Treatment of Fabry Disease management with migalastat-outcome from a prospective 24 months observational multicenter study (FAMOUS).

AIMS: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (GLA/AGAL), resulting in the lysosomal accumulation of globotriaosylceramide (Gb3). Patients with amenable GLA mutations can be treated with migalastat, an oral pharmacological chaperone increasing endogenous AGAL activity. In this prospective observational multicentre study, safety as well as cardiovascular, renal, and patient-reported outcomes and disease biomarkers were assessed after 12 and 24 months of migalastat treatment under 'real-world' conditions. METHODS AND RESULTS: A total of 54 patients (26 females) (33 of these [61.1%] pre-treated with enzyme replacement therapy) with amenable mutations were analysed. Treatment was generally safe and well tolerated. A total of 153 events per 1000 patient-years were detected. Overall left ventricular mass index decreased after 24 months (all: -7.5 ± 17.4 g/m2, P = 0.0118; females: -4.6 ± 9.1 g/m2, P = 0.0554; males: -9.9 ± 22.2 g/m2, P = 0.0699). After 24 months, females and males presented with a moderate yearly loss of estimated glomerular filtration rate (-2.6 and -4.4 mL/min/1.73 m2 per year; P = 0.0317 and P = 0.0028, respectively). FD-specific manifestations/symptoms remained stable (all P > 0.05). A total of 76.9% of females and 50% of males suffered from pain, which has not improved under treatment. FD-specific disease scores (Disease Severity Scoring System and Mainz Severity Score Index) remained stable during treatment. AGAL activities and plasma lyso-Gb3 values remained stable, although some male patients presented with increasing lyso-Gb3 levels over time. CONCLUSIONS: Treatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.

Treatment of Fabry's Disease With Migalastat: Outcome From a Prospective Observational Multicenter Study (FAMOUS).

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/m2 , 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 m2 ; 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.

Fabry disease under enzyme replacement therapy-new insights in efficacy of different dosages.

Background: Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index. Methods: In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38-57) months. Results: eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of - 4.6 ± 9.1 mL/min/1.73 m2 (P < 0.05). Patients in the re-switch group also had an eGFR loss of - 2.2 ± 4.4 mL/min/1.73 m2 after re-switch to agalsidase-beta, but to a lower degree compared with the switch group (P < 0.05). Patients in the re-switch group suffered less frequently from diarrhoea (relative risk 0.42; 95% confidence interval 0.19-0.93; P = 0.02). Lyso-Gb3 remained stable in the switch (P = 0.97) and the regular-dose (P = 0.48) groups, but decreased in the re-switch group after change of the therapy regimen (P < 0.05). Conclusions: After switch to agalsidase-alfa, Fabry patients experienced a continuous decline in eGFR, while this decline was attenuated in patients who were re-switched to agalsidase-beta. Decreasing lyso-Gb3 levels may indicate a better treatment response in the latter group.

Third-degree AV block sensitive to prednisolone 72 hours post AVNRT ablation.

A patient developed a transient first-degree AV block during a radiofrequency ablation of an atrioventricular nodal reentrant tachycardia. Three days later the patient presented with a third-degree AV block. It resolved within 24 h under antiphlogistic therapy. Patient was asymptomatic without necessity for pacemaker implantation at 12 months follow-up.

Segment-by-segment assessment of left ventricular myocardial affection in Anderson-Fabry disease by non-enhanced T1-mapping.

Background Anderson-Fabry disease (AFD) is an X-linked lysosomal enzyme disorder associated with an intracellular accumulation of sphingolipids, which shorten myocardial T1 relaxation times. Myocardial affection, however, varies between different segments. Purpose To evaluate the specific segmental distribution and degree of segmental affection in AFD patients. Material and Methods Twenty-five patients with AFD, 14 patients with hypertrophic cardiomyopathy (HCM), and 21 controls were included. A Modified Look-Locker Inversion Recovery sequence (MOLLI) was used for non-enhanced T1 mapping at 1.5 T in addition to standard cardiac imaging in 10-12 short axis views. T1 values were evaluated with a mixed model ANOVA and regression analysis to determine the best diagnostic cutoff values for T1 for each myocardial segment. Results Regression analysis showed the best diagnostic cutoff compared to controls in cardiac segments 1-4, 8-9, and 14. Mean differences between T1 for AFD versus HCM were greatest in segment 3, 4, and 9 (99 ms, 103 ms, 86 ms, respectively). Overall T1 times were 888 ± 70 ms and 903 ± 14 ms (AFD with and without LVH); 1014 ± 17 ms and 1001 ± 22 ms (HCM and controls, P < 0.05). Conclusion Myocardial segments are affected by a varying degree of T1 shortening in AFD patients. Segment-specific cutoff values allow the most specific detection and quantification of the extent of myocardial affection.

Usefulness of an Implantable Loop Recorder to Detect Clinically Relevant Arrhythmias in Patients With Advanced Fabry Cardiomyopathy.

Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holter electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 ± 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses ≥3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter-defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder.

Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant.

BACKGROUND: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. METHODS: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. RESULTS: p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. CONCLUSIONS: We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.

Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction and Switch-2-Year Follow-Up.

Because of the shortage of agalsidase-ß supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-ß (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3-0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C-based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-ß dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used.

Structural and functional cardiac analyses using modern and sensitive myocardial techniques in adult Pompe disease.

The purpose of this study was to analyze comprehensively the heart using modern and sensitive myocardial techniques in order to determine if structural or functional cardiac alterations are present in adult Pompe disease. Twelve patients with adult Pompe disease and a control group of 187 healthy subjects of similar age and gender were included. Structural and functional cardiac characteristics were analyzed by conventional and 2D speckle-tracking echocardiography. In addition, in a subgroup of adult Pompe patients, we analyzed the myocardial and musculoskeletal features by means of cardiac and whole-body muscle magnetic resonance imaging. Patients with Pompe disease had significant structural and functional musculoskeletal alterations such as atrophy with fatty replacement and weakness in trunk and extremities. In contrast, Pompe patients had similar structural and functional myocardial features to healthy subjects (LV strain -20.7 ± 1.9 vs. -21.3 ± 2.1%; RV strain -24.2 ± 5.3 vs. -24.8 ± 3.8%; LA strain 41.5 ± 10.3 vs. 44.8 ± 11.0%; P > 0.05; and no evidence of LV and RV hypertrophy or LA enlargement). In addition, there was no evidence of valvular cardiac alterations, electrocardiographic abnormalities, or myocardial fibrosis in Pompe patients. In the current study analyzing the heart with modern and sensitive myocardial techniques, we evidenced that functional and structural cardiac alterations are not present when Pompe disease begins in adulthood. Therefore, these findings suggest that adult Pompe disease should not be taken into consideration in the differential diagnostic of structural or functional cardiac disorders.

Global cardiac alterations detected by speckle-tracking echocardiography in Fabry disease: left ventricular, right ventricular, and left atrial dysfunction are common and linked to worse symptomatic status.

The aim of this study was to test the hypothesis that in patients with Fabry disease, 2D speckle-tracking echocardiography (2DSTE) could detect functional myocardial alterations such as left ventricular (LV), right ventricular (RV), and left atrial (LA) dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients. Fifty patients with Fabry disease and a control group of 118 healthy subjects of similar age and gender were included. The myocardial function and structural changes of the LV, RV, and LA were analyzed by 2DSTE and cardiac magnetic resonance imaging. Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 ± 4.0, -21.4 ± 4.9, and 29.7 ± 9.9 % vs. -21.6 ± 2.2, -25.2 ± 4.0, and 44.8 ± 11.1 %, respectively, P < 0.001) and elevated rates of LV, RV, and LA myocardial dysfunction (24, 20, and 26 %, respectively), even when conventional cardiac measurements such as LVEF, TAPSE, and LAVI were normal. LV septal wall thickness ≥15 mm, RV free wall thickness ≥7 mm, and LV longitudinal dysfunction were the principal factors linked to reduced LV, RV, and LA strain, respectively. In addition, but to a lesser extent, LV and RV fibrosis were linked to reduced LV and RV strain. Patients with reduced LV, RV, and LA strain had worse functional class (dyspnea-NYHA classification) than those with normal cardiac function. In conclusion, in patients with Fabry disease, 2DSTE analyses detect LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements are normal. These functional myocardial alterations are common and significantly associated with worse symptomatic status in Fabry patients. Therefore, these findings provide important evidence to introduce global myocardial analyses using 2DSTE in the early detection of functional cardiac alterations in Fabry disease.

Atrial fibrillation-induced cardiac troponin I release.

BACKGROUND: Cardiac troponin I (cTnI) is highly specific for myocardial damage and for the diagnosis of acute coronary syndrome. We investigated cTnI utility and predictive value in patients with atrial fibrillation (AF) in the acute setting. METHOD: We studied 354 consecutive patients with the primary diagnosis of AF and clinical symptoms suggestive of myocardial ischemia presenting to our emergency department. cTnI was obtained on presentation. Patients with ST-segment elevation myocardial infarction were excluded. Coronary angiography was performed in 100 patients. RESULTS: cTnI was elevated (>0.09 µg/L) in 51 of 354 (15%) patients. The mean cTnI in these patients was 0.37 µg/L (0.09-3.14). In 23 of 100 patients undergoing coronary angiography, cTnI was elevated. Only 6 of these 23 patients (26%) had significant stenosis. In 77 of 100 patients undergoing coronary angiography, cTnI was normal, revealing significant stenosis in 25 patients (33%). The positive predictive value of elevated cTnI for a coronary intervention was 26% and the negative predictive value was 68%. Using multivariate logistic regression, we found that heart rate on presentation, the presence of angina pectoris, left ventricular ejection fraction, serum creatinine, and hemoglobin independently predicted elevated cTnI level. CONCLUSION: These data are the first to show that AF in the acute setting is frequently associated with cTnI elevations. AF patients with high heart rate and/or angina pectoris often show false elevated cTnI levels. These findings are relevant for clinicians evaluating patients with acute AF and myocardial ischemia symptoms. Appropriate clinical guidelines must be established that also consider AF-related elevations in cTnI.

Polymorphic ventricular tachycardia in a patient with herpes encephalitis.

We present a patient with polymorphic ventricular tachycardia and subsequent ventricular fibrillation with acquired long QT syndrome secondary to herpes encephalitis.

Findings and outcome of fluoroscopic visualization of the oesophageal course during catheter ablation of atrial fibrillation.

AIMS: The close topographic relationship between the left atrial posterior wall (LAPW) and the oesophagus creates a potential hazard of thermal lesions to the oesophagus during radiofrequency (RF) catheter ablation of atrial fibrillation (AF). The purpose of the study was to describe topographic relation of the oesophagus behind the left atrium in the ablation situation, and to evaluate the clinical outcome of subsequent modifications to the strategy using continuous real-time fluoroscopic visualization of the oesophageal course. METHODS AND RESULTS: In 214 consecutive patients, a gastric tube (GT) was inserted before circumferential pulmonary vein isolation (CPVI) for the treatment of paroxysmal (n= 160) or persistent (n= 54) AF. In the real-time mapping situation at the LAPW, the tissue interface between catheter tip and oesophagus lumen measured only 2.9 ± 1.9 mm, and 2.5 ± 1.2 mm at the level of the upper and lower pulmonary vein (PV) ostia, respectively. Modifications of the intended antral CPVI approach due to an oesophageal course close to the left or right PV ostia (in 76.6% of patients) were associated with reduced success rate (sustained sinus rhythm) after one (54.9 vs. 72.0%, P = 0.03), or 1-3 ablation procedures (85.4 vs. 96.0%, P = 0.04) during a mean follow-up of 13 ± 10 months. CONCLUSION: Continuous real-time fluoroscopic visualization using a GT emphasizes the very small distance of the catheter tip and oesophageal lumen that may be present in the real-ablation situation and may help to avoid RF lesion application in close proximity to the oesophagus. However, accordant modification of AF ablation strategy may reduce efficacy of the procedure.

Sustained monomorphic ventricular tachycardia after adenosine infusion.

Adenosine is used as pharmacological treatment of the first choice for the termination of regular small complex tachycardia. Although it is considered safe in this context, several reports of short lasting proarrythmic effects have been described. We present a case of a sustained monomorphic ventricular tachycardia following adenosine infusion.