Human Leukocyte Antigen (HLA) Characterisation in Patients with Biopsy-Proven Myocarditis: A Prospective Cohort Study

Background: Myocarditis is an inflammatory disease of the myocardium with heterogenous pathogenesis and clinical presentation. Growing evidence suggests that autoimmune mechanisms contribute to pathogenesis of myocarditis. Human leukocyte antigen (HLA) molecules play a central role in peptide presentation to T cells and are strongly implicated in autoimmune diseases. However, evidence regarding HLA-associations in myocarditis remains scarce. HLA profiling may therefore provide new insights into disease susceptibility and phenotype. Aims: This study aims to characterise HLA allele distribution in patients with biopsy-proven myocarditis, investigate associations between HLA alleles and clinical phenotypes, and compare HLA patterns with those of healthy controls and previously reported findings. Materials/methods: This study included patients with biopsy-proven myocarditis, systemic immune-mediated disease with cardiac involvement, and selected patients with cardiac magnetic resonance (CMR)-proven myocarditis. Patients were consecutively followed at the Cardioimmunology Clinic at the Azienda Ospedale di Padova, between 2001 and 2026. Baseline and follow-up data were systematically recorded through the REDCap software, including symptoms at presentation, laboratory tests, ECG, echocardiography, CMR, histology, viral PCR, genetic testing, HLA profile, and therapy. HLA allele frequencies were compared to those of healthy donors. Categorical variables were analyzed using the Chi-square or Fisher’s exact test, and continuous variables using the Wilcoxon rank-sum test. Results: The study encompassed 74 patients (median age 47 years; 59% males), including 62 cases of biopsy-proven myocarditis, 7 cases of cardiac sarcoidosis, and 5 cases of CMR-proven myocarditis. Median follow-up duration was 87 (45.5-134.1) months. Compared with controls, HLA-B41 (6.8% patients vs 1.9% controls, p=0.022) and HLA-C17 (6.8% patients vs 1.5% controls, p=0.008) were more frequent among patients, with a trend towards increased HLA-DR12 (6.8% patients vs 3% controls, p=0.088). Conversely, HLA-A11 (5.4% patients vs 15% controls, p=0.024), HLA-B35 (20% patients vs 35% controls, p=0.008), HLA-C6 (6.8% patients vs 18% controls, p=0.01), HLA-DR11 (36% patients vs 51% controls, p=0.022), HLA-DR14 (4.1% patients vs 12% controls, p=0.037), and HLA-DQ5 (35% patients vs 50% controls, p=0.02) were less frequent among patients than controls, with a trend towards reduced HLA-A2 (35% patients vs 47% controls, p=0.054). Only HLA-A2 and HLA-B35 demonstrated significant clinical associations. At diagnosis, HLA-B35-positive patients showed less favourable right ventricular characteristics, including greater right ventricular end-diastolic volume (113 mL/m2 B35pos vs 75 mL/m2 B35neg, p=0.066) and reduced right ventricular ejection fraction (32% in B35pos vs 53% in B35neg; p=0.040), but had lower baseline troponin levels (17.2 ng/mL B35pos vs 3,000 ng/mL B35neg, p=0.055). At last follow-up, HLA-A2-positive patients had a higher frequency of inverted T waves (59% A2pos vs 16% A2neg, p=0.040). Conclusion: This study identified several differences in HLA distribution between myocarditis patients and healthy controls, although further research is needed to determine whether these alleles are implicated in disease susceptibility. Within the patient cohort, HLA-A2 was associated with inverted T waves at follow-up, suggesting a less favourable post-inflammatory ECG profile. HLA-B35 was associated with unfavourable right ventricular CMR parameters at diagnosis. Although no major causative HLA allele could be identified, the findings suggest that HLA alleles may contribute not only to susceptibility, but also to clinical phenotype in selected patients. The limited cohort size restricts interpretation, however, the presence of significant associations despite relatively few patients highlights the need for larger studies investigating the role of HLA in myocardits.