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Role of Pathologic Fluid Shear Stress in Early development of Calcific Aortic Valve Disease
Ling Sun, Philippe Sucosky.
University of Notre Dame, Notre Dame, IN, USA.

Background: Calcific aortic valve disease (CAVD) is a disorder presumably triggered by interplay between cardiovascular risk factors and hemodynamic cues. While studies demonstrated that progressive alterations in fluid shear stress (FSS) on the fibrosa could trigger leaflet inflammation, the mechanisms of CAVD pathogenesis secondary to side-specific FSS abnormalities are poorly understood. The objective of this study was to characterize ex vivo the contribution of isolated and combined abnormalities in FSS magnitude and frequency to early valvular pathogenesis, and to investigating the respective role played by BMP-4 and TGF-β1 in valvular pathogenesis in response to pathologic shear stress levels.
Methods: Porcine leaflets were subjected to sub-physiologic/physiologic/supra-physiologic FSS magnitude and frequency for 24, 48 and 72 hours in a double cone-and-plate device. Endothelial activation and paracrine signaling were investigated in terms of cell-adhesion molecules (ICAM-1, VCAM-1) and cytokines (BMP-4 and TGF-β1), respectively. Extracellular matrix (ECM) degradation was characterized by measuring the expression and activity of MMPs and cathepsins. Pro- and anti-osteogenic media were used to characterize the role of cytokines (BMP-4 and TGF-β1) in the FSS-induced pathological response.
Results: The effect of the FSS treatment yielding the most significant pathological response was examined over a 72-hour period to characterize the time-dependence of FSS mechanotransduction. While cytokine expression was stimulated under elevated FSS magnitude at normal frequency, ECM degradation was stimulated under both elevated FSS magnitude at normal frequency and physiologic FSS magnitude at abnormal frequency. In contrast, combined FSS magnitude and frequency abnormalities maintained valvular homeostasis. The pathological response under supra-physiologic FSS magnitude peaked at 48 hours but was then maintained until the 72-hour time point. Under non-physiologic FSS magnitude, TGF-β1 inhibition suppressed FSS-induced ECM degradation, while BMP-4 inhibition and supplementation had limited effects on the FSS-induced biological response.
Conclusions: This study confirms the sensitivity of valve leaflets to FSS magnitude and frequency and suggests the ability of supra-physiologic FSS levels or abnormal FSS frequencies to initiate CAVD pathogenesis. The results related to TGF-β1 inhibitor in response of pathological FSS provide new evidence about the transduction of valvular hemodynamic alterations into a pathological response.

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