Key result
Monocyte deficiency prevents myxomatous mitral valve degeneration and leaflet thickening in Marfan syndrome mice.
Why the study?
Although macrophages have been detected in myxomatous valves, the timing of their presence and their contributions to myxomatous valve degeneration progression remain unknown.
Does deficiency of circulating monocytes prevent progression of myxomatous valve degeneration in Marfan syndrome models?
Does deficiency of circulating monocytes prevent progression of myxomatous valve degeneration in Marfan syndrome models?
This study identifies sterile inflammation driven by recruited monocytes as a key mechanism in myxomatous valve degeneration, suggesting CCR2+ macrophages as a potential therapeutic target.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Our discovery challenges the conventional view of how myxomatous valve degeneration works. Until now, this was seen as a process driven entirely by the cells already in the valves. We found that an abnormal immune response involving cells recruited from outside the heart also plays a critical role in causing these valves to deteriorate.”
Monocyte-driven sterile inflammation emerges as a modifiable driver of myxomatous degeneration; leaves open whether CCR2-targeted therapy alters human valve progression.
Background: Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known. Methods: We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice ( Fbn1 C1039G/+ ), gene-edited MFS pigs ( FBN1 Glu433AsnfsX98/+ ), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)–tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages ( Fbn1 C1039G/+ ;Ccr2 RFP/RFP ) were generated to determine the requirements of recruited macrophages to MVD progression. Results: MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2–), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity. Conclusions: All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.
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Kim et al. (2020) studied Myxomatous valve degeneration in Marfan syndrome. CCR2 monocyte deficiency vs. Intact CCR2 monocytes was evaluated on Mitral valve thickening and extracellular matrix integrity. Deficiency of circulating monocytes protected against myxomatous valve degeneration progression, resulting in minimal leaflet thickening and preserved mitral valve integrity in Marfan syndrome mice.
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