Keywords
aortic valve replacement - cardiac surgery - hemodynamic evaluation - echocardiography
- flow velocity - pressure gradient
Introduction
Aortic valve replacement (AVR) is the therapy of choice for aortic valve stenosis.
Surgical success depends on a significant reduction of transvalvular gradients. Valve
gradients are assessed most commonly with echocardiographic measurement of flow velocity
and use of the modified Bernoulli's equation to derive the pressure gradient. Another
way to assess the hemodynamic performance of a valve is deriving the effective orifice
area (EOA), representing the smallest cross-sectional area of the transprosthetic
jet flow. EOA is measured by Doppler's echocardiography using flow velocity and the
area of the left ventricular outflow tract (LVOT; [Fig. 1]). Both pressure gradient and EOA are standards for determining hemodynamic outcome
after AVR. If gradients are too high or the EOA is too low, a mismatch between prosthesis
and patient may occur.[1] Prosthesis-patient mismatch (PPM) has been the subject of interest and controversy
for over 35 years and has regained interest with the advent of transcatheter aortic
valve replacement,[2] specifically in the context of patients with the option of valve-in-valve procedures.[3]
Fig. 1 Principle of echocardiographic determination of the effective orifice area (EOA)
through the continuity equation. A1 is the area of flow at the left ventricular outflow
tract, A2 is the area of flow at the vena contracta (EOA). D is the distance the fluid
advances during a given time (t). V is the velocity of the fluid. The advance in fluid
volume (A × D) is the same at the two different points, therefore A1 × D1 = A2 × D2.
A2 is the EOA. EOA, effective orifice area.
By definition, PPM is present when the opening of the inserted prosthetic valve is
smaller than that of the patient's normal, native valve.[1] Its main hemodynamic consequence is the development of elevated pressure gradients
through an otherwise normally functioning prosthetic valve. If significant, PPM may
be detrimental and dampen the benefits of AVR and possibly lead to an unfavorable
clinical outcome. To date, the indexed EOA (EOAi), that is, the EOA divided by the
patient's body surface area, is used frequently to quantify PPM.[4]
[5] Most studies comply with the classification that an EOAi ≤ 0.65 cm2/m2 represents severe, 0.65 to 0.85 cm2/m2 moderate, and > 0.85 cm2/m2 reflects insignificant PPM.[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] Unfortunately, this classification has not achieved a consensus among published
studies addressing the impact of PPM on postoperative survival, resulting in ongoing
controversy regarding the clinical importance of PPM. We have reviewed the literature
on this topic and have identified potential shortcomings in the assessment of PPM
that may shed some light on the inconsistent relationship between PPM and survival.
Methods
Search Strategy
The PubMed database was systematically searched in June 2016 to identify published
full-length English studies reporting outcome of patients after AVR, stratified by
the presence of PPM and/or measurements of EOA and pressure gradients. No year of
publication exclusion was implied. Studies were identified by a search using the following
key words in all fields: “mismatch OR PPM,” “AVR OR aortic valve replacement” and
“Aortic valve hemodynamics.”
Study Inclusion
The title and abstract of studies identified by the search were independently screened
using the following four criteria: (1) the publication was an original full-article
contribution in a peer-reviewed journal; (2) patients were adults; (3) patients had
undergone AVR with a bioprosthetic valve; and (4) either PPM was assessed or EOA and
pressure gradients were measured. For studies those met all these criteria, or in
case of uncertainty, the full texts were further evaluated. Studies were separated
between those that measured EOA as well as pressure gradients and those that addressed
the impact of PPM on outcome.
Methodology for EOA, EOAi and Pressure Gradient Determination
In the selected studies, we assessed which tools were used to assess PPM, EOA, EOAi,
and pressure gradients. The determination for PPM cut-off values was not uniform and
is described elsewhere in the text. All studies addressing PPM used EAO related to
body surface area (EOAi). We used the following terminology for reporting EOAs. Measured
EOA: assessment of the effective opening area (i.e., the vena contracta area) by continuity
equation using velocity time integrals of the preprosthetic flow determined in the
left ventricular outflow tract (LVOT) and of the transprosthetic flow. The measured
EOA is a patient-specific parameter which considers the geometry of LVOT as well as
of the prosthesis itself.
Projected EOA: EOA-value for a given valve size published by another study or an industry-generated
EAO chart. All presented pressure gradients were obtained in the studies based on
the modified Bernoulli's equation (see specifically [Supplementary Table S1], available in online version only).
Statistical Analysis
For the statistical evaluation of the relation between pressure gradients and Effective
orifice area, we applied random-effects meta-regression to account for heterogeneity
between the studies and investigated the association of mean pressure gradients and
EOA by considering a linear, quadratic, cubic, inverse, as well as logarithmic relationship
between EOA and pressure gradients, using SAS 9.4 for Windows, Cary, NC, USA. Here,
metaregression is similar in essence to simple regression, in which the mean pressure
gradient as the dependent variable is modeled by EOA as the only covariate. The difference
to simple regression is that the dependent variable is an effect estimate in the studies
included for the analysis rather than individual observations and that the covariate
information are characteristics of the studies. Thus, to account for different study
sizes and since larger studies have more influence on the considered relationship
than smaller studies, studies are weighted by the precision of their respective effect
estimate in applying metaregression. Incorporating a so called random effect in the
metaregression model, we allow that the true effect estimates may vary between different
studies which is not explained by the covariate (residual heterogeneity).
Results
Of the 76 analyzed studies, 48 assessed the association between PPM and mortality.
All of them are listed in [Table 1]. Reports were highly discrepant. Of the 48 studies, 25 demonstrated an impact on
survival (in three reports, presence of PPM was associated with age or LV function).
Regarding the source of the data in these publications, only 11 studies determined
patient-specific values for EOA (six studies with and five without a relevant association
between PPM and survival), whereas the vast majority (approximately 77%) used a projected
EOA (i.e., an EOA value for a given valve size published by another study or an industry-generated
EOA chart). [Fig. 2] schematically illustrates the influence of the LVOT dimension on the EOA for a given
tissue valve. If a given valve is implanted into a patient with larger anatomic dimensions
(panel A), the EOA becomes smaller than the actual opening of the tissue valve (i.e.,
the geometric opening area [GOA]). This effect is related to flow convergence and
reflects a principle of fluid dynamics.[17]
[18] If the same valve is implanted into a patient with smaller LVOT dimensions (Panel
B), EOA and GOA become similar to each other and possibly even converge. Thus, the
same valve may result in different EOAs depending on the size of the annulus/LVOT
dimensions. This recognition also means that using a projected EOA cannot take interindividual
differences into account for assessing the impact of PPM on outcome in actual patients.
Fig. 2 Schematic illustration of two identical bioprosthetic valves implanted into two anatomically
different aortic roots. Note that the effective orifice area (EOA; red circle) is
smaller than the geometric opening area (GOA, green circle) in panel (A) and equal
to the GOA in panel (B). Thus, two identical valves deliver two different hemodynamic
outcomes depending on the patients' anatomic dimensions.
Table 1
Studies assessing the relevance of PPM on mortality using measured or projected EOA
PPM relevant
|
EOA
|
PPM not relevant
|
EOA
|
Rao et al 2000
|
Projected
|
Pibarot et al 1996
|
Projected
|
Pibarot et al 2001
|
Measured
|
Moon et al 2006[a]
|
Projected
|
Blais et al 2003
|
Measured
|
Flameng et al 2006
|
Measured
|
Ennker et al 2005
|
Projected
|
Monin et al 2007
|
Projected
|
Walther et al 2006
|
Projected
|
Ryomoto et al 2008
|
Projected
|
Tasca et al 2006
|
Projected
|
Florath et al 2008
|
Projected
|
Moon et al 2006[a]
|
Projected
|
Mascherbauer et al 2008
|
Projected
|
Ruel et al 2006
|
Projected
|
Moon et al 2009[a]
|
Projected
|
Kulik et al 2006
|
Projected
|
Mohty et al 2009[b]
|
Projected
|
Yap et al 2007
|
Projected
|
Nozohoor et al 2008
|
Measured
|
Kato et al 2007
|
Projected
|
Vicchio et al 2008
|
Measured
|
Fuster et al 2007
|
Projected
|
Kato et al 2008
|
Projected
|
Kohsaka et al 2008
|
Projected
|
Urso et al 2009
|
Projected
|
Moon et al 2009[a]
|
Projected
|
Price et al 2009
|
Projected
|
Mohty et al 2009[b]
|
Projected
|
Jamieson et al 2010
|
Projected
|
Bleiziffer et al 2010
|
Measured
|
Cotoni et al 2011
|
Projected
|
Head et al 2012[c]
|
Measured
|
Jeong et al 2013
|
Measured
|
Hong et al 2012
|
Projected
|
Concistrè et al 2013
|
Projected
|
Hernández-Vaquero et al 2012
|
Projected
|
Kitamura et al 2013
|
Projected
|
Hong et al 2013
|
Measured
|
Koene et al 2013
|
Projected
|
Urso et al 2014
|
Projected
|
Dayan et al 2015[d]
|
Projected
|
Pibarot et al 2014
|
Measured
|
Sportelli et al 2016
|
Measured
|
Iosifescu et al 2014
|
Projected
|
Joshi et al 2016
|
Projected
|
Shahzeb et al 2014
|
Projected
|
|
|
Une et al 2015
|
Projected
|
|
|
Abbreviations: EOA, effective orifice area; LV, left ventricle; PPM, prosthesis-patient
mismatch.
a Authors reported impact of PPM was age dependent.
b Authors reported impact of PPM only on decreased LV-function.
c Largest systematic review and meta-analysis.
d PPM was not found to be associated with adverse outcome, after adjusting for confounders.
We therefore searched for additional studies that measured EOA as well as pressure
gradients after AVR. Based on the study-specific summary data about pressure gradients
and EOA, we performed a metaregression to gain insight into the association of measured
gradients and EOAs. In total, 28 studies,[11]
[13]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44] ([Supplementary Table 1]; supplementary table is available in online version only) were found with information
about mean EOA and mean pressure gradients. The results are presented in [Fig. 3] together with I
2 as a measure between study heterogeneity, that is, heterogeneity not explained by
the covariates in the regression. The numbers represent the size label of the prosthesis
while the size of the circle corresponds with the size of the sample. Note that, all
measured values report EOAs greater than 1 cm2 which is considerably different from most values obtained for the assessment of aortic
valves stenosis (severe < 1 cm2). As a result, the relationship of EOA to pressure gradients may not immediately
appear logarithmic as expected. In contrast, all five statistical approaches considered
in the analysis showed a highly significant association between pressure gradients
and EOA with high I
2 for each (p < 0.0001). In other words, the relationship between pressure gradients and EAO after
biological valve replacement may also be considered linear (it is important to again
emphasize, that this consideration can only be made for the EOA range above 1 cm2). Based on this finding, it is interesting to note that many studies relate EOA to
body surface area (BSA) but none relates pressure gradients to BSA.
Fig. 3 Postoperative mean pressure gradients as a function of the effective orifice area
(EOA) after bioprothetic aortic valve replacement taken from publications reporting
both values for the same patients (Epic,[30] Epic Supra,[33]
[41] Mosaic,[24]
[27]
[28]
[31]
[38]
[39]
[44] Perimount,[19]
[20]
[21]
[23]
[25]
[28]
[30]
[35]
[39]
[42] Magna,[20]
[23]
[24]
[27]
[41] Sorin Mitroflow,[23]
[29]
[43]
[48]
[49] and Trifecta[22]
[26]
[27]
[32]
[34]
[37]
[40]
[43]). The numbers represent the size label of the prosthesis and the size of the circle
corresponds with the size of the sample. The lines represent the fitting of the values
to different mathematical functions (quadratic, cubic, inverse, as well as linear
and logarithmic). Note that almost all published EOA values are larger than 1 cm2 and that all mathematical functions obtain a highly significant regression coefficient
(p < 0.0001). See text for further details.
Discussion
We demonstrate in this study that the majority of studies assessing PPM have used
false assumptions because EOA is a patient-specific parameter and cannot be transferred
to other patients. In addition, the use of EOAi to assess PPM may not be appropriate
and could explain the inconsistent relation between PPM and survival in previous studies.
There has been much controversy in the published literature about the impact of PPM
on postoperative outcomes. Differences in the classification of PPM have been pointed
out as a possible explanation for these conflicting findings regarding its impact
on survival.[10]
[45] However, the divergence persists even when evaluating studies using the same classification
as suggested by Blais et al in 2003.[5] Another explanation for the different opinions regarding PPM and survival may rely
on the fact that indexing EOA for body surface area can be misleading. The rationale
for using this parameter is that pressure gradients are essentially determined by
the valve opening area and transvalvular flow which in turn are largely related to
cardiac output requirements which may alter according to individual body size. Although
the use of EOAi is believed to account for these differences in physical constitution,
it relates a measure of flow velocity to individual parameters twice (i.e., LVOT area
and BSA), since both may vary according to body size. While EOAi may appropriately
account for different cardiac output requirements in “normal” patients (based on the
rationale that a mouse needs less valve opening than an elephant), this assumption
may be flawed in humans with obesity or those who are tall and thin. As illustrated
in [Fig. 3], a linear relationship can be found between the EOA values and mean pressure gradients
in patients after AVR. In addition to this finding, there is a high variability of
MPG among the studies for similar EOAs ([Fig. 3]). Therefore, despite speculation that the indexation of EOA may account for differences
in patient size and values move in a linear manner. Considering this “linearity” of
the direct EOA measurements and pressure gradients, the relation of EOA to body surface
area and hence the need to index EOA is questionable. Based on our findings, it is
conceivable that using EOAi to assess the presence and severity of PPM may not be
appropriate and its use could explain the contradictory outcomes of previous studies.
The figure also demonstrates that assessing the EOA does not increase our ability
to evaluate hemodynamic outcome compared with using the echocardiographic pressure
gradients directly. In theory, EOA assessment would be superior to pressure gradients
if examinations were made under stressed conditions with elevation of flow. However,
most evalulations, including all quoted in this text, evaluated hemodynamics only
at rest.
The most striking finding of our analysis is that the majority of studies of this
topic were based on projected EOA data rather than actually measured EOA values, despite
previous reports that the use of projected EOAs results in inaccurate comparison with
measured EOA values.[13]
[45]
[46] The EOA of a valve is a calculated value. It first estimates the area of the LVOT,
multiplying it by the velocity time integral (VTI) at the same point; assuming that
this product (area × VTI) is the same before and after the valve ([Fig. 1]). The VTI at or after the valve is measured at the point of highest flow compression,
the so called vena contracta, which (depending on how much the flow is compressed)
is smaller than the actual opening area of the prosthesis ([Fig. 2A]). Therefore, the same prosthesis could present different EOAs depending on how much
the flow is compressed by passing through the valve and thus by the individual patient's
LVOT area. As is apparent in [Fig. 2], it would not be appropriate to conclude that valve A is hemodynamically inferior
to valve B (although it would be appropriate to conclude that hemodynamics in setting
A are inferior to setting B). Using the same reasoning, it would be equally incorrect
to use the EOA from patient A to assess PPM on patient B. EOA is a patient-specific
measure of hemodynamic performance and not a valve-specific value (as suggested by
the globally available EOA charts) and by definition cannot be transferred from one
person to another. Nonetheless, this inappropriate inference has been used extensively
in the literature as the “projected” EOA when addressing PPM. Some studies have even
used values from in vitro measurements. The reason for this common mistake may be
the assumption that the EOA represents the actual opening area of the valve. As noted
above, this is only true on some occasions.[47] Hence, the reliability of studies using projected EOA to assess the relation between
PPM and survival is highly questionable. Until this conundrum has been replaced with
a more reliable way of quantifying PPM in daily practice, pressure gradients similarly
to their use in the determination of the severity of primary aortic valve stenosis
may suffice for decision-making.
Conclusion
Our study demonstrates severe limitations and inconsistencies in the literature regarding
the role of PPM for clinical practice. First, EOA is a patient-specific measure of
hemodynamic performance and cannot be reliably transferred to other patients; therefore
the majority of studies that have used projected EOA data may have reported inaccurate
data. Second, indexing the EOA for body surface area may not be appropriate for assessing
PPM and use of EOAi could explain the contradictory reports of previous studies regarding
the association of PPM and postoperative survival. We believe that PPM is relevant
and in some patients does have important clinical impact on symptoms and survival.
However, the way that we measure it is an issue that has led to considerable discordance
and controversy. It seems that (in the absence of structural cusp degeneration) currently
no echocardiographic analysis exceeds the value of the Bernoulli's pressure gradients
for assessing hemodynamic relevance of a bioprosthesis.
Perspectives
Competencies
In daily practice, PPM is defined by relating the EOA to body surface area (EOAi).
For values below 0.85 cm2/m2 and 0.65 cm2/m2 moderate and severe PPM has been defined, definitions which are used for clinical
decision making, for instance for the decision to treat a stenosed prosthetic valve.
The EOA reflects the area of the point of maximal flow compression over the prosthetic
valve (vena contracta) which is a function of the outflow tract area based on the
continuity equation (i.e., it is patient-specific). However, in four out of five studies
addressing PPM, EOAs were not measured but projected from other studies which originally
measured the EOA for their patient population. Thus, the majority of studies assumed
that the EOA is prostheses-specific.
Hence, EOA data in the majority of studies may be inherently inaccurate.
Translational Outlook
Since EOA is patient-specific based on its relation to the individual patient's outflow
tract area, relating the EOA to body surface area is questionable since the same echocardiographic
flow measurement is then related to two different patient-specific parameters. In
addition, based on a series of studies having measured Bernoulli's pressure gradients
and patient-specific EOAs, we identified a significant correlation of transprosthetic
pressure gradients to EOA. Thus, in clinical practice, the use of the questionable
EOAi may be redundant and the use of transvalvular pressure gradients appears sufficient.
In the future, hemodynamic assessment of prosthetic aortic valves requires thorough
re-evaluation. In the meantime, the use of pressure gradients, as assessed by the
modified Bernoulli's equation, may make daily life in the echolab easier.