Discrete Subaortic Stenosis: Perspective Roadmap to a Complex Disease

Abstract

Discrete subaortic stenosis (DSS) is a congenital heart disease that results in the formation of a fibro-membranous tissue, causing an increased pressure gradient in the left ventricular outflow tract (LVOT). While surgical resection of the membrane has shown some success in eliminating the obstruction, it poses significant risks associated with anesthesia, sternotomy, and heart bypass, and it remains associated with a high rate of recurrence. Although a genetic etiology had been initially proposed, the association between DSS and left ventricle (LV) geometrical abnormalities has provided more support to a hemodynamic etiology by which congenital or post-surgical LVOT geometric derangements could generate abnormal shear forces on the septal wall, triggering in turn a fibrotic response. Validating this hypothetical etiology and understanding the mechanobiological processes by which altered shear forces induce fibrosis in the LVOT are major knowledge gaps. This perspective paper describes the current state of knowledge of DSS, articulates the research needs to yield mechanistic insights into a significant pathologic process that is poorly understood, and proposes several strategies aimed at elucidating the potential mechanobiological synergies responsible for DSS pathogenesis. The proposed roadmap has the potential to improve DSS management by identifying early targets for prevention of the fibrotic lesion, and may also prove beneficial in other fibrotic cardiovascular diseases associated with altered flow.

Impact of Aortoseptal Angle Abnormalities and Discrete Subaortic Stenosis on Left-Ventricular Outflow Tract Hemodynamics: Preliminary Computational Assessment

“…The present results are also in agreement with a previous computational study suggesting an increase in near-wall spatial velocity gradient with decreasing AoSA in a simplified LV geometry (Cape et al, 1997). Interestingly, the magnitude of the WSS overloads reported in the present study near the crest of the septal wall (up to 23% vs. normal AoSA) is also quantitatively similar to the values reported during systole (up to 24% vs. normal AoSA) in a simplified 3D LV model published by our group (Massé et al, 2018).…”

“…Besides, while the quantitative WSS results obtained in 2D may not accurately reflect the levels experienced in the native 3D environment, the qualitative features and trends captured by the simplified models are not expected to differ substantially from those observed in 3D. In fact, the 2D models effectively resolved the main flow components and the dominant WSS component in the plane of observation, as suggested by the close agreement between the predicted increase in LVOT velocity magnitude in the DSS-LV model (23% increase vs. normal AoSA) and that reported in our previous simplified 3D model (24% increase vs. normal AoSA; Massé et al, 2018). Nevertheless, 3D modeling would enable the prediction of the two WSS components on the septal wall and a more complete characterization of the LVOT vortex dynamics.…”

“…For example, ex vivo experiments with porcine tissue have shown that WSS magnitude overloads on the aortic wall secondary to valvular defects contribute to the loss of tissue homeostasis and the progressive degeneration of the tunica media Atkins et al, , 2016. In light of those observations, the increased WSS magnitude and temporal gradient captured on the septal wall may promote fibrosis and explain the frequent association between DSS and steep LVOTs documented in the literature (Cape et al, 1997;Yap et al, 2008;Foker, 2013;Massé et al, 2018). In addition, in vitro studies in a step-flow channel have evidenced increased cellular proliferation in flow reattachment regions subjected to high WSS spatial gradients (Tardy et al, 1997;Chien, 2003).…”

“…Although early studies classified DSS as a congenital disorder, its rare incidence in newborns and its lack of inheritance patterns have weakened the support for a genetic etiology (Cape et al, 1997;Lampros and Cobanoglu, 1998;Darcin et al, 2003). Alternatively, the frequent occurrence of DSS in LVs with a steep aortoseptal angle (AoSA, angle between the long axis of the aorta and the septal wall) has provided support to a mechanobiological etiology by which LV hemodynamic abnormalities could interact with the endocardium to drive fibrosis and DSS membrane formation (Cape et al, 1997;Yap et al, 2008;Foker, 2013;Massé et al, 2018). Little is also known about the mechanisms by which valvular functionality may be altered by the obstruction.…”

ADAMTS19‐associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype

“…SAM is a shelf‐like membrane that forms below the aortic valve, consisting of several tissue layers including glycosaminoglycans in the subendothelial layer 16 . SAM results in subaortic stenosis and increased pressure gradient in the LVOT, it has unpredictable hemodynamic progression in childhood and high reoperation rate in up to 34% of patients 16,17 . Histopathology of SAM in studied families showed fibromuscular tissue fragments exhibiting secondary regenerative changes on a myxoid background and hypercellularity.…”