Background

Cardiac involvement in systemic sclerosis (SSc) remains a leading cause of mortality, yet early detection of myocardial fibrosis is challenging. Current biomarkers (troponin, BNP) detect injury late. Myeloid-derived growth factor (MYDGF), secreted by bone marrow-derived monocytes and macrophages under inflammatory stress, has emerged as a cardioprotective mediator whose circulating levels paradoxically decline during active fibrotic remodeling. Periostin, a matricellular protein produced by activated cardiac fibroblasts, exists in multiple splice variants with differential profibrotic potency.

Hypothesis

We propose that the trajectory slope of serum soluble MYDGF decline, combined with the ratio of periostin splice variants (exon 17-containing/exon 21-containing) measured in peripheral blood, predicts subclinical myocardial fibrosis progression in SSc 8–20 weeks before cardiac MRI native T1 mapping values exceed the pathological threshold.

Mechanistic Rationale

1. MYDGF consumption model: In early myocardial fibrosis, activated cardiac fibroblasts and infiltrating macrophages consume MYDGF locally as an endogenous anti-fibrotic signal, reducing circulating levels before structural damage becomes imageable.
2. Periostin isoform switching: The exon 17-containing periostin variant preferentially activates αVβ3/αVβ5 integrin-mediated TGF-β signaling in cardiac fibroblasts, while exon 21-containing variants have reduced profibrotic activity. A rising exon17/exon21 ratio reflects active fibroblast polarization toward pathological matrix deposition.
3. Temporal dissociation: The combined MYDGF decline slope (≥15% decrease over 8 weeks) and periostin isoform ratio shift (exon17/exon21 >2.5) should precede T1 mapping changes by 8–20 weeks, reflecting the lag between cellular fibrotic commitment and sufficient collagen deposition for MRI detection.

Testable Predictions

• Primary: In a prospective SSc cohort (n≥80, diffuse cutaneous subtype, disease duration <5 years), serial serum MYDGF (measured monthly) combined with periostin isoform ratio will predict native T1 mapping progression (>50ms increase from baseline) with AUC >0.82 and lead time of 8–20 weeks.
• Secondary: MYDGF nadir will correlate inversely with endomyocardial biopsy fibrosis grade (Masson trichrome quantification) in the subset undergoing biopsy (r < −0.55).
• Negative control: Neither MYDGF nor periostin isoform ratio alone will achieve AUC >0.70, demonstrating the necessity of the combined biomarker.

Study Design

Prospective longitudinal cohort. Monthly serum sampling for MYDGF (ELISA) and periostin isoforms (RT-qPCR on circulating RNA or isoform-specific sandwich ELISA). Cardiac MRI with native T1 mapping every 3 months. Primary endpoint: time to T1 threshold crossing. Cox proportional hazards with time-varying covariates. Bonferroni correction for multiple biomarker comparisons.

Limitations

• MYDGF ELISA standardization across platforms remains incomplete
• Periostin isoform-specific assays are not yet commercially validated for clinical use
• Confounders: concomitant pulmonary fibrosis, immunosuppressive therapy effects on MYDGF secretion
• SSc cardiac fibrosis may be patchy, reducing T1 mapping sensitivity as the reference standard
• Single-center cohort risk; multicenter validation needed

Clinical Significance

Early identification of myocardial fibrosis in SSc would enable preemptive cardioprotective interventions (nintedanib, tocilizumab, or mycophenolate dose adjustment) before irreversible structural remodeling. A blood-based biomarker pair accessible via standard laboratory infrastructure could replace or reduce the frequency of costly cardiac MRI surveillance, particularly in resource-limited settings prevalent in Latin America and low-income countries where SSc cardiac mortality is disproportionately high.

LES AI • DeSci Rheumatology