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Combining passive leg-lifting with transmural myocardial strain profile for enhanced predictive capability for subclinical left ventricular dysfunction in Duchenne muscular dystrophy
We previously reported that the transmural myocardial strain profile (TMSP) was an effective predictor for subclinical left ventricular (LV) dysfunction in patients with Duchenne muscular dystrophy (DMD) with preserved LV ejection fraction (LVEF), but its predictive power when used alone proved to be limited.
Methods
A total of 95 DMD patients with LVEF of 59 ± 5% (all ≥55%) and age 11.3 ± 3.0 years were analyzed retrospectively. Echocardiography was performed at baseline and 1-year follow-up, and all baseline measurements were repeated during a passive leg-lifting maneuver with legs elevated to approximately 45° from the horizontal position. TMSP of the posterior wall was evaluated from the mid-LV short-axis view. On the basis of our previous findings, TMSP with a notch was adopted as a predictor for evaluation of subclinical LV dysfunction in DMD patients whose LVEF remains preserved.
Results
At baseline, normal TMSP comprised 35 patients (37%), and the remaining 60 (63%) were classified as TMSP with a notch. Twenty-nine patients (48%) had developed LV wall motion abnormality at the 1-year follow-up, but this was observed only in the group of patients with TMSP with a notch at rest and also during passive leg-lifting. Furthermore, this group showed significantly more frequent development of LV wall motion abnormality at 1-year follow-up, with better sensitivity, specificity, and positive and negative predictive values for prediction of this abnormality than for other sub-groups.
Conclusions
Most DMD patients suffer from progressive skeletal muscle weakness, so that combining TMSP with passive leg-lifting may make TMSP even more effective as a simple and non-invasive predictor of LV subclinical dysfunction.
]. DMD is caused by mutations in the dystrophin gene that result in marked reduction or absence of the sarcolemmal protein dystrophin. Death is usually due to cardiac or respiratory failure [
]. The incidence of cardiac complications in DMD patients increases with age, affecting 30% of patients by the age of 14 years, 50% by the age of 18 years, and all older patients [
]. Since subclinical left ventricular (LV) myocardial dysfunction may develop and progress early in life, early detection of these changes in DMD patients, so that medical treatment can be administered earlier, is vital for prevention of the development of LV myocardial fibrosis. Previous investigators have reported that myocardial strain imaging is effective for the detection of subclinical LV myocardial dysfunction in DMD patients with preserved LV function [
]. In addition, we previously reported that the transmural myocardial strain profile (TMSP) was effective for predicting LV dysfunction in such patients [
]. However, these echocardiographic parameters alone proved to have limited predictive power for subclinical LV dysfunction. Although exercise or dobutamine stress echocardiography are well-established methods for the detection of subclinical LV myocardial dysfunction in patients with known or suspected cardiomyopathy whose LV function is normal compared to baseline echocardiographic assessment [
], it is difficult for DMD patients to undergo such stress tests due to progressive skeletal muscle weakness with loss of ambulatory ability. On the other hand, the passive leg-lifting maneuver is a non-invasive and cost-effective method to increase preload through a transient increase in venous return. The advantage of this simple maneuver over other stress tests for DMD patients is that it can be easily performed for such patients even when they are in poor physical condition with help from an attendant parent.
Accordingly, the objective of this study was to test the hypothesis that combining passive leg-lifting with assessment of TMSP enhances the capability of the latter to predict subclinical LV dysfunction for DMD patients with preserved LV ejection fraction (EF).
Materials and methods
Study population
Data for a total of 168 consecutive DMD patients who were treated at the Division of Pediatrics of Kobe University Hospital between August 2007 and December 2013 were analyzed retrospectively. The diagnosis of DMD was confirmed by genetic analysis. Mutation of the dystrophin gene, which forces the abnormal generation of dystrophin messenger RNA by the premature stop codon, was detected in all patients. We excluded DMD patients with (1) atrial fibrillation; (2) left-sided heart failure; and (3) more than mild aortic and/or mitral valvular heart disease. This study was approved by the local ethics committee of our institution, and written informed consent was obtained from all patients.
Echocardiographic examination
All echocardiographic studies were obtained with a commercially available system (Aplio XG; Toshiba Medical Systems, Tochigi, Japan) at baseline and 1-year follow-up. All baseline measurements were repeated during a passive leg-lifting maneuver, in which the legs are elevated to approximately 45° from the horizontal position with the assistance of attendant parents and kept at this position for about 1–2 min while continuously recording echocardiographic data. Digital routine cine loops were obtained from the standard parasternal and apical views from three consecutive beats at the end of expiratory apnea. Sector width was optimized to allow for complete myocardial visualization while maximizing the frame rate. Standard LV measurements were obtained from the parasternal long-axis view, and LV volumes and EF were calculated using the Teichholz rule [
Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
]. The pulsed-wave Doppler-derived early diastolic (E) and atrial transmitral flow velocity (A), the E/A ratio, and the E-wave deceleration time were obtained from the apical four-chamber view and used for the assessment of LV diastolic function [
]. Briefly, Doppler angle correction was performed toward the contraction center to obtain radial strain distribution in the posterior wall. Radial strain distribution throughout the myocardium in the form of M-mode color-coded images, as well as the profile of distribution at end-systole, was also obtained (Fig. 1). Moreover, the location of the peak strain was identified, which was determined as the percentage of the distance between the endocardium and the epicardium accounted for by the wall thickness (Fig. 1). Two TMSP patterns were observed at baseline in DMD patients [
] (Fig. 2). One featured a one-peak strain and was located in the endocardium (normal TMSP), and the other featured a two-peak strain with a notch and was located in the subendocardium (TMSP with a notch). Care must be taken to manually fine-tune the region of interest within the myocardium for TMSP analysis. On the basis of our previous findings, TMSP with a notch was determined as a predictor for subclinical early changes in DMD patients with preserved LVEF [
Fig. 1An example of color-coded tissue Doppler radial strain display from the mid-left ventricular (LV) short-axis view at end-systole (left), and corresponding M-mode color-coded transmural myocardial strain profile of the LV posterior wall (right). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 2Examples of two different patterns of transmural myocardial strain profile (TMSP), demonstrating one-peak strain located in the endocardium (left; normal TMSP), and a two-peak strain with a notch located in the endocardium (right; TMSP with a notch).
All group data were compared by using the two-tailed Student's t test for paired and unpaired data and are presented as mean ± SD. Proportional differences were evaluated by using either Fisher's exact test or the χ2 test as appropriate. Sensitivity, specificity, and positive and negative predictive values were estimated with their 95% confidence intervals (95% CI). For all steps, p-values <0.05 were considered statistically significant. All the analyses were performed with commercially available software R version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient characteristics
After exclusion of three patients (1.8%) with suboptimal images due to poor-quality echocardiographic windows, 53 (31.5%) due to LV regional wall motion abnormality, and 17 (10.1%) who refused to comply with the leg-lifting procedure, the final study group comprised the 95 remaining DMD patients for whom baseline and 1-year follow-up echocardiographic data were available (Fig. 3). The baseline clinical and echocardiographic characteristics of the DMD patients are summarized in Table 1. The mean age was 11.3 ± 3.0 years (range 4–23 years), and LVEF was 58.6 ± 5.3% (all ≥55%).
Fig. 3Enrollment of patients in this study. DMD, Duchenne muscular dystrophy; TMSP, transmural myocardial strain profile; LV, left ventricular.
At baseline, normal TMSP accounted for 35 patients (37%), and the remaining 60 (63%) were classified as TMSP with a notch. Baseline clinical and echocardiographic characteristics of the two groups are listed in Table 1. The two groups showed similar baseline clinical and echocardiographic characteristics, except for E-deceleration time for patients with TMSP with a notch, which was significantly longer (169.6 ± 28.7 ms vs. 151.1 ± 22.5 ms; p < 0.01), and peak strain, which was significantly lower (216.9 ± 96.8% vs. 137. 3 ± 64.0%; p < 0.01).
Response to passive leg-lifting
Passive leg-lifting resulted in a significant increase in LV end-diastolic and left atrial diameter, LVEF, and peak strain value, and a decrease in LV posterior wall thickness (Table 2). In addition, response to passive leg-lifting was similar for patients with normal TMSP and TMSP with a notch. Of the 35 patients with normal TMSP at rest, TMSP with a notch as a result of leg-lifting emerged in 10 patients, but not in the remaining 25. Similarly, of the 60 patients with TMSP with a notch, this condition persisted in 49 patients as a result of leg-lifting, but it disappeared in the remaining 11 patients (Fig. 4).
Table 2Response to passive leg-lifting.
All patients (n = 95)
Normal TMSP (n = 35)
TMSP with a notch (n = 60)
Rest
Leg-lifting
p-Value
Rest
Leg-lifting
p-Value
Rest
Leg-lifting
p-Value
Heart rate (bpm)
92 ± 12
91 ± 13
0.15
90 ± 13
90 ± 12
0.37
94 ± 12
92 ± 14
0.12
Echocardiographic parameters
LVDd (mm)
39.7 ± 4.2
41.2 ± 4.4
<0.01
39.6 ± 4.5
41.3 ± 4.7
<0.01
39.8 ± 4.1
41.1 ± 4.2
<0.01
LVDs (mm)
25.9 ± 3.6
26.2 ± 3.9
0.18
25.6 ± 3.8
26.1 ± 4.1
0.33
26.1 ± 3.6
26.4 ± 3.8
0.38
LVEF (%)
58.6 ± 5.3
60.4 ± 6.3
<0.01
59.5 ± 5.1
61.2 ± 6.8
0.03
58.4 ± 5.5
60.0 ± 6.0
0.03
LAD (mm)
23.1 ± 4.8
25.3 ± 4.7
<0.01
23.9 ± 3.2
25.9 ± 3
<0.01
22.6 ± 5.4
24.8 ± 5.4
<0.01
IVST (mm)
7.3 ± 1.3
7.4 ± 1.1
0.50
7.4 ± 1.3
7.5 ± 1.3
0.89
7.2 ± 1.3
7.3 ± 1.0
0.46
LVPWT (mm)
7.5 ± 1.5
6.8 ± 1.2
<0.01
7.9 ± 1.4
6.8 ± 1.1
<0.01
7.3 ± 1.5
6.8 ± 1.3
<0.01
Peak strain (%)
167 ± 86
193 ± 113
<0.01
217 ± 97
255 ± 132
0.02
137 ± 64
157 ± 82
0.04
TMSP, transmural strain profile; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; LAD, left atrial dimension; IVST, intra-ventricular septal thickness; LVPWT, left ventricular posterior wall thickness.
Fig. 4Prevalence of the development of left ventricular (LV) wall motion abnormality in the posterior wall at 1-year follow-up, demonstrating that patients with persisting transmural myocardial strain profile (TMSP) with a notch as a result of leg-lifting showed a significantly higher prevalence of development of LV wall motion abnormality than other sub-groups.
Prediction of LV wall motion abnormality in the posterior wall at 1-year follow-up
At the 1-year follow-up, 29 patients (48%) had developed LV wall motion abnormality in the posterior wall, which was observed in only patients with TMSP with a notch at rest, but not in those with normal TMSP at rest (Fig. 4). Interestingly, of the 60 patients with TMSP with a notch, 29 who had developed wall motion abnormality in the posterior wall at the 1-year follow-up showed persisting TMSP with a notch as a result of passive leg-lifting, but none of the patients whose TMSP with a notch had disappeared showed it (Fig. 4). In addition, patients with persisting TMSP with a notch following passive leg-lifting showed a significantly higher prevalence of the development of LV wall motion abnormality in the posterior wall at 1-year follow-up, and better sensitivity, specificity, and positive and negative predictive values for prediction of this abnormality than other sub-groups (Fig. 4 and Table 3). Fig. 5 shows a representative case in a patient with the development of LV wall motion abnormality in the posterior wall at 1-year follow-up.
Table 3Prediction of LV wall motion abnormality in the posterior wall at 1-year follow-up.
Fig. 5A representative case in a 13-year-old boy with the development of left ventricular (LV) wall motion abnormality in the posterior wall at 1-year follow-up. (A) Baseline echocardiography shows 58% of LV ejection fraction (LVEF) without LV wall motion abnormality. The patient had transmural myocardial strain profile (TMSP) with a notch at baseline (arrow), and this condition persisted as a result of passive leg-lifting (arrow). (B) 1-Year follow-up echocardiography shows 36% of LVEF with LV wall motion abnormality in the posterior wall. LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter.
The findings of our study demonstrate that combining the passive leg-lifting maneuver with assessment of TMSP may be more effective for predicting new development of LV posterior wall motion abnormality after 1 year for DMD patients with preserved LVEF. These findings may further enhance our previously reported capability of TMSP assessment to predict subclinical LV dysfunction.
Importance of early detection of cardiac involvement in DMD patients
Death of DMD patients is usually due to cardiac or respiratory failure [
]. The incidence of cardiac complications in DMD patients increases with age, affecting 30% of patients by the age of 14 years, 50% by the age of 18, and all older patients [
]. Since subclinical LV myocardial dysfunction may develop and progress early in life, the early detection of this abnormality in DMD patients when their LVEF remains preserved is important because medical treatment can be administered earlier, and is therefore vital for prevention of the development of myocardial fibrosis [
]. Fibrotic changes, however, do not always occur homogeneously in the heart and cardiac fibrosis in DMD patients begins in the outer half of the myocardium, especially in the LV posterior wall [
We previously reported in a study of 82 DMD patients with preserved LVEF that TMSP with a notch at rest functioned as a robust predictor of the presence of LV posterior wall motion abnormality detected at 1-year follow-up rather than simple strain values [
]. Since TMSP with a notch may link to regional myocardial thinning in systole (negative strain value which is just above the notch in Fig. 2), it may be associated with subtle LV fibrosis, which can be an accurate parameter of LV myocardial function. In addition, we speculated that TMSP with notch was also associated with the changes in the myofibrillar properties of the myocardial cells and disappearance of the transmural gradient of myofilament length-dependent activation. However, the predictive power of this method alone was limited by a relatively low specificity and positive predictive value as a predictor. Exercise stress echocardiography involving bicycle and treadmill exercise testing or low-dose dobutamine stress echocardiography are well-established methods for the detection of subclinical LV myocardial dysfunction in patients with known or suspected cardiomyopathy whose LV function is normal. In addition, passive leg-lifting is a non-invasive and cost-effective method to increase preload through a transient increase in venous return and therefore has several advantages over the above-mentioned stress test for the assessment of subclinical LV dysfunction in DMD patients, because it does not significantly affect blood pressure, heart rate, or afterload, and its effect lasts only a short time. This is important because most DMD patients are not capable of performing such stress testing due to their poor physical condition including progressive skeletal muscle weakness with loss of ambulatory ability. For this reason, passive leg-lifting as a means of increasing preload is a simple and suitable stress test, and it is recommended here as an alternative substitute test for the more conventional non-invasive method, because it can be easily performed by DMD patients during echocardiography with the help from an attendant parent. Therefore, the combination of the passive leg-lifting maneuver with assessment of TMSP can be expected to constitute a more effective predictor of subclinical LV dysfunction in DMD patients. Moreover, these findings appear to highlight the importance of early medical treatment to prevent the development of LV myocardial fibrosis for the risk stratification in DMD patients.
It would be considered that the increased preload by means of passive leg-lifting results in an increased peak strain value without the change of strain distribution in the normal segments because of Frank–Starling mechanism. On the other hand, such a phenomenon may not occur in the segments with subclinical myocardial dysfunction, and the persisting TMSP with a notch by passive leg-lifting may well reflect the presence of subclinical myocardial dysfunction. In this study, 10 patients with normal TMSP appeared TMSP with a notch by passive leg-lifting, and these patients did not develop LV wall motion abnormality in the posterior wall at 1-year follow-up. Although this phenomenon seems to be not a bad sign, the precise mechanism remains uncertain. A larger study population with longer follow-up period would be needed to validate this finding.
Study limitations
There are certain limitations to this study. First, this study covered a small number of patients in a single-center retrospective study, so that future studies of larger patient populations are necessary to assess our findings. Only radial strain in the LV posterior wall from the mid-LV short-axis view was assessed, and assessments of other directional strains or other LV segments were not a part of this study. Thus, the assessment of TMSP in the whole heart would be a better parameter than that of regional TMSP. Although it remains to be completely elucidated, the LV posterior wall is the preferred site for wall motion abnormalities in DMD patients. Second, the reproducibility of passive leg-lifting maneuver in DMD patients was not part of this study. Third, vital signs except heart rate were not collected during the passive leg-lifting maneuver. Finally, the passive leg-lifting maneuver may have shortcomings as a quantitative parameter, but in our study LV end-diastolic and left atrial diameter and LVEF significantly increased, while LV end-systolic diameter as well as heart rate remained unchanged in response to passive leg-lifting. We therefore believe that our findings confirmed the clinical utility of the passive leg-lifting maneuver as a means of increasing preload without altering afterload.
Conclusions
The combination of TMSP and passive leg-lifting maneuver may be even more effective than the former alone as a simple and non-invasive predictor of LV subclinical dysfunction. The findings presented here are thus expected to have clinical implications for better management of such patients.
Funding sources
None.
Disclosures
None.
Acknowledgment
We are grateful for the support of the entire staff of the echocardiography laboratory of Kobe University Hospital.
Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
Duchenne muscular dystrophy (DMD) is an X-linked hereditary muscular disorder that leads to degeneration and atrophy of skeletal and cardiac muscle. Skeletal muscle disease causes limb muscle weakness, with loss of ambulation at the ages of around 10 years or less. The majority of DMD patients develop dilated cardiomyopathy in their mid-teens, characterized by enlarged heart chambers and reduced cardiac wall thickness. On the other hand, intercostal and diaphragmatic respiratory muscle weakness and scoliosis leads to respiratory problems that force DMD patients to use respiratory devices.
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