Doppler Tissue, Strain, and Strain Rate Imaging in Pediatric Patients with Alström Syndrome: Are There Regional Functional Abnormalities?

Doppler Tissue, Strain, and Strain Rate Imaging in Pediatric Patients with Alström Syndrome: Are There Regional Functional Abnormalities? Alene Toulany, BSc, Sarah Shea, MD, FRCPC, and Andrew E. Warren, MD, MSc, FRCPC

Objective: We sought to determine the potential additive usefulness of Doppler tissue imaging (DTI), strain (⑀), and ⑀ rate (SR) imaging in assessing systolic function in pediatric patients with Alström syndrome. Methods: We conducted a case-control study at a pediatric hospital with 5 patients (age 5-18 years) with Alström syndrome living in Atlantic Canada and 21 age- and sex-matched healthy control subjects. Standard echocardiographic examination was followed by DTI of the interventricular septum (IVS) and left ventricle (LV) lateral wall, longitudinal ⑀, and SR at the basal, mid, and apical segments of the LV lateral, inferior, and anterior walls, and the IVS. We also imaged radial ⑀ and SR of the interventricular posterior wall. Results: For patients versus control subjects, conventional ejection fraction (0.65 vs 0.72) and fractional shortening (0.30 vs 0.35) did not distinguish

Alström syndrome (AS) is a rare and complex

autosomal recessive disorder that evolves continuously during childhood and affects numerous organ systems. Resulting from homozygosity for a mutation of the ALMS1 gene, the earliest manifestations of the disease include nystagmus, obesity, insulin resistance, and dilated cardiomyopathy.1-3 Although the cardiomyopathy frequently presents early in infancy,4 relatively late deterioration of cardiac function occurring in adolescence and early adulthood has also been documented.5

From the Division of Cardiology (A.T., A.E.W.), and Division of Child Development (G.S.), IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada. This work was supported by a Webster Summer Studentship in Medical Genetics, a grant from the Isaac Walton Killam (IWK) Research Office, and by the IWK Division of Pediatric Cardiology Research Fund. Reprint requests: Andrew E. Warren, MD, Children’s Heart Centre, IWK Health Centre, PO Box 9700, Halifax, Nova Scotia B3K 6R8. 0894-7317/$32.00 Copyright 2006 by the American Society of Echocardiography. doi:10.1016/j.echo.2005.07.008

14

between groups. DTI-derived s-waves consistently demonstrated significant differences in systolic function (LV lateral wall 0.073 vs 0.100; IVS 0.064 vs 0.080; LV anterior wall 0.066 vs 0.096; LV inferior wall 0.069 vs 0.092 [P < .05 in all positions]). ⑀ Differences were observed in the movement of the mid-LV lateral (ⴚ10.4 vs ⴚ15.2, P ⴝ .035), basal LV anterior wall (ⴚ16.3 vs ⴚ22.9, P ⴝ .004), and the apical IVS (ⴚ6.3 vs ⴚ13.8, P ⴝ .015). SR at the midposition of the LV lateral wall (ⴚ0.7 vs ⴚ1.4, P ⴝ .000) also differed between the groups. Substantial diastolic function differences were also observed between patients and control subjects. Conclusion: Detection of systolic and diastolic function abnormalities in patients with Alström syndrome can potentially be enhanced by the use of DTI, ⑀, and SR imaging. (J Am Soc Echocardiogr 2006; 19:14-20.)

There is significant phenotypic variability among patients with AS. This variability applies to the particular symptoms manifested, but also exists in relation to the time of appearance, progressive development, and magnitude of the clinical features.2,4,6-13 Generally, the presence of early-onset cardiomyopathy in patients with AS is followed by significant recovery of myocardial function in the short term.2 Of late, however, investigators are finding a recurrence of cardiomyopathy in the teenage years whereas other patients are developing cardiomyopathy for the first time during this period.5,14 The prediction of which children will develop cardiomyopathy is currently not possible, making long-term advice and counselling for parents difficult. This phenotypic variability is also reflected in the cardiac pathology of patients with AS. In the limited number of pathologic specimens available, varying degrees of myocardial fibrosis have been noted, ranging from mild to severe.5 Doppler tissue imaging (DTI) is a relatively new ultrasound-based technology that allows direct quantification of myocardial velocities throughout the cardiac cycle.15-17 Although it is proving useful in the analysis of systolic and diastolic function

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abnormalities in adults, its application in children is less well studied.18,19 In hypertrophic cardiomyopathy, there is hope that the use of DTI will provide a means of early identification of those at risk.20-22 Although children with AS develop dilated cardiomyopathy, rather than hypertrophic, the early diagnosis of systolic abnormalities would provide for similarly useful information. DTI has also spawned several other imaging modalities such as ultrasonic strain (⑀) and ⑀ rate (SR) imaging that allow assessment of local changes in myocardial deformation.23,24 Strain rate is derived by estimating the regional spatial gradient in myocardial velocities and represents the rate of local wall deformation.23,24 The time integral of the regional SR is ⑀, which represents the local magnitude of wall deformation expressed as a percentage.23,24 When compared with myocardial velocities, ⑀ and SR measurements have been shown to be less influenced by overall heart motion and tethering effects induced by rotation and contraction of adjacent myocardial segments.25 Therefore, ⑀ and SR imaging may better characterize regional differences in left ventricular (LV) function in patients with AS as compared with other standard imaging methods. The aim of this study was to describe the DTI, LV ⑀, and SR imaging profile of patients with AS with and without cardiomyopathy, in comparison with healthy control subjects. Preliminary data derived from these investigations will help to determine the potential clinical value and additive usefulness of DTI, ultrasonic ⑀, and SR imaging in assessing regional differences in LV function and deformation in patients with AS compared with standard ultrasound techniques. These new noninvasive imaging modalities may also be of value in identifying predictors of late-onset cardiomyopathy and prognostic factors for individual patients.

METHODS Participants Patients with AS living in Atlantic Canada were identified retrospectively through a search of a cardiology database. In an effort to maximize enrollment, AS parent group representatives were contacted to offer participation to their members. A total of 5 patients with AS were identified and their diagnoses were confirmed by review of all available medical records. Demographic information, organ system involvement, and cardiac status were also obtained from chart reviews. Information collected on cardiac status included symptoms, examination findings, electrocardiography findings, and echocardiography findings. A total of 21 age- and sex-matched healthy control participants without a history of cardiac disease and with normal findings on rest electrocardiogram and echocardiography were identified from the community using post-

Toulany, Shea, Warren 15

ers at our center and Dalhousie Medical School. As no reference data for normal ⑀ and SR in children existed at the time of the study, an age-matched control population was recruited. Given the small number of patients with AS, to enhance the reliability of the control data, 4 control participants were recruited for each study patient. Written informed consent was obtained from the parent or guardian of minors and, when appropriate, consent was also obtained from the patient. All study protocols were approved by the IWK Health Center research ethics board. Echocardiography Standard transthoracic M-mode, 2-dimensional, and Doppler electrocardiograms were performed in the left lateral decubitus position using a digital ultrasound scanner (Vivid V, GE Vingmed, Horten, Norway) equipped with 2.5- and 3.5-MHz phased-array transducers. Three consecutive cardiac cycles were acquired at end-expiratory apnea for each parameter under study and stored in digital format. Data were transferred to a computer workstation for offline analysis using dedicated software (EchoPAC, GE Vingmed). Height and weight measurements were obtained before the echocardiographic evaluation, whereas blood pressure and heart rate were recorded afterward. The electrocardiogram was recorded simultaneously. Standard M-mode, 2-dimensional, and Doppler measurements. Standard M-mode measurements of septal and

posterior wall thickness, LV end-diastolic and end-systolic dimensions, LV ejection fraction, and LV fractional shortening were obtained in the parasternal long-axis view according to the recommendations of the American Society of Echocardiography.26 Mitral flow velocities were recorded with pulsed wave Doppler in the standard apical 4-chamber view with the sample volume positioned at the tips of the mitral valve leaflets. The position and size of the sample volume were adjusted to obtain maximally and clearly defined velocity waveforms. Gains were minimized to allow a clear tissue signal with minimal background noise. The peak velocity in early diastole (E wave), peak filling velocity with atrial contraction (A wave), deceleration time (DT), time interval from the onset to the termination of A wave (A duration), and the E/A ratio were measured. The DT was measured by extrapolating the initial slope of the E wave to the baseline. Pulmonary venous flow was recorded by placing the sample volume 0.5 to 1 cm into the orifice of the right upper pulmonary vein with the aid of color flow imaging. The maximal velocities of pulmonary vein flow at systole, diastole, and atrial reversal were measured. Myocardial velocities were measured by placing the sample volume at the junction of the mitral annulus with the interventricular septum (IVS) and LV lateral basal myocardial segments from the 4-chamber view and inferior and anterior basal myocardial segments from the 2-chamber view. From the Doppler tissue recordings, the following measurements were made: peak systolic wall-

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16 Toulany, Shea, Warren

Table 1 Baseline characteristics of patients with Alström syndrome Patient No.

Age, y-mo

Sex

Cardiac symptoms

1

13-06

F

2

14-09

F

SOB with mild exertion (15 min on treadmill) No SOB with mild exercise (15 min on bike)

3

16-11

F

SOB at rest with marked limitation of activity, orthopnea, severe fatigue

4

19-01

M

5

5–10

F

SOB with mild-moderate exertion, lethargy No limitation of activity

Cardiac medications

ECG

EF

FS

NSR, diffuse T-wave abnormalities NSR, nonspecific lateral and inferior T⫺ wave changes

0.64

0.29

0.74

0.23

Lisinopril, digoxin, furosemide, spironolactone, carvedilol

NSR, left atrial enlargement, diffuse nonspecific T-wave flattening

0.54

0.23

None

NSR

0.74

0.36

None

NSR

0.62

0.27

None Spironolactone, furosemide

ECG, Electrocardiographic findings; EF, ejection fraction; F, female; FS, fractional shortening; M, male; NSR, normal sinus rhythm; SOB, shortness of breath.

motion velocity, and early (E’) and late diastolic wall motion velocities. ⑀ and SR imaging. Real-time 2-dimensional color Doppler myocardial imaging data for longitudinal ⑀ and SR were recorded from the right ventricular (RV) free wall, the IVS, and the LV lateral, inferior, and anterior walls using standard apical 4- and 2-chamber views. Radial ⑀ and SR of the LV posterior wall was recorded using the parasternal long-axis view. Longitudinal ⑀ and SR in the basal, mid, and apical segments of each wall were estimated by measuring the spatial velocity gradient over a computation area of 10 to 12 mm. Radial ⑀ and SR at the tip of the mitral valve leaflets in the LV posterior wall were estimated by measuring the spatial velocity gradient over a computation area of 4 to 6 mm to keep the computation area within the myocardial segment throughout diastole. A region of interest of 5 ⫻ 5 pixels was used for offline quantification of raw data. The cursor was continuously positioned within the interrogated segment using a semiautomatic tracking algorithm to keep the measurement site at approximately the same position throughout the heart cycle. Using a built-in algorithm, SR profiles were averaged over 3 consecutive heart cycles and integrated over time to derive natural ⑀ profiles using end diastole as the reference point. From the averaged ⑀ and SR curves, peak systolic SR, peak early diastolic SR, peak late diastolic SR, and systolic ⑀ were measured. In some cases, the heart rate variability caused more than 10% difference between the length of the different R-R intervals. In these cases, averaging over 3 consecutive heart cycles would have masked the real shape of the ⑀ and SR curves and, for this reason, the parameters were measured for each heart cycle separately and the mean parameter values were calculated afterward. Statistical Analysis Echocardiographic data for each group are presented as mean and SD. Differences between groups were com-

pared using t tests. As this was considered a pilot study, no correction was made for multiple comparisons. All analyses were carried out using software (SPSS for windows release 11.5.0; SPSS Inc., Chicago, IL).

RESULTS All 5 patients with AS (age range: 5-18 years) alive at the time of this investigation were successfully recruited for participation in this study. Baseline characteristics of these patients are provided in Table 1. A total of 21 age- and sex-matched healthy control participants were also examined. Color Doppler myocardial imaging data sets could be obtained from all of the children studied. The data were regularly of good quality and permitted subsequent offline analysis in all but a few segments of LV anterior and inferior walls. The reasons for excluding data from these myocardial segments were reverberation artefacts, low signal-to-noise ratio, or poor angle of insonation (␪). Although conventional M-mode measurements such as LV fractional shortening and ejection fraction failed to adequately distinguish between the two study groups (Table 2), Doppler tissuederived systolic myocardial velocities consistently demonstrated significant differences in systolic function (P ⬍ .05 in all positions) (Table 3). Individuals with AS demonstrated decreased systolic wall motion velocities in all of the regions measured. The greatest reduction in velocity occurred at the junction of the mitral valve with the LV anterior wall (P ⫽ .000). Regional ⑀ and SR imaging demonstrated local differences in myocardial function and deformation for patients with AS compared with healthy

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Toulany, Shea, Warren 17

Table 2 Standard M-mode measurements in patients with Alström syndrome and healthy control subjects Mean (SD)

AS

LV end-diastolic diameter, cm LV end-systolic diameter, cm LV ejection fraction LV fractional shortening

Control subjects

P value

5.32 (0.60) 4.76 (0.49)

.105

3.74 (0.53) 3.09 (0.40)

.050

0.65 (0.06) 0.72 (0.06) 0.30 (0.06) 0.35 (0.05)

.164 .142

AS, Alstrom syndrome; LV, left ventricle.

Table 3 Peak systolic myocardial velocities (m/s) obtained from the mitral valve junction with the interventricular septum and the left ventricular lateral, anterior, and inferior walls in patients with Alström syndrome and healthy control subjects Mean peak myocardial velocities (SD)

AS

LV lateral (4 Ch) IVS (4 Ch) LV anterior (2 Ch) LV inferior (2 Ch)

0.073 0.064 0.066 0.069

(0.014) (0.011) (0.010) (0.005)

Control subjects

0.100 0.080 0.096 0.092

(0.016) (0.008) (0.017) (0.014)

P value

.008 .032 .000 .000

AS, Alström syndrome; IVS, interventricular septum; LV, left ventricle; 2 Ch, apical 2 chamber view; 4 Ch, apical 4-chamber view.

control subjects. Peak systolic SR and ⑀ values of the basal, mid, and apical segments of the RV, IVS, and LV lateral, inferior, and anterior wall are summarized in Tables 4 and 5. Systolic SR was significantly reduced in the apical segment of the IVS, mid and apical segments of the LV lateral wall, apical segment of the LV inferior wall, and the mid and apical segments of the RV wall of patients with AS (Table 4). Similarly, peak systolic ⑀ was significantly reduced in the apical segment of the IVS and midsegment of the LV lateral wall of patients with AS. Significant ⑀ differences were also observed in the basal segment of the LV anterior wall. Deformation in the RV free wall appeared most severely affected in AS, with both the mid and apical segments showing significant reduction in systolic ⑀ (Table 5). The various measures of diastolic function assessed demonstrated a mixed picture (Table 6). DT was significantly shorter in the AS group than in the control group. E’ velocity was lower and the E/E’ ratio was higher in the AS group than in the control subjects. Both findings support a more restrictive filling pattern in the patients with AS. Other measures of diastolic function failed to show statistically significant differences.

DISCUSSION Alström Syndrome is a complicated disorder that evolves continuously during childhood and adolescence. The first manifestations of the disease are often severe dilated cardiomyopathy, cone-rod dystrophy, and nystagmus.4 Although a number of investigators have identified various aspects of the cardiac disease experienced by patients with AS,2,4 the origin and long-term natural history of the cardiac disease in patients with AS has not been fully described. Recently, clinicians have noticed a relatively late decline in cardiac function, occurring in adolescence or early adulthood.14 This observation, along with the findings of recurrence of dilated cardiomyopathy in a growing number of patients with AS who survived an initial episode of heart failure as infants, indicates that cardiac function should be regularly monitored throughout the lives of these patients. The prediction of which children will develop cardiomyopathy or when it will develop is currently not possible, making the longterm advice and counselling for patients and parents difficult. Noninvasive quantification of regional myocardial deformation properties by ultrasonic ⑀ and SR imaging has made it possible to study regional morphologic abnormalities and function in acquired or congenital heart disease. In particular, assessment of function in the longitudinal axis of contraction is facilitated by these methods. In this study, we evaluated regional LV systolic abnormalities in patients with AS with the use of DTI, ultrasonic ⑀, and SR imaging, highlighting the potential clinical use of these methods in assessing subtle differences in LV regional systolic function. We have shown that the regional longitudinal deformation parameters, ⑀ and SR, differentiate abnormalities in regional cardiac function in this population. Strain and SR imaging results suggest that longitudinal systolic shortening is most severely impaired in patients with AS at the basal segment of LV anterior wall, the apical portion of the IVS, and the mid and apical segments of the RV free wall, the latter being relatively more affected than other regions. Although reasons for these particular regions to be affected are speculative, it may be that the as yet undefined protein abnormality in AS is more important in longitudinal fiber function than in circular fiber function. In healthy control subjects, we found that longitudinal systolic ⑀ values were higher in the RV free wall than in any other wall measured. The highest systolic ⑀ was found in the midwall segment of the RV. These results are consistent with previously published ⑀ and SR imaging data in healthy children.19 The fact that longitudinal or oblique fibers are dominant within the RV free wall, whereas circular fibers are dominant in the LV lateral wall26,27 adds

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18 Toulany, Shea, Warren

Table 4 Regional peak systolic strain rate (sec-1) of the left and right ventricles in patients with Alström syndrome and healthy control subjects Mean peak systolic SR (SD) AS

LV lateral (4 Ch)

IVS (4 Ch)

RV (4 Ch)

LV anterior (2 Ch)

LV inferior (2 Ch)

Base Mid Apex Base Mid Apex Base Mid Apex Base Mid Apex Base Mid Apex

LV posterior wall (parasternal long axis)

⫺1.0 ⫺0.7 ⫺0.7 ⫺1.9 ⫺1.4 ⫺0.6 ⫺2.3 ⫺0.95 ⫺0.81 ⫺2.2 ⫺1.3 ⫺0.99 ⫺1.5 ⫺1.1 ⫺0.49 2.2

(0.53) (0.16) (0.34) (0.81) (0.44) (0.26) (0.45) (0.35) (0.60) (0.61) (0.56) (0.57) (0.63) (0.46) (0.48) (0.83)

Control subjects

⫺1.6 ⫺1.4 ⫺1.5 ⫺1.8 ⫺1.7 ⫺1.0 ⫺2.5 ⫺2.3 ⫺2.0 ⫺2.1 ⫺1.7 ⫺1.2 ⫺1.8 ⫺1.6 ⫺1.3 3.6

(0.79) (0.57) (0.97) (0.68) (0.48) (0.58) (1.5) (0.79) (1.1) (0.85) (0.61) (0.64) (1.2) (0.74) (0.74) (0.90)

P value

.080 .000 .013 .946 .148 .018 .634 .000 .006 .879 .170 .497 .490 .071 .016 .013

AS, Alström syndrome; apex, apical segment; base, basal segment; 2 Ch, apical 2-chamber view; 4 Ch, apical 4-chamber view; IVS, interventricular septum; LV, left ventricle; mid, midwall segment; RV, right ventricle; SR, strain rate.

Table 5 Regional peak systolic strain (%) of the left and right ventricles in patients with Alström syndrome and healthy control subjects Mean peak systolic strain (SD) AS

LV lateral (4 Ch)

IVS (4 Ch)

RV (4 Ch)

LV anterior (2 Ch)

LV inferior (2 Ch)

Base Mid Apex Base Mid Apex Base Mid Apex Base Mid Apex Base Mid Apex

LV posterior wall (parasternal long axis)

⫺10.9 ⫺10.4 ⫺8.6 ⫺20.4 ⫺20.1 ⫺6.3 ⫺24.6 ⫺15.9 ⫺11.1 ⫺16.3 ⫺12.9 ⫺11.0 ⫺19.4 ⫺19.4 ⫺11.0 30.3

(6.8) (2.8) (2.0) (8.5) (7.2) (4.4) (10.4) (5.9) (3.2) (2.9) (8.0) (3.2) (7.8) (9.6) (11.9) (4.9)

Control subjects

⫺16.8 ⫺15.2 ⫺11.6 ⫺24.2 ⫺22.5 ⫺13.8 ⫺26.3 ⫺27.0 ⫺18.3 ⫺22.9 ⫺20.8 ⫺11.7 ⫺17.0 ⫺18.6 ⫺12.7 76.3

(6.5) (7.7) (6.1) (4.8) (6.0) (7.0) (10.1) (7.6) (9.81) (6.7) (5.9) (8.1) (10.4) (9.3) (6.5) (29.5)

P value

.129 .035 .075 .383 .524 .015 .758 .008 .012 .004 .091 .755 .580 .873 .772 .000

AS, Alström syndrome; apex, apical segment; base, basal segment; 2 Ch, apical 2-chamber view; 4 Ch, apical 4-chamber view; IVS, interventricular septum; LV, left ventricle; mid, midwall segment; RV, right ventricle.

weight to the argument that these fibers may be more profoundly affected than circular fibers in patients with Alström Syndrome. In comparison with conventional M-mode echocardiography, our results suggest that detection of systolic abnormalities for patients with AS can be significantly enhanced by the use of Doppler tissue ultrasound. The systolic myocardial velocities obtained from the mitral valve junction with the IVS and the LV lateral, anterior, and inferior walls for

patients with AS were consistently reduced compared with healthy control subjects. In contrast, conventional parameters like ejection fraction and fractional shortening were not significantly different from control subjects. Doppler tissue imaging, therefore, holds promise for improved sensitivity in the detection of regional systolic function abnormalities. Our study has also demonstrated a new finding for patients with AS, namely that of diastolic function abnormalities. Although they demonstrated a mix-

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Toulany, Shea, Warren 19

Table 6 Diastolic function Mean (SD)

MV E wave velocity, m/s A wave velocity, m/s Deceleration time, s PV s velocity, m/s d velocity, m/s reverse a-wave velocity, m/s Doppler tissue, MV at septum E= velocity A= velocity Ratios E/A E/E= PV Arev time / MV A time

AS

Control subjects

P value

0.99 (0.14) 0.46 (0.05) 0.130 (0.036)

0.96 (0.17) 0.41 (0.11) 0.191 (0.030)

.704 .321 .036

0.58 (0.09) 0.69 (0.09) 0.28 (0.05)

0.48 (0.07) 0.65 (0.10) 0.24 (0.04)

.108 .459 .226

0.101 (0.016) 0.214 (0.026)

0.137 (0.017) 0.231 (0.048)

.003 .442

2.26 (0.49) 9.75 (1.65) 1.13 (0.17)

2.47 (0.63) 7.18 (1.89) 0.88 (0.11)

.492 .042 .119

A, late filling; A=, late filling (Doppler tissue imaging); AS, Alström syndrome; d, diastolic forward flow; E, early filling; E=, early filling (Doppler tissue imaging); MV, mitral valve; MV A time, duration of mitral valve A wave; PV, pulmonary vein; PV Arev time, duration of reverse A wave in PV; S, systolic foward flow.

ture of findings consistent, in some cases, with pseudonormalization (relatively normal E and A velocities and ratios, higher pulmonary vein d velocities than s velocities, and relatively low E’ and late diastolic wall motion velocities) and in others with restrictive physiology (short DT, high E/E’ ratio), there were enough differences in standard measures of diastolic function to suggest that diastolic dysfunction may be an important cause of morbidity in this group of patients. The presence of diastolic dysfunction is not implausible and may simply reflect the degree of myocardial fibrosis that is present. Very limited pathologic data is available, but the literature does appear to support a correlation between severity of cardiac disease and severity of fibrosis.5 From a clinical perspective, diastolic dysfunction should be specifically considered when a patient demonstrates clinical symptoms that are out of proportion to the degree of systolic dysfunction present. Given these results, we postulate that all patients with AS have a degree of heart muscle dysfunction. This dysfunction may be subclinical and undetectable by standard echocardiographic techniques. The reason some patients get clinical disease may relate to a second insult such as a superimposed viral illness, or to the degree of dysfunction of the as yet unknown protein that is coded for by the ALMS1 gene. Those with greater degrees of abnormality may have overt cardiomyopathy whereas others may have subclinical disease. Although potentially limited by problems such as noise within the data sets, significant angle dependency, and drift of the ⑀ curve, ultrasonic ⑀ and SR imaging offer advantages. These include derivation at the bedside with a minimum delay, being readily available, and being less influenced by overall car-

diac motion and tethering effects than myocardial velocities.25 In addition, regional ⑀ and SR values have been shown to be relatively independent of resting heart rate and age.19 These tests are also relatively inexpensive in comparison with other imaging modalities. This study has shown that ⑀ and SR imaging are practical and potentially useful clinical techniques that have important clinical applications in characterizing regional myocardial deformation in pediatric patients. The combined use of DTI and ⑀ and SR imaging is likely to offer a new noninvasive approach to the quantification and monitoring of systolic and diastolic function abnormalities and may also be of value in identifying prognostic factors for individual patients with AS. Although the results of this investigation are encouraging, they are limited by the small number of patients. Statistical comparisons, particularly those made in the M-mode data, must be considered in the context of the possibility of a type II error. However, these data can serve as pilot data for future multicenter investigations. Other limitations include the potential for interobserver bias when these techniques are applied to a wider population. These may limit the generalizability of the results, particularly in an obese population such as those with AS. Consequently, the impact of DTI and ultrasonic ⑀ and SR imaging on patient treatment needs further evaluation with regard to the clinical effectiveness beyond its established technical feasibility. REFERENCES 1. Alström CH, Hallgren B, Nilsson LB, et al. Retinal degeneration combined with obesity, diabetes mellitus, and neuroge-

20 Toulany, Shea, Warren

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