Can cell-based therapies bridge the gap between research and reality in the treatment of myocarditis? A systematic review and meta-analysis

Abstract

Introduction

Myocarditis is a non-ischaemic myocardial injury caused by infectious agents, immune-mediated diseases, cardiotoxic drugs, and vaccines. Treatment options are largely supportive, with emphasis on close monitoring, exclusion of other diseases explaining symptoms, adherence to heart failure treatment recommendations, and consideration of etiology-directed interventions, if applicable, such as antiviral or immunosuppressive agents, steroids, discontinuation of antineoplastic therapy, and strategies to increase left ventricular (LV) ejection fraction (LVEF). In this context, cell-based therapies (CBTs) have emerged as a new therapeutic strategy and were believed to fill this gap. However, results were inconsistent across studies, which necessitates the need for rigorous systematic reviews to analyze available evidence comprehensively.

Methods

The review protocol was registered on the PROSPERO website, and the study was conducted in accordance with PRISMA regulations. Searches were conducted in Embase, CINAHL Plus via EBSCO host, Web of Science, Scopus, and PubMed. A total of 60 original papers published between 2004 and 2022 in 48 peer-reviewed journals were included in the meta-analysis to determine the efficacy of CBTs on the LV fractional shortening (LVFS), LVEF, capillary density (CD), inflammatory cell infiltration rate (ICIR), and fibrotic area (FA). The risk of bias (RoB) and study quality were assessed using the SYRCLE RoB tool and CAMARADES checklist, respectively. As the preliminary assessment indicated substantial heterogeneity among the included studies, a random-effects model was applied to pool effect sizes. Subgroup analyses were performed to explore potential sources of heterogeneity across studies. Publication bias was assessed by visual inspection of funnel plots for asymmetry and statistically evaluated using Egger's regression test.

Results

In total, the adapted and optimized search strategy retrieved 14,503 records from five databases. The majority of studies exhibited an unclear or high risk of bias in several domains, particularly selection bias and performance bias. Quality assessment revealed that only four studies (6.7%) were classified as high quality and four (6.7%) as low quality, while the remaining 52 studies (86.7%) were rated as moderate quality, with scores ranging from 4 to 6. CBTs improved LVFS (%) by 7.17 [95 % CI: 5.67, 8.66], LVEF (%) by 9.00 [95 % CI: 7.03, 10.97], CD (capillaries/mm²) by 300.50 [95 % CI: 45.01, 555.99] and decreased ICIR (cells/mm²) and FA (%) by −178.99 [95 % CI: −225.91, −132.08] and −6.04 [95 % CI: −6.83, −5.25], respectively. However, significant heterogeneity between studies was maintained at I² = 84-99%.

Conclusion

Despite significant heterogeneity and moderate publication bias, the results were very encouraging, as reflected in the consistent effect directions across all studies in terms of cardiac function and histology. Overall, our results demonstrated the need for well-designed studies with adequate animal sample sizes, a standardized approach to reporting, and mechanistic investigations that directly link structural remodeling to functional recovery. Addressing these issues will be critical steps for conducting large-scale clinical trials.