Review Articles

Integrating hemodynamics with ventricular and

valvular remodeling in aortic stenosis. A
paradigm shift in therapeutic decision making
Gregory S. Pavlides, MD, PhD, Yannis S. Chatzizisis, MD, PhD, and Thomas R. Porter, MD Omaha, Nebraska

Abstract Aortic valve stenosis (AS) has traditionally been approached in hemodynamic terms. Although hemodynamics
and symptoms have formed the basis of recommending interventional treatment in AS, other factors reflecting left ventricular
and valvular and/or vascular remodeling are equally important for the prognosis and outcome of patients with AS. Left
ventricular and valvular/vascular remodeling in AS do not consistently correlate with hemodynamic severity of AS. Those
remodeling changes are reflected and can be detected by a variety of novel laboratory and imaging techniques, including
biomarkers, echocardiography, cardiac magnetic resonance and gated Computer Tomography (CT) imaging. Taking all
those elements into Heart Team therapeutic decision making in patients with AS, can significantly improve appropriate
patient selection for interventional treatment and patient outcomes. We review this novel approach and propose a simple
algorithm for decision making by the Heart Team, in patients with moderate or severe AS. (Am Heart J 2022;254:66–76.)

Background ters. Furthermore, there are series with asymptomatic AS

Aortic valve stenosis (AS) has traditionally been ap-
proached in hemodynamic terms.1 - 4 Aortic valve gradi-
ents and aortic valve area have formed the basis of classi-
fication of aortic stenosis as mild, moderate or severe. A
large amount of data has shown a relationship between
hemodynamic classification and patient prognosis. As
a result, hemodynamics together with symptoms have
formed the basis of recommending interventional treat-
ment by surgical or transcatheter aortic valve replace-
ment.5 - 7 However, in the era of transcatheter therapies,
there are several limitations with the traditional hemody-
namic approach. A great variability has been shown be-
tween hemodynamic classification and individual patient
symptoms and prognosis. Symptoms are notoriously dif-
ficult to assess, especially in older patients with aortic
stenosis who may have very limited physical activity.8
Frequently, there are discordant hemodynamic measure-
ments, especially in low-flow, low-gradient AS. Unpre-
dictable response to therapeutic intervention by Surgical
Aortic Valve Replacement (SAVR) or Transcatheter Aor-
tic Valve Replacement (TAVR) has been documented in
several cases, despite hemodynamic indication parame-
From the and The University of Nebraska Medical Center, Omaha, Nebraska
Submitted March 31, 2022; accepted August 6, 2022
Reprint requests: Gregory S. Pavlides, MD, PhD, 982265 Nebraska Medical Center,
Omaha, NE 68198-2265, Phone: 402.559.5151, Fax: 402.559.8355.
E-mail address: greg.pavlides@unmc.edu.
0002-8703
© 2022 The Author(s). Published by Elsevier
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://doi.org/10.1016/j.ahj.2022.08.004
patients whose outcome was improved by aortic valve
replacement (AVR) versus waiting for symptoms to ap-
pear.9
It appears that other factors, implicated in the patho-
physiology and progression of aortic stenosis, are equally
important for the prognosis and outcome of patients
with this disease. These are factors involved in AS re-
lated left ventricular remodeling, including left ventric-
ular hypertrophy (LVH), myocardial ischemia, apoptosis
and fibrosis, as well as diastolic and systolic dysfunc-
tion. The quantity of aortic valve calcification (AVC) may
reflect valvular remodeling in response to valve colla-
gen infiltration and vascular afterload changes. Signifi-
cant amounts of data are emerging, showing that these
structural changes in aortic stenosis are not accurately re-
flected by hemodynamic parameters. Furthermore, these
structural changes might be more accurate in assessing
prognosis and dictating the need and benefit of interven-
tional therapy.10 - 12 What is clinically important is the fact
that a number of non-invasive methods reflect the struc-
tural changes in aortic stenosis and can be used effec-
tively in clinical decision making. As the interventional
options for patients with AS are increasing, with the avail-
ability of TAVR in addition to traditional SAVR, the early
and accurate detection of patients with AS who will ben-
efit from early intervention, despite hemodynamic status,
is essential.
Approaching aortic stenosis as a pathophysiologic en-
Inc.
tity, where aortic valve gradients and effective aortic
valve area are only one component of the disease with
structural left ventricular (LV) and aortic valve remodel-

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American Heart Journal
Volume 254
ing being the other, will greatly improve our ability to
treat the increasing number of patients presenting with
what in the past was considered hemodynamically mod-
erate and/or asymptomatic severe AS. The aim of this
approach is to improve AS patient outcomes. Patients
with LV and/or valvular remodeling are at increased risk
for developing heart failure, despite “favorable” hemo-
dynamics and absence of symptoms, and have their out-
come worsened even with intervention at that time. This
strong association of LV and/or valvular remodeling to
outcome has been amply and increasingly reported, al-
though there is no direct evidence of a causative effect.
Even as such, we believe that identifying these patients
before a clinical event, will allow early consideration for
valve intervention, by SAVR or TAVR, or even intensify
our intervention on other factors contributing to remod-
eling, such as systemic hypertension. This might improve
patient outcomes, although, such an approach awaits
clinical proof. This is also true for developing new atrial
fibrillation and potentially suffering a stroke, events more
frequent in patients with AS and LV remodeling.13 The
importance of LV/valvular remodeling with hemodynam-
ics in decision making and treatment of patients with sig-
nificant aortic stenosis is the basis of our argument in this
review.
Pathophysiology of Ventricular,
Vascular, and Valvular Remodeling in
Aortic Stenosis
The process of aortic valve stenosis formation is a dy-
namic one with inflammation, leading to fibrosis and
valve calcification. As obstruction to flow increases, el-
evated intracavitary pressures lead invariably to compen-
satory left ventricular hypertrophy (LVH). Although LVH
is considered an adaptive process to reduce wall stress,
the response of the LV to pressure overload is not homo-
geneous.14 Left ventricular hypertrophy is the first stage
of left ventricular remodeling. The persisting pressure
overload progresses invariably to a series of structural
myocardial changes.15 , 16 A central event in LV remodel-
ing is the development of myocardial fibrosis.25 The my-
ocardial fibrosis, defined as an increased deposition of
extracellular matrix proteins, is initially reactive without
loss of cardiomyocytes. It is mostly perivascular and in-
terstitial, accompanying the hypertrophic myocytes. As
the process becomes more maladaptive, it can progress,
with myocyte cell death and apoptosis, and eventual re-
placement fibrosis.17 , 18 Ischemia can contribute to cell
death, and it could at least partially be due to the initial
reactive fibrosis around hypertrophied myocardial cells.
This sequence of events has been suggested by previous
investigations (Figure 1).
Focusing on fibrosis, fibroblasts regulate the process
of fibrosis by controlling the balance between synthe-
sis and degradation of extracellular matrix proteins and
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Pavlides, Chatzizisis, and Porter 67
Figure 1
Schematic illustration of continuous remodeling in pressure-
overload hypertrophy. From: Hein S, et al. Circulation
2003;107:984-991.
collagen. Important systems and factors involved in fi-
brosis are the renin-angiotensin- aldosterone system,
the transforming growth factor b (TGF-b), endothelin-
1, norepinephrine and reactive oxygen species among
others.19 - 22 TGF-b acts as a fibrogenic factor induc-
ing fibroblasts to synthesize matrix proteins and pro-
tease inhibitors, such as inhibitors of metalloproteinases
(TIMPs). Recent data also implicate neutrophils. Acti-
vated neutrophils form neutrophil traps (NETs), in a pro-
cess termed NETosis, activate fibroblasts to increased
proliferation, migration, and extracellular matrix produc-
tion.23 In contrast, factors like interleukin-1B (IL-1B) stim-
ulate matrix metalloproteinases (MMPs) degrading ma-
trix proteins.24 Increased collagen synthesis becomes the
dominant feature leading to fibrosis in aortic stenosis,
while matrix-degrading pathways usually are not attenu-
ated. Clinical attempts to modify risk factors associated
with the progression of aortic valve calcification have
failed in the past.25 On-going research is focusing on con-
trolling osteoblastic activity, which might be a more rea-
sonable target.26
Initially systolic LV function is maintained, while di-
astolic dysfunction is established early on. In advanced
stages of myocyte apoptosis and replacement fibrosis sys-
tolic LV function is also affected with worsening symp-
toms of heart failure.27 - 30 A correlation between fibro-
sis and EF and LVEDP has been found. In cases with ad-
vanced myocardial fibrosis aortic valve replacement was
not associated with LV systolic function recovery.17 , 31 , 32
Furthermore, fibrosis is one of the structural substrates
of arrhythmogenicity with a potential role in cases of sud-
den death observed in patients with AS.33
The above relationships have been initially studied by
examining myocardial biopsies in patients undergoing

68 Pavlides, Chatzizisis, and Porter
SAVR for significant AS. In this context, the fibrosis data
provided more important information than simple hemo-
dynamics on patient outcomes after SAVR.32 At the aor-
tic valve and vascular level, collagen deposition is also
part of the initial phase of sclerosis, which is mediated
by lipid deposition and inflammatory cells. This is fol-
lowed by a “propagation phase” in which osteoblast-like
cells dominate, leading to progressive calcium deposi-
tion. This propagation phase of valve calcification is me-
diated by several pathways, which unlike skeletal bone,
is not regulated, resulting in a dominant pro-osteoblastic
effect of nuclear factor kappa beta ligand on myofibrob-
lasts and smooth muscle cells.34
Left Ventricular Remodeling Assessment
and Clinical Significance
Myocardial biopsy remains the gold standard for de-
tecting myocardial fibrosis. In patients undergoing SAVR,
myocardial biopsy has been correlated with non-invasive
echocardiographic and Doppler indexes, as well as Car-
diac Magnetic Resonance (CMR) detection of fibrosis.35
Additionally, circulating biomarkers have been tested, in
relation to LV remodeling and patient outcomes in AS.
The obvious advantage of the non-invasive markers of LV
remodeling is that they can be applied in patients with
hemodynamically less severe forms of AS, where earlier
detection of LV remodeling could lead to a change in
their management, with either a closer follow-up, or ear-
lier valve intervention by SAVR or TAVR.
Echocardiography
Echocardiography is the most available and widely
used modality for assessment of LV remodeling. Several
parameters of the traditional measurements in AS should
be analyzed and interpreted carefully, since a better un-
derstanding of the myocardial consequences of the in-
creased afterload is paramount to optimize timing of
percutaneous or surgical intervention. It is well known
that Doppler- and catheter-derived gradients and effec-
tive orifice area are not always comparable. The values
used to define severe AS are derived from outcome stud-
ies using catheterization, whereas the guidelines recom-
mend echocardiography to evaluate AS severity. Doppler
echocardiography measures pressure gradients from the
maximal velocity measured at the vena contracta, be-
fore pressure recovery, whereas catheterization mea-
sures pressure gradients derived from actual recovery
pressure measurements. Gradients obtained by catheter-
ization are typically lower than Doppler-gradients be-
cause of pressure recovery, with Effective Orifice Area
(EOA) by catheter derived measurements typically larger
than EOA-echo. Pressure recovery is determined by the
relationship between the size of the cross-sectional area
of the vena contracta and the area of the ascending aorta,
and it is significant in small aortic roots (<3.0 cm). It
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American Heart Journal
Month 2022
is estimated that 25% to 50% of patients having severe
AS by indexed aortic valve area, based on Doppler-echo
measurements, are reclassified to non-severe AS when
pressure recovery is taken into account.36 , 37 This could
mean that a good number of patients referred for AVR
or TAVR have moderate AS by invasive hemodynamic cri-
teria. The traditional LVEF assessment may be problem-
atic in AS, due to adverse concentric remodeling. The
guideline recommended cut-off point of 50% EF may not
predict outcomes, since it has been shown repeatedly in
recent years that post-AVR prognosis is worse when LVEF
is less than 60%.38 The above limitations underscore the
importance of looking in LV remodeling as an integral
part of the echocardiographic AS severity assessment.
Echocardiographic parameters in assessing myocardial
remodeling, in addition to traditional EF, LV volumes,
LVH and AV gradients in AS, include tissue Doppler imag-
ing (TDI) assessment of the diastolic mitral annular dis-
placement and strain rate imaging.39 Strain is a measure-
ment of dimensional or deformation change during a car-
diac cycle. The most widely technique used to quantify
myocardial strain in clinical practice is speckle-tracking
echocardiography, a well-established technique.40 Stud-
ies have shown reduced myocardial strain and strain rate
in patients with AS, even with preserved EF. An associa-
tion was also found with increasing AS severity and im-
pairment in strain.41 Global longitudinal strain (GLS) by
speckle tracking has been found to be a strong, indepen-
dent predictor of all-cause mortality,42 as well as an in-
dependent predictor of outcome in patients with severe
asymptomatic AS.43 , 44 Significant inter-vendor variability
exists for GLS, but a value more positive than -14% is very
likely indicative of LV dysfunction. It appears that despite
unchanged LVEF, GLS gradually decreases as severity of
AS increases. In a group of 113 patients with AS and nor-
mal LVEF, GLS was measured from -17% in mild, to -16%
in moderate, to -14% in severe AS.45 So, in this contex
GLS reflects the progression of severity of AS, despite the
preserved LVEF.
A seminal myocardial biopsy-based study found an in-
verse relationship of the degree of fibrosis with longitu-
dinal strain, strain rate and mitral annular displacement.
In the trial, mitral annular displacement was significantly
decreased, while NT-proBNP and procollagen type III
amino-terminal pro-peptide were significantly higher in
patients with severe fibrosis. Patients with severe fibro-
sis did not differ in terms of aortic valve area and EF from
patients with mild or no fibrosis. Nine months after AVR
the patients with severe fibrosis had no improvement or
deteriorated in NYHA Class compared to patients with
mild or no fibrosis who invariably improved. Mitral an-
nular displacement predicted improved NYHA Class after
SAVR.31 In another trial, the baseline mitral annular dis-
placement was found predictive of LV diastolic function
improvement after TAVR.46 In a similar surgical biopsy-
based study, long-term prognosis was also found to be as-
American Heart Journal
Volume 254
sociated to the degree of fibrosis at the time of surgery.32
Another consistent observation, even in moderate aortic
stenosis, is the adverse outcome associated with abnor-
mal strain, independent of aortic valve replacement.47 It
appears from all the existing data that the global LV lon-
gitudinal strain change reflects to an extend the degree
of myocardial fibrosis in AS.
As it has been mentioned earlier, diastolic LV dysfunc-
tion (DD) is established early in AS. Although advanc-
ing DD is associated with worse post-operative outcome,
this is not considered in updated guidelines for tim-
ing of intervention. The echocardiographic diagnosis of
DD relies on indirect signs of elevated left ventricular
end diastolic pressure (LVEDP), including impaired relax-
ation (expressed as E/A and E/e’), pulmonary hyperten-
sion and left atrial dilatation.48 Left atrial (LA) dilatation
may be the best surrogate marker of chronically elevated
LVEDP, in absence of significant mitral regurgitation or
atrial fibrillation. LA strain is a relatively novel marker of
LA dysfunction, which provides additive information to
LA morphology only. Decreased LA strain is a predictor
of adverse outcomes in asymptomatic AS patients and a
useful predictor of post-operative atrial fibrillation.
Stress echocardiography plays an important role in spe-
cific clinical scenarios. In evaluating patients with mod-
erate aortic stenosis, an increase in valve gradient with-
out a change in functional valve area suggests severe
aortic stenosis.49 In addition, to detecting contractile re-
serve, stress echocardiography with dobutamine plays a
vital role in ruling out pseudo-severe aortic stenosis (with
normal or abnormal LVEF), by permitting the assessment
of EOA at valvular flow rates >200 ml/sec.50
Cardiac Magnetic Resonance Imaging (CMR)
CMR has emerged as the method of choice in assess-
ing LV mass, volume, function and myocardial fibrosis
in patients with AS. CMR late gadolinium enhancement
(LGE) imaging has been proven a very accurate way
to assess replacement myocardial fibrosis and scaring.51
CMR assessment of myocardial fibrosis and its distribu-
tion in patients with AS has been examined in several
studies.31 , 52 , 53 These studies confirmed the correlation
between myocardial fibrosis measured by histopathology
and by LGE, as well as the inverse relationship of the
degree of fibrosis with LV functional improvement after
SAVR.54 The prognostic significance of mid-wall replace-
ment fibrosis was assessed in patients with hemodynami-
cally moderate or severe AS. In a follow up 2.0±1.4 years
patients with mid-wall fibrosis had an 8-fold increase in
all-cause mortality, compared to patients with no such fi-
brosis, despite similar AS severity and CAD burden. This
mortality difference was partially attributed to arrhyth-
mic cardiac death.55 These and other investigators have
proposed a clinical risk score of myocardial fibrosis, in-
corporating age, sex, Vmax, high-sensitivity troponin and
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Pavlides, Chatzizisis, and Porter 69
ECG strain pattern, which predicted adverse clinical out-
comes.56
In addition to LGE, T1 mapping has emerged as a bet-
ter marker for the presence of diffuse myocardial fibrosis.
This technique detects diffuse interstitial fibrosis and is
associated with increased collagen content and increased
myocardial extracellular volume (ECV) fraction. Native
T1 values have been shown to be greater in patients with
severe asymptomatic AS, with a good correlation to histo-
logically confirmed fibrosis.57 More recent data has indi-
cated that ECV fraction is better than native T1 mapping
in predicting outcome, with ECV values of >30% being
an independent predictor of outcome in hemodynami-
cally severe aortic stenosis patients undergoing valve re-
placement.58 ECV measurements require gadolinium and
hematocrit measurements but may provide more robust
and vendor-independent measurements of replacement
fibrosis than native T1 mapping.
In a recent multicenter trial for discovery and rank-
ing of prognostically important CMR markers in patients
with AS undergoing AVR, the machine learning tech-
nique with random survival forest was utilized. Twenty-
nine variables, including 13 CMR, were utilized. The re-
sults demonstrated the powerful prognostic information
of myocardial fibrosis and biventricular remodeling mark-
ers by CMR, with the four most predictable CMR mark-
ers for mortality being ECV%, LGE%, LVEDV and RVEF.59
This was one of the few studies to emphasize the impor-
tance of right ventricular (RV) function in AS. While the
value of pulmonary hypertension as a predictor of out-
come has been confirmed in AS, the prognostic impact
of RV dysfunction has only recently been demonstrated.
Generaux et al. in a classification of extra valvular cardiac
damage in severe AS they proposed, stated that patients
with RV dysfunction (stage 4 in their classification) had
the worse prognosis.60 In a CMR study, RV dysfunction
defined as RVEF≤ 50% by CMR, was reported present in
25% of patients undergoing TAVR, and this was an inde-
pendent predictor of long-term mortality.61 Similar data
for RV dysfunction have been reported by using the in-
expensive method of tricuspid annular plane systolic ex-
cursion (TAPSE), by echocardiography.62
Electrocardiography
The old-honored 12 lead electrocardiogram (ECG) ap-
pears to be a valuable tool, reflecting LV remodeling.
Shah et al. reported the association of an ECG strain pat-
tern with CMR midwall fibrosis in a cohort of 102 pa-
tients with severe AS. All patients with ECG strain pattern
had midwall late gadolinium enhancement (positive and
negative predictive values 100% and 86% respectively).
In the outcome cohort, ECG strain was an independent
predictor of AVR or cardiovascular death (h 2.67, ci 1.35-
5.27; P < .01).63

70 Pavlides, Chatzizisis, and Porter
Biomarkers
Biomarkers such as NT-proBNP or BNP have been ex-
amined in AS. New biomarkers such as soluble ST2 (sup-
pression of tumorigenicity-2), galectin-3 (Gal-3), micro-
RNAs and growth differentiation factor 15 (GDF-15) ap-
pear promising.64 Additionally, the role of high sensitivity
troponin I (hsTnI) has been investigated in asymptomatic
patients with severe AS.65 The natriuretic peptides and
GDF-15 are wall stress-related factors, while ST2, Gal-3
and microRNAs are mostly associated with myocardial
hypertrophy and fibrosis. BNP levels in patients with AS
are associated with disease severity, symptoms and out-
come.66 Since levels of both BNP and NT-proBNP are
increased with aging, a baseline level preferably in the
asymptomatic phase of aortic stenosis can be very useful
in assessing and following these patients. BNP and NT-
pro-BNP in general are in concordance with symptoms
in AS, although many asymptomatic patients have high
levels of these biomarkers, and this has prognostic signif-
icance.66 - 68 In a cohort of 387 asymptomatic adults with
severe AS, elevated BNP levels were associated with an
increased 5 year risk of AS-related events, with hazard ra-
tio for a BNP level >300 pg/ml (3 times normal) of 7.38
(CI: 3.21-16.9).69 In patients with low-flow, low-gradient,
low EF AS, BNP levels were found to be higher in true-
severe AS versus pseudo-severe AS. In an outcomes study
(TOPAS), 1 year survival was predicted by BNP levels.70
BNP levels appear to respond favorably after intervention
in severe AS with decreasing levels after SAVR or TAVR.
Failure to respond predicted unfavorable outcome, ei-
ther reflecting prosthesis-patient mismatch or baseline fi-
brosis,71 , 72 or that other important factors, other than
valve obstruction (eg, underlying cardiomyopathy, vas-
cular stiffness, and calcification) were playing a role in
pathogenesis and outcome of these patients.
There is a substantial amount of data correlating BNP
and NT-proBNP levels with myocardial fibrosis, either
confirmed by biopsy during surgery and CMR, or re-
flected by 2D Echo/Doppler indices.31 A good relation-
ship has been reported with mitral annular displace-
ment, speckle tracking strain, impaired longitudinal sys-
tolic strain and peak stroke index.73 A risk score derived
from peak aortic velocity and BNP has been proposed for
asymptomatic AS patients.74
In the largest community study, addressing the signif-
icance of BNP in patients with moderate or severe AS,
a strong association was found between BNP and out-
comes in these patients. In a large cohort of 1,953 pa-
tients, including a group of 565 patients with asymp-
tomatic isolated AS, the investigators found in 3.8 years
of follow-up that BNP levels were predictive of survival.
Furthermore, they found that BNP clinical activation
combined with the level of BNP elevation, as a multiple
of normal for age values, was a quantitative determinant
of survival.75
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American Heart Journal
Month 2022
Both, 2020 AHA/ACC2 and 2017 ESC/EACTS76 guide-
lines indicate that valve replacement is reasonable
(Class IIa) in asymptomatic patients with a markedly
elevated natriuretic peptide level, defined as 3-fold
elevation of the corrected for age and sex normal
value.
The biomarkers soluble ST2 and Galectin-3 have been
approved by FDA for heart failure. Unlike natriuretic pep-
tides, they are biomarkers of myocardial stress and fibro-
sis.77 , 78 ST2 is a member of the interleukin-1 receptor
family and exists in 2 forms, a transmembrane recep-
tor (ST2L) as well as a soluble decoy receptor (sST2).
Excess sST2 is associated with cardiac fibrosis and ven-
tricular dysfunction. Mean normal values for males are
24.9 ng/ml and females 16.9 ng/ml. The current cut-off
level for a favorable outcome in heart failure is 35 ng/ml.
A similar cut-off value (31 ng/ml) was predictive of all-
cause mortality for patients undergoing AVR.79 Gal-3 is a
soluble beta-galactosidase-binding glycoprotein released
by activated cardiac macrophages and is reflective of on-
going fibrosis and cardiac remodeling. Both, in heart fail-
ure seem to be predictive of outcome in addition to BNP
or NT-pro-BNP. As biomarkers of fibrosis, they are promis-
ing for patients with AS. Recently Gal-3 was found pre-
dictive of the outcome of patients undergoing TAVR.80
In a recent prospective registry, three biomarkers (GDF
15, sST2, and NT pro-BNP) were associated with prog-
nosis in a group of 345 patients with AS, treated with
SAVR. It was found that the number of elevated biomark-
ers provided an STS category-free net reclassification of
mortality prognosis.81
The use of several biomarkers in clusters, in order
to improve their diagnostic value, has been utilized by
several investigators. Lindman et al. have evaluated 7
biomarkers (Troponin T, human epididymis protein, can-
cer antigen 125, GDF 15, NT-Pro-BNP, CRP, and sST-
2). They found that there was an incremental increase
in mortality as the number of positive biomarkers in-
creased, from 0-1, 4-6 to 7.82 The machine learning tech-
nique was recently utilized to assess 49 biomarkers, in
order to identify multimarker profiles associated with the
risk of death and death or heart failure hospital admis-
sions, in patients with AS, ranging from mild to severe.
They found that multimaker biomarker profiles were
strongly associated with outcomes. The association was
particularly strong between biomarkers related to extra-
cellular matrix remodeling and fibrosis.83
Valvular Remodeling Assessment and
Clinical Significance
Since the advent of AVC scoring by gated CT imag-
ing, a large body of data has demonstrated the predic-
tive value of AVC content in defining both disease sever-
ity and disease progression and outcome.84-86 The previ-
ously described collagen deposition that leads to myocar-
dial replacement fibrosis is also an important mediator
American Heart Journal
Volume 254
leading to calcium deposition in the aortic valve.85 Calci-
fication of the aortic valve, even in the absence of hemo-
dynamic AS, is associated with increased adverse events.
However, there is limited data on the potential for serial
AVC CT scoring to guide management of patients with
AS, despite existing data of AVC scoring in predicting
outcome in patients with hemodynamically discrepant
AS. Outcome is significantly worse in patients with the
highest AVC scores, and a linear relationship has been
demonstrated between AVC score and outcome follow-
ing TAVR.87 There is limited emerging data in patients
with moderate AS that gender differences in the rate of
calcification progression exist despite no difference in
hemodynamic progression.88
18F fluoride positron emission tomography in these pa-
tients has indicated a more rapid calcification process
in males that is not detected on hemodynamic measure-
ments. It is possible that pharmacologic interventions
(eg, more aggressive blood pressure control) may be
most effective during this “active calcification” period.
The PROGRESSA study found that AVC score progression
in patients with aortic stenosis was linked to systolic hy-
pertension.89 Since the AVC scoring technique requires
minimal radiation (<1 mSV) and does not require con-
trast, it is an ideal method of assessing the degree of
valvular remodeling and rate of progression, once hemo-
dynamically moderate AS has been identified. An AVC
score higher than 1,300 AU in women or 2,000 AU in
men should be considered severe.86 It also permits as-
sessment of vascular calcification in the aorta and major
blood vessels, which may play a role in systolic blood
pressure and baseline valvuloarterial impedance.90 On a
technical note, it is vital that only aortic valve and annular
calcification be included in the measurements to ensure
serial changes in AVC scoring are valid.84
Ongoing Clinical Trials Assessing
Biomarkers and LV Remodeling
Two prospective randomized trials have been address-
ing biomarkers and LV remodeling in AS. The EARLY
TAVR trial will enroll 1,109 patients, older than 65 years
of age, with severe asymptomatic AS. The study includes
a pre-defined biomarker sub-study, to evaluate the poten-
tial benefit of a biomarker-driven early intervention strat-
egy. The EVOLVED trial will involve severe asymptomatic
AS patients who will be screened initially by hsTnI and
ECG. Patients with elevated hsTnI levels and a strain pat-
tern in ECG will undergo CMR. Patients with mid-wall
fibrosis will be randomized to early TAVR or SAVR versus
a standard watchful waiting approach. The importance
of AVC score (or serial measurements of AVC score) is
not currently being evaluated in prospective randomized
studies.
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Pavlides, Chatzizisis, and Porter 71
Clinical decision making in patients
with AS, by integrating hemodynamics
and LV/Valvular Remodeling
A dedicated Heart Team is essential to optimally man-
age AS patients. In many patients with symptomatic se-
vere AS, the decision to intervene is straightforward.
However, in many patients with asymptomatic severe AS
or several cases of moderate AS, the decision to wait
or address interventional treatment remains a challenge.
Once hemodynamically moderate or severe AS is identi-
fied, we believe that by integrating increasingly emerging
data of LV/valvular remodeling, the following sequential
steps will improve our current decision making for the
appropriate treatment.
First, in patients whose symptomatic status remains un-
clear, an exercise stress test, with or without Doppler
echocardiography, should be considered. The percent-
age of patients who can undergo such a test remains un-
clear. In a recent comprehensive review, it was stated
that the majority of the patients with severe asymp-
tomatic AS can undergo some form of a stress test, with
only 20% unable to perform it.91 However, data for the
Euro Heart Survey on valvular heart disease recorded
that only 5.7% of asymptomatic patients with severe AS
underwent exercise testing, which indicates that exer-
cise test in real life was underutilized.92 In the recent
2020 ACC/AHA Guidelines for the management of valvu-
lar heart disease, the indication for exercise stress test
in asymptomatic patients with severe AS was upgraded
to 2a. On the technical part, when the test is not com-
bined with imaging, a modified Bruce treadmill test is
preferred. When imaging is performed, either a tread-
mill or a bicycle test is performed. When symptoms are
provoked by exercise testing, the patient is considered
symptomatic. Intervention is also favored when a fall of
≥ 10 mm Hg in systolic blood pressure is provoked by ex-
ercise. Up to about one third of asymptomatic patients
with severe AS who undergo an exercise stress test are
re-classified as symptomatic.93
All patients who are found by standard echocardiog-
raphy of having progressive moderate (stage B progres-
sive hemodynamic obstruction with AV velocity 3.0-3.9
m/sec or mean pressure gradient 20-39 mm Hg) or se-
vere asymptomatic AS should be assessed further for LV,
as well as for valvular remodeling. Biomarker measure-
ments, including BNP, NT pro-BNP, Gal-3 and sST2 and
GDF 15 and hsTnI can be measured, as a first step. An
ECG strain pattern should be sought and recorded.
Advanced echocardiographic techniques should be ap-
plied during the baseline and follow up echocardiogra-
phy studies, including transvalvular flow rate, TDI mi-
tral annular displacement, and global longitudinal my-
ocardial strain and strain rate measurements. Refinement
of hemodynamic assessments by measuring transvalvular
flow rate has recently been shown to provide incremen-
 American Heart Journal
72 Pavlides, Chatzizisis, and Porter
Month 2022

Figure 2

Heart Team, hemodynamic and LV/AV remodeling approach of patients with aortic stenosis, for a timelier interventional strategy in otherwise
moderate or severe asymptomatic AS.

tal prognostic data.94 - 96 This first stage approach does
not increase the cost of AS work up and allows for a pre-
cise selection of patients who might need further remod-
eling assessment (Figure 2).
In the group with clear biomarker elevation and evi-
dence of abnormal global longitudinal strain by echocar-
diography or profound ECG strain changes, CMR and
AVC scoring should be considered. In CMR both LGE
and T1 mapping should be obtained, especially in pa-
tients with diastolic LV dysfunction and low gradi-
ent, low flow, normal EF AS. Non-severe AVC scores
(<1,200 in women and <2,000 Agatston units in men)
could identify patients that, in the absence of fibro-
sis, may respond better to aggressive medical therapy
designed at lowering valvuloarterial impedance instead
of SAVR or TAVR.97 Conversely, AVC scores at very
high values (>2,500 AU) and/or extensive LV fibro-
sis by CMR, may indicate patients with advanced re-
modeling unlikely to benefit from intervention. How-
ever, the Heart Team might still recommend TAVR
or SAVR in this group of patients, since we cur-
rently lack accurate criteria of intervention futility,
not an uncommon question in patients referred for
TAVR.
All other patients with mid-wall fibrosis and/or high
AVC score, who are at high risk for progression of mal-

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American Heart Journal
Volume 254
adaptive LV remodeling and heart failure, should be con-
sidered for AV intervention, either TAVR or SAVR by the
Heart Team. Risks and benefits of intervention should be
considered carefully at this time, taking into account the
assumed prognosis reflected by the documented LV and
valvular remodeling.
The issue of the cost should of course be considered.
Although, this is not an approach to be followed in all
patients with significant aortic valve stenosis, when it is
applied, it will increase the cost of the patient’s work
up. The initial steps of detailed echocardiography and
biomarker detection add little to the cost. AVC scoring
by CT is not an expensive method either, with an ad-
ditional cost of around <$ 400. The single step that in-
creases the cost significantly is the CMR, which on aver-
age costs around $ 3,000. However, since this at a later
stage in this stepwise approach, a number of patients
will have already been selected for Heart Team assess-
ment, so CMR might not be necessary for all patients.
For those cases where CMR may lead to a potential ben-
efit of an earlier intervention, the additional cost may be
justified. It should be stressed again though, that this
approach still awaits definite clinical proof. Therefore,
there is clearly a need for future studies to evaluate this
combined anatomic and hemodynamic approach to the
management of aortic stenosis.
Conclusions
Although, traditionally hemodynamic assessment of pa-
tients with aortic stenosis has been utilized for assess-
ing the severity and guiding decision making for inter-
ventional treatment, hemodynamics and symptoms alone
frequently fail to select patients who will benefit from
SAVR or TAVR. Ample data support that left ventricu-
lar and valvular/vascular remodeling provide indepen-
dent prognostic information in AS. Novel biomarkers and
targeted imaging techniques focusing on left ventricular
and aortic valve remodeling may permit the detection of
patients who may benefit from valve replacement at a
more reversible state. A Heart Team approach, incorpo-
rating remodeling indices to hemodynamics can greatly
improve our approach to patients with AS.
Disclosures
Dr. Pavlides, no disclosures. Dr. Chatzizisis has received
speaker honoraria, advisory board fees and research
grant from Boston Scientific Inc. and research grant from
Medtronic Inc. Dr. Porter has research support from Lan-
theus Medical, for Research Equipment Support Philips
Health Care and a Speaker- Northwest Imaging Forums.
Funding
No extramural funding was used to support this work.
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2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
Pavlides, Chatzizisis, and Porter 73
Author’s Statement
The authors are solely responsible for the design and
conduct of this study, all study analyses, the drafting and
editing of the paper and its final content.
CRediT authorship contribution
statement
Gregory S. Pavlides: Conceptualization, Data cura-
tion, Formal analysis, Methodology, Supervision, Writing
– original draft, Writing – review & editing. Yannis S.
Chatzizisis: Data curation, Validation, Writing – review
& editing. Thomas R. Porter: Data curation, Formal
analysis, Validation, Writing – review & editing.
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