Table 2.

Pathologic Analysis by Mechanistic Hypothesis

Hypothesis	Analysis (Stain)	Hypothesis	Findings
Mechanical	Elastic fibers (Weigert Resorcin/Fuschin) Collagen fibers (trichrome) Leaflet thickness	Chronic flow drag forces and friction on the valve cause strain, stretch, and fibrotic tissue deposition	Compared with control valves, HCM residual leaflets showed: 1.An expanded spongiosa layer with increased, fragmented, and disorganized elastic fibers 2.An attenuated, disrupted, and disorganized collagenous fibrosa layer 3.An added layer of super-imposed collagenous tissue overlying both atrial and ventricular surfaces 4.Elongated, slack and curlicued chordae and a trend to decreased leaflet thickness
Developmental	Epicardium derived cells (TBX-18) Paracrine signaling from epicardium-derived cells (periostin)	Dysregulated stem cell differentiation during valve development	No difference in number of epicardium-derived cells No significant difference in amount of paracrine signaling
Adaptive	Endocardial-to-mesenchymal transition (CD31-αSMA) Valvular interstitial cells (vimentin) Inflammatory cells (CD45)	Adaptive cell lines activate in response to chronic tethering forces	No evidence of endocardial-to-mesenchymal transition in HCM or control valves No difference in valvular interstitial or inflammatory cells
Genetic	Cardiomyocytes (cardiac troponin I)	Persistence of mutated cardiomyocytes in the valve	No cardiomyocytes in HCM or control valves

HCM = hypertrophic cardiomyopathy; Tbx-18 = t-box transcription factor 18.