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Aortic Valve Interstitial Cell Activation in Patients with Continuous-Flow Left Ventricular Assist Device Support
Jan Willem van Rijswijk1, Jerson Martina2, Nicolaas de Jonge3, Roel A. de Weger1, Aryan Vink1, Jolanda Kluin2.
1Pathology, University Medical Center, Utrecht, Netherlands, 2Cardiothoracic Surgery, University Medical Center, Utrecht, Netherlands, 3Cardiology, University Medical Center, Utrecht, Netherlands.

OBJECTIVE: Phenotypic changes of valvular interstitial cells (VICs) play a key role in valve tissue remodeling and pathology. In patients with continuous-flow left ventricular assist devices (cf-LVADs), aortic valve commissural fusion and de novo aortic regurgitation have been reported. The underlying mechanisms of these phenomena are unknown. The aim of this study was to elucidate LVAD-induced changes in morphological structure and cellular behavior of the aortic valve.
METHODS: Aortic valves from hearts of 16 patients (11 male; mean age 52 year [26-68 years]) supported by cf-LVAD for an average duration of 754 days [7-1922 days] were examined after heart transplantation (n=11) or autopsy (n=5). Histology was assessed by staining with hematoxylin and eosin, Verhoeff-van Gieson, and Sirius red (SR). Immunohistochemistry was performed on markers for valve interstitial cell (VIC) activation (alpha-smooth muscle actin (αSMA)) and collagen synthesis (heat shock protein-47 (Hsp47)). Sections were graded semi-quantitatively and compared to patient clinical data.
RESULTS: De novo mild aortic regurgitation was observed in 77% of cf-LVAD patients. Fusion (>3mm) was observed in 69% (11/16) aortic valves. Fusion areas consist of loosely arranged, non-inflammatory, fibrous tissue at the coapting surface. VIC activation in the aortic valve leaflet, as indicated by αSMA expression, positively correlated to the duration of cf-LVAD support (r2=0.51; p<0.01), and with continuous aortic valve closure (r2=0.61; p<0.01). Collagen deposition and synthesis did not correlate to LVAD-support as indicated by SR staining and Hsp47 expression. Sclerotic change in the aortic root (mostly consisting of foam cells, cholesterol clefts and calcification) and aortic root diameter positively correlated to age (r2=0.48; p<0.001 and r2=0.54; p<0.001, respectively) but not to the duration of support (p=0.9 and p=0.7, respectively).
CONCLUSIONS: Duration of continuous flow support on LVAD and continuous aortic valve closure are associated with progressive VIC activation in aortic valve leaflets, eventually leading to leaflet fusion and/or regurgitation. These results suggest that short periods of valve opening may preserve a quiescent VIC phenotype and valve functionality, which is desirable especially in patients bridged to recovery.

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