Transthoracic and transesophageal echocardiography detected a left atrial mass attached to the intra-atrialseptum. Intravenous contrast agent ruled out atrial thrombus, sugesting a left atrial myxoma. This highlights theimportance of contrast echocardiography for differential diagnosis of left atrial findings.

Introduction: Secondary mitral regurgitation (SMR) is related with poor clinical outcome. Impact of right ventricular (RV) dysfunction with or without left ventricular (LV) dysfunction in SMR patients remains unclear. Hypothesis: This study aimed to investigate the prevalence of isolated LV, RV, and biventricular dysfunction, and to determine their prognostic implication in moderate-to-severe SMR without surgical and interventional treatment. Methods: A total of 1090 consecutive moderate-to-severe SMR patients without surgical and interventional treatment hospitalized in our hospital center between 2009 and 2018 (aged 75±12years, 60.4% male) were included. Clinical and echocardiographic characteristics were analyzed. All patients completed at least 1-year clinical follow-up. The primary endpoint was defined as all-cause death. Results: Mean left ventricular ejection fraction (LVEF) was 44.6±16.2%, and 59.3% of patients had LVEF <50% (defined as LV dysfunction). RV dysfunction was defined as a reduced tricuspid annular plane excursion (TAPSE<17mm) or an increased systolic pulmonary artery disease (sPAP>40mmHg). All-cause mortality was 47.8% [follow-up period: median 23 (8-40) months]. Patients were divided into 4 subgroups: 1) preserved biventricular function: n=136 (12.5%); 2) isolated LV dysfunction: n=97 (8.9%); 3) isolated RV dysfunction: n=308 (28.3%); 4) biventricular dysfunction: n=549 (50.4%). The mortality in above groups was 27.2%, 36.1%, 50.0% and 53.7%, respectively. Multivariable survival analysis showed that isolated LV dysfunction, isolated RV dysfunction, or biventricular dysfunction were all independently associated with increased all-cause mortality, after adjustment for age, sex and other clinical covariates associated with mortality. Conclusions: Compared to patients with preserved biventricular function or isolated LV dysfunction, RV and biventricular dysfunction are associated with significantly higher all-cause mortality in SMR patients without surgical/interventional treatment. This might constitute important implications for planning and timing of therapy.

Introduction: Several risk scores have been developed for outcome after heart surgery. However, risk factors associated with clinical outcome in patients undergoing transcatheter aortic valve replacement (TAVR) are still not well defined. This study aimed to determine laboratory and echocardiography determinants of short- and long-term outcome after TAVR. Methods: This retrospective study comprised 598 consecutive patients with sole aortic stenoseis (AS) who received balloon-expandable TAVR in our hospital (mean age 81.7±5.7 years, 48.7% male, median EuroSCORE II 5.0%). Pre-operative laboratory and imaging data including speckle-tracking echocardiography were analyzed. Clinical outcomes included cardiovascular (CV) death, CV hospitalization, and procedure related complications at 30 days, 1 year, and at 2 years after TAVR. Results: Semi-quantitative assessment defined as ≥3 LV wall segments with the apico-basal LS ratio >3.0 was used to define relative apical sparing pattern (RASP). The prevalence of RASP was 19.2%. RASP patients had higher prevalence of acute kidney injury (AKI, 10.4% vs. 3.3%, P=0.001) and new-onset left bundle branch block (LBBB) after TAVR (17.4% vs. 6.8%, P<0.001). CV mortality at 30 days (7.0% vs. 3.1%, P=0.062), 1 year (15.7% vs. 7.9%, P=0.010), and 2 years (22.6% vs. 9.9%, P<0.001) was also higher after TAVR. RASP remained the strongest determinant for AKI (OR=3.11, P=0.007), new-onset LBBB (OR=2.89, P<0.001), increased 30-day CV related hospitalization or death risk (OR=2.20, P=0.033). Lower albumin level and RASP were identified as independent determinants of increased 1-year and 2-year CV mortality risk (RASP: HR=1.83 and 2.18, P=0.039 and 0.002; albumin<4.0g/dl: HR=3.18 and 2.55, both P<0.001), regardless of TAVR approach and EuroSCORE II. After adjustment, the addition of RASP significantly improved prognostic power of a model including clinical variables and low albumin level for predicting CV death at 2-year follow-up ( χ 2 from 28.18 to 40.70, P=0.001). Conclusions: RASP represents a novel clinically relevant determinant of outcome after TAVR. Low albumin and RASP were identified as the strongest laboratory and echocardiography determinants for increased short- and long-term outcome after TAVR.

Aims: Chaperone therapy with migalastat is a novel therapy option in Fabry disease (FD). In contrast to biweekly intravenous enzyme-replacement-therapy in a healthcare setting, oral delivery of migalastat every other day re-lies on the patient self-administration. Therapy adherence to migalastat and patient reported outcomes have not yet been studied in a real-world scenario.Methods and results: Prospective multicenter 'MigALastat Therapy Adherence among FABRY patients' (MALTA-FABRY) study examined therapy adherence and patient-reported outcomes including quality of life in FD -patients receiving migalastat. Outcome measurements were elicited by the 'Medication Adherence Questionnaire (MAQ)', 'SF-36' and 'Fabry Pain Questionnaire' over a follow-up period of 24 months. Therapy adherence was graded as high (MAQ score of 4), medium (score of 2-3) or low (score 0-1). Within the recruitment period be-tween 2017 and 2021, 40 patients (19 females) from 3 German FD-centers were included in the study. Nearly all patients (n = 37, 92.5%) showed good therapy adherence (MAQ6Mmean:3.93, MAQ12Mmean:3.71 and MAQ24Mmean:3.7). Only one patient fulfilled criteria for low adherence. Patient reported outcomes with completed SF-36 questionnaires were available in 28 patients (14 females). Over 24 months, significant improve-ment of pain and life role limitations due to physical activity was reported (Pain: change from baseline: 8.57 points, 95%-CI: 1.32-15.82, p = 0.022; role limitations physical: change from baseline: 13.39 points, 95%-CI: 0.61-23.2, p = 0.048). Conclusion: Migalastat therapy adherence in FD-patients was high and remained high over a follow-up period of 2 years. Patient reported quality of life remained mostly stable, while pain and physical limitations improved over time.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Fabry disease (OMIM 301500) is an X-linked (Xq22.1)lysosomal storage disorder leading to a progressive multisystem disease with high variability in both genotype and phenotype expression.The pathophysiological origin is found in an enzyme deficiency of the α-galactosidase A (enzyme commission no.3.2.1.22)leading to accumulation of globotriaosylceramides in all lysosome carrying tissue.Especially organ manifestations of the heart, kidneys and nervous system are of significant prognostic value and might complicate with Fabry-associated pain, young aged cryptogenic stroke, proteinuria, kidney failure, hypertrophic cardiomyopathy, heart failure, malign cardiac rhythm disturbances and eventually sudden cardiac death.Up to the introduction of the first enzyme replacement agent in 2001, patients faced the disease's natural course with no disease-specific therapies available.Today, two recombinant enzyme replacement agents (Fabrazyme ® , Sanofi Genzyme, Cambridge, MA, USA; Replagal ® , Takeda Pharmaceutical, Tokio, Japan) and one oral chaperone therapy (Migalastat ® , Amicus Therapeutics, USA) are available and well-established in daily clinical practice.Substrate reduction therapy, second-generation enzyme replacement agents and different gene therapy approaches are currently undergoing preclinical and clinical trial phases and aim to improve therapeutic success and long-term outcome of patients with Fabry disease.This narrative review summarizes the currently available therapeutic options and future perspectives in Fabry disease.

Fabry's disease (FD) is an X‐linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α‐galactosidase A (α‐Gal A) leading to intracellular accumulation of globotriaosylceramide (Gb3). Patients with amenable mutations can be treated with migalastat, a recently approved oral pharmacologic chaperone to increase endogenous α‐Gal A activity. We assessed safety along with cardiovascular, renal, and patient‐reported outcomes and disease biomarkers in a prospective observational multicenter study after 12 months of migalastat treatment under “real‐world” conditions. Fifty‐nine (28 females) patients (34 (57.6%) pretreated with enzyme replacement therapy) with amenable mutations were recruited. Migalastat was generally safe and well tolerated. Females and males presented with a reduction of left ventricular mass index (primary end point) (−7.2 and −13.7 g/m 2 , P = 0.0050 and P = 0.0061). FD‐specific manifestations and symptoms remained stable (all P > 0.05). Both sexes presented with a reduction of estimated glomerular filtration rate (secondary end point) (−6.9 and −5.0 mL/minute/1.73 m 2 ; P = 0.0020 and P = 0.0004, respectively), which was most prominent in patients with low blood pressure ( P = 0.0271). α‐Gal A activity increased in male patients by 15% from 29% to 44% of the normal wild‐type activity ( P = 0.0106) and plasma lyso‐Gb3 levels were stable in females and males ( P = 0.3490 and P = 0.2009). Reevaluation of mutations with poor biochemical response revealed no marked activity increase in a zero activity background. We conclude that therapy with migalastat was generally safe and resulted in an amelioration of left ventricular mass. In terms of impaired renal function, blood pressure control seems to be an unattended important goal.

AbstractAimsFrom the various mechanical cardiac assist devices and indications available, the use of the percutaneous intraventricular Impella CP pump is usually restricted to acute ischaemic shock or prophylactic indications in high‐risk interventions. In the present study, we investigated clinical usefulness of the Impella CP device in patients with non‐ischaemic cardiogenic shock as compared with acute ischaemia.Methods and resultsIn this retrospective single‐centre analysis, patients who received an Impella CP at the University Hospital Würzburg between 2013 and 2017 due to non‐ischaemic cardiogenic shock were age‐matched 2:1 with patients receiving the device due to ischaemic cardiogenic shock. Inclusion criteria were therapy refractory haemodynamic instability with severe left ventricular systolic dysfunction and serum lactate >2.0 mmol/L at implantation. Basic clinical data, indications for mechanical ventricular support, and outcome were obtained in all patients with non‐ischaemic as well as ischaemic shock and compared between both groups. Continuous variables are expressed as mean ± standard deviation or median (quartiles). Categorical variables are presented as count and per cent. Twenty‐five patients had cardiogenic shock due to non‐ischaemic reasons and were compared with 50 patients with cardiogenic shock due to acute myocardial infarction. Resuscitation rates before implantation of Impella CP were high (32 vs. 42%; P = 0.402). At implantation, patients with non‐ischaemic cardiogenic shock had lower levels of high‐sensitive troponin T (110.65 [57.87–322.1] vs. 1610 [450.8–3861.5] pg/mL; P = 0.001) and lactate dehydrogenase (377 [279–608] vs. 616 [371.3–1109] U/L; P = 0.007), while age (59 ± 16 vs. 61.7 ± 11; P = 0.401), glomerular filtration rate (43.5 [33.2–59.7] vs. 48 [35.75–69] mL/min; P = 0.290), C‐reactive protein (5.17 [3.27–10.26] vs. 10.97 [3.23–17.2] mg/dL; P = 0.195), catecholamine index (30.6 [10.6–116.9] vs. 47.6 [11.7–90] μg/kg/min; P = 0.663), and serum lactate (2.6 [2.2–5.8] vs. 2.9 [1.3–6.6] mmol/L; P = 0.424) were comparable between both groups. There was a trend for longer duration of Impella support in the non‐ischaemic groups (5 [2–7.5] vs. 3 [2–5.25] days, P = 0.211). Rates of haemodialysis (52 vs. 47%; P = 0.680) and transition to extracorporeal membrane oxygenation (13.6 vs. 22.2%; P = 0.521) were comparable. No significant difference was found regarding both 30 day survival (48 vs. 30%; P = 0.126) and in‐hospital mortality (66.7 vs. 74%; P = 0.512), although there was a trend for better survival in the non‐ischaemic group.ConclusionsThese data suggest that temporary use of the Impella CP device might be a useful therapeutic option for bridge to recovery not only in ischaemic but also in non‐ischaemic cardiogenic shock.

A 64-year-old man with paroxysmal atrial fibrillation and a recent stroke presented with internal carotid artery restenosis after previous angioplasty. Cardiovascular risk factors included arterial hypertension, hyperlipidemia, obesity, positive family history, heart failure, and active smoking. Because of the high risk of cerebral ischemia and peri-interventional bleeding complications, the patient was scheduled for interventional left atrial appendage (LAA) closure before carotid artery surgery. After unproblematic transseptal puncture, contrast injection via a pigtail catheter revealed an accessory pulmonary vein (arrows in Figure 1A and Supplemental Video) in the late contrast injection phase with anomalous insertion into the roof of the LAA, which was confirmed by peri-interventional esophageal echocardiography. Due to this finding, planned LAA closure was abandoned. Computed tomography revealed direct connection of the LAA to the veins of the left inferior pulmonary lobe (Figure 1B; Ao = aorta; LV = left ventricle; PA = pulmonary artery; RV = right ventricle). Oral anticoagulants were stopped and antiplatelet therapy initiated. Partial anomalous pulmonary venous connection is a relatively uncommon congenital anomaly, found in only 0.5%–0.7% of the general population. More than 80% of cases involve a connection to the right lung, and the anomalous connection is often associated with an atrial septal defect.1Snellen H.A. van Ingen H.C. Hoefsmit E.C. Patterns of anomalous pulmonary venous drainage.Circulation. 1968; 38: 45-63Crossref PubMed Scopus (129) Google Scholar Whether the higher blood flow into the appendage lowers the risk of thrombus formation is unclear.2Khurram I.M. Dewire J. Mager M. et al.Relationship between left atrial appendage morphology and stroke in patients with atrial fibrillation.Heart Rhythm. 2013; 10: 1843-1849Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar In the present case, the risk of anticoagulation was believed to outweigh the risk of an atrial fibrillation-related stroke. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJiNDA4ZDUzMWFlYWJhMzhjOGY2ZDIyMjAyNzlkMzc3NSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NTI3ODk1fQ.WS_X2lgsRFJhfrzwGOndwWm-0C00v7GgXmOAkPTiPNCZjnVxqxHMD1neNytxvUvQHPDxFK2HAOfS5vGGJ-41d5mELLZiJGlIgZiw_SPLQE1-mAi8YahZ9yQPZL88Hb568mUsn-Ya8QWVj_bDkJmI3DLpyv2oRYGyGiWW7PVvrnCCscdvAxTeYxNKVpJPktIGICerxqKFaxTXstczpCWORSewN3LTaNjwZDc0Ew6JcZi5za_1SxdmQhVKgvF5NQ8uZ2ar1CV5f7EU05nTZRgmq0y17HfwIaEEpfaGb1KNRJ9P82Ba7HqvuUHUkwRRLLF6eeH-eZHUeigOz965evn6Rg Download .mp4 (0.89 MB) Help with .mp4 files Supplemental VideoContrasting the LAA after transseptal puncture. Insertion of an accessory pulmonary vein into the LAA.

Clinical Pharmacology & TherapeuticsVolume 106, Issue 5 p. 925-926 Letter to the Editor Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data Simon Körver, Simon Körver Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorUlla Feldt-Rasmussen, Ulla Feldt-Rasmussen Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorEinar Svarstad, Einar Svarstad Department of Medicine, Haukeland University Hospital, Bergen, NorwaySearch for more papers by this authorIlkka Kantola, Ilkka Kantola Division of Medicine, Turku University Hospital, Turku, FinlandSearch for more papers by this authorMirjam Langeveld, Corresponding Author Mirjam Langeveld m.langeveld@amsterdamumc.nl Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The NetherlandsCorrespondence: Mirjam Langeveld (m.langeveld@amsterdamumc.nl)Search for more papers by this author Simon Körver, Simon Körver Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorUlla Feldt-Rasmussen, Ulla Feldt-Rasmussen Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorEinar Svarstad, Einar Svarstad Department of Medicine, Haukeland University Hospital, Bergen, NorwaySearch for more papers by this authorIlkka Kantola, Ilkka Kantola Division of Medicine, Turku University Hospital, Turku, FinlandSearch for more papers by this authorMirjam Langeveld, Corresponding Author Mirjam Langeveld m.langeveld@amsterdamumc.nl Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The NetherlandsCorrespondence: Mirjam Langeveld (m.langeveld@amsterdamumc.nl)Search for more papers by this author First published: 12 July 2019 https://doi.org/10.1002/cpt.1536Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume106, Issue5Precision MedicineNovember 2019Pages 925-926 RelatedInformation

While improved treatment numerically decreased ventricular aneurysms after myocardial infarction, respective cases still represent a clinical challenge due to difficulties in diagnosis, complications like tachycardia, and controversies in state-of-the-art treatment. Our case illustrates good long-term outcome of surgical aneurysmectomy in cases where ventricular geometry can be restored to near-physiological dimensions.

BACKGROUND:Fast progression of the transaortic mean gradient (P mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. METHODS:This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index ≥30 Kg/m2, and history of smoking) were analyzed. Patients were divided into slow (P mean < 5 mmHg/year) or fast (P mean ≥ 5 mmHg/year) progression groups. RESULTS:A total of 402 patients (mean age 78 ± 9.4 years, 58% males) were included in the study. Mean follow-up duration was 3.4 ± 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 ± 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 ± 1.5 vs 2.9 ± 1.7; P=0.036). Patients in slow progression group had more often coronary heart disease (49.2% vs 33.6%; P=0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 ± 32.6 mg/dl vs 110.8 ± 36.6 mg/dl; P=0.005). CONCLUSION:These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.

ObjectivesCurrent guidelines highlight important therapy implications of cardiac fibrosis in patients with Fabry disease (FD). However, association between morphological and functional impairments with cardiac fibrosis in hereditary cardiomyopathies remains elusive. We investigated the association between echocardiography-determined cardiac dysfunction and cardiac MRI (cMRI)-detected myocardial fibrosis (late gadolinium enhancement, LE) in patients with FD with preserved left ventricular ejection fraction (≥50%).Methods146 patients with FD (aged 39±14 years, 57 men) were analysed, all receiving echocardiography and cMRI within a 1 week interval. Longitudinal systolic strain (LS_sys), strain rate (LSr_sys) and diastolic strain rate (LSr_E/LSr_A) were assessed using speckle-tracking imaging. Receiver operating characteristic (ROC) analysis was performed to identify the diagnostic performance of various markers for LE.ResultsLE was detected in 57 (39%) patients with FD. LV wall thickness, left atrial volume, septal E/e′, diastolic dysfunction grade, global LS_sys and E/LSr_E, mid-lateral LS_sys and LSr_E, as well as N-terminal pro-brain natriuretic peptide were all associated with LE independent of age, sex, body mass index, New York Heart Association functional class and kidney function. In ROC curve analysis, septal E/e′ performed best (area under the curve=0.86, 95% CI=0.79 to 0.92). Septal E/e′>14.8 was strongly associated with LE (specificity=97.8% and sensitivity=49.1%). In 9% of patients, localised LE was present even though no other cardiac or kidney abnormalities were detected.ConclusionsEchocardiography-derived diastolic dysfunction is closely linked to LE in FD. Septal E/e′ ratio is the best echocardiographic marker suggestive of LE. Diastolic dysfunction is not a prerequisite for LE in FD, since LE can be detected in the absence of measurable cardiac functional impairments.Trial registration numberClinicalTrials.gov Identifier (NCT03362164).

Background: Fabry Disease (FD) is an X-linked hereditary lysosomal storage disorder which leads to a multisystemic intralysosomal accumulation of globotriaosylceramid (Gb3). Besides prominent renal and cardiac organ involvement, patients commonly complain about vestibulocochlear symptoms like high-frequency hearing loss, tinnitus and vertigo. However, comprehensive data especially on vertigo remain scarce. The aim of this study was to examine the prevalence and characteristics of vertigo and hearing loss in patients with FD, depending on renal and cardiac parameters and get hints about the site and the pattern of the lesions. Methods: Single-center study with 57 FD patients. Every patient underwent an oto-rhino-laryngological examination as well as videonystagmography and vestibular evoked myogenic potentials (VEMPs) and audiological measurements using pure tone audiometry and auditory brainstem response audiometry (ABR). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results: More than one out of three patients (35.1%) complained about hearing loss, 54.4% about vertigo and 28. 1% about both symptom. In 74% a sensorineural hearing loss of at least 25 dB was found, ABR could exclude any retrocochlear lesion. Caloric testing showed abnormal values in 71.9%, VEMPs were pathological in 68%. A correlation between the side or the shape of hearing loss and pathological vestibular testing could not be revealed. Conclusions: Hearing loss and vertigo show a high prevalence in FD. While hearing loss seems due to a cochlear lesion, peripheral vestibular as well as central nervous pathologies cause vertigo. Thus, both the site of lesion and the pathophysiological patterns seem to differ.

Fabry disease is a rare inborn error of the enzyme α-galactosidase (α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years, in particular since enzyme replacement therapy (ERT) has become widely available in 2001. With rising awareness and rising numbers of (diagnosed) patients, physicians encounter new challenges. Over 900 α-Gal gene mutations are currently known, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician and a lot of uncertainty for patients. Another challenge are patients who develop neutralising antibodies to ERT, which possibly leads to reduced therapy effectiveness. In this article, we summarise the latest developments in the science community regarding diagnostics and management of this rare lysosomal storage disorder and offer an outlook to future treatments.

To evaluate potential risk factors for stroke or transient ischemic attacks (TIA) and to test the feasibility and efficacy of a Fabry-specific stroke risk score in Fabry disease (FD) patients without atrial fibrillation (AF).

Abstract Single nucleotide polymorphisms (SNPs) in the alpha-galactosidase A gene region (GLA) have been discussed as potential cause of symptoms and organ manifestations similarly to those seen in Fabry disease (FD). However, due to scarce data, clinical implications remain limited. The aim of the present study was to investigate the clinical impact of -10C>T SNP in the GLA. Prospective single-center observational study to determine the natural history and outcome of FD. Subjects initially referred to the Fabry Center for Interdisciplinary Therapy Würzburg (FAZIT) for management of suspected FD (11 women, 2 men, mean age 42 ± 10 years) who were tested negative for coding GLA mutations but positive for the noncoding -10C>T SNP underwent comprehensive characterization for therapy recommendation. All subjects reported at least 1 neurological, but no cardiac or renal symptoms. In 7 patients, pain of unknown etiology was reported and 3 patients had a history of cryptogenic stroke. In all patients, &agr;-GAL activity was at a lower limit, ranging between 0.27 and 0.45 nmol/min per mg protein (reference: 0.4–1.0), while plasma Lyso-Gb3 levels remained normal (range 0.39 ± 0.33; reference: ⩽0.9 ng/mL). For both hemizygous subjects investigated, brain magnetic resonance imaging revealed unspecific white matter lesions. One of these subjects had suffered from severe early-onset stroke, the other showed mild hypertrophic cardiomyopathy. Presence of isolated heterozygous -10C >T SNP is not associated with clinically relevant symptoms or organ manifestations as seen in FD. Respective polymorphisms might, however, play a role in modifying disease severity in FD. Great care has to be taken in respective subjects suspected to suffer from nonclassical FD in order to prevent unnecessary Fabry-specific therapy.

A 52-year-old male patient diagnosed for hypertrophic cardiomyopathy was admitted to our clinic in October 2015 for unusual rapid worsening of heart failure symptoms.The electrocardiogram showed negative T-waves in inferior leads and a positive Sokolow index for left ventricular (LV) hypertrophy (Panel A).Echocardiography confirmed non-obstructive LV hypertrophy (Panel B).Cardiac serum biomarkers showed troponin and N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels of 49.1 and 365 pg/mL.Cardiac magnetic resonance imaging revealed diffuse late gadolinium enhancement (LGE) in the posterolateral wall (Panels C and F).Genetic analysis excluded sarcomeric hypertrophic cardiomyopathy but revealed the mutation N215S in the alpha-galactosidase A gene, one of the most prevalent Fabry mutations in Europe and recently described for a specific cardiac form of the disease.Heart failure medication was started, but enzyme replacement therapy refused by the patient.Due to further disease progression at 10 months follow-up regarding symptoms, further

Background Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature. Objective To examine hearing loss in patients with FD depending on cardiac and renal function. Material and methods Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Würzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA6 (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05). Conclusions High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used.

Background— Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific &agr;-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. Methods and Results— All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14–74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) &agr;-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7–23] mm; left ventricular posterior wall, 11±4 [7–21] mm; left ventricular mass, 86±41 [46–195] g/m2) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9–3.9] L/min per m2), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in loco typico (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte &agr;-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3–9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70–1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84–113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria. Conclusions— &agr;-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to a significant delay in diagnosis and Fabry-specific therapy.