Role of Longitudinal Strain in the Evaluation of Contractile Dysfunction in Japanese Fabry Disease Patients

Ayumi Nojiri; Satoshi Morimoto; Eiko Fukuro; Toraaki Okuyama; Ikuko Anan; Makoto Kawai; Ken Sakurai; Masahisa Kobayashi; Hiroshi Kobayashi; Hiroyuki Ida; Toya Ohashi; Michihiro Yoshimura; Yoshikatsu Eto; Kenichi Hongo

doi:10.1253/circj.CJ-24-0509

Abstract

Background: Fabry disease is a hereditary metabolic disorder caused by a decrease in or deficiency of the lysosomal enzyme α-galactosidase A. Enzyme replacement therapy or pharmacological chaperone therapy can improve prognosis, especially in patients in the early phase of cardiac involvement. Longitudinal strain (LS) evaluated using speckle tracking echocardiography can detect early contractile dysfunction. However, there have been no reports of LS in Japanese Fabry disease patients.

Methods and Results: We recruited 56 patients with Fabry disease (22 men, 34 women) who were followed up at Jikei University Hospital. Fifty-eight control subjects without overt cardiac diseases were also included in the study. We evaluated LS in each patient, and the values of each of the 17 segments of the left ventricle (LV) were averaged, and global LS (GLS) was also calculated. GLS was significantly worse in Fabry disease patients without LV hypertrophy than in control subjects (−18.5±2.8% vs. −20.4±1.6%; P<0.05). In addition, Fabry disease patients without LV hypertrophy had significantly worse lateral LS (−16.4±5.0% vs. −19.3±1.8%; P<0.05), basal LS (−16.5±3.2% vs. −18.5±1.7%; P<0.05), and mid LS (−18.7±1.7% vs. −20.8±1.6%; P<0.05) than control subjects.

Conclusions: These results suggest that early contractile dysfunction in Fabry disease can be observed using GLS, lateral LS, basal LS, and mid LS, even without LV hypertrophy.

Fabry disease is an X-linked inherited lysosomal storage disease characterized by a decrease in or deficiency of lysosomal enzyme α-galactosidase A activity due to the pathogenic mutation of the GLA gene.¹^–³ The resultant accumulation of sphingoglycolipids, mainly globotriaosylceramide, in various organs is a typical manifestation of Fabry disease.⁴^,⁵

Male hemizygous patients are classified into 2 clinical phenotypes: classical and late-onset Fabry disease. Patients with the classical phenotype show early onset of acroparesthesia, hypo/a-hidrosis, angiokeratoma, and corneal opacity, which manifest during childhood and adolescence.⁶ In contrast, patients with the late-onset phenotype of Fabry disease do not exhibit the systemic symptoms or the appearance seen in the classical type, with only vital organ damage (e.g., cardiac hypertrophy and renal damage) appearing in adulthood.⁷ Female heterozygous patients also manifest various symptoms, similar to male hemizygous patients, although these symptoms are usually milder with a later onset.⁸

In all 3 types (classical, late-onset, and female heterozygous) of Fabry disease, cardiac involvement occurs in most patients,⁹ with more than half of deaths due to cardiovascular complications.¹⁰ Two specific treatments for Fabry disease are available worldwide: enzyme replacement therapy (ERT)¹¹^,¹² and pharmacological chaperone therapy.¹³ Both approaches have been reported to prevent or delay the progression of organ damage.¹⁴^–¹⁶ However, early treatment is vital for a significant benefit of these specific therapies.¹⁷

Given the benefits of early treatment, the early detection of cardiac involvement is important. Electrocardiograms (ECGs),¹⁸^,¹⁹ echocardiography,¹⁵^,²⁰ and cardiac magnetic resonance imaging²¹^,²² have been used to evaluate cardiac involvement in Fabry disease.²³ On echocardiography, progressive concentric left ventricular hypertrophy (LVH) is a typical finding in Fabry disease, and diastolic and systolic dysfunction can appear at advanced stages.²⁴^,²⁵

Recently, a new speckle tracking echocardiography modality, known as a strain analysis, has enabled the detection of early contractile dysfunction in various heart diseases.²⁶ There are 3 directions available for strain analysis: longitudinal, circumferential, and radial. Of these, longitudinal strain (LS) is most commonly used to evaluate early contractile dysfunction.²⁷ In Fabry disease, global LS (GLS) and LS in the basal region of the left ventricle (LV) have been reported to reflect early contractile dysfunction.²⁸^,²⁹ However, there are no reports on GLS and LS in Japanese patients with Fabry disease.

In the present study we evaluated GLS and LS in a cohort of patients with Fabry disease because previous research, including studies specifically on Fabry disease,²⁸^,²⁹ has shown a reduction in LS to be an indicator of early contractile dysfunction. We further analyzed the circumferential strain (CS) and ECG parameters in control subjects and in patients with Fabry disease without LVH.

Methods

Population

Fifty-six patients with Fabry disease (22 men, 34 women) who were followed up at Jikei University Hospital were included in the study. The diagnosis of Fabry disease was based on measurement of α-galactosidase A activity in white blood cells in male hemizygous patients and mutation analysis of the GLA gene in male hemizygous and female heterozygous patients. Demographic data for all patients were extracted from their medical records. As a control group, we obtained data for 58 subjects with normal echocardiographic findings, no risk factors for cardiac diseases (e.g., hypertension, diabetes, or dyslipidemia) and no malignancies from the echocardiography database of Jikei University Hospital. The control subjects were divided into 2 groups: younger subjects (Control 1) for comparison with Fabry disease patients without LVH and older subjects (Control 2) for comparison with Fabry disease patients with LVH.

Echocardiography

Comprehensive echocardiography was performed using a Vivid E9 or E95 ultrasound scanner (GE Vingmed Ultrasound, Horten, Norway) with an M5Cs transducer, with traditional measurements performed according to the American Society of Echocardiography guidelines.³⁰ Standard 2-dimensional echocardiographic images from parasternal views were used to measure the interventricular septum thickness, posterior wall thickness, end-diastolic dimension, and end-systolic dimension. The end-diastolic volume, end-systolic volume, and ejection fraction were calculated. The LV mass index (LVMI) was also calculated according to recommendations³¹ using the values obtained from the 2-dimensional method, with LVH defined as >115 g/m² in men and >95 g/m² in women. LV diastolic measurements were performed according to the American Society of Echocardiography and European Association of Cardiovascular Imaging diastolic function guidelines.³² Using the apical approach, septal e′, lateral e′, and the left atrial volume index were measured, and E/e′ was calculated as the E wave of mitral inflow divided by the averaged septal and lateral e′.

A 2-dimensional strain analysis was performed retrospectively for all patients using a customized offline computer software program (EchoPAC PC version 203; GE Vingmed Ultrasound). Cardiac mechanics were analyzed using the 2-dimensional speckle tracking technique via GE Echo PAC Automated Function Imaging and Q-Analysis software according to the consensus statements on the quantitation of cardiac mechanics.²⁷ Three apical views were obtained (4-, 2-, and 3-chamber views) at high frame rates (>50 frames/s), and the strain values of each of the 17 segments of the LV were averaged for all patients with standardized myocardial segmentation³³ (Figure 1A). The GLS for each patient was also calculated. We then evaluated CS at the basal 6 segments of the parasternal short-axis view, as well as a global CS.²⁸

Figure 1.

Analysis of longitudinal strain. (A) Bull’s eye diagram of segmentation of the left ventricle according to the guideline.³³ (B) Representative images of apical views of speckle tracking echocardiography from the 4-, 2-, and 3-chamber (ch) views. (C) Representative longitudinal strain in 17 segments with calculated global longitudinal strain (GLS). ANT, Anterior; ANT_SEPT, Antero-septal; INF, Inferior; LAT, Lateral; POST, Posterior; SEPT, Septal.

Electrocardiogram

ECGs were analyzed and the following parameters were measured according to a previous report:¹⁹ PQ interval, PQ interval minus P wave duration in Lead II (Pend-Q), QRS duration, and QT interval normalized by the RR interval (QTc).

Ethical Considerations

This study conformed to the ethical guidelines of the 2013 Declaration of Helsinki and was approved by the Ethics Committee of The Jikei University School of Medicine (No. 23-211; No. 36-055).

Statistical Analyses

Continuous variables are expressed as the mean±SD and/or as the median with interquartile range. Categorical data are presented as numbers and percentages. For the comparison of 2 datasets, Student’s t-test was used for continuous variables, and the Chi-squared test was used for categorical data. For comparison of multiple datasets, analysis of variance (ANOVA) with Tukey’s post hoc test was used. Receiver operating characteristic (ROC) curve analysis was used to differentiate between 2 groups. The level of significance level was set at a two-tailed P<0.05. To assess intraobserver variability, 10 randomly selected control subjects were reviewed by the same investigator 4 weeks apart. Interobserver variability was assessed by having the 10 subjects reviewed by another investigator. Subsequently, intraclass correlation coefficients were calculated. All statistical analyses were performed using SPSS version 25 (IBM SPSS Statistics, SPSS Japan Inc., Tokyo, Japan).

Results

Representative Images of LS in Fabry Disease Patients

Figure 1A shows a bull’s eye image of 17 standardized LV segments, according to the recommendations of the American Heart Association.³³ Figure 1B shows typical echocardiography images of 4-, 2-, and 3-chamber views from the apical approach. Figure 1C shows a bull’s eye image of the calculated LS of 17 LV segments in a female patient with Fabry disease, along with the calculated GLS for this patient.

Characteristics of Fabry Disease Patients and Control Subjects

Table 1 presents baseline characteristics of the control subjects and patients with Fabry disease. There were no significant differences in age, sex, blood pressure, heart rate, or estimated glomerular filtration rate (eGFR) between the control and Fabry disease groups. Genetic analysis revealed that 44 Fabry disease patients had mutations indicative of the classical-type of Fabry disease, and that 12 patients had mutations indicative of the late-onset type. Detailed mutations of the GLA gene are provided in Supplementary Table 1.²^,³ There were no significant differences in age, sex, blood pressure, heart rate, and eGFR between male and female patients with Fabry disease. In terms of the different symptoms of Fabry disease, only angiokeratoma and proteinuria were significantly more frequent in male than female patients with Fabry disease. There were no significant differences in the incidence of heart failure or device implantation between male and female patients with Fabry disease.

Table 1.

Baseline Characteristics of Control Subjects and Fabry Disease Patients

	Control subjects			Fabry disease patients
	All	Male	Female	All	Male	Female
N	58	22	36	56	22	34
Age (years)
Mean±SD	42.3±12.8	43.4±12.2	41.6±13.2	44.5±14.7	41.0±12.6	46.8±15.7
Median [IQR]	43 [33.5–58]	45 [34–47.8]	40.5 [30.3–52.8]	44.5 [32.5–54]	45 [30.8–51.5]	44.5 [36.3–56.3]
SBP (mmHg)	121.6±20.9	128.5±11.6	117.2±24.3	115.9±14.0	117.5±12.3	115.1±15.1
DBP (mmHg)	71.4±11.7	74.5±11.0	69.5±11.8	69.5±10.6	70.4±9.4	69.2±11.4
Heart rate (beats/min)	73.8±12.4	74.6±10.6	73.4±14.3	69.2±12.0	73.6±12.7	67.0±11.1
eGFR (mL/min/1.73 m²)	82.7±18.5	78.4±15.9	85.1±19.6	80.7±30.5	78.7±39.4	84.1±22.9
Fabry disease genotype (n)
Classical				44	17	27
Late-onset				12	5	7
Symptoms/complications (n)
Acroparesthesia				35	16	19
Hypohidrosis				24	12	12
Angiokeratoma				8	8	0**
Hearing disorder				34	11	23
GI tract disorder				17	8	9
Cerebral infarction				6	4	2
Proteinuria				6	6	0**
End-stage renal disease				3	3	0
Heart failure				18	10	8
Pacemaker/ICD				3	2	1

**P<0.01 compared with male Fabry disease patients. IQR, interquartile range; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; GI tract, gastrointestinal tract; ICD, implantable cardioverter defibrillator.

Comparison of Fabry Disease Patients With and Without LVH

Patients with Fabry disease were divided into 2 groups based on the presence (LVH(+)) or absence (LVH(−)) of LVH. Table 2 presents baseline characteristics and conventional echocardiographic parameters for the Control 1 (younger subjects), Fabry LVH(−), Control 2 (older subjects), and Fabry LVH(+) groups. There were no significant differences in baseline characteristics between the Control 1 and Fabry LVH(−) groups. Only B-type natriuretic peptide concentrations differed significantly between the Fabry LVH(+) and Control 2 groups, being significantly higher in the former. Of conventional echocardiographic parameters, ejection fraction and E/e′ were significantly higher, and septal e′ and lateral e′ were significantly lower, in the Fabry LVH(−) than Control 1 group. In contrast, all echocardiographic parameters, with the exception of LV diastolic dimension and ejection fraction, differed significantly between the Fabry LVH(+) and Control 2 groups.

Table 2.

Baseline Characteristics and Conventional Echocardiography Parameters

	Control 1	Fabry LVH(−)	Control 2	Fabry LVH(+)
N	30	33	28	23
Age (years)
Mean±SD	34.5±10.5	37.0±12.3	50.6±9.4	55.2±10.8
Median [IQR]	34 [24.5–41.5]	37 [26–43]	50 [44.5–57.8]	53 [48–58]
Male sex	10 (33.3)	11 (33.3)	12 (42.9)	11 (47.9)
SBP (mmHg)	122.2±14.6	115.4±14.5	121.1±73.7	116.7±13.5
DBP (mmHg)	69.2±12.9	68.8±9.6	73.7±10.1	70.4±12.0
Heart rate (beats/min)	73.3±14.3	72.5±11.7	74.3±11.8	64.5±10.9
eGFR (mL/min/1.73 m²)	89.8±21.1	92.4±25.4	76.2±13.0	63.8±29.7
BNP (pg/mL)	14.6±14.9	37.0±88.6	26.3±25.7	240.2±323.4^††
Echocardiography
IVS (mm)	7.7±0.9	8.3±1.2	8.1±0.9	16.1±4.3^††
PWT (mm)	7.8±0.7	8.5±1.1	8.1±0.8	14.7±4.3^††
Dd (mm)	45.1±3.3	44.7±3.5	45.1±2.9	42.6±5.3
Ds (mm)	29.3±2.3	28.3±2.6	28.9±2.2	25.4±4.6^†
EF (%)	63.9±3.8	66.6±3.3*	65.5±4.1	69.4±5.0
LVMI (g/m²)	67.5±13.6	75.8±14.3	72.1±10.7	171.7±68.5^††
Septal e′ (cm/s)	11.7±2.2	10.1±3.0*	9.0±2.4	4.6±1.6^††
Lateral e′ (cm/s)	16.5±3.3	13.6±3.7**	12.3±3.3	6.4±2.7^††
LAVI (mL/m²)	24.1±6.1	26.9±7.1	26.1±4.5	37.7±9.4^††
E/e′	5.9±1.2	7.2±2.2*	6.7±1.9	12.5±4.6^††

Unless indicated otherwise, data are given as the mean±SD or n (%). *P<0.05, **P<0.01 compared with Control 1; ^†P<0.05, ^††P<0.01 compared with Control 2. Fabry LVH(−), Fabry disease patients without left ventricular hypertrophy; Fabry LVH(+), Fabry disease patients with left ventricular hypertrophy; BNP, B-type natriuretic peptide; IVS, interventricular septum; PWT, posterior wall thickness; Dd, diastolic dimension; Ds, systolic dimension; EF, ejection fraction; LVMI, left ventricular mass index; LAVI, left atrial volume index; E/e′, E wave of mitral inflow divided by averaged e′. Other abbreviations as in Table 1.

Strain analysis revealed that GLS and LS from all 17 segments were significantly worse in the Fabry LVH(+) group than in both control and Fabry LVH(−) groups (Table 3). In contrast, only GLS and LS from the mid-anteroseptal and mid-anterolateral segments were significantly worse in the Fabry LVH(−) than Control 1 group. Figure 2 shows bull’s eye images of the averaged LS values for the 17 LV segments in the 4 groups, as well as mean GLS for the 4 groups. Figure 3A shows GLS in each of the 4 groups, and Figure 3B shows LS from the lateral region of the LV (Segments 5, 6, 11 and 12; lateral LS). The GLS and lateral LS were significantly worse in the Fabry LVH(−) than Control 1 group, and even worse in the Fabry LVH(+) group than Control 2. LS values from the basal region (Segments 1–6), mid region (Segments 7–12), and apical region (Segments 13–17) in each of the 4 groups are shown in Figure 4 and indicate that LS values from the basal and mid-regions were significantly worse in the Fabry LVH(−) than Control 1 group.

Table 3.

Longitudinal Strain Values

	Control 1	Fabry LVH(−)	Control 2	Fabry LVH(+)
N	30	33	28	23
Age (years)
Mean±SD	34.5±10.5	37.0±12.3	50.6±9.4	55.2±10.8
Median [IQR]	34 [24.5–41.5]	37 [26–43]	50 [44.5–57.8]	53 [48–58]
Male sex	10 (33.3)	11 (33.3)	12 (42.9)	11 (47.9)
Strain (%)
GLS	−20.4±1.6	−18.5±2.8*	−20.2±1.3	−11.0±3.7^††
Basal anterior	−19.3±4.3	−18.1±5.2	−19.3±3.7	−9.2±4.9^††
Basal anteroseptal	−17.3±3.2	−15.5±3.9	−15.6±3.9	−6.8±6.4^††
Basal inferoseptal	−16.3±2.6	−16.3±3.3	−15.6±3.8	−11.8±4.3^††
Basal inferior	−20.7±3.9	−17.0±7.5	−19.9±3.9	−10.1±6.3^††
Basal inferolateral	−19.1±3.1	−16.4±6.4	−19.1±4.0	−7.8±6.5^††
Basal anterolateral	−18.3±3.9	−16.0±6.1	−20.0±3.8	−6.7±6.3^††
Mid-anterior	−20.6±3.7	−19.2±3.2	−20.9±2.7	−10.7±3.9^††
Mid-anteroseptal	−23.0±2.8	−20.1±4.9*	−21.3±2.9	−12.0±6.2^††
Mid-inferoseptal	−20.3±2.6	−19.7±3.5	−21.1±2.9	−11.7±5.6^††
Mid-inferior	−21.4±3.0	−19.8±3.9	−21.8±3.5	−10.0±5.6^††
Mid-inferolateral	−20.1±2.7	−17.2±4.6	−20.0±3.7	−7.8±6.5^††
Mid-anterolateral	−19.5±3.2	−16.2±6.2*	−19.4±3.4	−6.7±5.5^††
Apical anterior	−20.0±5.5	−19.2±6.3	−19.0±2.4	−11.3±6.4^††
Apical septal	−24.9±4.3	−22.9±4.8	−24.3±4.3	−13.6±7.2^††
Apical inferior	−23.8±3.4	−21.1±5.4	−24.1±3.2	−10.6±7.3^††
Apical lateral	−22.4±4.9	−19.2±6.0	−20.9±2.9	−11.0±7.9^††
Apex	−23.7±5.0	−21.5±4.6	−24.5±2.2	−13.6±6.4^††
Combination of segments^A
Basal	−18.5±1.7	−16.5±3.2*	−18.3±2.0	−8.8±4.4^††
Mid	−20.8±1.6	−18.7±3.2*	−20.7±1.7	−9.8±4.7^††
Apical	−23.0±3.0	−20.8±4.2	−22.6±1.8	−12.0±6.3^††
Anterior	−20.0±2.9	−18.6±3.3	−20.1±2.4	−9.9±3.9^††
Anteroseptal	−20.1±2.3	−17.8±3.8	−18.4±2.7	−9.4±5.9^††
Inferoseptal	−18.3±2.1	−18.0±2.7	−18.4±2.6	−11.8±4.4^††
Inferior	−21.1±3.1	−18.4±4.7	−20.8±3.1	−10.1±5.5^††
Inferolateral	−19.6±1.9	−16.8±4.9*	−19.6±3.1	−7.8±5.9^††
Anterolateral	−18.9±2.8	−16.1±6.0	−19.7±2.7	−6.7±5.1^††
Septal	−19.2±1.8	−17.8±3.0	−18.4±2.2	−10.6±4.7^††
Lateral	−19.3±1.8	−16.4±5.0*	−19.6±2.4	−7.3±4.8^††

Unless indicated otherwise, data are given as the mean±SD or n (%). *P<0.05, **P<0.01 compared with Control 1; ^†P<0.05, ^††P<0.01 compared with Control 2. ^ASegment combinations are defined as follows: Basal, mean of basal 6 segments; Mid, mean of 6 mid segments; Apical, mean of 5 apical segments; Anterior, mean of 2 anterior segments; Anteroseptal, mean of 2 anteroseptal segments; Inferoseptal, mean of 2 inferoseptal segments; Inferior, mean of 2 inferior segments; Inferolateral, mean of 2 inferolateral segments; Anterolateral, mean of 2 anterolateral segments; Septal, average of 4 septal segments; and Lateral, mean of 4 lateral segments. GLS, global longitudinal strain. Other abbreviations as in Tables 1,2.

Figure 2.

Mean longitudinal strain values for (A) control subjects for comparison with Fabry disease patients without left ventricular hypertrophy (LVH(−)), (B) LVH(−) patients, (C) control subjects for comparison with Fabry disease patients with left ventricular hypertrophy (LVH(+)), and (D) LVH(+) patients. Mean global longitudinal strain (GLS) values are also shown. ANT, Anterior; ANT_SEPT, Antero-septal; INF, Inferior; LAT, Lateral; POST, Posterior; SEPT, Septal.

Figure 3.

(A) Mean global longitudinal strain (GLS) and (B) longitudinal strain (LS) from the lateral region of the left ventricle in control (Control 1 and Control 2) subjects and Fabry disease patients with and without left ventricular hypertrophy (LVH(+) and LVH(−), respectively). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. P values are from post hoc analysis following analysis of variance.

Figure 4.

Mean (A) basal, (B) mid, and (C) apical longitudinal strain (LS). A. Longitudinal strain from the basal region of the left ventricle (basal LS) in control (Control 1 and Control 2) subjects and Fabry disease patients with and without left ventricular hypertrophy (LVH(+) and LVH(−), respectively). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. P values are from post hoc analysis following analysis of variance.

We next performed ROC curve analysis to discriminate LVH(−) patients from the Control 1 group (Figure 5). Using a cut-off value of −20.35% for GLS discriminated the Fabry LVH(−) group from the Control 1 group with 71.9% sensitivity and 63.3% specificity. Using a cut-off value of −18.13% for lateral LS discriminated the Fabry LVH(−) group from the Control 1 group with 56.3% sensitivity and 73.3% specificity. Using a cut-off value of −17.32% for basal LS discriminated the Fabry LVH(−) group from the Control 1 group with 56.3% sensitivity and 76.7% specificity. Using a cut-off value of −20.32% for mid LS discriminated the Fabry LVH(−) group from the Control 1 group with 62.5% sensitivity and 70.0% specificity.

Figure 5.

Receiver operating characteristics analysis to discriminate Fabry disease patients from control subjects using global longitudinal strain (LS) and longitudinal strain (LS) values from the lateral, basal, and mid region of the left ventricle.

Evaluation of CS and ECG Parameters in Control Subjects and LVH(−) Patients

Global CS and CS from the basal 6 segments did not differ significantly between the LVH(−) and Control 1 groups. Among the ECG parameters, only Pend-Q was significantly shortened in the Fabry LVH(−) group relative to the Control 1 group (Supplementary Table 2).

Intra- and Interobserver Variability

The intraclass correlation coefficients in GLS were 0.937 (95% CI: 0.781–0.984) for intraobserver variability and 0.928 (95% CI: 0.738–0.982) for interobserver variability.

Discussion

The results of the present study show that early contractile dysfunction in Fabry disease can be detected by GLS, as well as lateral LS, basal LS, and mid LS, even in the absence of LVH.

Using a 2-dimensional speckle tracking method, Saccheri et al. reported the early detection of myocardial damage as a reduction in basal-lateral and basal-posterior LS in Fabry disease patients without LVH compared with controls, although their patients had only 3 different missense mutations.³⁴ In contrast, Gruner et al. reported a significant reduction in GLS in patients with Fabry disease with or without LVH compared with controls.³⁵ Costanzo et al. also reported a reduction in GLS in mutation-positive Fabry disease patients without LVH.³⁶ However, there was no information on GLA mutations in these studies (e.g., classical or late-onset, missense or non-missense). A recent publication from Taiwan clearly showed the deterioration of GLS with the development of LVH in patients with Fabry disease, mostly due to the specific late-onset mutation of IVS4+919G>A.²⁸ In the present study, we confirmed the validity of the use of GLS to identify early contractile dysfunction in Japanese patients with Fabry disease, even without LVH, due to various mutations in the GLA gene²^,³ (Supplementary Table 1). We also found that lateral LS, basal LS, and mid LS could be used to detect early contractile dysfunction, which is in accordance with the findings of other reports.²⁹^,³⁷

Diastolic dysfunction has been reported using tissue Doppler imaging in patients with Fabry disease even without LVH.²⁴^,³⁸ We found that LVH(−) patients had higher E/e′ and lower septal and lateral e′ compared with control subjects, indicating diastolic dysfunction. Because we found a significant difference in GLS, the strain values reflect changes in the structural features of cardiomyocytes as early as changes in the diastolic function.

A previous study reported that a reduction in LS in patients with heart failure with preserved ejection fraction was associated with cardiac events, such as hospitalization for heart failure, aborted cardiac arrest, and cardiovascular death.³⁹ The reduction in GLS in patients with hypertrophic cardiomyopathy has also been reported as a predictor of events such as all-cause mortality, aborted sudden cardiac death, and appropriate ICD therapy.⁴⁰ In patients with Fabry disease, altered basal LS may be associated with major cardiovascular events.²⁹ The role of LS in predicting events in Japanese patients with Fabry disease should be investigated in the future.

The timing of the start of specific treatments is very important, because earlier treatment can have greater benefit for patients. According to the Japanese guidelines, ERT is recommended for male patients with the classical type of Fabry disease with the appearance of acroparesthesia. In contrast, ERT is recommended for male patients with late-onset Fabry disease and for female patients when the overt renal, cardiac, or cerebrovascular complications appear. Similar recommendations regarding indications for ERT have been published as expert opinions.⁴¹^,⁴² In a previous study we showed that the early start of ERT had profound benefit for female patients.¹⁵ Therefore, if changes in LS can be used to help decide to start ERT or pharmacological chaperone therapy for Fabry disease, patients would likely benefit, especially male patients with late-onset disease and female patients. However, the implications of LS in therapeutic decision making should be carefully evaluated in future large-scale trials.

The present study has several limitations. This was a single-center retrospective observational study. Therefore, a relatively small number of patients were included. Because we selected subjects who had normal echocardiographic findings and did not have any risk factors (e.g., hypertension, diabetes, or dyslipidemia) or malignancies, there was a possible selection bias in the control groups. In addition, the echocardiography data were analyzed at the cross-sectional point and we did not follow time-dependent changes in parameters, including LS. Furthermore, we did not include other modalities, such as cardiac magnetic resonance imaging.

Acknowledgment

The authors thank Brian Quinn (Japan Medical Communication) for help with the English language editing of a draft of this manuscript.

Sources of Funding

This study did not receive any specific funding.

Disclosures

K.H. has received speaker honoraria from Takeda Pharmaceutical Company and Sanofi. K.S. has received speaker honoraria from Sumitomo Pharma and Sanofi and is an adviser for Takeda Pharmaceutical Company. M. Kobayashi has received speaker honoraria from Sanofi and Takeda Pharmaceutical Company. H.K. has received research funding from Sumitomo Pharma, JCR Pharmaceuticals, and Amicus Therapeutics, and has conducted joint research with JCR Pharmaceuticals. T. Ohashi has received research funding from Sanofi, Sumitomo Pharma, and Amicus Therapeutics; has conducted joint research with JCR Pharmaceuticals; and is an adviser for JCR Pharmaceuticals. Y.E. has received research funding from Sanofi. M.Y. is a member of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

This study conformed to the ethical guidelines of the 2013 Declaration of Helsinki and was approved by the Ethics Committee of The Jikei University School of Medicine (No. 23-211; No. 36-055).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0509

References

1. Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, et al. Fabry disease: Guidelines for the evaluation and management of multi-organ system involvement. Genet Med 2006; 8: 539–548.
2. Kobayashi M, Ohashi T, Kaneshiro E, Higuchi T, Ida H. Mutation spectrum of α-galactosidase gene in Japanese patients with Fabry disease. J Hum Genet 2019; 64: 695–699.
3. Higuchi T, Kobayashi M, Ogata J, Kaneshiro E, Shimada Y, Kobayashi H, et al. Identification of cryptic novel α-galactosidase a gene mutations: Abnormal mRNA splicing and large deletions. JIMD Rep 2016; 30: 63–72.
4. Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, et al. Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003; 138: 338–346.
5. Hongo K, Harada T, Fukuro E, Kobayashi M, Ohashi T, Eto Y. Massive accumulation of globotriaosylceramide in various tissues from a Fabry patient with a high antibody titer against alpha-galactosidase A after 6 years of enzyme replacement therapy. Mol Genet Metab Rep 2020; 24: 100623.
6. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: Baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004; 34: 236–242.
7. Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, et al. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 1995; 333: 288–293.
8. Kobayashi M, Ohashi T, Sakuma M, Ida H, Eto Y. Clinical manifestations and natural history of Japanese heterozygous females with Fabry disease. J Inherit Metab Dis 2008; 31(Suppl 3): 483–487.
9. Kubo T. Fabry disease and its cardiac involvement. J Gen Fam Med 2017; 18: 225–229.
10. Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: Findings from the Fabry Registry. Genet Med 2009; 11: 790–796.
11. Desnick RJ, Banikazemi M, Wasserstein M. Enzyme replacement therapy for Fabry disease, an inherited nephropathy. Clin Nephrol 2002; 57: 1–8.
12. Eto Y, Ohashi T, Utsunomiya Y, Fujiwara M, Mizuno A, Inui K, et al. Enzyme replacement therapy in Japanese Fabry disease patients: The results of a phase 2 bridging study. J Inherit Metab Dis 2005; 28: 575–583.
13. Benjamin ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, et al. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet Med 2017; 19: 430–438.
14. Kampmann C, Perrin A, Beck M. Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: Cardiac outcomes after 10 years’ treatment. Orphanet J Rare Dis 2015; 10: 125.
15. Hongo K, Ito K, Date T, Anan I, Inoue Y, Morimoto S, et al. The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients. Mol Genet Metab 2018; 124: 143–151.
16. Hughes DA, Bichet DG, Giugliani R, Hopkin RJ, Krusinska E, Nicholls K, et al. Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes. J Med Genet 2023; 60: 722–731.
17. Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Störk S, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: Evidence for a better outcome with early treatment. Circulation 2009; 119: 524–529.
18. Namdar M. Electrocardiographic changes and arrhythmia in Fabry disease. Front Cardiovasc Med 2016; 3: 7.
19. Morimoto S, Nojiri A, Fukuro E, Anan I, Kawai M, Sakurai K, et al. Characteristics of the electrocardiogram in Japanese Fabry patients under long-term enzyme replacement therapy. Front Cardiovasc Med 2021; 7: 614129.
20. Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet 2015; 52: 353–358.
21. Nojiri A, Anan I, Morimoto S, Kawai M, Sakuma T, Kobayashi M, et al. Clinical findings of gadolinium-enhanced cardiac magnetic resonance in Fabry patients. J Cardiol 2020; 75: 27–33.
22. Anan I, Sakuma T, Fukuro E, Morimoto S, Nojiri A, Kawai M, et al. The role of native T1 values on the evaluation of cardiac manifestation in Japanese Fabry disease patients. Mol Genet Metab Rep 2022; 31: 100858.
23. Hongo K. Cardiac involvement in Fabry disease: A non-invasive assessment and the role of specific therapies. Mol Genet Metab 2022; 137: 179–186.
24. Pieroni M, Chimenti C, Ricci R, Sale P, Russo MA, Frustaci A. Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003; 107: 1978–1984.
25. Takenaka T, Teraguchi H, Yoshida A, Taguchi S, Ninomiya K, Umekita Y, et al. Terminal stage cardiac findings in patients with cardiac Fabry disease: An electrocardiographic, echocardiographic, and autopsy study. J Cardiol 2008; 51: 50–59.
26. Mondillo S, Galderisi M, Mele D, Cameli M, Lomoriello VS, Zacà V, et al. Speckle-tracking echocardiography: A new technique for assessing myocardial function. J Ultrasound Med 2011; 30: 71–83.
27. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr 2011; 24: 277–313.
28. Lu DY, Huang WM, Wang WT, Hung SC, Sung SH, Chen CH, et al. Reduced global longitudinal strain as a marker for early detection of Fabry cardiomyopathy. Eur Heart J Cardiovasc Imaging 2022; 23: 487–495.
29. Zada M, Lo Q, Boyd AC, Bradley S, Devine K, Denaro CP, et al. Basal segmental longitudinal strain: A marker of subclinical myocardial involvement in Anderson-Fabry disease. J Am Soc Echocardiogr 2021; 34: 405–413.
30. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16: 233–270.
31. Marwick TH, Gillebert TC, Aurigemma G, Chirinos J, Derumeaux G, Galderisi M, et al. Recommendations on the use of echocardiography in adult hypertension: A report from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE). J Am Soc Echocardiogr 2015; 28: 727–754.
32. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016; 29: 277–314.
33. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002; 105: 539–542.
34. Saccheri MC, Cianciulli TF, Lax JA, Gagliardi JA, Cáceres GL, Quarin AE, et al. Two-dimensional speckle tracking echocardiography for early detection of myocardial damage in young patients with Fabry disease. Echocardiography 2013; 30: 1069–1077.
35. Gruner C, Verocai F, Carasso S, Vannan MA, Jamorski M, Clarke JT, et al. Systolic myocardial mechanics in patients with Anderson-Fabry disease with and without left ventricular hypertrophy and in comparison to nonobstructive hypertrophic cardiomyopathy. Echocardiography 2012; 29: 810–817.
36. Costanzo L, Buccheri S, Capranzano P, Di Pino L, Curatolo G, Rodolico M, et al. Early cardiovascular remodelling in Fabry disease. J Inherit Metab Dis 2014; 37: 109–116.
37. Esposito R, Galderisi M, Santoro C, Imbriaco M, Riccio E, Maria Pellegrino A, et al. Prominent longitudinal strain reduction of left ventricular basal segments in treatment-naïve Anderson-Fabry disease patients. Eur Heart J Cardiovasc Imaging 2019; 20: 438–445.
38. Toro R, Perez-Isla L, Doxastaquis G, Barba MA, Gallego AR, Pintos G, et al. Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy. Int J Cardiol 2009; 132: 38–44.
39. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, Liu L, et al. Prognostic importance of impaired systolic function in heart failure with preserved ejection fraction and the impact of spironolactone. Circulation 2015; 132: 402–414.
40. Hiemstra YL, Debonnaire P, Bootsma M, van Zwet EW, Delgado V, Schalij MJ, et al. Global longitudinal strain and left atrial volume index provide incremental prognostic value in patients with hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 2017; 10: e005706.
41. Biegstraaten M, Arngrímsson R, Barbey F, Boks L, Cecchi F, Deegan PB, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: The European Fabry Working Group consensus document. Orphanet J Rare Dis 2015; 10: 36.
42. Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416–427.

Corresponding author

Register with J-STAGE for free!