Visual Estimation of the Severity of Aortic Stenosis and the Calcium Burden by 2-Dimensional Echocardiography

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1 ORIGINAL RESEARCH Visual Estimation of the Severity of Aortic Stenosis and the Calcium Burden by 2-Dimensional Echocardiography Is It Reliable? Nishath Quader, MD, Susan Wilansky, MD, Roger L. Click, MD, Minako Katayama, MD, Hari P. Chaliki, MD Received November 18, 2014, from the Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona USA (N.Q., S.W., M.K., H.P.C.); and Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota USA (R.L.C.). Revision requested December 7, Revised manuscript accepted for publication December 16, We thank Machiko T. Anderson for recruiting and research assistance. This study was supported by a Mayo Clinic intramural career development grant. Address correspondence to Hari P. Chaliki, MD, Division of Cardiovascular Diseases, Mayo Clinic, E Shea Blvd, Scottsdale, AZ USA. chaliki.hari@mayo.edu Abbreviations ACC, American College of Cardiology; AHA, American Heart Association; AU, arbitrary unit; CI, confidence interval; CT, computed tomography; PPV, positive predictive value; 2D, 2-dimensional doi: /ultra Objectives Guidelines have recommended aortic valve surgery in asymptomatic patients with severe aortic stenosis and a large aortic valve calcium burden. The purpose of this study was to determine whether visual assessment of aortic valve calcium and stenosis severity are reliable based on 2-dimensional echocardiography alone. Methods We prospectively enrolled 68 patients with aortic stenosis and compared them with 30 control participants without aortic stenosis. All had aortic valve calcium score assessment by computed tomography. In a random order, 2-dimensional images without hemodynamic data were independently reviewed by 2 level 3 trained echocardiographers, who then classified these patients into categories based on aortic valve calcium and stenosis severity. Results The 68 patients (mean age ± SD, 74 ± 10 years) were classified as having mild (n = 28), moderate (n = 22), and severe (n = 18) aortic stenosis. When the observers were asked to grade the degree of valve calcification, the agreement between them was poor (κ = ). The visual ability to determine stenosis severity compared with Doppler echocardiography had high specificity (81% and 88% for observers 1 and 2). However, sensitivity was unacceptably low (56% 67%), and the positive predictive value was poor (44% 50%). Agreement was fair (κ = ) between the observers for determining severe stenosis. Conclusions Our results suggest that visual assessment of aortic valve calcium has high interobserver variability; the visual ability to determine severe aortic stenosis has low sensitivity but high specificity. Our results may have important implications for treatment of patients with aortic stenosis and guiding the use of handheld echocardiography. Further research with larger cohorts is needed to validate the variability, sensitivity, and specificity reported in our study. Key Words aortic valve stenosis; echocardiography; computed tomography A ortic stenosis has substantial implications for overall health care associated costs, since the burden of this disease is projected to increase due to an aging population. In fact, according to the American Heart Association (AHA), the prevalence of moderate or severe aortic stenosis in patients 75 years and older is 2.8%. 1 Most common causes of aortic stenosis include calcification of a bicuspid or trileaflet aortic valve by the American Institute of Ultrasound in Medicine J Ultrasound Med 2015; 34:

2 Echocardiography has been a well-established method of diagnosing this disease, and cardiac catheterization is only recommended when echocardiography is nondiagnostic. 2 4 Currently, an aortic valve area of less than 1 cm 2 is considered severe according to the current American College of Cardiology ACC/AHA guidelines. 2 The aortic valve area can be calculated by using Doppler echocardiographic parameters. The aortic valve area can also be measured directly by visualization of the valve orifice on 2-dimensional (2D) 5 or 3-dimensional 6 transthoracic echocardiography or transesophageal echocardiography. 7 The American Society of Echocardiography has suggested that planimetry may be an alternative to aortic valve area measurement when Doppler methods are unreliable. 8 Over the years, we have encountered many clinicians who often ask the echocardiographer the questions Does the aortic valve stenosis look severe? and Is there a significant amount of calcium on the valve?. Similar questions will also invariably be raised in the era of handheld echo - cardiography, which lacks the capability of Doppler hemodynamics. Incorrect diagnosis using these newer handheld ultrasound devices, especially in some settings, such as emergency departments and intensive care units where time and resources are limited, may have profound implications. European Society of Cardiology and ACC/AHA guidelines have recommended aortic valve surgery in asymptomatic patients with severe aortic stenosis and a large aortic valve calcium burden. 2,9 However, it is not clear whether visual assessment of aortic valve calcium and stenosis severity are reliable based on 2D echocardiography alone. The aim of the study was to understand the accuracy of determining various degrees of aortic stenosis severity and calcium burden by visual impressions of highly experienced level 3 trained practicing echocardiographers at an academic institution. Materials and Methods We prospectively enrolled 68 patients with aortic stenosis and compared them with 30 controls without stenosis. Patients were only included if they had a clinical indication for an echocardiographic study. Exclusion criteria were an ejection fraction of less than 50%, greater than mild aortic regurgitation, moderate or greater stenosis or regurgitation in valves other than the aortic valve, prior myocardial infarction (defined as a wall motion abnormality on a resting echocardiogram), previous cardiac surgery, atrial fibrillation or flutter, the presence of a left bundle branch block, a pacemaker, poor echocardiographic images, infiltrative heart disease, hypertrophic cardiomyopathy, constriction or restriction, pregnancy or nursing, and a history of pulmonary embolism. The protocol was approved by the Mayo Foundation Institutional Review Board and written informed consent was obtained to participate in the study. Detailed baseline demographic and echocardiographic characteristics were recorded. All patients had assessment of their aortic valve calcium score by computed tomography (CT). Hemodynamic Assessment by Echocardiography The left ventricular outflow tract diameter was measured from a parasternal long-axis view according to the American Society of Echocardiography recommendations. 8 The left ventricular outflow tract time-velocity integral was then measured from the apical long-axis view by placing the pulsed wave Doppler sample volume at the left ventricular outflow tract, 5 mm proximal to the aortic valve to avoid spectral broadening and also to visualize the aortic valve closure click. Mean and peak gradients were measured from multiple windows by continuous wave Doppler imaging. The aortic valve area was then calculated by the continuity method. 8 Other standard echocardiographic characteristics were also measured. Visual Assessment of the Severity of Valve Calcification and Aortic Stenosis In a random order, 2D images of the aortic valve at parasternal long-axis, parasternal short-axis, and apical long-axis views (without hemodynamic data) were independently reviewed by 2 level 3 trained echocardiographers. These echocardiographers then classified these patients into 4 categories (none, mild, moderate, and severe) based on visual valve calcification and severity of aortic stenosis. Their assessment of stenosis severity and valve calcification was then compared with Doppler-derived hemodynamic measurements and CT-derived aortic valve calcium scores. Aortic Valve Calcium Scoring by CT Computed tomography of the heart was performed with commercially available multidetector scanners according to a coronary artery calcification scoring protocol with prospective electrocardiographic R-wave triggering and reconstruction of 2.5- to 3.0-mm axial images at 70% to 80% of the R-R interval. Aortic valve calcium scoring was performed, using accepted methods, 10,11 within valve leaflets, carefully excluding the calcium in the aortic wall, aortic annulus, and coronary arteries. The Agaston-Janowitz scale with a 130 Hounsfield unit threshold was used J Ultrasound Med 2015; 34:

3 Statistical Analysis The data are presented as mean ± standard deviation and median. Patients were divided into 4 groups according to stenosis severity determined by the mean gradient through the aortic valve. Comparisons between groups were performed by a Kruskal-Wallis tests for continuous variables and χ 2 test for categorical variables. P <.05 was considered a statistically significant difference. Interobserver agreement between the echocardiographers was assessed by the κ method. Results The 68 patients (mean age, 74 ± 10 years; 62% male) were classified as having mild (mean gradient, mm Hg; n = 28), moderate (mean gradient, mm Hg; n = 22), and severe (mean gradient, >40 mm Hg; n = 18) aortic stenosis,compared with the 30 control participants without stenosis (mean gradient, <10 mm Hg). Age, sex, and comorbid conditions were not different among patients without stenosis and those with mild, moderate, or severe stenosis. The left ventricular ejection fraction was also not different among the 4 groups (Table 1). As expected, the mean gradient was minimal (4 ± 2 mm Hg) in patients with no aortic stenosis, whereas patients with mild, moderate, and severe stenosis had mean gradients of 17 ± 5, 32 ± 5, and 54 ± 9 mm Hg (P <.0001), respectively. Aortic Valve Calcium Score by CT and Visual Assessment by Echocardiography Computed tomographically measured aortic valve calcium scores were different among the 4 groups (92 ± 161 arbitrary units [AU] in patients with no stenosis versus 689 ± 616 AU in patients with mild stenosis, 1292 ± 693 AU in patients with moderate stenosis, and 2537 ± 1170 AU in patients with severe stenosis; P <.0001; Table 1). Visual assessment of valve calcification by echocardiography compared with the aortic valve calcium score by CT is presented in Table 2 and Figure 1. Mean calcium scores of controls and each grade of valve calcification determined visually by the observers as shown in Table 2 reveal that observer 2 had higher calcium scores for each grade of valve calcification compared with observer 1. Specifically, when observer 1 was asked to visually assess the calcium, that observer classified 1 patient as having no aortic valve calcification, corresponding to an aortic valve calcification score of 0 AU on CT, whereas observer 2 classified 12 patients as having no aortic valve calcification, corresponding to a score of 8 ± 17 AU on CT. Similarly, observer 1 classified 39 patients as having severe aortic valve calcification, corresponding to a CT-derived aortic valve calcium score of 1673 ± 1145 AU, whereas observer 2 classified 13 patients as having severe aortic valve calcification, corresponding to a CT-derived score of 2300 ± 1242 AU. Table 1. Baseline Demographics in Each Group Stenosis None Mild Moderate Severe Characteristic (n = 30) (n = 28) (n = 22) (n = 18) P Age, y 70 ± ± ± 5 75 ± Male, % Hypertension, % Hyperlipidemia, % Coronary artery disease, % Ejection fraction, % 64 ± 4 64 ± 5 67 ± 5 67 ± 4.09 Gradient, mm Hg 4 ± 2 17 ± 5 32 ± 5 54 ± 9 <.0001 Calcium score, AU 92 ± ± ± ± 1170 <.001 Table 2. Visual Assessment of Valve Calcification on Echocardiography and Aortic Valve Calcium Score on CT Calcium Score by Visual Calcification Assessment, AU (n) Observer None Mild Moderate Severe P 1 0 (1) 153 ± 392 (30) 939 ± 897 (28) 1673 ± 1145 (39) < ± 17 (12) 596 ± 914 (40) 1283 ± 832 (33) 2300 ± 1242 (13) <.0001 J Ultrasound Med 2015; 34:

4 When an aortic valve calcium score higher than 1000 AU was used to define severe aortic valve calcification, as defined by the current ACC/AHA guidelines, 2 40 patients (41%) had severe aortic valve calcification by the CT score. determined that 29 patients had severe calcification, resulting in sensitivity of 73%, whereas observer 2 determined that 12 patients had severe calcification, resulting in sensitivity of 30%. Specificity for observer 1 was slightly lower at 83% compared to 98% for observer 2 (Table 3). Agreement when compared with the CT score for observer 1 had a κ value of 0.55 (95% confidence interval [CI], ), whereas it was 0.32 (95% CI, ) for observer 2. However, when the echocardiographers assessments of whether severe aortic valve calcification was present was compared with each other, interobserver agreement was poor, with a κ value of 0.33 (95% CI, ; Table 4). Interobserver agreement on visual assessment of calcium was slightly better, with a κ of 0.39 (95% CI, ), when 4 categories were used (Table 5). Despite the Figure 1. Visual estimation of calcium and aortic valve calcium (AVC) scores between observers 1 and 2. Even though observers 1 and 2 classified the patients into the various categories ranging from no valve calcium to severe valve calcium, there were significant overlaps in the various categories compared to the CT-derived calcium score, indicating that visual estimation of calcium may not be so reliable given that even with experienced eyes, the level of discrepancy between visual assessment and the actual CT-derived calcium score can be significant. poor agreement between the observers regarding the visual calcium burden of a particular valve, each observer was able to discriminate the amount of calcium between various grades of aortic stenosis (Figure 1 and Table 2). Visual Assessment of Aortic Valve Stenosis Severity When the visual assessment of hemodynamic severity of aortic stenosis was categorized as severe versus not severe, sensitivity was poor (observer 1, 67%; observer 2, 56%) compared with Doppler echocardiography, whereas specificity was fair (observer 1, 81%; observer 2, 88%; Table 6). However, the positive predictive value (PPV) was not acceptable (observer 1, 44%; observer 2, 50%). Interobserver agreement on visual assessment of stenosis severity was acceptable, with a κ value of 0.58 (95% CI, ; Table 7). When 4 categories were used, the κ value was 0.69 (95% CI, ; Table 8). Table 3. Visual Assessment of Valve Calcification by Observers 1 and 2 Calcium Score Visual Estimate > Severe Nonsevere Sensitivity, 73%; specificity, 83%; κ = 0.55 ( ) Observer 2 Severe 12 1 Nonsevere Sensitivity, 30%; specificity, 98%; κ = 0.32 ( ) Table 4. Interobserver Agreement on Visual Assessment of Valve Calcification for Severe Versus Nonsevere Stenosis Observer 2 Severe Nonsevere Severe 12 1 Nonsevere κ = 0.33 ( ) Table 5. Interobserver Agreement on Visual Assessment of Valve Calcification for Stenosis Categories Observer 2 None Mild Moderate Severe Total None Mild Moderate Severe Total κ = 0.39 ( ) 1714 J Ultrasound Med 2015; 34:

5 Discussion This is the first study to our knowledge that compared visual assessment of aortic valve calcification with a CT-measured aortic valve calcium score. Our study shows that visual grading of aortic valve calcium compared with CT-measured calcium is discordant even in the eyes of experienced echocardiographers. More importantly, the interobserver agreement for classifying patients into 4 categories based on visual assessment alone is poor (κ = ). In terms of the hemodynamic severity of aortic stenosis, without the knowledge of Doppler data, interobserver agreement was fair (κ = ). When compared with Doppler-derived hemodynamic severity, visual assessment by the echocardiographers was specific (81% and 88%) for severe aortic stenosis, but sensitivity (67% and 56%) and PPVs (44% and 50%) were lower than acceptable levels. Table 6. Visual Assessment of Stenosis Severity by Observers 1 and 2 Hemodynamic Severity Visual Assessment Severe Nonsevere Severe Nonsevere 6 64 Sensitivity, 67%; specificity, 81%; PPV, 44% Observer 2 Severe Nonsevere 8 70 Sensitivity, 56%; specificity, 88%; PPV, 50% Table 7. Interobserver Agreement on Visual Assessment of Stenosis Severity Observer 2 Severe Nonsevere Severe 16 4 Nonsevere κ = 0.58 ( ) Table 8. Interobserver Agreement on Visual Assessment of Stenosis Severity for Stenosis Categories Observer 2 None Mild Moderate Severe Total None Mild Moderate Severe Total κ = 0.69 ( ) The example shown in Figure 2 further highlights the discrepancies even between the experienced eyes of level 3 trained echocardiographers and actual hemodynamic data and aortic valve calcium scores. In general, visual assessment is a mental process in which we qualitatively judge the aortic valve opening and intuitively compare it with the anatomic valve area proposed by guidelines (<1 cm 2 in cases of severe aortic stenosis). As shown in our study, this mental translation has low sensitivity but reasonable specificity. In other words, by visual assessment alone, we may misclassify patients with severe aortic stenosis as not having severe stenosis in the absence of Doppler data. Similarly, what one person considers severe calcification may vary from person to person depending on individual interpretation of severe valve calcification. In addition, thresholds of CT-derived aortic valve calcium scores separating various grades of aortic stenosis are variable between observers. Our study emphasizes the need for a full echocardiographic study in patients suspected to have more than mild aortic stenosis and CT-derived aortic valve calcium scores in selected patients with aortic stenosis before subjecting them to any intervention. Even though visual assessment is a surrogate of planimetry of the aortic valve, planimetry of the aortic valve to assess aortic stenosis severity has its own limitations. This technique may be inaccurate when there is excessive valve calcification, and one has to be able to differentiate the effective orifice area from the anatomic or geometric valve area. 4 In brief, the anatomic or geometric orifice area is the area of valve opening measured by planimetry. However, the effective orifice area refers to the crosssectional area of the jet downstream of the vena contracta as the jet accelerates out of the stenotic valve. 13 The differences between either effective or anatomic valve areas depend on valve geometry and can be affected by valve morphologic characteristics (bicuspid versus trileaflet valve). 14 It has been proposed that the anatomic valve area may have values higher than those calculated by a continuity equation in special cases of valve stenosis related to valve geometry. 15 Another limitation of 2D echocardiography and planimetry is acoustic shadowing due to valve calcification, as is frequently seen in severe aortic stenosis. In addition, the valve orifice could be miscalculated due to nonplanar alignment of the ultrasonic beam. 16 Threedimensional echocardiography with multiplanar reconstruction may provide better assessment of the anatomic valve orifice area because of the ease of aligning multiple planes orthogonal to the valve. 17 These factors may explain low sensitivity and low PPV in determining the severity of aortic stenosis by visual assessment alone in our study. J Ultrasound Med 2015; 34:

6 There is evidence suggesting that an aortic valve calcium score higher than 1100 AU has good sensitivity and specificity for diagnosing severe aortic stenosis. 10 Aortic valve calcium on multidetector CT is measured by using the valvular Agatston score. 12,18 This score is calculated by using a weighted value assigned to the highest density of valve calcium; the density is measured in Hounsfield units. This score is then multiplied by the area of valve calcification. Valve calcium is measured within the valve leaflets. On the contrary, visual impression of a 2D echocardiogram may overestimate valve calcium if there is annular calcification or if the image is overgained. It is also possible that a 2D echocardiogram could underestimate total valve calcium if there is substantial acoustic shadowing related to the valve calcium or annular calcification. Poor agreement between the observers may be partly related to the abovementioned factors in our study. Why should we care about visual assessment of aortic valve calcification? In the current era of transfemoral/ apical aortic valve replacement, the amount of valve calcification and location of valve calcium are predictive of procedural success and perivalvular aortic regurgitation, which in turn is linked to long-term mortality after the procedure. 19 In addition, decreased event-free survival was reported in patients with severe aortic valve calcium in one study 20 and valve calcium scores higher than 500 AU in another second study. 10 Furthermore the ACC/AHA guidelines recommend valve surgery in patients who have a high like lihood of rapid progression based on the amount of valve calcification. 2 Both visual assessment of the calcium burden and visual assessment of severity of aortic stenosis are linked. This relationship may be important with the recent advent and wide availability of handheld echocardiographic machines that display 2D images but without Doppler data. As demonstrated in this study, even when highly experienced level 3 echocardiographers were asked to review and classify patients with aortic stenosis into various categories based on the amount of valve calcium and aortic stenosis severity by visual impression alone, the sensitivity for determining severe aortic stenosis was poor and likely will be even worse when one uses the handheld echocardiographic machines, not only because of image size and quality but also because of their use by less experienced users in some cases. There were several limitations in this study. First, there is no standardized criterion for visual assessment of valve calcification using 2D echocardiography. Therefore, we did not provide the echocardiographers specific instructions for classification into none, mild, moderate, or severe valve calcification. This aspect might have caused less agreement between the observers because of different preconceptions of the severity of the valve calcification. Second, aortic valve calcium scoring by CT is a relatively new method within the past 10 to 20 years. The threshold for an aortic valve calcium score 10 indicating severe aortic Figure 2. Two-dimensional images from patients with severe aortic stenosis: examples of cases of aortic stenosis that can be seen in an echocardiography laboratory. The aortic valve calcium score was 3244 AU on CT. The mean gradient through the aortic valve was 51 mm Hg; the peak velocity was 4.4 m/s; and the calculated aortic valve area was 0.88 cm2 on echocardiography. When the observers were asked to classify these patients calcium burden and aortic stenosis severity, observer 1 classified them as having severe valve calcium and severe aortic stenosis, and observer 2 classified them as having moderate valve calcium and moderate aortic stenosis. Ao indicates aorta; LA, left atrium; LCC, left coronary cusp; LV, left ventricle; NCC, noncoronary cusp; RA, right atrium; RCC, right coronary cusp; and RVOT, right ventricular outflow tract J Ultrasound Med 2015; 34:

7 stenosis might be revised according to the progress of new scanners and medical physics. Also, the threshold for the severity of calcification 2 may need to be reconsidered according to the outcome measure or according to different age groups. Third, classification of the hemodynamic severity of aortic stenosis by a Doppler method has been also debated. 21 We used a mean gradient for categorizing aortic stenosis types into mild, moderate, and severe stenosis. Some cases have inconsistency between the mean gradient, peak velocity, and calculated aortic valve area. Different measures provide slightly different classifications for the aortic stenosis severity. In conclusion, visual assessment of aortic valve calcium has high interobserver variability. Computed tomography offers a more quantitative approach. The visual ability to determine severe aortic stenosis in older patients has low sensitivity but high specificity. Therefore, a full hemodynamic study is recommended in most cases of aortic stenosis regardless of the visual impression, especially in older patients. Our study results may have important implications in the management of asymptomatic severe aortic stenosis and in guiding the use of handheld echocardiographic machines in patients with aortic stenosis. Further research is needed with larger cohorts of patients to validate the interobserver variability, sensitivity, and specificity reported in our study. References 1. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics 2013 update: a report from the American Heart Association. Circulation 2013; 127: Nishimura RA, Otto CM, Bonow RO, et al AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 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