Ultrasound in Med. & Biol., Vol. 37, No. 1, pp. 37–43, 2011 Copyright Ó 2011 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter doi:10.1016/j.ultrasmedbio.2010.10.017 d Original Contribution PROMINENT PAPILLARY MUSCLES IN FABRY DISEASE: A DIAGNOSTIC MARKER? MARKUS NIEMANN, DAN LIU, KAI HU, SEBASTIAN HERRMANN, FRANK BREUNIG, JÖRG STROTMANN, STEFAN STÖRK, WOLFRAM VOELKER, GEORG ERTL, CHRISTOPH WANNER, and FRANK WEIDEMANN Department of Internal Medicine I/Center of Cardiovascular Disease, University of Wuerzburg, Germany (Received 19 May 2010; revised 2 September 2010; in final form 14 October 2010) Abstract—Fabry disease is often linked with a prominent papillary muscle. It remains unknown whether this sign could be used as a diagnostic marker to screen for Fabry patients. Standard echo was performed in 101 consecutive patients with concentric left ventricular (LV) hypertrophy (28 Fabry, 30 Friedreich, 34 isolated arterial hypertension, 9 amyloidosis) and 50 healthy controls. In addition, the areas of both papillary muscles, as well as the LV endocardial circumference, were manually traced in short axis views. A ratio of papillary muscle size to LV circumference was calculated (PM_LV_ratio). The papillary muscle area was positively correlated to LV wall thickness in this cohort (p , 0.0001; r 5 0.58). In all patient subgroups, the absolute papillary muscle area was significantly enlarged and the PM_LV_ratio was significantly higher when compared with controls. However, Fabry patients showed a significantly larger absolute papillary muscle area than Friedreich and amyloidosis patients and a higher PM_LV_ratio than hypertensive and amyloidosis patients. Enlarged absolute papillary muscle area was evidenced in 21 (75%), and increased PM_LV_ratio was found in 22 (78%) of 28 Fabry patients. Combining these two parameters yields a sensitivity of 75% and specificity of 86% for diagnosing Fabry disease with LV hypertrophy. Only 10 of 73 non-Fabry patients (14%) (4 Friedreich, 1 amyloidosis, 5 hypertensive) showed an increased absolute papillary muscle area and PM_LV_ratio. In conclusion, this study confirmed the assumption that the prominent papillary muscle could be an echocardiographic marker for detection of Fabry patients with concentric LV hypertrophy. (E-mail: Weidemann_F@medizin.uni-wuerzburg.de) Ó 2011 World Federation for Ultrasound in Medicine & Biology. Key Words: Fabry, Papillary muscle, Echocardiography, Cardiomyopathy. In contrast, little is known about the echocardiographic quantification of the papillary muscle size itself. Fabry disease (FD) is an X-chromosomal–linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A (Desnick et al. 1995). The lack of this enzyme leads to a typical cardiomyopathy characterized by concentric LV hypertrophy, which can exceed a wall thickness of 20 mm (Hoigne et al. 2006; Linhart et al. 2001; Strotmann et al. 2005; Takenaka et al. 2008; Weidemann et al. 2005; Weidemann et al. 2008). From autopsy studies, it is known that the papillary muscle hypertrophies as well (Ueno et al. 1991), and thus it was speculated in case reports and review articles that a prominent papillary muscle is a typical Fabry feature and might be of diagnostic use (Fig. 1) (Linhart et al. 2001; Strotmann et al. 2005; Weidemann et al. 2008). Moreover, it is possible that other cardiac pathologies with concentric LV INTRODUCTION The papillary muscle of the left ventricle (LV) is important for the functionality of the mitral valve apparatus and can be involved in many pathologies, e.g., myocardial infarction or LV outflow tract obstruction (Abouliatim et al. 2009; Austin et al. 2009; Bolman 2009; Delgado et al. 2009; He and Bhattacharya 2008; Rama et al. 2008; Rankin et al. 2008). Moreover, the papillary muscle is a leading visual landmark in standard echocardiography. So far, imaging studies have focused mainly on the position of the papillary muscle in the LV or its regional function (via strain rate imaging) (Dagdelen et al. 2003; Harrigan et al. 2008; Karvounis et al. 2006). Address correspondence to: Frank Weidemann, Medizinische Klinik und Poliklinik I, Zentrum f€ur Innere Medizin, Oberd€urrbacher Str. 6, 97080 W€ urzburg, Germany. E-mail: Weidemann_F@medizin. uni-wuerzburg.de 37 38 Ultrasound in Medicine and Biology Fig. 1. A four-chamber view of a patient with a typical Fabry cardiomyopathy. Note the prominent papillary muscle arising from the LV lateral wall. hypertrophy like hypertension and Friedreich ataxia could also lead to a prominent papillary muscle. Since 2001, a specific therapy for Fabry disease, called enzyme replacement therapy, has been available (Eng et al. 2001, 2006; Schiffmann et al. 2001; Weidemann et al. 2003). Thus, early diagnosis of this disease is important to slow the disease progression (Pieroni et al. 2003; Weidemann et al. 2005). In the past, Fabry disease was screened (using alpha-galactosidase A measurements) in cohorts with unclear concentric LV hypertrophy (Monserrat et al. 2007; Nakao et al. 1995; Sachdev et al. 2002). However, the prevalence in those cohorts was only about 1–3% in the general echocardiographic laboratories using this screening approach (Linthorst et al. 2009). Thus, finding more specific markers (for example, comparable with the sparkling texture in cardiac amyloidosis) for the cardiac involvement in Fabry disease would be desirable to preselect patients. So far, there is no systematic echocardiographic study on the quantification of the papillary muscle size, and data on the papillary muscle as a specific diagnostic marker for Fabry disease are lacking. Thus, the aims of this study were: (i) To establish a method to quantify the papillary muscle size by echocardiography, (ii) to evaluate whether the papillary muscle is enlarged in Fabry disease and (iii) whether a prominent papillary muscle in Fabry disease is of diagnostic use to distinguish Fabry patients from patients with other concentric LV hypertrophy diseases. METHODS Study population Between November 2008 and September 2009, 197 consecutive patients with the diagnosis of Fabry disease (n 5 63), Friedreich ataxia (n 5 71), cardiac Volume 37, Number 1, 2011 amyloidosis (n 5 10) and isolated arterial hypertension (n 5 53) presenting in our echo-lab were screened for this prospective study. (The University Hospital Wuerzburg acts as a reference center for patients with Fabry disease and Friedreich ataxia. Currently, a cohort of 146 Fabry and 122 Friedreich patients are followed prospectively with echocardiography. During the observation time slot, 63 of the 146 Fabry patients presented at our center and all were included in the study). Finally, only the 101 hypertrophic patients (defined as a septal or posterior wall thickness $12 mm) were included in the study for further analysis. Hypertension was defined by a repeatedly measured systolic blood pressure (SBP) $140 mm Hg and/or diastolic blood pressure (DBP) $90 mm Hg, or if the subject was receiving antihypertensive pharmacotherapy. In all patients with essential hypertension, coronary artery disease was excluded according to negative history, normal treadmill exercise test and normal coronary angiograms. Further exclusion criteria were: moderate and severe valvular heart diseases, diabetes mellitus and other endocrine or systemic diseases. The patient data were compared with those from 50 healthy controls that were acquired from the hospital staff and their relatives. Ten of the 28 Fabry patients showed mild hypertension, which agrees with latest findings that hypertension is common (as high as 50%) in patients with Fabry disease (Kleinert et al. 2006) and therefore we did not exclude these patients from further analysis. Hypertension in these patients was easy to control with mainly one and never more than two antihypertensive drugs, and all patients were normotensive at study entry. The study conformed to the principles outlined in the Declaration of Helsinki, and the locally appointed ethics committee approved the research protocol; informed consent was obtained from all patients. Standard echocardiographic measurements Left ventricular end-diastolic (LVEDD) and endsystolic dimensions (LVESD) as well as end-diastolic thickness of the posterior wall (LVPWD) and the septum (IVSD) were measured using standard M-mode echocardiographic methods and parasternal LV long-axis images (GE Vingmed Vivid 7, Horten, Norway; 3.5 MHz). Ejection fraction (EF) was calculated using the modified Simpson method. Blood pool pulsed Doppler of the mitral valve inflow was used to extract the ratio of early to late diastolic flow velocity (E/A) and the deceleration time (DT). Evaluation of the papillary muscle In an initial study of 60 screened subjects (20 controls and 10 patients of each patient group), the ability to see both papillary muscles in one end-diastolic image Papillary muscle in Fabry disease d M. NIEMANN et al. was evaluated. Parasternal long- and short-axis views, as well as apical two-, three- and four-chamber views were investigated. In parasternal short-axis view, both papillary muscles could be seen simultaneously in 56 subjects (93%) and in the apical two-chamber views in 14%. In all other standard echocardiographic views, it was not possible to detect both papillary muscles in one image (Table 1). Thus, for further analysis only parasternal short-axis views were used and patients who showed only one papillary muscle in short axis were excluded from final analysis. Thereafter, the areas of both papillary muscles were manually traced (GE, Echopac, Horten, Norway) from the parasternal short-axis view at papillary muscle level and the results of both papillary muscles were summed in all subjects included in the final study (101 hypertrophied patients and 50 controls) (Fig. 2). In addition, LV cavity circumference was measured using manual circumscription of the endocardial border (Fig. 2). A ratio of the papillary muscle area and the circumference of the LV cavity was performed (PM_LV_ratio). Data analysis Data are presented as the mean 61 standard deviation (SD) or as absolute patient numbers. Differences between the groups were tested using one-way analysis of variance followed by Duncan’s post hoc analysis, Fisher’s exact test and Kruskal-Wallis test, as indicated. Inter- and intraobserver variability were determined in 25 patients (5 consecutive patients of each patient group and controls) and intraclass correlations were performed. A p-value , 0.05 was considered statistically significant. STATISTICAVersion 8.0 (StatSoft Inc, Tulsa, OK, USA) and SPSS Version 17.0 (SPSS, Inc., Chicago, IL, USA) were used. 39 Table 1. Visibility of the papillary muscles in different standard echo views Long-axis view (n) Short-axis view (n) Apical 4-chamber (n) Apical 2-chamber (n) Apical 3-chamber (n) One PM Two PM 30 (50%) 4 (7%) 34 (57%) 14 (24%) 13 (24%) 0 (0%) 56 (93%) 0 (0%) 8 (14%) 0 (0%) PM 5 papillary muscle. patients (141 6 23 mm Hg) was significantly higher than in Fabry (122 6 16 mm Hg) and Friedreich (110 6 14 mm Hg) patients and three hypertensive patients showed elevated systolic blood pressure .140 mm Hg. Heart rate differed significantly among the subgroups and was the lowest in Fabry patients (63 6 10 bpm) and the highest in amyloidosis patients (90 6 13 bpm). Standard echocardiographic measurements The standard echocardiographic parameters are presented in Table 3. Left ventricular wall thickness was significantly higher in all patient subgroups compared with controls, and Fabry and amyloidosis patients had the most hypertrophy. Ejection fraction and fractional shortening were normal in all patient subgroups. Assessment of the papillary muscle When analyzing all subjects (n 5 151), a significant positive correlation between the papillary muscle area RESULTS Left ventricular hypertrophy (LV wall thickness $12 mm) was evidenced in 101 of 197 patients (Fabry n 5 28, Friedreich n 5 30, hypertension n 5 34, amyloidosis n 5 9), and these patients and the controls were included in the final analysis. The general data of the 101 patients and 50 controls are shown in Table 2. Age was similar between Fabry patients and controls, whereas Friedreich patients were significantly younger, hypertensive and amyloidosis patients were older when compared with Fabry patients and controls. The hypertensive patients showed a significantly higher body mass index (28.8 6 4.5 kg/m2) than the other three patient subgroups. There was no difference in the diastolic blood pressure among the patient subgroups. However, diastolic blood pressure was elevated (.90 mm Hg) in six (18%) hypertensive patients. Systolic blood pressure in hypertensive Fig. 2. A short-axis view of a Fabry patient for the quantification of the papillary muscle area and the ratio of papillary muscle area to LV circumference (PM_LV_ratio): The papillary muscles (1 1 2) and the LV cavity (endocardial circumference; 3) are manually traced. The amount of the whole papillary muscle area is calculated by adding the posteromedial and the anterolateral papillary muscle area (1.9 cm2 1 2.4 cm2 5 4.3 cm2). The PM_LV_ratio is performed by dividing the papillary muscle area and the cavity size (4.3 cm2/11.3 cm2 5 0.38). Note that both values, 4.3 cm2 for the papillary muscle area and 0.38 for the PM_LV_ratio, are above the 95% confidence interval of the controls. 40 Ultrasound in Medicine and Biology Volume 37, Number 1, 2011 Table 2. Clinical baseline characteristics of the controls and patient subgroups Age (y) Male (%) HT (n) NYHA class (median) Beta-blockade Ca channel Diuretics ACE inhibitor Anticoagulation Controls n 5 50 Fabry n 5 28 FA n 5 30 HT n 5 34 Amyloidosis n59 45 6 14 54 0 0 0 0 0 0 0 50 6 11 50 10* 1* 6* 1 4* 12* 11* 22 6 6*y 70 1y 1* 1y 0 0y 1y 0y 66 6 13*yz 59 34*y 2.75*yz 25*yz 10*yz 23*yz 16*z 14*z 66 6 14*yz 89 5*x 2*z 5*z 1 7*yz 6*z 6*z ACE 5 angiotensin-converting enzyme; Ca 5 calcium; FA 5 Friedreich ataxia; HR 5 heart rate; HT 5 hypertension. * p , 0.05 vs. controls. y p , 0.05 vs. Fabry disease. z p , 0.05 vs. Friedreich ataxia. x p , 0.05 vs. hypertension. and LV end-diastolic wall thickness of the septal wall could be documented (p , 0.0001; r 5 0.58; Fig. 3). The absolute papillary muscle area in short-axis views are shown in Table 4. The papillary muscle area was highest in Fabry patients, followed by the hypertensive patients. Fabry patients showed a significantly higher absolute papillary muscle area than Friedreich ataxia, amyloidosis patients and controls. In addition, Fabry patients presented a significantly higher PM_LV_ratio than hypertensive patients, amyloidosis patients and controls (Table 4). Because the New York Heart Association (NYHA) class in the hypertensive patients was higher than in Fabry patients, we also analyzed 10 additional patients with mild isolated arterial hypertension and NYHA class I (matched to Fabry patients) to avoid a preselection bias. Mean LV wall thickness in this group was 12.6 6 1.0 mm, LVEDD 46 6 7 mm. These mild hypertensive patients showed no difference in absolute papillary muscle area (2.8 6 0.4 cm2) and PM_LV_ratio (0.15 6 0.03) compared with controls, whereas both parameters were significantly higher in Fabry patients (p , 0.0001). To define a prominent papillary muscle, the 95% confidence interval was calculated in the control group. The upper limit of the 95% confidence interval in the control cohort of the absolute papillary muscle area was 3.6 cm2 and for PM_LV_ratio 0.18 (5 cut-off values). Thus, a prominent papillary muscle was defined when both parameters were higher than these cut-off values. In Fabry disease, 21 of the 28 patients (75%) and 10 of 73 non-Fabry patients (14%) (4 Friedreich, 1 amyloidosis, 5 hypertensive) showed both an increased absolute papillary muscle area and PM_LV_ratio. This resulted in a sensitivity of 75% and a specificity of 86% for detecting Fabry disease with LV hypertrophy in this special subgroup of patients. The positive predictive value in our cohort was 68% and the negative predictive value was 90%. With a wall thickness .13 mm, all Fabry patients showed a higher than normal papillary muscle area and PM_LV_ratio (sensitivity 100%). Table 3. Standard echocardiographic parameters of the patient subgroups and controls LVPWD (mm) IVSD (mm) LVEDD (mm) LVESD (mm) FS EF (%) E/A DT (ms) Controls n 5 50 Fabry n 5 28 FA n 5 30 HT n 5 34 Amyloidosis n59 9.0 6 1.4 9.0 6 1.4 49.8 6 4.1 31.2 6 4.4 37 6 7 62 6 4 1.3 6 0.3 210 6 43 13.7 6 3.4* 14.4 6 3.3* 47.4 6 6.7 29.4 6 6.0 37 6 6 64 6 7 1.2 6 0.4 239 6 57 12.0 6 1.2*y 12.3 6 1.0*y 41.7 6 9.1*y 27.4 6 5.4 36 6 6 64 6 6 1.7 6 0.7*y 179 6 54y 12.6 6 2.3* 13.0 6 2.2* 49.6 6 7.4z 34.0 6 7.9z 32 6 8 59 6 11 1.0 6 0.5z 258 6 82*z 14.7 6 1.7*zx 15.6 6 2.1*zx 47.0 6 6.5z 31.6 6 7.2 33 6 9 58 6 13 0.9 6 0.3z* 206 6 62x DT 5 deceleration time; EF 5 ejection fraction; FA 5 Friedreich ataxia; FS 5 fractional shortening; HT 5 hypertension; IVSD 5 interventricular septal wall thickness; LVEDD 5 left ventricular end-diastolic diameter; LVESD 5 left ventricular end-systolic diameter; LVPWD 5 diastolic left ventricular posterior wall thickness. * p , 0.05 vs. controls. y p , 0.05 vs. Fabry disease. z p , 0.05 vs. Friedreich ataxia. x p , 0.05 vs. hypertension. 41 Papillary muscle in Fabry disease d M. NIEMANN et al. DISCUSSION This study is a systematic echocardiographic evaluation of the papillary muscle in patients with concentric LV hypertrophy. Using a cross-sectional study design in a large cohort of patients, the main results are: (i) A prominent papillary muscle should be defined by both the absolute and relative size (in relation to LV cavity), (ii) the best echocardiographic view to extract these parameters is the parasternal short axis and (iii) Fabry disease in advanced stages (with hypertrophy) is often linked to a prominent papillary muscle and might serve as a marker to screen for Fabry disease in patients with concentric left LV hypertrophy. Fig. 3. Scatter-plot of the intraventricular septal wall thickness (IVSD) in mm and the absolute size of the papillary muscle area (area_pm) in cm2 in the study cohort. IVSD is displayed on the x-axis, area_pm on the y-axis (n 5 151; r 5 0.58; p , 0.0001). Eyeball screening In addition to quantitative assessment, the papillary muscles of the 28 Fabry patients were classified as hypertrophied or not by visual impression. Nineteen of the 21 quantitatively hypertrophied papillary muscles were also assessed as hypertrophied by eyeball screening, and two were not. One of the seven quantitatively non hypertrophied papillary muscles was ‘‘false’’-classified as hypertrophied by visual impression (in this patient, absolute papillary muscle area was slightly below the cut-off: 3.4 cm2). Intra- and interobserver correlation For the absolute papillary muscle area, an intraobserver variability of 5 6 4% and a ratio of 6 6 5% for the PM_LV_ were found. The intraobserver intraclass correlations were 0.99 for the absolute papillary muscle area and 0.96 for PM_LV_ratio. The interobserver variability was 14 6 11% and 16 6 15% for the absolute papillary muscle area and PM_LV_ratio, respectively. The interobserver intraclass correlations were 0.9 for the absolute papillary muscle area and 0.67 for the PM_LV_ratio. The prominent papillary muscle Echocardiography is an easy and widely available method for the assessment of both the typical geometry of the cavity and specific structures within the myocardium as diagnostic markers for several cardiac diseases. Thus, the echocardiographic finding of a two-layered LV apex with a thin compacted and a thick noncompacted layer is groundbreaking for the diagnosis of the noncompaction cardiomyopathy (Jenni et al. 2001, 2007). Several reviews and case reports about Fabry disease have suggested that the typical echocardiographic feature for Fabry cardiomyopathy might be a prominent papillary muscle of the LV (Linhart et al. 2001; Strotmann et al. 2005; Weidemann et al. 2008, 2009). Our study confirms that in advanced stages of Fabry cardiomyopathy, the visual impression of a prominent papillary muscle is supported by quantification of the absolute and relative size of the papillary muscles. Our data prove that other cardiac diseases coinciding with LV hypertrophy also lead to a detectable hypertrophy of the papillary muscle when compared with controls. In hypertensive heart disease, the high wall stress leads to an increased wall thickness, which seems to be accompanied by an increased absolute papillary muscle size in later disease stage. However, because during disease progression the LV also starts to dilate, the relative papillary muscle size is not as highlighted Table 4. Papillary muscle area and PM_LV_ratio of the subgroups and controls PM_area (cm2) PM_LV_ratio Controls n 5 50 Fabry n 5 28 FA n 5 30 HT n 5 34 Amyloidosis n59 2.6 6 0.6 0.14 6 0.02 4.3 6 1.3* 0.23 6 0.07* 3.2 6 0.8*y 0.21 6 0.05* 3.8 6 1.0* 0.18 6 0.03*y 3.5 6 0.6*y 0.18 6 0.02*yz FA 5 Friedreich ataxia; HT 5 hypertension; PM_area 5 area of the papillary muscle; PM_LV_ratio 5 ratio of the papillary muscle area to left ventricular cavity circumference. * p , 0.05 vs. controls. y p , 0.05 vs. Fabry disease. z p , 0.05 vs. Friedreich ataxia. 42 Ultrasound in Medicine and Biology as in Fabry disease. Because Friedreich ataxia is a mitochondrial disease, the loss of energy supply induces LV hypertrophy. However, in Friedreich ataxia, the enddiastolic wall thickness rarely exceeds 14 mm (Dutka et al. 2000) and thus the absolutely papillary muscle is not as increased as in Fabry disease. In our small amyloidosis cohort, a relatively high degree of LV hypertrophy was seen. However, the papillary muscle seems not to hypertrophy similarly. Only in Fabry cardiomyopathy do a pronounced LV and papillary hypertrophy in combination with a relatively small LV cavity lead to both the increased absolute and relative papillary muscle size. Thus, when analyzing our cohort, the combination of these two parameters was of diagnostic use. Clinical implications Screening for Fabry disease in special populations is very effective for early diagnosis. Pieroni et al proposed a binary appearance of the endocardial LV border as an echocardiographic sign of Fabry disease (Pieroni et al. 2006), but other groups showed a lack of strength in differential diagnosis (Koskenvuo et al. 2009; Kounas et al. 2008). Havndrup et al. (2010) clearly showed that in female patients with hypertrophy of unknown origin, genetic testing is mandatory to diagnose Fabry disease as the underlying pathology. However, in cardiology, most screening studies were done in patients with LV hypertrophy measuring a-galactosidase A activity. If this is done in special hypertrophic cardiomyopathy centers, as many as 12% of these screened patients could be discovered to have Fabry disease (Chimenti et al. 2004). However, in nonspecialized cardiology centers, only very few patients with LV hypertrophy could be detected as having Fabry disease, mostly a result of unselective screening because preselecting criteria are missing. Thus, in these centers, an additional echocardiographic sign like the prominent papillary muscle might be helpful to increase the Fabry disease–positive patients during screening and help with pre-exclusion of patients. Because the current study cannot provide a clear cut-off value, we are not recommending quantifying the size of the papillary muscle in each patient with unclear LV hypertrophy. Because the human eye is very good in the recognition of special image patterns (Kvitting et al. 1999; Picano et al. 1991), the visual impression of a prominent papillary muscle (in patients with unclear LV hypertrophy) should lead the echocardiographer to screen for Fabry disease. Thus, especially in these patients, the enzyme activity of a-galactosidase A should be measured to confirm the diagnosis. Whether the prominent papillary muscle is of use not only to screen in hypertrophic patients, but also to help diagnose nonhypertrophic Fabry disease patients is a task for future studies. Volume 37, Number 1, 2011 Limitation The fact that the papillary muscles are 3-D structures that cannot be captured entirely by using 2-D echocardiography is a limitation. However, 2-D echocardiography is still the standard echo evaluation and the echo method used for screening in everyday cardiac routine. The current study did only include pathologies leading primarily to symmetric LV hypertrophy. Thus, patients with asymmetrical LV hypertrophy as in idiopathic hypertrophic cardiomyopathy were not included because this pattern is very unusual for Fabry cardiomyopathy. In addition, patients with aortic stenosis were not examined because in these patients the aortic valve is the primary pathology, which cannot be mistaken for Fabry disease. Between November 2008 and September 2009, only 10 patients with cardiac amyloidosis were seen in our echo lab. This group has limitations because of its sample size. For ethical reasons, we did not undertake myocardial biopsies in the Fabry patients to determine the underlying histological morphology in the patients with LV hypertrophy. CONCLUSION The current study confirms the assumption that Fabry disease presenting as a concentric LV hypertrophy is linked to a prominent papillary muscle. 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