improves both sensitivity and specificity. [1,10,11,17,18,23]

The choice of reference comparator strongly affects reported test accuracy. Comparisons against healthy volunteers or a clinically adjudicated case definition may generate high specificity and sometimes contain incorporation bias when troponin or CMR helps establish the reference diagnosis. The 2024 biopsy-defined active-versus-healed cohort therefore addresses a narrower and more clinically challenging use case than studies of acute myocarditis against healthy individuals. Meta-analytic numerical comparisons across those study types should not be treated as proof of one test being superior without a paired, common reference standard and similar test thresholds. [11–14]

These findings have practical consequences for the workup of unexplained nonischemic cardiomyopathy. Multiparametric CMR should characterize ventricular size and systolic function, fibrosis patterns and edema using validated local mapping ranges. Troponin, CRP and natriuretic peptides may assist in assessing injury activity and heart failure burden. Patients with unexplained progressive ventricular dysfunction, high-grade conduction disease, malignant ventricular arrhythmias, severe heart failure, or concern for a treatable inflammatory subtype require multidisciplinary consideration of EMB. CMR-guided localization and comprehensive immunohistology, viral testing or genetic evaluation may be important in selected cases. [1,2,21–23]

Clinical specificity is particularly challenging when patients present with immunologic disease, recurrent myocarditis-like episodes or genetically associated myocardial inflammation. Contemporary guidelines and consensus recommendations favor combining clinical examination with CMR and blood testing rather than relying on one modality. A negative CMR study does not categorically exclude persistent myocardial inflammation, and an isolated troponin elevation should not be equated with a diagnosis of myocarditis-associated cardiomyopathy. [1,2,26,27,37,39,40]

Observational follow-up studies further show that LGE is relevant to prognosis, not simply diagnostic classification: its presence and anteroseptal distribution may be associated with adverse outcomes in myocarditis. These prognostic associations should be kept separate from the sensitivity and specificity of CMR for diagnosing active inflammation. [34,35,42]

4.1 Strengths and limitations

Strengths of this analysis are use of reconstructable 2 × 2 data, explicit separation of diagnostic targets, detailed presentation of each index test, and recognition of acute-versus-chronic heterogeneity. Interpretation is constrained by only three biopsy-referenced CMR datasets, small and nonuniform cohorts, variation in positivity thresholds, sparse paired biomarker data, possible EMB sampling error, and the inability of separate univariate models to account for sensitivity–specificity correlation. The absence of standardized paired measurements across all cohorts precludes a direct pooled superiority comparison between CMR and circulating biomarkers. The applicability limitations summarized in Table 5 should be considered when translating these findings to clinical decision-making.

4.2 Future research

Multicenter studies should enroll consecutive patients with otherwise unexplained cardiomyopathy, apply prespecified 2018 Lake Louise and segmental T2 thresholds, collect serial high-sensitivity troponin, NT-proBNP and CRP measurements, and use uniform blinded biopsy criteria where clinically justified. Reporting complete paired 2×2 data, timing relative to symptom onset, scanner-specific reference ranges and genetic alternative diagnoses will enable reliable future pooled accuracy and incremental diagnostic-value analyses. Such studies should distinguish active inflammatory cardiomyopathy, post-inflammatory fibrosis, and other nonischemic cardiomyopathies rather than aggregating them into one category.

CMR, particularly multiparametric tissue characterization with T2 mapping, is a valuable noninvasive component of myocarditis and inflammatory cardiomyopathy assessment. Circulating biomarkers add information about myocardial injury, systemic inflammation and heart failure burden but cannot reliably diagnose myocarditis-associated cardiomyopathy in isolation. Biopsy-referenced accuracy varies markedly with disease stage and test definition. In the small exploratory quantitative synthesis, between-study heterogeneity was too high to support a universal pooled performance estimate. Integrated, phenotype-specific evaluation and selective tissue confirmation remain essential.

1.       Schulz-Menger J, Collini V, Gröschel J, et al. 2025 ESC Guidelines for the management of myocarditis and pericarditis. Eur Heart J. 2025;46(40):3952–4041. doi:10.1093/eurheartj/ehaf192.

2.       Drazner MH, Bozkurt B, Cooper LT, et al. 2024 ACC Expert Consensus Decision Pathway on strategies and criteria for the diagnosis and management of myocarditis. J Am Coll Cardiol. 2025;85(4):391–431. doi:10.1016/j.jacc.2024.10.080.

3.       Ferreira VM, Schulz-Menger J, Holmvang G, et al. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol. 2018;72(24):3158–3176. doi:10.1016/j.jacc.2018.09.072.

4.       Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53(17):1475–1487. doi:10.1016/j.jacc.2009.02.007.

5.       Lurz P, Eitel I, Adam J, et al. Diagnostic performance of CMR imaging compared with EMB in patients with suspected myocarditis. JACC Cardiovasc Imaging. 2012;5(5):513–524. doi:10.1016/j.jcmg.2011.11.022.

6.       Šramko M, Kubánek M, Tintěra J, et al. Utility of combination of cardiac magnetic resonance imaging and high-sensitivity cardiac troponin T assay in diagnosis of inflammatory cardiomyopathy. Am J Cardiol. 2013;111(2):258–264. doi:10.1016/j.amjcard.2012.09.024.

7.       Lurz P, Luecke C, Eitel I, et al. Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: the MyoRacer-Trial. J Am Coll Cardiol. 2016. PMID:27081020.

8.       Luetkens JA, Faron A, Isaak A, et al. Comparison of original and 2018 Lake Louise criteria for diagnosis of acute myocarditis: results of a validation cohort. Radiol Cardiothorac Imaging. 2019;1(3):e190010. doi:10.1148/ryct.2019190010.

9.       Li S, Duan X, Feng G, et al. Multiparametric cardiovascular magnetic resonance in acute myocarditis: comparison of 2009 and 2018 Lake Louise criteria with endomyocardial biopsy confirmation. Front Cardiovasc Med. 2021;8:739892. doi:10.3389/fcvm.2021.739892.

10.    Zainal H, Rolf A, Zhou H, et al. Comparison of diagnostic algorithms in clinically suspected viral myocarditis: agreement between cardiovascular magnetic resonance, endomyocardial biopsy, and troponin T. J Cardiovasc Magn Reson. 2024;26(2):101087. doi:10.1016/j.jocmr.2024.101087.

11.    Brendel JM, Klingel K, Gräni C, et al. Multiparametric cardiac magnetic resonance imaging to discriminate endomyocardial biopsy-proven chronic myocarditis from healed myocarditis. JACC Cardiovasc Imaging. 2024;17(10):1182–1195. doi:10.1016/j.jcmg.2024.06.009.

12.    Pan JA, Lee YJ, Salerno M. Diagnostic performance of extracellular volume, native T1, and T2 mapping versus Lake Louise criteria by cardiac magnetic resonance for detection of acute myocarditis: a meta-analysis. Circ Cardiovasc Imaging. 2018;11(7):e007598. doi:10.1161/CIRCIMAGING.118.007598.

13.    Jia Z, Wang L, Jia Y, et al. Detection of acute myocarditis using T1 and T2 mapping cardiovascular magnetic resonance: a systematic review and meta-analysis. J Appl Clin Med Phys. 2021;22(10):239–248. doi:10.1002/acm2.13365.

14.    Giri L, Singh R, Marey A, et al. Diagnostic performance of cardiovascular magnetic resonance parametric mapping as per modified Lake Louise Criteria in acute myocarditis: an updated systematic review and meta-analysis. J Cardiovasc Imaging. 2025;33:5. doi:10.1186/s44348-025-00048-3.

15.    Blanco-Domínguez R, Sánchez-Díaz R, de la Fuente H, et al. A novel circulating noncoding small RNA for the detection of acute myocarditis. N Engl J Med. 2021;384:2014–2027. doi:10.1056/NEJMoa2003608.

16.    A novel circulating microRNA for the detection of acute myocarditis [correspondence]. N Engl J Med. 2022;387:1240–1241. doi:10.1056/NEJMc2115639.

17.    Lauer B, Niederau C, Kühl U, et al. Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol. 1997;30(5):1354–1359. doi:10.1016/S0735-1097(97)00317-3.

18.    Smith SC, Ladenson JH, Mason JW, Jaffe AS. Elevations of cardiac troponin I associated with myocarditis: experimental and clinical correlates. Circulation. 1997;95(1):163–168. PMID:8994432.

19.    McInnes MDF, Moher D, Thombs BD, et al. Preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the PRISMA-DTA statement. JAMA. 2018;319(4):388–396. doi:10.1001/jama.2017.19163.

20.    Whiting PF, Rutjes AWS, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):529–536. doi:10.7326/0003-4819-155-8-201110180-00009.

21.    Caobelli F, Broncano Cabrero J, Galea N, et al. Cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) imaging in the diagnosis and follow-up of patients with acute myocarditis and chronic inflammatory cardiomyopathy. Int J Cardiovasc Imaging. 2023;39:2221–2235. doi:10.1007/s10554-023-02927-6.

22.    Heart Failure Association of the ESC, Heart Failure Society of America, and Japanese Heart Failure Society. Position statement on endomyocardial biopsy. Eur J Heart Fail. 2021;23(6):854–871.

23.    Japanese Circulation Society. JCS 2023 guideline on the diagnosis and treatment of myocarditis. Circ J. 2023;87.

24.    Khanna S, Amarasekera AT, Li C, et al. The utility of cardiac magnetic resonance imaging in the diagnosis of adult patients with acute myocarditis: a systematic review and meta-analysis. Int J Cardiol. 2022;363:225–239. doi:10.1016/j.ijcard.2022.06.047.

25.    Cooper LT Jr. Myocarditis. N Engl J Med. 2009;360:1526–1538. doi:10.1056/NEJMra0800028.

26.    Caforio ALP, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(33):2636–2648. doi:10.1093/eurheartj/eht210.

27.    Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the AHA, ACC and ESC. Circulation. 2007;116(19):2216–2233. doi:10.1161/CIRCULATIONAHA.107.186093.

28.    Ferreira VM, Piechnik SK, Dall’Armellina E, et al. T1 mapping for the diagnosis of acute myocarditis using CMR: comparison to T2-weighted and late gadolinium enhanced imaging. JACC Cardiovasc Imaging. 2013;6(10):1048–1058. doi:10.1016/j.jcmg.2013.03.008.

29.    Ferreira VM, Piechnik SK, Dall’Armellina E, et al. Native T1-mapping detects the location, extent and patterns of acute myocarditis without the need for gadolinium contrast agents. J Cardiovasc Magn Reson. 2014;16:36. doi:10.1186/1532-429X-16-36.

30.    Thavendiranathan P, Walls M, Giri S, et al. Improved detection of myocardial involvement in acute inflammatory cardiomyopathies using T2 mapping. Circ Cardiovasc Imaging. 2012;5(1):102–110. doi:10.1161/CIRCIMAGING.111.967836.

31.    Luetkens JA, Homsi R, Sprinkart AM, et al. Incremental value of quantitative CMR including parametric mapping for the diagnosis of acute myocarditis. Eur Heart J Cardiovasc Imaging. 2016;17(2):154–161. doi:10.1093/ehjci/jev246.

32.    Reitsma JB, Glas AS, Rutjes AWS, et al. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58(10):982–990. doi:10.1016/j.jclinepi.2005.02.022.

33.    Rutter CM, Gatsonis CA. A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations. Stat Med. 2001;20(19):2865–2884. doi:10.1002/sim.942.

34.    Grün S, Schumm J, Greulich S, et al. Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery. J Am Coll Cardiol. 2012;59(18):1604–1615. doi:10.1016/j.jacc.2012.01.007.

35.    Greulich S, Seitz A, Müller KAL, et al. Predictors of mortality in patients with biopsy-proven viral myocarditis: 10-year outcome data. J Am Heart Assoc. 2020;9(16):e015351. doi:10.1161/JAHA.119.015351.

36.    Blissett S, Chocron Y, Kovacina B, Afilalo J. Diagnostic and prognostic value of cardiac magnetic resonance in acute myocarditis: a systematic review and meta-analysis. Int J Cardiovasc Imaging. 2019;35(12):2221–2229. doi:10.1007/s10554-019-01674-x.

37.    Domínguez F, et al. Diagnosis and treatment of myocarditis and inflammatory cardiomyopathy: consensus document of the SEC-Working Group on Myocarditis. Rev Esp Cardiol (Engl Ed). 2024;77(8):667–679. doi:10.1016/j.rec.2024.02.022.

38.    Sikking MA, Stroeks SLVM, Henkens MTHM, et al. Cardiac inflammation in adult-onset genetic dilated cardiomyopathy. J Clin Med. 2023;12(12):3937. doi:10.3390/jcm12123937.

39.    Hua A, Domenech-Ximenos B, Lopez B, et al. Diagnostic utility of the revised Lake Louise criteria in myocarditis associated with active autoimmune rheumatic disease. J Cardiovasc Magn Reson. 2025;27(2):101916. doi:10.1016/j.jocmr.2025.101916.

40.    Monda E, Bakalakos A, Cannie D, et al. Prevalence of pathogenic variants in cardiomyopathy-associated genes in acute myocarditis: a systematic review and meta-analysis. JACC Heart Fail. 2024;12(6):1101–1111. doi:10.1016/j.jchf.2024.02.012.

41.    Vignale D, Bruno E, Palmisano A, et al. Cardiovascular magnetic resonance parametric mapping in the risk stratification of patients affected by chronic myocarditis. Eur Radiol. 2025;35(2):776–788. doi:10.1007/s00330-024-10978-z.

42.    Georgiopoulos G, Figliozzi S, Sanguineti F, et al. Prognostic impact of late gadolinium enhancement by cardiovascular magnetic resonance in myocarditis: a systematic review and meta-analysis. Circ Cardiovasc Imaging. 2021;14(1):e011492. doi:10.1161/CIRCIMAGING.120.011492.

43.    Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71.