JACC: CARDIOVASCULAR IMAGING VOL. 16, NO.

3, 2023

ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

SPECIAL ISSUE: EVIDENCE-BASED IMAGING

ORIGINAL RESEARCH

Aortic Stenosis Progression

A Systematic Review and Meta-Analysis

Nadav Willner, MD,a,* Graeme Prosperi-Porta, MD, MASC,a,* Lawrence Lau, MD,a Angel Yi Nam Fu, MD,a
Kevin Boczar, MD,a Anthony Poulin, MD,a Pietro Di Santo, MD,a Rudy R. Unni, MD,a Sarah Visintini, BA, MLIS,b
Paul E. Ronksley, PHD,c Kwan-Leung Chan, MD,a Luc Beauchesne, MD,a Ian G. Burwash, MD,a
David Messika-Zeitoun, MD, PHDa

ABSTRACT

BACKGROUND Aortic valve stenosis is a progressive disorder with variable progression rates. The factors affecting
aortic stenosis (AS) progression remain largely unknown.

OBJECTIVES This systematic review and meta-analysis sought to determine AS progression rates and to assess the
impact of baseline AS severity and sex on disease progression.

METHODS The authors searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from
inception to July 1, 2020, for prospective studies evaluating the progression of AS with the use of echocardiography
(mean gradient [MG], peak velocity [PV], peak gradient [PG], or aortic valve area [AVA]) or computed tomography
(calcium score [AVC]). Random-effects meta-analysis was performed to evaluate the rate of AS progression for each
parameter stratified by baseline severity, and meta-regression was performed to determine the impact of baseline
severity and of sex on AS progression rate.

RESULTS A total of 24 studies including 5,450 patients (40% female) met inclusion criteria. The pooled annualized
progression of MG was þ4.10 mm Hg (95% CI: 2.80-5.41 mm Hg), AVA 0.08 cm2 (95% CI: 0.06-0.10 cm2),
PV þ0.19 m/s (95% CI: 0.13-0.24 m/s), PG þ7.86 mm Hg (95% CI: 4.98-10.75 mm Hg), and AVC þ158.5 AU (95% CI:
55.0-261.9 AU). Increasing baseline severity of AS was predictive of higher rates of progression for MG (P < 0.001), PV
(P ¼ 0.001), and AVC (P < 0.001), but not AVA (P ¼ 0.34) or PG (P ¼ 0.21). Only 4 studies reported AS progression
stratified by sex, with only PV and AVC having 3 studies to perform a meta-analysis. No difference between sex was
observed for PV (P ¼ 0.397) or AVC (P ¼ 0.572), but the level of confidence was low.

CONCLUSIONS This study provides progression rates for both hemodynamic and anatomic parameters of AS and
shows that increasing hemodynamic and anatomic baseline severity is associated with faster AS progression. More
studies are needed to determine if sex differences affect AS progression. (Aortic Valve Stenosis Progression Rate:
A Systematic Review and Meta-Analysis; CRD42021207726) (J Am Coll Cardiol Img 2023;16:314–328)
© 2023 by the American College of Cardiology Foundation.

From the aDepartment of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada; bBerkman Library, University of
Ottawa Heart Institute, Ottawa, Ontario, Canada; and the cDepartment of Community Health Sciences, University of Calgary,
Calgary, Alberta, Canada. *Drs Willner and Prosperi-Porta contributed equally to this work.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received June 28, 2022; revised manuscript received October 11, 2022, accepted October 14, 2022.

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2022.10.009

JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023
MARCH 2023:314–328
D systematic searches,22,23 and peer-reviewed
egenerative aortic stenosis (AS) is the most
common valvular disease in the Western
world, representing a substantial and
increasing disease burden in the aging population.1,2
Current evidence links AS with progressive inflamma-
tion, fibrosis, and calcification leading to impaired
leaflet opening, with marked interstudy rates of pro-
3,4
gression. The clinical factors governing AS progres-
sion remain largely unknown. Previous studies
addressing AS progression have been mostly retro-
spective and performed on selected patient cohorts,
while prospective cohorts are relatively small and
report progression with the use of different hemody-
namic or anatomic indices. This has resulted in signif-
icant heterogeneity in the reported rates of AS
progression in the published reports. 5-9 More specif-
ically, data regarding the impact of baseline AS
severity and sex on AS hemodynamic or anatomic
progression is scarce and contradictory10-15 and have
not been evaluated systematically. 16-18
Currently, no medical therapies exist to prevent or
slow AS progression, with aortic valve (AV) replace-
ment being the only curative therapy. 19,20 A better
understanding of the expected AS progression and its
determinants portends important clinical implica-
tions. The frequency of clinical follow-up and
repeated imaging as well as designing future studies
aimed at slowing AS progression or evaluating pa-
tients who could benefit from early intervention are
largely based on AS progression data.
We performed a systematic review and meta-
analysis of prospective studies to determine pooled
rates of AS hemodynamic and anatomic progression
and to assess whether baseline severity or sex are
associated with faster progression.
METHODS
This systematic review follows a prespecified study
protocol that was registered on the PROSPERO inter-
national prospective register of systematic reviews
(Aortic Valve Stenosis Progression Rate: A Systematic
Review and Meta-Analysis; CRD42021207726) on
January 6, 2020, and is reported according to the
PRISMA 2020 statement (Supplemental Table 1). 21
PUBLISHED REPORTS SEARCH AND STUDY SELECTION.
We searched Medline (from inception to July 1, 2020),
Embase (from inception to July 1, 2020), and
Cochrane Central Register of Controlled Trials (from
inception to July 1, 2020) with the assistance of a
medical research librarian (Supplemental Data). We
focused on Medical Subject Headings and key words
related to “aortic stenosis” and “progression.” The
search was informed by previously conducted
Willner et al 315
Aortic Stenosis Progression
ABBREVIATIONS
by a second librarian. 24 Bibliographies of all AND ACRONYMS
included studies were reviewed for other
AS = aortic stenosis
relevant articles.
AU = arbitrary units
ELIGIBILITY CRITERIA. Articles were eligible
AV = aortic valve
for inclusion if they prospectively evaluated
AVA = aortic valve area
adult patients (age $18 years) with baseline
AVC = aortic valve calcium
AS severity assessed by means of echocardi-
MG = mean gradient
ography (mean gradient [MG], mm Hg; peak
velocity [PV], m/s; peak gradient [PG], PG = peak gradient
mm Hg; or aortic valve area [AVA], cm2) or PV = peak velocity
computed tomography (aortic valve calcium score
[AVC], arbitrary units [AU]) and reported the annu-
alized hemodynamic or anatomic AS progression rate.
Only original articles that evaluated the progression
of AS prospectively were included. Studies were
excluded if: 1) the length of follow-up
was <12 months; 2) AS progression was evaluated
retrospectively; 3) studies were of nonhuman partic-
ipants; 4) studies were case reports, case series, re-
views, or editorials; or 5) full text articles were not
available after contacting primary authors.
SELECTION PROCESS. The search results were
uploaded into an online systematic review manage-
ment platform (Covidence systematic review soft-
ware, Veritas Health Innovation). Articles were
screened for inclusion by title and abstract indepen-
dently by 2 reviewers, and discrepancies were
resolved by consensus. For any articles meeting the
screening criteria, full texts were reviewed indepen-
dently by 2 reviewers, and any discrepancies were
resolved by consensus. If multiple articles with the
same patient cohort met inclusion criteria, the report
containing the largest number of patients or that re-
ported the most inclusive data evaluating the pro-
gression of AS was included.
DATA EXTRACTION. Data from each included article
were independently extracted by 2 reviewers, and
any discrepancies were resolved by consensus. Data
were entered into an electronic spreadsheet for
analysis. This included details such as author, publi-
cation year, study design, patient demographics,
method to quantify AS severity and progression, and
duration of follow-up. We specifically recorded the
baseline echocardiographic hemodynamic and
computed tomography AVC parameters and annual-
ized rate of progression. If data were unclear or
incomplete, corresponding authors were contacted
for additional information.
RISK OF BIAS ASSESSMENT. The methodologic
quality of each included study was assessed inde-
pendently by 2 reviewers using the MINOR (Method-
ological Index for Nonrandomized Trials) tool for
316 Willner et al JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023

Aortic Stenosis Progression MARCH 2023:314–328

F I G U R E 1 PRISMA Flow Diagram

Identification of studies via databases and registers (inception to July 1, 2020)

Identification
Records identified from: Records removed before screening:
MEDLINE (n = 2,307) Duplicate records removed
Embase (n = 3,400) (n = 1,793)
Cochrane (n = 233)

Records screened Records excluded

(n = 4,147) (n = 3,899)

Reports sought for retrieval Reports not retrieved

(n = 248) (n = 7)
Screening

Reports assessed for eligibility Reports excluded:

(n = 241) Retrospective studies (n = 122)
Reported wrong outcomes (n = 49)
Duplicate study (n = 29)
Not a study (n = 15)
Non-AS population (n = 2)
Included

Studies included in review

(n = 24)

AS ¼ aortic stenosis.

prospective cohort studies 25 and the ROB (Cochrane
Risk of Bias) assessment tool for randomized control
trials.26 The MINOR tool allows for the assessment of
internal validity based on 8 criteria for non-
comparative studies (clearly stated aim, inclusion of
consecutive patients, prospective collection of data,
endpoints appropriate to the aim of the study, unbi-
ased assessment of the study endpoint, follow-up
period appropriate to the aim of the study, loss to
follow-up <5%, and prospective calculation of the
study size) and 4 additional criteria for comparative
studies (adequate control group,
groups, baseline equivalence of the groups, and
adequate statistical analyses).25 Based on these
criteria, each category is given a score from 0 to 2. The
ROB tool evaluates each bias domain as “high,” “un-
sure,” or “low” risk of bias in domains including
sequence generation, allocation concealment, blind-
ing of participants and personnel, blinding of
outcome assessment, incomplete outcome data, se-
lective outcome reporting, and other issues. 26
SYNTHESIS. We used mean  SD as the common
measure of effect. If mean was not reported, mean
and SD were estimated from the reported median
(IQR).27 Inter-rater agreement was assessed using
percentage agreement and the kappa statistic.
Between-study heterogeneity was examined and
quantified using Cochran’s Q test and I 2 statistics.
Meta-analysis and forest plots were generated and
stratified by baseline severity grade of AS defined as
mild (MG: <20 mm Hg, PG: <36 mm Hg, PV: 2.5-3.0 m/s,
AVA: >1.5 cm 2), moderate (MG: 20-40 mm Hg, PG:
contemporary 36-64 mm Hg, PV: 3.0-4.0 m/s, or AVA: 1.0-1.5 cm 2), or
severe (MG: >40 mm Hg, PG: >64 mm Hg, PV: >4 m/s,
or AVA: <1.0 cm 2). To determine the relationship be-
tween baseline severity of AS and rate of progression,
meta-regression was performed and visualized with
the use of bubble plots. For all analyses the most
stratified baseline aortic stenosis severity data,
whenever available, were used, referred to henceforth
as subsets (ie, a study that stratified patients by mild,
moderate, and severe baseline AS would constitute 3
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023 Willner et al 317
MARCH 2023:314–328 Aortic Stenosis Progression

F I G U R E 2 Forest Plots

A
AS Severity Progression of MG (mm Hg/Year) Weight
Author and Year With 95% CI (%)
Mild AS (MG <20 mm Hg)
Kearney et al. (2012) 4.00 [3.28, 4.72] 7.84
Capoulade et al. (2015) 2.44 [2.39, 2.50] 8.02
Nguyen et al. (2015) 1.00 [0.72, 1.28] 8.00
Brandenburg et al. (2017) 1.42 [−1.24, 4.08] 6.02
Heterogeneity: T2 = 1.74, I2 = 98.48%, H2 = 65.73 2.30 [0.90, 3.70]
Test of θi = θj: Q(3) = 120.00, P < 0.01

Moderate AS (MG 20-40 mm Hg)

Otto et al. (1997) 7.00 [5.76, 8.24] 7.49
Moura et al. (2007) 3.56 [2.17, 4.95] 7.36
Dichtl et al. (2008) 4.14 [−2.06, 10.34] 2.86
Rossebo et al. (2008) 2.75 [2.74, 2.75] 8.02
Chan et al. (2010) 3.85 [3.29, 4.41] 7.91
Kearney et al. (2012) 6.00 [5.37, 6.63] 7.88
Panahi et al. (2013) 2.62 [−0.54, 5.78] 5.46
Nguyen et al. (2015) 3.00 [2.44, 3.56] 7.91
Nguyen et al. (2015) 5.00 [3.89, 6.11] 7.59
Heterogeneity: T2 = 2.16, I2 = 95.81%, H2 = 23.84 4.28 [3.20, 5.37]
Test of θi = θj: Q(8) = 179.49, P < 0.01

Severe AS (MG >40 mm Hg)

Kearney et al. (2012) 10.00 [8.99, 11.01] 7.65
10.00 [8.99, 11.01]

Overall 4.10 [2.80, 5.41]

Heterogeneity: T2 = 5.54, I2 = 99.91%, H2 = 1,153.58
Test of θi = θj: Q(13) = 659.47, P < 0.01
Test of group differences: Qb(2) = 95.62, P < 0.01

−5 0 5 10
Random-effects REML model

Forest plots showing the pooled rates of AS progression stratified by baseline AS severity (mild, moderate, and severe) based on (A) mean
gradient (MG), (B) peak velocity (PV), (C) peak gradient (PG), (D) aortic valve area (AVA), and (E) aortic valve calcium (AVC). REML ¼
restricted maximum likelihood; other abbreviation as in Figure 1.

Continued on the next page

subsets). Sensitivity analysis was also performed on RESULTS

study-level data. If progression data were reported
separately (ie, for control and experimental study
arms) data were combined according to Table 6.5.a
from the Cochrane Handbook for Systematic Reviews
of Interventions.28 We assessed for publication bias
using an Egger analysis moderated by baseline
severity and visualized with the use of funnel plots. All
analyses were performed with the use of Stata 17
(StataCorp). The level of significance was set at
a ¼ 0.05.
ARTICLE SELECTION. A total of 5,940 citations were
identified as of July 1, 2020, with 1,793 duplicates,
leaving 4,147 citations included for screening, as
depicted in the PRISMA flow diagram (Figure 1). The
inter-rater agreement for screening was 92.9%
(k ¼ 0.43, 95% CI: 0.40-0.46). A total of 248 articles
underwent full-text review for eligibility. From these,
217 articles were excluded, leaving 24 articles for data
extraction. The inter-rater study agreement for
318 Willner et al JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023

Aortic Stenosis Progression MARCH 2023:314–328

F I G U R E 2 Continued

B
AS Severity Progression of PV (m/s/Year) Weight
Author and Year With 95% CI (%)
Mild AS (PV 2.5-3.0 m/s)
Capoulade et al. (2015) 0.14 [0.11, 0.17] 9.02
Brandenburg et al. (2017) 0.02 [−0.07, 0.11] 7.61
Heterogeneity: T2 = 0.01, I2 = 85.40%, H2 = 6.85 0.09 [−0.04, 0.21]
Test of θi = θj: Q(1) = 6.85, P = 0.01

Moderate AS (PV 3.0-4.0 m/s)

Otto et al. (1997) 0.32 [0.26, 0.38] 8.44
Cowell et al. (2005) 0.18 [0.14, 0.22] 8.92
Moura et al. (2007) 0.14 [0.08, 0.20] 8.36
Rossebo et al. (2008) 0.15 [0.15, 0.16] 9.23
Stewart et al. (2008) 0.27 [0.18, 0.36] 7.50
Bull et al. (2015) 0.04 [−0.05, 0.13] 7.59
Kubota et al. (2018) 0.18 [0.16, 0.20] 9.13
Peeters et al. (2020) 0.11 [0.05, 0.18] 8.32
Heterogeneity: T2 = 0.01, I2 = 96.16%, H2 = 26.03 0.18 [0.12, 0.23]
Test of θi = θj: Q(7) = 50.12, P < 0.01

Severe AS (PV >4.0 m/s)

Faggiano et al. (1992) 0.40 [0.31, 0.49] 7.70
Cowell et al. (2005) 0.27 [0.20, 0.34] 8.17
Heterogeneity: T2 = 0.01, I2 = 80.46%, H2 = 5.12 0.33 [0.21, 0.46]
Test of θi = θj: Q(1) = 5.12, P = 0.02

Overall 0.19 [0.13, 0.24]

Heterogeneity: T2 = 0.01, I2 = 97.56%, H2 = 40.96
Test of θi = θj: Q(11) = 99.82, P < 0.01
Test of group differences: Qb(2) = 7.63, P = 0.02

0 .2 .4 .6
Random-effects REML model

full-text review was 84.3% (k ¼ 0.40, 95% CI: 0.28-
0.52). The most common reasons for exclusion were
studies being retrospective, reporting the wrong
outcomes, or being a duplicate study.
RESULTS OF INDIVIDUAL STUDIES. From the 24
included studies, 20 studies contained unique pa-
tients, amounting to a total of 5,450 study patients
evaluating AS progression; 3,244 patients (60%)
were male. The 4 other studies reported subgroup
analyses of already included studies but stratified by
sex or baseline AS severity. The pooled age of par-
ticipants was 68 years (95% CI: 66-70 years; reported
in 19/20 studies]. The prevalence of severe AS
documented in 11/20 studies was 5.4% (190/3,498),
and the prevalence of bicuspid AV reported in 10/20
studies was 12% (380/3,718). Twelve studies (60%)
were prospective cohorts and 8 (40%) were ran-
domized controlled trials. Four articles (17%)
included subgroup data stratified by sex, and 3 ar-
ticles (13%) provided the rate of progression strati-
fied by baseline AS grade (mild, moderate, or
severe). Detailed study information is presented in
Supplemental Table 2.
HEMODYNAMIC PROGRESSION.
Mean gradient. Ten studies including 3,498 patients
reported the annualized rate of progression for MG.
Based on the MG, mean baseline AS severity was mild
in 4 subsets, moderate in 9 subsets, and severe in 1
subset. The pooled annualized MG progression
was þ4.10 mm Hg/y (95% CI: 2.80-5.41; I 2 ¼ 99.9%)
(Figure 2A). Higher baseline MG was associated with
faster MG progression (P < 0.001) (Figure 3A).
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023 Willner et al 319
MARCH 2023:314–328 Aortic Stenosis Progression

F I G U R E 2 Continued

C
AS Severity Progression of PG (mm Hg/Year) Weight
Author and Year With 95% CI (%)
Mild AS (PG <36 mm Hg)
Panahi et al. (2013) 5.68 [0.09, 11.28] 10.72
5.68 [0.09, 11.28]

Moderate AS (PG 36-64 mm Hg)

Peter et al. (1993) 10.60 [7.52, 13.68] 14.91
Cowell et al. (2005) 6.52 [5.86, 7.18] 17.79
Moura et al. (2007) 4.83 [2.75, 6.91] 16.43
Dichtl et al. (2008) 4.76 [−3.44, 12.96] 7.33
Chan et al. (2010) 6.20 [5.30, 7.10] 17.65
Heterogeneity: T2 = 2.19, I2 = 81.51%, H2 = 5.41 6.62 [4.97, 8.27]
Test of θi = θj: Q(4) = 9.80, P = 0.04

Severe AS (PG >64 mm Hg)

Faggiano et al. (1992) 15.00 [12.08, 17.92] 15.17
15.00 [12.08, 17.92]

Overall 7.86 [4.98, 10.75]

Heterogeneity: T2 = 12.06, I2 = 94.68%, H2 = 18.81
Test of θi = θj: Q(6) = 42.06, P < 0.01
Test of group differences: Qb(2) = 24.99, P < 0.01

−10 0 10 20
Random-effects REML model

Peak velocity. Eleven studies including 3,061 patients
reported the annualized rate of progression for PV.
Based on the PV, mean baseline AS severity was mild
in 2 subsets, moderate in 8 subsets, and severe in 2
subsets. The pooled mean annualized PV progression
was þ0.19 m/s per year (95% CI: 0.13-0.24; I 2 ¼ 80.5%)
(Figure 2B). Higher baseline PV was associated with
faster PV progression (P ¼ 0.001) (Figure 3B).
Peak gradient. Seven studies including 1,050 patients
reported the annualized progression of PG. Based on
the PG, mean baseline AS severity was mild in 1
subset, moderate in 5 subsets, and severe in 1 subset.
The pooled mean annualized PG progression
was þ7.86 mm Hg/y (95% CI: 4.98-10.75 mm Hg/y;
I 2 ¼ 94.7%) (Figure 2C). We did not find a significant
association between baseline PG and the rate of pro-
gression (P ¼ 0.210) (Figure 3C).
Aortic valve area. Eleven studies including 3,825 pa-
tients reported the annualized progression of AVA.
Based on the AVA, mean baseline AS severity was
mild in 2 subsets, moderate in 7 subsets, and severe in
2 subsets. On average, AVA decreased by 0.08 cm 2/y
(95% CI: 0.06-0.10 cm 2/y; I 2 ¼ 94.2%) (Figure 2D). A
lower baseline AVA was not significantly associated
with a faster decrease in AVA (P ¼ 0.335) (Figure 3D).
The estimated AS progression rates according to
baseline MG, PV, PG, and AVA, derived from the
meta-regression are presented in Table 1.
ANATOMIC PROGRESSION. Eight studies including
1,471 patients reported the annualized progression of
AVC. Mean AVC progression rate was þ158.5 AU/y
(95% CI: 55.0-261.9 AU/y; I 2 ¼ 99.9%) (Figure 2E).
Higher baseline AVC was associated with faster pro-
gression in AVC (P < 0.001) (Figure 3E). The estimated
AS progression rates according to baseline AVC
derived from the meta-regression are presented in
Table 1.
There was no difference in the annualized
progression of hemodynamic or anatomic AS
(Supplemental Figure 1) or the relationship between
baseline AS severity and rate of progression when
using only study-level data rather than the most
stratified groups (Supplemental Figure 2).
320 Willner et al JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023

Aortic Stenosis Progression MARCH 2023:314–328

F I G U R E 2 Continued

D
AS Severity Progression of AVA (cm2/Year) Weight
Author and Year With 95% CI (%)

Mild AS (AVA >1.5 cm2)

livanainen et al. (1996) −0.06 [−0.14, 0.03] 3.79
Chan et al. (2010) −0.08 [−0.10, −0.05] 11.41
Heterogeneity: T2 = 0.00, I2 = 0.02%, H2 = 1.00 −0.07 [−0.10, −0.05]
Test of θi = θj: Q(1) = 0.16, P = 0.69

Moderate AS (AVA 1.5-1.0 cm2)

Otto et al. (1997) −0.12 [−0.15, −0.09] 9.61
Cowell et al. (2005) −0.08 [−0.09, −0.07] 12.80
Mohler et al. (2007) −0.02 [−0.09, 0.04] 5.71
Moura et al. (2007) −0.07 [−0.09, −0.06] 11.75
Rossebo et al. (2008) −0.03 [−0.03, −0.03] 13.21
Capoulade et al. (2015) −0.06 [−0.15, 0.03] 3.58
Kubota et al. (2018) −0.09 [−0.10, −0.08] 12.76
Heterogeneity: T2 = 0.00, I2 = 96.43%, H2 = 28.01 −0.07 [−0.10, −0.05]
Test of θi = θj: Q(6) = 283.05, P < 0.01

Severe AS (AVA <1.0 cm2)

Faggiano et al. (1992) −0.10 [−0.14, −0.06] 8.93
Stewart et al. (2008) −0.14 [−0.20, −0.09] 6.45
Heterogeneity: T2 = 0.00, I2 = 39.49%, H2 = 1.65 −0.12 [−0.16, −0.07]
Test of θi = θj: Q(1) = 1.65, P = 0.20

Overall −0.08 [−0.10, −0.06]

Heterogeneity: T2 = 0.00, I2 = 94.20%, H2 = 17.25
Test of θi = θj: Q(10) = 328.42, P < 0.01
Test of group differences: = Qb (2) = 3.70, P = 0.16

−.2 −.1 0 .1
Random-effects REML model

E
Progression of AVC (AU/Year) Weight
Author and Year With 95% CI (%)

Mohler et al. (2007) 255.65 [122.73, 388.57] 11.78

Messika-Zeitoun et al. (2007) 39.00 [26.58, 51.42] 14.59
Dichtl et al. (2008) 369.23 [−294.21, 1,032.67] 2.08
Nguyen et al. (2015) 45.00 [38.07, 51.93] 14.61
Nguyen et al. (2015) 138.00 [128.20, 147.80] 14.60
Nguyen et al. (2015) 379.00 [330.49, 427.51] 14.16
Bartnick et al. (2019) 2.10 [−0.48, 4.68] 14.62
Peeters et al. (2020) 253.00 [177.46, 328.54] 13.56
Overall 158.51 [55.08, 261.94]
Heterogeneity: T2 = 19,048.68, I2 = 99.86%, H2 = 689.80
Test of θi = θj: Q(7) = 1,053.89, P < 0.01
Test of θ = 0: z = 3.00, P < 0.01
−500 0 500 1,000
Random-effects REML model
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023 Willner et al 321
MARCH 2023:314–328 Aortic Stenosis Progression

F I G U R E 3 Bubble Plots

A
Progression of MG (mm Hg/Year)
10 Kearney et al. (2012)

Otto et al. (1997)

Kearney et al. (2012)

5 Kearney et al. (2012)

Nguyen et al. (2015)

Dichtl et al. (2008)

Chan et al. (2010)
Nguyen et al. (2015) Moura et al. (2007)

Rossebo et al. (2008)

Capoulade et al. (2015)
Panahi et al. (2013)

Brandenburg et al. (2017)

Nguyen et al. (2015)

0
0 20 40 60
Baseline MG (mm Hg)
Weights: Random-effects

B
.4 Faggiano et al. (1992)
Progression of PV (m/s/Year)

Otto et al. (1997)

.3 Cowell et al. (2005)
Stewart et al. (2008)

.2
Kubota et al. (2018) Cowell et al. (2005)

Rossebo et al. (2008)

Moura et al. (2007)
Capoulade et al. (2015)
Peeters et al. (2020)
.1

Brandenburg et al. (2017) Bull et al. (2015)

0
2.5 3 3.5 4 4.5
Baseline PV (m/s)
Weights: Random-effects

C
Faggiano et al. (1992)
15
Progression of PG (mm Hg/Year)

Peter et al. (1993)

10

Cowell et al. (2005)

Chan et al. (2010)
Panahi et al. (2013)

Dichtl et al. (2008) Moura et al. (2007)

5

0
30 40 50 60 70
Baseline PG (mm Hg)
Weights: Random-effects

Continued on the next page

322 Willner et al JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023

Aortic Stenosis Progression MARCH 2023:314–328

F I G U R E 3 Continued

D
0
Mohler et al. (2007)

Progression of AVA (cm2/Year)

Rossebo et al. (2008)

−.05 Iivanainen et al. (1996)

Capoulade et al. (2015)

Moura et al. (2007)

Cowell et al. (2005) Chan et al. (2010)

Kubota et al. (2018)

Faggiano et al. (1992)
−.1

Otto et al. (1997)

Stewart et al. (2008)

−.15
.5 1 1.5 2
Baseline AVA (cm2)
Weights: Random-effects
E

500
Progression of AVC (AU/Year)

Nguyen et al. (2015)

Dichtl et al. (2008)
400

300
Peeters et al. (2020) Mohler et al. (2007)

200

Nguyen et al. (2015)

100
Messika-Zeitoun et al. (2007)

Nguyen et al. (2015)

0
Bortnick et al. (2019)
Messika-Zeitoun et al. (2007)

0 500 1,000 1,500 2,000 2,500

Baseline AVC (AU)
Weights: Random-effects

Bubble plots showing the effect of baseline aortic stenosis severity on the rate of aortic stenosis progression using the most stratified baseline
severity data for (A) MG, (B) PV, (C) PG, (D) AVA, and (E) AVC. Red shaded areas represent 95% CIs in the meta-regression. Abbreviations as
in Figure 2.

IMPACT OF SEX ON AORTIC STENOSIS PROGRESSION. men [95% CI: 8.2 to 359.9 AU; I 2 ¼ 99.1%]; P ¼ 0.572)
Only 4 studies reported AS progression stratified by (Figure 4B). We were unable to perform a
sex, including 2 that reported progression of MG, 3 meta-regression to evaluate the effect of baseline
that reported PV, 2 that reported AVA, and 3 that re- severity of AS sex-related progression, because few
ported AVC, and none that reported PG. We did not studies reporting sex stratified AS progression rates.
find differences in the annualized progression of PV QUALITY ASSESSMENT. We found a low risk of bias
(þ0.19 m/s/y [95% CI: 0.12-0.26 m/s/y; I 2 ¼ 85.2%] in the 24 included studies (Supplemental Table 3). In
in women vs þ0.16 m/s/y in men [95% CI: 0.14- the cohort studies, definite bias in the domains
0.21 m/s/y; I2 ¼ 87.4%]; P ¼ 0.397) (Figure 4A) or in the evaluated in the MINOR tool were infrequent, with 2
annualized AVC progression (þ108 AU in women studies losing points for “inclusion of consecutive
[95% CI: 19.3 to 235.1 AU; I 2 ¼ 96.3%] vs þ176 AU in patients,” 1 study losing points for “follow-up period
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023 Willner et al 323
MARCH 2023:314–328 Aortic Stenosis Progression

T A B L E 1 Average Hemodynamic and Anatomic Progression Rates According to the Baseline Severity of AS Interpolated From Meta-Regression Results

Mean Gradient Peak Velocity Peak Gradient Aortic Valve Area Aortic Valve Calcium

Threshold, Progression, Threshold, Progression, Threshold, Progression, Threshold, Progression, Threshold,a Progression,
mm Hg mm Hg/y m/s m/s/y mm Hg mm Hg/y cm2 cm 2/y AU AU/y

Mild AS <20 þ3.0 2.5-3.0 þ0.09 <36 þ5.8 >1.5 0.07 <500 þ101
Moderate AS 20-30 þ4.0 3.0-3.5 þ0.17 36-64 þ8.4 1-1.5 0.08 500-1,500 þ202
30-40 þ6.0 3.5-4.0 þ0.24
Severe AS >40 þ7.0 >4.0 þ0.28 >64 þ11.1 <1 0.09 >1,500 þ323

a
Average threshold for a mixed population of men and women.40
AS ¼ aortic stenosis.

appropriate to the aim of the study,” and in
the comparative studies 3 studies losing points for
“baseline equivalence of groups.”
all studies were missing reported methodology
pertaining to at least 1 domain in the MINOR assess-
ment tool, which introduces some uncertainty in the
bias assessment. In the randomized control trials,
definite bias was infrequent, with “high” risk of bias
in the domain “blinding of participants
personnel” in 2 studies due to being single blinded, in
the domain “incomplete outcome data” in 2 studies,
in the domain of “selective reporting” in 1 study, and
in the domain “other sources of bias” in 1 study.
PUBLICATION BIAS. We found no evidence of pub-
lication bias according to Egger’s analysis moderated
by baseline severity for each measure of AS, that
is, MG (P ¼ 0.859), PG (P ¼ 0.302), PV (P ¼ 0.841), AVA
(P ¼ 0.520), and AVC (P ¼ 0.950) (Supplemental
Figure 3).
DISCUSSION
This systematic review and meta-analysis of pro-
spective studies included 5,450 unique patients from
24 studies and evaluated the pooled annualized
change in hemodynamic parameters of AS severity
including MG, PV, PG, and AVA and anatomic pro-
gression using AVC by computed tomography. We
found that the pooled annual rate of progression for
MG was þ4.2 mm Hg/y, for PG þ7.9 mm Hg/y,
for PV þ0.20 m/s/y, for AVA 0.08 cm 2/y, and for
AVC þ154 AU/y. We also identified that increasing
baseline AS severity according to both hemodynamic
and anatomic parameters was predictive of faster AS
progression (Central Illustration). In addition, we
attempted to evaluate the impact of sex on AS pro-
gression, but there were too few studies with sex-
stratified data to confidently establish
associations.
This study provides valuable data on the average
echocardiography-based hemodynamic progression.
The 2020 American College of Cardiology/American
Heart Association guidelines report average annual
However, rates of progression in PV of þ0.3 m/s/y, in MG
of þ7 mm Hg/y, and in AVA of 0.1 cm 2/y in patients
with moderate AS.19 However, we identified that in
subsets of patients with moderate average baseline
AS, we identified lower rates of progression for MG
(þ4.3 mm Hg/y [95% CI: 3.2-5.4 mm Hg/y]), PV
and (þ0.18 m/s/y [95% CI: 0.12-0.23 m/s/y]), and AVA
decline (0.08 cm 2/y [95% CI: 0.06-0.10 cm 2/y]).
These results, based on 20 unique prospective studies
including more than 5,000 patients, provide new and
overall lower reference values. In addition, Rosenhek
et al12,13 retrospectively studied a small group of pa-
tients with mild and moderate AS, reporting an
average increase in aortic jet velocity of 0.24 
0.30 m/s/y, and defined rapid hemodynamic pro-
gression as an aortic jet velocity progression
of $0.3 m/s/y. This contributed to the Class IIa
recommendation for intervention on asymptomatic
severe AS with “rapid yearly progression,” defined as
a PV increase >0.3 m/s/y. 19 Our finding of the upper
95% CI for PV progression of þ0.23 m/s/y agrees with
these prior findings and may suggest that the defini-
tion of rapid progression may have a lower threshold
than previously reported.
We identified a strong relationship between base-
line AS severity and rate of hemodynamic and
anatomic progression, which has not been previously
evaluated systematically. Notably, AS progression
rate was strongly associated with baseline MG, PV,
and AVC but not PG or AVA. We hypothesize that
although a graphic trend showed increasing baseline
PG resulted in faster progression, there were rela-
tively few studies and patients evaluating PG pro-
gression, which likely reduced the ability to identify
this relationship. Furthermore, because PG is derived
any from the single measurement of PV by a quadratic
relationship (PG ¼ 4PV 2), absolute measurement
variations or errors in PV have a proportionally
greater impact on PG compared with PV and reduce
324 Willner et al JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023

Aortic Stenosis Progression MARCH 2023:314–328

F I G U R E 4 Forest Plots

A
Sex Progression of PV (m/s/Year) Weight
Author and Year With 95% CI (%)

Females
Cramariuc et al. (2015) 0.21 [0.19, 0.23] 21.06
Peeters et al. (2020) 0.10 [0.02, 0.18] 11.65
Nguyen et al. (2016) 0.23 [0.18, 0.28] 15.64
Heterogeneity: T2 = 0.00, I2 = 85.23%, H2 = 6.77 0.19 [0.12, 0.26]
Test of θi = θj: Q(2) = 8.42, P = 0.01

Males
Cramariuc et al. (2015) 0.19 [0.17, 0.21] 21.17
Peeters et al. (2020) 0.12 [0.03, 0.21] 9.68
Nguyen et al. (2016) 0.14 [0.12, 0.16] 20.80
Heterogeneity: T2 = 0.00, I2 = 81.78%, H2 = 5.49 0.16 [0.12, 0.20]
Test of θi = θj: Q(2) = 12.07, P < 0.01

Overall 0.17 [0.14, 0.21]

Heterogeneity: T2 = 0.00, I2 = 87.39%, H2 = 7.93
Test of θi = θj: Q(5) = 31.17, P < 0.01

Test of group differences: Qb(1) = 0.43, P = 0.51

0 .1 .2 .3
Random-effects REML model

B
Sex Progression of AVC (AU/Year) Weight
Author and Year With 95% CI (%)

Females
Peeters et al. (2020) 11.00 [62.99, 159.01] 16.92
Bortnick et al. (2019) 1.00 [−0.56, 2.56] 17.56
Nguyen et al. (2016) 228.00 [143.74, 312.26] 15.72
Heterogeneity: T2 = 11,858.96, I2 = 96.32%, H2 = 27.15 107.89 [−19.28, 235.06]
Test of θi = θj: Q(2) = 47.99, P < 0.01

Males
Peeters et al. (2020) 324.00 [220.81, 427.19] 14.94
Bortnick et al. (2019) 3.30 [−0.06, 6.66] 17.56
Nguyen et al. (2016) 215.00 [184.32, 245.68] 17.29
Heterogeneity: T2 = 25,503.57, I2 = 99.11%, H2 = 112.92 175.81 [−8.24, 359.85]
Test of θi = θj: Q(2) = 217.20, P < 0.01

Overall 140.98 [37.68, 244.29]

Heterogeneity: T2 = 15,819.23, I2 = 99.94%, H2 = 1,806.78
Test of θi = θj: Q(5) = 272.11, P < 0.01

Test of group differences: Qb(1) = 0.35, P = 0.55

0 100 200 300 400

Random-effects REML model

Forest plots showing the pooled rate of aortic stenosis progression stratified by sex for (A) PV and (B) AVC. Abbreviations as in Figure 2.
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023 Willner et al 325
MARCH 2023:314–328 Aortic Stenosis Progression

C ENTR AL I LL U STRA T I O N Relationship Between Baseline Aortic Stenosis Severity and Progression

20 Mild Moderate Severe

15
Progression of MG (mm Hg/y)

10 Kearney et al. (2012)

Otto et al. (1997)

Kearney et al. (2012)

5 Kearney et al. (2012) Nguyen et al. (2015)

Dichtl et al. (2008)
Chan et al. (2010) Moura et al. (2007)
Nguyen et al. (2015)
Capoulade et al. (2015) Rossebo et al. (2008)
Panahi et al. (2013)
Brandenburg et al. (2017)
Nguyen et al. (2015)
0
0 20 40 60
Baseline MG (mm Hg)
Willner N, et al. J Am Coll Cardiol Img. 2023;16(3):314–328.

Higher baseline severity of aortic stenosis is associated with faster progression. Bubble plot and meta-regression shows relationship between baseline
aortic stenosis severity and rate of progression. MG ¼ mean gradient.

the sensitivity of PG to identify any relationships. The
calculation of AVA requires measurement of 3 sepa-
rate parameters, increasing potential sources of er-
ror,29,30 with no formal consensus regarding the site
where the left ventricular outflow tract should be
measured (at the level of the insertion of the leaflets
or 5 mm below).31 Although the prognostic impor-
tance of AVA is undisputed, these methodologic is-
sues and important interstudy variabilities likely
contribute to the absence of correlation between
baseline AVA and progression. Importantly, in one of
the few studies specifically examining this relation-
ship, Nguyen et al17 showed the relationship between
baseline AS severity and progression rate regardless
of the parameter considered. Similarly to our results
showing faster anatomic progression with higher
baseline AVC, previous data have also shown that
baseline calcification correlated with increased in
aortic jet velocity.13 The observation of higher pro-
gression rates with baseline severity according to
2 independent parameters (hemodynamic and
anatomic) further strengthen the degree of confi-
dence of our findings.
Unfortunately, we were unable to confidently
assess sex differences as intended in our protocol
because of few studies reporting sex-stratified AS
progression rates. Previous reports have identified
contradictory data regarding sex differences in AS
hemodynamic and anatomic progression.7,32-34 Cur-
rent evidence has identified a lower threshold of
calcification in women that correlates with severe
AS,35,36 which is reflected in the current guidelines
identifying different calcium load thresholds
between men and women to define severe AS.19
Future studies are needed to further evaluate the
discordant differences in sex-related progression of
AS previously reported.
STUDY LIMITATIONS. Despite using the most strati-
fied baseline AS severity data available, most patient
groups had moderate AS, which may limit our ability
326 Willner et al
Aortic Stenosis Progression
to extrapolate the data specifically into patients with
severe AS. However, progression of AS in patients
with severe AS is of less importance because they
have already met this clinical endpoint, especially
in the era of early intervention in asymptomatic
disease.37 Significant between-study heterogeneity
(I 2 > 80% for all pooled rates of progression) led to
relatively wide CIs in the pooled annualized rates of
progression of AS. This heterogeneity is at least
partially caused by the relationship between baseline
severity and disease progression. Interaction with
other parameters, such as age or valve morphology,
on AS progression rate could not be assessed in the
absence of patient-level data. Although we found no
evidence of publication bias for any measures of AS,
the degree of heterogeneity between and likely
within studies caused by the variability in baseline AS
severity limited our ability to conclude definitively
that no publication bias exists. Patient-level data
would be required to evaluate publication bias more
accurately.
These data have important potential clinical im-
plications. First, these data may provide additional
evidence to refine the recommended follow-up in-
tervals for patients with moderate AS. For example,
based on this meta-analysis, a patient with a MG of
30 mm Hg would be expected to have a maximum
average rate of progression of 5.4 mm Hg/y (upper
95% CI) meaning that severe AS is unlikely to occur
before 1.86 years, allowing for individualized
follow-up to optimize resource utilization. This
study provides data on the expected annualized
progression, which may assist clinicians to better
inform patients when AS may progress to severe
and therefore better predict the timing of inter-
vention. In addition, it may allow clinicians to
identify patients with more aggressive disease (ie,
faster than expected progression) who might benefit
from closer follow-up or earlier intervention.19
Although too few studies evaluated patients with
severe AS at baseline for adequate subgroup anal-
ysis, rapid rates of progression were seen in these
groups, which may explain why asymptomatic pa-
tients have been recently shown to benefit from
38
early surgical aortic valve replacement. This study
also provides insights and possible future research
directions related to the pathophysiology of AS
progression. Degenerative calcific aortic stenosis is
an active process defined by the disruption of aortic
valvular endothelium and endothelial dysfunction,
leading to lipid accumulation and lymphocyte and
macrophage infiltration with release of proin-
flammatory molecules that recruit fibroblasts and
activate osteoblasts, ultimately leading to valve
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023
MARCH 2023:314–328
fibrosis and calcification. 39 Faster AVC progression
with greater AS severity may be explained by the
centripetal growth of hydroxyapatite within the
aortic valve leaflets. Although the present study
does not identify a causative mechanism explaining
why patients with more severe baseline AS incur
faster progression, it does support that relationship.
Future research is required to understand the dif-
ference in pathophysiologic mechanisms and de-
terminants that result in more rapid AS progression.
Finally, the AS progression rates provided in this
meta-analysis will be critical for the calculation of
sample sizes for future randomized controlled trials
aiming to slow down AS progression as potential
new medical therapies emerge.
CONCLUSIONS
In this systematic review and meta-analysis, we
identified 24 prospective studies including 5,450 pa-
tients evaluating the most up-to-date and accurate
mean annualized rates of AS progression determined
by hemodynamic and anatomic indices. We found
that increasing baseline AS severity was associated
with more rapid AS progression. This data provides
important clinical implications that may assist clini-
cians personalize follow-up and monitoring, estimate
timing of valve intervention, identify patients with
more aggressive disease, and help researchers design
future prospective studies and further evaluate the
pathophysiology explaining why increasing baseline
AS severity predicts faster hemodynamic and
anatomic progression. Future studies evaluating sex-
related differences in AS progression are required to
validate or refute differences in AS progression re-
ported in published reports.
ACKNOWLEDGMENTS The authors thank Dr Wolf-
gang Dichtl (Innsbruck Medical University) and Dr
Romain Capoulade (L‘Institut du Thorax, Inserm
UMR 1087) for sharing their valuable data with us,
and Marie-Cécile Domecq, MLIS (Health Sciences Li-
brary, University of Ottawa), for peer review of the
Medline search strategy.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
The authors have reported that they have no relationships relevant to
the contents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr David
Messika-Zeitoun, Department of Cardiology, Univer-
sity of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario K1Y 4W7, Canada. E-mail:
DMessika-zeitoun@ottawaheart.ca.
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023 Willner et al 327
MARCH 2023:314–328 Aortic Stenosis Progression

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: TRANSLATIONAL OUTLOOK: Future research is

Increasing baseline hemodynamic and anatomic AS
severity is associated with more rapid progression.AS
progression rate may assist clinicians in recognizing
patients with aggressive disease and to improve
communication with patients and their understanding and
expectations when valve intervention is being considered.
Data on AS progression rate are crucial for improved
design of future prospective studies and selection of
study populations.
needed to evaluate additional clinical, biochemical, and
imaging features that might be associated with more
rapid AS progression; specifically, sex differences in pro-
gression should be evaluated. Additional research on the
pathophysiology implicated in AS progression is required
to identify methods to slow or halt the rate of progres-
sion. Individualized risk-prediction models of AS
progression are needed to assist clinicians in guiding
follow-up and patient management.

REFERENCES

1. Osnabrugge RLJ, Mylotte D, Head SJ, et al.
Aortic stenosis in the elderly: disease prevalence
and number of candidates for transcatheter aortic
valve replacement: a meta-analysis and modeling
study. J Am Coll Cardiol. 2013;62:1002–1012.
2. Bonow RO, Greenland P. Population-wide
trends in aortic stenosis incidence and outcomes.
Circulation. 2015;131:969–971.
3. Peeters F, Meex SJR, Dweck MR, et al. Calcific
aortic valve stenosis: hard disease in the heart: a
biomolecular approach toward diagnosis and
treatment. Eur Heart J. 2018;39:2618–2624.
4. Dweck MR, Khaw HJ, Sng GKZ, et al. Aortic
stenosis, atherosclerosis, and skeletal bone: is
there a common link with calcification and
inflammation? Eur Heart J. 2013;34:1567–1574.
5. Otto CM, Prendergast B. Aortic-valve stenosis—
from patients at risk to severe valve obstruction.
N Engl J Med. 2014;371:744–756.
6. Otto CM, Burwash IG, Legget ME, et al. Pro-
spective study of asymptomatic valvular aortic
stenosis. Circulation. 1997;95:2262–2270.
7. Nguyen V, Mathieu T, Melissopoulou M, et al. Sex
differences in the progression of aortic stenosis and
prognostic implication: the COFRASA-GENERAC
study. J Am Coll Cardiol Img. 2016;9:499–501.
8. Capoulade R, Clavel MA, Dumesnil JG, et al.
Impact of metabolic syndrome on progression of
aortic stenosis: influence of age and statin ther-
apy. J Am Coll Cardiol. 2012;60:216–223.
9. Heuvelman HJ, van Geldorp MW, Eijkemans MJ,
et al. Progression of aortic valve stenosis in adults:
a systematic review. J Heart Valve Dis. 2012;21:
454–462.
10. Zilberszac R, Gabriel H, Schemper M, Laufer G,
Maurer G, Rosenhek R. Asymptomatic severe
aortic stenosis in the elderly. J Am Coll Cardiol
Img. 2017;10:43–50.
11. Pohle K, Mäffert R, Ropers D, et al. Progression
of aortic valve calcification. Circulation. 2001;104:
1927–1932.
12. Rosenhek R, Binder T, Porenta G, et al. Pre-
dictors of outcome in severe, asymptomatic aortic
stenosis. N Engl J Med. 2000;343:611–617.
13. Rosenhek R, Klaar U, Schemper M, et al. Mild
and moderate aortic stenosis. Natural history and
risk stratification by echocardiography. Eur Heart
J. 2004;25:199–205.
14. Tastet L, Enriquez-Sarano M, Capoulade R,
et al. Impact of aortic valve calcification and sex on
hemodynamic progression and clinical outcomes in
AS. J Am Coll Cardiol. 2017;69:2096–2098.
15. Kume T, Kawamoto T, Okura H, et al. Rapid
progression of mild to moderate aortic stenosis in
patients older than 80 years. J Am Soc Echo-
cardiogr. 2007;20:1243–1246.
16. Cowell SJ, Newby DE, Prescott RJ, et al.
A randomized trial of intensive lipid-lowering
therapy in calcific aortic stenosis. N Engl J Med.
2005;352:2389–2397.
17. Nguyen V, Cimadevilla C, Estellat C, et al.
Haemodynamic and anatomic progression of aortic
stenosis. Heart. 2015;101:943–947.
18. Kearney L, Ord M, Buxton B, et al. Usefulness
of the Charlson co-morbidity index to predict
outcomes in patients >60 years old with aortic
stenosis during 18 years of follow-up. Am J Car-
diol. 2012;110:695–701.
19. Otto CM, Nishimura RA, Bonow RO, et al. 2020
ACC/AHA guideline for the management of pa-
tients with valvular heart disease: a report of the
American College of Cardiology/American Heart
Association Joint Committee on Clinical Practice
Guidelines. J Am Coll Cardiol. 2021;77(4):e25–
e197.
20. Vahanian A, Beyersdorf F, Praz F, et al. 2021
ESC/EACTS guidelines for the management of
valvular heart disease. Eur Heart J. 2022;43:561–
632.
21. Page MJ, McKenzie JE, Bossuyt PM, et al. The
PRISMA 2020 statement: an updated guideline for
reporting systematic reviews. BMJ. 2021;372:n71.
22. Kolkailah AA, Doukky R, Pelletier MP,
Volgman AS, Kaneko T, Nabhan AF. Transcatheter
aortic valve implantation versus surgical aortic
valve replacement for severe aortic stenosis in
people with low surgical risk. Cochrane Database
Syst Rev. 2019;12:CD013319.
23. Thiago L, Tsuji SR, Nyong J, et al. Statins for
aortic valve stenosis. Cochrane Database Syst Rev.
2016;9:CD009571.
24. McGowan J, Sampson M, Salzwedel DM,
Cogo E, Foerster V, Lefebvre C. PRESS Peer Re-
view of Electronic Search Strategies: 2015 guide-
line statement. J Clin Epidemiol. 2016;75:40–46.
25. Slim K, Nini E, Forestier D, Kwiatkowski F,
Panis Y, Chipponi J. Methodological Index for
Nonrandomized Studies (MINORS): development
and validation of a new instrument. ANZ J Surg.
2003;73:712–716.
26. Sterne JAC, Savovic J, Page MJ, et al. ROB 2: a
revised tool for assessing risk of bias in rando-
mised trials. BMJ. 2019;366:l4898.
27. McGrath S, Zhao X, Steele R, Thombs BD,
Benedetti A. Estimating the sample mean and
standard deviation from commonly reported
quantiles in meta-analysis. Stat Methods Med Res.
2020;29:2520–2537.
28. Higgins J, Thomas J, Chandler J, et al., eds.
Cochrane Handbook for Systematic Reviews of In-
terventions. Version 6.3. 2022. Accessed June 15,
2022. https://training.cochrane.org/handbook/current
29. Clavel M-A, Burwash Ian G, Pibarot P. Cardiac
imaging for assessing low-gradient severe aortic
stenosis. J Am Coll Cardiol Img. 2017;10:185–202.
30. Michelena HI, Margaryan E, Miller FA, et al.
Inconsistent echocardiographic grading of aortic
stenosis: is the left ventricular outflow tract
important? Heart. 2013;99:921–931.
31. Baumgartner H, Hung J, Bermejo J, et al. Rec-
ommendations on the echocardiographic assess-
ment of aortic valve stenosis: a focused update
from the European Association of Cardiovascular
Imaging and the American Society of Echocardi-
ography. J Am So Echocardiogr. 2017;30:372–392.
32. Cramariuc D, Rogge BP, Lønnebakken MT,
et al. Sex differences in cardiovascular outcome
during progression of aortic valve stenosis. Heart.
2015;101:209–214.
33. Peeters Frederique ECM, Doris Mhairi K, Car-
tlidge Timothy RG, et al. Sex differences in valve-
calcification activity and calcification progression
328 Willner et al
Aortic Stenosis Progression
in aortic stenosis. J Am Coll Cardiol Img. 2020;13:
2045–2046.
34. Bortnick AE, Xu S, Kim RS, et al. Biomarkers of
mineral metabolism and progression of aortic
valve and mitral annular calcification: the Multi-
Ethnic Study of Atherosclerosis. Atherosclerosis.
2019;285:79–86.
35. Aggarwal SR, Clavel M-A, Messika-Zeitoun D,
et al. Sex differences in aortic valve calcification
measured by multidetector computed tomography
in aortic stenosis. Circ Cardiovasc Imaging. 2013;6:
40–47.
36. Simard L, Côté N, Dagenais F, et al. Sex-
related discordance between aortic valve
JACC: CARDIOVASCULAR IMAGING, VOL. 16, NO. 3, 2023
calcification and hemodynamic severity of aortic
stenosis: is valvular fibrosis the explanation? Circ
Res. 2017;120:681–691.
37. Kang D-H, Park S-J, Lee S-A, et al. Early sur-
gery or conservative care for asymptomatic aortic
stenosis. N Engl J Med. 2019;382:111–119.
38. Maron DJ, Hochman JS, Reynolds HR, et al.
Initial invasive or conservative strategy for stable
coronary disease. N Engl J Med. 2020;382:1395–
1407.
39. Sverdlov AL, Ngo DT, Chapman MJ, Ali OA,
Chirkov YY, Horowitz JD. Pathogenesis of aortic
stenosis: not just a matter of wear and tear. Am J
Cardiovasc Dis. 2011;1:185–199.
MARCH 2023:314–328
40. Cueff C, Serfaty JM, Cimadevilla C, et al.
Measurement of aortic valve calcification using
multislice computed tomography: correlation with
haemodynamic severity of aortic stenosis and
clinical implication for patients with low ejection
fraction. Heart. 2011;97:721–726.
KEY WORDS aortic valve stenosis, baseline
severity, progression
A PPE NDI X For supplemental data, figures,
tables, and references, please see the online
version of this paper.