Macrophage recruitment is a hallmark of non-syndromic myxomatous mitral valve disease.

AIMS: Myxomatous mitral valve disease (MMVD) is a progressive cardiac disease characterized by extracellular matrix remodelling, leaflet thickening, and proteoglycan accumulation. Despite its significant contribution to cardiovascular morbidity and mortality, the underlying pathophysiological mechanisms involved in its development and progression remain unclear. Recent investigations have revealed a genetic component to the disease, such as mutations in the FLNA gene, and suggested potential involvement of immune cells in the pathogenesis of MMVD. In this study, we investigated the role of macrophages in MMVD using a large collection of human non-syndromic MMVD samples and a unique animal model, the Filamin-A knock-in (KI) rat.

METHODS AND

RESULTS

Transciptomic analysis of 78 human non-syndromic MMVD samples revealed significant enrichment of pathways associated with immune activation and macrophage recruitment. Comparative analyses between human and rat MMVD identified shared molecular signatures, validating the Filamin-A KI rat model for studying human MMVD pathophysiology. Analyses of wild-type (WT) and KI rat MVs demontrated a gradual activation of valvular cells from birth, which translated into phenotypic MV remodelling by postnatal day 7. These early events were associated with the development of a pro-inflammatory valvular environment, despite no initial increase in myeloid cells. The subsequent accumulation of macrophages in the already remodelled MV leaflets indicated the initiation of an active recruitment process, likely involved in the progression of non-syndromic MMVD.

CONCLUSION

This study highlights the central role of chemotaxis and macrophage recruitment and activation in the pathophysiological processes leading to non-syndromic MMVD. Macrophage involvement emerges as a hallmark of non-syndromic MMVD, a disease previously described as non-inflammatory, and opens new avenues to identify potential therapeutic targets to mitigate disease progression.