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European Heart Journal Advance Access originally published online on October 30, 2007
European Heart Journal 2007 28(23):2886-2894; doi:10.1093/eurheartj/ehm444
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Regional myocardial deformation in children with hypertrophic cardiomyopathy: morphological and clinical correlations

Javier Ganame1, Luc Mertens1, Benjamin W. Eidem2, Piet Claus3, Jan D'hooge3, Luke M. Havemann4, Colin J. McMahon4, Mac Arthur A. Elayda5, William K. Vaughn5, Jeffrey A. Towbin4, Nancy A. Ayres4 and Ricardo H. Pignatelli4,*

1 Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium
2 Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA
3 Cardiology Department, University Hospitals Leuven, Leuven, Belgium
4 Lillie Frank Abercrombie Section of Pediatric Cardiology, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin, Houston, TX 77030, USA
5 Division of Biostatistics and Epidemiology, Texas Heart Institute, Houston, TX, USA

Received 9 March 2007; revised 10 August 2007; accepted 13 September 2007; online publish-ahead-of-print 30 October 2007.

* Corresponding author. Tel: +1 832 826 5659; fax: +1 832 825 5899. E-mail address: cardop{at}bcm.tmc.edu or rhpignat{at}texaschildrenshospital.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Aims: Hypertrophic cardiomyopathy (HCM) is a disease with marked regional differences in wall thickness. However, the relation between myocardial function and wall thickness has not been well studied. Ultrasonic strain rate (SR) imaging makes it possible to study the regional myocardial deformation. We investigated whether regional systolic deformation is reduced in paediatric patients with HCM and evaluated its relation with wall thickness, electrocardiographic pattern, and exercise capacity.

Methods and results: We studied 41 children with asymmetric HCM (mean age 12.3 years) and 29 controls. Electrocardiograms, exercise testing (when feasible), and echocardiograms with tissue Doppler imaging were performed. Peak systolic SR, strain, post-systolic shortening, and time to maximal strain were calculated in the longitudinal direction from the basal septum, mid-septum, and basal lateral myocardial segments and in the radial direction from the basal antero-septal and infero-lateral myocardial segments. Children with HCM had a significant reduction in deformation in all myocardial segments when compared with controls. In the HCM group, peak systolic SR and strain were significantly lower in the basal septum when compared with the mid-septal and basal lateral myocardial segments. In the basal septum, post-systolic shortening was significantly higher and time to maximal strain significantly longer than in mid-septal and lateral myocardial segments. A strong inverse curvilinear relation between peak systolic strain and wall thickness was found (r = –0.86, P < 0.001), with no further decrease in the regional myocardial function demonstrated once maximal wall thickness exceeded a Z-score of 3.5. Peak systolic strain in the basal part of the septum correlated inversely with exercise capacity (r = 0.68, P < 0.01).

Conclusion: Systolic deformation is significantly and inhomogeneously reduced in children with HCM. This reduction in myocardial function is related to maximal wall thickness and decreased exercise capacity.

Key Words: Hypertrophy cardiomyopathy • Strain rate • Tissue Doppler • Echocardiography • Electrocardiogram


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Hypertrophic cardiomyopathy (HCM) is a disease with a heterogeneous morphological and clinical presentation.1 The familial form is caused in the majority of patients by mutations in genes encoding for sarcomeric proteins.2–7

From a clinical perspective, HCM is considered to be a predominantly diastolic disorder with relaxation abnormalities in the early stages that can progress towards a more restrictive physiology later on in the disease process.8–12 In the early stages, systolic function has been believed to be preserved. The commonly used echocardiographic measures of ejection performance, namely, ejection fraction and fractional shortening, might not reliably reflect intrinsic myocardial contractile function in the presence of remodelled hearts such as in HCM.13,14 Secondly, most traditional echocardiographic techniques assess global systolic function, whereas HCM is known to be a disease with marked regional differences. Most patients have an asymmetric form of the disease with predominant involvement of the interventricular septum.15 Therefore, the assessment of regional myocardial function would provide additional information.

Recently, new echocardiographic techniques such as tissue Doppler and strain rate (SR) imaging have become clinically available. They provide direct quantitative information on regional systolic and diastolic myocardial function without using geometrical assumptions.16,17 SR imaging has been shown to be a sensitive method to quantify regional systolic myocardial function in a variety of cardiac diseases.18–21 It enables the evaluation of regional myocardial deformation in different myocardial segments, both in the radial and in the longitudinal directions and more recently also in the circumferential direction.22 Therefore, it may be ideal to characterize inhomogeneties in myocardial function in cardiomyopathies as well.

This study sought to (i) investigate the systolic myocardial deformation and timing of deformation in different myocardial segments in paediatric patients with HCM and (ii) determine the relation between systolic myocardial deformation and wall thickness, with the occurrence of ventricular arrhythmia, electrocardiographic characteristics, and exercise capacity.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 References
 
Study group
In this retrospective study, we included 47 paediatric patients diagnosed with HCM and 29 healthy controls examined either at Texas Children's Hospital Houston, TX, USA or University Hospitals, Leuven, Belgium. HCM was defined as an otherwise unexplained increase in the end-diastolic wall thickness (Z > 2) in at least one myocardial segment or a proven genetic diagnosis in a child with an affected relative. Patients were included if a recent (<12 months old) and full echocardiogram with tissue Doppler imaging data and a surface electrocardiogram (ECG) were available. This led to the exclusion of six HCM patients because of incomplete data sets. Patients with ventricular hypertrophy secondary to hypertension, syndromic disorders (Noonan's syndrome), neuromuscular diseases (such as Friedreich's ataxia), or inborn errors in metabolism were excluded. Healthy controls were relatives/acquaintances of hospital personnel of similar age to HCM patients.

Data acquisition
Standard transthoracic echocardiograms, blood pool Doppler, and two-dimensional tissue Doppler studies were performed using a commercially available echocardiographic system (Vivid 7, GE Vingmed, Horten, Norway) equipped with a 2.5 MHz transducer. In each patient, standard parasternal and apical views were recorded. Real-time tissue Doppler data were recorded to evaluate the longitudinal function in the interventricular septum and lateral left ventricular (LV)-free wall using an apical four-chamber view. To evaluate radial function in the infero-lateral and antero-septal LV walls, tissue Doppler data were recorded from the parasternal short-axis view, as described previously.23,24 To obtain high frames rates (180 ± 30 frames/s), each myocardial wall had to be acquired separately.

An ECG was performed in all patients. The Sokolow criteria, where the sum of the depth of S-wave in V1 or V2 and the height of R-wave in V5 or V6, were used to identify ventricular hypertrophy.25 An ECG ‘strain pattern’ was defined as tall lateral precordial voltages in association with ST-T-depression in V5–V6 and was qualitatively assessed as: 0, strain pattern not present and 1, strain pattern present. Dyssynchronous ventricular activation was defined on the ECG by the presence of a QRS complex longer than 120 ms or left bundle branch block. Data on the history of ventricular arrhythmias were collected from the patients' medical charts or Holter monitoring. A patient was considered to have ventricular arrhythmia if a history of sustained, or non-sustained ventricular tachycardia (VT), were identified.

Exercise tests were performed in 19 patients within 3 months of the echocardiogram. Exercise capacity was determined using a ramp protocol (Bruce or modified Bruce protocol). Maximum oxygen consumption (VO2) was measured and the percentage of predicted exercise capacity according to age, gender, and body surface area was calculated.

Standard echocardiographic data analysis
The maximal end-diastolic thickness of the interventricular septum and LV infero-lateral wall as well as the LV end-diastolic and end-systolic dimensions were determined by M-mode recordings taken at the level of the tips of the mitral leaflets from the parasternal short-axis view. From these measurements, LV fractional shortening was calculated. For all ventricular dimensions, the Z-score, compared with control subjects, was calculated. The modified Simpson's method was used for the determination of LV ejection fraction. Pulsed Doppler recordings at the tip of the mitral leaflets were used to measure peak early filling (E-wave) velocity, peak atrial filling (A-wave) velocity, E/A ratio, and E-wave deceleration time. The peak systolic gradient within the LV outflow tract was measured at rest using the modified Bernoulli equation.

Tissue Doppler imaging data analysis
All data were digitally transferred from the ultrasound machine (Vivid 7, GE Healthcare, Milwaukee) and post-processed on an off-line workstation. The tissue Doppler imaging data sets were analysed using the dedicated software (Software Package For Echocardiographic Quantification Leuven, Speqle 4©, Catholic University of Leuven, Belgium), allowing the offline computation of regional myocardial velocities, natural SR, and {varepsilon} values, as described previously.23

Longitudinal peak systolic SR and {varepsilon} were estimated from the apical four-chamber view at the following myocardial segments: (i) basal-mid segment of the interventricular septum in the region of maximal wall thickness; (ii) mid-apical segment of the interventricular septum, where the hypertrophy was less pronounced; and (iii) basal-mid-LV lateral segment. Radial peak systolic SR and {varepsilon} were measured at (i) basal-mid infero-lateral LV and (ii) basal-mid antero-septal myocardial segments from a parasternal short-axis view. A computational area of 10 mm was used for longitudinal myocardial motion/deformation calculation. A computational area of 5 mm was used for radial myocardial motion/deformation calculation. A semi-automatic M-mode-based tracking algorithm was applied to maintain the sample volume within the mid-myocardial region of interest throughout the cardiac cycle. Myocardial velocity and SR data were averaged over three consecutive cycles and then smoothened with a mask of 5x1 pixels (axial-lateral) to reduce noise. The regional SR profiles were integrated over time to obtain the natural {epsilon} profiles. To determine the duration of systole, the aortic valve opening and closure clicks were introduced from blood pool pulsed or continuous wave Doppler tracings recorded from cycles with comparable R–R interval. The aortic valve closure click was considered the end of the systole.

In each myocardial segment, the peak systolic and peak early diastolic (E') and late diastolic (A’) myocardial velocities were measured. The mitral E-wave to basal septal E' and mitral E-wave to basal lateral E' ratios were calculated. The high temporal resolution of the technique allows identification of abnormal timing of myocardial events, including post-systolic shortening. Post-systolic shortening has been shown to be an important clinical marker of regional myocardial dysfunction, especially when associated with reduced peak systolic strain ({epsilon}).26–28 Post-systolic thickening index (in the radial direction) or shortening index (in the longitudinal direction) was also calculated. Post-systolic thickening/shortening index was calculated as follows: [(Maximal {varepsilon} – end-systolic {varepsilon})/end-systolic {varepsilon})]x100. A representative example of the deformation pattern in the interventricular septum in a patient with HCM showing reduced systolic deformation with systolic lengthening and post-systolic shortening in the basal septum with preserved deformation in the mid-apical septum is shown in Figure 1. It is also possible to assess the dyssynchrony with these techniques, which has been described to be another prognostic marker in adults with dilated and HCM.29,30 As a marker of mechanical dyssynchrony, the time from the beginning of the heart cycle (beginning of the QRS complex) to maximal {epsilon} was measured in each myocardial segment.


Figure 1
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  		Figure 1 Representative example of the deformation pattern in the interventricular septum in a patient with hypertrophic cardiomyopathy with asymmetric septal hypertrophy with the sample volume placed in the basal septum (dashed line) and in the mid-apical septum (full line). In the basal septum, there is severely reduced systolic strain. In addition, there is abnormal systolic lengthening and post-systolic shortening occurs after aortic valve closure. The mid-apical septal myocardial segment shows relatively preserved systolic deformation and no post-systolic shortening. The dashed arrows show where peak systolic strain was measured. The full arrows show where maximal strain was measured. AVC, aortic valve closure.

 
Statistical analysis
Statistical analysis was performed using Statistica data analysis software system (Stat Soft, Inc. 2001, version 6.0). Normally distributed continuous variables are reported as mean value ± standard deviation. Unpaired two-sided t-tests were used to assess the differences between groups (HCM vs. control group). Paired two-sided t-tests were used to assess the differences between myocardial segments in the HCM group followed by Bonferroni correction if the difference was significant. A P-value less than 0.05 was considered statistically significant for all comparisons. An exponential model with three parameters with an upper horizontal asymptote was used to examine the relationship between wall thickness, ECG pattern, and exercise capacity with systolic deformation in the basal septum.31 Owing to the exploratory nature of the study, no adjustment to the significance level was made. The intra-observer variability in the quantitation of regional deformation data was assessed by one reader (J.G.), analysing blindly five randomly chosen data sets twice with at least a 1-week period in between readings. Interobserver variability was assessed by two readers (J.G. and R.H.P.), analysing the same five echocardiograms. The mean difference and 95% confidence intervals between the two measurements are reported.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 References
 
Patient characteristics
Overall, 41 HCM patients were studied. At the time of examination, the mean patient age was 12.3 ± 5.5 years. The pattern of LV hypertrophy was asymmetric basal septal hypertrophy in 31 patients, concentric hypertrophy in 9, and isolated posterior wall hypertrophy in one patient. Nineteen patients had a history of familial HCM, with seven of those having a mutation known to cause HCM. Nine patients had LV outflow tract obstruction with a peak systolic gradient >30 mmHg (average peak gradient 19.6 mmHg, range 6–121 mmHg).

Standard echocardiographic indices
Two-dimensional and mitral Doppler echocardiographic variables comparing HCM patients with controls are presented in Table 1. In all patients and controls, it was possible to perform all echocardiographic measurements. The LV end-diastolic diameter was significantly smaller and LV wall thickness significantly greater in the HCM group when compared with controls. The E/A ratio was significantly lower and the E/E' ratios at the basal septal and basal lateral myocardial segments were significantly higher in children with HCM when compared with controls.


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  		Table 1 Standard echocardiographic data

 
Tissue Doppler imaging indices of myocardial function
Intra- and inter-observer variability for peak systolic longitudinal and radial SR and {varepsilon} and time to maximal {varepsilon} are shown in Table 2. Indices of radial myocardial function from the antero-septal and infero-lateral LV myocardial segments are shown in Table 3. In these segments, peak early diastolic myocardial velocity, peak systolic SR, and peak systolic {epsilon} were all significantly lower in HCM patients when compared with controls. Peak systolic myocardial velocity, post-systolic thickening index, and time to maximal {epsilon} were significantly lower in the antero-septal myocardial segment in patients with HCM when compared with controls; however, no differences in these indices were seen between groups in the infero-lateral myocardial segment. The post-systolic thickening index was significantly higher, and time to maximal {epsilon} was significantly longer in the basal antero-septal segment when compared with the infero-lateral segment in patients with HCM. These differences between myocardial segments were not present in control subjects.


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  		Table 2 Intra- and inter-observer variability of regional deformation data

 

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  		Table 3 Radial myocardial function of the left ventricle

 
Indices of myocardial function from the three myocardial segments studied in the longitudinal direction are shown in Table 4. Peak systolic myocardial velocity, peak early diastolic myocardial velocity, peak systolic SR, and peak systolic {epsilon} were significantly reduced and post-systolic shortening index was significantly increased in all the myocardial segments studied. Moreover, the homogeneous SR, {epsilon} and time to maximal {epsilon} distribution seen in normal subjects was not present in children with HCM. Peak systolic SR and {epsilon} were reduced and the time to maximal {epsilon} prolonged in the basal septum when compared with the mid-apical septum and basal lateral segments (P < 0.01). In 13 (31%) HCM patients, systolic lengthening was observed instead of shortening at the basal septum with all of these children having a septal Z > 5.2. In contrast, this phenomenon occurred in only three patients at the mid-apical septum. In HCM patients, the post-systolic shortening index was significantly higher in the basal septum when compared with other myocardial segments (P < 0.05) as well as corresponding segments from controls (P < 0.01).


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  		Table 4 Longitudinal myocardial function of the left ventricle

 
In the basal septum, significant correlations could be demonstrated between longitudinal peak systolic SR, peak systolic {epsilon}, and post-systolic shortening index with peak early diastolic myocardial velocities (r = 0.71, 0.79, 0.45, respectively, all P-<0.01).

Relationship between systolic myocardial deformation and morphological and clinical characteristics
Wall thickness
Peak systolic SR, {epsilon}, and E' from the basal septum were all strongly and inversely correlated with maximal wall thickness (SR: r = –0.82; {epsilon}: r = –0.86; E' = –0.78, all P < 0.01). These correlations appeared to be curvilinear. In patients with a Z-score >3.5, no further deterioration in systolic deformation was seen (Figure 2).


Figure 2
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  		Figure 2 Relation between left ventricular wall thickness and peak systolic strain (A) and peak systolic strain rate (B). Full line shows the non-linear fit curve. Dashed lines show the 95% confidence interval.

 
Electrocardiogram
The degree of LV hypertrophy, as assessed by the Sokolow criteria (range 21–96 mV), correlated significantly with the reduction in the LV systolic deformation at the basal septum (vs. SR: r = –0.66, P < 0.01; vs. {epsilon}: r = –0.77, P < 0.01). An ECG consistent with a defined strain pattern was seen in 27 of 41 (66%) patients. In children with HCM, mean QRS complex duration was 112 ± 41 ms. A strong correlation between the strain pattern on ECG and decreased peak systolic SR and {epsilon} was found (r = –0.68, P < 0.01; r = –0.76, P < 0.01, respectively). A significant but weak correlation between ECG pattern with time to maximal {epsilon} was found (r = 0.38, P = 0.02). No significant correlation between QRS duration and time to maximal {epsilon} was seen (r = 0.31, P = 0.06). An ECG compatible with dyssynchronous activation was found in 13 patients. All of these patients had an end-diastolic wall thickness Z-score >4.6. Seven of these 13 patients had longitudinal systolic lengthening in early systole in the basal septum.

Exercise capacity
Upright exercise testing was performed in 19 patients who were over 10 years of age. Maximum VO2 strongly and inversely correlated with basal septal peak systolic SR, {epsilon}, and E' (r = –0.74, –0.70, –0.67, respectively, all P < 0.01). Also, maximum VO2 correlated inversely with maximal end-diastolic septal thickness (r = –0.70, P < 0.01).

Left ventricular outflow tract obstruction
No differences in tissue Doppler indices were demonstrated in HCM patients either with or without LV outflow tract obstruction. In addition, no correlation was found between deformation indices and peak systolic gradient (data not shown).

History of ventricular arrhythmia
Seven patients had a history of documented sustained VT and/or non-sustained VT. In this subgroup, peak systolic SR, peak systolic {epsilon}, and early diastolic myocardial velocities were significantly lower, whereas post-systolic shortening and time to maximal {epsilon} were significantly higher, compared with HCM patients without a history of arrhythmia (Table 5).


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  		Table 5 Clinical characteristics and echocardiographic indices of LV function at the basal septum in children with HCM, with and without ventricular tachycardia

 
Echocardiographic data on deformation and end-diastolic wall thickness in the seven patients with a history of documented V or syncope are shown in Table 6. Six of these patients had a septal wall thickness Z score of >5 and an ECG with strain pattern. All these patients had severely reduced peak systolic {epsilon} (<–5%) and six of them actually had abnormal systolic lengthening. The seventh patient had a septal wall thickness Z-score of 1.17 with no evidence of hypertrophy on the ECG. However, peak systolic {epsilon} (–13.5%) was reduced by 50% when compared with controls.


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  		Table 6 Deformation and wall thickness at the basal septum in patients with a history of ventricular tachycardia or syncope (n = 7)

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 References
 
Our study shows that, despite normal echocardiographic indices of global LV systolic function, longitudinal and radial systolic myocardial deformation is reduced in children with HCM. The reduction in myocardial deformation is inhomogeneous and more pronounced in the more severely hypertrophied myocardial segments. The reduced systolic deformation is also associated with increased post-systolic shortening and delayed mechanical activation. These abnormalities in regional systolic deformation correlate with a reduced exercise capacity and are more prominent in patients with ventricular arrhythmia.

When looking at the deformation characteristics of the different LV segments, we find a reduced peak systolic SR and {epsilon} both in the radial and in the longitudinal directions, compared with normal controls. This reduction in systolic deformation correlated with the degree of hypertrophy in a curvilinear fashion, in that no further reduction in peak systolic {epsilon} was observed when the wall thickness exceeded a Z-score of 3.5 (Figure 2). At this particular point, longitudinal {epsilon} is already severely reduced (to <10%), so that further reduction is not likely possible. Different factors explain this relation. Myocardial structural abnormalities with more pronounced fibre disarray are present in the more severely hypertrophied myocardial segments. When fibres are not geometrically arranged in a coherent direction but are randomly structured, contraction of these fibres will not result in an organized deformation pattern.32 Additionally, changes in passive mechanical characteristics caused by fibrosis and altered collagen deposition also affect deformation when active force is developed within a myocardial segment.33 Finally, increased hypertrophy can cause an imbalance between oxygen demand and delivery exceeding regional coronary flow reserve, potentially resulting in regional ischaemia.34

There are discrepancies between measures of regional and global myocardial functions for several reasons. First, endocardial indices of LV function such as fractional shortening and ejection fraction are known to overestimate systolic function in the presence of LV hypertrophy.12–14,35–37 Normally, endocardial wall thickening is higher than epicardial wall thickening and this difference becomes more pronounced with greater degrees of hypertrophy. For this reason, one should be cautious when using endocardial indices in the setting of increased wall thickness. Secondly, patients with HCM have a smaller end-diastolic diameter and increased wall thickness, resulting in a decreased ventricular afterload.14 The load dependency of both fractional shortening and ejection fraction is a well-known shortcoming of these indices. In the presence of significant hypertrophy, higher values of fractional shortening and ejection fraction are seen, despite reduced wall thickening.11,12,35–37 Finally, marked differences in regional function among myocardial segments in children with HCM are present. Some segments have a marked reduction in deformation, whereas in other segments, these deformation characteristics are more preserved. This heterogeneity can result in a more preserved global ventricular function, despite the presence of marked regional dysfunction.38

It is generally believed that in patients with HCM, diastolic dysfunction precedes systolic dysfunction.10,11,39 Our results obtained in children with HCM challenge this concept as we can demonstrate the presence of reduced regional systolic function, especially in the segments with more pronounced hypertrophy. These findings are in agreement with transgenic mice models of HCM in which sarcomere length, systolic shortening, and shear strains were lower in hypertrophied segments with myofiber disarray.32 Similarly, magnetic resonance tagging data have suggested that myocardial shortening and thickening are heterogeneously reduced and inversely correlated with end-diastolic wall thickness in HCM patients.40,41 A magnetic resonance tagging study looking at the regional myocardial function found a marked reduction in longitudinal deformation in all myocardial segments, which was more pronounced in the more hypertrophied septum. In addition, a reduced circumferential {epsilon} was found only in the septal segments.42 These magnetic resonance data are all consistent with our findings. However, magnetic resonance tagging is not widely available and has lower temporal resolution than the ultrasound-based deformation analysis.

In our present study, we demonstrate that high temporal resolution can be of particular importance in HCM patients. With accurate timing of mechanical events, we were capable of detecting abnormal post-systolic shortening and thickening as well as delayed time to peak {epsilon}. This was more prominent in the thickest myocardial segments where deformation was severely reduced. In these segments, post-systolic shortening is often preceded by abnormal systolic lengthening. Similar findings in HCM patients have also been reported by Yang et al.43 and Sengupta et al.44 This abnormal lengthening of the dysfunctional, hypertrophied segments is not seen in the non-hypertrophic segments and highlights that HCM is a disease with marked differences in the regional myocardial function. Systolic lengthening and post-systolic shortening can be explained by the absence of active systolic deformation in the affected segment and the tethering of adjacent normal myocardial segments that shorten appropriately during systole. During systole, the non-contractile hypertrophic segments are pulled by the adjacent contractile segments that shorten, resulting in a passive lengthening of the segment. After aortic valve closure, the pulling forces from the surrounding segments are released and the ‘stretched’ segments shorten as intracavitary pressure drops. This results in post-systolic shortening and thickening.45 This phenomenon reflects the inhomogeneity in deformation between different myocardial segments in HCM. This is further appreciated by the delayed time to peak {epsilon} in different wall segments with the thickest segments taking longer to reach peak systolic deformation after electrical activation.46

Recent reports have shown a close relationship between myocardial systolic activation delay and an increased risk for ventricular arrhythmias in adults with either dilated or HCM.29,30 Consistent with this finding, in our patients with a documented ventricular arrhythmia, we found a more pronounced prolongation of the time to peak {epsilon} as well as significantly increased post-systolic shortening in the basal septal segment. Our findings suggest that increased wall thickness results in increased electromechanical dyssynchrony, which could result in an increased propensity for arrhythmia. The prognostic significance of this finding should further be studied in a prospective study.

When further evaluating the relationship between post-systolic shortening and the surface ECG, we could detect a relationship between the presence of a strain pattern on the ECG and post-systolic shortening. All patients (n = 20) with a post-systolic shortening index >10% had a concomitant strain pattern on the ECG. Moreover, none of the patients without a strain pattern on the ECG (n = 14) had a post-systolic shortening index >6% and all but one patient had a wall thickness Z-score of <3.4. Repolarization abnormalities are possibly related to the electromechanical dyssynchrony. These preliminary findings are compelling and suggest that further prospective evaluation of these screening ECG parameters for the identification of ventricular dyssynchrony in children with HCM is warranted.

We also found a relation between exercise capacity and altered myocardial deformation. A confounding factor, however, is that those patients with decreased exercise capacity had the thickest ventricles. It is therefore uncertain whether decreased deformation is an independent variable explaining the decreased exercise capacity in these children. Moreover, the impact of hypertrophy on diastolic function during exercise is also well recognized and needs further study. Unfortunately, our cohort was too small to perform multiple regression analysis to address these important issues.

Another interesting observation is the high correlation between systolic deformation and early diastolic myocardial velocities in the basal septum. The reduction in systolic deformation is associated with reduced early diastolic function in the same segment. It seems logical to assume that when contraction is abnormal in a myocardial segment, relaxation will also be affected. This shows that, actually, there is no discrepancy between systolic and diastolic myocardial functions in HCM patients as the underlying contractile protein dysfunction should affect both systole and diastole. A similar relation has also been recently demonstrated between systolic twisting and diastolic untwisting in adult patients with HCM.47

HCM has a broad spectrum of clinical, morphological, and pathological phenotypes. It remains difficult to identify predictors of poor outcome in children with HCM. A combination of phenotypic and genotypic variables can be used. The measurement of ultrasound-based regional myocardial deformation could become an integral part of the diagnostic algorithm to stratify clinical risk in children with HCM, but this requires further study.

Study limitations
This was a cross-sectional retrospective study in a relatively small study group. HCM remains a rare diagnosis in childhood. On the basis of our data, the deformation abnormalities cannot be proven to be an independent risk factor for unfavourable outcomes. Therefore, further longitudinal follow-up in a larger cohort of patients is required. Secondly, deformation was only studied in the radial and longitudinal directions. The analysis of circumferential deformation was not available at the time we performed our study. Thirdly, our exercise data are incomplete as exercise testing was not feasible in younger patients (<9 years). In addition, the tissue Doppler and blood pool data were not acquired simultaneously. Although care was taken to restore cardiac cycles with similar R–R interval duration, some difference in the R–R interval might have occurred. This is a potential source of error when calculating the post-systolic shortening index.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 References
 
The use of SR imaging allows the non-invasive detection of abnormal systolic regional deformation in children with HCM. This reduction in regional systolic myocardial function is inhomogeneous and correlates with the regional pattern of hypertrophy as well as decreased exercise capacity. Increased post-systolic shortening and delayed mechanical activation are associated with the decreased peak systolic deformation. Moreover, the deformational changes were more pronounced in patients with arrhythmia propensity. A prospective study is required to evaluate the prognostic significance of these findings in children with HCM.

Conflict of interest: none declared.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
References
 
L.M. is a Clinical Researcher and P.C. a Post-doctoral Fellow of the Fund for Scientific Research (FWO).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 

  1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA (2002) 287:1308–1320.[Abstract/Free Full Text]
  2. Towbin JA. Molecular genetics of hypertrophic cardiomyopathy. Curr Cardiol Rep (2000) 2:134–140.[Medline]
  3. Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol (2001) 33:655–670.[CrossRef][Web of Science][Medline]
  4. Watkins H, Seidman CE, Seidman JG, Feng HS, Sweeney HL. Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action. J Clin Invest (1996) 98:2456–2461.[Web of Science][Medline]
  5. Marian AJ, Wu Y, Lim DS, McCluggage M, Youker K, Yu QT, Brugada R, DeMayo F, Quinones M, Roberts R. A transgenic rabbit model for human hypertrophic cardiomyopathy. J Clin Invest (1999) 104:1683–1692.[Web of Science][Medline]
  6. Marian AJ, Zhao G, Seta Y, Roberts R, Yu QT. Expression of a mutant (Arg92Gln) human cardiac troponin T, known to cause hypertrophic cardiomyopathy, impairs adult cardiac myocyte contractility. Circ Res (1997) 81:76–85.[Abstract/Free Full Text]
  7. Towbin JA. The failing heart. Nature (2002) 415:227–233.[CrossRef][Medline]
  8. Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH III, Zoghbi WA, Quinones MA. Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation (1999) 99:254–261.[Abstract/Free Full Text]
  9. McMahon CJ, Nagueh SF, Pignatelli RH, Denfield SW, Dreyer WJ, Price JF, Clunie S, Bezold LI, Hays AL, Towbin JA, Eidem BW. Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation (2004) 109:1756–1762.[Abstract/Free Full Text]
  10. Severino S, Caso P, Galderisi M, De Simone L, Petrocelli A, de Divitiis O, Mininni N. Use of pulsed Doppler tissue imaging to assess regional left ventricular diastolic dysfunction in hypertrophic cardiomyopathy. Am J Cardiol (1998) 82:1394–1398.[CrossRef][Web of Science][Medline]
  11. Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J. Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol (1987) 10:733–742.[Abstract]
  12. Kato T, Noda A, Izawa H, Nishizawa T, Somura F, Yamada A, Nagata K, Iwase M, Nakao A, Yokota M. Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol (2003) 42:278–285.[Abstract/Free Full Text]
  13. Connelly KA, Prior DL, Kelly DJ, Feneley MP, Krum H, Gilbert RE. Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures. Am J Physiol Heart Circ Physiol (2006) 290:H1699–H1705.[Abstract/Free Full Text]
  14. Hirota Y, Furubayashi K, Kaku K, Shimizu G, Kino M, Kawamura K, Takatsu T. Hypertrophic nonobstructive cardiomyopathy: a precise assessment of hemodynamic characteristics and clinical implications. Am J Cardiol (1982) 50:990–997.[CrossRef][Web of Science][Medline]
  15. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy. Am J Cardiol (1981) 48:418–428.[CrossRef][Web of Science][Medline]
  16. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, Quinones MA, Roberts R, Marian AJ. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation (2001) 104:128–130.[Abstract/Free Full Text]
  17. Sutherland GR, Di Salvo G, Claus P, D'hooge J, Bijnens B. Strain and strain rate imaging: a new clinical approach to quantifying regional myocardial function. J Am Soc Echocardiogr (2004) 17:788–802.[CrossRef][Web of Science][Medline]
  18. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation (2003) 107:2446–2452.[Abstract/Free Full Text]
  19. Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B, Goossens W, Goemans N, Sutherland GR, Van Hove JL. Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring. Neurology (2003) 60:1679–1681.[Abstract/Free Full Text]
  20. Fang ZY, Yuda S, Anderson V, Short L, Case C, Marwick TH. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol (2003) 41:611–617.[Abstract/Free Full Text]
  21. Kukulski T, Jamal F, Herbots L, D'hooge J, Bijnens B, Hatle L, De Scheerder I, Sutherland GR. Identification of acutely ischemic myocardium using ultrasonic strain measurements. A clinical study in patients undergoing coronary angioplasty. J Am Coll Cardiol (2003) 41:810–819.[Abstract/Free Full Text]
  22. Notomi Y, Lysyansky P, Setser RM, Shiota T, Popovic ZB, Martin-Miklovic MG, Weaver JA, Oryszak SJ, Greenberg NL, White RD, Thomas JD. Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol (2005) 45:2034–2041.[Abstract/Free Full Text]
  23. D'hooge J, Heimdal A, Jamal F, Kukulski T, Bijnens B, Rademakers F, Hatle L, Suetens P, Sutherland GR. Regional strain and strain rate measurements by cardiac ultrasound: principles, implementation and limitations. Eur J Echocardiography (2000) 1:154–170.[CrossRef]
  24. Weidemann F, Eyskens B, Jamal F, Mertens L, Kowalski M, D'Hooge J, Bijnens B, Gewillig M, Rademakers F, Hatle L, Sutherland GR. Quantification of regional left and right ventricular radial and longitudinal function in healthy children using ultrasound-based strain rate and strain imaging. J Am Soc Echocardiogr (2002) 15:20–28.[CrossRef][Web of Science][Medline]
  25. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J (1949) 15:161–168.
  26. Brown MA, Norris RM, Takayama M, White HD. Post-systolic shortening: a marker of potential for early recovery of acutely ischaemic myocardium in the dog. Cardiovasc Res (1987) 2l:703–716.
  27. Jamal F, Szilard M, Kukulski T, Liu XS, D'hooge J, Bijnens B, Rademakers F, Hatle L, Descheerder I, Sutherland GR. Changes in systolic and postsystolic wall thickening during acute coronary occlusion and reperfusion in closed-chest pigs: implications for the assessment of regional myocardial function. J Am Soc Echocardiogr (2001) 14:691–697.[CrossRef][Web of Science][Medline]
  28. Voigt JU, Lindenmeier G, Exner B, Regenfus M, Werner D, Reulbach U, Nixdorff U, Flachskampf FA, Daniel WG. Incidence and characteristics of segmental postsystolic longitudinal shortening in normal, acutely ischemic, and scarred myocardium. J Am Soc Echocardiogr (2003) 16:415–423.[CrossRef][Web of Science][Medline]
  29. D'Andrea A, Caso P, Severino S, Cuomo S, Capozzi G, Calabro P, Cice G, Ascione L, Scherillo M, Calabro R. Prognostic value of intra-left ventricular electromechanical asynchrony in patients with hypertrophic cardiomyopathy. Eur Heart J (2006) 27:1311–1318.[Abstract/Free Full Text]
  30. Cho GY, Song JK, Park WJ, Han SW, Choi SH, Doo YC, Oh DJ, Lee Y. Mechanical dyssynchrony assessed by tissue Doppler imaging is a powerful predictor of mortality in congestive heart failure with normal QRS duration. J Am Coll Cardiol (2005) 46:2237–2243.[Abstract/Free Full Text]
  31. McElree B, Pylkkanen L, Pickering MJ, Traxler MJ. A time course analysis of enriched composition. Psychon Bull Rev (2006) 13:53–59.[Web of Science][Medline]
  32. Karlon WJ, McCulloch AD, Covell JW, Hunter JJ, Omens JH. Regional dysfunction correlates with myofiber disarray in transgenic mice with ventricular expression of ras. Am J Physiol Heart Circ Physiol (2000) 278:H898–H906.[Abstract/Free Full Text]
  33. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol (2000) 35:36–44.[Abstract/Free Full Text]
  34. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Hum Pathol (2000) 8:988–998.
  35. Shimizu G, Hirota Y, Kita Y, Keishero K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension: myocardial function is depressed in pressure-overload hypertrophy. Circulation (1991) 83:1676–1684.[Abstract/Free Full Text]
  36. Palmon L, Reichek N, Yeon SB, Clark NR, Brownson D, Hoffman E, Axel L. Intramyocardial shortening in hypertensive left ventricular hypertrophy with normal pump function. Circulation (1994) 89:122–131.[Abstract/Free Full Text]
  37. Aurigemma GP, Silver KH, Priest MA, Gaasch WH. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol (1995) 26:195–202.[Abstract]
  38. Betocchi S, Hess OM, Losi MA, Nonogi H, Krayenbuehl HP. Regional left ventricular mechanics in hypertrophic cardiomyopathy. Circulation (1993) 88:2206–2214.[Abstract/Free Full Text]
  39. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol (2001) 88:53–58.[CrossRef][Web of Science][Medline]
  40. Dong SJ, MacGregor JH, Crawley AP, McVeigh E, Belenkie I, Smith ER, Tyberg JV, Beyar R. Left ventricular wall thickness and regional systolic function in patients with hypertrophic cardiomyopathy. A three-dimensional tagged magnetic resonance imaging study. Circulation (1994) 90:1200–1209.[Abstract/Free Full Text]
  41. Kramer CM, Reichek N, Ferrari VA, Theobald T, Dawson J, Axel L. Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation (1994) 90:186–194.[Abstract/Free Full Text]
  42. Young AA, Kramer CM, Ferrari VA, Axel L, Reichek N. Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy. Circulation (1994) 90:854–867.[Abstract/Free Full Text]
  43. Yang H, Sun JP, Lever HM, Popovic ZB, Drinko JK, Greenberg NL, Shiota T, Thomas JD, Garcia MJ. Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr (2003) 16:233–239.[CrossRef][Web of Science][Medline]
  44. Sengupta PP, Mehta V, Arora R, Mohan JC, Khandheria BK. Quantification of regional nonuniformity and paradoxical intramural mechanics in hypertrophic cardiomyopathy by high frame rate ultrasound myocardial strain mapping. J Am Soc Echocardiogr (2005) 18:737–742.[CrossRef][Web of Science][Medline]
  45. Skulstad H, Edvardsen T, Urheim S, Rabben SI, Stugaard M, Lyseggen E, Ihlen H, Smiseth OA. Postsystolic shortening in ischemic myocardium: active contraction or passive recoil? Circulation (2002) 106:718–724.[Abstract/Free Full Text]
  46. Claus P, Bijnens B, Weidemann F, Sutherland GR. Post systolic thickening in ischaemic myocardium: a simple mathematical model for simulating regional deformation. Functional imaging and modelling of the heart. Lect Notes Comput Sci (2001) 2230:134–139.
  47. Notomi Y, Martin-Miklovic MG, Oryszak SJ, Shiota T, Deserranno D, Popovic ZB, Garcia MJ, Greenberg NL, Thomas JD. Enhanced ventricular untwisting during exercise: a mechanistic manifestation of elastic recoil described by Doppler tissue imaging. Circulation (2006) 113:2524–2533.[Abstract/Free Full Text]

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