Background
Right ventricular (RV) involvement has been described in Anderson-Fabry disease (AFD), especially in patients with established Fabry cardiomyopathy (FC). However, few and controversial data on RV systolic function are available, and there are no specific tissue Doppler studies.
Methods
Detailed echocardiographic examinations were performed in 45 patients with AFD. FC, defined as maximal left ventricular wall thickness ≥ 15 mm, was present in 12. The Mainz Severity Score Index was calculated for each patient. Pulsed tissue Doppler was applied to the RV free wall at the tricuspid annular level and at the septal and lateral corners at the mitral annular level to obtain systolic tissue Doppler velocities (RV S a , septal S a , and lateral S a , respectively). Twelve patients with amyloid light-chain cardiac amyloidosis were studied as a control group.
Results
Echocardiography revealed RV hypertrophy (RVH) in 31% of patients with AFD, all but one of whom were male and all of whom had concomitant left ventricular hypertrophy (LVH). All patients with AFD had normal RV fractional area change (47.9 ± 6.5%) and tricuspid annular plane systolic excursion (21.7 ± 3.2 mm) and all but one also had normal RV S a (13.2 ± 2.2 cm/sec). RVH positively correlated with indices of LVH ( r = 0.8, P = .0001, for all parameters evaluated), as well as with Mainz Severity Score Index ( r = 0.70, P = .0001). Septal and lateral S a were decreased in almost all patients (means, 7.7 ± 1.8 and 7.9 ± 1.9 cm/sec, respectively), irrespective of the presence of LVH. Compared with control subjects with cardiac amyloidosis, patients with FC showed better indices of RV systolic function ( P < .001 for all: tricuspid annular plane systolic excursion, RV fractional area change, and RV S a ) despite similar RV wall thickness (6.2 ± 1.2 vs 6.9 ± 1.9 mm, P = NS).
Conclusions
RVH is common in patients with AFD and correlates with disease severity and LVH. RVH, however, does not significantly affect RV systolic function. Patients with FC have better RV systolic function compared with those with cardiac amyloidosis with similar levels of RV thickness. The combination of low LV S a values and normal RV S a values might be helpful in the differential diagnosis of infiltrative heart disease.
Anderson-Fabry disease (AFD) is a rare genetic lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A, leading to progressive intracellular accumulation of neutral glycosphingolipids in different organs, including the heart.
Cardiac involvement is common and remains one of the most important causes of morbidity and mortality in affected patients.
Left ventricular (LV) hypertrophy (LVH) is the hallmark of cardiac involvement in AFD, and concentric hypertrophic cardiomyopathy (also called Fabry cardiomyopathy [FC]) is the classic cardiac phenotype, affecting mainly middle-aged men. Of note, although conventional measures of LV systolic function are usually within the normal range in patients with AFD, tissue Doppler (TD) studies revealed abnormal contraction velocities not only in patients with FC but also in carriers of the α-galactosidase A gene mutation without LVH.
Although right ventricular (RV) involvement has been described in patients with AFD, few and conflicting data regarding RV systolic function are available, and none of them included TD.
Thus, in this study we aimed to assess the prevalence of RV hypertrophy (RVH) and RV systolic function, as detected by standard echocardiography, as well as its relation with disease severity, in patients with AFD.
Methods
Study Population
We performed detailed echocardiographic examinations in 45 patients (25 men; mean age, 52 ± 16) belonging to 20 different families, with documented diagnoses of AFD, on the basis of reduced α-galactosidase A activity in peripheral blood lymphocytes and/or genetic analysis. Exclusion criteria included age < 18 years and inadequate image quality. Weight, height, blood pressure, and heart rate were measured at the time of echocardiography.
All patients underwent extensive clinical and instrumental assessment of AFD manifestations, and the Mainz Severity Score Index (MSSI), as an expression of disease severity, was obtained for each patient as previously described. In brief, the MSSI is composed of four sections, each assessing the general, neurologic, cardiovascular, and renal involvement of the disease (each with a 0- to 4-point score). Higher scores indicate more severe involvement. The individual scores are summed to calculate the total MSSI score, on the basis of which patients are classified as having mild (<20), moderate (20–40), or severe (>40) AFD. Briefly, organ and system involvement was defined as follows: kidney involvement was defined as presence of glomerular filtration rate (GFR) < 60 mL/m 2 , microalbuminuria or proteinuria >300 mg/day, previous kidney transplantation, or need for hemodialysis. Brain involvement was defined by a history of cerebrovascular event requiring hospitalization or white matter lesions on magnetic resonance imaging compatible with AFD. Neuropathy was assessed clinically with acroparesthesia, diaphoresis, heat or cold intolerance, or fever pain crisis. Ear involvement was defined by tinnitus, vertigo, dizziness, high-frequency hearing loss, or sudden deafness. Eye involvement was defined as the presence of cornea verticillata, posterior subcapsular cataract, or tortuous vessels. Skin involvement was defined as the presence of angiokeratoma or telangiectasia. Gastrointestinal involvement was defined clinically by the presence of gastritis or ulcer, pancreatitis, or symptoms such as abdominal pain, nausea, vomiting, and diarrhea or constipation with no other explanation.
The presence of FC was defined by echocardiographic LV maximal wall thickness (MWT) ≥ 15 mm. Patients with AFD were thus classified as FC+ (MWT ≥ 15 mm) or FC− (MWT < 15 mm).
To assess whether RV characteristics were distinctive of FC, we compared echocardiographic data from FC+ patients with those of a group of patients ( n = 12) with cardiac amyloidosis (CA) who also showed significant LVH (MWT ≥ 15 mm) on echocardiography. All these patients had biopsy-proven diagnoses of systemic amyloid light-chain amyloidosis, with a clonal plasma cell disorder.
The study was in compliance with the Declaration of Helsinki. The research protocol was approved by the local ethics committee, and informed consent was obtained from all participants.
Echocardiography
All echocardiographic studies were performed using a Toshiba Artida ultrasound system (TA-700; Toshiba, Tokyo, Japan) equipped with a 3.5-MHz probe according to American Society of Echocardiography guidelines.
Patients were imaged and data analyzed by two independent operators; measurements were averaged over three heartbeats in sinus rhythm and five heartbeats in atrial fibrillation.
The following echocardiographic M-mode and bidimensional parameters were evaluated: LV end-diastolic diameter, LV end-systolic diameter, septal wall thickness (SWT), and LV posterior wall thickness (PWT).
LV end-diastolic and end-systolic volumes and LV ejection fraction (LVEF) were estimated using the biplane Simpson method. Pulsed-wave Doppler recordings of mitral and tricuspid inflow velocities were obtained.
A comprehensive assessment of RV geometry and systolic function was obtained from apical four-chamber ( Figure 1 A), RV-focused apical four-chamber, and modified apical four-chamber, left parasternal long- and short-axis, left parasternal RV inflow, and subcostal views. Two-dimensional (2D) linear and 2D-guided M-mode measurement of RV free wall thickness (RVWT) were performed from the subcostal view ( Figure 1 B) at end-diastole, below the tricuspid annulus, at a distance approximating the length of the anterior tricuspid leaflet when it was fully open and parallel to the RV free wall. Trabeculae, papillary muscles and epicardial fat were excluded from the measurement. Zoomed imaging with focus on the RV mid-wall and respiratory maneuvers were used to improve endocardial border definition. The two measures were averaged.
RVH was defined as RV wall thickness (RVWT) > 5 mm. Tricuspid annular plane systolic excursion (TAPSE) was measured by 2D-guided M-mode tracing with the cursor optimally aligned along the direction of the tricuspid lateral annulus in the apical four-chamber view ( Video 1 available at www.onlinejase.com ). TAPSE < 17 mm was considered suggestive of RV systolic dysfunction.
RV fractional area change (FAC) was assessed to provide an estimate of global RV systolic function, using the formula RV FAC (%) = 100 × (end-diastolic area − end-systolic area)/end-diastolic area. Measurements were performed ensuring that the entire RV chamber was contained in the imaging sector, including the apex and the free wall, during both systole and diastole. While tracing the RV area, care was taken to include the trabeculae in the RV cavity. RV FAC < 35% was considered indicative of RV systolic dysfunction.
TD was applied using pulsed spectral mode to record mitral annular velocities at septal ( Figure 1 C) and lateral corners. Systolic (septal S a , lateral S a ), early diastolic (E a ), and late diastolic (A a ) TD velocities were measured. Normal septal S a was considered >8.5 cm/sec, and normal lateral S a was considered >10 cm/sec.
Pulsed spectral Doppler was also applied to the RV free wall ( Figure 1 D) at the tricuspid annular level (RV S a ). An RV S a velocity < 9.5 cm/sec measured on the free wall side was considered suggestive of RV systolic dysfunction.
Myocardial performance index was obtained by Color TD recordings by the sum of isovolumetric contraction and relaxation times divided by the ejection time, and a value >0.54 was considered abnormal. RV diastolic function was defined according to American Society of Echocardiography guidelines.
Statistical Analysis
Continuous variables are expressed as mean ± SD, and dichotomous variables are shown as numbers and percentages. Differences between groups were assessed using two-tailed unpaired Student’s t tests and χ 2 tests for continuous and dichotomous variables, respectively.
Linear regression analysis was performed to correlate the echocardiographic parameters and the clinical variables, such as age and MSSI. Multivariate logistic regression analysis was performed to identify independent predictors of RV S a in the AFD population. Variables with P values <.05 on univariate analysis were included in the model. Beta values and P values are reported. Statistical analyses were done using SPSS version 20.0 (SPSS Italia, Florence, Italy). Statistical significance was defined as P < .05.
Results
General Characteristics of Patients with AFD
Clinical characteristics and extracardiac manifestations in patients with AFD according to the presence or absence of FC are reported in Table 1 . Causal mutations identified in the 20 families are reported in Table 2 .
| Overall n = 45 | FC− n = 33 | FC+ n = 12 | P | RVH− n = 31 | RVH+ n = 14 | P | |
|---|---|---|---|---|---|---|---|
| Age (y) | 52 ± 16 | 48 ± 16 | 61 ± 10 | ∗ | 49 ± 17 | 58 ± 12 | ∗ |
| Male/female | 25/20 | 14/19 | 11/1 | ∗ | 13/18 | 13/1 | ∗ |
| Weight (kg) | 73.3 ± 11.7 | 74 ± 11 | 72 ± 14 | NS | 73 ± 11 | 74 ± 14 | NS |
| BMI (kg/m 2 ) | 24.9 ± 3.8 | 25 ± 3 | 24 ± 4 | NS | 25 ± 4 | 24 ± 4 | NS |
| Systolic BP (mm Hg) | 121 ± 14 | 121 ± 14 | 124 ± 16 | NS | 121 ± 14 | 122 ± 15 | NS |
| Diastolic BP (mm Hg) | 76 ± 9 | 77 ± 9 | 74 ± 10 | NS | 77 ± 9 | 76 ± 10 | NS |
| Hypertension | 16 (36) | 8 (24%) | 8 (67%) | ∗ | 8 (26) | 8 (57) | ∗ |
| Diabetes | 2 (4) | 1 (3%) | 1 (8%) | NS | 1 (4) | 1 (7) | NS |
| Kidney | 24 (53) | 14 (42%) | 10 (83%) | ∗ | 12 (39) | 12 (86) | ∗ |
| Brain | 7 (15) | 5 (15%) | 2 (17%) | ∗ | 6 (20) | 1 (7) | NS |
| Neuropathy | 20 (44) | 14 (42%) | 6 (50%) | NS | 11 (36) | 9 (64) | NS |
| Ear | 18 (40) | 9 (28%) | 9 (75%) | ∗ | 7 (23) | 11 (79) | ∗ |
| Eye | 16 (36) | 9 (28%) | 7 (58%) | NS | 7 (23) | 9 (64) | ∗ |
| Skin | 11 (24) | 8 (24%) | 3 (25%) | NS | 7 (23) | 4 (29) | NS |
| Gastrointestinal | 13 (29) | 10 (30%) | 3 (25%) | NS | 9 (29) | 4 (29) | NS |
| Creatinine (mg/dL) | 1.0 ± 0.56 | 0.8 ± 0.2 | 1.5 ± 0.9 | † | 0.8 ± 0.2 | 1.5 ± 0.8 | † |
| GFR (mL/min) | 98.2 ± 36.1 | 110 ± 28 | 62 ± 34 | † | 112 ± 29 | 70 ± 33 | † |
| Proteinuria (g/L) | 0.3 ± 0.4 | 0.25 ± 0.46 | 0.41 ± 0.34 | NS | 0.3 ± 0.5 | 0.3 ± 0.3 | NS |
| MSSI | 22 ± 16 | 15 ± 11 | 38 ± 13 | † | 13 ± 9 | 39 ± 11 | † |
| ERT | 32 (71) | 20 (60%) | 12 (100%) | ∗ | 18 (58) | 14 (100) | ∗ |
| Family | Age/gender | α-GAL-A activity on leukocytes | GLA mutation | α-GAL A protein effect | Reference | |
|---|---|---|---|---|---|---|
| (nmol/mg/hr) | (%) | |||||
| 1 | 44/F | — | — | c.937G>T | p.(Asp313Tyr) | Lenders et al. , 2013 |
| 1 | 79/M | 6.9 | 16 | c.937G>T | p.(Asp313Tyr) | Lenders et al. , 2013 |
| 2 | 41/F | — | — | c.868A>C | p.Met290Leu | Davies et al. , 1993 |
| 3 | 63/M | 4.4 | 13.6 | c.647A>G | p.Tyr216Cys | Filoni et al. , 2010 |
| 3 | 65/F | — | — | c.647A>G | p.Tyr216Cys | Filoni et al. , 2010 |
| 4 | 28/M | 6.1 | 14.4 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 5 | 57/M | 4.0 | 9.5 | c.548G>C | p. Gly183Ala | Filoni et al. , 2010 |
| 5 | 56/M | 0.9 | 2.2 | c.548G>C | p. Gly183Ala | Filoni et al. , 2010 |
| 5 | 29/F | — | — | c.548G>C | p. Gly183Ala | Filoni et al. , 2010 |
| 5 | 26/F | — | — | c.548G>C | p. Gly183Ala | Filoni et al. , 2010 |
| 6 | 40/M | 3.1 | 7.2 | c.123_126dupCATG | p.(Gly43Hisfs*14) | Morrone et al. , 2003 |
| 7 | 47/M | 5.1 | 12 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 8 | 43/F | — | — | c.758T>C | p.Ile253Thr | Scott et al. , 2013 |
| 8 | 68/M | 0.8 | 2.0 | c.758T>C | p.Ile253Thr | Scott et al. , 2013 |
| 9 | 44/M | 4.1 | 9.7 | c.1133G>A | p.Cys378Tyr | Topaloglu et al. , 1999 |
| 10 | 70/F | — | — | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 11 | 52/M | 2.1 | 4.9 | c.639+1G>A | Splicing alteration | Rodriguez Mari et al. , 2003 |
| 12 | 80/F | — | — | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 13 | 38/M | 6.7 | 15.7 | c.730G>A | p.(Asp244Asn) | Guffon et al. , 1998 |
| 14 | 36/M | 2.5 | 5.8 | c907A>T | p.(Ile303Phe) | Novel |
| 15 | 30/M | 2.1 | 4.9 | c.439G>A | p.(Gly147Arg) | Schafer et al. , 2005 |
| 10 | 49/M | 5.1 | 12 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 10 | 44/F | — | — | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 15 | 58/F | — | — | c.439G>A | p.(Gly147Arg) | Schafer et al. , 2005 |
| 16 | 58/M | 6.7 | 15.7 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 17 | 66/F | — | — | c.680G>A | p.(arg227Gln) | Eng et al. , 1993 |
| 10 | 70/M | 7.7 | 18.2 | c.644A>G | p.(ans215Ser) | Davies et al. , 1999 |
| 4 | 70/F | — | — | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 4 | 67/M | 8.1 | 19.6 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 16 | 78/M | 2.0 | 4.7 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 18 | 29/F | — | — | c.747C>A | p.(Ans249Lys) | Duro et al. , 2014 |
| 18 | 25/F | — | — | c.747C>A | p.(Ans249Lys) | Duro et al. , 2014 |
| 18 | 50/M | 3.2 | 7.7 | c.747C>A | p.(Ans249Lys) | Duro et al. , 2014 |
| 18 | 31/F | — | — | c.747C>A | p.(Ans249Lys) | Duro et al. , 2014 |
| 2 | 46/M | 3.0 | 7.1 | c.868A>C | p.Met290Leu | Davies et al. , 1993 |
| 6 | 72/F | — | — | c.123_126dupCATG | p.(Gly43Hisfs*14) | Morrone et al. , 2003 |
| 19 | 52/M | 2.5 | 5.8 | c.547+1G>T | Splicing alteration | Ashton-Prolla et al. , 2000 |
| 19 | 54/F | — | — | c.547+1G>T | Splicing alteration | Ashton-Prolla et al. , 2000 |
| 12 | 40/M | 6.5 | 15.4 | c.644A>G | p.(ans215Ser) | Davies et al. , 1993 |
| 20 | 49/M | 2.6 | 6.1 | c.119C>T | p.Pro40Leu | Ashton-Prolla et al. , 2000 |
| 2 | 63/F | — | — | c.868A>C | p.Met290Leu | Davies et al. , 1993 |
| 2 | 74/F | — | — | c.868A>C | p.Met290Leu | Davies et al. , 1993 |
| 2 | 71/F | — | — | c.868A>C | p.Met290Leu | Davies et al. , 1993 |
| 17 | 39/M | 0.6 | 1.5 | c.680G>A | p.(arg227Gln) | Eng et al. , 1993 |
| 17 | 42/M | 6.1 | 14.4 | c.680G>A | p.(arg227Gln) | Eng et al. , 1993 |
Kidney involvement was present in 24 patients (53%; 16 men), three of whom had undergone kidney transplantation and had GFRs <30 mL/min (all men). The remaining 21 patients had GFRs between 49 and 163 mL/min with some degree of proteinuria.
Histories of cerebrovascular events (three ischemic, one hemorrhagic) were present in four patients. Other relevant findings included neuropathic pain in 20 patients (44%; 12 men), eye involvement (mainly cornea verticillata) in 19 (36%; 11 men), angiokeratoma in 11 (24%; eight men), and audiovestibular dysfunction in 18 (40%; 13 men).
In terms of cardiac involvement, 29 patients were in New York Heart Association functional class I, 14 in class II, and two in class III (both men with severe LVH and on hemodialysis). None had been hospitalized for heart failure in the previous 4 years. Paroxysmal atrial fibrillation was documented in one patient, whereas permanent atrial fibrillation was present in two; episodes of nonsustained ventricular tachycardia were detected on Holter monitoring in five patients (all men). Four patients were on thiazide diuretic therapy for hypertension (two men), and no patients were on loop diuretics.
Five patients (11%) had histories of typical angina, two of whom underwent percutaneous coronary intervention (both men), whereas three showed no obstructive coronary atherosclerosis (all men with severe LVH).
Echocardiographic Findings
LV Findings in AFD
The main echocardiographic findings according to the presence of FC and RVH are summarized in Table 3 . FC was found in 12 patients (27%; 11 men, six with MWT > 20 mm). No LVH (MWT < 12 mm) was found in 16 patients (35%; four men), whereas mild to moderate LVH (MWT 12–14.9 mm) was found in 17 (38%; 10 men).
| FC− n = 33 | FC+ n = 12 | P | RVH− n = 31 | RVH+ n = 14 | P | |
|---|---|---|---|---|---|---|
| Age (yrs) | 48 ± 16 | 61 ± 10 | † | 49 ± 17 | 58 ± 12 | ∗ |
| Range | 25–80 | 49–78 | † | 25–80 | 36–78 | ∗ |
| LVEDD (mm) | 47.3 ± 4.2 | 48.2 ± 4.3 | NS | 46.9 ± 4.0 | 49.0 ± 4.4 | NS |
| LVESD (mm) | 28.2 ± 4.3 | 28.2 ± 5.2 | NS | 27.9 ± 4.3 | 28.8 ± 5.1 | NS |
| LVEF (%) | 64.9 ± 4.5 | 56.4 ± 5.8 | ‡ | 64.5 ± 4.7 | 58.5 ± 7.1 | † |
| LA diameter (mm) | 34.9 ± 4.8 | 40.4 ± 5.2 | † | 34.6 ± 4.7 | 40.3 ± 4.9 | † |
| SWT (mm) | 10.7 ± 2.1 | 20.3 ± 3.9 | ‡ | 10.7 ± 2.4 | 18.9 ± 4.8 | ‡ |
| PWT (mm) | 10.2 ± 1.9 | 17.7 ± 3.4 | ‡ | 10.2 ± 2.1 | 16.5 ± 4 | ‡ |
| LV mass (g) | 181.4 ± 59.4 | 446.3 ± 123.2 | ‡ | 179.8 ± 63.8 | 412.1 ± 139.9 | ‡ |
| LV mass index (g/m 2 ) | 96.1 ± 27 | 243 ± 70.7 | ‡ | 96.1 ± 31.0 | 222.2 ± 81.2 | ‡ |
| LV E wave (cm/sec) | 74.8 ± 17.9 | 65.3 ± 18.6 | NS | 74.2 ± 18.8 | 67.9 ± 17.3 | NS |
| LV A wave (cm/sec) | 63.6 ± 17.1 | 73.3 ± 16.1 | NS | 64.6 ± 17.9 | 69.6 ± 15.7 | NS |
| LV E/A ratio | 1.3 ± 0.6 | 0.9 ± 0.3 | ∗ | 1.26 ± 0.6 | 1 ± 0.3 | NS |
| LV E/E′ ratio | 6.9 ± 1.8 | 12.4 ± 1.6 | ‡ | 6.9 ± 1.9 | 11.6 ± 5.9 | ‡ |
| LA volume (mL) | 55.2 ± 19.9 | 80.7 ± 25.5 | ∗ | 55.4 ± 20.7 | 78.2 ± 25.7 | ∗ |
| Septal S a (cm/sec) | 8.4 ± 1.3 | 5.6 ± 1.5 | ‡ | 8.4 ± 1.3 | 6.1 ± 1.9 | ‡ |
| Lateral S a (cm/sec) | 8.9 ± 1.7 | 6.8 ± 2.0 | † | 8.9 ± 1.7 | 6.9 ± 1.9 | ‡ |
| RVWT (mm) | 3.5 ± 1.0 | 6.9 ± 1.9 | ‡ | 3.2 ± 0.6 | 6.9 ± 1.5 | † |
| RV mid diameter (mm) | 23.9 ± 4.1 | 27 ± 5.4 | NS | 23.7 ± 4.4 | 27.3 ± 4.6 | NS |
| RV E wave (cm/sec) | 49.7 ± 16 | 41.9 ± 7.6 | NS | 48.6 ± 16.5 | 43.5 ± 10.8 | NS |
| RV A wave (cm/sec) | 34 ± 11.1 | 40 ± 8.3 | NS | 31.7 ± 8.8 | 43.9 ± 8.7 | † |
| RV E/A ratio | 1.4 ± 0.4 | 1 ± 0.2 | † | 1.5 ± 0.3 | 1 ± 0.2 | ‡ |
| RA volume (mL) | 39.9 ± 17.3 | 51.3 ± 24.1 | NS | 36.2 ± 15.8 | 52.9 ± 22.1 | NS |
| RV MPI | 0.48 ± 0.1 | 0.51 ± 0.1 | NS | 0.45 ± 0.05 | 0.52 ± 0.05 | NS |
| IVC size (mm) | 13.8 ± 4.4 | 10.4 ± 4.2 | NS | 13.8 ± 4.9 | 11 ± 4.4 | NS |
| TR jet velocity (cm/sec) | 206 ± 22 | 235 ± 13.8 | NS | 197 ± 19.9 | 230 ± 11.4 | † |
| TAPSE (mm) | 21.8 ± 2.6 | 21.5 ± 4.5 | NS | 22.2 ± 2.7 | 21 ± 3.5 | NS |
| RV FAC (%) | 49.3 ± 5.9 | 44.8 ± 7.3 | NS | 49.3 ± 5.6 | 44.6 ± 7.3 | ∗ |
| RV S a (cm/sec) | 13.5 ± 1.8 | 12.1 ± 2.7 | NS | 13.7 ± 1.8 | 12 ± 2.6 | ∗ |
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