Mechanisms Of Regionalized Left Ventricular Fibrosis In Mitral Valve Prolapse
Jordan Ellis Morningstar1, Cortney Gensemer1, Tyler Beck1, Ayesha Vohra1, Diana Fulmer1, Christina Wang1, Kelsey Moore1, Natalie Koren1, Lilong Guo1, Reece Moore1, Franz Sieg2, Yasufumi Nagata3, Philippe Bertrand4, Ricardo Spampinato2, Janiece Glover1, William Richardson5, Robert A. Levine3, Michael Borger2, Russell Norris1.
1Medical University of South Carolina, Charleston, SC, USA, 2Leipzig Heart Institute, Leipzig, Germany, 3Massachusetts General Hospital, Boston, MA, USA, 4Massachusetts general hospital, Boston, MA, USA, 5Clemson University, Clemson, SC, USA.
OBJECTIVE: Recent clinical studies have demonstrated an association between mitral valve prolapse (MVP), regionalized left ventricular (LV) fibrosis, and increased frequency of ventricular arrhythmias. However, a causal link between MVP and the development of LV fibrosis has not been demonstrated.
METHODS: We performed histopathologic analysis on endomyocardial biopsies taken from six patients who underwent surgical repair for mitral valve prolapse. We also performed longitudinal histopathologic analysis on hearts harvested from a mouse model of human non-syndromic MVP (Dzip1S14R/+). To assess the cellular response to increased mechanical tension, we performed RNA-Seq along with ATAC-Seq on human cardiac fibroblasts subjected to pathologic strain.
RESULTS: Biopsies taken from septal/apical and peripapillary left ventricle demonstrated regionalized myocardial fibrosis (mean collagen fraction of 5.4% in septum/apex vs 20% in peripapillary myocardium, p=0.0016) that correlated with increased macrophages (Fold change=3.2, p=0.01), and myofibroblasts (Fold change=1.98, p=0.03). Our mouse model demonstrated similar regionalized increases in collagen over time (2-way ANOVA p=0.004), along with an increase in macrophages and myofibroblasts. Mechanical stretch affected gene expression of 232 genes (Bonferroni p<1.7*10-6). Gene Ontology analysis demonstrated enrichment of pathways related to extracellular matrix homeostasis (p=1.0*10-24). Differential ATAC-Seq analysis identified chromatin opening in the EGR1 gene in response to stretch (adjusted p=0.01). EGR1 has previously been implicated in fibrosis, and binds to the DNA motif 5'-GCG(T/G)GGGCG-3'. Open chromatin enrichment analysis identified putative EGR1 binding sites at 541 distinct locations within 10kb of stretch responsive genes (P-value for enrichment=1.1*10-100), including within the promoter region of COL1A1, COL1A2, LOX, and FN1. These data suggest EGR1 may be a master transcriptional regulator of the stretch response in human cardiac fibroblasts.
CONCLUSIONS: Collectively, our data support a causal role for MVP induced mechanical alterations in the onset of regionalized LV fibrosis, as well as a role for EGR1 in mechanotransduction.
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