Comment
In this retrospective study of a matched cohort, we demonstrate that
presence of BAV was not statistically significantly associated with more
rapid hemodynamic progression of mild or moderate aortic stenosis.
Despite this, patients with BAV were more likely to undergo AVR.
It is well-established that BAV patients develop AS more frequently and
at an earlier age compared to the general population. This is reflected
in our study in the significantly younger age of the BAV cohort.
However, there is discordance in the literature about whether BAV is
associated with faster progression of AS, once established. Two studies
have found no association between valve morphology and annual
progression rate of mean transvalvular gradient, even after adjusting
for age.5, 11 Conversely, Ryu et al. and Shen et al.
both report that after adjusting for age and baseline hemodynamic
measurements, BAV is independently associated with faster annual
progression.9, 10 However, in both the above studies,
the BAV patients differed significantly from TAV patients in terms of
baseline AS grade and hemodynamic parameters. It is now well-established
that initial severity is an important predictor of more rapid
progression.5, 11, 14 As a result, the confounding
effect on progression rate introduced by differences in baseline
severity between groups may bias the comparison.
The present study is novel in that we analyzed a larger cohort of BAV
patients than prior studies, and we matched our BAV and TAV patients by
initial AS grade. After doing so, we found no statistically significant
association between aortic valve phenotype and unadjusted progression
rate of mean gradient and peak velocity. Furthermore, risk of rapid
progression was similar between groups, even after adjusting for
comorbidities. In concordance with prior studies, older age and baseline
severity were associated with more rapid progression.
Several cellular mechanisms have been proposed for the development and
progression of AS. Regardless of valve phenotype, AS progression is
thought to share similar pathways with atherosclerosis. Namely, oxidized
lipid accumulation, inflammatory stimulation, and shear stress promote
osteogenic differentiation of valvular interstitial cells (i.e.
fibroblasts and smooth muscle cells).15-18 After
induction of an osteoblast-like phenotype, valvular interstitial cells
then upregulate calcium production, via BMP2 and matrix
metalloproteinases, leading to calcification and stenosis. Several
clinical studies have reported that these same cardiometabolic factors
driving development of AS also lead to more rapid hemodynamic
progression and calcification.19-21 However, in
patients with BAV, the accelerated development of AS is driven by
increased shear stress due to abnormal valve morphology, as well as by
genetic mutations resulting in downregulation of the NOTCH1 gene, which
is important in preventing osteogenic
differentiation.22 While the pathogenesis of AS in BAV
versus TAV is driven by separate processes, our findings suggest that
this distinction does not result in clinically significant differences
in rate of progression.
Despite this, we observed that over similar follow-up periods, BAV
patients had shorter time to AVR (surgical or transcatheter) following
diagnosis of mild or moderate AS, after adjusting for baseline mean
transvalvular gradient. We were unable to fully account for the complex
factors involved in preoperative decision making for these patients,
which limits our ability to adequately determine differences in timing
of intervention. Nevertheless, the decreased hazard of intervention in
TAV patients could be driven by their older age or perceived operative
risk, as shown in some studies of elderly patients who were not operated
on despite severe symptomatic AS.23, 24 Additionally,
BAV patients are at increased risk for developing thoracic aortic
aneurysms, and present for aneurysm surgery more frequently than TAV
patients.25 This may reflect the surgeon’s lower
threshold for replacing the aortic valve during concomitant aortic
surgery; however, differences in AS severity and symptoms at time of
surgery in BAV vs. TAV has not been reported in the literature. While
BAV patients develop AS earlier in life, surveillance patterns and
threshold for procedural intervention should not be driven by phenotype
alone. Rather, presence of atherosclerotic risk factors, baseline
severity and clinically observed progression rate may be more accurate
predictors of long-term outcome.