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\begin{document}

\title{Progression of Aortic Stenosis in Patients with Bicuspid Aortic Valve}



\author[1]{Michael Shang}%
\author[1]{Arianna Kahler-Quesada}%
\author[2]{Makoto Mori}%
\author[1]{Sameh Yousef}%
\author[2]{Arnar Geirsson}%
\author[1]{Prashanth Vallabhajosyula}%
\affil[1]{Yale School of Medicine}%
\affil[2]{Yale University School of Medicine}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Bicuspid aortic valve is the most common congenital heart
defect and predisposes patients to developing aortic stenosis more
frequently and at a younger age than the general population. However,
the influence of bicuspid aortic valve on the rate of progression of
aortic stenosis remains unclear. Methods: In 236 patients (177 tricuspid
aortic valve, 59 bicuspid aortic valve) matched by initial severity of
mild or moderate aortic stenosis, we retrospectively analyzed baseline
echocardiogram at diagnosis with latest available follow-up
echocardiogram. Baseline comorbidities, annualized progression rate of
hemodynamic parameters, and hazard of aortic valve replacement were
compared between valve phenotypes. Results: Median echocardiographic
follow-up was 2.6 (IQR 1.6-4.2) years. Patients with tricuspid aortic
stenosis were significantly older with more frequent comorbid
hypertension and congestive heart failure. Median annualized progression
rate of mean gradient was 2.3 (IQR 0.6-5.0) mmHg/year vs. 1.5 (IQR
0.5-4.1) mmHg/year (p=0.5), and that of peak velocity was 0.14 (IQR
0-0.31) m/s/year vs. 0.10 (IQR 0.04-0.26) m/s/year (p=0.7) for tricuspid
vs. bicuspid aortic valve, respectively. On multivariate analyses,
bicuspid aortic valve was not significantly associated with more rapid
progression of aortic stenosis. In a stepwise Cox proportional hazards
model adjusted for baseline mean gradient, bicuspid aortic valve was
associated with increased hazard of aortic valve replacement (HR: 1.7,
95\% CI {[}1.0, 3.0{]}, p=0.049). Conclusion: Bicuspid aortic valve may
not significantly predispose patients to more rapid progression of mild
or moderate aortic stenosis. Guidelines for echocardiographic
surveillance of aortic stenosis need not be influenced by valve
phenotype.%
\end{abstract}%



\sloppy


\textbf{Progression of Aortic Stenosis in Patients with Bicuspid Aortic
Valve}

Running head: \emph{Progression of bicuspid aortic stenosis}

Michael Shang BS,\textsuperscript{1} Arianna Kahler-Quesada
BS,\textsuperscript{1} Makoto Mori MD,1 Sameh Yousef
MD,\textsuperscript{1} Arnar Geirsson MD,\textsuperscript{1} Prashanth
Vallabhajosyula MD\textsuperscript{1}

Division of Cardiac Surgery, Yale University School of Medicine, New
Haven, CT

\textbf{Sources of Fundings:} No funding sources were used for this
study.

\textbf{Corresponding Author:}

Prashanth Vallabhajosyula, MD, MS

Associate Professor of Surgery

Division of Cardiac Surgery

Yale School of Medicine

330 Cedar Street, Boardman Building 204

New Haven, CT 06520-8062

Email: prashanth.vallabhajosyula@yale.edu

Phone: 203-785-5000

\emph{Abstract}

\textbf{Background:} Bicuspid aortic valve is the most common congenital
heart defect and predisposes patients to developing aortic stenosis more
frequently and at a younger age than the general population. However,
the influence of bicuspid aortic valve on the rate of progression of
aortic stenosis remains unclear.

\textbf{Methods:} In 236 patients (177 tricuspid aortic valve, 59
bicuspid aortic valve) matched by initial severity of mild or moderate
aortic stenosis, we retrospectively analyzed baseline echocardiogram at
diagnosis with latest available follow-up echocardiogram. Baseline
comorbidities, annualized progression rate of hemodynamic parameters,
and hazard of aortic valve replacement were compared between valve
phenotypes.

\textbf{Results:} Median echocardiographic follow-up was 2.6 (IQR
1.6-4.2) years. Patients with tricuspid aortic stenosis were
significantly older with more frequent comorbid hypertension and
congestive heart failure. Median annualized progression rate of mean
gradient was 2.3 (IQR 0.6-5.0) mmHg/year vs. 1.5 (IQR 0.5-4.1) mmHg/year
(p=0.5), and that of peak velocity was 0.14 (IQR 0-0.31) m/s/year vs.
0.10 (IQR 0.04-0.26) m/s/year (p=0.7) for tricuspid vs. bicuspid aortic
valve, respectively. On multivariate analyses, bicuspid aortic valve was
not significantly associated with more rapid progression of aortic
stenosis. In a stepwise Cox proportional hazards model adjusted for
baseline mean gradient, bicuspid aortic valve was associated with
increased hazard of aortic valve replacement (HR: 1.7, 95\% CI {[}1.0,
3.0{]}, p=0.049).

\textbf{Conclusion:} Bicuspid aortic valve may not significantly
predispose patients to more rapid progression of mild or moderate aortic
stenosis. Guidelines for echocardiographic surveillance of aortic
stenosis need not be influenced by valve phenotype.

\emph{Text}

\textbf{Introduction}

Aortic stenosis (AS) is a common cause of valvular heart disease
worldwide. Its prevalence increases with age, ranging from 4.6\%-6.4\%
in U.S. adults aged 75 years and older.\textsuperscript{1, 2} The most
common etiology of aortic stenosis is degenerative calcification, which
is primarily associated with aging as well as other cardiovascular
disease. However, the presence of bicuspid aortic valve (BAV) represents
a major risk factor in the development of AS in younger populations and
is present in 65\% of adults aged 60 and younger undergoing aortic valve
replacement for aortic stenosis.\textsuperscript{3} While patients with
BAV are known to develop AS more frequently and earlier than patients
with tricuspid aortic valve (TAV), it remains uncertain whether BAV is
associated with faster progression of AS severity once AS develops,
which is important to guide screening and intervention
practices.\textsuperscript{4}

While the progression rate of AS varies widely among individuals, older
age, male sex, coronary artery disease, plasma levels of oxidized
phospholipids, and baseline hemodynamic severity have all been
associated with more rapid progression.\textsuperscript{5-8} BAV has
been implicated in certain studies,\textsuperscript{9, 10} but others
have shown no difference in AS progression rate between BAV and TAV
phenotypes.\textsuperscript{5, 11} Furthermore, these findings were
drawn from post hoc analyses of clinical trials aimed at determining
effects of metabolic syndrome and plasma lipids on AS disease
progression. As a result, these studies examined very small cohorts of
BAV patients (N\textless{}41), representing a significant limitation in
the current literature. These findings attest to the need for more
investigations to better understand progression of more-than-mild AS in
BAV patients.

Using a healthcare system-wide echocardiographic database, we aim to
determine the hemodynamic progression rate of mild and moderate severe
aortic stenosis in patients with BAV as compared to patients with TAV.

\textbf{Materials and Methods}

\emph{Study Population}

A total of 236 patients (59 BAV and 177 TAV) were selected from our
health system-wide database of 60,383 echocardiography reports from
2013-2018. These included echocardiograms obtained for any indication at
32 sites encompassing 5 tertiary-care hospitals and over 120 clinics at
satellite locations throughout the state. For the BAV cohort, the
database was queried for all mentions of ``bicuspid aortic valve'' or
``BAV''. Initially, 222 patients with BAV confirmed by echocardiography
were identified. We then reviewed the records of these patients and
included patients with an initial diagnosis of mild or moderate AS and
echocardiographic follow-up greater than or equal to 6 months from
initial diagnosis of AS. Patients were excluded if they never progressed
beyond ``trace'' severity or if they had an initial severity of
``severe''. Other exclusion criteria were active atrial fibrillation,
active endocarditis, and history of aortic valve or aortic surgery prior
to the initial echocardiogram. Ultimately, 59 patients with BAV were
included in this study.

To identify our TAV cohort, we randomly sampled from our echo database
for reports of mild and moderate AS in proportions identical to that of
the initial BAV cohort. For each patient selected, we reviewed the
medical record and enrolled them based on the criteria described above.
Sampling continued until the cohort consisted of 177 TAV patients,
stratified by mild or moderate initial severity in a 3:1 TAV-to-BAV
ratio.

This study was approved by the Yale Institutional Review Board and
written informed consent was waived.

\emph{Clinical Data}

Comorbidity data were obtained by extracting ICD-10 data from each
patient's medical record and converted using the Elixhauser Comorbidity
Index.\textsuperscript{12} Patient demographic information, surgical
history, and mortality data up to November 1, 2020 was obtained by
review of the medical record.

\emph{Echocardiography}

Echocardiographic data were drawn from complete echocardiograms
including 2D, M-mode, and color doppler. Peak velocity was calculated by
continuous wave doppler, mean gradient was calculated by averaging
instantaneous pressure gradients converted from measured velocities
using the Bernoulli equation, and aortic valve area (AVA) was calculated
by the continuity equation. Biplane Simpson's technique was used to
estimate ejection fraction (EF). Aortic valve phenotype was assessed in
the parasternal short-axis view. Severity of aortic stenosis was
assessed using established criteria for mean gradient, peak velocity,
and aortic valve area. Though the echocardiography reports used to
identify patients were only obtained from exams occurring between
2013-2018, we reviewed the electronic medical record for the first and
last available echocardiograms between the period of January 1, 2005 and
November 1, 2020. These were used to calculate the yearly progression
rate of mean gradient (mmHg/year) and peak velocity (m/s/year).

\emph{Statistical Analysis}

Continuous variables were assessed using median (interquartile range
{[}IQR{]}), and categorical variables are presented as N (\%). Wilcoxon
rank-sum test was used to compare differences in continuous variables
between BAV and TAV. Chi-square test and Fisher's exact test were used
for categorical variables, as appropriate.

To determine risk factors associated with rapid progression of AS, we
dichotomized patients based on progression rate of mean gradient greater
than (rapid progressor) or less than or equal to (slow progressor) the
average annualized progression of mean gradient for the whole cohort, as
previously described.\textsuperscript{10, 13} Univariate and
multivariable logistic regression analysis was used to determine whether
BAV is associated with rapid progression of AS. Variables with
p\textless{}0.10 on univariate analysis were included in the
multivariate model. Kaplan-Meier curves were generated to compare BAV
and TAV patients for occurrence of surgical or transcatheter aortic
valve replacement (AVR) after initial diagnosis of AS. Stepwise
multivariable Cox proportional hazards model was used to assess the
association of BAV with AVR, adjusting for potential confounders.
P-values \textless{}0.05 were considered statistically significant. All
statistical analyses were performed using RStudio, version 1.2.1335
(Boston, MA, USA).

\textbf{Results}

\emph{Baseline Patient Characteristics}

A total of 236 patients with mild or moderate AS were included in this
analysis. The BAV cohort consisted of 59 patients, of which 40 had an
initial AS severity of mild (68\%) and 19 patients had moderate initial
severity (32\%). The TAV cohort consisted of 177 patients, matched by
initial severity with our BAV cohort (120 mild AS, 57 moderate AS). Of
the 236 patients, 136 (58\%) were male and 199 (84\%) were Caucasian,
without significant differences in sex and race between BAV and TAV
cohorts. The BAV cohort was significantly younger than the TAV cohort
(59 years vs. 78 years, p\textless{}.001) and had a longer median
echocardiography follow-up period (3.17 years vs. 2.40 years, p=0.02).
The BAV cohort also had lower baseline prevalence of hypertension (69\%
vs. 82\%, p=0.043) and congestive heart failure (6.8\% vs. 28\%,
p\textless{}0.001) than the TAV cohort. There were no significant
differences between the two groups in terms of tobacco use, body mass
index, pulmonary disease, chronic kidney disease, or peripheral vascular
disease. \textbf{Table 1} summarizes these demographics and
comorbidities.

Baseline hemodynamics were similar between BAV and TAV groups
(\textbf{Table 2} ). Among all patients, mean gradient was 17.0 (IQR
13.0-21.1) mmHg, peak velocity was 2.8 (IQR 2.5-3.1) m/s, and indexed
aortic valve area was 0.71 (IQR 0.59-0.86)
cm\textsuperscript{2}/m\textsuperscript{2}.

\emph{Hemodynamic Progression of AS}

Progression of hemodynamic parameters is shown in \textbf{Table 2} .
Median echocardiographic interval was 2.6 (IQR 1.6-4.2) years and was
significantly longer in the BAV cohort (p=0.011). Despite longer
echocardiographic follow-up, the proportion of BAV patients who had
progressed beyond initial baseline severity was similar to TAV patients
(56\% and 55\%, respectively, p=0.9). However, at latest follow-up, 22
(37\%) BAV patients had developed severe AS compared to 50 (28\%) TAV
patients (p=0.062). Annualized progression rate was similar between
groups, regardless of hemodynamic parameter used (\textbf{Figure 1} ).
Median annualized progression of mean gradient was 2.3 (IQR 0.6-5.0)
mmHg/year for patients with TAV vs. 1.5 (IQR 0.5-4.1) mmHg/year for
patients with BAV (p=0.5). Median annualized progression of peak
velocity was 0.14 (IQR 0-0.31) m/s/year for patients with TAV vs. 0.10
(IQR 0.04-0.26) m/s/year in patients with BAV (p=0.4).

Patients were dichotomized into slow and rapid progressors based on the
overall average annualized progression of mean gradient of 2.85 \selectlanguage{ngerman}± 5.31
mmHg/year. The proportion of rapid progressors was similar between
cohorts, with 74 (43\%) rapid progressors in the TAV group and 21 (36\%)
in the BAV group (p=0.4), \textbf{Table 2} .

\emph{Factors Associated with Faster Hemodynamic Progression of Aortic
Stenosis}

On univariate analysis, there was no significant difference between
aortic valve morphology and rapid progressor phenotype (\textbf{Table 3}
). Factors that were significantly associated with rapid progression
were age (OR: 1.02, 95\% CI {[}1.00, 1.04{]}; p=0.03) and baseline mean
gradient (OR: 1.04, 95\% CI {[}1.00, 1.08{]}; p=0.04). On the other
hand, higher BMI was associated with slow progression (OR 0.95, 95\% CI
{[}0.91, 0.99{]}; p=0.02). When comparing comorbidities between the
cohorts, BMI and presence of diabetes mellitus, chronic kidney disease,
or hypertension was not significant between rapid and slow progressors
and did not play a role in the progression of mean aortic gradient. On
multivariate analysis adjusted for age, BMI, and baseline mean gradient,
BAV was not significantly associated with rapid progression, p=0.7
(\textbf{Table 3} ).

\emph{Association of Valve Phenotype with Aortic Valve Replacement}

Median clinical follow-up time was similar between groups (TAV: 6.2 (IQR
1.7-10.6) years vs. BAV: 6.4 (IQR 3.4-9.4) years, p=0.43). During the
study period, 33 (19\%) TAV patients and 22 (37\%) BAV patients
underwent surgical or transcatheter AVR (\textbf{Figure 2} ). However,
median time to AVR after initial diagnosis of AS was similar between
cohorts at 2.7 (IQR 2.1-5.5) years in TAV patients and 3.3 (2.3-4.8)
years in BAV patients (p=0.09). A stepwise Cox proportional hazards
model revealed that BAV (HR: 1.73, 95\% CI {[}1.00, 2.99{]}, p=0.049)
and baseline mean gradient (HR: 1.07, 95\% CI {[}1.04, 1.10{]},
p\textless{}0.001) were significantly associated with increased hazard
of AVR (\textbf{Table 4} ).

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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).\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{23, 24} Additionally,
BAV patients are at increased risk for developing thoracic aortic
aneurysms, and present for aneurysm surgery more frequently than TAV
patients.\textsuperscript{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.

\emph{Limitations}

Due to the retrospective nature of this study, the hemodynamic data
limited to what was documented in echocardiography reports. We did not
evaluate interobserver variability by independent review of hemodynamic
parameters. As such, we were unable to account for effects of BAV
morphology (i.e. cusp fusion pattern, presence of raphe) as they were
inconsistently reported on. In addition, this was a single center study,
which limits generalizability and raises the possibility of not
capturing outside imaging and operative records, though an extensive
chart review was conducted using our electronic medical record. Lastly,
the power of statistical conclusions drawn from this sample are limited
by the sample size of the BAV cohort. Our findings warrant future
multicenter studies in order to achieve larger a sample of BAV patients.

\textbf{Conclusion}

Overall, this study adds to the growing body of evidence to suggest that
aortic stenosis in bicuspid aortic valves may not progress faster than
that in tricuspid valves. While frequent monitoring according to current
guidelines will continue to be crucial to the management of aortic
stenosis, our data suggests that the severity of AS and observed
progression rate are more predictive of future progression than valve
phenotype.

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Gualano SK. Evaluation of patients with severe symptomatic aortic
stenosis who do not undergo aortic valve replacement: the potential role
of subjectively overestimated operative risk. \emph{Circ Cardiovasc Qual
Outcomes} . 2009;2:533-9.

24. Iung B, Cachier A, Baron G, Messika-Zeitoun D, Delahaye F, Tornos P,
Gohlke-Barwolf C, Boersma E, Ravaud P and Vahanian A. Decision-making in
elderly patients with severe aortic stenosis: why are so many denied
surgery? \emph{Eur Heart J} . 2005;26:2714-20.

25. Davies RR, Kaple RK, Mandapati D, Gallo A, Botta DM, Jr.,
Elefteriades JA and Coady MA. Natural history of ascending aortic
aneurysms in the setting of an unreplaced bicuspid aortic
valve.\emph{Ann Thorac Surg} . 2007;83:1338-44.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{TAV}, N=177 & \textbf{BAV}, N=59 &
\textbf{p-value}\tabularnewline
\midrule
\endhead
\textbf{Age (years)} & 80 (73,86) & 60 (51,68) &
\textbf{\textless{}0.001}\tabularnewline
\textbf{Race} & & & 0.4\tabularnewline
African American & 16 (9.0\%) & 8 (14\%) &\tabularnewline
Other & 9 (5.1\%) & 4 (6.8\%) &\tabularnewline
Caucasian & 152 (86\%) & 47 (80\%) &\tabularnewline
\textbf{Sex} & & & 0.11\tabularnewline
Female & 81 (46\%) & 20 (34\%) &\tabularnewline
Male & 96 (54\%) & 39 (66\%) &\tabularnewline
\textbf{Tobacco Use (years)} & 28 (17) & 28 (18) & 0.7\tabularnewline
\textbf{Body Mass Index (kg/m\textsuperscript{2})} & 28 (7) & 29 (6) &
0.12\tabularnewline
\textbf{Hypertension} & 145 (82\%) & 41 (69\%) &
\textbf{0.043}\tabularnewline
\textbf{Pulmonary Disease} & 43 (24\%) & 14 (24\%) &
\textgreater{}0.9\tabularnewline
\textbf{Chronic Kidney Disease} & 23 (13\%) & 9 (15\%) &
0.7\tabularnewline
\textbf{Diabetes Mellitus} & 52 (29\%) & 13 (22\%) & 0.3\tabularnewline
\textbf{Peripheral Vascular Disease} & 23 (13\%) & 11 (19\%) &
0.3\tabularnewline
\textbf{Congestive Heart Failure} & 51 (29\%) & 4 (6.8\%) &
\textbf{\textless{}0.001}\tabularnewline
\bottomrule
\end{longtable}

\emph{Tables}

\textbf{Table 1: Patient Demographics and Comorbidities.} Continuous
variables are expressed as median (IQR) and categorical variables are
expressed as N (\%). Statistically significant p-values are bolded.

BAV: bicuspid aortic valve, TAV: tricuspid aortic valve

\emph{}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{TAV}, N=177 & \textbf{BAV}, N=59 &
\textbf{p-value}\tabularnewline
\midrule
\endhead
\textbf{Median follow-up (years)} & 2.40 (1.48-3.93) & 3.17 (1.92-4.92)
& \textbf{0.02}\tabularnewline
\textbf{Baseline AS grade} & & & \textgreater{}0.9\tabularnewline
Mild & 120 (68\%) & 40 (68\%) &\tabularnewline
Moderate & 57 (32\%) & 19 (32\%) &\tabularnewline
\textbf{AS grade at last follow-up} & & & 0.062\tabularnewline
None & 8 (4.5\%) & 7 (12\%) &\tabularnewline
Mild & 50 (28\%) & 15 (25\%) &\tabularnewline
Moderate & 69 (39\%) & 15 (25\%) &\tabularnewline
Severe & 50 (28\%) & 22 (37\%) &\tabularnewline
\textbf{Baseline Mean Gradient (mmHg)} & 16 (13-20) & 18 (14-22) &
0.2\tabularnewline
\textbf{Baseline Peak Velocity (m/s)} & 2.70 (2.50-3.00) & 2.80
(2.50-3.11) & 0.5\tabularnewline
\textbf{Baseline Aortic Valve Area (cm2)} & 1.30 (1.10-1.60) & 1.35
(1.18-1.70) & 0.2\tabularnewline
\textbf{Baseline AVA Index (cm2/m2)} & 0.72 (0.59-0.86) & 0.70
(0.60-0.82) & 0.7\tabularnewline
\textbf{Progression Rate of Mean Gradient (mmHg/year)} & 2.3 (0.6-5.0) &
1.5 (0.5-4.1) & 0.5\tabularnewline
\textbf{Progression Rate of Peak Velocity (m/s/year)} & 0.14 (0.00-0.31)
& 0.10 (0.04-0.26) & 0.7\tabularnewline
\textbf{Progression of AS grade} & 105 (59\%) & 40 (68\%) &
0.2\tabularnewline
\textbf{Rapid Progressors (\textgreater{}2.85mmHg/year)} & 74 (43\%) &
21 (36\%) & 0.4\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2: Baseline Echocardiography and Progression Rate of
Aortic Stenosis.} Continuous variables are expressed as median (IQR) and
categorical variables are expressed as N (\%). Progression rate was
calculated by dividing the difference in mean gradient or peak velocity
between first and last echocardiograms by time elapsed between scans.
Patients were determined to be rapid progressors if annualized
progression of mean gradient was greater than the average of that for
the entire study cohort.

AS: aortic stenosis, AVA: aortic valve area\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
& Univariate & Univariate & Univariate & Univariate & Multivariate &
Multivariate & Multivariate\tabularnewline
\midrule
\endhead
& \textbf{OR} & \textbf{95\% CI} & \textbf{95\% CI} & \textbf{p-value} &
\textbf{OR} & \textbf{95\% CI} & \textbf{p-value}\tabularnewline
\textbf{Age} & 1.02 & {[}1.00, 1.04{]} & {[}1.00, 1.04{]} &
\textbf{0.031} & 1.02 & {[}1.00, 1.05{]} & 0.1\tabularnewline
\textbf{Race} & & & & & & &\tabularnewline
African American & --- & --- & --- & & & &\tabularnewline
Other & 0.19 & {[}0.01, 1.28{]} & {[}0.01, 1.28{]} & 0.14 & &
&\tabularnewline
Caucasian & 1.84 & {[}0.75, 4.97{]} & {[}0.75, 4.97{]} & 0.2 & &
&\tabularnewline
\textbf{Sex} & & & & & & &\tabularnewline
Female & --- & --- & --- & & & &\tabularnewline
Male & 1.31 & {[}0.77, 2.25{]} & {[}0.77, 2.25{]} & 0.3 & &
&\tabularnewline
\textbf{Tobacco Use (years)} & 1 & {[}0.97, 1.02{]} & {[}0.97, 1.02{]} &
0.8 & & &\tabularnewline
\textbf{Body Mass Index} & 0.95 & {[}0.91, 0.99{]} & {[}0.91, 0.99{]} &
\textbf{0.02} & 0.95 & {[}0.91, 0.99{]} & \textbf{0.022}\tabularnewline
\textbf{Hypertension} & 0.7 & {[}0.37, 1.32{]} & {[}0.37, 1.32{]} & 0.3
& & &\tabularnewline
\textbf{Pulmonary Disease} & 1 & {[}0.54, 1.83{]} & {[}0.54, 1.83{]} &
\textgreater{}0.9 & & &\tabularnewline
\textbf{Chronic Kidney Disease} & 1.13 & {[}0.53, 2.40{]} & {[}0.53,
2.40{]} & 0.7 & & &\tabularnewline
\textbf{Diabetes Mellitus} & 1.01 & {[}0.56, 1.81{]} & {[}0.56, 1.81{]}
& \textgreater{}0.9 & & &\tabularnewline
\textbf{Peripheral Vascular Disease} & 0.72 & {[}0.32, 1.54{]} &
{[}0.32, 1.54{]} & 0.4 & & &\tabularnewline
\textbf{Congestive Heart Failure} & 1.02 & {[}0.54, 1.90{]} & {[}0.54,
1.90{]} & \textgreater{}0.9 & & &\tabularnewline
\textbf{LV Ejection Fraction} & 0.99 & {[}0.96, 1.01{]} & {[}0.96,
1.01{]} & 0.4 & & &\tabularnewline
\textbf{BAV} & 0.76 & {[}0.41, 1.39{]} & {[}0.41, 1.39{]} & 0.4 & 1.14 &
{[}0.51, 2.55{]} & 0.7\tabularnewline
\textbf{Baseline Mean Gradient} & 1.04 & {[}1.00, 1.08{]} & {[}1.00,
1.08{]} & \textbf{0.037} & 1.05 & {[}1.01,1.10{]} &
\textbf{0.008}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3: Univariate and multivariate logistic regression for
rapid progression of aortic stenosis.} Rapid progression is defined as
annualized progression of mean gradient greater than the average for the
whole study cohort (\textgreater{}2.85mmHg/year). Statistically
significant p-values are bolded.

BAV: bicuspid aortic valve, CI: confidence interval, LV: left ventricle,
OR: odds ratio\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Covariate} & \selectlanguage{greek}\textbf{β} & \textbf{HR} & \textbf{95\% CI} &
\textbf{p-value}\tabularnewline
\midrule
\endhead
BAV & 0.55 & 1.73 & {[}1.00,2.99{]} & \textbf{0.049}\tabularnewline
Baseline Mean Gradient & 0.068 & 1.07 & {[}1.04,1.10{]} &
\textbf{\textless{}0.001}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4:} \textbf{Stepwise Cox proportional hazards model for
freedom from aortic valve replacement} . Both surgical and transcatheter
aortic valve replacement were included. Bicuspid aortic valve and
baseline mean gradient were included in the model after stepwise
adjustment.

BAV: bicuspid aortic valve, HR: hazard ratio, CI: confidence interval

\emph{Figure Legends}

\textbf{Figure 1:} \textbf{Annualized progression rate of peak velocity
and mean gradient between TAV and BAV cohorts.} \textbf{(A} ) Annualized
progression of peak velocity (m/s/year). \textbf{(B)} Annualized
progression of mean gradient (mmHg/year). Box shows
25\textsuperscript{th} and 75\textsuperscript{th} percentiles, bolded
line shows median value, and error bars show 10\textsuperscript{th} and
90\textsuperscript{th} percentiles. Median {[}interquartile range{]} are
shown at the top of the graphs.

BAV: bicuspid aortic valve, TAV: tricuspid aortic valve

\textbf{Figure 2: Kaplan-Meier curve for freedom from aortic valve
replacement (surgical or transcatheter).} Curve is truncated at 5 years.
Censoring events include death and loss to follow-up. Shading represents
95\% confidence interval. P-value was derived from log-rank test.

AVR: aortic valve replacement, BAV: bicuspid aortic valve, TAV:
tricuspid aortic valve\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\selectlanguage{english}
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