Mitral Valve Prolapse Induces Regionalized Myocardial Fibrosis

Simple item page
dc.contributor.authorMorningstar, Jordan E.en
dc.contributor.authorGensemer, Cortneyen
dc.contributor.authorMoore, Reeceen
dc.contributor.authorFulmer, Dianaen
dc.contributor.authorBeck, Tyler C.en
dc.contributor.authorWang, Christinaen
dc.contributor.authorMoore, Kelseyen
dc.contributor.authorGuo, Lilongen
dc.contributor.authorSieg, Franzen
dc.contributor.authorNagata, Yasufumien
dc.contributor.authorBertrand, Philippeen
dc.contributor.authorSpampinato, Ricardo A.en
dc.contributor.authorGlover, Janieceen
dc.contributor.authorPoelzing, Stevenen
dc.contributor.authorGourdie, Robert G.en
dc.contributor.authorWatts, Kelseyen
dc.contributor.authorRichardson, William J.en
dc.contributor.authorLevine, Robert A.en
dc.contributor.authorBorger, Michael A.en
dc.contributor.authorNorris, Russell A.en
dc.date.accessioned2022-09-02T19:36:39Zen
dc.date.available2022-09-02T19:36:39Zen
dc.date.issued2021-12-12en
dc.description.abstractBackground Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 2% to 3% of the population. Previous imaging reports have indicated that myocardial fibrosis is common in MVP and described its association with sudden cardiac death. These data combined with evidence for postrepair ventricular dysfunction in surgical patients with MVP support a link between fibrosis and MVP. Methods and Results We performed histopathologic analysis of left ventricular (LV) biopsies from peripapillary regions, inferobasal LV wall and apex on surgical patients with MVP, as well as in a mouse model of human MVP (Dzip1(S14R)(/+)). Tension-dependent molecular pathways were subsequently assessed using both computational modeling and cyclical stretch of primary human cardiac fibroblasts in vitro. Histopathology of LV biopsies revealed regionalized fibrosis in the peripapillary myocardium that correlated with increased macrophages and myofibroblasts. The MVP mouse model exhibited similar regional increases in collagen deposition that progress over time. As observed in the patient biopsies, increased macrophages and myofibroblasts were observed in fibrotic areas within the murine heart. Computational modeling revealed tension-dependent profibrotic cellular and molecular responses consistent with fibrosis locations related to valve-induced stress. These simulations also identified mechanosensing primary cilia as involved in profibrotic pathways, which was validated in vitro and in human biopsies. Finally, in vitro stretching of primary human cardiac fibroblasts showed that stretch directly activates profibrotic pathways and increases extracellular matrix protein production. Conclusions The presence of prominent regional LV fibrosis in patients and mice with MVP supports a relationship between MVP and progressive damaging effects on LV structure before overt alterations in cardiac function. The regionalized molecular and cellular changes suggest a reactive response of the papillary and inferobasal myocardium to increased chordal tension from a prolapsing valve. These studies raise the question whether surgical intervention on patients with MVP should occur earlier than indicated by current guidelines to prevent advanced LV fibrosis and potentially reduce residual risk of LV dysfunction and sudden cardiac death.en
dc.description.notesThis work was supported by the National Institutes of Health grant numbers: HL131546 (Norris), GM103444 (Norris), HL149696 (Norris), T32HL007260 (Beck, Gensemer, and Moore), F31152494 (Moore), T32GM132055 (Gensemer), F31HL142159 (Fulmer), GM12132 (Richardson), HL144927 (Richardson), HL141855 (Gourdie), HL56728 (Gourdie), HL128099 (Levine), and HL141917 (Levine). Grant sponsor: American Heart Association grant numbers: 19TPA34850095 (Norris), 17CSA33590067 (Norris), and 18PRE34080172 (Guo), and a contribution from the Ellison Foundation (Levine) Boston, Massachusetts. This project was supported, in part, by the National Center for Advancing Translational Sciences of the National Institutes of Health under grant number UL1 TR001450. The work at the Medical University of South Carolina was performed in a facility constructed with support from the National Institutes of Health grant number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources.en
dc.description.sponsorshipNational Institutes of Health [HL131546, GM103444, HL149696, T32HL007260, F31152494, T32GM132055, F31HL142159, GM12132, HL144927, HL141855, HL56728, HL128099, HL141917, C06 RR018823]; American Heart Association [19TPA34850095, 17CSA33590067, 18PRE34080172]; Ellison Foundation (Levine) Boston, Massachusetts; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR001450]; National Institutes of Health from the Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1161/JAHA.121.022332en
dc.identifier.eissn2047-9980en
dc.identifier.issue24en
dc.identifier.othere022332en
dc.identifier.pmid34873924en
dc.identifier.urihttp://hdl.handle.net/10919/111702en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherWileyen
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectcomputational modelingen
dc.subjectDZIP1en
dc.subjectfibrosisen
dc.subjectmitral valve prolapseen
dc.subjectprimary ciliaen
dc.titleMitral Valve Prolapse Induces Regionalized Myocardial Fibrosisen
dc.title.serialJournal of the American Heart Associationen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
JAHA.121.022332.pdf
Size:
5.31 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

Scholarly Works, Fralin Biomedical Research Institute at VTC