Journal of the American College of Cardiology
Volume 62, Issue 24, December 2013 DOI: 10.1016/j.jacc.2013.08.1621
PDF Article
Cardiac Imaging

The Complex Nature of Discordant Severe Calcified Aortic Valve Disease Grading
New Insights From Combined Doppler Echocardiographic and Computed Tomographic Study

Marie-Annick Clavel, David Messika-Zeitoun, Philippe Pibarot, Shivani R. Aggarwal, Joseph Malouf, Phillip A. Araoz, Hector I. Michelena, Caroline Cueff, Eric Larose, Romain Capoulade, Alec Vahanian and Maurice Enriquez-Sarano

Author + information

vol. 62 no. 24 2329-2338
DOI: 
https://doi.org/10.1016/j.jacc.2013.08.1621
Published By: 
Journal of the American College of Cardiology
Print ISSN: 
0735-1097
Online ISSN: 
1558-3597
History: 
  • Received May 2, 2013
  • Revision received July 17, 2013
  • Accepted August 17, 2013
  • Published online December 17, 2013.
Copyright & Usage: 
American College of Cardiology Foundation

Author Information

  1. Marie-Annick Clavel, DVM, PhD∗,
  2. David Messika-Zeitoun, MD, PhD†,‡,
  3. Philippe Pibarot, DVM, PhD§,
  4. Shivani R. Aggarwal, MBBS∗,
  5. Joseph Malouf, MD∗,
  6. Phillip A. Araoz, MD∗,
  7. Hector I. Michelena, MD∗,
  8. Caroline Cueff, MD†,
  9. Eric Larose, MD, MSc§,
  10. Romain Capoulade, MSc§,
  11. Alec Vahanian, MD†,‡ and
  12. Maurice Enriquez-Sarano, MD∗∗ (sarano.maurice{at}mayo.edu)
  1. ∗Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
  2. †Cardiology Department, AP-HP, Bichat Hospital, Paris, France
  3. ‡INSERM U698 and University Paris 7–Diderot, Paris, France
  4. §Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, Québec, Canada
  1. ↵∗Reprint requests and correspondence:
    Dr. Maurice Enriquez-Sarano, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905.

Abstract

Objectives With concomitant Doppler echocardiography and multidetector computed tomography (MDCT) measuring aortic valve calcification (AVC) load, this study aimed at defining: 1) independent physiologic/structural determinants of aortic valve area (AVA)/mean gradient (MG) relationship; 2) AVC thresholds best associated with severe aortic stenosis (AS); and 3) whether, in AS with discordant MG, severe calcified aortic valve disease is generally detected.

Background Aortic stenosis with discordant markers of severity, AVA in severe range but low MG, is a conundrum, unresolved by outcome studies.

Methods Patients (n = 646) with normal left ventricular ejection fraction AS underwent Doppler echocardiography and AVC measurement by MDCT. On the basis of AVA-indexed-to-body surface area (AVAi) and MG, patients were categorized as concordant severity grading (CG) with moderate AS (AVAi >0.6 cm²/m², MG <40 mm Hg), severe AS (AVAi ≤0.6 cm²/m², MG ≥ 40 mm Hg), discordant-severity-grading (DG) with low-MG (AVAi ≤0.6 cm2/m2, MG <40 mm Hg), or high-MG (AVAi >0.6 cm2/m2, MG ≥40 mm Hg).

Results The MG (discordant in 29%) was strongly determined by AVA and flow but also independently and strongly influenced by AVC-load (p < 0.0001) and systemic arterial compliance (p < 0.0001). The AVC-load (median [interquartile range]) was similar within patients with DG (low-MG: 1,619 [965 to 2,528] arbitrary units [AU]; high-MG: 1,736 [1,209 to 2,894] AU; p = 0.49), higher than CG-moderate-AS (861 [427 to 1,519] AU; p < 0.0001) but lower than CG-severe-AS (2,931 [1,924 to 4,292] AU; p < 0.0001). The AVC-load thresholds separating severe/moderate AS were defined in CG-AS with normal flow (stroke-volume-index >35 ml/m2). The AVC-load, absolute or indexed, identified severe AS accurately (area under the curve ≥0.89, sensitivity ≥86%, specificity ≥79%) in men and women. Upon application of these criteria to DG-low MG, at least one-half of the patients were identified as severe calcified aortic valve disease, irrespective of flow.

Conclusions Among patients with AS, MG is often discordant from AVA and is determined by multiple factors, valvular (AVC) and non-valvular (arterial compliance) independently of flow. The AVC-load by MDCT, strongly associated with AS severity, allows diagnosis of severe calcified aortic valve disease. At least one-half of the patients with discordant low gradient present with heavy AVC-load reflective of severe calcified aortic valve disease, emphasizing the clinical yield of AVC quantification by MDCT to diagnose and manage these complex patients.

Key Words

According to American and European clinical guidelines for the management of patients with valvular heart disease, severe aortic stenosis (AS) is defined by several criteria, including aortic valve area (AVA) ≤1.0 cm2 or AVA indexed to body surface area (AVAi) ≤0.6 cm2/m2 and transvalvular mean gradient (MG) ≥40 mm Hg or peak aortic jet velocity (Vmax) ≥4 m/s (1,2). This combination of criteria is simple to apply in clinical practice when concordant, but recent studies emphasized the frequency of discordant severity grading (DG), most often the coexistence of AVA ≤1 cm2 or AVAi ≤0.6 cm2/m2 consistent with severe AS, with MG <40 mm Hg or Vmax <4 m/s that conversely indicates moderate AS (3–5). This situation raises uncertainty with regard to actual severity of AS and the potential indication of aortic valve replacement. Such decisions are crucial in mostly elderly patients, who incur high natural risks of AS if they are not referred to surgery (6) but also notable risks of cardiac surgery when referred to aortic valve replacement (7). These hesitations and risks are potential reasons for under-treatment of AS emphasized in publications from multiple sources, European and U.S., in academic centers or in the community (5,6,8,9).

A discordance in the AVA-gradient findings (i.e., tight AVA but low MG) is best known with depressed left ventricular ejection fraction (LVEF), understood as a low flow state (10) and widely considered logical. Patients with preserved LVEF and tight AVA might also present with low-gradient, and AS severity in such cases is controversial. This entity is described with variable prevalence and labeled “paradoxical low-gradient AS” (4,11) and is controversial in that it is considered alternatively severe (4,5) or moderate (12). Thus, it is currently unclear whether patients who present with AS and DG carry or do not carry a severe valve lesion and, clinically, which criteria to use in defining those severe valve lesions, warranting the use of an independent method to assess severity of the calcified aortic valve disease. Aortic valve calcification (AVC) load can be accurately quantified by multidetector computed tomography (MDCT) and is a fundamental marker of the aortic valve lesion of “degenerative” AS (13,14). This method provided important insight into sex differences with regard to pathophysiology of calcified aortic valve disease (15).

The objectives of our multi-imaging study of AS were to: 1) identify independent variables affecting the AVA-MG relationship and yielding low gradient; 2) define AVC load thresholds best segregating moderate and severe AS in the unadulterated AS form with normal LVEF, normal flow, and concordant grading (CG); and 3) assess, with these thresholds, the severity of calcified aortic valve disease in AS with discordant grading.

Methods

We prospectively recruited 646 adult AS patients with normal LVEF and at least moderate AS (MG ≥25 mm Hg, Vmax ≥2.5 m/s or AVA ≤1.5 cm2) who underwent comprehensive Doppler echocardiography and MDCT within the same episode of care (<3 months between evaluations) in 3 centers: Mayo Clinic (Rochester, Minnesota), Hôpital Bichat (Paris, France), and Institut Universitaire de Cardiologie et de Pneumologie (Québec City, Québec, Canada). We excluded children <18 years of age, patients with identified sequels of rheumatic disease or endocarditis, those with moderate or severe mitral valve disease, and those with previous valve repair or replacement.

Patients from Hôpital Bichat and IUCPQ were enrolled in 3 ongoing prospective studies on AVC/stenosis (COFRASA [Aortic Stenosis in Elderly: Determinant of Progression (French Cohort)]; GENERAC [Genetic of Aortic Valve Stenosis–Clinical and Therapeutic Implications], and PROGRESSA [Metabolic Determinants of the Progression of Aortic Stenosis]). Mayo patients were enrolled in a prospective clinical research study initiated in the Valvular Heart Disease Clinic. An informed consent was obtained according to approval by each institutional review board.

Doppler echocardiography measurements

The left ventricular (LV) dimensions and LVEF were measured according to recommendations of the American Society of Echocardiography. Doppler echocardiographic left ventricular outflow tract (LVOT), Vmax, and time velocity integral allowed calculation of mean transvalvular pressure gradient (MG) by modified Bernoulli formula, dimension less velocity index, stroke volume (SV), and AVA by continuity equation. The AVA was also indexed to body surface area (AVAi). Peak aortic flow was obtained as the product of LVOT area and maximal flow velocity.

On the basis of AVAi and MG, patients were categorized in 4 groups:

2 CG groups:

  • • with moderate AS (AVAi >0.6 cm²/m², MG <40 mm Hg) (CG-ModerateAS)

  • • with severe AS (AVA ≤0.6 cm²/m², MG ≥40 mm Hg) (CG-SevereAS)

2DG groups:

  • • with low-MG (AVAi ≤0.6 cm2/m2, MG <40 mm Hg) (DG-LowMG)

  • • with high-MG (AVAi >0.6 cm2/m2, MG ≥40 mm Hg) (DG-HighMG)

Systemic arterial pressure was measured by arm-cuff sphygmomanometer simultaneous to Doppler SV measurement. The ratio of SV indexed to body surface area (SVi) to systemic pulse pressure was used as an indirect measure of systemic arterial compliance:SystemicArterialCompliance=StrokeVolumeIndexSystolicBloodPressure−DiastolicBloodPressure

Multidetector computed tomography measurements

The non-contrast computed tomography was performed with multidetector scanners (SENSATION or SOMATOM, Siemens Medical Systems, Fordheim, Germany; MX 8000 IDT 16, Phillips Medical Systems, Andover, Massachusetts). The same methodology of image acquisition and interpretation was used in the 3 centers and was previously described (14,15).

Briefly, a scan run consisted of contiguous transverse slices triggered at 75% to 80% of the electrocardiographic R-to-R-wave interval. These were performed with a tube current of 42 to 1,312 A and a voltage of 120 to 130 kV. No contrast enhancement was needed, nor was beta-blocker administered for the purpose of the examination. Measurements of AVC were performed offline on dedicated workstations with validated software (heartbeat calcium scoring; Philips Medical Systems or Aquarius iNtuition, TeraRecon, Foster City, California) with the use of the Agatston method (16) and expressed in arbitrary units (AU). The aortic valve was visualized in multiple planes, and careful measurement section by section aimed to accurately exclude contiguous calcium in coronary arteries, mitral valve annulus, or aortic wall. Radiation exposure was typically 2 to 3 mSV. To account for inter-individual variability in body size, we calculated, besides the total AVC load, the following indexes: 1) AVC index (AVCi), where AVC was indexed to body surface area; and 2) AVC density (AVCd), where AVC was indexed to the cross-sectional area of the aortic annulus calculated from LVOT diameter measured by echocardiography at insertion of aortic valve cusps:AVCd=AVCπ×(LVOutflowTractDiameter2)2

The technologists and cardiologists performing the CT acquisitions and measurements were kept blinded to the clinical and Doppler echocardiographic data.

Statistical analysis

Results are expressed as mean ± SD, median (interquartile range), or percentages when appropriate. Continuous variables were tested for normality by the Shapiro-Wilk test, and testing of differences was selected accordingly. For normally distributed continuous variables, differences between groups were analyzed with the use of one-way ANOVA followed by the Tukey’s post-hoc test for inter-group comparisons. The AVC, AVCi, and AVCd were not normally distributed and were thus presented by median and interquartile range and analyzed by Kruskal Wallis test followed by the Dunn’s post-hoc test for inter-group comparisons. We used a squared root transformation to normalize AVC, AVCi, and AVCd; and all linear regression, correlation, and receiver-operating characteristic (ROC) curve analysis used squared-root-transformed levels. After squared-root transformation, these 3 variables were normally distributed with a p > 0.52.

Multivariable linear regression analysis was used to identify the independent predictors of MG and Vmax. Results were presented as estimate ± SE, standardized beta (that represent standardized partial regression weight of each parameter), and p value. Clinically relevant variables with a value of p ≤ 0.05 on individual analysis were included in the multivariable model. Correlations between echocardiographic stenotic indexes and AVC were assessed with multiple regression models, and the equation providing the best fit was retained. Receiver-operating characteristic curve analysis was used to determine the sensitivity, specificity, and positive and negative predictive values of the various cutoff values of MDCT AVC parameters for the prediction of severe AS. The best thresholds are the ones with the best sum of sensitivity and specificity. The sensitive/specific thresholds are the thresholds with at least 95% sensitivity or 95% specificity. Percentages of correct classification were tested between variables by McNemar’s test. A p value ≤0.05 was considered statistically significant. Statistical analyses were performed with SPSS (version 20.0, SPSS, Chicago, Illinois) and Table Curve (version 5.01, Systat Software, San Jose, California) software programs.

Results

AS grading

Among the 646 patients included in this study (Mayo clinic: 374; Hôpital Bichat: 165; Institut Universitaire de Cardiologie et de Pneumonogie de Québec: 107), 460 had concordant AS grading (CG), 174 (27%) with CG-moderate AS (AVAi >0.6 cm²/m² and MG <40 mm Hg); 286 (44%) with CG-severe AS (AVA ≤0.6 cm²/m² and MG ≥40 mm Hg). The remaining 186 patients had DG, 172 (27%) with low MG (AVAi ≤0.6 cm2/m2 and MG <40 mm Hg, DG-LowMG) and 14 (2%) with high MG (AVAi >0.6 cm2/m2 and MG ≥40 mm Hg, DG-HighMG) (Table 1).

View this table:
Table 1

Classification of Patients According to Doppler Echocardiographic Assessment of Stenosis Severity

Baseline characteristics according to AS grading

Overall, we included 258 (40%) women and 388 (60%) men with mean age of 74 ± 12 years; diabetes prevalence 22%, hypertension 69%, and coronary artery disease 39% (including 21% with history of coronary artery bypass grafting); overall, Vmax was 4.0 ± 0.9 m/s, MG was 40 ± 19 mm Hg, AVA was 0.99 ± 0.26 cm2, AVAi was 0.53 ± 0.14 cm2/m2, and LVEF was 64 ± 6%.

Table 2 shows the comparison of baseline characteristics between groups with concordant and discordant AS grading, with highMG and lowMG. Clinical data showed rare differences of small magnitude. A remarkable finding was the trend toward fewer women in the DG-LowMG group with consequent differences in body surface area but without differences in body mass index between CG-severe AS and the 2 DG groups. Doppler echocardiography showed differences in measures of AS severity directly related to the stratification. Some differences warrant emphasizing: the DG-LowMG group was characterized by lower flow as expected. Furthermore, the DG-LowMG was associated with slightly smaller LVOT area indexed-to-body surface area and low aortic compliance, particularly in contrast to the DG-HighMG. By MDCT, AVC, AVCi, and AVCd—overall and stratified by sex—were similar in the 2 DG groups, and these measures of severity of the calcified aortic valve disease were higher in the DG groups than in the CG-moderate AS (Figs. 1A and 1B, Table 2). The AVC, AVCi, and AVCd were also significantly higher in the CG-severe AS group than in all other groups. Among the DG-LowMG group, female sex (67% vs. 72%; p = 0.64), AVC (1,659 [976 to 2,531] vs. 1,364 [852 to 2,354] AU; p = 0.56), AVCi (887 [571 to 1,349] vs. 657 [382 to 1,182] AU/m2; p = 0.51), and AVCd (417 [281 to 630] vs. 474 [258 to 720] AU/cm2; p = 0.82) were similar in the 147 patients with normal flow (SVi >35 ml/m2) and in the 25 patients with low flow (SVi ≤35 ml/m2).

Figure 1
Figure 1

Distribution of Aortic Valve Calcification by Sex in the Various AS Groups

Concordant grading-moderate aortic stenosis (AS), discordant grading with low mean gradient (MG), discordant grading with high MG, and concordant grading-severe AS; x-axis in box-plot format, whereby the box indicates the 25th to 75th percentiles, the line within the box indicates the median, and the vertical bar indicates the 95% range. The y-axis indicates the aortic valve calcification load. (A) Data in men; (B) data in women. Of note, among patients with low MG, the overlap of aortic valve calcification between patients with severe AS (small AVA) and moderate AS (larger AVA) is more prominent in men than in women. AU = arbitrary units; AVAi = aortic valve area indexed to body surface area.

View this table:
Table 2

Clinical, Doppler Echocardiographic, and MDCT Data According to Group Classification

Determinants of MG and Vmax

In univariable analysis, MG and Vmax were associated with age (p = 0.0004 and p = 0.002, respectively), systolic blood pressure (p = 0.004 and p = 0.007, respectively), peak aortic flow (p < 0.0001 and p < 0.0001, respectively), SVi (p < 0.0001 and p < 0.0001, respectively), systemic arterial compliance (p < 0.0001 and p < 0.0001, respectively), AVAi (p < 0.0001 and p < 0.0001, respectively), AVC (p < 0.0001 and p < 0.0001, respectively), AVCi (p < 0.0001 and p < 0.0001, respectively), and AVCd (p < 0.0001 and p < 0.0001, respectively). After adjustment for age and sex, the independent predictors of MG or Vmax were peak aortic flow, systemic arterial compliance, AVAi, and AVCd (Table 3). Models using SVi as a measure of flow and predicting MG or Vmax were equivalent in beta coefficient and p values to those using peak aortic flow, but the latter were preferred to avoid tautological relationship with the compliance presented in Table 3.

View this table:
Table 3

Univariable and Multivariable Analysis of Predictors of MG or Vmax

Diagnostic value of MDCT for severe AS with CG and normal flow

In the 451 patients with normal flow (SVi >35 ml/m2) and concordant AS grading (moderate or severe AS), AVC, AVCi, and AVCd were well-associated with all Doppler echocardiographic AS severity measures (i.e., AVAi, Vmax, and MG) (all |r| > 0.68 and all p < 0.0001) in men and women separately. The ROC curve analyses, in men and women separately, showed that best cutoff values to identify severe AS were AVC ≥1,275 AU in women and 2,065 AU in men, AVCi ≥637 AU/m2 in women and 1,067 AU/m2 in men, and AVCd ≥292 AU/cm2 in women and 476 AU/cm2 in men (Fig. 2, Table 4). Table 4 also indicates, in men and women separately, the specific or sensitive thresholds that provide either specificity ≥95% or sensitivity ≥95%, so that all values of AVC load measured can be interpreted in context. The AVCd was associated with the highest area under the ROC curve and percentage of correct classification, rather than AVC and AVCi (correct classification: 87 vs. 86 and 85%, respectively), but these differences did not reach statistical significance (all p > 0.20).

Figure 2
Figure 2

Receiver-Operating Characteristic Curves to Identify Severe AS

Receiver-operating characteristic curves to identify severe aortic stenosis (AS) in the subset of 451 patients with normal flow (stroke volume indexed to body surface area [SVi] >35 ml/m2) for the different multidetector computed tomography indexes. Aortic valve calcification (A), aortic valve calcification indexed to body surface area (B), and aortic valve calcification indexed to cross-sectional area of left ventricular outflow tract (C). The dashed lines represent 95% specificity (vertical) or 95% sensitivity (horizontal). AUC = area under the curve.

View this table:
Table 4

Accuracy of AVC, AVCi, and AVCd to Identify Severe AS

AVC load in patients with DG

We then used these cutoff values of AVC, AVCi, or AVCd established in patients with CG and normal flow to corroborate the presence of severe calcified aortic valve disease in patients with DG. Among patients with DG-HighMG AS, most of the patients (71% to 86% of patients, depending on the used criteria) had a high AVC load consistent with severe calcified aortic valve disease. In patients with DG-LowMG AS, at least one-half of the patients (45% to 66% of patients, depending on the used criteria) present high AVC load (Table 5).

View this table:
Table 5

Prevalence of Patients With Evidence of Severe Stenosis on the Basis of AVC or AVCd Criteria

Among patients with DG-LowMG, those with and without severe AVCd displayed small statistical differences in age (76 ± 10 years vs. 71 ± 11 years; p = 0.03) and systolic blood pressure (128 ± 18 mm Hg vs. 135 ± 18 mm Hg; p = 0.03). Hemodynamically, patients with and without severe AVCd had slightly different MG (32 ± 5 mm Hg vs. 27 ± 7 mm Hg; p < 0.0001), Vmax (3.7 ± 0.3 vs. 3.4 ± 0.5; p < 0.0001), although within the same range (gradient: 15 to 38 mm Hg; Vmax: 2.4 to 4.2 m/s). However, such minimal differences were clinically almost indistinguishable, emphasizing the importance of MDCT as being often the only tool to affirm severe calcific aortic valve disease.

Discussion

The main findings of this multicenter study are that: 1) among patients evaluated in clinical practice for AS, a large percentage present with discordant grading by Doppler; 2) although flow and AVA are major contributors to the observed MG, other factors, arterial compliance, and severity of valvular calcification affect considerably the MG due to AS and can lead to low MG despite severe AS; 3) in patients with concordant-AS grading, specific thresholds of AVC, AVCi, and AVCd well-identify severe AS, making MDCT an important clinical tool; and 4) among patients with discordant-AS grading, one-half of those with tight AVA but low gradient present with severe AVC load, consistent with severe calcified aortic valve disease.

In current American clinical guidelines (1), there is no specific recommendation for the management of patients with DG-LowMG. In recent European guidelines (2), aortic valve replacement should be considered in symptomatic low-flow DG-LowMG AS after careful confirmation of AS severity. However, this subset of DG-LowMG patients is frequent, between 30% and 70% of diagnosed AS (5,12), and is challenging in terms of diagnosis and management. Indeed, a recent study (12) reported similar outcomes with DG-LowMG and with CG-moderate AS (better than with CG-severe AS) and thus should be followed under conservative management. However, other outcome studies reached different conclusions, suggesting that patients with AS and discordant grading, characterized by tight AS and low gradient, are at high risk for complications and mortality (4,5,17) and should be considered as having severe AS and be treated with aortic valve replacement (18–21). Thus, the nature of this syndrome of DG-LowMG AS has not been resolved by available outcome studies warranting novel analysis that takes into account the valvular lesion for which MDCT can provide new insights.

Indeed, since the early description of degenerative AS, the importance of valvular calcification has been emphasized as the main disease mechanism (22), for initiation (23) as well as progression (24). Thus, the magnitude of the calcified aortic valve disease defines the valve lesion (13,14,25) but also demonstrates the complexity of the AS hemodynamic status. The link between valve area and gradient, once thought to be purely related to flow, is shown by our study to be far more complex (26). Indeed, the presence of a relatively low gradient due to low flow (low SV) is much less frequent than low gradient with normal flow (27). Different studies suggested that reduced aortic compliance tends to be associated with decreased MG (28,29). Our multicenter clinical cross-sectional study is coherent with these observations, because reduced aortic compliance was found to independently determine lower gradient for any given flow and valve area. Moreover in the present study we showed that the association between systemic arterial compliance and gradient/velocity was as strong as that between flow and gradient/velocity (by similar standardized partial weight [beta] in the correlation models). This component of AS hemodynamic status is important (30) and might explain discordances between invasive hemodynamic status and Doppler in the context of hypertension and emphasizes the interest of measuring the total LV impedance in the context of AS (31). Another component of gradient variability is related to the AVC load. Patients with the largest load tend to present with the highest gradient independently of AVA and flow, probably in relation to differences in valvular inertia or shape (32), which might affect the C coefficient linking these variables in the Gorlin formula (33,34). Although errors in the Doppler echocardiographic measurements (i.e., underestimation of SV and AVA) might play a role in discordant grading (12,35), the strong link between echocardiographic AVA and survival (5) and in the present study the larger AVC load with DG-LowMG compared with CG-moderate AS suggest that errors should not be universally blamed for DG AS and that the diagnosis should be carefully individualized with appropriate tools and in particular with MDCT. Thus, our study underscores the complexity of the determinants of transvalvular gradient in the adult with AS and emphasizes the importance of MDCT as a clinical tool to assess the severity of the calcified aortic valve disease in the DG-low gradient patients that represent a conundrum in clinical practice.

Our large multicenter study provided the opportunity to analyze AVC thresholds separating most effectively moderate versus severe AS in a relatively pure subset with CG and normal SVi. We were thus able to define thresholds coherent with severe AS, particular to men and women, and also providing a sensitive, specific, and most accurate detection of severe AS, allowing fine-tuning for clinical interpretation. These criteria applied to patients with DG, particularly to those with low gradient, showed that one-half of these patients had evidence of severe calcified aortic valve disease on the basis of AVC load measured by MDCT, much more frequently than in patients with CG moderate AS. Hence, this large series provides evidence that patients with DG-Low MG should be comprehensively evaluated for AS, particularly by MDCT. An important finding is that the range of AVC load in patients with DG is wide, suggesting that this group is heterogeneous. Those with DG-LowG and low calcification might be the result of possible measurement errors (36), asymmetry of LVOT (37), inaccuracy of indexation to body size (particularly in obese patients), or low flow leading to pseudo-severe AS (38).

This heterogeneity underscores the importance of integrating all the information available. Although, in patients with low LVEF, dobutamine echocardiography is an important tool—allowing detection of pseudo-severe AS (39–41)—it is unclear how useful the test is in patients with preserved LVEF that might be in a low-flow state (4,17,38,42). In this context, AVC load is important, because it provides direct evidence of the aortic valve lesion severity in patients that cannot be recognized by any other clinical or rest echocardiographic mean. Higher AVC load is also associated with worse outcome (13,43), so that higher AVC load is a marker not just of hefty calcified aortic valve disease but also of future complications warranting—in addition to the other markers of severity of AS—consideration for aortic valve replacement. Our results suggest that AVC density (indexed to the area of the aortic annulus) provides the highest diagnostic value to corroborate AS severity, and AVC density ≥292 AU/cm2 in women and 476 AU/cm2 in men provide the highest sum of sensitivity and specificity to identify severe AS. Further studies are needed to assess the impact of AVC and AVC density on clinical outcome.

Study limitations and strengths

Doppler echocardiography has limitations in evaluating AS severity, but it is now the basis of guidelines for clinical management of AS. The reference grading by Doppler echocardiography was based on the purest set of patients, combining concordant grading by AVAi and MG, with normal flow and LVEF, leaving little room to doubt the AS severity.

The MDCT measurements were done in each institution, and this international collaboration was challenging for the exchange of images between centers. However, the training for calcium measurement was common and standardized in the 3 centers, and we arranged an inter-center investigator visit to address inter-observer variability as previously published (15). Moreover, all centers displayed similar relationships between hemodynamic AS severity and AVC load (the main aim of the present study) by covariance analysis (p = 0.42). The MDCT was used as a global AVC load, without specifying the spatial distribution of this load. In that regard, it is possible that future studies analyzing valve tissue versus annular and leaflet versus commissural calcification load might provide additional information on AS pathophysiology, but the present large study of global AVC load is the first to provide specific criteria allowing integration of MDCT into clinical practice management of AS in men and women.

The use of indexed AVA to classify AS severity was justified by the obvious link between body size and cardiac size, particularly aortic valve size, and hence AVA. Although AVAi might influence the group distribution, use of non-indexed AVA would overestimate stenosis severity in small patients and would introduce a bias between sexes and potentially limit the relevance of AVC threshold values. This approach did not lead to overestimate the DG-LowMG syndrome, which has been proven to be of high frequency in community studies (5,27).

Conclusions

This large multicenter series of patients with AS diagnosed in clinical practice shows that discordant grading of AS by AVA and gradient is frequent. The combination of Doppler and MDCT with AVC measurement provides unique pathophysiologic insights into the determinants of discordant low gradients. Although flow and AVA are major contributors to the observed MG, other factors, arterial compliance, and severity of valvular calcification affect considerably the MG due to AS and can lead to low MG, despite severe AS. Hence, patients with discordant AVA-gradient at echocardiography require particular attention and might need additional diagnostic tests to confirm stenosis severity. To this effect, AVC quantification by MDCT might be helpful to identify patients with severe AS, specifically with AVC ≥1,274 AU in women and 2,065 AU in men or with AVC density (indexed to annulus cross-sectional area) ≥292 AU/cm2 in women and 476 AU/cm2 in men. Hence, among patients with discordant-AS grading, with tight AVA but low gradient, heavy AVC load—consistent with severe calcified aortic valve disease—is present in one-half of the patients, underscoring the potential of MDCT as an important clinical tool. However, the new thresholds of AVC proposed in the present study need to be validated by longitudinal studies with outcome data.

Footnotes

  • The study was funded in part by grants from the Assistance Publique–Hopitaux de Paris (PHRC national 2005 and PHRC regional 2007) and a grant (MOP# 114997) from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada. Dr. Clavel holds a Vanier Canada Graduate Scholarship and a Michael Smith Foreign Study Supplements Scholarship, Canadian Institutes of Health Research, Ottawa, Ontario, Canada. Dr. Messika-Zeitoun has served as consultant to and received lecture fees from Edwards, Valtech, and Abbott. Dr. Pibarot holds the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research. R. Capoulade was supported by a studentship grant of International Chair of Cardiometabolic Risk, Quebec, Quebec, Canada. Dr. Vahanian has received honoraria and/or Speakers fees from Edwards Lifesciences, Abbot, Medtronc, and Valtech. Dr. Enriquez-Sarano has received research support from Abbott Vascular; and has served on the board of Valtech. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms
AU
arbitrary units
AVAi
aortic valve area indexed to body surface area
AVC
aortic valve calcification
AVCd
aortic valve calcification indexed to the cross-sectional area of the aortic annulus
AVCi
aortic valve calcification indexed to body surface area
CG
concordant grading
DG
discordant grading
LV
left ventricular
LVEF
left ventricular ejection fraction
LVOT
left ventricular outflow tract
MDCT
multidetector computed tomography
MG
mean gradient
ROC
receiver-operating characteristic
SV
stroke volume
SVi
stroke volume indexed to body surface area
Vmax
peak aortic jet velocity
  • Received May 2, 2013.
  • Revision received July 17, 2013.
  • Accepted August 17, 2013.

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