Alteration in Subendocardial and Subepicardial Myocardial Strain in Patients with Aortic Valve Stenosis: An Early Marker of Left Ventricular Dysfunction?

CLINICAL INVESTIGATIONS VALVULAR HEART DISEASE

Alteration in Subendocardial and Subepicardial Myocardial Strain in Patients with Aortic Valve Stenosis: An Early Marker of Left Ventricular Dysfunction? Eiichi Hyodo, MD, Kotaro Arai, MD, Agnes Koczo, BA, Yuichi J. Shimada, MD, Kohei Fujimoto, MD, Marco R. Di Tullio, MD, Shunichi Homma, MD, Linda D. Gillam, MD, and Rebecca T. Hahn, MD, New York, New York

Background: It has been suggested that myocardial systolic impairment may not be accurately detected by the evaluation of endocardial excursion alone. The aim of this study was to test the hypothesis that changes in left ventricular (LV) subendocardial and subepicardial strain are sensitive markers of severity of aortic stenosis (AS) and LV function in patients with AS. Methods: Transthoracic echocardiography was performed in 73 consecutive patients with AS who had preserved systolic function and in 20 controls. Longitudinal strain, subendocardial radial strain, subepicardial radial strain, and transmural radial strain were measured using LV apical and short-axis images. Results: The 73 patients enrolled in this study were classified according to AS severity: mild (n = 10), moderate (n = 15), or severe (n = 48). Although transmural and subepicardial radial strain showed similar values in all groups, subendocardial radial strain and longitudinal strain could differentiate mild or moderate AS from severe AS. Only the ratio of subendocardial to subepicardial radial strain (the bilayer ratio) decreased significantly as the severity of AS increased. Bilayer ratio showed weak correlations with LV ejection fraction (r = 0.37) and E/E0 ratio (r = 0.33) and moderate correlations with LV mass (r = 0.55) and aortic valve area (r = 0.71). Moreover, bilayer ratio was independently associated with AS severity (P = .001). In 21 patients who underwent aortic valve replacement, subendocardial radial strain and bilayer ratio increased 7 days after surgery, whereas other echocardiographic parameters of LV function showed no improvement. Conclusions: Bilayer ratio can reliably differentiate patients with varying degrees of AS severity and is a sensitive marker of LV function. These findings suggest that the evaluation of subendocardial and subepicardial radial strain might be a novel method for assessing LV mechanics in patients with AS. (J Am Soc Echocardiogr 2012;25:153-9.) Keywords: Aortic stenosis, Subendocardial strain, Subepicardial strain

The prevalence of symptomatic aortic stenosis (AS) increases with age, and if left untreated, AS results in a high mortality rate.1 In these patients, aortic valve replacement improves survival, left ventricular (LV) ejection fraction, and regression of LV mass.1,2 However the management of asymptomatic patients with severe AS remains controversial, particularly with respect to the timing of surgical intervention.3 Because of the adaptive remodeling of the left ventricle, patients can remain asymptomatic or minimally symptomatic for prolonged periods of time, despite the presence of severe AS. From Columbia University Medical Center, New York, New York. Reprint requests: Eiichi Hyodo, MD, Columbia University Medical Center, Cardiology Department, 622 W. 168th Street, PH3-133, New York, NY 10032 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2012 by the American Society of Echocardiography. doi:10.1016/j.echo.2011.11.003

However, once LV function is impaired, outcomes after surgical intervention are suboptimal.4 Hence, it is of crucial clinical importance to identify the onset of LV dysfunction in its early phase so that surgical intervention can be performed in a timely manner.3 The most commonly used ejection phase indices, such as ejection fraction, may not be early indicators of cardiac alteration.5,6 As a result, the development of more accurate, noninvasive methods for assessing subclinical LV dysfunction is necessary in patients with AS. It is well known that the subendocardial layer of the left ventricle plays an important role in ventricular function.7-9 In normal subjects, the subendocardium contributes more to the overall myocardial thickening and uses more oxygen than the subepicardium.7,8,10 As a result, when myocardial blood flow decreases, the subendocardium is affected to a greater degree than the subepicardium.11,12 In addition, transmural thickening is not uniform, with the endocardial portion of the wall thickening more than the epicardial portion, in part because of nonuniform 153

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transmission of end-systolic stress.13 Previous reports have AS = Aortic stenosis suggested that myocardial systolic impairment in LV hypertroAVA = Aortic valve area phy may originate at the LV = Left ventricular endocardial side and then extend toward the epicardium.14 VVI = Velocity Vector Imaging Therefore, the evaluation of differences in subendocardial and subepicardial LV deformation might be useful in detecting subclinical LV systolic dysfunction in patients with LV hypertrophy secondary to AS. The aim of this study was to examine (1) whether the severity of AS affects subepicardial and subendocardial deformation (i.e., subendocardial and subepicardial radial strain), (2) whether changes in subepicardial and subendocardial radial strain may reflect subclinical changes in LV function in patients with AS, and (3) whether the assessment of subendocardial and subepicardial radial strain may detect an early phase of recovery of LV function after aortic valve replacement.

Continuous-wave Doppler recordings were obtained from multiple views, including apical, right parasternal or clavicular, and subcostal views, and the peak and mean aortic valve velocity profiles were measured. LV outflow tract velocity was measured using pulsed-wave Doppler with the sample volume in the LV outflow tract just below the region of proximal flow convergence. Aortic valve area (AVA) was calculated using the continuity equation according to standard protocol.19 The study population was divided into three groups on the basis of echocardiographic AVA: the mild AS group included patients with AVAs > 1.5 cm2, the moderate AS group included patients with AVAs $ 1.0 and # 1.5 cm2, and the severe AS group included patients with AVAs < 1.0 cm2. Early diastolic transmitral velocity (E) and late diastolic transmitral velocity (A) were recorded by pulsed-wave Doppler in the apical four-chamber view. Early diastolic tissue velocity (E0 ) and the diastolic tissue velocity (A0 ) were recorded in the same view with the sample volume positioned at the lateral mitral annulus. Measurements were averaged over at least three cardiac cycles. An experienced operator blinded to the clinical data performed these measurements.

METHODS

Longitudinal and Radial Strain Measurements

Study Population A total of 168 patients who had different level of AS severity and were planned to undergo coronary angiography and LV pressure recordings were recruited for this study from a patient population referred to our hospital between March 2007 and March 2010. Exclusion criteria were obstructive epicardial coronary artery disease (>50% reduction in absolute luminal diameter of a major artery or major branch vessel), ejection fraction # 50% by echocardiography, regional myocardial wall motion abnormalities, left bundle branch block, atrial fibrillation or flutter, renal insufficiency, moderate or severe hypertension (diastolic blood pressure > 100 mm Hg and/or systolic blood pressure > 160 mm Hg), significant mitral valve stenosis and regurgitation or aortic valve regurgitation, and history of coronary bypass surgery or valve surgery. Finally, 80 patients (33 men; mean age, 85 6 9 years) were included in this study population. All patients underwent complete transthoracic echocardiography at baseline, and patients who underwent aortic valve replacement had follow-up echocardiographic studies 7 days and 6 months after surgery. Controls were an age-matched and gender-matched population from the same region who had undergone echocardiography and had normal echocardiographic findings. Written consent for the study was obtained from all patients. This study protocol was approved by the institutional ethics committee.

Two-dimensional LV apical four-chamber, two-chamber, long-axis, and parasternal short-axis (at the level of the papillary muscle) images were recorded to obtain strain measurements. Three consecutive cardiac cycle loops were recorded, and the measurements were averaged. The frame rate was kept between 70 and 100 Hz, and offline software (Syngo Velocity Vector Imaging [VVI]; Siemens Medical Solutions USA, Inc., Mountain View, CA) was used to analyze the Digital Imaging and Communications in Medicine–formatted grayscale images. B-mode pixel-tracking algorithms for measuring strain have been previously validated.20,21 Recently, measurements of subendocardial and subepicardial function by strain analysis were reported.22-25 For the measurements of transmural radial strain, a circular region of interest was traced on the endocardium using the end-diastolic frame. Then, a second larger concentric circle was automatically generated and manually adjusted near the epicardium. Finally, a point of reference was placed at the center of the cavity for the calculation of radial strain. For the measurement of subendocardial radial strain, the endocardial tracing remained the same, but the second larger concentric circle was manually adjusted in the midwall of the myocardium using the end-diastolic frame. For the measurement of subepicardial radial strain, the first circular region of interest was traced on the midwall of the myocardium, and the second larger concentric circle was manually adjusted near the epicardium. For the measurement of longitudinal strain, the subendocardial border was traced manually. A region of interest was manually adjusted to include the entire myocardial thickness. VVI software automatically divided the LV mid short-axis image into six equal segments and the apical images into 18 segments and then generated time-strain curves from each segment. The maximum strain values of the mid six segments of the left ventricle were averaged and taken as the radial and longitudinal strain values for each patient (Figures 1 and 2).

Abbreviations

Echocardiographic Measurements Conventional transthoracic echocardiographic examinations were performed using commercially available ultrasound transducer and equipment (S5-1, iE33; Philips Medical Systems, Andover, MA). All two-dimensional grayscale echocardiographic images were obtained using the second harmonic mode. Standard two-dimensional measurements were performed, including the thickness of the interventricular septum and posterior wall at end-diastole, LV dimension at end-diastole, and LV dimension at end-systole.15 LV ejection fraction was calculated using the modified biplane Simpson method as recommended by the American Society of Echocardiography. LV mass and LV mass index were calculated using the formula proposed by Devereux and Reichek.16 Fractional shortening and midwall fractional shortening were calculated using standard formulas.17,18

Cardiac Catheterization All patients underwent left-sided cardiac catheterization within 7 days of echocardiography, including coronary angiography and LV pressure recordings. Patients with mild to moderate AS underwent catheterization on suspicion of angina pectoris and those with severe AS for aortic valve evaluation.

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Figure 1 Longitudinal strain (left), transmural radial strain (middle left), subendocardial radial strain (middle right), and subepicardial radial strain (right) in a patient with mild AS. The bilayer ratio was 2.7 in this patient.

Figure 2 Longitudinal strain (left), transmural radial strain (middle left), subendocardial radial strain (middle right), and subepicardial radial strain (right) in a patient with severe AS. The bilayer ratio was 1.3 in this patient. Reproducibility of the VVI Method Interobserver and intraobserver variability was assessed for longitudinal, transmural, subendocardial, and subepicardial radial strain measurements by VVI software in 10 randomly selected subjects. Interobserver variability was calculated as the SD of the differences between the measurements of two independent observers who were unaware of the other patient data and expressed as a percentage of the average value. Intraobserver variability was calculated as the SD of the differences between the first and second determinations (2-week interval) for a single observer and expressed as a percentage of the average value. Statistical Analysis Continuous variables are expressed as mean 6 SD. Differences of continuous and normally distributed variables among groups were compared using analysis of variance. Differences between two groups were assessed using c2 or Fisher’s exact tests for categorical variables, and comparisons of continuous variables were made using unpaired

Student’s t tests. Serial measurements within each group were compared using paired Student’s t tests. Correlation coefficients between various measurements and strain parameters were determined by linear regression analysis. Variables with P values < .10 on univariate analysis were incorporated in to the multiple linear regression model to identify determinants of the ratio of subendocardial to subepicardial radial strain (bilayer ratio). Differences were considered significant when the P value was < .05. All statistical analyses were performed using StatView version 5.0 for Windows (SAS Institute Inc., Cary, NC). RESULTS Patient Characteristics Among the 80 consecutive patients who had met eligibility criteria, seven patients were excluded from this study because of inadequate image quality for the measurement of strain values. The remaining 73 patients (29 men, 44 women; mean age, 84 6 8 years) were

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Table 1 Baseline characteristics AS Moderate (n = 15)

Severe (n = 48)

Mild (n = 10)

Age (y) Men NYHA classification I II III IV Body surface area (m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LV systolic pressure (mm Hg) LV end-diastolic pressure (mm Hg) Heart rate (beats/min) Echocardiography LV end-diastolic volume/body surface area (mL/m2) LV end-systolic volume/body surface area (mL/m2) Relative wall thickness Stroke volume (mL) LVEF (%) MWFS (%) E/E0 ratio LV mass index (g/m2) AVA (cm2) Peak PG (mm Hg) Mean PG (mm Hg) Longitudinal strain (%) Transmural radial strain (%) Subendocardial radial strain (%) Subepicardial radial strain (%) Bilayer ratio§

82 6 10 6

80 6 9 6

10 (100%) 0 (0%) 0 (0%) 0 (0%) 1.9 6 0.2 139 6 26 65 6 12 166 6 18 22 6 5 69 6 16

13 (87%) 2 (13%) 0 (0%) 0 (0%) 1.8 6 0.3 131 6 27 62 6 12 171 6 26 18 6 11 68 6 10

24 (50%)*,†,‡ 18 (38%)*,†,‡ 5 (10%) 1 (2%) 1.7 6 0.2 137 6 22 60 6 11 190 6 29† 18 6 6 66 6 9

20 (100%) 0 (0%) 0 (0%) 0 (0%) 1.8 6 0.2 130 6 22 62 6 11 — — 66 6 10

<.001 <.001 .18 .82 .29 .71 .67 — — .73

46 6 8 14 6 4 0.47 6 0.12 85 6 20 63 6 5 16 6 3 12 6 3 78 6 15 1.6 6 0.5 29 6 11* 16 6 8* 18 6 3 34 6 13 56 6 5 24 6 5 2.4 6 0.5*

48 6 13 15 6 8 0.51 6 0.08 73 6 22 61 6 2 15 6 3* 15 6 10 104 6 20* 1.1 6 0.1† 50 6 19*,† 30 6 12*,† 17 6 3* 34 6 11 49 6 16* 28 6 8 1.7 6 0.3*,†

48 6 12 14 6 6 0.61 6 0.15*,†,‡ 66 6 21*,† 61 6 4 14 6 3*,†,‡ 22 6 8*,†,‡ 137 6 31*,†,‡ 0.7 6 0.2†,‡ 82 6 24*,†,‡ 48 6 17*,†,‡ 14 6 3*,†,‡ 30 6 9* 37 6 10*,†,‡ 28 6 7* 1.3 6 0.3*,†,‡

47 6 10 16 6 6 0.44 6 0.09 86 6 18 62 6 4 18 6 3 11 6 4 75 6 21 — 963 562 20 6 3 35 6 8 59 6 10 22 6 5 2.7 6 0.6

.88 .88 <.001 <.001 .53 <.001 <.001 <.001 — <.001 <.001 <.001 .18 <.001 .38 <.001

86 6 7 17

Control (n = 20)

P

Variable

82 6 8 12

.10 .20

LVEF, LV ejection fraction; NYHA, New York Heart Association; MWFS, midwall fractional shortening; PG, transaortic pressure gradient. Data are expressed as mean 6 SD or as number (percentage). *P < .05 versus control. † P < .05 versus mild AS. ‡ P < .05 versus moderate AS. § Ratio of subendocardial to subepicardial radial strain.

classified into three groups: 10 with mild AS, 15 with moderate AS, and 48 with severe AS. Characteristics of the 73 patients and 20 controls are shown in Table 1. As expected, there were significant differences regarding New York Heart Association class, relative wall thickness, stroke volume, midwall fractional shortening, E/E0 ratio, LV mass index, and peak and mean pressure gradient among the all groups.

tions between longitudinal strain or subendocardial radial strain and LV ejection fraction, LV mass index, AVA, and peak pressure gradient, these correlations were stronger for bilayer ratio. Moreover, there was a moderate correlation between bilayer ratio and E/E0 ratio that was not seen with longitudinal strain or subendocardial radial strain. By multivariate linear analysis, AVA was independently associated with bilayer ratio (Table 3).

Longitudinal and Radial Strain Parameters Longitudinal, transmural, subendocardial, and subepicardial radial strain and bilayer ratio at baseline are shown in Table 1. Although there were no differences among groups for transmural and subepicardial radial strain, bilayer ratio decreased significantly as the severity of AS became more serious (Figures 1 and 2). Longitudinal strain and subendocardial radial strain could not differentiate mild and moderate AS patients. In addition, linear regression analysis showed the relationship between AS parameters and strain parameters (Table 2). Although there were weak correla-

Changes in Echocardiographic and Strain Parameters before and after Aortic Valve Replacement Among 73 patients, 21 patients underwent aortic valve replacement because they developed symptoms, such as palpitation, dyspnea, and chest pain, for which surgery was the answer to provide relief for the patients. Echocardiographic parameters before, 7 days after, and 6 months after aortic valve replacement for 21 patients are shown in Table 4. Heart rate significantly increased after aortic valve replacement in these patients. In addition, peak and mean pressure gradients significantly decreased after surgery. No changes were observed in LV

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Table 2 Correlations between strain parameters and echocardiographic parameters Longitudinal Subendocardial strain strain Bilayer ratio‡

Variable

LV systolic pressure LV end-diastolic pressure LVEF E/E0 ratio LV mass index AVA Peak PG Mean PG

0.20 0.18 0.25* 0.16 0.30* 0.45† 0.25* 0.15

0.059 0.16 0.25* 0.15 0.35* 0.50† 0.24* 0.17

0.24 0.17 0.37* 0.33* 0.55† 0.71† 0.54† 0.50†

LVEF, LV ejection fraction; PG, transaortic pressure gradient. *P < .05. † P < .001. ‡ Ratio of subendocardial to subepicardial radial strain.

Table 3 Multivariate analysis for bilayer ratio* Variable

b

SE

P

Model R2

Age LV systolic pressure Relative wall thickness Stroke volume LV mass index E/E0 ratio AVA

0.030 0.036 0.035 0.13 0.035 0.072 0.70

0.006 0.002 0.39 0.002 0.002 0.006 0.19

.75 .73 .74 .19 .77 .49 <.001

0.58 (P < .001)

Table 4 Echocardiographic parameters before and after AVR (n = 21) Variable

Before AVR

Heart rate (beats/min) 63 6 9 LV end-diastolic volume/body 52 6 15 surface area (mL/m2) 17 6 6 LV end-systolic volume/body surface area (mL/m2) IVS thickness (mm) 13 6 1 PW thickness (mm) 13 6 2 LVEF (%) 61 6 4 LVFS (%) 37 6 7 MWFS (%) 15 6 9 LV mass index (g/m2) 134 6 28 Peak PG (mm Hg) 81 6 25 Mean PG (mm Hg) 47 6 17 E velocity (cm/sec) 122 6 34 A velocity (cm/sec) 78 6 30 E/A ratio 1.9 6 1.1 DcT (msec) 223 6 53 5.8 6 1.1 E0 velocity (cm/sec) 5.9 6 2.1 A0 velocity (cm/sec) 22 6 7 E/E0 ratio Longitudinal strain (%) 14 6 3 Transmural radial strain (%) 31 6 7 Subendocardial radial 37 6 8 strain (%) Subepicardial strain (%) 27 6 6 1.4 6 0.2 Bilayer ratio‡

7 days after AVR

6 months after AVR

73 6 13* 52 6 12

66 6 6 52 6 12

16 6 5

16 6 5

12 6 1 11 6 1† 12 6 2 11 6 1*,† 61 6 3 62 6 3 37 6 8 38 6 8 14 6 2 16 6 3† 124 6 33 114 6 26*,† 23 6 8* 26 6 16* 12 6 7* 12 6 6* 106 6 30 86 6 19*,† 79 6 30 78 6 25 1.7 6 1.1 1.3 6 0.9*,† 217 6 48 226 6 48 6.3 6 1.6 6.2 6 1.3 5.5 6 1.8 5.6 6 1.5 18 6 6 15 6 5*,† 15 6 4 17 6 3*,† 32 6 6 33 6 5 47 6 11* 50 6 7* 25 6 6 24 6 4 1.9 6 0.2* 2.0 6 0.1*

*Ratio of subendocardial to subepicardial radial strain.

volume, wall thickness, LV mass index, LV systolic function (ejection fraction and fractional shortening), midwall fractional shortening, and diastolic function 7 days after surgery. However, wall thickness and LV mass index decreased, midwall fractional shortening increased, and diastolic function improved 6 months after surgery. In addition, significant increases were observed in subendocardial radial strain and bilayer ratio 7 days and 6 months after aortic valve replacement, but not in transmural and subepicardial radial strain. Longitudinal strain increased significantly 6 months after aortic valve replacement, while no difference was found between baseline and 7 days after aortic valve replacement. The changes in bilayer ratio before and 7 days after or before and 6 months after surgery were significantly correlated with the changes of peak pressure gradient (r = 0.47, P = .03, and r = 0.43, P < .05, respectively). In addition, the changes in LV mass index and those in peak pressure gradient showed a significant correlation 6 months after surgery (r = 0.45, P < .05). Intraobserver and Interobserver Variability The mean absolute differences of all strain measurements by VVI software were 5.0 6 3.3% (interobserver) and 4.8 6 3.2% (intraobserver).

DISCUSSION A progressively aging population, in addition to an increasing life expectancy observed in recent decades, has resulted in a growing number of patients with significant AS. Aortic valve replacement is

AVR, Aortic valve replacement; DcT, deceleration time; IVS, interventricular septal; LVEF, LV ejection fraction; LVFS, LV fractional change; MWFS, midwall fractional shortening; PG, transaortic pressure gradient; PW, posterior wall. Data are expressed as mean 6 SD. *P < .05 versus before AVR. † P < .05 versus 7 days after AVR. ‡ Ratio of subendocardial to subepicardial radial strain.

the only effective treatment for AS, and yet numerous studies have suggested that up to 30% of patients with severe, symptomatic AS go untreated.26,27 Iung et al.27 showed that one of the primary factors influencing physician decisions to withhold therapy is the reduction in ejection fraction. This decision may be driven by the increased operative risk seen with the development of LV dysfunction.28 Hence, to reduce operative risk and to identify the appropriate patients who may benefit most from intervention, a more accurate assessment of LV dysfunction is needed. Manaka et al.14 showed that myocardial systolic impairment may originate at the endocardial side and then extend to the epicardium, as shown in this study. This might be explained by subendocardial underperfusion. It is hypothesized that increased extravascular resistance leads to deformation of vessels in the myocardial microvasculature by the mechanical motion of the beating heart, and reduction in diastolic perfusion is responsible for myocardial ischemia in the absence of epicardial coronary artery stenosis.29 With continued ischemia, myocardial hibernation and subsequent fibrotic tissue replacement ensue, which are particularly prominent in the subendocardial myocardium and lead to the reduction of subendocardial thickening.

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Conventional echocardiographic measures of ventricular function, such as ejection fraction and fractional shortening, may not accurately reflect the complex mechanics of the ventricular wall function or the relationship between the subendocardium and subepicardium. Because of the complex nature of myocardial fiber orientation as well as endocardial to epicardial transmission of afterload, numerous studies have suggested that midwall fractional shortening may be a better measure of systolic function than endocardial fraction shortening.17,18 However, we found that midwall fractional shortening was not a sensitive marker for differentiating AS severity. This might be explained by the fact that midwall fractional shortening was mainly related to LV mass and to LV geometry,30 while bilayer ratio was affected by the combination of LV afterload, LV systolic and diastolic function, and LV mass, as shown in Table 2. Thus, bilayer ratio may be superior to midwall fractional shortening for detecting changes in LV hemodynamics and mechanics associated with AS. Bilayer ratio may also be a better marker for the detection of early improvement of LV mechanics after aortic valve replacement, as early as 7 days after surgery. In contrast, no changes were observed at that time with the conventional echocardiographic parameters, including ejection fraction and midwall fractional shortening. Because of the relationship between midwall fractional shortening and LV mass index, which clearly cannot remodel acutely, this parameter may not be able to detect the acute changes of LV mechanics associated with aortic valve replacement. However, when bilayer ratio is measured, it can be an early marker for detecting the hemodynamic changes, which was reflected in the relationship between changes in bilayer ratio and maximal pressure gradient in patients undergoing aortic valve replacement. Previous studies using strain imaging have shown that patients with AS have lower transmural strain.31-33 Iwahashi et al.31 showed that tissue Doppler–derived transmural strain was a sensitive marker for myocardial function 2 weeks after aortic valve replacement in patients with AS. Furthermore, Delgado et al.32 reported a significant increase in radial, circumferential, and longitudinal transmural strain and strain rate 17 months after aortic valve replacement, whereas LV ejection fraction remained unchanged. Likewise, other studies demonstrated that the longitudinal strain was reduced in patients with AS.33,34 Although our study confirmed lower transmural radial strain in patients with severe AS compared with those with mild or moderate AS, we found that transmural strain cannot distinguish the all groups. However, when longitudinal strain, subendocardial radial strain, and bilayer ratio were assessed, those stain values accurately discriminated among the all groups, which showed the superiority of longitudinal strain, subendocardial radial strain, and bilayer ratio rather than transmural strain in patients with AS. It is interesting to note that subepicardial strain tends to increase in patients with moderate to severe AS and decrease after aortic valve replacement. The increase in subepicardial thickening could be an attribute of the decrease in the subendocardial thickening due to the subendocardial ischemia, as it compensates for the reduction of transmural thickening of myocardium. This finding indicated that bilayer ratio could be the best parameter for the assessment of LV function in patients with AS taken independently, rather than longitudinal strain or subendocardial radial strain, which might represent only subendocardial function. Therefore, we recommend bilayer ratio analyzed by radial direction as a novel parameter for assessing LV mechanics in patients with AS. The evaluation of bilayer ratio thus has potential utility in the assessing patients with severe AS. The relationship between bilayer ratio and AVA and the results of multivariate analysis support the

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importance of this ratio as a marker of AS severity. The high correlation between the ratio and valve area may allow this parameter to be used as a surrogate in patients with AS whose severity is difficult to assess. It may overcome the limitations of midwall fractional shortening after acute changes in hemodynamics and absence of LV remodeling. It may also be applicable not only in patients with AS but also in patients with high arterial impedance for other reasons, whose subendocardial perfusion may be impaired in the setting of high intracavitary pressures. Study Limitations The relatively small sample size of this study should be kept in mind, and further studies are required to confirm our observations. A high-quality image is needed, and special care must be taken in drawing the outline of the region of interest, because VVI is based on two-dimensional grayscale image. Because of these technical issues, we were not able to analyze the studies of seven patients (9%). Moreover, we chose a group without coronary artery disease and moderate or severe hypertension to avoid the confounding effects associated with these conditions. Therefore, our results may not be extrapolated to different patient populations. Finally, the prognostic significance of this finding needs to be explored in appropriately designed and powered outcome studies.

CONCLUSIONS This study showed that (1) bilayer ratio can reliably differentiate patients with varying degrees of AS severity, (2) bilayer ratio may be a better determinant of LV function in the setting of increased afterload compared with ejection fraction or midwall fractional shortening, and (3) bilayer ratio may be an accurate determinant of early recovery of LV function after aortic valve replacement. Thus, the evaluation of subendocardial and subepicardial strain is a novel method for assessing LV mechanics in patients with AS.

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