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.