Abstract 12630: Developmental Processes Mediate Mitral Valve Elongation in Hypertrophic Cardiomyopathy

Introduction:MV elongation has been established as a primary HCM phenotype, and contributes to obstruction, but the mechanism by which a sarcomeric disease affects valve morphology is unclear.Hypotheses:We tested for 3 mechanisms that might cause elongation: 1) Developmental: dysregulated differentiation of epicardium-derived cells (EPDC) in utero, in response to biomechanical signals from mutated cardiomyocytes. 2) Adaptive: endocardial to mesenchymal transition due to lifelong tethering forces. 3) Genetic: presence of mutated cardiomyocytes in the valve.Methods:Structural and immunohistochemical staining were performed on 9 residual anterior mitral leaflets excised as an ancillary procedure during septal myectomy, and compared with 4 control autopsy leaflets. Markers included TBX18 for EPDCs, periostin for EPDC paracrine signaling, vimentin for valvular interstitial cells (VIC), CD31/?-SMA sequential multiplex staining for endocardial to mesenchymal transition, cardiac troponin I for cardiomyocytes. Slides stained for TBX18 and vimentin were analyzed using ImageJ.Results:HCM valves are structurally disorganized. There is expansion of the spongiosa and increased, fragmented elastic fibers. The fibrosa is attenuated and patches of abnormal fibrosis are scattered throughout. More EPDCs are present in HCM valves than in control mid-leaflets (405?152 vs. 190?56 cells/hpf, p < 0.001) and control free edges (405?152 vs. 316?101 cells/hpf, p < 0.001). Periostin staining is on the surface of all valves, and is increased in intensity in HCM. There are significantly more VICs in HCM valves than in both control mid-leaflets (VIM+ area/hpf: 24.5?8.1% vs. 7.1?3.0%, p < 0.001) and control free edges (VIM+ area/hpf: 24.5?8.1% vs.13.8?4.0%, p < 0.001). There are no areas of CD31/?-SMA colocalization or cardiac troponin I staining, providing no evidence for adaptive tethering or myocyte hypertrophy.Conclusions:MVs in HCM patients are characterized by structural disorganization, expansion of the spongiosa, and proliferation of VICs. The observed increase in number of EPDCs and intensity of periostin paracrine signaling indicate that MV elongation is caused by enhanced migration and abnormal differentiation of EPDCs during development.