Background
Fabry disease is associated with left ventricular hypertrophy (LVH) and myocardial fibrosis. The aim of this study was to evaluate left atrial (LA) size and function using tissue Doppler–derived strain in patients with Fabry disease.
Methods
Echocardiography was performed in 33 Fabry patients (14 without LVH, 19 with LVH) before commencement of enzyme replacement therapy, and results were compared with those from age-matched and gender-matched controls (n=28 and n=38, respectively). Atrial strain and strain rate were measured from four segments in the apical four-chamber and two-chamber views of the LA, and global values were calculated. Systolic strain, systolic strain rate, early diastolic strain rate, and late diastolic strain rate were measured. Phasic LA volumes and fractions were calculated. Mitral inflow and tissue Doppler E′ velocities were used to estimate left ventricular (LV) diastolic function.
Results
LA volume was increased in Fabry patients, even in the absence of LVH. Importantly, diastolic function was normal in this subgroup without LVH, with E′ velocities similar to those in controls. LA systolic strain and early diastolic strain rate were selectively reduced in Fabry patients with LVH and reflect reductions in LA and LV relaxation, respectively, consequent to increased LV mass. However, independent of LVH, both Fabry groups had significant reductions in systolic strain rate and increased LA stiffness index.
Conclusions
Fabry disease is associated with LA enlargement and reduced atrial compliance that occurs before the development of LVH. This suggests that Fabry cardiomyopathy may not only cause ventricular hypertrophy and fibrosis but also alters atrial myocardial properties early in the disease process. Consequently, measurements of LA size and function may be useful in the early diagnosis of Fabry disease, before the development of LVH.
Fabry disease is a rare X-linked disorder due to mutations in the GLA gene encoding α-galactosidase, resulting in the deposition of complex glycosphingolipids including globotriasylceramide in multiple organ systems, including the cardiovascular, renal, and neurologic systems. Fabry disease is associated with progressive concentric left ventricular (LV) hypertrophy (LVH), which is determined by age and α-galactosidase activity. There is a high incidence of cardiac morbidity associated with Fabry disease, especially in the presence of LVH. The prevalence of Fabry disease has been reported as 1% in a hypertrophic cardiomyopathy population and 1 in 40,000 to 1 in 117,000 in the general population, although underdiagnosis is common, and the true prevalence may be significantly greater.
The increase in myocyte mass, which subsequently causes LVH, is due to a combination of factors, including the intracellular accumulation of lipid and the presence of trophic factors and/or neurohormonal activation in the plasma that promote hypertrophic activation. Fabry cardiomyopathy has been largely associated with “preserved” LV systolic function. However, altered LV diastolic function is a common characteristic in patients with Fabry disease, as a consequence of interference of sarcomere performance from myocardial fibrosis. Fabry disease has also been associated with a reduction in the Tei index, a global measure of both systolic and diastolic function.
The thin-walled left atrium (LA) is sensitive to changes in LV filling pressure, enabling it to be a robust marker of the severity and chronicity of LV diastolic function. However, there is a paucity of studies investigating the effects of Fabry disease on LA size and function. The LA has multiple functions: to act as a reservoir for blood during ventricular systole, as a conduit for the passage of blood from the pulmonary veins to the LV in early diastole, and as a contractile chamber to augment LV filling in late diastole. Strain and strain rate techniques enable the evaluation of phasic atrial function throughout the cardiac cycle, providing a sensitive and accurate assessment of atrial function. Atrial strain and strain rate have been previously used to quantify LA function in patients with cardiomyopathies with increased LV wall thickness, including hypertrophic cardiomyopathy and amyloidosis.
The aim of this study was to evaluate LA size and function in Fabry disease. We hypothesized that patients with Fabry disease would have LA enlargement with a reduction in atrial conduit function due to impaired LV diastolic function, consequent to LVH and myocardial fibrosis. We further hypothesized that LA changes would be more marked in the subgroup of Fabry patients with LVH.
Methods
Study approval was obtained from the South Western Sydney Local Health District Human Research and Ethics Committee at Liverpool Hospital (Sydney, Australia) and all participants provided written consent. Fabry patients were screened at Westmead Hospital, which is the only referral center for Fabry patients in New South Wales. All patients were prospectively recruited at diagnosis for this cross-sectional study. No patient was receiving enzyme replacement therapy at the time of echocardiographic assessment. Fabry disease was confirmed in all patients by mutation analysis genetic testing and leukocyte α-galactosidase activity in the hemizygotes (male subjects). All subjects underwent detailed clinical histories for cardiovascular symptoms, medication use, and family histories. Height, weight, heart rate, and blood pressure were recorded; electrocardiography and routine blood tests were performed to exclude any coexistent pathology. All patients were in sinus rhythm, and none had more than mild valvular disease. Control subjects, recruited as volunteers from hospital staff members or the community, were obtained from a departmental database and had no histories of ischemic or other heart disease, peripheral vascular or cerebrovascular disease, hypertension, or diabetes and were not on any cardioactive medications. All control subjects had normal LV wall thickness, mass, and systolic function; no more than mild valvular regurgitation; no valvular stenosis; and no other structural heart disease on echocardiography.
All participants underwent comprehensive transthoracic echocardiography, performed according to established laboratory practice using commercially available ultrasound systems (GE Vivid 5 and 7; GE Vingmed Ultrasound AS, Horten, Norway). Measurements were performed offline using EchoPAC PC version 6.1.0. (GE Vingmed Ultrasound AS).
Patient Groups
Fabry patients ( n = 33) were divided in two groups: those without LVH ( n = 14) and with LVH ( n = 19). LVH was defined as a septal or posterior wall thickness > 11 mm and LV mass > 102 g/m 2 for men and LV mass > 88 g/m 2 for women, on the basis of the American Society of Echocardiography guidelines using the two-dimensional area-length method. Fabry patients were also compared with age-matched and gender-matched controls in a 1:2 ratio (controls to group without LVH, n=28; controls to group with LVH, n=38).
LV Size and Function
LV septal and posterior wall thicknesses were measured, and relative wall thickness and fractional shortening were calculated. Biplane LV volumes were determined from the apical four-chamber and two-chamber views using the modified Simpson’s method of disks, and LV systolic function was determined by calculation of LV ejection fraction (LVEF). LV mass was measured using the area-length method from the apical four-chamber and parasternal short-axis views at the level of the papillary muscles.
Doppler Parameters
Mitral inflow velocity was obtained using pulsed-wave Doppler examination at a sweep speed of 100 mm/sec from the apical four-chamber view by placing the sample volume at the tips of the mitral leaflets. Peak velocity in early diastole (E-wave, LV relaxation) and late diastole (A-wave, LA contraction) and deceleration time of the E-wave were measured. The atrial emptying fraction was estimated as the A-wave velocity-time integral divided by the total mitral inflow velocity-time integral. Atrial ejection force was calculated using the following equation; atrial ejection force = 0.5 × ρ (density of blood = 1.06 g/cm 3 ) × mitral orifice area × (peak A velocity) 2 . Isovolumic relaxation time was measured from the continuous-wave Doppler LV outflow tract signal.
Pulmonary vein velocities were obtained by pulsed-wave Doppler examination from the apical four-chamber view by placing the sample within the proximal 2 cm of the right upper pulmonary vein. Peak velocities in systole, diastole, and atrial reversal were measured, and the systolic/diastolic ratio was calculated. The systolic fraction was calculated as the systolic velocity-time integral divided by the total forward pulmonary vein flow velocity-time integral. The difference between the atrial reversal duration and the mitral A-wave duration was calculated.
Pulsed-wave Doppler tissue imaging was used to measure peak velocity in systole (S′), early diastole (E′), and late diastole (A′), with the sample volume placed at the septal and lateral annulus. An average of the septal and lateral segments was calculated. The E/E′ ratio was calculated as a measure of LV diastolic pressure. LV diastolic function was classified as normal, impaired, pseudonormal, or restrictive on the basis of American Society of Echocardiography guidelines.
LA Size and Function
LA maximum volume, just before mitral valve opening; LA minimum volume, at mitral valve closure; and LA pre-a volume, at the onset of the P wave on the electrocardiogram, were measured using the biplane method of disks. All volumes were indexed to body surface area. Phasic LA volumes and fractions (reservoir, conduit, and contractile function) were calculated as follows : reservoir function: LA total emptying volume = LA maximum volume − LA minimum volume; LA expansion index = LA total emptying volume/LA minimum volume; conduit function: passive emptying volume = LA maximum volume − LA pre-a volume; passive emptying fraction = passive emptying volume/LA maximum volume; contractile function: active emptying volume = LA pre-a volume − LA minimum volume; active emptying fraction = active emptying volume/LA pre-a volume.
Doppler Tissue Imaging: Strain and Strain Rate
Tissue Doppler–derived strain and strain rate were used for the analysis of phasic atrial function because of the associated high temporal resolution. Color Doppler tissue imaging can be affected by the angle of interrogation, and therefore care was taken to ensure that the ultrasound beam was aligned parallel to the myocardial wall to optimize measurements. LA strain and strain rate were measured offline (EchoPAC version 6.2) from color tissue Doppler images of the atria (obtained at >100 frames/sec) from the apical four-chamber and two-chamber views, as previously described. Segmental analysis was measured using a narrow (10 × 2 mm) sample volume placed superiorly in each of the four walls: the septal and lateral walls in the apical four-chamber view and the inferior and anterior walls in the apical two-chamber view ( Figure 1 ). The image was tracked frame by frame to prevent sampling of blood pool and a Gaussian 60 smoothing was applied. Peak positive systolic strain and systolic strain rate (S sr) were used as measures of LA compliance during the reservoir phase ( Figures 2 and 3 ). Early diastolic strain rate (E sr) was used as a measure of conduit function and late diastolic strain rate (A sr) as a measure of active atrial contraction ( Figure 3 ). Three consecutive beats were averaged. Global strain and strain rate were calculated by averaging the four segments. The LA stiffness index was calculated as ratio of E/E′ to global systolic strain.
Observer Variability
Ten studies were randomly selected for interobserver and intraobserver variability assessment. LA volume, strain, and strain rate were remeasured by the same observer and by a second independent observer from the digital data using an offline system. Interstudy variability was determined in 10 subjects by repeating their imaging later that day.
Statistical Analysis
All values are expressed as mean ± SD. Student’s t tests and χ 2 analysis were used, as appropriate, to examine the differences between the Fabry groups and their respective control groups. The general linear method (univariate analysis of variance) with adjustment for age and gender was used to examine the differences between the Fabry groups. The relationship between variables was examined by performing Pearson’s or Spearman’s rank correlations as appropriate. Bland-Altman analysis was performed to measure interobserver and intraobserver and interstudy variability. Data were considered significant at P < .05. Data were analyzed using SPSS version 20.0 (SPSS, Inc, Chicago, IL).
Results
The mutations and organ involvement in Fabry patients are listed in Table 1 . The leukocyte α-galactosidase activity in the hemizygotes (male subjects) was 0.08 ± 0.05 nmol/min/mg (range, 0.03–0.11 nmol/min/mg). Fabry patients with LVH had a higher incidence of renal disease (42% vs 7%, P = .015) and abnormal brain scan results (53% vs 7%, P = .002) compared to those without LVH. Five patients with LVH had histories of arrhythmias, while no patient without LVH had documented arrhythmias (26% vs 0%, P = .04), reflecting greater cardiac involvement with disease progression. Three of these five patients had histories of paroxysmal atrial fibrillation but were in sinus rhythm at the time of echocardiography, one had an accessory pathway, and one had ventricular fibrillation cardiac arrest, followed by insertion of a defibrillator. However, LV systolic function was normal (LVEF, 59%) in the latter patient, who was in sinus rhythm at the time of echocardiography. In those with LVH, two patients had reported histories of angina, and another had ischemic heart disease with coronary artery stents; LV systolic function remained normal (LVEF, 56%). In contrast, the group without LVH had no associated cardiac symptoms or cardiac history. There was no difference in the incidence of bradycardia (heart rate < 60 beats/min) between the Fabry patients with and without LVH (47% vs 27%, P = .14). Twenty-one of 33 Fabry patients commenced enzyme replacement therapy subsequent to the present study.
| Fabry patients without LVH ( n = 14) | Fabry patients with LVH ( n = 19) | |
|---|---|---|
| Genotype (number of patients) | ||
| A37T | 2 | 1 |
| c.157_160del | 1 | 0 |
| c.931delC | 2 | 0 |
| c.988delC | 1 | 0 |
| C223Y | 0 | 1 |
| Del I239 | 0 | 1 |
| E48Q | 2 | 0 |
| F169S | 0 | 1 |
| I91T | 1 | 2 |
| ivs4+861C>T | 0 | 1 |
| M1871 | 0 | 1 |
| N215S | 2 | 1 |
| N224S | 0 | 3 |
| N298K | 0 | 1 |
| p.D266N | 2 | 1 |
| p.Q111X | 1 | 0 |
| R220X | 0 | 1 |
| T141I | 0 | 1 |
| W226R | 0 | 1 |
| Y365X | 0 | 2 |
| Extracardiac manifestations | ||
| Acroparesthesia | 5/14 | 5/19 |
| Skin (hypohidrosis) | 5/14 | 8/19 |
| Ears (tinnitus, vertigo) | 4/14 | 8/19 |
| Abdominal pain | 5/14 | 6/19 |
| Diarrhea | 6/14 | 7/19 |
| Proteinuria | 8/14 | 12/19 |
| Renal disease | 1/14 | 8/19 |
| Abnormal brain scan results | 1/14 | 10/19 |
| Peripheral neuropathy | 1/14 | 5/19 |
| Cardiac manifestations | ||
| Bradycardia ∗ | 4/14 | 9/19 |
| Arrhythmia † | 0/14 | 5/19 |
| Heart disease | 0/14 | 5/19 |
Demographic and LV echocardiographic parameters among the Fabry subgroups and controls are listed in Table 2 . Fabry patients with LVH were older and had a male predominance compared with those without LVH. There was no difference in LVEF between groups.
| Variable | Controls to group without LVH ( n = 28) | Fabry patients without LVH ( n = 14) | Controls to group with LVH ( n = 38) | Fabry patients with LVH ( n = 19) |
|---|---|---|---|---|
| Age (y) | 34 ± 10 | 34 ± 10 | 44 ± 10 | 44 ± 10 † |
| Men | 36% | 36% | 74% | 74% † |
| Body surface area (m 2 ) | 1.8 ± 0.2 | 1.7 ± 0.2 ∗ | 1.9 ± 0.2 | 1.9 ± 0.2 † |
| Systolic blood pressure (mm Hg) | 117 ± 12 | 120 ± 10 | 119 ± 13 | 124 ± 15 |
| Diastolic blood pressure (mm Hg) | 72 ± 9 | 76 ± 11 | 75 ± 8 | 80 ± 10 |
| Mean arterial pressure (mm Hg) | 87 ± 9 | 91 ± 10 | 90 ± 9 | 95 ± 10 |
| Heart rate (beats/min) | 72 ± 13 | 68 ± 12 | 68 ± 7 | 68 ± 13 |
| Interventricular septal wall thickness (mm) | 9.0 ± 1.5 | 8.6 ± 1.3 | 9.5 ± 1.8 | 15.0 ± 2.8 ∗ , † |
| Posterior wall thickness (mm) | 9.0 ± 1.6 | 9.1 ± 1.5 | 9.3 ± 1.6 | 14.2 ± 3.1 ∗ , † |
| Fractional shortening (%) | 39.9 ± 6.1 | 42.0 ± 6.1 | 36.2 ± 7.6 | 43.5 ± 7.2 ∗ |
| Relative wall thickness (cm) | 0.37 ± 0.07 | 0.39 ± 0.07 | 0.38 ± 0.06 | 0.61 ± 0.18 ∗ , † |
| 2D area-length LV mass (g/m 2 ) | 66.3 ± 17.4 | 77.1 ± 16.8 | 71.7 ± 16.9 | 121.3 ± 19.6 ∗ , † |
| LVEF (%) | 60 ± 3 | 60 ± 2 | 59 ± 5 | 61 ± 5 |
∗ P < .05 versus controls and † P < .05 versus Fabry patients without LVH (age and gender adjusted).
Doppler Parameters
Traditional Doppler parameters are listed in Table 3 . The majority (79%) of Fabry patients with LVH had diastolic dysfunction (normal in 18%, impaired relaxation in 77%, pseudonormal in 6%, restrictive in none). In contrast, only 7% had diastolic dysfunction in the Fabry group without LVH (normal in 93%, impaired relaxation in 7%, pseudonormal or restrictive in none). Importantly, in those without LVH, E′ velocities were similar to those in controls. Control subjects had a 4% and 8% incidence of diastolic dysfunction (all impaired relaxation; none pseudonormal or restrictive).
| Variable | Controls to group without LVH ( n = 28) | Fabry patients without LVH ( n = 14) | Controls to group with LVH ( n = 38) | Fabry patients with LVH ( n = 19) |
|---|---|---|---|---|
| Mitral inflow | ||||
| E-wave velocity (cm/sec) | 0.77 ± 0.12 | 0.84 ± 0.17 | 0.72 ± 0.14 | 0.85 ± 0.16 ∗ |
| A-wave velocity (cm/sec) | 0.52 ± 0.15 | 0.58 ± 0.15 | 0.57 ± 0.15 | 0.68 ± 0.16 ∗ |
| E/A ratio | 1.6 ± 0.4 | 1.6 ± 0.6 | 1.3 ± 0.4 | 1.3 ± 0.4 |
| Deceleration time (msec) | 198 ± 43 | 178 ± 21 | 206 ± 37 | 222 ± 34 † |
| Atrial fraction (%) | 31.7 ± 9.1 | 30.1 ± 6.3 | 35.2 ± 7.2 | 34.7 ± 8.2 |
| Atrial ejection force (kdyne/m 2 ) | 10.6 ± 6.5 | 13.0 ± 7.5 | 13.4 ± 7.7 | 24.3 ± 14.4 ∗ |
| Pulmonary vein | ||||
| Systolic velocity (cm/sec) | 0.50 ± 0.09 | 0.50 ± 0.10 | 0.50 ± 0.08 | 0.56 ± 0.13 ∗ |
| Diastolic velocity (cm/sec) | 0.57 ± 0.12 | 0.51 ± 0.13 | 0.48 ± 0.12 | 0.57 ± 0.16 ∗ , † |
| Systolic/diastolic ratio | 0.93 ± 0.3 | 1.0 ± 0.3 | 1.1 ± 0.3 | 1.1 ± 0.3 |
| Systolic fraction (%) | 50.7 ± 8.4 | 56.0 ± 8.0 | 56.7 ± 9.8 | 55.0 ± 9.8 |
| Atrial reversal velocity (cm/sec) | 0.25 ± 0.06 | 0.25 ± 0.06 | 0.23 ± 0.04 | 0.31 ± 0.12 ∗ |
| Atrial reversal duration − A-wave duration (msec) | −50 ± 77 | −40 ± 25 | −50 ± 46 | −12 ± 45 ∗ |
| Isovolumetric relaxation time (msec) | 84 ± 13 | 86 ± 15 | 91 ± 12 | 93 ± 16 |
| Doppler tissue imaging | ||||
| S’ velocity (cm/sec) | 9.0 ± 1.7 | 8.7 ± 1.5 | 8.7 ± 1.8 | 7.7 ± 1.5 ∗ , † |
| E’ velocity (cm/sec) | 12.8 ± 2.6 | 12.2 ± 2.4 | 11.4 ± 3.1 | 8.1 ± 2.2 ∗ , † |
| E/E′ ratio | 6.3 ± 1.7 | 7.1 ± 1.7 | 6.5 ± 1.6 | 11.0 ± 3.1 ∗ , † |
| A′ velocity (cm/sec) | 9.2 ± 1.6 | 8.3 ± 1.4 | 9.4 ± 1.7 | 9.4 ± 2.0 † |
| Diastolic dysfunction | 4% | 7% | 8% | 79% ∗ , † |
∗ P < .05 versus controls and † P < .05 versus Fabry patients without LVH (age and gender adjusted).
Fabry patients with LVH had a higher atrial ejection force compared with both the control group and Fabry patients without LVH ( Table 3 ). Pulmonary vein flow systolic and atrial reversal velocities were significantly higher in Fabry patients with LVH compared with the other groups. Additionally, the Fabry subgroup with LVH had a greater difference between atrial reversal duration and mitral A-wave duration. Fabry patients with LVH had lower S′ and E′ velocities, with a corresponding increase in E/E′ ratio, compared with patients without LVH and controls.
LA Volumes and Phasic Function
LA maximum, pre- A-wave, total emptying, and active emptying volumes were significantly increased in both Fabry groups compared with controls ( Table 4 ). LA enlargement was present in patients with Fabry disease, irrespective of LVH, compared with controls. Passive emptying and total emptying fraction were reduced only in Fabry patients with LVH compared with controls. There were no differences in active emptying fraction among the groups.
