Int J Cardiovasc Imaging DOI 10.1007/s10554-014-0551-4
ORIGINAL PAPER
Global cardiac alterations detected by speckle-tracking echocardiography in Fabry disease: left ventricular, right ventricular, and left atrial dysfunction are common and linked to worse symptomatic status Daniel A. Morris • Daniela Blaschke • Sima Canaan-Ku¨hl • Alice Krebs • Gesine Knobloch Thula C. Walter • Wilhelm Haverkamp
•
Received: 31 August 2014 / Accepted: 7 October 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The aim of this study was to test the hypothesis that in patients with Fabry disease, 2D speckle-tracking echocardiography (2DSTE) could detect functional myocardial alterations such as left ventricular (LV), right ventricular (RV), and left atrial (LA) dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients. Fifty patients with Fabry disease and a control group of 118 healthy subjects of similar age and gender were included. The myocardial function and structural changes of the LV, RV, and LA were analyzed by 2DSTE and cardiac magnetic resonance imaging. Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 ± 4.0, -21.4 ± 4.9, and 29.7 ± 9.9 % vs. -21.6 ± 2.2, -25.2 ± 4.0, and 44.8 ± 11.1 %, respectively, P \ 0.001) and elevated rates of LV, RV, and LA myocardial dysfunction (24, 20, and 26 %, respectively), even when conventional cardiac measurements such as LVEF, TAPSE, and LAVI were normal. LV septal wall thickness C15 mm, RV free wall thickness C7 mm, and LV longitudinal dysfunction were the
Electronic supplementary material The online version of this article (doi:10.1007/s10554-014-0551-4) contains supplementary material, which is available to authorized users. D. A. Morris (&) D. Blaschke S. Canaan-Ku¨hl A. Krebs G. Knobloch T. C. Walter W. Haverkamp Department of Cardiology, Charite´ University Hospital, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany e-mail: [email protected]
principal factors linked to reduced LV, RV, and LA strain, respectively. In addition, but to a lesser extent, LV and RV fibrosis were linked to reduced LV and RV strain. Patients with reduced LV, RV, and LA strain had worse functional class (dyspnea–NYHA classification) than those with normal cardiac function. In conclusion, in patients with Fabry disease, 2DSTE analyses detect LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements are normal. These functional myocardial alterations are common and significantly associated with worse symptomatic status in Fabry patients. Therefore, these findings provide important evidence to introduce global myocardial analyses using 2DSTE in the early detection of functional cardiac alterations in Fabry disease. Keywords Left atrial Right ventricular Strain Speckle-tracking Fabry disease
Introduction Cardiac involvement in Fabry disease has been characterized by accumulation of globotriaosylceramide (Gb3) in the left ventricle (LV) with consequent LV myocardial alterations [1–6]. Recent studies using two-dimensional speckle-tracking echocardiography (2DSTE) demonstrated that patients with Fabry disease had significantly lower functional myocardial values of the LV than healthy subjects, even when LV ejection fraction (LVEF) was normal [5, 6]. Nevertheless, despite these interesting studies, the rate of LV myocardial dysfunction in this disease as well as its relation with the symptomatic status in these patients have not been investigated. In spite of the fact that structural myocardial alterations have long been considered exclusively in the LV in Fabry
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Int J Cardiovasc Imaging Table 1 Clinical characteristics and conventional measurements in Fabry patients and healthy subjects
P value
Healthy subjects (n = 118)
Fabry patients (n = 50)
Age (years)
42.8 ± 11.5
46.1 ± 11.4
.096
Women
58.5 %
74 %
.057
Clinical characteristics
2
\.001
Body mass index (kg/m )
22.2 ± 2.5
25.8 ± 7.2
Systolic blood pressure (mmHg)
119.0 ± 10.7
116.1 ± 11.2
.123
Diastolic blood pressure (mmHg)
71.8 ± 8.2
71.7 ± 8.8
.923
64.4 ± 5.8
60.5 ± 3.7
\.001
Conventional left ventricular measurements LV ejection fraction (%) 2
Data are expressed as mean ± SD or percentages TDI tissue Doppler imaging. e’ early-diastolic, FAC fractional area change, TAPSE tricuspid annular plane systolic excursion, LAVI maximal left atrial volume index In accordance with the guidelines on Fabry disease,1 all men and women with some evidence of organ involvement had enzyme replacement therapy.Septal and posterior wall thickness were measured at end-diastole from parasternal long-axis view
LV mass (g/m )
73.3 ± 14.3
105.9 ± 41.1
\.001
LV septal wall thickness (mm)
8.6 ± 1.3
11.7 ± 3.0
\.001
LV posterior wall thickness (mm) Septal e’ mitral annular velocity by TDI (cm/s)
8.3 ± 1.2 11.0 ± 2.1
11.1 ± 2.7 7.4 ± 3.0
\.001 \.001
Lateral e’ mitral annular velocity by TDI (cm/s)
13.6 ± 2.5
9.5 ± 3.1
\ .001 \.001
Mitral E/e’ septal–lateral ratio
6.7 ± 1.6
10.6 ± 4.8
Mitral E/A inflow ratio
1.5 ± 0.4
1.3 ± 0.5
.091
Conventional right ventricular measurements TAPSE (mm)
20.0 ± 2.8
18.8 ± 3.4
.014
RV FAC (%)
51.1 ± 8.0
39.8 ± 6.6
\.001
RV free wall thickness (mm)
3.5 ± 0.4
4.8 ± 1.7
\.001
Conventional left atrial measurements LAVI (ml/m2)
18.8 ± 5.9
25.9 ± 10.0
\.001
LA ejection fraction (%)
66.9 ± 9.2
55.5 ± 14.5
\.001
Table 2 Global cardiac myocardial function in patients with Fabry disease
Healthy subjects (n = 118)
Fabry patients (n = 50)
LV myocardial function LV global longitudinal systolic strain Mean ± SD
-21.6 ± 2.2 %
-18.1 ± 4.0 %
LV systolic dysfunction (LV strain [-16 %)
0.0 %
24 %
Mean ± SD
1.55 ± 0.29 s-1
1.24 ± 0.44 s-1
LV diastolic dysfunction (LV strain rate \1.00 s-1)
0.0 %
24 %
-25.2 ± 4.0 %
-21.4 ± 4.9 %
0.0 %
20 %
Mean ± SD
-29.8 ± 5.1 %
-25.4 ± 6.9 %
RV systolic dysfunction (RV free wall strain [-19 %)
0.0 %
18 %
Mean ± SD
44.8 ± 11.1 %
29.7 ± 9.9 %
LA myocardial dysfunction (LA strain \23 %)
0.0 %
26 %
-2.12 ± 0.57 s-1
-1.62 ± 0.68 s-1
0.0 %
16 %
LV global longitudinal diastolic strain rate
RV myocardial function RV global systolic strain Mean ± SD RV systolic dysfunction (RV strain [-17 %) RV free wall systolic strain
LA myocardial function Data are expressed as mean ± SD and percentages. The differences between healthy subjects and Fabry patients were statistically significant in all the measurements (P \ 0.001) SD standard deviation
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LA strain
LA strain rate Mean ± SD -1
LA myocardial dysfunction (LA strain rate [-0.90 s )
Int J Cardiovasc Imaging
disease [1–4], recent anatomopathological studies analyzing the whole myocardium [i.e. LV, right ventricle (RV), and left atrium (LA)] demonstrated that in these patients the accumulation of globotriaosylceramide is not only localized in the LV, but also in the RV and LA [7–9]. Nonetheless, it remains poorly understood if RV and LA functional myocardial alterations are present in Fabry disease. Furthermore, the role that RV and LA myocardial alterations could have on the functional class (dyspnea– NYHA) of these patients is not known. The aim of this study was to test the hypothesis that in patients with Fabry disease, 2DSTE could detect functional myocardial alterations such as LV, RV, and LA dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients.
Methods Study population We included patients with Fabry disease C18 years of age derived to our Department of Cardiology (Charite´ University Hospital) for evaluation of cardiac involvement between March 2009 and March 2014. In addition, we included a control group of healthy subjects of similar age and gender, which were enrolled in previous studies of our research group [10–13]. Healthy subjects were defined as all those individuals with absence of any disease and cardiovascular risk factors such as obesity, diabetes, hypertension, and hypercholesterolemia. The institutional review board approved this research project and informed consent was obtained from all of the subjects. Transthoracic echocardiography All subjects were examined at rest in the left lateral decubitus position using one the following ultrasound systems: Vivid 7 or Vivid E9 from GE Healthcare. LV, RV, and LA measurements were performed as recommended by the American Society of Echocardiography (ASE) [14–17]. All echocardiographic measurements using 2DSTE, Doppler, and conventional 2D echocardiography were calculated as the average of 3 measurements. Myocardial analyses of the left ventricle, right ventricle, and left atrium The myocardial analyses by 2DSTE were performed offline and blinded to the clinical characteristics of the subjects using the following ultrasound software-package: Echo-
Pac version 113.0 from GE [10–13]. The analyses in longitudinal direction of the LV were performed in the whole myocardium in the basal, mid, and apical segments in the apical 4-chamber, 2-chamber, and long-axis views (i.e. 18 segments of the LV) [10–13]. LV global longitudinal systolic strain (LV strain) was determined by the average value of the longitudinal systolic strain peak across 18 LV segments [10–13]. LV measurements in circumferential and radial direction were performed in the entire myocardium in the three short-axis views of the LV (basal, midventricular, and apical levels) [11, 13]. LV global circumferential and radial systolic strain were evaluated by the average value of the radial and circumferential systolic strain peak from 18 LV segments [11, 13]. In addition, the multidirectional global systolic function of the LV was analyzed by means of 2 indices [11, 13]: longitudinal– circumferential systolic index = average of the longitudinal and circumferential global systolic strain; and global systolic index = average of the longitudinal, circumferential, and radial global systolic strain. Furthermore, we analyzed the longitudinal, circumferential, and radial diastolic function of the LV analyzing the early-diastolic peak strain rate (SRe) using the same 18-segment LV model of the aforementioned measurements [10–13]. The myocardial function of the RV was evaluated by means of the average value of the longitudinal systolic strain peak from all segments of the free and septal wall (i.e. RV strain) and just from the free wall of the RV (i.e. RV free-wall strain) in the apical 4-chamber view [18–20]. The myocardial function of the LA was analyzed by means of LA strain rate peak during LA contraction (LASRa) (namely, at the time of the late-diastole of the LV) and LA strain peak during LA relaxation (LA strain) (i.e. at the time of the systole of the LV) [12, 21]. In accordance with the consensus of experts of the ASE on myocardial mechanisms [16], these LA measurements were performed in the apical 4-chamber and 2-chamber views (i.e. 12 LA segments) and using QRS onset as reference point [16]. On the basis of the recommendations on chamber quantification of the ASE [14], LV, RV, and LA myocardial dysfunctions were defined as -1.96 standard deviation (SD) from the mean of healthy subjects using the aforementioned myocardial measurements. In addition, determination of normal cardiac parameters by means of conventional echocardiographic measurements such as LVEF C 55 %, tricuspid annular plane systolic excursion (TAPSE) C16 mm, RV fractional area change (FAC) C35 %, and LA maximal volume index (LAVI) B28 ml/m2 were also used according the guidelines of the ASE [14]. Furthermore, myocardial structural changes such as myocardial fibrosis were analyzed by means of late gadolinium enhancement cardiac magnetic resonance imaging (LGE-MRI) (1.5-T MRI unit, TwinSpeed-Excite; GE
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Fig. 1 Left ventricular, right ventricular, and left atrial myocardial dysfunction in Fabry disease. a (upper) Patient with Fabry disease with increased LV wall thickness and consequently LV myocardial dysfunction. On the contrary, the same figure (below) shows a patient with Fabry without increased LV wall thickness and in consequence without LV myocardial dysfunction. b (upper) Same patient of a (upper) with increased RV wall thickness and consequently RV
myocardial dysfunction. On the contrary, the same figure (below) shows the same patient of a (below) without increased RV wall thickness and in consequence without RV myocardial dysfunction. c (upper) Same patient of a and b (upper) with a significant LA myocardial dysfunction. On the contrary, the same figure (below) shows the same patient of a and b (below) without LA myocardial dysfunction
Healthcare), which was performed in the Department of Radiology (Charite´ University Hospital) within 3 months after the echocardiographic analysis following a cardiac MRI protocol previously described for our institution [22].
t test. Categorical variables were compared by Chi square test and Fisher exact-test as appropriate. Comparisons between three or more groups were analyzed using a oneway analysis of variance (ANOVA). The relationship of LV, RV, and LA functional alterations with myocardial structural changes were evaluated analyzing the area under the curve (AUC) of receiver operating characteristic (ROC) curves. In addition, in order to determine the value of those structural changes linked to LV, RV, LA functional alterations, ROC curves using the Youden index were
Statistical analysis Continuous data were presented as mean ± SD and dichotomous data in percentage. Differences in continuous variables between groups were analyzed using Student’s
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performed (an optimal cutoff value was chosen as one with the maximal sensitivity and specificity). The reproducibility of the functional myocardial analyses of the LV, RV, and LA using 2DSTE in our laboratory was previously reported [10–13, 18, 21], which was adequate [10–13, 18, 21]. All statistical analyses were performed with Statview 5.0 (SAS Institute) and SPSS 22.0 (IBM). Differences were considered statistically significant when P \ 0.05.
relation to these findings, the rates of LV, RV, and LA myocardial dysfunction in patients with Fabry were between 20 and 26 % (see Table 2; Fig. 1a–c, and supplemental Tables 1 and 2 for multidirectional LV measurements). In addition, in patients with Fabry, global cardiac analyses using 2DSTE detected LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements such as LVEF, TAPSE, FAC, and LAVI were normal (see Fig. 2a, b).
Results
Structural changes linked to functional myocardial alterations in Fabry patients
Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 ± 4.0, -21.4 ± 4.9, and 29.7 ± 9.9 % vs. -21.6 ± 2.2, -25.2 ± 4.0, and 44.8 ± 11.1 %, respectively, P \ 0.001) (see Table 2). In
Increased LV septal thickness was significantly related to LV myocardial dysfunction (see Table 3; Figs. 1a, 3, and supplemental Table 3 for LV diastolic analyses). In line, in ROC curves analysis a value of the septum C15 mm was the strongest cutoff associated with reduced LV strain (see Fig. 3). In relation to these findings, RV functional myocardial alterations were also significantly linked to increased septal thickness and RV free wall (see Table 4; Figs. 1b, 4). Likewise, in ROC curves analysis a value of the septum C15 mm and a value of RV free wall C7 mm were strongly linked to reduced RV strain (see Fig. 4 and supplemental Table 4 for RV myocardial analyses in RV free wall). Concerning the cardiac changes related to functional myocardial alterations of the LA, we found that a longitudinal systolic and diastolic dysfunction of the LV were the principal factors linked to LA myocardial dysfunction in patients with Fabry disease (see Table 5; Figs. 1c, 5). In line with these findings, in ROC curves analysis a value of LV global longitudinal systolic strain
Fig. 2 a, b. Global cardiac analyses using 2DSTE detect LV, RV, and LA functional myocardial alterations in patients with Fabry disease, even when conventional cardiac measurements such as
LVEF, TAPSE, FAC, and LAVI are normal. LV, RV, and LA functional myocardial alterations were determined as LV, RV, and LA global longitudinal strain [-16, [-17, and \23 %, respectively
Study population A total of 59 patients with Fabry disease were initially enrolled. However, 9 subjects could not be included because of inadequate imaging quality for an analysis by 2DSTE (n = 2) and due to comorbidities such as coronary artery disease, diabetes, arterial hypertension, and atrial fibrillation (n = 7). Accordingly, 50 patients with Fabry disease were finally included. Clinical characteristics and conventional echocardiographic measurements in Fabry patients and the control group are shown in Table 1. Functional myocardial alterations in patients with Fabry disease
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Int J Cardiovasc Imaging Table 3 Structural changes linked to LV functional myocardial alterations in patients with Fabry disease Normal LV Myocardial Function(n = 38)
Altered LV Myocardial Function(n = 12)
P value
Increased LV wall thickness Septal or posterior wall C11 mm
34.2 %
100 %
\.001
Septal or posterior wall C15 mm LV fibrosis
0.0 %
91.7 %
\.001
LV fibrosis in 1–2 LV segments
18.8 %
22.2 %
.821
LV fibrosis in 3–5 LV segments
21.9 %
11.1 %
.484
LV fibrosis in C6 LV segments
9.4 %
44.4 %
.012
Subendocardial and midmyocardial fibrosis
37.5 %
66.7 %
.125
Only subendocardial fibrosis
12.5 %
11.1 %
.913
10.5 %
16.7 %
.577
5.3 %
8.3 %
.703
Systemic alterations Hemoglobin \12 g/dl Glomerular filtration rate \30 ml/min/1.73 m2
Data are expressed as percentages. LV myocardial function, indicates LV global longitudinal systolic strain. Altered and normal LV myocardial function, indicate LV global longitudinal systolic strain [-16 and B-16 %, respectively. Septal and posterior wall thickness were measured at end-diastole from parasternal long-axis view. LV fibrosis was analyzed by means of late gadolinium enhancement cardiac magnetic resonance imaging (LGE-MRI). Evaluation of LV fibrosis using LGE-MRI was performed in 9 patients with altered LV myocardial function and in 32 patients with normal LV myocardial function
Fig. 3 Association of increased LV wall thickness with LV myocardial dysfunction in patients with Fabry disease. Area under the curve (AUC) of receiver operating characteristic (ROC) curves. Se sensitivity; Sp specificity
[-16 % was strongly linked to reduced LA strain (see Fig. 5). Furthermore, in order to evaluate other possible structural changes linked to functional cardiac alterations, we analyzed by means of LGE-MRI the grade of myocardial
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fibrosis in patients with Fabry disease. In this respect, we found that only when the fibrotic changes of the LV were extensive (i.e. C6 LV segments), the functional LV alterations were more evident (see Table 3; Fig. 6). In line with these findings, but to a lesser extent, the presence of RV
Int J Cardiovasc Imaging Table 4 Structural changes linked to RV functional myocardial alterations in patients with Fabry disease Normal RV Myocardial Function(n = 40)
Altered RV Myocardial Function(n = 10)
P value
RV free wall [5 mm
10 %
100 %
\.001
RV free wall C7 mm RV septal wall C11 mm
0.0 % 37.5 %
100 % 100 %
\.001 \.001
RV septal wall C15 mm
2.5 %
100 %
\.001
Increased RV wall thickness
RV fibrosis RV free wall fibrosis
3%
25 %
.032
RV septal wall fibrosis
30.3 %
50 %
.303
RV and LV interactions LV myocardial systolic dysfunction
5%
100 %
\.001
LV myocardial diastolic dysfunction
10 %
80 %
\.001
Systemic alterations Hemoglobin \12 g/dl
10 %
20 %
.394
Glomerular filtration rate \30 ml/min/1.73 m2
5%
10 %
.560
Pulmonary arterial systolic pressure [40 mmHg
0.0 %
10 %
.044
Data are expressed as percentages. RV myocardial function, indicates RV global (septal and free wall) longitudinal systolic strain. Altered and normal RV myocardial function, indicate RV global longitudinal systolic strain [-17 and B-17 %, respectively. RV septal and free wall thickness were measured at end-diastole from the parasternal long-axis and subcostal views, respectively. RV fibrosis was analyzed by means of late gadolinium enhancement cardiac magnetic resonance imaging (LGE-MRI). Evaluation of RV fibrosis using LGE-MRI was performed in 8 patients with altered RV myocardial function and in 33 patients with normal RV myocardial function. LV myocardial systolic function, indicates LV global longitudinal systolic strain [-16 %. LV myocardial diastolic dysfunction, indicates LV global longitudinal early-diastolic strain rate \1.00 s-1. Pulmonary arterial systolic pressure was estimated by Doppler echocardiography using the maximal gradient of tricuspid insufficient more a fixed-value of central venous pressure at 10 mmHg
myocardial fibrosis was also linked to functional alterations of the RV (see Table 4). Clinical consequences of functional myocardial alterations in patients with Fabry disease Concerning the clinical consequences of functional myocardial alterations of the LV, RV, and LA detected by 2DSTE in patients with Fabry disease, we found that these cardiac dysfunctions were significantly linked to the symptomatic status of the patients. In this regard, we evidenced that the functional class (dyspnea–NYHA classification) was inversely linked to the myocardial function of the LV, RV, and LA (see Table 6). In line, the percentage of patients with dyspnea (NYHA class C2) was significantly more elevated in those with reduced LV, RV, and LA strain than in patients with normal cardiac function (all P \ 0.001; see Fig. 7a–c).
Discussion In the present study performing comprehensive myocardial analyses with 2DSTE and cardiac MRI in patients with Fabry disease and in a large cohort of healthy subjects, we
evidenced that patients with Fabry had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects, even when conventional cardiac parameters were normal. In addition, we found that these functional myocardial alterations detected by 2DSTE were significantly associated with worse symptomatic status and strongly linked to increased cardiac wall thickness. Functional myocardial alterations in patients with Fabry disease Cardiac involvement in Fabry disease has been characterized by accumulation of globotriaosylceramide (Gb3) in the LV with consequent LV myocardial alterations [1–6]. In this regard, recent studies using 2DSTE demonstrated that patients with Fabry disease, despite a normal LVEF, had significantly lower functional myocardial values of the LV than healthy subjects [5, 6]. Notwithstanding these studies, the rate of LV myocardial dysfunction in this disease as well as the link between functional LV alterations and the symptomatic status in these patients has not been investigated. The present study confirms previous reports regarding the lower functional myocardial values of the LV in Fabry patients in comparison with healthy subjects and additionally shows that the rate of LV
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Int J Cardiovasc Imaging Fig. 4 Association of increased RV Wall thickness with RV myocardial dysfunction in patients with Fabry disease. Area under the curve (AUC). Se sensitivity; Sp specificity
myocardial dysfunction in this disease is of until 24 %. In addition, we evidenced that functional myocardial alterations of the LV detected by 2DSTE are significantly linked to worse symptomatic status in Fabry disease. These findings are in agreement with previous studies using 2DSTE in patients with hypertrophic cardiomyopathy [23–25], which found a strong association between LV functional myocardial alterations and the functional class of the patients [23–25]. While the majority of the investigations regarding the cardiac involvement in Fabry disease were focused on the LV [1–6], recent anatomopathological findings demonstrated that structural changes such as the accumulation of globotriaosylceramide take place also in the RV and the LA [7–9]. Nevertheless, despite these interesting studies, it remains poorly understood if RV and LA functional myocardial alterations are present in Fabry disease. In the current study using 2DSTE, we evidenced that functional myocardial alterations in Fabry disease do not occur only in the LV, but also in the RV and the LA. In addition, we found that both RV and LA myocardial dysfunctions were significantly linked to worse symptomatic status in these patients. Consistent with these findings, previous studies using 2DSTE also demonstrated that RV and LA functional myocardial alterations are significantly related to worse functional class in patients with hypertrophic cardiomyopathy [26, 27].
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Conventional versus myocardial cardiac analyses in patients with Fabry disease In the present study, RV and LA functional alterations were also detected using conventional measurements such as TAPSE, FAC, and LAVI in patients with Fabry, which is in agreement with previous reports using these analyses [28– 30]. However, 2DSTE analyses were more sensitive parameters to detect functional myocardial alterations in these patients. In this regard, global myocardial analyses using 2DSTE detected LV, RV, and LA myocardial dysfunction in patients with Fabry, even when conventional cardiac measurements such as LVEF, TAPSE, FAC, and LAVI were normal. These findings are in agreement with previous studies in other cardiovascular diseases, which also showed that 2DSTE analyses have higher sensitivity to detect functional myocardial alterations than conventional cardiac parameters [12, 18, 31]. Structural changes linked to functional myocardial alterations in Fabry patients In patients with Fabry disease, the principal molecular and histologic cardiac change is the infiltration and accumulation of sphingolipids (Gb3) in the cardiac myocytes [1–4], which leads a gain of the size of the myocytes and activation of diverse mechanisms with consequent increase of
Int J Cardiovasc Imaging Table 5 Structural changes linked to LA functional myocardial alterations in patients with Fabry disease Normal LA Myocardial Function(n = 37)
Altered LA Myocardial Function(n = 13)
P value
LV myocardial systolic dysfunction LV longitudinal systolic dysfunction
2.7 %
84.6 %
\.001
LV circumferential systolic dysfunction LV radial systolic dysfunction
2.7 % 0.0 %
53.8 % 53.8 %
\.001 \.001
LV myocardial diastolic dysfunction LV longitudinal diastolic dysfunction
8.1 %
69.2 %
\.001
LV circumferential diastolic dysfunction
2.7 %
53.8 %
\.001
LV radial diastolic dysfunction
0.0 %
46.2 %
\.001
Increased LV wall thickness Septal or posterior wall C11 mm
32.4 %
100 %
\.001
Septal or posterior wall C15 mm
2.7 %
76.9 %
\.001
10.8 %
15.4 %
.670
5.4 %
7.7 %
.770
Systemic alterations Hemoglobin \12 g/dl Glomerular filtration rate \30 ml/min/1.73 m2
Data are expressed as percentages. LA myocardial function, indicates LA longitudinal strain. Altered and normal LA myocardial function, indicate LA longitudinal strain \23 and C23 %, respectively. LV longitudinal, circumferential, and radial systolic function, indicate LV global longitudinal, circumferential, and radial systolic strain[-16,[-15, and\20 %, respectively. LV longitudinal, circumferential, and radial earlydiastolic function, indicate LV global longitudinal, circumferential, and radial early-diastolic strain rate \1.00, \0.90, and [-1.20 s-1, respectively. Septal and posterior wall thickness was measured in end-diastole
Fig. 5 Association of LV myocardial dysfunction with LA myocardial dysfunction in patients with Fabry disease. Area under the curve (AUC). Se sensitivity; Sp specificity
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Int J Cardiovasc Imaging Fig. 6 Association of LV fibrosis with LV myocardial dysfunction in patients with Fabry disease. This figure (upper) shows a patient with Fabry disease with extended LV fibrosis (C6 segments) and in consequence with LV myocardial dysfunction. On the contrary, the same figure (below) shows a patient with Fabry without LV fibrosis and consequently without LV myocardial dysfunction. Noting also the significant difference in LV wall thickness between patients with and without LV fibrosis (LV wall thickness 19 vs. 8 mm, respectively)
Table 6 Worsening of symptomatic status linked to deterioration of LV, RV, and LA myocardial function in patients with Fabry disease
NYHA functional class
P anova
Class I (n = 37)
Class II (n = 8)
Class III–IV (n = 5)
LV myocardial function (LV strain) (%)
-19.9 ± 2.4
-13.9 ± 3.6*
-11.9 ± 2.9
\.001
RV myocardial function (RV strain) (%)
-23.2 ± 3.7
-17.5 ± 4.2*
-14.3 ± 4.2
\.001
LA myocardial function (LA strain) (%)
33.6 ± 7.5
21.8 ± 7.3*
13.5 ± 3.9
\.001
60.8 ± 3.1
60.6 ± 4.1
58.6 ± 6.5
Myocardial analyses
Data are expressed as mean ± SD. LV, RV, LA myocardial function, indicate LV, RV, and LA global longitudinal strain Anova analysis of variance * P \ .05, NYHA class II versus class I
P \ .05, NYHA class III–IV versus class I
Volumetric analyses LV ejection fraction (LVEF) (%) LV diastolic mitral inflow (E/A ratio) Pulmonary arterial systolic pressure (mmHg)
1.3 ± 0.9 30.8 ± 5.4
.105 .061
\.001
1.8 ± 0.6 32.4 ± 10.6
LA volume index (LAVI) (ml/m2)
23.5 ± 9.3
33.9 ± 9.3*
31.1 ± 9.7
RV fractional area change (FAC) (%)
41.9 ± 4.1
34.5 ± 9.3*
32.0 ± 7.8
cardiac wall thickness and LV hypertrophy [1–4]. While these changes have been linked to LV myocardial alterations [1–4], the cutoff-value of LV wall thickness associated with LV systolic and diastolic dysfunction is poorly understood in Fabry disease. In the present study we found that a septal wall thickness C15 mm was strongly linked LV systolic and diastolic myocardial dysfunction. In addition, but to a
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1.3 ± 0.3 27.4 ± 4.1
.459
.011
lesser magnitude, we found that an extended LV myocardial fibrosis (C6 LV segments) determined by LGEMRI was significantly linked to a global LV myocardial dysfunction. These findings are in agreement with recent studies using LGE-MRI and 2DSTE in patients with hypertrophic cardiomyopathy, which demonstrated that an increased LV wall thickness (such as a septum C15 mm) and into lesser extent the amount of LV
Int J Cardiovasc Imaging
fibrosis are significantly linked to a global LV myocardial dysfunction [32–35]. >Studies analyzing the structural changes linked to RV and LA functional myocardial alterations in patients with Fabry disease are lacking. Nonetheless, in the present study using global myocardial analyses in these patients, we evidenced that the principal factors linked to RV and LA myocardial dysfunction were an increased RV wall thickness (RV septal wall C15 mm and RV free wall C7 mm) and a longitudinal dysfunction of the LV, respectively. These findings are consistent with previous studies using 2DSTE in hypertrophic cardiomyopathy, which demonstrated that RV hypertrophy and LV longitudinal systolic dysfunction were the strongest factors associated with RV and LA dysfunction, respectively [26, 27].
Limitations Some considerations should be taken into account on this study. Given that Fabry disease is an uncommon disorder, we were not able to include a large number of patients despite the fact that we enrolled consecutives patients during a period of 5 years. Nonetheless, our cohort was very homogenous (i.e. without comorbidities such as diabetes, arterial hypertension, or coronary artery disease which could bias the functional cardiac alterations attributable to Fabry disease) and significantly larger than previous investigations using myocardial analyses with 2DSTE [6]. In addition, it is important to note that the group control was considerably large and of similar age and gender than Fabry patients. Furthermore, it is worth mentioning that we did not determine the prognostic value of functional myocardial alterations in the cohort studied. Hence, prospective clinical studies should address the prognostic significance of LV, RV, and LA functional myocardial dysfunction in patients with Fabry disease.
Conclusions
Fig. 7 a–c Symptomatic status (dyspnea) linked to LV, RV, and LA myocardial dysfunction in patients with Fabry disease. LV, RV, and LA myocardial dysfunction were determined as LV, RV, and LA global longitudinal strain [-16, [-17, and \23 %, respectively
In the present study performing comprehensive myocardial analyses with 2DSTE and cardiac MRI in patients with Fabry disease and in a large cohort of healthy subjects, we evidenced that patients with Fabry have significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects, even when conventional cardiac parameters are normal. In addition, we found that these functional myocardial alterations detected by 2DSTE are significantly associated with worse symptomatic status and strongly linked to increased cardiac wall thickness. Therefore, we consider that these findings could be of great importance in
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the management of patients with Fabry disease, because global myocardial analyses using 2DSTE could early detect functional cardiac alterations in this disease, which are linked to worse symptomatic status in these patients. Acknowledgments The authors thank the Department of Nephrology and Radiology of our Institution (Campus Virchow Klinikum, Charite´ University Hospital) for the excellent assessment and management of patients with Fabry disease. Conflict of interest of interest.
13.
14.
The authors declare that they have no conflict 15.
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ORIGINAL PAPER
Global cardiac alterations detected by speckle-tracking echocardiography in Fabry disease: left ventricular, right ventricular, and left atrial dysfunction are common and linked to worse symptomatic status Daniel A. Morris • Daniela Blaschke • Sima Canaan-Ku¨hl • Alice Krebs • Gesine Knobloch Thula C. Walter • Wilhelm Haverkamp
•
Received: 31 August 2014 / Accepted: 7 October 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The aim of this study was to test the hypothesis that in patients with Fabry disease, 2D speckle-tracking echocardiography (2DSTE) could detect functional myocardial alterations such as left ventricular (LV), right ventricular (RV), and left atrial (LA) dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients. Fifty patients with Fabry disease and a control group of 118 healthy subjects of similar age and gender were included. The myocardial function and structural changes of the LV, RV, and LA were analyzed by 2DSTE and cardiac magnetic resonance imaging. Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 ± 4.0, -21.4 ± 4.9, and 29.7 ± 9.9 % vs. -21.6 ± 2.2, -25.2 ± 4.0, and 44.8 ± 11.1 %, respectively, P \ 0.001) and elevated rates of LV, RV, and LA myocardial dysfunction (24, 20, and 26 %, respectively), even when conventional cardiac measurements such as LVEF, TAPSE, and LAVI were normal. LV septal wall thickness C15 mm, RV free wall thickness C7 mm, and LV longitudinal dysfunction were the
Electronic supplementary material The online version of this article (doi:10.1007/s10554-014-0551-4) contains supplementary material, which is available to authorized users. D. A. Morris (&) D. Blaschke S. Canaan-Ku¨hl A. Krebs G. Knobloch T. C. Walter W. Haverkamp Department of Cardiology, Charite´ University Hospital, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany e-mail: [email protected]
principal factors linked to reduced LV, RV, and LA strain, respectively. In addition, but to a lesser extent, LV and RV fibrosis were linked to reduced LV and RV strain. Patients with reduced LV, RV, and LA strain had worse functional class (dyspnea–NYHA classification) than those with normal cardiac function. In conclusion, in patients with Fabry disease, 2DSTE analyses detect LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements are normal. These functional myocardial alterations are common and significantly associated with worse symptomatic status in Fabry patients. Therefore, these findings provide important evidence to introduce global myocardial analyses using 2DSTE in the early detection of functional cardiac alterations in Fabry disease. Keywords Left atrial Right ventricular Strain Speckle-tracking Fabry disease
Introduction Cardiac involvement in Fabry disease has been characterized by accumulation of globotriaosylceramide (Gb3) in the left ventricle (LV) with consequent LV myocardial alterations [1–6]. Recent studies using two-dimensional speckle-tracking echocardiography (2DSTE) demonstrated that patients with Fabry disease had significantly lower functional myocardial values of the LV than healthy subjects, even when LV ejection fraction (LVEF) was normal [5, 6]. Nevertheless, despite these interesting studies, the rate of LV myocardial dysfunction in this disease as well as its relation with the symptomatic status in these patients have not been investigated. In spite of the fact that structural myocardial alterations have long been considered exclusively in the LV in Fabry
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Int J Cardiovasc Imaging Table 1 Clinical characteristics and conventional measurements in Fabry patients and healthy subjects
P value
Healthy subjects (n = 118)
Fabry patients (n = 50)
Age (years)
42.8 ± 11.5
46.1 ± 11.4
.096
Women
58.5 %
74 %
.057
Clinical characteristics
2
\.001
Body mass index (kg/m )
22.2 ± 2.5
25.8 ± 7.2
Systolic blood pressure (mmHg)
119.0 ± 10.7
116.1 ± 11.2
.123
Diastolic blood pressure (mmHg)
71.8 ± 8.2
71.7 ± 8.8
.923
64.4 ± 5.8
60.5 ± 3.7
\.001
Conventional left ventricular measurements LV ejection fraction (%) 2
Data are expressed as mean ± SD or percentages TDI tissue Doppler imaging. e’ early-diastolic, FAC fractional area change, TAPSE tricuspid annular plane systolic excursion, LAVI maximal left atrial volume index In accordance with the guidelines on Fabry disease,1 all men and women with some evidence of organ involvement had enzyme replacement therapy.Septal and posterior wall thickness were measured at end-diastole from parasternal long-axis view
LV mass (g/m )
73.3 ± 14.3
105.9 ± 41.1
\.001
LV septal wall thickness (mm)
8.6 ± 1.3
11.7 ± 3.0
\.001
LV posterior wall thickness (mm) Septal e’ mitral annular velocity by TDI (cm/s)
8.3 ± 1.2 11.0 ± 2.1
11.1 ± 2.7 7.4 ± 3.0
\.001 \.001
Lateral e’ mitral annular velocity by TDI (cm/s)
13.6 ± 2.5
9.5 ± 3.1
\ .001 \.001
Mitral E/e’ septal–lateral ratio
6.7 ± 1.6
10.6 ± 4.8
Mitral E/A inflow ratio
1.5 ± 0.4
1.3 ± 0.5
.091
Conventional right ventricular measurements TAPSE (mm)
20.0 ± 2.8
18.8 ± 3.4
.014
RV FAC (%)
51.1 ± 8.0
39.8 ± 6.6
\.001
RV free wall thickness (mm)
3.5 ± 0.4
4.8 ± 1.7
\.001
Conventional left atrial measurements LAVI (ml/m2)
18.8 ± 5.9
25.9 ± 10.0
\.001
LA ejection fraction (%)
66.9 ± 9.2
55.5 ± 14.5
\.001
Table 2 Global cardiac myocardial function in patients with Fabry disease
Healthy subjects (n = 118)
Fabry patients (n = 50)
LV myocardial function LV global longitudinal systolic strain Mean ± SD
-21.6 ± 2.2 %
-18.1 ± 4.0 %
LV systolic dysfunction (LV strain [-16 %)
0.0 %
24 %
Mean ± SD
1.55 ± 0.29 s-1
1.24 ± 0.44 s-1
LV diastolic dysfunction (LV strain rate \1.00 s-1)
0.0 %
24 %
-25.2 ± 4.0 %
-21.4 ± 4.9 %
0.0 %
20 %
Mean ± SD
-29.8 ± 5.1 %
-25.4 ± 6.9 %
RV systolic dysfunction (RV free wall strain [-19 %)
0.0 %
18 %
Mean ± SD
44.8 ± 11.1 %
29.7 ± 9.9 %
LA myocardial dysfunction (LA strain \23 %)
0.0 %
26 %
-2.12 ± 0.57 s-1
-1.62 ± 0.68 s-1
0.0 %
16 %
LV global longitudinal diastolic strain rate
RV myocardial function RV global systolic strain Mean ± SD RV systolic dysfunction (RV strain [-17 %) RV free wall systolic strain
LA myocardial function Data are expressed as mean ± SD and percentages. The differences between healthy subjects and Fabry patients were statistically significant in all the measurements (P \ 0.001) SD standard deviation
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LA strain
LA strain rate Mean ± SD -1
LA myocardial dysfunction (LA strain rate [-0.90 s )
Int J Cardiovasc Imaging
disease [1–4], recent anatomopathological studies analyzing the whole myocardium [i.e. LV, right ventricle (RV), and left atrium (LA)] demonstrated that in these patients the accumulation of globotriaosylceramide is not only localized in the LV, but also in the RV and LA [7–9]. Nonetheless, it remains poorly understood if RV and LA functional myocardial alterations are present in Fabry disease. Furthermore, the role that RV and LA myocardial alterations could have on the functional class (dyspnea– NYHA) of these patients is not known. The aim of this study was to test the hypothesis that in patients with Fabry disease, 2DSTE could detect functional myocardial alterations such as LV, RV, and LA dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients.
Methods Study population We included patients with Fabry disease C18 years of age derived to our Department of Cardiology (Charite´ University Hospital) for evaluation of cardiac involvement between March 2009 and March 2014. In addition, we included a control group of healthy subjects of similar age and gender, which were enrolled in previous studies of our research group [10–13]. Healthy subjects were defined as all those individuals with absence of any disease and cardiovascular risk factors such as obesity, diabetes, hypertension, and hypercholesterolemia. The institutional review board approved this research project and informed consent was obtained from all of the subjects. Transthoracic echocardiography All subjects were examined at rest in the left lateral decubitus position using one the following ultrasound systems: Vivid 7 or Vivid E9 from GE Healthcare. LV, RV, and LA measurements were performed as recommended by the American Society of Echocardiography (ASE) [14–17]. All echocardiographic measurements using 2DSTE, Doppler, and conventional 2D echocardiography were calculated as the average of 3 measurements. Myocardial analyses of the left ventricle, right ventricle, and left atrium The myocardial analyses by 2DSTE were performed offline and blinded to the clinical characteristics of the subjects using the following ultrasound software-package: Echo-
Pac version 113.0 from GE [10–13]. The analyses in longitudinal direction of the LV were performed in the whole myocardium in the basal, mid, and apical segments in the apical 4-chamber, 2-chamber, and long-axis views (i.e. 18 segments of the LV) [10–13]. LV global longitudinal systolic strain (LV strain) was determined by the average value of the longitudinal systolic strain peak across 18 LV segments [10–13]. LV measurements in circumferential and radial direction were performed in the entire myocardium in the three short-axis views of the LV (basal, midventricular, and apical levels) [11, 13]. LV global circumferential and radial systolic strain were evaluated by the average value of the radial and circumferential systolic strain peak from 18 LV segments [11, 13]. In addition, the multidirectional global systolic function of the LV was analyzed by means of 2 indices [11, 13]: longitudinal– circumferential systolic index = average of the longitudinal and circumferential global systolic strain; and global systolic index = average of the longitudinal, circumferential, and radial global systolic strain. Furthermore, we analyzed the longitudinal, circumferential, and radial diastolic function of the LV analyzing the early-diastolic peak strain rate (SRe) using the same 18-segment LV model of the aforementioned measurements [10–13]. The myocardial function of the RV was evaluated by means of the average value of the longitudinal systolic strain peak from all segments of the free and septal wall (i.e. RV strain) and just from the free wall of the RV (i.e. RV free-wall strain) in the apical 4-chamber view [18–20]. The myocardial function of the LA was analyzed by means of LA strain rate peak during LA contraction (LASRa) (namely, at the time of the late-diastole of the LV) and LA strain peak during LA relaxation (LA strain) (i.e. at the time of the systole of the LV) [12, 21]. In accordance with the consensus of experts of the ASE on myocardial mechanisms [16], these LA measurements were performed in the apical 4-chamber and 2-chamber views (i.e. 12 LA segments) and using QRS onset as reference point [16]. On the basis of the recommendations on chamber quantification of the ASE [14], LV, RV, and LA myocardial dysfunctions were defined as -1.96 standard deviation (SD) from the mean of healthy subjects using the aforementioned myocardial measurements. In addition, determination of normal cardiac parameters by means of conventional echocardiographic measurements such as LVEF C 55 %, tricuspid annular plane systolic excursion (TAPSE) C16 mm, RV fractional area change (FAC) C35 %, and LA maximal volume index (LAVI) B28 ml/m2 were also used according the guidelines of the ASE [14]. Furthermore, myocardial structural changes such as myocardial fibrosis were analyzed by means of late gadolinium enhancement cardiac magnetic resonance imaging (LGE-MRI) (1.5-T MRI unit, TwinSpeed-Excite; GE
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Int J Cardiovasc Imaging
Fig. 1 Left ventricular, right ventricular, and left atrial myocardial dysfunction in Fabry disease. a (upper) Patient with Fabry disease with increased LV wall thickness and consequently LV myocardial dysfunction. On the contrary, the same figure (below) shows a patient with Fabry without increased LV wall thickness and in consequence without LV myocardial dysfunction. b (upper) Same patient of a (upper) with increased RV wall thickness and consequently RV
myocardial dysfunction. On the contrary, the same figure (below) shows the same patient of a (below) without increased RV wall thickness and in consequence without RV myocardial dysfunction. c (upper) Same patient of a and b (upper) with a significant LA myocardial dysfunction. On the contrary, the same figure (below) shows the same patient of a and b (below) without LA myocardial dysfunction
Healthcare), which was performed in the Department of Radiology (Charite´ University Hospital) within 3 months after the echocardiographic analysis following a cardiac MRI protocol previously described for our institution [22].
t test. Categorical variables were compared by Chi square test and Fisher exact-test as appropriate. Comparisons between three or more groups were analyzed using a oneway analysis of variance (ANOVA). The relationship of LV, RV, and LA functional alterations with myocardial structural changes were evaluated analyzing the area under the curve (AUC) of receiver operating characteristic (ROC) curves. In addition, in order to determine the value of those structural changes linked to LV, RV, LA functional alterations, ROC curves using the Youden index were
Statistical analysis Continuous data were presented as mean ± SD and dichotomous data in percentage. Differences in continuous variables between groups were analyzed using Student’s
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Int J Cardiovasc Imaging
performed (an optimal cutoff value was chosen as one with the maximal sensitivity and specificity). The reproducibility of the functional myocardial analyses of the LV, RV, and LA using 2DSTE in our laboratory was previously reported [10–13, 18, 21], which was adequate [10–13, 18, 21]. All statistical analyses were performed with Statview 5.0 (SAS Institute) and SPSS 22.0 (IBM). Differences were considered statistically significant when P \ 0.05.
relation to these findings, the rates of LV, RV, and LA myocardial dysfunction in patients with Fabry were between 20 and 26 % (see Table 2; Fig. 1a–c, and supplemental Tables 1 and 2 for multidirectional LV measurements). In addition, in patients with Fabry, global cardiac analyses using 2DSTE detected LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements such as LVEF, TAPSE, FAC, and LAVI were normal (see Fig. 2a, b).
Results
Structural changes linked to functional myocardial alterations in Fabry patients
Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 ± 4.0, -21.4 ± 4.9, and 29.7 ± 9.9 % vs. -21.6 ± 2.2, -25.2 ± 4.0, and 44.8 ± 11.1 %, respectively, P \ 0.001) (see Table 2). In
Increased LV septal thickness was significantly related to LV myocardial dysfunction (see Table 3; Figs. 1a, 3, and supplemental Table 3 for LV diastolic analyses). In line, in ROC curves analysis a value of the septum C15 mm was the strongest cutoff associated with reduced LV strain (see Fig. 3). In relation to these findings, RV functional myocardial alterations were also significantly linked to increased septal thickness and RV free wall (see Table 4; Figs. 1b, 4). Likewise, in ROC curves analysis a value of the septum C15 mm and a value of RV free wall C7 mm were strongly linked to reduced RV strain (see Fig. 4 and supplemental Table 4 for RV myocardial analyses in RV free wall). Concerning the cardiac changes related to functional myocardial alterations of the LA, we found that a longitudinal systolic and diastolic dysfunction of the LV were the principal factors linked to LA myocardial dysfunction in patients with Fabry disease (see Table 5; Figs. 1c, 5). In line with these findings, in ROC curves analysis a value of LV global longitudinal systolic strain
Fig. 2 a, b. Global cardiac analyses using 2DSTE detect LV, RV, and LA functional myocardial alterations in patients with Fabry disease, even when conventional cardiac measurements such as
LVEF, TAPSE, FAC, and LAVI are normal. LV, RV, and LA functional myocardial alterations were determined as LV, RV, and LA global longitudinal strain [-16, [-17, and \23 %, respectively
Study population A total of 59 patients with Fabry disease were initially enrolled. However, 9 subjects could not be included because of inadequate imaging quality for an analysis by 2DSTE (n = 2) and due to comorbidities such as coronary artery disease, diabetes, arterial hypertension, and atrial fibrillation (n = 7). Accordingly, 50 patients with Fabry disease were finally included. Clinical characteristics and conventional echocardiographic measurements in Fabry patients and the control group are shown in Table 1. Functional myocardial alterations in patients with Fabry disease
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Int J Cardiovasc Imaging Table 3 Structural changes linked to LV functional myocardial alterations in patients with Fabry disease Normal LV Myocardial Function(n = 38)
Altered LV Myocardial Function(n = 12)
P value
Increased LV wall thickness Septal or posterior wall C11 mm
34.2 %
100 %
\.001
Septal or posterior wall C15 mm LV fibrosis
0.0 %
91.7 %
\.001
LV fibrosis in 1–2 LV segments
18.8 %
22.2 %
.821
LV fibrosis in 3–5 LV segments
21.9 %
11.1 %
.484
LV fibrosis in C6 LV segments
9.4 %
44.4 %
.012
Subendocardial and midmyocardial fibrosis
37.5 %
66.7 %
.125
Only subendocardial fibrosis
12.5 %
11.1 %
.913
10.5 %
16.7 %
.577
5.3 %
8.3 %
.703
Systemic alterations Hemoglobin \12 g/dl Glomerular filtration rate \30 ml/min/1.73 m2
Data are expressed as percentages. LV myocardial function, indicates LV global longitudinal systolic strain. Altered and normal LV myocardial function, indicate LV global longitudinal systolic strain [-16 and B-16 %, respectively. Septal and posterior wall thickness were measured at end-diastole from parasternal long-axis view. LV fibrosis was analyzed by means of late gadolinium enhancement cardiac magnetic resonance imaging (LGE-MRI). Evaluation of LV fibrosis using LGE-MRI was performed in 9 patients with altered LV myocardial function and in 32 patients with normal LV myocardial function
Fig. 3 Association of increased LV wall thickness with LV myocardial dysfunction in patients with Fabry disease. Area under the curve (AUC) of receiver operating characteristic (ROC) curves. Se sensitivity; Sp specificity
[-16 % was strongly linked to reduced LA strain (see Fig. 5). Furthermore, in order to evaluate other possible structural changes linked to functional cardiac alterations, we analyzed by means of LGE-MRI the grade of myocardial
123
fibrosis in patients with Fabry disease. In this respect, we found that only when the fibrotic changes of the LV were extensive (i.e. C6 LV segments), the functional LV alterations were more evident (see Table 3; Fig. 6). In line with these findings, but to a lesser extent, the presence of RV
Int J Cardiovasc Imaging Table 4 Structural changes linked to RV functional myocardial alterations in patients with Fabry disease Normal RV Myocardial Function(n = 40)
Altered RV Myocardial Function(n = 10)
P value
RV free wall [5 mm
10 %
100 %
\.001
RV free wall C7 mm RV septal wall C11 mm
0.0 % 37.5 %
100 % 100 %
\.001 \.001
RV septal wall C15 mm
2.5 %
100 %
\.001
Increased RV wall thickness
RV fibrosis RV free wall fibrosis
3%
25 %
.032
RV septal wall fibrosis
30.3 %
50 %
.303
RV and LV interactions LV myocardial systolic dysfunction
5%
100 %
\.001
LV myocardial diastolic dysfunction
10 %
80 %
\.001
Systemic alterations Hemoglobin \12 g/dl
10 %
20 %
.394
Glomerular filtration rate \30 ml/min/1.73 m2
5%
10 %
.560
Pulmonary arterial systolic pressure [40 mmHg
0.0 %
10 %
.044
Data are expressed as percentages. RV myocardial function, indicates RV global (septal and free wall) longitudinal systolic strain. Altered and normal RV myocardial function, indicate RV global longitudinal systolic strain [-17 and B-17 %, respectively. RV septal and free wall thickness were measured at end-diastole from the parasternal long-axis and subcostal views, respectively. RV fibrosis was analyzed by means of late gadolinium enhancement cardiac magnetic resonance imaging (LGE-MRI). Evaluation of RV fibrosis using LGE-MRI was performed in 8 patients with altered RV myocardial function and in 33 patients with normal RV myocardial function. LV myocardial systolic function, indicates LV global longitudinal systolic strain [-16 %. LV myocardial diastolic dysfunction, indicates LV global longitudinal early-diastolic strain rate \1.00 s-1. Pulmonary arterial systolic pressure was estimated by Doppler echocardiography using the maximal gradient of tricuspid insufficient more a fixed-value of central venous pressure at 10 mmHg
myocardial fibrosis was also linked to functional alterations of the RV (see Table 4). Clinical consequences of functional myocardial alterations in patients with Fabry disease Concerning the clinical consequences of functional myocardial alterations of the LV, RV, and LA detected by 2DSTE in patients with Fabry disease, we found that these cardiac dysfunctions were significantly linked to the symptomatic status of the patients. In this regard, we evidenced that the functional class (dyspnea–NYHA classification) was inversely linked to the myocardial function of the LV, RV, and LA (see Table 6). In line, the percentage of patients with dyspnea (NYHA class C2) was significantly more elevated in those with reduced LV, RV, and LA strain than in patients with normal cardiac function (all P \ 0.001; see Fig. 7a–c).
Discussion In the present study performing comprehensive myocardial analyses with 2DSTE and cardiac MRI in patients with Fabry disease and in a large cohort of healthy subjects, we
evidenced that patients with Fabry had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects, even when conventional cardiac parameters were normal. In addition, we found that these functional myocardial alterations detected by 2DSTE were significantly associated with worse symptomatic status and strongly linked to increased cardiac wall thickness. Functional myocardial alterations in patients with Fabry disease Cardiac involvement in Fabry disease has been characterized by accumulation of globotriaosylceramide (Gb3) in the LV with consequent LV myocardial alterations [1–6]. In this regard, recent studies using 2DSTE demonstrated that patients with Fabry disease, despite a normal LVEF, had significantly lower functional myocardial values of the LV than healthy subjects [5, 6]. Notwithstanding these studies, the rate of LV myocardial dysfunction in this disease as well as the link between functional LV alterations and the symptomatic status in these patients has not been investigated. The present study confirms previous reports regarding the lower functional myocardial values of the LV in Fabry patients in comparison with healthy subjects and additionally shows that the rate of LV
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Int J Cardiovasc Imaging Fig. 4 Association of increased RV Wall thickness with RV myocardial dysfunction in patients with Fabry disease. Area under the curve (AUC). Se sensitivity; Sp specificity
myocardial dysfunction in this disease is of until 24 %. In addition, we evidenced that functional myocardial alterations of the LV detected by 2DSTE are significantly linked to worse symptomatic status in Fabry disease. These findings are in agreement with previous studies using 2DSTE in patients with hypertrophic cardiomyopathy [23–25], which found a strong association between LV functional myocardial alterations and the functional class of the patients [23–25]. While the majority of the investigations regarding the cardiac involvement in Fabry disease were focused on the LV [1–6], recent anatomopathological findings demonstrated that structural changes such as the accumulation of globotriaosylceramide take place also in the RV and the LA [7–9]. Nevertheless, despite these interesting studies, it remains poorly understood if RV and LA functional myocardial alterations are present in Fabry disease. In the current study using 2DSTE, we evidenced that functional myocardial alterations in Fabry disease do not occur only in the LV, but also in the RV and the LA. In addition, we found that both RV and LA myocardial dysfunctions were significantly linked to worse symptomatic status in these patients. Consistent with these findings, previous studies using 2DSTE also demonstrated that RV and LA functional myocardial alterations are significantly related to worse functional class in patients with hypertrophic cardiomyopathy [26, 27].
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Conventional versus myocardial cardiac analyses in patients with Fabry disease In the present study, RV and LA functional alterations were also detected using conventional measurements such as TAPSE, FAC, and LAVI in patients with Fabry, which is in agreement with previous reports using these analyses [28– 30]. However, 2DSTE analyses were more sensitive parameters to detect functional myocardial alterations in these patients. In this regard, global myocardial analyses using 2DSTE detected LV, RV, and LA myocardial dysfunction in patients with Fabry, even when conventional cardiac measurements such as LVEF, TAPSE, FAC, and LAVI were normal. These findings are in agreement with previous studies in other cardiovascular diseases, which also showed that 2DSTE analyses have higher sensitivity to detect functional myocardial alterations than conventional cardiac parameters [12, 18, 31]. Structural changes linked to functional myocardial alterations in Fabry patients In patients with Fabry disease, the principal molecular and histologic cardiac change is the infiltration and accumulation of sphingolipids (Gb3) in the cardiac myocytes [1–4], which leads a gain of the size of the myocytes and activation of diverse mechanisms with consequent increase of
Int J Cardiovasc Imaging Table 5 Structural changes linked to LA functional myocardial alterations in patients with Fabry disease Normal LA Myocardial Function(n = 37)
Altered LA Myocardial Function(n = 13)
P value
LV myocardial systolic dysfunction LV longitudinal systolic dysfunction
2.7 %
84.6 %
\.001
LV circumferential systolic dysfunction LV radial systolic dysfunction
2.7 % 0.0 %
53.8 % 53.8 %
\.001 \.001
LV myocardial diastolic dysfunction LV longitudinal diastolic dysfunction
8.1 %
69.2 %
\.001
LV circumferential diastolic dysfunction
2.7 %
53.8 %
\.001
LV radial diastolic dysfunction
0.0 %
46.2 %
\.001
Increased LV wall thickness Septal or posterior wall C11 mm
32.4 %
100 %
\.001
Septal or posterior wall C15 mm
2.7 %
76.9 %
\.001
10.8 %
15.4 %
.670
5.4 %
7.7 %
.770
Systemic alterations Hemoglobin \12 g/dl Glomerular filtration rate \30 ml/min/1.73 m2
Data are expressed as percentages. LA myocardial function, indicates LA longitudinal strain. Altered and normal LA myocardial function, indicate LA longitudinal strain \23 and C23 %, respectively. LV longitudinal, circumferential, and radial systolic function, indicate LV global longitudinal, circumferential, and radial systolic strain[-16,[-15, and\20 %, respectively. LV longitudinal, circumferential, and radial earlydiastolic function, indicate LV global longitudinal, circumferential, and radial early-diastolic strain rate \1.00, \0.90, and [-1.20 s-1, respectively. Septal and posterior wall thickness was measured in end-diastole
Fig. 5 Association of LV myocardial dysfunction with LA myocardial dysfunction in patients with Fabry disease. Area under the curve (AUC). Se sensitivity; Sp specificity
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Int J Cardiovasc Imaging Fig. 6 Association of LV fibrosis with LV myocardial dysfunction in patients with Fabry disease. This figure (upper) shows a patient with Fabry disease with extended LV fibrosis (C6 segments) and in consequence with LV myocardial dysfunction. On the contrary, the same figure (below) shows a patient with Fabry without LV fibrosis and consequently without LV myocardial dysfunction. Noting also the significant difference in LV wall thickness between patients with and without LV fibrosis (LV wall thickness 19 vs. 8 mm, respectively)
Table 6 Worsening of symptomatic status linked to deterioration of LV, RV, and LA myocardial function in patients with Fabry disease
NYHA functional class
P anova
Class I (n = 37)
Class II (n = 8)
Class III–IV (n = 5)
LV myocardial function (LV strain) (%)
-19.9 ± 2.4
-13.9 ± 3.6*
-11.9 ± 2.9
\.001
RV myocardial function (RV strain) (%)
-23.2 ± 3.7
-17.5 ± 4.2*
-14.3 ± 4.2
\.001
LA myocardial function (LA strain) (%)
33.6 ± 7.5
21.8 ± 7.3*
13.5 ± 3.9
\.001
60.8 ± 3.1
60.6 ± 4.1
58.6 ± 6.5
Myocardial analyses
Data are expressed as mean ± SD. LV, RV, LA myocardial function, indicate LV, RV, and LA global longitudinal strain Anova analysis of variance * P \ .05, NYHA class II versus class I
P \ .05, NYHA class III–IV versus class I
Volumetric analyses LV ejection fraction (LVEF) (%) LV diastolic mitral inflow (E/A ratio) Pulmonary arterial systolic pressure (mmHg)
1.3 ± 0.9 30.8 ± 5.4
.105 .061
\.001
1.8 ± 0.6 32.4 ± 10.6
LA volume index (LAVI) (ml/m2)
23.5 ± 9.3
33.9 ± 9.3*
31.1 ± 9.7
RV fractional area change (FAC) (%)
41.9 ± 4.1
34.5 ± 9.3*
32.0 ± 7.8
cardiac wall thickness and LV hypertrophy [1–4]. While these changes have been linked to LV myocardial alterations [1–4], the cutoff-value of LV wall thickness associated with LV systolic and diastolic dysfunction is poorly understood in Fabry disease. In the present study we found that a septal wall thickness C15 mm was strongly linked LV systolic and diastolic myocardial dysfunction. In addition, but to a
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1.3 ± 0.3 27.4 ± 4.1
.459
.011
lesser magnitude, we found that an extended LV myocardial fibrosis (C6 LV segments) determined by LGEMRI was significantly linked to a global LV myocardial dysfunction. These findings are in agreement with recent studies using LGE-MRI and 2DSTE in patients with hypertrophic cardiomyopathy, which demonstrated that an increased LV wall thickness (such as a septum C15 mm) and into lesser extent the amount of LV
Int J Cardiovasc Imaging
fibrosis are significantly linked to a global LV myocardial dysfunction [32–35]. >Studies analyzing the structural changes linked to RV and LA functional myocardial alterations in patients with Fabry disease are lacking. Nonetheless, in the present study using global myocardial analyses in these patients, we evidenced that the principal factors linked to RV and LA myocardial dysfunction were an increased RV wall thickness (RV septal wall C15 mm and RV free wall C7 mm) and a longitudinal dysfunction of the LV, respectively. These findings are consistent with previous studies using 2DSTE in hypertrophic cardiomyopathy, which demonstrated that RV hypertrophy and LV longitudinal systolic dysfunction were the strongest factors associated with RV and LA dysfunction, respectively [26, 27].
Limitations Some considerations should be taken into account on this study. Given that Fabry disease is an uncommon disorder, we were not able to include a large number of patients despite the fact that we enrolled consecutives patients during a period of 5 years. Nonetheless, our cohort was very homogenous (i.e. without comorbidities such as diabetes, arterial hypertension, or coronary artery disease which could bias the functional cardiac alterations attributable to Fabry disease) and significantly larger than previous investigations using myocardial analyses with 2DSTE [6]. In addition, it is important to note that the group control was considerably large and of similar age and gender than Fabry patients. Furthermore, it is worth mentioning that we did not determine the prognostic value of functional myocardial alterations in the cohort studied. Hence, prospective clinical studies should address the prognostic significance of LV, RV, and LA functional myocardial dysfunction in patients with Fabry disease.
Conclusions
Fig. 7 a–c Symptomatic status (dyspnea) linked to LV, RV, and LA myocardial dysfunction in patients with Fabry disease. LV, RV, and LA myocardial dysfunction were determined as LV, RV, and LA global longitudinal strain [-16, [-17, and \23 %, respectively
In the present study performing comprehensive myocardial analyses with 2DSTE and cardiac MRI in patients with Fabry disease and in a large cohort of healthy subjects, we evidenced that patients with Fabry have significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects, even when conventional cardiac parameters are normal. In addition, we found that these functional myocardial alterations detected by 2DSTE are significantly associated with worse symptomatic status and strongly linked to increased cardiac wall thickness. Therefore, we consider that these findings could be of great importance in
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Int J Cardiovasc Imaging
the management of patients with Fabry disease, because global myocardial analyses using 2DSTE could early detect functional cardiac alterations in this disease, which are linked to worse symptomatic status in these patients. Acknowledgments The authors thank the Department of Nephrology and Radiology of our Institution (Campus Virchow Klinikum, Charite´ University Hospital) for the excellent assessment and management of patients with Fabry disease. Conflict of interest of interest.
13.
14.
The authors declare that they have no conflict 15.
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